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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
10-K
(Mark One)
Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
for the fiscal year ended
December 31, 2021
or
Transition report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934.
for the transition period from
 
to
 
.
Commission File Number
 
001-41058
VAXXINITY, INC.
(Exact name of registrant as specified in its charter)
Delaware
 
86-2083865
(State or other jurisdiction of incorporation or organization)
(IRS Employer Identification No.)
1717 Main St
.,
Ste 3388
Dallas
,
TX
75201
(Address of principal executive offices, including zip code)
Registrant’s telephone number, including area code:
(
254
)
244-5739
Securities registered pursuant to Section 12(b) of the Act:
Title of each class
Trading Symbol
Name of exchange on which registered
Class A Common Stock, par value $0.0001 per
share
VAXX
The
Nasdaq
 
Global Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes
No
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes
No
Indicate by
 
check mark
 
whether the
 
registrant (1) has
 
filed all
 
reports required
 
to be
 
filed by
 
Section 13 or
 
15(d) of the
 
Securities Exchange
 
Act of
1934 during the preceding 12 months (or for such shorter
 
period that the registrant was required to file such
 
reports), and (2) has been subject to such
filing requirements for the past 90 days.
Yes
 
No
Indicate by check mark
 
whether the registrant has
 
submitted electronically every Interactive
 
Data File required to
 
be submitted pursuant to
 
Rule 405
of Regulation S-T (§ 232.405 of
 
this chapter) during the preceding
 
12 months (or for such shorter period
 
that the registrant was required
 
to submit such
files).
Yes
 
No
Indicate by check mark whether
 
the registrant is a
 
large accelerated filer,
 
an accelerated filer,
 
a non-accelerated filer,
 
a smaller reporting company or
an emerging growth company. See the definitions of “large accelerated filer,”
 
“accelerated filer,” “smaller reporting company” and "emerging growth
company" in Rule 12b-2 of the Exchange Act.
Large Accelerated Filer
Accelerated Filer
Non-Accelerated Filer
 
Smaller Reporting Company
Emerging Growth Company
If an emerging growth company,
 
indicate by check mark if the registrant has
 
elected not to use the extended transition period for
 
complying with any
new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal
control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that
prepared or issued its audit report.
 
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes
 
No
The registrant was not a public company as of June 30, 2021, the last business day of its most recently completed second fiscal quarter,
 
and therefore,
cannot calculate the aggregate market value
 
of its voting and non-voting common equity
 
held by non-affiliates as of such
 
date. The registrant’s Class
A common stock began trading on the Nasdaq Global Market on November 11, 2021. As of March 24, 2022, the registrant had
111,966,892
 
shares of
$0.0001 par value Class A common stock outstanding and
13,874,132
 
shares of $0.0001 par value Class B common stock outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of
 
the following document
 
are incorporated
 
by reference in
 
Part III of this
 
Report: the
 
registrant’s definitive
 
proxy statement relating
 
to its
2022 Annual Meeting of
 
Shareholders. We
 
currently anticipate that our
 
definitive proxy statement will
 
be filed with the
 
SEC not later than
 
120 days
after December 31, 2021, pursuant to Regulation 14A of the Securities Exchange Act of 1934, as amended.
 
2
PART
 
I
Unless otherwise indicated
 
in this report,
 
“Vaxxinity
 
,” “we,” “us,”
 
“our,” and similar terms
 
refer to Vaxxinity,
 
Inc. and our
 
consolidated
subsidiaries.
SPECIAL NOTE REGARDING FORWARD
 
-LOOKING STATEMENTS
This Annual Report
 
on Form 10-K
 
for the
 
year ended December
 
31, 2021 (“Report”)
 
contains forward-looking statements.
 
Forward-
looking
 
statements
 
are
 
neither
 
historical
 
facts
 
nor
 
assurances of
 
future
 
performance.
 
Instead,
 
they
 
are
 
based
 
on
 
our
 
current
 
beliefs,
expectations and assumptions
 
regarding the future
 
of our business,
 
future plans and
 
strategies and other
 
future conditions. In
 
some cases,
you can identify forward-looking
 
statements because they contain
 
words such as “anticipate,”
 
“believe,” “estimate,” “expect,” “intend,”
“may,” “predict,” “project,” “target,” “potential,” “seek,” “will,” “would,” “could,” “should,” “continue,” “contemplate,” “plan,” other
words and terms of similar meaning and the negative of these words or similar terms.
Forward-looking statements are subject to known and unknown risks and uncertainties, many of which may be beyond our control.
 
We
caution you
 
that forward-looking
 
statements are
 
not guarantees
 
of future
 
performance or
 
outcomes and
 
that actual
 
performance and
outcomes may differ
 
materially from those
 
made in or
 
suggested by the
 
forward-looking statements
 
contained in this
 
Report. In addition,
even
 
if
 
our results
 
of
 
operations, financial
 
condition
 
and cash
 
flows,
 
and
 
the development
 
of
 
the
 
markets in
 
which we
 
operate,
 
are
consistent with the forward-looking statements contained in this Report, those results or developments may not be indicative
 
of results
or developments in subsequent periods.
 
New factors emerge from time to
 
time that may cause our
 
business not to develop as
 
we expect,
and it is not possible for us to predict all
 
of them. Factors that could cause actual results and outcomes to differ
 
from those reflected in
forward-looking statements include, among others, the following:
 
the prospects of UB-612
 
and other product
 
candidates, including the timing
 
of data from our
 
clinical trials for UB-612
and other product candidates and our ability to obtain and maintain regulatory approval for our product candidates;
 
our ability to develop and commercialize new products and product candidates;
 
our ability to leverage our Vaxxine Platform;
 
the rate and degree of market acceptance of our products and product candidates;
 
our
 
status
 
as
 
a
 
clinical-stage
 
company
 
and
 
estimates
 
of
 
our
 
addressable
 
market,
 
market
 
growth,
 
future
 
revenue,
expenses, capital requirements and our needs for additional financing;
 
our ability
 
to comply
 
with multiple
 
legal and
 
regulatory systems
 
relating to
 
privacy,
 
tax, anti-corruption
 
and other
applicable laws;
 
our ability to hire and retain key personnel and to manage our future growth effectively;
 
competitive companies and technologies and our industry and our ability to compete;
 
our and our
 
collaborators’, including United
 
Biomedical’s (“UBI”), ability and
 
willingness to obtain,
 
maintain, defend
and enforce our
 
intellectual property
 
protection for our
 
proprietary and collaborative
 
product candidates,
 
and the scope
of such protection;
 
the
 
performance
 
of
 
third
 
party
 
suppliers
 
and
 
manufacturers
 
and
 
our
 
ability
 
to
 
find
 
additional
 
suppliers
 
and
manufacturers;
 
our ability and the potential to successfully manufacture our product candidates for pre-clinical use, for clinical trials
and on a larger scale for commercial use, if approved;
 
the
 
ability
 
and
 
willingness
 
of
 
our
 
third-party
 
collaborators,
 
including
 
UBI,
 
to
 
continue
 
research
 
and
 
development
activities relating to our product candidates;
 
general economic,
 
political, demographic
 
and business conditions
 
in the United
 
States, Taiwan and other
 
jurisdictions;
 
the
 
potential
 
effects
 
of
 
government
 
regulation,
 
including
 
regulatory
 
developments
 
in
 
the
 
United
 
States
 
and
 
other
jurisdictions;
 
ability to obtain additional financing in future offerings;
 
3
 
expectations about market trends; and
 
the
 
effects
 
of
 
the
 
Russia-Ukraine
 
conflict
 
and
 
the
 
COVID-19
 
pandemic
 
on
 
business
 
operations,
 
the
 
initiation,
development and operation of our clinical trials and patient enrollment of our clinical trials.
We discuss many of
 
these factors
 
in greater
 
detail under
 
Item 1A. “Risk
 
Factors.” These
 
risk factors are
 
not exhaustive
 
and other sections
of
 
this
 
report
 
may
 
include
 
additional
 
factors
 
which
 
could
 
adversely
 
impact
 
our
 
business
 
and
 
financial
 
performance.
 
Given
 
these
uncertainties, you should not place undue reliance on these forward-looking statements.
You
 
should read
 
this Report
 
and the
 
documents that
 
we reference
 
in this
 
Report and
 
have filed
 
as exhibits
 
completely and
 
with the
understanding that
 
our actual
 
future results
 
may be
 
materially different
 
from what
 
we expect.
 
We
 
qualify all
 
of the
 
forward- looking
statements in this Report by these cautionary statements. Except as required by law, we undertake no obligation to publicly update any
forward-looking statements, whether as a result of new information, future events or otherwise.
 
Item 1. Business.
Overview
We
 
are a purpose-driven biotechnology company
 
committed to democratizing healthcare across the
 
globe. Our vision is
 
to disrupt the
existing treatment
 
paradigm for chronic
 
diseases, increasingly
 
dominated by
 
drugs, particularly monoclonal
 
antibodies (“mAbs”), which
suffer
 
from
 
prohibitive
 
costs
 
and
 
cumbersome
 
administration.
 
We
 
believe
 
our
 
synthetic
 
peptide
 
vaccine
 
platform
 
(“Vaxxine
Platform”) has the potential
 
to enable
 
a new
 
class of
 
therapeutics that will
 
improve the quality
 
and convenience of
 
care, reduce
 
costs
and increase access to
 
treatments for a wide
 
range of indications. Our
 
Vaxxine
 
Platform is designed to
 
harness the immune system
 
to
convert the
 
body into
 
its own
 
“drug factory,”
 
stimulating the
 
production of
 
antibodies with
 
a therapeutic
 
or protective
 
effect. While
traditional vaccines have been
 
able to leverage this
 
approach against infectious diseases, they
 
have historically been unable
 
to resolve
key challenges in the fight
 
against chronic diseases. We
 
believe our Vaxxine
 
Platform has the potential to
 
overcome these challenges,
and has the potential
 
to bring the efficiency
 
of vaccines to a
 
whole new class of
 
medical conditions. Specifically,
 
our technology uses
synthetic peptides to
 
mimic and optimally
 
combine biological epitopes
 
in order to
 
selectively activate the
 
immune system, producing
antibodies against only the desired
 
targets, including self- antigens, making
 
possible the safe and effective treatment
 
of chronic diseases
by vaccines. The modular
 
and synthetic nature of
 
our Vaxxine Platform generally provides significant speed and
 
efficiency in candidate
development and has
 
generated multiple product
 
candidates that we
 
are designing to
 
have safety and
 
efficacy equal to
 
or greater than
the
 
standard-of-care treatments
 
for many
 
chronic diseases,
 
with
 
more convenient
 
administration and
 
meaningfully lower
 
costs. Our
current pipeline
 
consists of
 
five chronic
 
disease product
 
candidates from
 
early to
 
late-stage development
 
across multiple
 
therapeutic
areas, including
 
Alzheimer’s Disease
 
(“AD”), Parkinson’s Disease
 
(“PD”), migraine
 
and hypercholesterolemia.
 
Additionally, we believe
our Vaxxine
 
Platform may be used to disrupt the treatment paradigm for a
 
wide range of other chronic diseases, including any that are
or could
 
potentially be
 
successfully treated
 
by mAbs.
 
We
 
also will
 
opportunistically pursue
 
infectious disease
 
treatments. When
 
the
COVID-19
 
pandemic
 
struck
 
the
 
world
 
in
 
March
 
2020,
 
we
 
quickly
 
reallocated
 
our
 
resources
 
to
 
develop
 
vaccine
 
candidates
 
for
 
the
condition. We
 
have assembled an
 
industry-leading team with
 
extensive experience developing
 
and commercializing successful
 
drugs
that is
 
committed to
 
realizing our
 
mission of
 
democratizing healthcare.
 
Our website
 
address is
 
www.vaxxinity.com.
 
The information
contained on, or that can be accessed through, our website is not part of, and is not incorporated into, this Report.
Limitations of the Current Healthcare Paradigm
The current healthcare paradigm favors the development of drugs that are primarily intended for
 
the U.S. market, for niche indications
and
 
for
 
treatment
 
of
 
disease
 
rather
 
than
 
prevention.
 
Furthermore,
 
these
 
drugs
 
are
 
expected
 
to
 
be
 
sold
 
at
 
price
 
points
 
that
 
are
 
only
accessible to healthcare systems
 
in developed countries. One
 
class of drugs in
 
particular exemplifies the current
 
environment: biologics,
particularly mAbs. In 2019,
 
biologics represented eight
 
of the ten top
 
selling drugs in the
 
United States, of which
 
seven were mAbs. The
global
 
market
 
for
 
mAbs
 
totaled
 
approximately
 
$163 billion
 
in
 
2019,
 
representing
 
approximately
 
70%
 
of
 
the
 
total
 
sales
 
for
 
all
biopharmaceutical products.
While mAbs can provide life-altering care with generally favorable safety characteristics and significant health benefits
 
for the patients
who receive them, regular
 
in-office transfusions and annual
 
treatment costs, which can
 
exceed hundreds of thousands
 
of dollars, present
challenges to both patients and payors. These price
 
and administration hurdles cause mAb treatments to be available
 
to only a fraction
of the population who could benefit from them. Furthermore, mAbs are often restricted
 
to moderate to severe disease and to later lines
of treatment due to their high cost. Based on internal estimates, less
 
than 1% of the worldwide population is on mAbs. Meanwhile, the
alternative to
 
mAbs treatments
 
tends to
 
be small
 
molecules, which
 
are accessible
 
to most
 
patients, but
 
are often
 
comparatively less
effective with
 
more significant
 
side effects.
 
Collectively,
 
this perpetuates
 
a profound
 
inequity in
 
healthcare access,
 
domestically but
even more so globally, that we believe represents a tremendous social and market opportunity.
4
Our Solution
Monoclonal antibodies are developed, produced and purified outside the body and then transfused into
 
the patient on a regular basis, as
frequently as bi-weekly. Therefore,
 
mAbs are inherently
 
less efficient than
 
vaccines, which instead
 
stimulate antibody
 
production within
the patient’s immune system, requiring both less active material and less frequent treatments. However, while traditional vaccines have
historically been
 
successful addressing
 
infectious diseases,
 
previous attempts
 
to utilize
 
vaccines to
 
address chronic
 
disease have
 
not
achieved both acceptable
 
safety and efficacy. This limitation is
 
driven by a traditional
 
vaccine’s inability to either stimulate
 
the requisite
antibody response
 
against harmful
 
self-antigens, that
 
is, break
 
immune tolerance,
 
or produce
 
acceptable levels
 
of reactogenicity,
 
the
physical manifestation of
 
the immune response
 
to vaccination. Our
 
Vaxxin
 
e
 
Platform technology contains
 
modular components custom-
designed to
 
mimic select
 
biology and
 
activate the
 
immune system, enabling
 
our product
 
candidates to
 
break immune
 
tolerance when
targeting self- antigens, a property observed across multiple clinical and pre-clinical studies. Our Vaxxine Platform depends heavily on
intellectual property licensed
 
from UBI and
 
its affiliates, a
 
related party and
 
a commercial partner
 
for us, who
 
first developed the
 
peptide
vaccine technology utilized
 
by our Vaxxine Platform. The formulation
 
of peptide-based medicines
 
is also complex,
 
requiring significant
expertise from UBI, its affiliates and our other contract manufacturers to produce our product candidates.
We
 
believe
 
our
 
Vaxxine
 
Platform
 
has
 
the
 
potential
 
to
 
generate
 
product
 
candidates
 
with
 
attributes
 
that
 
collectively
 
offer
 
significant
advantages over both mAbs and small molecule therapeutics:
Cost
:
 
Monoclonal
 
antibodies
 
require
 
costly
 
and
 
complex
 
biological
 
manufacturing
 
processes.
 
Our
manufacturing process
 
is chemically
 
based and
 
highly scalable
 
and requires
 
lower capital expenditures.
 
In addition, we
 
designed our
product
 
candidates to
 
generate
 
antibody
 
production
 
in
 
the
 
body,
 
thus
 
requiring
 
meaningfully
 
less
 
drug
 
substance
 
relative
 
to
 
mAbs,
leading to commensurately lower costs.
Administration
:
 
Our
 
product
 
candidates
 
are
 
designed
 
to
 
be
 
injected
 
in
 
quarterly
 
or
 
longer
 
intervals
 
via
intramuscular injection similar to a flu shot. We believe this offers
 
considerable convenience compared to mAbs, which can require up
to bi-weekly dosing via intravenous infusion or subcutaneous injections, and small molecules, which often require daily dosing.
Efficacy
: In
 
our clinical
 
trials conducted
 
to date,
 
our product
 
candidates have
 
yielded high
 
response rates
(95% or above at target dose levels)
 
for UB-311, UB-312 and UB-612,
 
high target-specific antibodies against self-antigens (as seen in
UB-311 and UB-312
 
clinical trials) and long
 
durations of action for
 
UB-311 (based on
 
titer levels remaining elevated
 
between doses)
and UB-612 (based
 
on half-life). See
 
our descriptions of
 
these clinical trials
 
under “—Our Product
 
Candidates.” We
 
also believe that
the improved convenience of our product candidates as compared to mAbs has the potential to lead to increased adherence by patients.
Furthermore, our
 
Vaxxine
 
Platform enables
 
the combining
 
of target
 
antigens into
 
a single
 
formulation. For
 
indications that
 
could be
treated more effectively with a multivalent approach, we believe our Vaxxine Platform would have an advantage over other modalities.
Finally,
 
because our
 
Vaxxine
 
Platform is
 
designed to
 
elicit endogenous
 
antibodies, we
 
believe our
 
product candidates
 
may lessen
 
or
avoid altogether the phenomenon of anti-drug antibodies which has limited the efficacy of certain mAbs over time.
Safety
:
 
Based
 
on
 
our
 
clinical
 
trials
 
to
 
date,
 
our
 
product
 
candidates
 
have
 
been
 
well
 
tolerated,
 
with
 
safety
profiles comparable to placebo.
 
We
 
aim to offer
 
product candidates with
 
safety profiles at least
 
comparable to the
 
competing mAb or
small molecule alternative for the relevant disease.
vaxxq410kp6i0.jpg
5
Our Pipeline
The following chart reflects our current product candidate pipeline:
As used in the chart above, “IND” signifies a program has begun investigational new drug (“IND”)-enabling studies.
Our pipeline
 
consists of five
 
lead programs focused
 
on chronic
 
disease, particularly neurodegenerative
 
disorders, in
 
addition to other
neurology and cardiovascular indications.
Neurodegenerative Disease Programs:
UB-311
: Targets toxic forms of aggregated amyloid-b
 
(“Ab”) in the brain to
 
fight AD. Phase 1,
 
Phase 2a and
Phase 2a
 
Long Term
 
Extension (“LTE”)
 
trials have
 
shown UB-311
 
to be
 
well tolerated
 
in mild-to-moderate
 
AD subjects
 
over three
years of
 
repeat dosing,
 
with a
 
safety profile
 
comparable to
 
placebo, with
 
no cases
 
of amyloid-
 
related imaging
 
abnormalities-edema
(“ARIA-E”) observed in the Phase 2a trial, and immunogenic, with a high responder rate and antibodies that bind to the desired target.
We expect to initiate a Phase 2b early AD efficacy trial in the second half of 2022.
UB-312
: Targets toxic forms of aggregated α-synuclein in the brain to fight PD and
 
other synucleinopathies,
such as Lewy body dementia (“LBD”)
 
and multiple system atrophy (“MSA”). The first part of a Phase 1 trial in
 
healthy volunteers has
shown UB-312
 
to be
 
well tolerated,
 
with no
 
significant safety
 
findings, and
 
immunogenic, with
 
a high
 
responder rate
 
and antibodies
that cross the
 
blood-brain barrier (“BBB”). No
 
serious adverse events
 
were observed in
 
Part A of
 
the Phase 1
 
trial. We
 
have initiated
the second part of this Phase
 
1 trial in PD subjects,
 
and anticipate the completion of an end-of-treatment
 
analysis in the second half of
2022.
Anti-tau
:
 
We
 
are
 
developing
 
an
 
anti-tau
 
product
 
candidate
 
that
 
has
 
the
 
potential
 
to
 
address
 
multiple
neurodegenerative
 
conditions,
 
including
 
AD,
 
by
 
targeting
 
abnormal
 
tau
 
proteins
 
alone
 
and
 
in
 
potential
 
combination
 
with
 
other
pathological proteins such as Aβ
 
to combat multiple pathological processes
 
at once. We
 
expect to identify a
 
lead product candidate in
the next two years.
Next Wave Chronic
 
Disease Programs:
UB-313
:
 
Targets
 
Calcitonin
 
Gene-Related
 
Peptide
 
(“CGRP”) to
 
fight
 
migraines.
 
We
 
have
 
initiated
 
IND-
enabling studies and expect to begin a first-in-human Phase 1 clinical trial in 2022.
Anti-PCSK9
: Targets proprotein convertase subtilisin/kexin type 9 serine protease (“PCSK9”) to lower low-
density
 
lipoprotein
 
(“LDL”) cholesterol
 
and
 
reduce
 
the
 
risk
 
of
 
cardiac
 
events.
 
We
 
expect
 
to
 
initiate
 
IND-enabling
 
studies
 
for
 
this
program in 2022.
Given the global COVID-19 pandemic
 
and our Vaxxine
 
Platform’s applicability to
 
infectious disease, we also have
 
advanced product
candidates that address SARS-CoV-2.
6
COVID-19
UB-612
:
 
Employs
 
a
 
“multitope”
 
approach
 
to
 
neutralizing
 
the
 
SARS-CoV-2
 
virus,
 
meaning
 
the
 
product
candidate is designed to activate both antibody and cellular immunity against multiple viral epitopes.
 
Phase 1 and Phase 2 trials of UB-
612 have shown
 
UB-612 to be
 
well tolerated, with
 
no significant safety
 
findings to date
 
(over 7,500 doses
 
have been administered
 
to
over 3,750 subjects).
 
No serious adverse
 
events were observed in
 
the Phase 1
 
trial. In the
 
Phase 2 trial,
 
twenty serious adverse
 
events
were observed
 
through interim
 
analysis. Only
 
one led
 
to discontinuation
 
of the
 
study,
 
and none
 
were considered
 
UB-612-related. In
these trials we observed
 
that UB-612 generated antibodies
 
that can bind to
 
the S1-RBD protein and
 
neutralize SARS-CoV-2, in addition
to driving
 
T-lymphocytes
 
(“T-cell”)
 
response. An
 
emergency use
 
authorization (“EUA”)
 
application for
 
UB-612 was
 
denied by
 
the
Taiwan Food and Drug Administration (“TFDA”) in August 2021, but, in collaboration with our partner United Biomedical, Inc., Asia
(“UBIA”),
 
we
 
are
 
appealing
 
that
 
decision.
 
At
 
the
 
same
 
time,
 
we
 
are
 
still
 
pursuing
 
approval
 
of
 
UB-612
 
elsewhere,
 
including
 
as
 
a
heterologous boost (boosting the immunity of a subject who has already received a different vaccine). In collaboration with University
College London
 
and VisMederi
 
,
 
we analyzed
 
sera from
 
subjects immunized
 
with a
 
booster dose
 
of UB-612.
 
Data demonstrated
 
that
UB-612
 
elicited
 
a
 
broad
 
IgG
 
antibody
 
response
 
against
 
multiple
 
SARS-CoV-2
 
variants
 
of
 
concern,
 
including
 
Alpha,
 
Beta,
 
Delta,
Gamma,
 
and Omicron,
 
and higher
 
levels of
 
neutralizing antibodies
 
against Omicron
 
than
 
reported with
 
three doses
 
of
 
an approved
mRNA vaccine.
 
We
 
believe our Vaxxine
 
Platform has application across a
 
multitude of chronic and infectious
 
disease indications beyond our
 
existing
pipeline. We
 
also are
 
developing additional product
 
candidates that we
 
believe may
 
address significant unmet
 
needs both
 
within and
beyond our current pipeline’s therapeutic areas.
Our Team
We
 
have assembled an
 
experienced group of
 
executives with deep
 
scientific, business and
 
leadership expertise in
 
pharmaceutical and
vaccine
 
discovery
 
and
 
development,
 
manufacturing,
 
regulatory
 
and
 
commercialization.
 
Mei
 
Mei
 
Hu,
 
our
 
co-founder
 
and
 
Chief
Executive Officer, has
 
been a
 
member of the
 
executive committee
 
of UBI since
 
2010. Our
 
board of
 
directors is
 
chaired by
 
our co-founder
Louis
 
Reese,
 
who
 
has
 
been
 
a
 
member
 
of
 
the
 
executive
 
committee
 
of
 
UBI
 
since
 
2014.
 
Our
 
research
 
efforts
 
are
 
guided
 
by
 
highly
experienced
 
scientists
 
and
 
physicians
 
on
 
our
 
leadership
 
team
 
including
 
Dr.
 
Ulo
 
Palm,
 
our
 
Chief
 
Medical
 
Officer,
 
and
 
Dr.
 
Farshad
Guirakhoo,
 
our
 
Chief
 
Scientific
 
Officer.
 
Our
 
leadership
 
team
 
contributes
 
a
 
diverse
 
range
 
of
 
experiences
 
from
 
leading
 
companies
including
 
Acambis,
 
Allergan,
 
Amgen,
 
Dendreon,
 
Eli
 
Lilly,
 
Merck,
 
Novavax,
 
Novartis,
 
Sanofi,
 
and
 
Schering-Plough,
 
and
 
were
executives in multiple successful
 
mAb and vaccine launches,
 
including Dupixent, Kevzara, Provenge,
 
PreveNile, Ervebo, Imojev and
Dengvaxia. As of December 31, 2021, we have
 
assembled an exceptional team of approximately 86 employees, the majority of
 
whom
hold
 
Ph.D.,
 
M.D.,
 
J.D.
 
or
 
Master’s
 
degrees,
 
and
 
we
 
are
 
regularly
 
hiring
 
additional
 
personnel.
 
We
 
also
 
have
 
a
 
highly
 
experienced
scientific advisory board consisting of 13 doctors and scientists.
Our Strategy
Our mission is
 
to develop product
 
candidates that
 
improve the
 
quality of care
 
for chronic diseases
 
and are accessible
 
to all patients
 
across
the globe. In order to achieve this mission, we seek to:
Advance our chronic disease pipeline through
 
clinical stage development
: We
 
plan to advance UB-311 and
UB-312
 
through
 
clinical
 
stage
 
development
 
for
 
the
 
treatment
 
of
 
neurodegenerative
 
disorders.
 
In
 
addition,
 
we
 
are
 
conducting
 
IND-
enabling studies
 
on multiple
 
pre-clinical product
 
candidates that
 
are focused
 
on the
 
treatment of
 
chronic migraines,
 
hypercholesterolemia
and additional neurodegenerative disorders. We
 
believe that our differentiated Vaxxine
 
Platform will enable our product candidates, if
successful, to
 
potentially disrupt
 
the treatment
 
paradigm for
 
their respective
 
indications. However,
 
there can
 
be no
 
guarantee that
 
we
will achieve commercialization of any such product candidates.
Expand our pipeline of product candidates
: Chronic diseases are prevalent globally and expected to worsen
over the next several decades. In furtherance of our mission, we plan to expand our pipeline
 
by developing new product candidates that
address additional indications. In
 
expanding our pipeline,
 
we rely on
 
our proprietary filtering
 
methodology, which
 
evaluates potential
product
 
candidates
 
across
 
five
 
principal
 
criteria
 
 
(i)
 
probability
 
of
 
technical
 
and
 
regulatory
 
success,
 
(ii)
 
addressable
 
market,
 
(iii)
development cost, (iv) competitive dynamics and (v) disruptive potential.
Opportunistically develop
 
treatments for infectious
 
diseases
: While
 
our core
 
mission focuses
 
on the
 
treatment
of chronic diseases, we are committed to bringing accessible medicines to people around the world
 
and will address infectious diseases
opportunistically. For example, when the COVID-19 pandemic struck the world, we rapidly deployed resources in pursuit of a product
candidate currently embodied in UB-612.
Expand
 
and
 
scale
 
our
 
existing
 
capabilities
:
 
We
 
are
 
investing
 
in
 
our
 
operational
 
processes,
 
facilities
 
and
human capital to accelerate the speed with which we can bring product candidates
 
through the development pipeline, and to expand the
capacity for developing more product candidates simultaneously.
7
Continue to
 
improve our
 
Vaxxine
 
Platform
: In
 
addition to,
 
and in
 
conjunction with,
 
our product
 
candidate
development
 
efforts,
 
we
 
are
 
continuously
 
working
 
to
 
improve
 
and
 
enhance
 
the
 
richness,
 
breadth
 
and
 
effectiveness
 
of
 
our
 
Vaxxine
Platform. As
 
our Vaxxine Platform further
 
develops, we
 
believe that
 
we can
 
both increase
 
the number
 
of product
 
candidates in
 
concurrent
development and accelerate the process of advancing product candidates through pre-clinical and clinical development.
Maximize the value
 
of our product candidates
 
through potential partnerships
: We currently retain
 
worldwide
rights for the majority of our product
 
candidates and will consider entering into development and
 
commercialization partnerships with
third parties that align with our mission on an opportunistic basis.
Background
 
and Limitations of Traditional Vaccines
 
and Monoclonal Antibodies
The immune
 
system, the
 
body’s
 
mechanism for
 
fighting off
 
potential threats,
 
is comprised
 
of cells
 
that form
 
the innate
 
and adaptive
immune responses.
 
The main
 
purpose of
 
the innate
 
immune system
 
is to
 
immediately prevent
 
the spread
 
and movement
 
of
 
foreign
pathogens throughout the body. The adaptive immune response is specific
 
to the pathogen presented to T-cells and B lymphocytes (“B-
cells”) and leads to an enhanced
 
response upon future encounters with those
 
antigens. Antibodies represent an important
 
tool within the
adaptive immune system’s arsenal. Upon
 
detection of a potential
 
threat, B-cells produce antibodies
 
that recognize, bind
 
to and eliminate
the threatening pathogen. Over
 
time, the immune system
 
develops the ability to
 
produce countless types of
 
antibodies, each finely tuned
against a specific threat.
Generally, the immune system is able to function effectively by neutralizing
 
viruses, bacteria and even self-generated cells and
 
proteins
from within our own bodies that could
 
cause harm if unchecked. However,
 
as powerful as the immune system is,
 
there are threats that
it
 
cannot
 
overcome
 
on
 
its
 
own,
 
generating
 
the
 
need
 
for
 
medicine.
 
Conventional
 
forms
 
of
 
medicine
 
include
 
small
 
molecules
 
(e.g.,
antibiotics), which
 
can inhibit or
 
promote action within
 
the body by, for
 
instance, binding
 
to a receptor
 
on the surface
 
of a cell,
 
or directly
inducing toxic effects
 
upon bacteria. These
 
medicines do not
 
necessarily modulate the
 
immune system directly
 
in order to
 
work. Instead,
they work alongside it.
 
While small molecules have
 
provided substantial benefits to
 
human health, they are
 
not designed to interact
 
with
the immune system. They may also have limited
 
efficacy in cases where an immune response
 
to a target can be used
 
against a chronic
condition.
Vaccines
In the first
 
part of the
 
twentieth century,
 
vaccines revolutionized healthcare
 
by directly interacting
 
with, and modulating,
 
the immune
system — training
 
it to recognize
 
a dangerous pathogen
 
by introducing the
 
immune system
 
to a relatively
 
harmless form
 
of the pathogen,
its toxins
 
or one
 
of its
 
surface proteins,
 
thereby promoting
 
the body’s
 
own production
 
of binding
 
antibodies. Once
 
immunized
 
to a
specific pathogen, the immune system can recognize it and generate the antibodies to fight it more quickly and robustly.
Traditional vaccine technologies have generally
 
focused on the prevention of bacterial and
 
viral infections and not on chronic disease.
In
 
chronic
 
disease
 
settings,
 
the
 
disease-causing
 
agents
 
frequently
 
come
 
from
 
within
 
the
 
body.
 
These
 
self-antigens
 
are
 
proteins
 
that
become too abundant, misfolded or aggregated such
 
that they can no longer perform their
 
healthy function and even may induce
 
toxic
effects.
 
The body
 
can
 
sometimes produce
 
antibodies
 
against
 
such proteins,
 
but
 
this often
 
falls
 
short of
 
providing
 
the right
 
types of
antibodies in the
 
right concentrations to
 
ward off disease.
 
Historically, vaccine technologies developed
 
to target these
 
proteins have been
unable to
 
break immune
 
tolerance —
 
that is,
 
the immune
 
system’s
 
general avoidance
 
of reactivity
 
towards self-antigens
 
— with
 
an
acceptable level of reactogenicity.
 
The challenges faced by prior efforts to
 
advance vaccine technologies for chronic diseases included
low response rates, low titer levels, off-
 
target responses and other safety concerns such as T-cell mediated inflammation.
Monoclonal Antibodies
The first
 
mAbs were
 
developed in
 
the later
 
part of
 
the twentieth
 
century.
 
In contrast
 
to vaccines,
 
which prompt
 
the body
 
to produce
antibodies, mAbs are antibodies manufactured outside of the patient’s body and then injected or infused into the body to recognize and
eliminate
 
harmful
 
targets.
 
Monoclonal
 
antibodies
 
have
 
revolutionized
 
the
 
standard-of-care
 
treatment
 
for
 
many
 
chronic
 
diseases.
However, manufacturing mAbs
 
is often
 
an expensive
 
and complex
 
process and
 
administering mAbs
 
is cumbersome,
 
sometimes requiring
infusions as
 
frequently as
 
bi-weekly.
 
These factors
 
have generally
 
limited mAbs’
 
availability to
 
moderate-to-severe disease,
 
to later
lines of therapy and to wealthier geographies, thus denying access to a substantial portion of the patients who could benefit from them.
Finally,
 
patients
 
on
 
mAbs
 
often
 
experience
 
a
 
loss
 
of
 
effectiveness
 
over
 
time
 
due
 
to
 
a
 
phenomenon
 
known
 
as
 
anti-drug
 
antibodies,
whereby the
 
immune system
 
begins to
 
recognize therapeutic
 
mAbs as
 
foreign, and
 
mounts a
 
response against
 
them, eventually
 
mitigating
their efficacy.
Our Vaxxine Platform
Our Vaxxine
 
Platform is designed to stimulate the patient’s own immune system to generate antibodies and overcome the limitation of
traditional
 
vaccines
 
to
 
effectively
 
and
 
safely
 
target
 
self-antigens
 
in
 
chronic
 
diseases.
 
Our
 
product
 
candidates
 
have
 
broken
 
immune
tolerance against self-antigens consistently. As described in the
 
section titled “Our Product Candidates”
 
below, across six clinical trials,
we have consistently observed
 
that our product candidates
 
have stimulated the development
 
of antibodies against the
 
desired target at
vaxxq410kp9i0.jpg
8
relevant doses in clinical trial subjects, including the elderly. We have observed favorable tolerability and reactogenicity of our product
candidates
 
across
 
studies of
 
UB-311,
 
UB-312
 
and
 
UB-612,
 
with
 
no
 
significant
 
safety findings
 
to
 
date.
 
We
 
aim
 
to
 
develop
 
product
candidates
 
that
 
possess
 
clinical
 
advantages
 
against,
 
and
 
safety
 
profiles
 
at
 
least
 
comparable
 
to,
 
relevant
 
mAbs
 
and
 
small
 
molecule
treatments. We
 
believe our product candidates have the potential to
 
eventually capture meaningful market share from mAbs and small
molecules, and to provide therapeutic benefit
 
to large patient populations who
 
currently receive neither form of
 
treatment. This would
represent
 
an
 
unprecedented
 
shift
 
in
 
the
 
treatment
 
paradigm,
 
potentially
 
providing
 
better
 
global
 
access
 
to
 
treatments
 
that
 
have
 
been
previously limited
 
to
 
the wealthiest
 
nations.
 
In particular,
 
we believe
 
our
 
treatments for
 
chronic disease
 
could reflect
 
the
 
following
benefits as compared with the relevant mAbs and small molecule alternatives:
Characteristics of our Product Candidates versus Monoclonal Antibodies and Small Molecules
History and Design
Our Vaxxine Platform utilizes a peptide vaccine technology first developed by UBI and subsequently
 
refined over the last two decades,
with more than three billion doses of animal vaccines sold to date. UBI initiated the development of this technology for human
 
use; the
business
 
focused
 
on
 
human
 
use
 
was
 
then
 
separated
 
from
 
UBI
 
through
 
two
 
separate
 
transactions:
 
a
 
spin-out
 
from
 
UBI
 
in
 
2014
 
of
operations focused on developing chronic
 
disease product candidates that resulted
 
in United Neuroscience, a Cayman
 
Islands exempted
company (“UNS”),
 
and a
 
second spin-out
 
from UBI
 
in 2020
 
of operations
 
focused on
 
the development
 
of a
 
COVID-19 vaccine
 
that
resulted in C19 Corp., a
 
Delaware corporation (“COVAXX”)
 
.
 
Our current company,
 
Vaxxinity,
 
Inc., was incorporated under the laws
of the State of Delaware on February 2, 2021 for the purpose of acquiring UNS and COVAXX in March of 2021.
 
On March 2,
 
2021, in
 
accordance with
 
a contribution
 
and exchange
 
agreement among Vaxxinity,
 
UNS, COVAXX
 
and the
 
UNS and
COVAXX stockholders party thereto (the “Contribution and
 
Exchange Agreement”), the
 
existing equity holders
 
of UNS and COVAXX
contributed their equity interests
 
in each of
 
UNS and COVAXX
 
in exchange for equity
 
interests in Vaxxinity
 
(the “Reorganization”).
In
 
connection
 
with
 
the
 
Reorganization,
 
(i) all
 
outstanding
 
shares
 
of
 
UNS
 
and
 
COVAXX
 
preferred
 
stock
 
and
 
common
 
stock
 
were
contributed to
 
Vaxxinity
 
and exchanged
 
for like
 
shares of
 
stock in
 
Vaxxinity,
 
(ii) the outstanding options
 
to purchase
 
shares of
 
UNS
and COVAXX
 
common stock were terminated and substituted with options to purchase shares of Class A common stock in Vaxxinity,
(iii) the outstanding
 
warrant to
 
purchase shares
 
of
 
COVAXX
 
common stock
 
was cancelled
 
and
 
exchanged for
 
a warrant
 
to acquire
Class A common
 
stock in
 
Vaxxinity,
 
and (iv) the
 
outstanding convertible
 
notes
 
and a
 
related party
 
not payable
 
were contributed
 
to
Vaxxinity
 
and the former holders of such notes received Series A preferred stock in Vaxxinity.
 
UBI has used
 
its capabilities in peptide
 
technology for innovations across
 
an array of
 
business endeavors: antibody
 
testing for human
diagnostics, animal health vaccines and the manufacture of
 
medical products. Its innovative products include one of
 
the first approved
peptide-based blood antibody tests in
 
the world (for HIV), one
 
of the first approved peptide
 
vaccines against an infectious disease
 
in the
world in animal health (for a food-and-mouth disease virus) and one of the first approved peptide vaccines against a self-antigen in the
world in
 
animal health
 
(an anti-luteinizing
 
hormone-releasing hormone
 
(“LHRH”) vaccine
 
used for
 
the immunocastration
 
of swine).
Grant funding from the
 
National Institutes of Health
 
supported some of UBI’s
 
work in the fields
 
of vaccines and antibody
 
testing. To
commercialize its
 
animal health vaccine
 
business, UBI and
 
its affiliates scaled
 
up GMP vaccine
 
manufacturing to over
 
500 million doses
per
 
year
 
and
 
partnered
 
with
 
a
 
top-ten
 
animal
 
health
 
company
 
for
 
commercialization
 
of
 
its
 
anti-LHRH
 
vaccine;
 
all
 
together,
 
UBI’s
technology platform is utilized for the vaccination of approximately 25% of the global swine population annually.
We are
 
advancing our peptide-based Vaxxine
 
Platform to develop product candidates that target chronic diseases and COVID-19.
 
Our
Vaxxine
 
Platform
 
comprises
 
a
 
custom,
 
rationally
 
designed
 
antigen
 
capable
 
of
 
evoking
 
an
 
immune
 
response
 
(an
 
“immunogen”)
formulated with
 
a proprietary
 
CpG oligonucleotide.
 
The immunogen
 
contains several
 
advanced synthetic
 
peptides, including
 
B-cell
epitopes, T-helper
 
(“Th”) antigen carrier constructs and epitope linker configurations. This composition enables us
 
to achieve a highly
vaxxq410kp10i0.jpg
9
specific immune response
 
to the target
 
antigen, with limited
 
inflammation and off-target
 
effects that
 
could cause reactogenicity.
 
This
design process has evolved into a repeatable series of well-defined steps, which has enabled the development of our current pipeline of
product candidates.
Key Elements of our Vaxxine Platform Constructs and Formulations
When developing a
 
product candidate, we
 
use publicly available
 
information and sophisticated
 
bioinformatics tools to
 
investigate the
entire protein structure of a target in a comprehensive manner to identify functional B-cell epitopes that may provide
 
optimal antigens.
We then synthesize custom
 
peptides that mimic
 
these identified antigens
 
to elicit highly
 
specific antibodies
 
against these B-cell
 
epitopes.
To yield favorable tolerability profiles, we design our product
 
candidates such that they lack
 
T-cell epitopes and screen them for lack of
T-cell mediated inflammation and toxicity,
 
as well as reactogenicity. Such screening tests include the measuring of immunogenicity of
each B-cell
 
antigen with
 
and without
 
conjugation to
 
a Th
 
carrier peptide (a
 
response only
 
when conjugated to
 
a Th
 
carrier peptide is
desired), epitope mapping assays
 
and in vivo and
 
ex vivo tests of
 
lymphocyte proliferation, pro-inflammatory cytokine release
 
and T-
cell infiltration. To
 
enhance effectiveness, we seek to optimize the size
 
and sequence of our custom peptides to elicit a
 
robust, specific
antibody response when linked to a carrier molecule.
We
 
then
 
attach
 
a
 
proprietary
 
carrier
 
molecule,
 
an
 
artificial
 
Th
 
carrier
 
peptide
 
that
 
delivers
 
the
 
synthetic
 
peptide
 
into
 
cells.
 
Carrier
molecules used in traditional vaccines often elicit a strong T-cell mediated immune response, resulting in significant off-target activity.
In our
 
pre-clinical trials
 
and clinical
 
trials to
 
date, our
 
product candidates
 
have displayed
 
specific immunogenicity,
 
or the
 
ability to
stimulate
 
an
 
immune
 
response,
 
thereby
 
greatly
 
reducing
 
potential
 
off-target
 
effects
 
and
 
increasing
 
the
 
potential
 
for
 
our
 
product
candidates to
 
be well
 
tolerated and
 
efficacious. We
 
have observed
 
that our
 
carrier molecules
 
have produced
 
consistent results
 
across
multiple
 
species
 
and
 
against
 
multiple
 
targets
 
in
 
our
 
six
 
human
 
clinical
 
trials
 
to
 
date.
 
Traditional
 
vaccines
 
have
 
faced
 
challenges
 
in
achieving specific responses because
 
they rely on conjugating
 
the antigen to a
 
large toxoid molecule
 
carrier protein, to which
 
most of
the antibody response is directed, causing off-target effects such as inflammation.
vaxxq410kp11i0.jpg
10
Our Product Candidate Does not Induce an Antibody Response against its Carrier Molecule
The graph
 
above illustrates
 
that our
 
peptide carriers
 
induce a
 
strong immune response
 
against the
 
target antigen, and
 
a minimal
 
immune
response against themselves, as compared to traditional vaccines formulated with other types of carrier molecules.
Our peptide
 
carriers have
 
short sequence
 
lengths, which
 
contribute to
 
their immunosilence
 
and ability
 
to avoid
 
a direct
 
response by
cytotoxic T-cells. However,
 
the carriers’ sequences mirror those found in naturally ubiquitous pathogens, so they are easily recognized
by T-helper
 
cells. This encourages robust T-helper
 
cell exposure to the
 
carrier peptide and promotes activation
 
of other immune cells.
In turn,
 
B-cells are
 
exposed to
 
the B-cell
 
antigen and
 
begin antibody
 
production against
 
the antigen,
 
while avoiding
 
exposure to
 
the
carrier peptide, which avoids antibody response to the carrier. We believe that B-cell exposure to the carrier peptide is avoided because
of its relatively small size
 
and its high affinity
 
to T-helper
 
cells, such that T-helper
 
cells are exposed to the
 
carrier peptide rapidly and
robustly,
 
more so than
 
other cell types.
 
UBI first developed
 
a library of
 
such peptide carriers,
 
which contain various
 
Th cell
 
epitopes
and are of critical importance to our vaccine configuration. Our library of peptide carriers
 
enables the use of different carrier molecules
or different combinations
 
of carrier molecules,
 
which allows us
 
to potentially regulate the
 
speed of immune
 
response onset as
 
well as
the magnitude and
 
duration of
 
that response. For
 
example, a longer
 
duration of
 
response would allow
 
for less
 
frequent dosing.
 
Other
variables that can
 
be adjusted to
 
modulate the immune
 
response include dosing
 
and formulation optimization. In
 
the case of
 
vaccines
targeting
 
infectious diseases, T-cell mediated activity is desirable, while in the case of chronic diseases, it is not. Our Vaxxine Platform
affords
 
the
 
flexibility
 
to
 
design
 
immunogen
 
constructs
 
that
 
specifically
 
promote
 
cytotoxic
 
T-cell
 
activity
 
when
 
warranted
 
(e.g.,
 
for
infectious diseases).
We utilize our linker construct to
 
attach our peptide
 
carriers with our
 
custom antigens. In
 
addition to their binding
 
function, these linkers
also enhance the immune system response further by enabling conformational changes
 
to optimize presentation of the B-cell epitope to
antigen-presenting cells (“APCs”), such as B-cells and dendritic cells (“DC”).
Our Vaxxine Platform also enables the construction of
 
multitope configurations, whereby we
 
can attach multiple immunogens
 
targeting
multiple
 
B-cell
 
epitopes
 
simultaneously,
 
each
 
with
 
different
 
targets,
 
within
 
a
 
single
 
product
 
candidate.
 
Combinations
 
of
 
therapies
targeting
 
different
 
molecular
 
mechanisms
 
are
 
common
 
in
 
treating
 
neurologic,
 
cardiovascular,
 
psychiatric,
 
metabolic,
 
respiratory,
infectious and oncologic disease. Our Vaxxine
 
Platform’s favorable cost of goods
 
and efficient manufacturing process could allow for
viable combinations
 
of targeted
 
therapies in
 
a single
 
formulation. This
 
concept could
 
be applied
 
in an
 
array of
 
potential therapeutic
areas. Our current
 
pipeline has candidates
 
against amyloid-β, α-synuclein
 
and tau; combinations
 
of two or
 
more of these
 
might prove
more effective than
 
any single therapy
 
in some patients.
 
Pre-clinical data to
 
date suggests that
 
we can elicit
 
antibody titers against
 
all
three targets
 
in a
 
single formulation.
 
For mAb-based
 
treatments, such
 
combinations might
 
require the
 
individual dosing
 
of multiple
separate mAb therapies, thereby compounding cost and administration burdens.
vaxxq410kp12i0.jpg
11
Immunogenicity of Single- Versus Combination-Target
 
Formulations in Guinea Pigs
Guinea
 
pigs
 
(three
 
per
 
dose)
 
were
 
tested
 
with
 
either
 
single-target
 
or
 
combination-target
 
formulations,
 
then
 
serum
 
was
 
drawn
 
and
antibody titers compared via enzyme immunoassays
 
(“EIA”). Combination-target formulations elicited similar titer
 
levels against each
target as
 
corresponding single-target
 
formulations. This suggests
 
we can
 
create product
 
candidates with multiple
 
neurodegenerative
targets in a single formulation and achieve sustainable titer levels.
Product Candidate Formulations
In
 
addition
 
to
 
our
 
immunogen
 
construct,
 
each
 
product
 
candidate
 
formulation
 
includes
 
custom
 
CpG
 
oligonucleotides
 
and
 
adjuvant
selection. CpG
 
oligonucleotides are
 
negatively charged, and
 
we utilize
 
proprietary CpG
 
configurations to
 
stabilize the
 
positively charged
peptides.
 
This
 
stabilization
 
acts
 
to
 
optimize
 
display
 
of
 
the
 
B-cell
 
epitope
 
to
 
APCs.
 
In
 
this
 
way,
 
the
 
primary
 
function
 
of
 
CpG
oligonucleotides in our formulations is that of an excipient, even though it has the secondary function of an adjuvant.
A potential secondary
 
function of CpG
 
is that of
 
an adjuvant. Certain
 
CpG configurations are known
 
to act as
 
immunostimulants and
promote direct
 
cytotoxic T-cell activity, while others
 
do not.
 
Accordingly, our selection
 
of the
 
specific CpG
 
modality is
 
highly dependent
on the target indication. For
 
infectious disease indications, the T-cell
 
response generated by the CpG configuration
 
is independent and
in addition to that of the T-cell response generated by the peptide carrier.
The final formulation includes the addition
 
of an adjuvant, such as a well-recognized,
 
alum-derived Adju-Phos or Alhydrogel to further
enhance
 
the
 
immunogenicity
 
of
 
our
 
product
 
candidate.
 
Alum-derived
 
adjuvants
 
are
 
commonly
 
used
 
in
 
vaccines
 
to
 
enhance
 
the
stimulation of an
 
immune response. This
 
is not the
 
same adjuvant used
 
in other companies’
 
failed neurodegenerative
 
vaccine candidates.
How our Product Candidates Function
Our immunogens
 
stimulate the
 
body’s
 
adaptive immune
 
system to
 
produce antibodies
 
against a
 
variety of
 
antigen targets,
 
including
secreted
 
peptides
 
or
 
proteins,
 
degenerative
 
or
 
dysfunctional
 
proteins
 
and
 
membrane
 
proteins,
 
as
 
well
 
as
 
infectious
 
pathogens.
 
The
mechanism of action involves the following sequence of steps:
1.
 
The immunogen is taken up
 
by an APC, such as
 
a DC. Antigen uptake leads
 
to DC maturation and
 
migration
to the draining lymph nodes where the DCs interact with CD4+ T-helper cells.
2.
 
DCs engulf and process the
 
antigen internally and present the
 
T-helper
 
epitope on major histocompatibility
complex (“MHC”)
 
Class II
 
molecules. The
 
presentation activates
 
immunogen-specific CD4+
 
T-helper
 
cells causing
 
them to
 
mature,
proliferate and promote B-cell stimulatory activity.
3.
 
B-cells with receptors that recognize the target B-cell
 
epitope bind, internalize and process the immunogen.
The binding of the B-cell receptor to the immunogen provides the first activation signal to the B-cells.
4.
 
When B-cells
 
function as
 
APCs and
 
present the
 
T-helper
 
epitope on
 
MHC Class
 
II molecules,
 
interaction
with immunogen-specific CD4+
 
T-helper
 
cells provides a
 
second activation signal
 
to B-cells, which
 
causes them
 
to differentiate
 
into
plasma cells.
5.
 
B-cell
 
epitope-specific plasma
 
cells produce
 
high
 
affinity
 
antibodies
 
against the
 
target
 
B-cell
 
epitope. Of
particular importance for neurodegeneration targets, these antibodies are produced in sufficient concentrations to cross the BBB.
vaxxq410kp13i1.jpg vaxxq410kp13i0.jpg
12
Overview of How our Product Candidates Function
Importantly, from both
 
clinical trials and pre-clinical studies, we have
 
observed the rapid expansion of antibodies upon
 
administration
of a booster of our
 
product candidates. Based on
 
the available data to
 
date, we can infer that
 
while antibody titers decline with
 
time after
administration, a small number of memory B-cells
 
and antibody secreting cells are maintained
 
in the lymphoid organs, spleen or
 
bone
marrow. We believe this is important because if a
 
patient misses a dose
 
of our product candidate,
 
they may be able
 
to recall the antibody
response, and therefore the therapeutic effect of the antibodies, with a single booster, even after a long period of time has passed.
Vaxxine
 
Platform Immunogenicity upon Re-dosing
As shown
 
in the
 
above graph,
 
a repeatable
 
immune response
 
elicited from
 
our product
 
candidates has been
 
observed with
 
a booster
dose over one year after the priming regimen.
Furthermore, the antibodies elicited
 
by our product candidates
 
have different properties than those
 
of mAbs targeting similar pathology.
In general,
 
we aim
 
to achieve
 
binding affinity,
 
specificity and
 
functionality similar
 
or improved
 
compared to
 
mAbs targeting
 
similar
pathology.
 
We
 
use Bio-Layer
 
Interferometry (ForteBio®)
 
to compare
 
kon, koff
 
and kD
 
values of
 
antibodies elicited
 
by our
 
product
candidates versus mAbs. We
 
also use Western
 
blot or slot blot to
 
evaluate the binding specificity of antibodies
 
elicited by our product
13
candidates against the toxic, misfolded or aggregated forms of the target protein, and avoidance of monomers
 
or healthy forms. We use
immunohistochemical analyses to observe the binding of antibodies to pathological inclusions on brain sections of patients. Moreover,
we use cell-based models and animal models to measure the induced antibodies’ functionality. Additionally, a major challenge in mAb
drug
 
discovery
 
is
 
that
 
mAbs
 
are
 
prone
 
to
 
induce
 
an
 
immune
 
response
 
against
 
themselves,
 
resulting
 
in
 
a
 
potential
inactivation/neutralization of the mAb by
 
the host (i.e., the patient).
 
This is not a concern
 
with our vaccine approach as
 
each patient will
produce its own antibodies against the target. Finally,
 
mAbs have a potential for off-target binding, which
 
could result in non- specific
safety and toxicity issues. We believe that this is
 
unlikely to happen using our vaccine
 
approach since antibodies elicited by
 
our product
candidates come
 
from the
 
body’s
 
own B-cells
 
and are
 
therefore unlikely
 
to induce
 
antibodies against
 
other self-proteins
 
as a
 
foreign
antibody may.
Product Candidate Selection Process
Because our Vaxxine Platform may
 
have applicability across
 
a range of
 
chronic diseases, we
 
employ a proprietary
 
filtering methodology
to best identify new product candidates for development. We evaluate potential product candidates across five principal criteria:
Probability
 
of
 
technical
 
and
 
regulatory
 
success
:
 
We
 
examine
 
the
 
probability
 
of
 
success
 
for
 
a
 
product
candidate based on stage of
 
development and therapeutic area, and
 
then make target-
 
specific adjustments for design
 
difficulty, industry
knowledge and
 
clarity of biological
 
mechanism, general
 
safety risk and
 
estimated titer
 
level required
 
for therapeutic
 
effect. This criterion
accounts for the known validity of a given target in the relevant disease context.
Market
 
opportunity
:
 
We
 
account
 
for
 
the
 
prevalence,
 
unmet
 
need
 
and
 
drug
 
market
 
size
 
for
 
each
 
likely
indication associated with a given target, as well as the number of potential indications.
Development cost
: We
 
estimate the
 
cost of
 
development through
 
BLA submission,
 
the time
 
to submission
and the number of patient-years to proof-of-concept.
Competitive advantages
: We
 
evaluate the extent to which the advantages of
 
our Vaxxine
 
Platform compare
to the current and potential future standard of care, including convenience, dosing, safety, efficacy and cost.
Disruptive opportunities
: We evaluate the extent to which the potential disruptive properties of our Vaxxine
Platform may play
 
a role in
 
treatment paradigms, including
 
the ability to
 
“leap-frog” mAbs
 
and treat patients
 
in earlier lines
 
of treatment,
to be used as a prophylactic, to combine multiple targets into a single formulation and to be used as an adjuvant therapy.
After assigning values to
 
each criterion for a
 
given product candidate, we
 
weight each criterion according
 
to a confidential algorithm,
and thereby prioritize product candidates for development. We update these values on a regular basis based on new scientific
 
literature,
trial results and our Vaxxine Platform advancements.
As an example, in light of these criteria, AD and other neurodegenerative
 
diseases that involve misfolded proteins are an attractive area
for development. First, as the field has gained knowledge and clinical experience
 
around the biology of targeting aberrant proteins with
antibodies, the relative
 
technical, safety and
 
regulatory risk has
 
decreased. AD and
 
PD have high
 
prevalence worldwide, and
 
large unmet
need with
 
no disease-modifying
 
products readily
 
available to
 
patients. Moreover, the
 
underlying pathologies
 
often begin
 
years or
 
decades
before symptoms may appear
 
and as a
 
result, early intervention in
 
the disease state, as
 
well as prevention or
 
delay of onset strategies,
may be optimal
 
and more practically
 
achievable with a
 
vaccine approach. While
 
mAbs can target
 
the pathology, they face
 
the limitations
of high cost, cumbersome and inefficient administration and limited access, and are not suited for early treatment or
 
prevention, which
we believe provides a disruptive opportunity for our Vaxxine Platform.
We
 
do not
 
currently evaluate
 
oncology and
 
infectious diseases
 
through the
 
above framework.
 
We
 
generally do
 
not pursue
 
oncology
targets given
 
the hyper-segmentation
 
of subjects
 
common in
 
clinical development
 
efforts in
 
oncology that
 
leads to
 
relatively narrow
labels, and
 
due to
 
the strengths
 
of other
 
new modalities
 
such as
 
cell-based therapy
 
in this
 
area. We
 
only consider
 
infectious disease
opportunistically. However, our approach with respect to oncology and infection diseases could change in the future.
We believe that our Vaxxine
 
Platform, and our strategy more generally, will create a significant opportunity for drug development well
beyond our current
 
pipeline of clinical
 
and pre-clinical indications,
 
in therapeutic areas
 
including allergy
 
(e.g., chronic rhinosinusitis,
atopic
 
dermatitis,
 
food
 
allergy),
 
autoimmune
 
disease
 
(e.g.,
 
psoriasis,
 
psoriatic
 
arthritis,
 
Crohn’s
 
disease),
 
pain
 
(e.g.,
 
peripheral
neuropathy, diabetic neuropathy) and bone and muscle atrophy (e.g., sarcopenia of aging, osteopenia).
Underlying Drivers of Our Platform Advantages
Our Vaxxine Platform’s properties drive the unique
 
combination of attributes
 
that we believe
 
will be reflected
 
in our product
 
candidates:
14
Cost
: Our reliance on chemically
 
linked, custom peptide sequences fuels cost
 
efficiencies that we expect to
enable
 
broad
 
accessibility
 
to
 
our
 
product
 
candidates.
 
Foremost
 
among
 
these
 
relates
 
to
 
dosing.
 
Monoclonal
 
antibodies
 
require
 
more
physical material for annual dosing because the patient needs to
 
be delivered the externally manufactured therapeutic antibodies, which
have high molecular weight. In
 
contrast, our product candidates
 
are designed to stimulate the
 
body’s immune system to produce its own
antibodies and
 
have relatively
 
low molecular weight.
 
While an
 
annual supply
 
of mAbs
 
doses may
 
include grams
 
or tens
 
of grams
 
of
drug substance, our current product candidates only require 1 to 2 milligrams each, or even less, leading to a relatively low annual cost
of goods. In our
 
development programs to date,
 
we have achieved a
 
cost of goods amounting
 
to a small fraction
 
of the typical
 
cost of
mAbs (as low as <1%).
Administration
: Administration of our product
 
candidates generally requires three
 
priming doses, each in the
range of several
 
hundred micrograms, followed
 
by booster doses
 
of a similar
 
magnitude 2 to
 
4 times per
 
year. As described in
 
the section
titled “Our
 
Product Candidates”
 
below,
 
in clinical
 
trials we
 
have observed
 
that our
 
product candidates
 
elicited a
 
sustained antibody
response, with elevated antibody
 
levels lasting six
 
months or longer. We believe this presents a
 
meaningful advantage over
 
many mAbs,
which commonly require either bi-weekly
 
or monthly injections, or
 
monthly or quarterly infusions, and
 
many small molecules, which
commonly require a daily pill.
Safety
: The
 
antibodies generated by
 
our product
 
candidates are
 
designed to
 
be highly
 
specific to the
 
target
antigen and to
 
avoid an off-target
 
immune response to
 
the peptide carrier,
 
thereby limiting inflammation and
 
other off-target
 
activity.
We
 
believe these
 
characteristics have
 
yielded the
 
high tolerability
 
observed in
 
the clinical
 
studies of
 
our product
 
candidates to
 
date.
Furthermore, the
 
titer response
 
to our
 
product candidates
 
is naturally
 
titrated, which
 
may reduce
 
the likelihood
 
of an
 
antibody Cmax
safety side effect, and is naturally reversible, thus avoiding an uncontrolled or permanent immune response.
Efficacy
: In
 
our clinical
 
trials conducted
 
to date,
 
our product
 
candidates have
 
yielded comparatively
 
high
response
 
rates (95%
 
or
 
above at
 
target
 
dose levels)
 
for UB-311,
 
UB-312 and
 
UB-612, high
 
target-
 
specific antibodies
 
against
 
self-
antigens (as
 
seen in
 
UB-311 and UB-312
 
clinical trials)
 
and long
 
durations of
 
action for
 
UB-311 (based on
 
titer levels
 
remaining elevated
between doses)
 
and UB-612
 
(based on
 
half-life). Furthermore,
 
our Vaxxine
 
Platform enables
 
the combining
 
of target
 
antigens into
 
a
single formulation. For indications that
 
could be treated more effectively
 
with a multivalent approach, we
 
believe our Vaxxine Platform
would have an advantage over other modalities. Finally, because our Vaxxine
 
Platform is designed to elicit endogenous antibodies, we
believe our product candidates may
 
lessen or avoid altogether the
 
phenomenon of anti-drug antibodies which
 
has limited the efficacy of
certain mAbs over time.
Additionally,
 
our Vaxxine
 
Platform possesses
 
important benefits
 
reflected at
 
the platform
 
level, as
 
opposed to
 
the product
 
candidate
level:
Product Candidate Discovery
: Our Vaxxine
 
Platform enables the efficient iteration of product candidates in
the discovery phase
 
through rapid, rational
 
design and formulation.
 
We
 
are able to
 
screen in high
 
throughput rapidly and
 
at low cost.
Upon nominating
 
a target
 
for drug
 
discovery,
 
we can
 
formulate several
 
dozen product
 
candidate compounds
 
for preliminary
 
in vivo
immunogenicity and cross-reactivity
 
screening within 2 to
 
3 months. This process
 
allows nonviable product
 
candidates to “fail fast”
 
and
allows
 
us
 
to
 
carry
 
top
 
product
 
candidates
 
forward
 
through
 
subsequent
 
pre-clinical
 
development
 
to
 
lead
 
identification.
 
In
 
contrast,
biologics require the maintenance and
 
adjustment of living cultures to design,
 
formulate and iterate, and therefore discovery
 
and early
development is inherently less efficient.
Process Development
: Scaling the formulation of a drug product from research grade
 
to clinical grade, then
to commercial grade, typically
 
consumes a great deal
 
of resources. This, together
 
with the development of
 
assays for quality control
 
and
quality assurance,
 
comprise process
 
development. Through
 
our manufacturing
 
partnership with
 
UBI and
 
certain of
 
its affiliates,
 
we
leverage their
 
experience scaling
 
the manufacture
 
of both
 
clinical and
 
commercial compounds
 
that use
 
our Vaxxine Platform technology.
Unlike process development
 
for mAbs, which
 
has inherent challenges
 
such as risk
 
of contamination in
 
cell culture or
 
bioreactors and
time-consuming adjustments
 
to cell
 
lines for
 
any formulation
 
adjustment, our
 
peptide platform
 
relies on
 
chemical synthesis
 
which is
more reproducible and scalable, and relatively quick to manipulate for any modifications.
Our Product Candidates
Neurodegenerative Disease Programs
Neurodegenerative diseases are a collection of conditions defined by progressive nervous system dysfunction, degeneration or death of
neurons, which can cause cognitive decline,
 
functional impairment and eventually death. Neurodegeneration
 
represents one of the most
significant unmet medical needs of our time due to an aging population and lack of effective therapeutic options.
Two of the most common
 
neurodegenerative diseases are
 
AD and PD.
 
In the United
 
States, currently more
 
than six million people
 
suffer
from
 
AD,
 
and
 
approximately
 
one million
 
people
 
suffer
 
from
 
PD
 
according
 
to
 
estimates
 
from
 
the
 
Alzheimer’s
 
Association
 
and
 
the
Parkinson’s Disease
 
Foundation, respectively.
 
As a result,
 
AD and PD
 
bring a heavy
 
burden on our
 
society’s cost
 
of care. The
 
direct
costs of caring for individuals with AD and
 
other dementias in the United States were estimated at
 
$305 billion in 2020 according to a
15
study
 
published
 
by
 
the
 
American
 
Journal of
 
Managed
 
Care,
 
and
 
are
 
projected
 
to
 
increase to
 
$1.1
 
trillion by
 
2050
 
according
 
to
 
the
Alzheimer’s Association. The financial burden of PD exceeded $50 billion in the United States in 2019. Many more people around the
world suffer from these two diseases and their related social and economic implications.
UB-311
An Overview of Alzheimer’s Disease
Alzheimer’s disease
 
is a
 
progressive neurodegenerative disorder
 
that slowly destroys
 
memory and cognitive
 
skills and
 
eventually the
ability to
 
carry out
 
simple tasks.
 
Its symptoms
 
include cognitive
 
dysfunction, memory
 
abnormalities, progressive
 
impairment in
 
activities
of daily
 
living and
 
a host
 
of other
 
behavioral and
 
neuropsychiatric symptoms.
 
The exact
 
cause of
 
AD is
 
unknown, but
 
genetic and
environmental
 
factors
 
are
 
established
 
contributors.
 
AD
 
affects
 
more
 
than
 
six million
 
people
 
in
 
the
 
United
 
States
 
and
 
44 million
worldwide. The economic burden of AD is expected to surpass $2.8 trillion by 2030.
Many molecular and cellular changes take place in the brain of a person with AD. Aβ plaques and neurofibrillary tangles of tau
 
protein
in the brain are the pathological hallmarks of the disease.
 
These abnormal depositions lead to loss of neurons and
 
neuronal connectivity
and the signs and symptoms of AD.
The Aβ
 
protein involved
 
in AD
 
comes in
 
several different
 
molecular forms
 
that accumulate
 
between neurons.
 
One form,
 
Aβ 42,
 
is
thought to be especially
 
toxic. In the brains
 
of patients with AD,
 
abnormal levels of this naturally
 
occurring protein clump together
 
to
form plaques that collect between neurons and disrupt cell function.
 
Research is ongoing to better understand how, and at what stage of
the disease, the various forms of Aβ influence AD.
Neurofibrillary tangles are
 
abnormal accumulations of
 
a protein called
 
tau that collect
 
inside neurons. Healthy
 
neurons are
 
supported
internally,
 
in part,
 
by structures called
 
microtubules, which help
 
to guide nutrients
 
and molecules from
 
the cell
 
body to
 
the axon
 
and
dendrites. In healthy neurons, tau normally
 
binds to and stabilizes microtubules. In
 
AD, abnormal chemical changes cause tau
 
to detach
from microtubules and to
 
stick to other tau
 
molecules, forming threads that
 
eventually join to form
 
tangles inside neurons. These
 
tangles
block the neuron’s transport system, which harms the synaptic communication between neurons.
Converging
 
lines of
 
evidence suggest
 
that AD-related
 
brain changes
 
may result
 
from a
 
complex interplay
 
among abnormal
 
tau, Aβ
proteins and several other
 
factors. It appears that
 
abnormal tau accumulates in
 
specific brain regions involved
 
in memory. Concurrently,
Aβ clumps into
 
plaques between
 
neurons. As the
 
level of
 
Aβ reaches a
 
tipping point,
 
tau rapidly spreads
 
throughout the
 
brain. In addition
to the spread of Aβ and tau,
 
chronic inflammation and its effect on the
 
cellular functions of microglia and astrocytes,
 
as well as changes
to the vasculature, are thought to be involved in AD’s pathology and progression.
Limitations of Current Therapies
Two
 
classes
 
of
 
small
 
molecules
 
approved
 
for
 
the
 
treatment
 
of
 
AD’s
 
symptoms
 
are
 
acetylcholinesterase
 
inhibitors
 
(“AChEIs”)
 
and
glutamatergic
 
modulators.
 
AChEIs
 
are
 
designed
 
to
 
slow
 
the
 
degradation
 
of
 
the
 
neurotransmitter
 
acetylcholine,
 
helping
 
to
 
preserve
neuronal communication and function
 
temporarily. Glutamatergic
 
modulators are designed to
 
block sustained, low-level
 
activation of
the
 
N-methyl-D-aspartate
 
(“NMDA”)
 
receptor,
 
without
 
inhibiting
 
the
 
normal
 
function
 
of
 
the
 
receptor
 
in
 
memory
 
and
 
cognition.
However,
 
these therapeutic
 
products only
 
address the
 
symptoms of
 
AD and
 
do not
 
modify or
 
alter the
 
progression of
 
the underlying
disease.
Aducanumab, marketed under the trade name Aduhelm, is
 
a mAb developed by Biogen, Inc. (“Biogen”) that
 
targets aggregated forms
of Aß. The FDA approved
 
aducanumab in June 2021, making
 
it the first approved immunotherapy
 
for AD, the first new
 
FDA-approved
treatment since 2003 and, importantly, the first to receive accelerated
 
approval based on a biomarker. By approving aducanumab
 
on the
basis of
 
biomarker evidence,
 
we believe
 
the FDA
 
set a
 
precedent for
 
developers of
 
anti-Aβ immunotherapies.
 
Soon after
 
the FDA’s
decision, Eli
 
Lilly and
 
Company (“Lilly”)
 
announced that
 
it would
 
file for
 
approval of
 
its anti-Aβ
 
mAb, donanemab,
 
in 2022
 
on the
basis
 
of
 
Phase
 
2
 
data.
 
Despite
 
the
 
milestone
 
in
 
the
 
treatment
 
of
 
AD
 
that
 
aducanumab’s
 
approval
 
represents,
 
the
 
drug
 
has
 
several
limitations. Approximately one-third of
 
patients experience ARIA-E related adverse
 
events, which can manifest
 
as symptoms ranging
from headaches
 
to confusion
 
to coma.
 
In addition,
 
the drug
 
must be
 
administered monthly via
 
intravenous infusion
 
in locations
 
with
healthcare professionals trained
 
to administer infusion
 
therapies in facilities
 
specifically configured to
 
support an hours-long
 
infusion
process, creating a
 
burden for patients
 
and additional costs
 
resulting from the
 
complex administration process.
 
Because of the
 
risk of
developing
 
ARIA-E,
 
physicians
 
who
 
prescribe
 
aducanumab
 
must
 
titrate
 
dosing
 
and
 
carefully
 
monitor
 
each
 
patient
 
using
 
magnetic
resonance imaging (“MRI”). This process is costly and burdensome, and thus expected to limit the prescribing of and regular access to
aducanumab. In addition, aducanumab launched at a price
 
of $56,000 annually for the drug product
 
only, not including
 
administration
and ongoing monitoring costs such
 
as positron emission topography
 
(“PET”) and MRI scans.
 
Since that time, Biogen has
 
reduced the
price of Aduhelm.
 
The combination of price,
 
side effects, extra
 
costs and extra
 
administration burden highlight the
 
challenges of, and
have limited access to, this mAb.
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16
Our Product Candidate: UB-311
We are developing a novel product candidate,
 
UB-311, as a potential disease-modifying
 
therapy for the treatment
 
of AD. We completed
a Phase 1 open label trial (V118-AD) and a Phase 2a randomized, double-blinded, placebo-controlled trial (the “Phase 2a Main Trial”)
in 2021 and believe
 
that UB-311 may offer several
 
differentiators versus aducanumab, including
 
the preferential targeting of
 
aggregated
Aβ oligomers over
 
monomers with modest
 
clearance of Aβ
 
plaques, and a
 
tolerability profile comparable
 
to placebo. No
 
signs of ARIA-
E related adverse events were reported in the Phase 2a Main Trial
 
despite more than two-thirds of the study participants being APOE4
carriers.
Post hoc
 
exploratory analyses
 
of UB-311’s
 
Phase 2a
 
clinical data
 
also suggest
 
that quarterly
 
dosing of
 
UB-311
 
might slow
cognitive decline in some
 
subjects by up to
 
50% when compared to
 
placebo, as measured by
 
Clinical Dementia Rating Sum of
 
Boxes
(“CDR-SB”), Alzheimer’s Disease Assessment Scale – Cognitive Subscale (“ADAS-Cog”), Alzheimer’s Disease Cooperative Study –
Activities of Daily Living (“ADCS-ADL”) and Mini-Mental State Examination (“MMSE”) scores, all clinically validated measures of
cognition or
 
function in
 
AD. In
 
this small
 
Phase 2a
 
study,
 
these were
 
secondary measures,
 
as the
 
study was
 
not designed
 
to assess
cognitive decline.
 
Although our
 
Phase 2a
 
trial was
 
a proof-of-concept
 
study,
 
not powered
 
to demonstrate
 
significant changes
 
in any
endpoint, we believe the data are suggestive of potential therapeutic efficacy and may lead to clinical benefit.
UB-311
 
is
 
formulated
 
for
 
intramuscular
 
administration
 
on
 
a
 
dosing
 
schedule
 
of
 
every
 
three
 
or
 
six
 
months.
 
In
 
addition,
 
lower
manufacturing costs may support meaningfully lower pricing. We
 
believe such advantages of UB-311,
 
if ever approved for use, could
position it not only to disrupt the emerging mAb-based treatment for early AD as both
 
a monotherapy and adjuvant therapy to existing
mAbs, but also to open up a new paradigm (i.e., for potential prophylactic use to delay or interrupt early disease onset).
Clinical Development
We
 
completed a randomized, double-blind, placebo-controlled Phase 2a
 
trial of two dosing regimens of
 
UB-311 in subjects with
 
mild
AD. The primary objective
 
of this trial was
 
to assess safety and
 
immunogenicity. Secondary measures for exploratory analyses
 
included
assessment of
 
changes in
 
the ADAS-Cog,
 
CDR-SB, ADCS-ADL
 
and MMSE
 
ratings, along
 
with amyloid
 
PET imaging
 
evaluations.
This study was
 
intended for proof-of-concept,
 
so no statistical
 
hypothesis testing was
 
planned, and exploratory
 
analyses were performed
to evaluate trends as described below.
A total
 
of 43
 
patients diagnosed
 
with mild
 
AD were
 
randomized (1:1:1)
 
to one
 
of three
 
treatment groups:
 
UB-311
 
high- frequency
(quarterly dosing, or “Q3M”) receiving a total of seven doses, UB-311 low-frequency (every six month dosing, or “Q6M”) receiving a
total of
 
five doses,
 
and placebo.
 
The high-frequency
 
cohort, which
 
included 14
 
subjects, received
 
an initial
 
regimen of
 
three 300μg
injections, one
 
injection at
 
the trial
 
start, one
 
at week
 
4 and
 
the final
 
at week
 
12, followed
 
by four
 
single 300μg
 
booster doses
 
administered
in three-month
 
intervals over
 
the subsequent
 
12
 
months. The
 
low-frequency cohort,
 
which included
 
15
 
subjects, involved
 
the same
initial schedule
 
of
 
three 300μg
 
injections administered
 
over
 
the
 
first
 
12-week
 
period,
 
followed by
 
the
 
administration of
 
two
 
300μg
booster doses given at six-month intervals. The placebo group comprised 14 subjects.
In the Phase
 
2a Main Trial,
 
UB-311 generated
 
an immune response
 
as measured by
 
ELISA in 28
 
out of 29
 
subjects. Across this
 
trial
and the
 
Phase 1
 
trial, 47
 
of the
 
48 subjects
 
(98%) that
 
received UB-311
 
registered an
 
immune response
 
(which we
 
define as
 
a 95%
confidence interval separation from placebo) as measured by ELISA. The intramuscular injection produced appreciable antibody titers
against
 
Aβ.
 
The antibody
 
titers
 
remained
 
elevated
 
through the
 
trial’s
 
duration.
 
Moreover,
 
in vitro
 
studies demonstrate
 
that
 
UB-311
generated serum anti-Aβ
 
antibody titers against
 
oligomers, the components
 
that form Aβ,
 
comparable or greater
 
than those measured
after maximum
 
therapeutic dosing
 
with aducanumab.
 
We
 
believe these
 
results underscore
 
the significant
 
promise of
 
our therapeutic
approach.
Generation of Antibodies Repeatable Across Clinical Studies, and Antibodies Bind Target with High
Specificity as Compared to Monoclonal Antibody
vaxxq410kp18i1.jpg vaxxq410kp18i0.jpg
17
Across Phase
 
1 and Phase
 
2a trials, UB-311
 
generated an over
 
95% response
 
rates in subjects.
 
In a comparative
 
in vitro
 
study with
aducanumab, we observed that UB-311 elicited titer levels comparable to mAbs.
Our Phase
 
1 and
 
Phase 2a
 
trials demonstrated
 
a repeatable
 
anti-Aβ titer
 
response. In
 
an in
 
vitro comparison
 
of titers
 
in serum
 
from
subjects dosed
 
with UB-311 versus
 
pre-immune serum
 
spiked with
 
aducanumab at
 
the published
 
Cmax concentration
 
following 10mg/kg
administration (183μg/mL),
 
antibodies generated
 
by UB-311 bond
 
to Aβ oligomers
 
similarly to or
 
greater than aducanumab
 
as measured
by EIA.
Exploratory analyses
 
of clinical and
 
imaging measures
 
were conducted.
 
Trends of changes
 
in disease assessment
 
scores suggest showing
of cognitive decline.
 
Changes in the
 
CDR-SB assessment at
 
week 78 of
 
the Phase 2a
 
Main Trial
 
showed a 48%
 
slowing in cognitive
decline from baseline relative to the placebo group; changes in ADAS-Cog measurements showed a 50% slowing in decline relative to
placebo and showed a 54% slowing in decline in ADCS-ADL relative to placebo.
UB-311 Phase 2a Suggests Slowing of Cognitive Decline in Mild Alzheimer’s Subjects (mITT)
UB-311 Phase 2a secondary endpoint data suggested possible slowing of clinical
 
decline by up to 50% in subjects with
 
mild AD. These
are exploratory analyses and no statistical inference was performed.
 
In addition,
 
functional MRI
 
suggested marginal
 
increases in
 
connectivity in
 
some brain
 
regions and
 
PET imaging
 
showed a
 
modest
reduction in
 
amyloid plaque
 
burden as
 
measured by
 
standard uptake
 
value ratio.
 
We
 
believe these
 
clinical and
 
biomarker endpoints
suggest a causal
 
effect of UB-311 impacting
 
the underlying
 
molecular pathology
 
of the disease
 
and slowing
 
of clinical
 
decline. Together,
these findings offer
 
some evidence that UB-311 may exhibit disease-modifying effects.
UB-311 Phase 2a Analysis of Clinical and Biomarker Endpoints Suggests Overall Disease-Modifying Effect
Compared to placebo,
 
UB-311
 
low-frequency dosing and
 
high-frequency dosing demonstrated
 
slowing of overall disease progression
in an independent analysis conducted by Pentara Corporation.
 
In addition to the
 
composite above, Pentara Corporation
 
performed a post hoc
 
analysis to estimate the
 
performance of UB-311
 
on the
integrated Alzheimer’s Disease Rating Scale (“iADRS”) versus placebo in the Phase 2a trial. The results of this analysis suggested
 
that
the UB-311 target dosing regimen (quarterly dosing) on average slowed decline versus placebo by approximately 59% over 78 weeks.
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18
iADRS Change from Baseline over Time vs. Placebo (Exploratory Analysis)
Compared to placebo, UB-311 (quarterly dosing) declined less on an iADRS-like clinical endpoint over
 
78 weeks in mild-moderate AD
subjects in
 
the Phase
 
2a Main
 
Trial. This analysis
 
was performed
 
by Pentara
 
Corporation. The
 
UB-311 Q6M group showed
 
26% decline
versus placebo which is not shown on the plot.
We
 
have
 
provided
 
a
 
side-by-side
 
summary
 
table
 
of
 
subject
 
baseline
 
characteristics below,
 
with
 
anti-Aβ
 
mAbs
 
using
 
data
 
from
 
the
exploratory endpoints of the Phase 2a Main
 
Trial, in particular CDR-SB, as
 
well as using the post hoc
 
iADRS-like endpoint (no head-
to-head clinical trials of UB-311 against mAbs
 
have been performed). We
 
believe the performance of aducanumab and donanemab on
CDR-SB and iADRS change from baseline over time, the respective primary
 
endpoints from the pivotal trials of those mAbs, represent
meaningful references.
Post hoc
 
side-by-side analyses suggested that UB-311 has
 
the potential to perform comparably to aducanumab
on
 
CDR-SB
 
change
 
from
 
baseline
 
over
 
time,
 
and
 
comparably
 
to
 
donanemab
 
on
 
iADRS
 
change
 
from
 
baseline
 
over
 
time,
 
in
 
an
appropriately powered
 
study, noting that
 
the UB-311 Phase
 
2a Main
 
Trial was a
 
proof-of-concept study
 
not powered
 
to detect
 
statistically
significant changes, and these are indirect comparisons with aducanumab and donanemab
 
trials. We have
 
provided an overview of the
sample sizes and baseline characteristics of the UB-311 Main Trial and various anti-Aβ mAb trials below.
Baseline Characteristics of Various Anti-Aβ Immunotherapy Clinical Trials
The Phase
 
2a Main
 
Trial recapitulated
 
the safety
 
and tolerability
 
profile of
 
UB-311 that
 
was observed
 
in an
 
earlier Phase
 
1 trial.
 
No
subjects discontinued trial
 
participation due to
 
a treatment emergent
 
adverse effect (“TEAE”).
 
No ARIA-E was
 
observed in quarterly
MRI
 
scans.
 
Aβ-related
 
imaging
 
abnormalities
 
related
 
to
 
microhemorrhages
 
or
 
hemosiderosis
 
seemed
 
similar
 
between
 
the
 
UB-311
treatment groups and placebo group. In the Phase 2a Main Trial, six serious adverse events were observed, including three in
 
the Q6M
dosing arm and one in the Q3M dosing arm. None was deemed related or likely related to UB-311.
Titers generated by UB-311 ramped up gradually over the
 
course of several months, as
 
opposed to titers following the
 
administration of
anti-Aβ mAbs,
 
which immediately
 
reach Cmax.
 
We
 
believe this
 
lead to
 
the relatively
 
low rates
 
of ARIA-E
 
observed in
 
our clinical
studies of UB-311 as compared to those observed in clinical studies of mAbs. No meningoencephalitis was observed.
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19
Summary of Safety Data from UB-311 Phase 1 and Phase 2a Trials
As depicted
 
in the
 
table above,
 
UB-311 was well
 
tolerated across Phase
 
1 and
 
Phase 2a
 
trials. The
 
most common
 
TEAE was
 
site injection
reactivity, and there
 
were no discontinuations or withdrawals due to TEAEs
An
 
extension
 
of
 
the
 
Phase
 
2a
 
Main
 
Trial,
 
the
 
Phase
 
2a
 
LTE
 
trial,
 
involved
 
the
 
continued
 
participation
 
by
 
34
 
of
 
the
 
subjects
 
who
participated in the Phase 2a Main Tri
 
al for an additional 78 weeks. The objectives of
 
the Phase 2a LTE
 
trial were to assess the longer-
term tolerability of extended treatment with UB-311. Following a non-treatment period of up to 26 weeks, participants in the LTE
 
trial
were segmented
 
into two
 
groups: those
 
previously on drug
 
in the
 
Phase 2a
 
Main Trial
 
would receive
 
two placebo
 
doses and
 
a single
300μg priming dose at the start of the LTE
 
treatment period and those previously on placebo would receive three 300μg priming doses
over an
 
initial 12-week
 
period. Due
 
to an
 
error by
 
the CRO
 
responsible for
 
administering blinded
 
placebo and
 
active doses
 
to trial
subjects, which reduced the confidence of subsequently collected data, we decided to discontinue the LTE trial, having determined that
we had collected
 
sufficient data on
 
UB-311’s tolerability and immunogenicity. Analysis of
 
the data collected
 
before trial discontinuation
indicated that
 
UB-311 was
 
well tolerated,
 
with return
 
of anti-Aβ
 
antibody titers to
 
peak levels
 
achieved after
 
a gap of
 
as much
 
as 12
months between
 
doses and
 
a continued
 
trend toward evidence
 
of disease
 
modification. In
 
the Phase
 
2a LTE
 
trial, six
 
serious adverse
events were observed. One case of ARIA-E was observed in the Phase 2a LTE
 
trial. None was deemed related or likely related to UB-
311,
 
and all
 
such events
 
were recovered/resolved
 
by the
 
end of
 
the study.
 
Exploratory analyses
 
of the
 
clinical data
 
generated in
 
this
portion of the trial suggested that subjects in
 
the treatment cohorts showed sustained improvement, as
 
measured by the change in CDR-
SB from baseline.
We completed an open-label Phase 1 trial of UB-311 in 19 subjects with mild-to-moderate AD between the ages of 51 to 78 years. The
primary objective
 
of the
 
trial was
 
to assess
 
safety and
 
tolerability.
 
Secondary measures
 
included UB-311
 
antibody titers
 
along with
changes in the ADAS-Cog,
 
MMSE and the Alzheimer’s
 
Disease Cooperative Study-Clinician’s
 
Global Impression of Change
 
disease
assessment ratings. The 24-week,
 
open label trial was
 
designed as three intramuscular
 
injections of 300μg, the first
 
dose administered
at the start of the trial, a second at week four and a third at week 12. An observation study included additional follow-up visits up to 48
weeks after the
 
first injection to
 
assess the long-term
 
immunogenicity and safety
 
of UB-311.
 
In this trial,
 
UB-311 was
 
well tolerated,
with the most common TEAE being injection site redness and swelling. No TEAE resulted in the discontinuation or withdrawal of any
study participant in
 
the trial. In
 
the Phase 1
 
trial, one serious
 
adverse event was
 
observed: a case
 
of herpes zoster
 
deemed unlikely related
to UB-311.
Anti-Aβ
 
antibody
 
titers,
 
recorded
 
among
 
all
 
study
 
participants,
 
approached
 
a
 
100-fold
 
increase
 
during
 
weeks
 
16
 
to
 
48
 
after
administration of
 
the third
 
300μg injection
 
at week
 
12, demonstrating
 
the ability
 
of UB-311 to
 
elicit a
 
strong immune
 
response. Durability
of the response was reflected in elevated anti-Aβ antibody titers measurable well beyond the 24-week duration of the trial.
In a Western blot assay, we observed that UB-311 elicited antibody titers specific to toxic
 
forms of Aβ with minimal binding
 
to normal,
non-plaque-causing, forms of Aβ.
Pre-Clinical Data
Pre-clinical trials of UB-311
 
included multiple antibody titer studies involving
 
mice, guinea pigs, macaques and baboons. Application
of
 
specific
 
transgenic
 
animal
 
models
 
was
 
intended
 
to
 
emulate
 
both
 
therapeutic
 
and
 
preventive
 
treatment
 
paradigms.
 
These
 
trials
demonstrated that UB-311 generated high
 
antibody titers across
 
multiple species that selectively
 
target aggregated Aβ and
 
both slow the
accumulation of and reduce existing Aβ pathology.
vaxxq410kp21i0.jpg
20
We also observed the ability of UB-311
 
induced antibodies to penetrate the BBB, as well as preferentially bind to toxic Aβ aggregates.
In our study of UB-311 in cynomolgus
 
monkeys, we tested five escalating
 
dose levels of UB-311: 0μg, 30μg, 100μg,
 
300μg and 900μg.
Each dose level was
 
administered on weeks zero,
 
three and six by
 
intramuscular injection and the
 
cerebrospinal fluid (“CSF”): serum
ratio of
 
UB-311
 
calculated on
 
week eight
 
(two weeks
 
after the
 
last dose).
 
This analysis
 
concluded that
 
UB-311
 
antibody titers
 
were
detectable in the CSF in a
 
dose-dependent manner with CSF: serum
 
antibody ratios of 0.1% to
 
0.2%, ratios similar to published
 
data for
mAbs in development for neurodegenerative diseases.
UB-311 Shows Dependent Response in CSF in Pre-Clinical Study
The above graphs demonstrates that UB-311 achieved CSF: serum ratios in the 0.1% to 0.2% range across five doses in a pre
 
-clinical
study involving cynomolgus monkeys.
Development Plans for UB-311
We have completed a pre-Phase 3 meeting with the FDA and obtained guidance on the further development of UB-311.
Subject to the FDA’s review,
 
we expect to conduct a
 
randomized, double-blinded, placebo-controlled Phase
 
2b efficacy trial of UB-311
in approximately
 
670 subjects
 
with early
 
AD. The
 
Phase 2b
 
trial will
 
include subjects
 
diagnosed with
 
early AD
 
with MMSE
 
scores
between 22 and 30.
 
We will also screen to enrich
 
for positive amyloid
 
PET, positive tau PET and
 
positive plasma p-tau181, in
 
quantities
consistent with an early AD population. Subjects in the active arm will receive UB-311 as three 300μg priming doses at weeks 0, 4 and
12, followed by four 300μg
 
booster doses every three months
 
thereafter. The
 
primary objective of this trial will
 
be to assess the
 
effect
of
 
UB-311
 
on
 
the
 
decline
 
of
 
cognitive
 
and
 
functional
 
performance
 
as
 
measured
 
by
 
the
 
iADRS
 
over
 
the
 
78-week
 
treatment
 
period.
Secondary endpoints
 
will include
 
the changes
 
from baseline
 
measurements of
 
other validated
 
clinical outcomes
 
scores. The
 
effect of
UB-311 on specific AD biomarkers will also
 
be evaluated, including neurofilament light
 
arm (“NfL”), p-tau, total-tau, brain amyloid
 
as
measured by PET, Aβ-40 and Aβ-42, hippocampal volume and whole brain volume as measured by MRI, and an assessment of certain
CSF biomarkers. We expect to initiate this trial in the second half of 2022.
Assuming positive results in the
 
Phase 2b trial, we expect
 
to initiate a Phase 3
 
trial in subjects with early
 
AD. The Phase 3 program
 
may
involve one, but more
 
likely two, clinical trials,
 
conducted at multiple international
 
sites. Assuming positive
 
results in the Phase
 
2b trial,
we may also seek
 
FDA approval under the
 
accelerated approval pathway,
 
which allows for earlier
 
approval of drugs that
 
treat serious
conditions, and that fill an unmet medical need based on a surrogate endpoint.
 
We expect that together, the Phase 2b trial and the Phase
3 program, if successful, will provide sufficient data to enable BLA filing with the FDA, but there can be no guarantee that we will not
need to conduct additional trials or studies prior to a BLA filing with the FDA.
We believe UB-311 could
 
also have
 
a potential
 
therapeutic benefit
 
in a
 
prophylactic setting
 
for the
 
prevention of
 
AD in
 
high-risk patients.
We may seek to further develop UB-311
 
for the prevention of AD.
UB-312
An Overview of Parkinson’s
 
Disease
Parkinson’s disease currently affects approximately
 
one million people in
 
the United States
 
and more than
 
10 million people worldwide.
The economic burden of
 
PD is estimated at
 
$52 billion in the United
 
States alone. PD
 
is a chronic and
 
progressive neurodegenerative
disorder that affects
 
predominately dopamine-producing (“dopaminergic”) neurons
 
in the substantia
 
nigra area of
 
the brain. Although
the
 
mechanisms responsible
 
for
 
the
 
dopaminergic
 
cell
 
loss in
 
PD
 
are not
 
fully
 
elucidated, several
 
lines
 
of
 
evidence
 
suggest
 
that
 
α-
synuclein plays a central role in the neurodegenerative process.
21
Alpha-synuclein
 
is
 
a
 
protein
 
highly
 
expressed
 
in
 
neurons,
 
mostly
 
at
 
presynaptic
 
terminals,
 
suggesting
 
a
 
role
 
in
 
synaptic
 
vesicle
trafficking,
 
synaptic
 
functions
 
and
 
in
 
regulation
 
of
 
neurotransmitter
 
release
 
at
 
the
 
synapse.
 
Duplications,
 
point
 
mutations
 
or
 
single
nucleotide polymorphisms
 
in the
 
gene encoding
 
α-synuclein are
 
known to
 
cause or
 
increase the
 
risk of
 
developing PD
 
or LBD.
 
Mutations
have been shown to primarily alter the
 
secondary structure of α-synuclein, resulting in misfolded and aggregated
 
forms of α-synuclein
(i.e., pathological
 
forms). While
 
mutations in
 
the α-synuclein
 
gene are rare,
 
aggregates of
 
α-synuclein in
 
the form
 
of Lewy bodies
 
(“LB”)
and Lewy neurites are common neuropathological hallmarks of
 
both familial and sporadic PD, suggesting a
 
key role of α-synuclein in
PD
 
neuropathogenesis.
 
Moreover,
 
preformed
 
fibrils
 
of
 
α-synuclein
 
can
 
induce
 
the
 
formation
 
of
 
LB-like
 
inclusions
 
and
 
cellular
dysfunction in
 
cell-based assays
 
as well
 
as in
 
pre-clinical animal
 
models. Together, these data
 
strongly suggest
 
that targeting
 
pathological
forms of α-synuclein has therapeutic potential.
Limitations of Current Therapies
Most approved
 
therapeutic products
 
are aimed
 
at compensating
 
for the
 
dopaminergic deficits
 
and only
 
provide symptomatic
 
relief. While
existing products can indeed
 
provide meaningful symptomatic relief,
 
they often produce significant
 
side effects and lose their
 
beneficial
effects overtime. On the other hand, there are no currently approved disease-modifying therapeutics for PD.
Immunotherapy approaches targeting
 
α-synuclein have been
 
shown to ameliorate
 
α-synuclein pathology as
 
well as functional
 
deficits
in mouse models of PD
 
and are now being investigated in
 
the clinic. These include passive immunization
 
therapy using humanized or
human anti-α-synuclein mAbs or active immunization therapy aimed at inducing a humoral response against pathological α-synuclein.
These approaches have thus far demonstrated good tolerability profiles in Phase 1 clinical trials. A Phase 2 clinical trial in PD subjects
with prasinezumab, a
 
mAb that preferentially
 
recognizes oligomeric and
 
fibrillar forms of
 
α-synuclein significantly reduced
 
subjects’
motor function decline and delayed clinically meaningful worsening or motor symptoms, compared with placebo. Despite encouraging
preliminary data
 
observed with
 
this mAb,
 
we expect
 
that mAbs,
 
even if
 
approved as
 
therapeutic for
 
PD, would
 
be burdened
 
by the
general challenges of cost and administration.
Our Product Candidate: UB-312
We are developing UB-312,
 
an anti-α-synuclein product candidate, as a treatment for PD and other synucleinopathies. We
 
believe that
UB-312 has
 
the potential
 
to be
 
established as
 
a disease-modifying
 
treatment modality
 
for PD,
 
and possibly
 
for LBD
 
and MSA.
 
Pre-
clinical data indicated
 
that UB-312 elicits
 
antibodies that preferentially
 
recognize pathological forms
 
of a-synuclein and
 
improves motor
performance in
 
mouse models
 
of α-synucleinopathies.
 
Preliminary clinical
 
data from
 
our ongoing
 
Phase 1
 
trial indicate
 
that UB-312
elicits antibody levels
 
sufficient to
 
cross the BBB
 
(i.e., detectable in
 
CSF). In 2018,
 
the European Medical
 
Agency (“EMA”) granted
UB-312 orphan designation for MSA.
Clinical Development
We have conducted Part A of a randomized, placebo-controlled, double-blind, dose-escalating, single- center Phase 1 clinical trial of
UB-312 in which 50 healthy volunteers between the ages of 40 and 85 years received three intramuscular doses of either UB-312 or
placebo. During this 44-week Part A trial, subjects received three doses (on weeks 1, 5 and 13) with escalating doses ranging from
40μg to 2,000μg. Immunogenicity was evaluated by measuring changes in serum anti-α-synuclein antibody concentrations during
 
the
course of the study. Data from Part A indicated that UB-312 is generally well tolerated, with no significant safety findings. Data from
Part A also suggested that UB-312 is highly immunogenic, with all individuals in the 300μg/dose group showing detectable anti-α-
synuclein antibodies in both serum and CSF samples. CSF: serum ratios appeared similar to those observed in UB-311 non-human
primate studies (approximately 0.2%), and to those observed in clinical trials of mAbs. Based on these results, we are now evaluating
two dosing regimens of UB-312 in Part B of the Phase 1 trial: three doses of 300μg, and one dose of 300μg followed by two doses of
100μg. Part B will evaluate UB-312 and placebo in 20 PD subjects and began enrollment in January 2022. In addition to the endpoints
evaluated in Part A, an exploratory endpoint involving a clinical assessment using the Movement Disorder Society – Unified
Parkinson’s Disease Response Score will be used.
The Michael J. Fox Foundation (“MJFF”) is funding a 2-year collaborative project between Vaxxinity,
 
Mayo Clinic, and University of
Texas Houston using CSF collected from individuals enrolled in Part B of the Phase 1 trial of UB-312.
 
This work will evaluate the
potential of protein misfolding cyclic amplification (“PMCA”) to assess target engagement and will also aim to characterize the anti-
α-synuclein antibodies produced after immunization with UB-312. Demonstrating whether pathological forms of α-synuclein are
detectable in the CSF of PD subjects, and whether UB-312-derived antibodies prevent the formation of α-synuclein seeds measured by
PMCA, might provide a meaningful surrogate marker of target engagement.
 
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UB-312 Demonstrated Dose-Dependent Response in Phase 1 Part A Trial Including Penetration of Titers into CSF
Across
 
four cohorts,
 
UB-312 demonstrated
 
a dose-dependent
 
immunogenic response.
 
Antibodies generated
 
by UB-312
 
were
 
readily
detectable in CSF,
 
indicating BBB penetration with a CSF: serum ratio of approximately 0.2%.
We paused dosing in high dose
 
cohorts in Part A
 
of the trial after
 
one subject developed
 
an adverse effect (“AE”)
 
of special interest
 
(i.e.,
Grade 3 flu-like
 
symptoms) shortly after
 
receiving the second
 
1000μg dose of
 
UB-312. Although this AE
 
was transient and
 
not a serious
adverse event (“SAE”), data collected
 
until that point suggested that
 
the 100μg and 300μg dose
 
levels were well tolerated and
 
yielded
relatively high anti-α- synuclein titers.
 
During the evaluation of the AE,
 
the COVID-19 pandemic was becoming
 
increasingly pervasive
throughout Europe, increasing the risk to healthy
 
volunteers participating in the trial. We
 
therefore did not resume dose escalation and
selected 100μg and 300μg doses for Part B in PD subjects.
Pre-Clinical Data
We
 
have
 
conducted
 
pre-clinical
 
studies
 
of
 
UB-312
 
across
 
multiple
 
animal
 
species,
 
including
 
mice
 
and
 
guinea
 
pigs.
 
These
 
trials
demonstrated that
 
our product
 
candidates, including
 
UB-312, generated
 
high antibody
 
titers to
 
α-synuclein across
 
animal species.
 
In
addition, in vitro studies provided
 
evidence that anti-α-synuclein antibodies produced
 
after UB-312 immunization are highly
 
selective
to pathological α-synuclein, and do not bind to normal α-synuclein.
UB-312 Demonstrates Selective Binding Towards α-Synuclein Fibrils and Ribbons
This in vitro slot blot analysis of sera from guinea pigs dosed with UB-312 demonstrates that antibodies induced by UB-312 bind to α-
synuclein fibrils
 
and ribbons,
 
the toxic
 
forms of
 
α-synuclein believed
 
to underlie
 
PD, more
 
strongly than
 
they bind
 
to monomers,
 
the
normal form of α-synuclein in
 
the body. We believe this preference
 
will allow UB-312 antibodies to
 
avoid target-mediated clearance by
monomers and bind selectively to the toxic species
(Nimmo et al., Alzheimers Res Ther. 2020;12:159).
Anti-α-synuclein
 
antibodies
 
produced
 
by
 
UB-312
 
immunization
 
specifically
 
bind
 
pathogenic
 
species
 
of
 
α-synuclein,
 
including
aggregated fibrils, oligomers
 
and ribbons, while
 
demonstrating low affinity
 
for the monomer.
 
This species selectivity
 
contrasted with
Syn-1, a commercial research mAb used as a control, which failed to differentiate the toxic variants.
In an in vivo study of UB-312 using a transgenic mouse model of PD, we demonstrated prevention
 
of motor deficits in treated animals,
which was associated with significant
 
reduction of brain oligomeric forms
 
of α- synuclein. We
 
believe this data supports the
 
potential
of UB-312 to prevent behavioral motor deficits and reduce toxic forms of α-synuclein.
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23
UB-312 Demonstrates Improvement in Motor Symptoms in Pre-Clinical Study
UB-312
 
immunization
 
in a
 
transgenic mouse
 
model
 
(α-synuclein
 
overexpression)
 
demonstrates
 
improvement
 
in
 
beam
 
test
 
and
 
wire
hanging test, and reductions in α-synuclein oligomers in various brain regions (Nimmo et al., Acta Neuropathol. 2022;143:55-73).
We
 
have also observed
 
by immunohistochemistry that
 
serum antibodies from
 
guinea pigs dosed
 
with UB-312 can
 
bind to aberrant
 
α-
synuclein in PD, LBD and MSA brain sections.
Finally,
 
antibodies
 
derived
 
from
 
UB-312
 
showed
 
no
 
off-target
 
binding
 
on
 
human
 
tissue
 
sections.
 
UB-312-treated
 
transgenic
 
mice
showed no signs of neuroinflammation,
 
and GLP toxicity studies
 
in rats indicated a
 
good non-clinical safety and
 
tolerability profile. We
believe
 
our
 
preclinical
 
data
 
suggest
 
that
 
UB-312
 
may
 
potentially
 
induce
 
a
 
well-tolerated,
 
strong
 
and
 
specific
 
IgG
 
response
 
against
pathological forms of
a-synuclein
in PD subjects.
Development Strategy
While certain portions of
 
this Phase 1 trial
 
were interrupted by the
 
COVID-19 pandemic, Part
 
A in 50 healthy
 
volunteers was completed
in 2020,
 
and we
 
began dosing
 
PD subjects
 
in Part
 
B in
 
early 2022.
 
In Part
 
B we
 
expect to
 
include exploratory
 
endpoints potentially
relevant to
 
PD, such
 
as total
 
and free
 
α-synuclein in
 
serum and
 
CSF, in addition
 
to T-cell ELISpot analyses
 
and antibody
 
characterization.
Upon the completion of
 
the Phase 1
 
trial, we expect
 
to advance UB-312
 
into further clinical development,
 
which may comprise
 
trials
for various synucleinopathies.
Other Neurodegeneration Programs
We are
 
actively engaged in additional initiatives related to neurodegenerative disorders. One of these programs focuses specifically on
tau-protein pathology
 
and its
 
involvement in
 
diseases such
 
as AD
 
and related
 
tauopathies. We believe
 
that targeting
 
different pathological
tau variants simultaneously may enhance treatment efficacy,
 
which will most likely require targeting
 
multiple epitopes concomitantly.
Using
 
our
 
Vaxxine
 
Platform,
 
we
 
have
 
constructed
 
combination
 
product
 
candidates
 
that
 
target
 
these
 
multiple
 
epitopes
 
and
 
have
successfully demonstrated their utility to raise therapeutic antibody titers in in vitro studies as well as early in vivo animal models.
We are also investigating the use of a combination of product candidates targeting Aβ, α-synuclein, tau and C9ORF79 dipeptide repeat
proteins, as multiple proteins could be implicated in neurodegenerative diseases.
Next Wave Chronic Disease Treatments
Pathological
 
endogenous
 
proteins
 
(“self-proteins”)
 
drive
 
a
 
wide
 
range
 
of
 
chronic
 
diseases.
 
While
 
mAbs
 
and
 
small
 
molecules
 
have
provided therapeutic
 
benefits in
 
the treatment
 
of these
 
diseases, inherent
 
limitations of
 
these drug
 
classes have
 
restricted access
 
and
adherence to these treatment modalities globally.
Our next
 
wave chronic disease
 
program is
 
initially focused on
 
migraine and
 
hypercholesterolemia. Monoclonal antibodies
 
have been
approved in both therapeutic areas; however, their high costs have limited access and generally limited use to relatively severe disease.
We aim to develop product candidates in these therapeutic areas that could offer similar efficacy as mAbs at a meaningfully lower cost
24
and
 
improved
 
administrative
 
convenience
 
to
 
patients,
 
thereby
 
potentially
 
allowing
 
for
 
access
 
to
 
broader
 
patient
 
populations
 
versus
mAbs, and greater efficacy than small molecules.
UB-313
An Overview of Migraine
Migraine
 
is
 
a
 
chronic
 
and
 
debilitating disorder
 
characterized by
 
recurrent attacks
 
lasting four
 
to
 
72
 
hours
 
with
 
multiple symptoms,
including typically
 
one-sided, pulsating
 
headaches of
 
moderate to
 
severe pain
 
intensity that
 
are associated
 
with nausea
 
or vomiting,
sensitivity to sound
 
and sensitivity to
 
light. Over 90%
 
of the patients
 
are unable to
 
function normally during
 
a migraine attack. Many
experience comorbid conditions such as depression, anxiety and insomnia.
The Migraine Research
 
Foundation ranks migraine
 
as the world’s third
 
most prevalent illness.
 
The disease affects
 
39 million individuals
in the
 
United States and
 
approximately one billion individuals
 
globally.
 
Patients generally suffer
 
from chronic or
 
episodic migraines.
Chronic migraine is defined
 
as 15 headache days or
 
more per month, while
 
episodic migraine is defined
 
as fewer than 15 headache
 
days
per month. Both acute and prophylactic treatments are used to address chronic and episodic migraines.
CGRP’s
 
Role in Migraine
CGRP
 
is
 
a
 
neuropeptide
 
found
 
throughout
 
the
 
body,
 
including
 
in
 
the
 
spinal
 
cord.
 
CGRP
 
activates
 
CGRP
 
receptor
 
in
 
the
trigeminovascular system, which is
 
located within pain-signaling pathways,
 
intracranial arteries and mast
 
cells. Activation of the
 
CGRP
receptor has been demonstrated to induce migraine in migraineurs. Multiple anti-CGRP therapies
 
have been approved for the treatment
of migraine.
Limitations of Current Therapies
Since the early 1990s,
 
there has been minimal
 
improvement in the standard
 
treatment for migraine. Treatments are
 
characterized as elite
acute or prophylactic.
 
Triptans are
 
the current first-line
 
prescription therapy for
 
the acute treatment
 
of migraine, with
 
over 15 million
annual prescriptions written in the United States.
Prophylactic medications
 
approved for migraine
 
include beta
 
blockers, such
 
as propranolol, topiramate,
 
sodium valproate
 
and botulinum
toxin,
 
branded
 
as
 
Botox.
 
However,
 
many
 
of
 
these
 
medications
 
provide
 
limited
 
clinical
 
benefit.
 
In
 
addition,
 
they
 
are
 
often
 
not
 
well
tolerated, with AEs such as cognitive impairment, nausea, fatigue and sleep disturbance.
Therapeutics targeting
 
the CGRP pathway
 
represent an emerging
 
treatment paradigm. Three
 
anti-CGRP mAbs were
 
approved by the
FDA in
 
2018 for
 
the prophylactic
 
treatment of
 
migraine in
 
adults. These
 
mAbs, erenumab-aooe
 
(Aimovig), fremanezumab-vfrm
 
(Ajovy)
and
 
galcanezumab-gnlm
 
(Emgality),
 
are
 
all
 
administered
 
subcutaneously.
 
Their
 
side
 
effects
 
are
 
generally
 
mild,
 
including
 
pain
 
and
redness at the
 
site of injection,
 
nasal congestion and
 
constipation. Studies show that
 
these mAbs reduce
 
the number of
 
headache days
by 50% or more in approximately 50% of patients. Sales for marketed and clinical-stage anti-CGRP therapeutics are projected to reach
approximately $7.4 billion by
 
2026. Despite the commercial
 
success that this
 
class represents, many
 
of these treatments
 
require frequent
administration, creating inconvenience for patients.
Our Product Candidate: UB-313
We are developing UB-313
 
as a prophylactic treatment initially for chronic migraine. We
 
believe UB-313 has the potential to improve
upon the current
 
treatments for chronic
 
migraine in multiple
 
aspects: we expect
 
UB-313 will require
 
administration quarterly to
 
annually
in
 
contrast
 
to
 
monthly
 
to
 
quarterly
 
for
 
currently
 
marketed
 
mAbs
 
and
 
frequent
 
administration
 
for
 
small
 
molecules.
 
Furthermore,
 
a
potential long durability of response may offer physicians and patients
 
the option to administer UB-313 in an office setting, which
 
can
potentially improve adherence. We expect the cost of UB-313 treatment, if approved, to be lower than that of mAbs for migraine.
Pre-Clinical Studies
We
 
have completed both
 
in vitro
 
and in vivo
 
pre-clinical studies of
 
UB-313. We
 
used an
 
in vivo proof-of-concept
 
capsaicin-induced
dermal blood flow model in
 
mice to demonstrate target engagement
 
of the marketed CGRP-targeting mAbs.
 
In this model, we observed
similar rates in reduction of dermal blood flow as fremanezumab in a head-to-head comparison against fremanezumab.
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25
UB-313 Reduces Capsaicin-Induced Dermal Blood Flow in Mice
**Dunnett’s:
 
Ctl vs Vac
 
1p < 0.05; Ctl vs Vac
 
2 p < 0.05
In this preliminary study, dermal blood flow measurements were
 
taken 17 weeks following the first dose of UB-313. There were 3 to 11
animals per treatment group. Reduced dermal blood flow indicates target engagement with CGRP.
 
UB-313 reduced dermal blood flow
versus the control with an approximately similar magnitude to fremanezumab, which was administered 24 hours prior to the capsaicin
test.
We observed similar results in a capsaicin / dermal blood flow model in rats, comparing a rat version of UB-313 head-to-head against
galcanezumab.
Our
in vivo
 
studies of
 
UB-313 have
 
involved multiple
 
animal species.
 
High immunogenicity
 
was observed
 
in all
 
pre-clinical species
tested. Characterization of the antibodies produced after
 
immunization with UB-313 indicated that they have
 
limited, if any,
 
off-target
potential, are primarily IgG1
 
and IgG2, potently bind
 
to CGRP and potently
 
block CGRP activity
in vitro
. We
 
refer to potency
 
as the
amount
 
of
 
drug
 
required
 
to
 
produce
 
a
 
pharmacological
 
effect
 
of
 
given
 
intensity
 
and
 
is
 
not
 
a
 
measure
 
of
 
therapeutic
 
efficacy.
 
In
 
a
comparison
 
of
 
binding
 
affinities
 
with
 
fremanezumab
 
and galcanezumab,
 
UB-313-induced
 
IgG
 
antibodies
 
demonstrated
 
comparable
binding affinities.
UB-313 Demonstrated Induced Antibodies Comparable to Approved CGRP mAbs
We evaluated UB-313 formulations with two different
 
adjuvants in comparison to
 
fremanezumab and galcanezumab; both
 
formulations
demonstrated comparable IgG to these two approved CGRP mAbs.
Additional
in vitro
 
studies using human
 
SK-N-MC cells demonstrated
 
that UB-313-induced IgG
 
antibodies also had
 
comparable
in vitro
activity to CGRP-targeted mAbs.
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26
UB-313 Induced IgGs Have Comparable In Vitro Activities to Marketed CGRP mAbs
In a cyclic AMP
 
(“cAMP”) production assay
 
conducted in human SK-N-MC
 
cells, antibodies taken from
 
the serum of guinea
 
pigs 15
weeks following the first injection of UB-313 demonstrated similar properties to two approved CGRP mAbs.
Moreover, the binding potency of UB-313 was determined to be comparable to these mAbs.
UB-313 Induced IgGs Demonstrate Comparable Binding Potencies to Marketed CGRP mAbs
Antibodies taken from the serum
 
of guinea pigs 15
 
weeks following the first
 
injection of UB-313 demonstrated
 
similar binding potencies
to two approved CGRP mAbs as measured by ELISA.
Development Strategy
We
 
have identified
 
a lead
 
candidate and
 
anticipate submitting
 
a clinical
 
trial application
 
(“CTA”)
 
or an
 
IND in
 
2022. While
 
we are
currently developing
 
UB-313 as
 
a potential
 
treatment of
 
chronic migraine,
 
depending on
 
successful clinical
 
results, we
 
may seek
 
to
address episodic migraine and cluster headaches as well.
27
PCSK9
An Overview of Hypercholesterolemia
Hypercholesterolemia is
 
the presence
 
of high
 
levels of
 
cholesterol in
 
the blood
 
and typically
 
results from
 
a combination
 
of environmental
and genetic
 
factors. Cholesterol
 
is transported
 
in the
 
blood plasma
 
within particles
 
called lipoproteins.
 
Lipoproteins are
 
classified by
their density:
 
very low-density
 
lipoprotein, intermediate
 
density lipoprotein,
 
LDL and
 
high density
 
lipoprotein (“HDL”).
 
All lipoproteins
carry
 
cholesterol,
 
but
 
elevated
 
levels
 
of
 
lipoproteins
 
other
 
than
 
HDL,
 
particularly
 
LDL,
 
are
 
associated
 
with
 
the
 
development
 
of
cardiovascular disease.
 
Approximately 2 billion
 
people worldwide
 
have elevated
 
levels of
 
LDL, potentially
 
putting
 
them at
 
risk for
cardiovascular disease.
Although hypercholesterolemia itself is asymptomatic, elevation of serum cholesterol can over time
 
lead to atherosclerosis. Over many
years, elevated
 
serum cholesterol
 
contributes to
 
formation of
 
atheromatous plaques
 
in the
 
arteries. These
 
plaque deposits
 
can in
 
turn
lead to progressive narrowing of the
 
involved arteries. Smaller plaques may rupture
 
and cause a clot to form and
 
obstruct blood flow. A
sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the
development
 
of
 
the
 
stenosis
 
or
 
occlusion
 
is
 
gradual,
 
blood
 
supply
 
to
 
the
 
tissues
 
and
 
organs
 
slowly
 
diminishes until
 
organ
 
function
becomes impaired.
PCSK9 is mainly expressed in
 
the liver and, to a
 
lesser extent, in the small intestine,
 
kidney, pancreas and
 
the central nervous system.
The LDL receptors (“LDLR”) at the cell surface bind and initiate ingestion of LDL particles from extracellular fluid into cells, leading
to a reduction in serum LDL
 
levels. PCSK9 protein plays a
 
major regulatory role in cholesterol
 
homeostasis, mainly by reducing LDLR
levels on the plasma membrane, which leads
 
to decreased metabolism of LDL by the
 
cells. Inhibition of PCSK9 prevents this reduction
in LDLR levels
 
on the plasma
 
membrane, and in
 
consequence the cellular
 
process of internalizing
 
LDL particles, resulting
 
in a reduction
of LDL.
Limitations of Current Therapies
Statins are the
 
most commonly used
 
drugs to treat
 
hypercholesterolemia and result
 
in a pronounced
 
reduction in LDL.
 
The unambiguous
benefits of
 
statins, together with
 
the prevalence of
 
coronary heart disease,
 
have made statins
 
the most highly
 
prescribed drug
 
class in
developed countries. However,
 
many patients are
 
unable to achieve
 
targeted lipid levels
 
despite intensive statins
 
therapy.
 
In addition,
continued patient adherence to statin therapy,
 
which is necessary to maintain a lower risk for cardiac events, is variable but
 
considered
to be low – as low as 30% to
 
40% after two years in persons following a
 
myocardial infarction. Importantly, at the transcriptional level,
statins
 
up-regulate
 
not
 
only
 
LDLR,
 
but
 
also
 
PCSK9,
 
causing
 
the
 
so-called
 
paradox
 
of
 
statin
 
treatment.
 
Although
 
statins
 
induce
 
a
beneficial increase in LDLR, they also increase
 
PCSK9, thus leading to LDLR degradation, which
 
indirectly increases LDL, mitigating
the overall LDL
 
reduction that statins
 
otherwise cause. Given
 
the limitations in
 
efficacy and adherence,
 
targeting PCSK9 in
 
combination
with statins treatment is an emerging treatment paradigm for hypercholesterolemia.
Two
 
mAbs
 
that
 
inhibit
 
activity
 
have
 
received
 
FDA
 
approval,
 
alirocumab
 
(Praluent)
 
and
 
evolocumab
 
(Repatha).
 
These
 
drugs
 
were
initially approved
 
to treat
 
the genetic
 
condition heterozygous
 
familial hypercholesterolemia,
 
although the
 
approved indications
 
were
expanded after
 
the publication
 
of studies
 
demonstrating that
 
the use
 
of a
 
PCSK9 inhibitor
 
in conjunction
 
with a
 
statin significantly
reduced the risk for major cardiovascular events, including heart attack, stroke, unstable angina requiring hospitalization or death from
coronary heart disease. In addition,
 
inclisiran (Leqvio), an siRNA
 
inhibitor of PCSK9 synthesis,
 
was approved by the EMA
 
in late 2020
for the treatment of heterozygous familial hypercholesterolemia in addition to other dyslipidemia.
While alirocumab
 
and evolucumab
 
have demonstrated clinical
 
benefit, their commercial
 
potential has been
 
limited by their
 
pricing. Both
launched
 
with
 
a
 
wholesale
 
acquisition
 
price
 
exceeding
 
$14,000
 
annually,
 
but
 
prices
 
for
 
both
 
were
 
subsequently
 
reduced
 
in
 
2018.
Nevertheless, this drug
 
class generated sales
 
of approximately $1.3 billion
 
in 2020 and
 
is expected to
 
grow to approximately
 
$5.2 billion
by 2026, including the addition of inclisiran to the market. In addition,
 
both must be administered bi-weekly, which represents what we
believe to be a
 
frequent and inconvenient administration schedule for
 
patients. While inclisiran represents an
 
improved administration
schedule compared
 
to alirocumab
 
and evolucumab, as
 
it must
 
be administered
 
only twice
 
annually,
 
we believe
 
that it
 
may encounter
similar pricing challenges due to the published cost effectiveness price.
Our Hypercholesterolemia Program
We
 
are developing an anti-PCSK9 product candidate
 
to treat hypercholesterolemia. Our program is
 
dedicated to developing a product
candidate that has long-acting treatment duration,
 
which we believe will offer
 
a more convenient treatment regimen of
 
every six to 12
months compared to
 
the up to
 
bi-weekly dosing required
 
by some mAbs.
 
We believe that lower manufacturing
 
costs commensurate with
the requirement of meaningfully less drug substance relative to mAbs, coupled with our ability to achieve commercial
 
scale production
rapidly may promote expanded use
 
of this drug class
 
as a first-line therapy treating
 
a greater number of hypercholesterolemia
 
patients
than currently treated with mAbs.
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28
Pre-Clinical Studies
Pre-clinical
 
studies
 
of
 
our
 
anti-PCSK9
 
vaccine
 
indicate
 
that
 
our
 
product
 
candidate
 
generates
 
therapeutic titer
 
levels
 
of
 
anti-PCSK9
antibodies. These studies
 
also indicate that it
 
produces a high
 
response rate among dosed
 
animals. We
 
achieved proof-of-concept in a
guinea pig
 
model, reducing
 
LDL cholesterol
 
by more
 
than 30%
 
over the
 
15-week treatment
 
duration, comparable
 
to the
 
reductions
observed with the use of anti-PCSK9 mAbs.
Anti-PCSK9 Product Candidate Reduces LDL by 30 to 50% Over 15 Weeks in Guinea Pigs (n=6)
Development Strategy
We plan to initiate IND-enabling studies of a lead anti-PCSK9 candidate in 2022.
 
Next Stage Development Candidates
In addition to
 
our initial focus
 
on migraines and
 
hypercholesterolemia, we
 
believe our Vaxxine Platform can
 
generate product candidates
for
 
a
 
range
 
of
 
chronic
 
diseases.
 
We
 
are
 
evaluating
 
opportunities
 
across
 
multiple
 
disease
 
areas,
 
including
 
allergy
 
(e.g.,
 
chronic
rhinosinusitis, atopic
 
dermatitis, food
 
allergy), autoimmune (e.g.,
 
psoriasis, psoriatic
 
arthritis), pain
 
(e.g., peripheral
 
neuropathy, diabetic
neuropathy) and bone
 
and muscle deterioration
 
(e.g., osteopenia, sarcopenia
 
of aging) indications
 
as they may
 
apply to geriatrics
 
and
space travel health.
COVID-19 Program
An Overview of COVID-19
COVID-19, caused
 
by SARS-CoV-2, has rapidly
 
swept throughout
 
the world.
 
The WHO
 
declared COVID-19
 
a public
 
health emergency
of international concern. As
 
of February 22, 2022, there
 
have been more than
 
420 million laboratory-confirmed COVID-19
 
patients and
more than 5.8 million deaths worldwide. Common symptoms of COVID-19 are fever, cough, lymphocytopenia and chest radiographic
abnormality. A proportion of
 
patients recovering from
 
COVID-19 continue shedding
 
virus for days,
 
and asymptomatic carriers
 
may also
transmit SARS-CoV-2, indicating a
 
risk of
 
a continuous
 
and long-term
 
pandemic. According
 
to Our
 
World in Data (ourworldindata.org),
as of March 2, 2022, approximately 87% of people in low-income countries have not received a single dose of a COVID-19 vaccine.
SARS-CoV-2
 
is an
 
enveloped, single-stranded,
 
positive-sense RNA
 
virus belonging
 
to the
 
family
Coronavidae
 
within the
 
genus β-
coronavirus. The genome of SARS-CoV-2 encodes one large Spike (“S”) protein that plays a pivotal role during
 
viral attachment to the
host receptor, angiotensin converting enzyme 2 (“ACE2”), and
 
entry into host cells. The S protein is the major principal antigen
 
target
for
 
vaccines
 
against
 
human
 
coronavirus,
 
including
 
SARS-Co-V-2.
 
Neutralizing
 
antibodies
 
targeting
 
the
 
receptor
 
binding
 
domain
(“RBD”) subunit
 
of the S
 
protein block the
 
virus from
 
binding to
 
host cells.
 
Over 90% of
 
all neutralizing
 
antibodies produced
 
in response
to infection are directed to the RBD subunit, and mAbs that have shown therapeutic activity target epitopes on the RBD.
More than twenty vaccines are
 
authorized for use in one
 
or more countries around the
 
world, including three in the
 
United States. These
vaccines are
 
based on
 
the S
 
protein of
 
the SARS-CoV-2, but rely
 
on different mechanisms
 
for presentation
 
or expression
 
of the
 
S antigen,
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29
including whole inactivated
 
virus, defective adenovirus
 
vectors (three different
 
types) or mRNA.
 
All have been
 
shown to be
 
safe and
effective in placebo- controlled clinical trials. Antiviral drugs and mAbs have limited availability and effectiveness.
COVID-19 Vaccine Market
Disparities in
 
COVID-19 vaccine
 
availability and distribution
 
continue to grow
 
despite the
 
myriad of
 
procurement efforts
 
underway.
There exists a shortfall
 
in the supply of
 
COVID-19 vaccines globally
 
for primary immunization,
 
driven by supply constraints
 
along with
substantial challenges
 
around distribution,
 
delivery and
 
poor logistical
 
capacity to
 
administer doses.
 
This primary
 
immunization shortfall
is
 
disproportionately pronounced
 
in low-
 
and middle-income
 
countries (“LMICs”).
 
We
 
estimate
 
that in
 
order
 
for
 
these
 
countries to
approach herd immunity (modeled at 70% vaccinated), there remains
 
a shortfall of hundreds of millions of doses
 
(excluding India and
China).
Furthermore,
 
as
 
knowledge of
 
SARS-CoV-2
 
and
 
its
 
circulating variants
 
(e.g.,
 
Omicron)
 
and
 
vaccination
 
efforts
 
grow,
 
the
 
need
 
for
booster immunizations has become more apparent. We estimate that the size of the COVID-19 vaccine booster dose market globally in
2022 will exceed 1.5 billion
 
doses. We
 
expect the need for heterologous
 
booster vaccines with low reactogenic
 
profiles, broad variant
coverage, durable immunity and mechanisms of action different from presently authorized vaccines to continue through 2022.
UB-612: Our COVID-19 Vaccine Initiative
We are
 
developing UB-612 as a product candidate for the prevention of COVID-19. UB-612 is
 
designed to activate both antibody and
cellular immunity against multiple viral targets. The vaccine is composed of a recombinant S1-RBD-sFc fusion protein combined with
rationally designed
 
synthetic Th
 
and CTL
 
epitope peptides
 
selected from
 
the S2
 
domain of
 
the spike,
 
membrane (“M”),
 
and nucleocapsid
(“N”) proteins. These peptides bind
 
to MHC I and II
 
without significant genetic restriction, so
 
that they may be recognized
 
by the entire
human population. Our mixture of peptides is designed to elicit T-cell activation, memory recall and effector
 
functions similar to those
of natural COVID-19. The
 
S1-RBD-sFc fusion protein
 
incorporates essential B-cell
 
epitopes that promote the
 
generation of neutralizing
antibodies to
 
the RBD of
 
SARS-CoV-2.
 
UB-612 is
 
formulated with
 
Adju-Phos, an
 
adjuvant widely used
 
in many
 
approved vaccines
globally. For
 
added safety,
 
synthetic peptides in UB-612
 
are adsorbed by our
 
propriety CpG1 excipient, a
 
Toll-like
 
receptor 9 agonist
molecule, known to
 
help to stimulate
 
balanced T-cell immunity in humans.
 
UB-612 can be
 
stored and shipped
 
at 2° to
 
8°C (conventional
cold chain
 
refrigerated temperatures).
 
An EUA
 
application for
 
UB-612 was
 
denied by
 
the TFDA
 
in August
 
2021 because
 
the neutralizing
antibody response generated by UB-612, as compared to a designated adenovirus vectored vaccine, did not meet the TFDA’s
 
specified
evaluation criteria but, in collaboration with UBIA, we are appealing the decision. We are now also pursuing paths to authorization for
UB-612 as a heterologous boost and have agreement with a high income regulator about our development approach.
Components of the UB-612 Multitope Vaccine Product Candidate
UB-612’s
 
construct contains an S1-RBD-sFc fusion protein
 
for the B-cell epitopes, plus five synthetic
 
Th/CTL peptides for class I and
II MHC molecules derived from
 
SARS-CoV-2 S2, M and
 
N proteins, and the UBITh1a
 
peptide. These components are formulated with
CpG1, which
 
binds the
 
positively charged
 
(by design)
 
peptides by
 
dipolar interactions
 
and also
 
serves as
 
an adjuvant,
 
which is
 
then
bound to Adju-Phos adjuvant to constitute the UB-612 product candidate.
Clinical Development
In
 
March
 
2022,
 
Vaxxinity
 
initiated
 
a
 
Phase
 
3
 
pivotal
 
study
 
to
 
compare
 
the
 
immune
 
responses
 
stimulated
 
by
 
mRNA
 
(BNT162b2),
adenovirus (ChAdOx1-S),
 
inactivated virus
 
(Sinopharm BIBP)
 
COVID-19 vaccines,
 
and UB-612,
 
when delivered
 
as third
 
dose boosters.
This is an
 
active-controlled, randomized, multicenter
 
study being conducted
 
in several countries
 
under a platform
 
protocol which enrolls
subjects 16
 
years and
 
older who
 
completed a
 
two-dose primary
 
immunization with
 
one or
 
more of
 
the vaccines
 
mentioned above.
 
Eligible
subjects will be
 
randomized into one
 
of two treatment
 
arms to receive
 
a single dose
 
of UB-612 or
 
an active comparator.
 
The primary
objective of
 
the study
 
is to
 
determine non-inferiority
 
of UB-612-stimulated
 
neutralizing antibodies
 
against the
 
comparator vaccines.
Additionally, Omicron
 
neutralizing antibodies, non-neutralizing antibodies and
 
T cell responses will
 
be analyzed as part
 
of secondary
vaxxq410kp31i0.jpg
30
and exploratory objectives.
 
We expect that, if successful,
 
this study may
 
enable conditional approval
 
of UB-612 in
 
multiple high income
countries and LMICs.
3-Dose Data: Phase 1 Extension Trial
In early 2021, we completed an open-label dose escalation Phase 1 clinical trial to evaluate the safety, tolerability and
immunogenicity of UB-612 in healthy adults in Taiwan. This trial consisted of three cohorts of 20 subjects each. The first cohort
received two intramuscular injections of 10μg doses of UB-612, the second cohort received two 30μg
 
doses and the third cohort
received two 100μg doses. The first dose in each cohort was administered at the start of the trial, with the second dose administered
on day 28.
In a Phase 1 extension trial, 50 subjects from Phase 1 received a third booster dose of UB-612 approximately 7-9 months after their
second dose (100µg).
After one and two doses in the Phase 1 trial, UB-612 was considered to be generally safe and well tolerated, with a low frequency of
solicited and unsolicited AEs, which were all Grade 1 (mild) in severity.
 
We selected the highest dose (100μg) to take into the Phase
2 trial.
Similarly, in the Phase 1 extension trial, UB-612 was generally well tolerated after a third dose, with no vaccine-related SAEs
reported.
Local and Systemic Solicited Adverse Events Following 1, 2, and 3 Doses of UB-612 at Varying Dose Levels
Solicited adverse event data from Phase 1 and Phase 1 extension (n=50) suggests UB-612 is well tolerated after each of three doses
across varying dose levels.
 
Immunogenicity and safety data from the Phase 1 extension suggests that UB-612 elicits a multi-fold increase in neutralizing
antibody titers upon third dose, significantly exceeding those observed in human convalescent sera, and that the third dose is well
tolerated with no vaccine-related SAEs reported.
 
Published studies have shown a correlation between efficacy in randomized
controlled trials and the ratio of neutralizing titers in sera from vaccinated subjects to titers in human
convalescent sera.
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31
UB-612 Neutralizing Antibodies Against Wuhan
 
Strain of SARS-CoV-2
(GMT, WHO International Units)
UB-612 Phase 1 extension (n=50) demonstrated that a dose of 100μg UB-612 following three doses of various sizes of UB-612 elicits
a multi-fold increase in neutralizing antibody titers.
In collaboration with University College London and VisMederi,
 
we analyzed sera from subjects immunized with three doses of UB-
612. Data demonstrated that UB-612 elicited a broad IgG antibody response against multiple SARS-CoV-2 variants of concern,
including, Alpha, Beta, Delta, and Gamma, and Omicron, and higher levels of neutralizing antibodies against Omicron than three
doses of an approved mRNA vaccine.
IgG Binding to RBD by Variant of Concern after 2 and 3 Doses of UB-612
IgG binding titers against SARS-CoV-2 major variants of concern in sera collected 28 days after 2 doses and 14 days after 3 doses of
UB-612 (100µg) from Phase 1 trial participants (n=15).
 
The loss of antibody bindings to RBD of variants compared with the original
RBD (Wuhan) remains stable between 2 doses and 3 doses of UB-612 vaccine, along with a high overall increase in levels of binding
antibodies to RBD.
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32
Third immunization with UB-612 Produces Neutralizing Antibodies Against Omicron
 
Phase 1 extension subjects (n=15) received primary series with UB-612 100µg. Serum is taken 28 days after the second dose and 14
days after the third booster immunization administered 7-9 months after the primary series. Live virus neutralization test against
Wuhan and Omicron are
 
performed at VisMederi; results are
 
expressed as virus neutralization antibody GMT ± 95% CI.
2-Dose Data: Phase 2 Trial
A randomized, placebo-controlled,
 
multi-center Phase 2
 
trial of UB-612
 
in 3,850 healthy
 
volunteers aged 12
 
to 85 is ongoing
 
in Taiwan.
Subjects in this trial receive
 
two doses of 100μg UB-612, or
 
placebo, 28 days apart. The
 
objectives of this trial include
 
the analysis of
safety
 
and
 
immunogenicity
 
of
 
UB-612,
 
in
 
particular,
 
antigen-specific
 
antibodies
 
to
 
UB-612,
 
the
 
seroconversion
 
rate
 
and
 
lot-to-lot
consistency of antibody responses. An interim analysis of data from this Phase 2 trial in healthy volunteers 18 years and
 
older based on
the data cut-off
 
date of June 27,
 
2021 was submitted
 
to the TFDA
 
as part of
 
a filing for
 
an EUA in
 
Taiwan.
 
The EUA was
 
denied in
August 2021 by the TFDA, but, in collaboration with UBIA, we are appealing that decision.
 
In data from over 3,750 subjects, UB-612 appears well tolerated, with no significant safety findings to date. AEs were generally
mild, and no related SAEs were observed. Local injection site AEs occurred in half of the subjects, the most frequent being injection
site pain. Systemic AEs occurred in less than half of the subjects, and the incidence was similar in the active and placebo groups,
except for muscle pain which was more frequent in the active group. Aside from muscle pain, systemic reactions were comparable
across the active and placebo groups, with less than 10% of subjects in either group experiencing fever or chills. Systemic AEs were
similar after the first and second doses. The vast majority of AEs were mild (Grade 1), and all were self-limited. No subject had a
severe (Grade 3) local reaction. The incidence of severe (Grade 3) systemic reactions was <0.1%.
The Phase 2 interim
 
analysis suggests that Phase 1
 
observations on immunogenicity,
 
neutralizing titers and tolerability are
 
repeatable,
with an overall seroconversion rate of
 
94.7% one month after the second
 
dose. In a live virus (Wuhan) neutralization test,
 
sera collected
from UB-612 vaccinated
 
younger adults (19-64
 
years, n=322), 28
 
days after the
 
second dose (day
 
57) were estimated
 
to reach geometric
mean titers (“GMT”) of
 
102 of 50% virus-neutralizing
 
antibodies (VNT
50
).
Sera collected from a
 
subset of subjects (n=48)
 
28 days after
the second immunization was
 
shown to neutralize several
 
SARS-CoV-2
 
variants, with the loss
 
of neutralization activity against
 
Delta
estimated at 1.39-fold when compared to the neutralizing antibodies against the parental Wuhan virus.
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33
Immunogenicity Results from Phase 2 & Phase 1 were Consistent:
 
Live Virus Neutralization Versus
 
Convalescent Sera
Phase 1 (n=20 in 100μg dose group) and Phase 2 (n=322) sera (taken 28 days after the second dose) titer neutralizing activity, versus
a panel of human convalescent
 
serum titers taken from patients hospitalized with
 
COVID-19, as measured by a live virus
 
neutralization
test, VNT50, shows that two doses of UB-612 may yield neutralizing antibodies comparable to those found in convalescent patients.
Immunization with UB-612 in both
 
Phase 2 and Phase
 
1 studies led to
 
detectable T-cell
 
responses observed in a
 
subset of subjects. In
Phase 2, a total
 
of 88 subjects receiving UB-612
 
and 12 receiving placebo were
 
tested for T cell
 
responses at baseline and on
 
Day 57.
Preliminary results of ELISpot
 
(Interferon-γ and IL-4) and
 
intracellular cytokine staining indicate
 
robust responses to UB-612,
 
with a
strong
 
Th1
 
orientation.
 
Intracellular
 
cytokine
 
staining
 
(ICS)
 
confirmed
 
the
 
Th1
 
orientation
 
of
 
T
 
cell
 
responses.
 
UB-612
 
induced
measurable CD8+ T cell responses and CD107a+/Granzyme secreting cells, which are putative cytotoxic T cells.
UB-612 stimulates T-cell responses with predominately Th1 polarity
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34
Top panel: ELISPOT analysis of PBMCs collected on day 57 Phase 2 study. Bottom panels (A, B and C): ICS analysis of PBMCs
collected on day 57 Phase 2 study. Placebo (n=14) subjects without IgG ELISA, ACE2 and neutralizing antibody responses. UB-
612 n=86 subjects. Statistical analysis was performed using Mann-Whitney t test. (* p<0.05; ** p<0.01; ***p<0.001; ****
p<0.0001).
 
2-Dose Data: Phase 1 Trial
In early 2021, we completed an open-label dose escalation Phase 1 clinical trial to evaluate the safety, tolerability and immunogenicity
of UB-612 in healthy volunteers between
 
the ages of 20 and 55 in
 
Taiwan. This six-month trial consisted of three cohorts of 20
 
subjects
each. The first cohort received two intramuscular
 
injections of 10μg doses of UB-612, the
 
second cohort received two 30μg doses and
the third cohort received two 100μg doses. The first dose
 
in each cohort was administered at the start of the
 
trial, with the second dose
administered
 
on
 
day
 
28.
 
The
 
mean
 
titer
 
of
 
antigen-specific
 
antibodies
 
to
 
UB-612
 
and
 
the
 
seroconversion
 
rate
 
was
 
be
 
evaluated
throughout
 
the
 
six-month
 
duration
 
of
 
the
 
study
 
to
 
determine
 
the
 
humoral
 
immune
 
response
 
and
 
persistence
 
of
 
immunogenicity.
 
In
addition, T-cell responses were evaluated by interferon-γ ELISpot assay and intracellular cytokine staining by flow cytometry.
The Phase 1 clinical trial was sponsored by UBIA. UBIA
 
conducted the trial on our behalf in accordance with one
 
of our related party
master services agreements.
 
After one
 
and two
 
doses, UB-612
 
was considered
 
to be
 
generally safe
 
and well
 
tolerated, with
 
a low
 
frequency of
 
solicited and
 
unsolicited
AEs, which
 
were all
 
Grade 1
 
(mild) in
 
severity.
 
After each
 
vaccination, the
 
most common
 
AE was
 
injection site
 
pain, with
 
no clear
difference in reactogenicity between dose levels. In all dose groups, there was a trend towards
 
increased reactogenicity with increase in
dose.
 
Three
 
cases
 
of
 
mild
 
allergic
 
reactions
 
were
 
reported
 
(e.g.,
 
itching
 
at
 
vaccine
 
site),
 
which
 
were
 
all
 
resolved
 
within
 
1-3
 
days.
Importantly, and
 
in distinction to certain
 
vaccines authorized for emergency
 
use, no other increase
 
in AEs was seen
 
at second dose as
compared to first injection. We selected the highest dose (100μg) to take into the Phase 2 trial.
In an
 
anti-S1-RBD ELISA assay,
 
we observed that
 
all three dose
 
levels of UB-612
 
induced titer levels
 
comparable to or
 
greater than
those in sera
 
from patients hospitalized with
 
COVID-19. Furthermore, in a
 
cytopathic effect viral
 
neutralization assay (CPE VNT50),
we observed neutralizing titers comparable to those in sera from patients hospitalized with COVID-19.
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35
Since September 2020, a number of
 
genotypic variants of SARS-CoV-2
 
have emerged and contributed to
 
epidemic spread in multiple
countries. Notable among these
 
are the Alpha or B.1.1.7
 
(United Kingdom), Beta or B.1.351
 
(South Africa), Gamma or
 
P.1 (Brazil) and
the Delta
 
or B.1.617.2
 
variant (India)
 
and Omicron
 
(B.1.1.529).
 
Some SARS-CoV-2
 
variants containing
 
mutations in
 
the S
 
protein,
especially the N-terminal domain
 
and the RBD, show
 
reduced neutralization by antibody
 
against the Wuhan
 
strain, evidenced both in
persons
 
naturally
 
infected
 
and
 
in
 
vaccinated
 
individuals.
 
The
 
Beta
 
(South
 
Africa)
 
and
 
Omicron
 
variants
 
show
 
the
 
highest
 
level
 
of
resistance, with 13-fold
 
to over 30-fold
 
reduction in neutralization,
 
respectively,
 
and vaccines have
 
shown reduced protection
 
against
these variants.
 
Neutralizing activities of sample
 
sera from the Phase 1
 
trial were assessed against
 
live virus variants at the
 
Viral and Rickettsial Disease
Laboratory of the
 
California State Department
 
of Public
 
Health. The
 
results indicate
 
that UB-612
 
induces viral neutralizing
 
antibody
titers against the Alpha, Gamma and Delta variants of SARS-CoV-2, close to the neutralizing titer level against the original (wild-type,
WT) Wuhan
 
strain, while
 
the titer
 
level against
 
the Beta
 
variant is
 
lower in
 
comparison. The
 
latter finding
 
is anticipated
 
by
 
results
published for other COVID-19
 
vaccines, as pointed out
 
above. These data align
 
with observations taken from
 
a cynomolgus macaque
study of UB-612 as well.
We measured viral-neutralizing antibody titers
 
up to 154 days after the second dose (day 196) in the
 
Phase 1 trial of UB-612; the level
of VNT50 antibodies remained
 
at 52% of the
 
maximum level observed following
 
the second dose, on
 
average. Based on the
 
interim six-
month cutoff, the UB-612-specific neutralizing antibody half-life was estimated to be 195 days using an exponential model.
Time Course of SARS-CoV-2 Antibody Neutralization Responses after Vaccination
Data from a
 
micro-neutralization assay of
 
sera from subjects
 
who received two
 
100μg doses
 
of UB-612
 
yielded an
 
estimated neutralizing
titer half-life of 195 days (CI: 136, 349) using an exponential model.
Pre-Clinical Study Results for UB-612
 
Initial work to select
 
the S1-RBD-sFc antigen
 
was performed in
 
guinea pig immunogenicity
 
studies, which demonstrated
 
the superiority
of S1-RBD-sFc over other protein
 
designs tested. Product candidate dose
 
and formulation were explored in
 
rat immunogenicity studies,
which allowed the
 
selection of the current
 
formulation of UB-612.
 
Efficacy studies were
 
carried out in mouse
 
and nonhuman primate
models, in which
 
UB-612 showed protective
 
efficacy against
 
live viral challenge.
 
In a nonhuman
 
primate model challenge
 
study,
 
we
observed full protection against SARS-CoV-2.
A GLP toxicology study
 
in rats demonstrated an
 
acceptable safety profile and
 
enabled clinical testing of
 
UB-612. In addition to
 
these
studies, a Developmental and Reproductive Toxicity study yielded no significant findings.
Development Strategy
Based on UB-612 three-dose
 
titer data from the
 
Phase 1 extension, and
 
our belief in UB-612’s potential utility
 
as a heterologous booster
dose
 
(boosting
 
the
 
immunity
 
of
 
a
 
subject
 
who
 
has
 
already
 
received
 
a
 
different
 
vaccine),
 
we
 
are
 
pursuing
 
accelerated
 
pathways
 
to
authorization with regulators
 
in multiple jurisdictions,
including high income
 
countries and LMICs
 
based on a
 
heterologous booster trial
of UB-612 beginning in
 
the first half of
 
2022, with the first dose
 
administered in the U.S. in
 
the first quarter of 2022
 
under
FDA IND
clearance.
36
COVID-19 Diagnostics Program
We have developed an ELISA test that can quickly detect antibodies
 
in human sera or plasma to
 
determine if a patient has had a
 
SARS-
CoV-2 infection post fourteen days of onset. It
 
employs synthetic peptides derived
 
from the M, S and
 
N proteins of SARS-CoV2 for
 
the
detection
 
of
 
IgG
 
antibodies
 
to
 
SARS-CoV2
 
in
 
human
 
sera
 
or
 
plasma.
 
These
 
synthetic
 
peptides
 
bind
 
antibodies
 
specific
 
to
 
highly
antigenic segments of SARS- CoV2 structural
 
M, N and S proteins and
 
constitute the solid phase antigenic immunosorbant. The
 
FDA
issued an EUA for our ELISA test in January 2021. We are not actively pursuing commercialization of our ELISA tests at this time.
 
Competition
The
 
pharmaceutical
 
industry
 
is
 
characterized
 
by
 
rapidly
 
advancing
 
technologies,
 
intense
 
competition
 
and
 
a
 
strong
 
emphasis
 
on
proprietary
 
products.
 
While
 
we
 
believe
 
that
 
our
 
technology,
 
the
 
expertise
 
of
 
our
 
executive
 
and
 
scientific
 
teams,
 
research,
 
clinical
capabilities, development experience and scientific knowledge
 
provide us with competitive advantages, we face
 
increasing competition
from multiple
 
sources, including
 
pharmaceutical and
 
biotechnology companies,
 
academic institutions,
 
governmental agencies
 
and public
and private research institutions.
Vaccines
The global
 
vaccine market
 
is highly
 
concentrated among
 
a small
 
number of
 
multinational pharmaceutical
 
companies: Pfizer,
 
Merck,
GlaxoSmithKline and Sanofi together control most
 
of the global vaccine market.
 
Other pharmaceutical and biotechnology companies,
academic institutions, governmental agencies and public and private research institutions are also working toward new solutions
 
given
the continuing global unmet need.
More than twenty COVID-19
 
vaccines are currently authorized
 
for use in one
 
or more countries around
 
the world, including three
 
in the
United States. All have
 
been shown to be
 
safe and effective in
 
placebo-controlled clinical trials. All these
 
vaccines are based on
 
the S
protein of the
 
SARS-CoV-2
 
virus, but rely
 
on different
 
mechanisms for presentation
 
or expression of
 
the S antigen,
 
including whole,
inactivated virus, defective adenovirus vectors (three different types) or mRNA.
Neurodegenerative Disorders
We
 
expect
 
that,
 
if
 
approved,
 
our
 
product
 
candidates
 
will
 
compete
 
with
 
the
 
currently
 
approved
 
therapies
 
for
 
management
 
of
neurodegenerative diseases, such as AD and
 
PD. In AD, four drugs are
 
currently approved by the FDA for the
 
treatment of symptoms
of AD, based on
 
acetylcholinesterase (“AChE”) inhibition and NMDA receptor
 
antagonism. In addition to the
 
marketed therapies, we
are
 
aware
 
of
 
several
 
companies
 
currently
 
developing
 
therapies
 
for
 
AD,
 
including
 
Eisai,
 
Eli
 
Lilly,
 
Hoffman-LaRoche,
 
Otsuka
Pharmaceuticals, Novartis
 
and Biohaven
 
Pharmaceuticals. Biogen’s
 
aducanumab was
 
approved by
 
the FDA
 
in June
 
2021 under
 
the
accelerated approval pathway,
 
which allows for
 
earlier approval of
 
drugs that
 
treat serious
 
conditions, and that
 
fill an
 
unmet medical
need based on a surrogate endpoint. Regulatory approval of aducanumab is pending in Europe and Japan.
Pharmaceutical treatments for PD address its symptoms
 
only and do not treat the underlying causes
 
of PD. The majority of prescription
drugs
 
are
 
dopaminergic
 
medications
 
and
 
act
 
by
 
increasing
 
dopamine,
 
a
 
neurotransmitter.
 
We
 
are
 
aware
 
of
 
several
 
companies
 
with
product
 
candidates
 
at
 
various
 
stages
 
of
 
clinical
 
development,
 
including
 
Sanofi,
 
Kyowa
 
Kirin,
 
Cerevel
 
Therapeutics
 
and
 
Hoffman
LaRoche. Hoffman LaRoche is developing prasinezumab, a mAb, as a potential treatment for PD.
CGRP-Directed Migraine Treatments
Six migraine treatments have been approved by the FDA that target
 
CGRP.
 
Four of these therapeutics are mAbs and were approved to
prevent or reduce
 
the number of
 
migraine episodes. These
 
medications are galcanezumab
 
(Emgality), which was
 
developed by Lilly;
erenumabb (Aimovig), which was developed by Amgen in collaboration
 
with Novartis; fremanezumab (Ajovy), which was developed
by
 
Teva;
 
and
 
eptinezumab
 
(Vyepti),
 
which
 
was
 
developed
 
by
 
Alder,
 
acquired
 
by
 
Lundbeck.
 
Ubrogepant
 
(Ubvelvy),
 
developed
 
by
Allergan, was
 
approved for
 
the treatment
 
of acute
 
migraine episodes;
 
rimegepant (Nurtec),
 
also approved
 
for the
 
treatment of
 
acute
migraine, is sold by Biohaven.
PCSK-9 Inhibitors
Two
 
companies currently
 
have
 
PCSK-9
 
inhibitors
 
approved by
 
the
 
FDA
 
to
 
treat
 
hypercholesterolemia. Both
 
are mAbs.
 
Regeneron
Pharmaceuticals
 
developed
 
alirocumab
 
(Praluent),
 
in
 
collaboration
 
with
 
Sanofi,
 
and
 
Amgen
 
developed
 
evolocumab
 
(Repatha).
 
The
Medicines Company,
 
a
 
subsidiary of
 
Novartis, is
 
developing inclisiran,
 
an
 
RNAi construct,
 
to down-regulate
 
synthesis of
 
PCSK-9.
Inclisiran was approved by the EMA in December 2020.
37
Collaborations
From time
 
to time,
 
we may
 
enter into
 
licensing and
 
commercialization agreements
 
when they
 
align with
 
our mission,
 
including the
Platform
 
License
 
Agreement
 
described
 
under
 
“—Intellectual
 
Property—Platform
 
License
 
Agreement”
 
and
 
the
 
agreement
 
with
 
our
partner Aurobindo.
Aurobindo License Agreement
In
 
December
 
2020,
 
we
 
entered
 
into
 
an
 
exclusive
 
license
 
agreement
 
with
 
Aurobindo
 
(as
 
amended,
 
the
 
“Aurobindo
 
Agreement”)
 
to
develop and
 
commercialize UB-612
 
to India
 
and other
 
territories. Pursuant
 
to the
 
Aurobindo Agreement,
 
we granted
 
Aurobindo an
exclusive license (with
 
certain rights reserved
 
to us) to
 
develop, manufacture and
 
commercialize UB-612 in India
 
and other countries
through
 
UNICEF
 
and
 
a
 
non-exclusive
 
license
 
to
 
develop,
 
manufacture
 
and
 
commercialize
 
UB-612
 
in
 
other
 
selected
 
emerging
 
and
developing markets.
 
The Aurobindo Agreement may be terminated
 
(i) by Aurobindo, without cause at any
 
time after three years following the effective date
or
 
prior
 
to
 
such
 
time
 
if
 
UB-612
 
fails
 
to
 
meet
 
clinical
 
end-points
 
or
 
fails
 
in
 
development,
 
(ii)
 
by
 
us,
 
(a)
 
if
 
Aurobindo
 
disputes
 
the
patentability, enforceability or validity of our patent rights related to the UB-612 technology,
 
(b) in case of a suit alleging Aurobindo’s
use of
 
the licensed intellectual
 
property infringes a
 
third party’s
 
intellectual property rights
 
if we
 
reasonably believe the
 
license is no
longer commercially reasonable in light of such claim or (c) without cause at any time
 
after four years following the effective date, (iii)
by either
 
party in
 
the event
 
of the
 
other party’s
 
material breach
 
of its
 
obligations under
 
the Aurobindo
 
Agreement (subject
 
to a
 
cure
period) or (iv) by either party in the event of the other party’s insolvency.
Manufacturing
The manufacture of
 
our product candidates
 
encompasses both
 
the manufacture
 
of custom components
 
and the formulation,
 
fill and finish
of the final product.
 
We
 
do not currently own
 
or operate manufacturing facilities
 
for these processes. We
 
currently rely upon contract
manufacturing organizations, including those mentioned below, to produce our product candidates for both pre-clinical and clinical use
and will
 
continue to
 
rely upon
 
these relationships
 
for commercial
 
manufacturing if
 
any of
 
our product
 
candidates obtain
 
regulatory
approval. Although
 
we rely
 
upon contract
 
manufacturers, we
 
also have
 
personnel with
 
extensive manufacturing
 
experience that
 
can
oversee the relationships with our manufacturing partners.
Historically,
 
we
 
have
 
depended
 
heavily
 
on
 
UBI
 
and
 
its
 
affiliates
 
for
 
our
 
business
 
operations,
 
including
 
the
 
provision
 
of
 
research,
development
 
and
 
manufacturing
 
services.
 
Currently,
 
UBIA
 
provides
 
testing
 
services
 
for
 
UB-312
 
and
 
UB-612,
 
UBI
 
Pharma
 
Inc.
(“UBIP”)
 
provides
 
testing
 
relating
 
to
 
formulation-fill-finish
 
services
 
for
 
UB-312,
 
and
 
United
 
BioPharma,
 
Inc.
 
(“UBP”)
 
is
 
the
 
sole
manufacturer of protein for UB-612. Our commercial arrangements with UBI and its affiliates are described in more detail below.
Formulation-fill-finish services for UB-612 are provided by multiple contract manufacturers to ensure adequate capacity and minimize
supply
 
chain
 
risks.
 
For
 
supply
 
of
 
our
 
other
 
custom
 
components,
 
in
 
addition
 
to
 
protein
 
manufacturing
 
conducted
 
by
 
UBP,
 
we
 
have
engaged third party CMOs, including
 
C S Bio Co. (“CSBio”)
 
as our primary peptide supplier for
 
UB-612 peptides and Wuxi
 
STA
 
for
process development and manufacturing services of oligonucleotides.
 
UBI Group Manufacturing Partnership
We
 
primarily rely
 
on our
 
relationships with
 
third-party contract
 
manufacturing organizations
 
to produce
 
product candidates
 
for our
clinical trials. Historically, we have heavily depended on UBI as a
 
manufacturing partner for these efforts. In support
 
of our COVID-19
program (UB-612), we have entered into a
 
master services agreement with UBP and
 
an additional master services agreement with
 
UBI,
UBIA and UBP.
 
Pursuant to these agreements, UBI
 
and its affiliates have
 
provided research, development, testing
 
and manufacturing
services to us
 
and continue to
 
provide manufacturing services
 
for our protein.
 
Payment terms are
 
mutually agreed in
 
connection with
each work order relating
 
to services rendered. Our
 
agreement with UBP will
 
expire on the later
 
of March 2024 and
 
the completion of
all services
 
under the
 
last work
 
order executed
 
prior to
 
such scheduled
 
expiration and our
 
agreement with UBI,
 
UBIA and
 
UBP will
expire on
 
the later
 
of September
 
2023 and
 
the completion
 
of all
 
services under
 
the last
 
work order
 
executed prior
 
to such
 
scheduled
expiration. We also have
 
a management services
 
agreement with
 
UBI pursuant to
 
which UBI has
 
provided research and
 
prior back office
administrative services to us and acts as our agent with respect
 
to certain matters relating our COVID-19 program. UBI is compensated
for its services on a cost-plus basis. The agreement terminates upon mutual agreement between the parties.
In support of our
 
chronic disease pipeline,
 
we have entered into
 
master service agreements with
 
each of UBI, UBIA
 
and UBIP. Pursuant
to these agreements, UBI currently provides limited research services to us on a cost-plus basis, UBIA provides
 
testing services related
to UB-312 clinical trial material already manufactured
 
and UBIP has provided manufacturing, quality control,
 
testing, validation, GMP
warehousing and
 
supply services
 
to us
 
for UB-312
 
on payment
 
terms agreed
 
in connection
 
with work
 
orders relating
 
to the
 
services
rendered. UBI and its
 
affiliates no longer provide
 
clinical or manufacturing services for
 
other programs. These agreements
 
may all be
terminated for convenience upon 180 days’ notice or less.
38
We have
 
also entered into a research and development services agreement
 
with UBI. Pursuant to this agreement, UBI and
 
its affiliates
provide research and development services to us. Service fees payable by
 
us to UBI for research and development projects undertaken
in accordance with the research and development plan
 
will be determined by a joint steering
 
committee and set forth in a research and
development plan. The
 
aggregate services fees payable
 
by us under
 
the research and
 
development services agreement are
 
subject to a
quarterly cap throughout the term of the agreement. The research and development services agreement expires in August
 
2026.
Intellectual Property
Our ability to
 
obtain and maintain
 
intellectual property protection
 
for our product
 
candidates and core
 
technologies is fundamental
 
to
the
 
long-term
 
success
 
of
 
our
 
business.
 
We
 
rely
 
on
 
a
 
combination
 
of
 
intellectual
 
property
 
protection
 
strategies,
 
including
 
patents,
trademarks, trade secrets, license agreements, confidentiality policies and procedures, nondisclosure agreements, invention assignment
agreements and technical
 
measures designed to
 
protect the intellectual
 
property and commercially
 
valuable confidential information
 
and
data used in our business.
In summary, our patent estate includes issued patents and patent applications which claims cover our
 
Vaxxine
 
Platform and each of our
product candidates. As of December 31, 2021, our patent estate included ten U.S. issued patents, twelve U.S. patent applications, three
U.S. provisional patent
 
applications, four pending
 
Patent Cooperation Treaty
 
(“PCT”) patent applications,
 
98 issued non-U.S.
 
patents
and 194 pending non-U.S. patent applications.
For our
 
product candidates
 
targeting the
 
prevention and
 
treatment of
 
neurodegenerative disease,
 
including claims
 
covering UB-311,
UB-312, patent rights are provided by patents and patent applications, the majority of which are being prosecuted in the
 
United States,
Australia,
 
Brazil,
 
Canada,
 
China,
 
the
 
EPO,
 
Hong
 
Kong,
 
Indonesia,
 
India,
 
Israel,
 
Japan,
 
the
 
Republic
 
of
 
Korea,
 
Mexico,
 
Russia,
Singapore,
 
South
 
Africa,
 
Taiwan
 
and
 
the
 
United
 
Arab
 
Emirates
 
directed
 
to
 
peptide
 
vaccines
 
for
 
the
 
prevention
 
and
 
treatment
 
of
neurodegenerative diseases.
 
These issued
 
patents and
 
patent applications,
 
if issued,
 
are expected
 
to expire
 
between 2022
 
and 2039,
excluding any patent term adjustments or patent term extensions.
For our product candidates directed to peptide immunogens targeting CGRP and formulations thereof
 
for the prevention and treatment
of migraine, including
 
UB-313, patent rights
 
may be provided
 
by a patent
 
family being prosecuted
 
in the United
 
States, Australia, Brazil,
Canada, China,
 
India, Indonesia,
 
Japan, Mexico, Russia,
 
the Republic
 
of Korea, Singapore,
 
Taiwan and the United
 
Arab Emirates. These
patent applications, if issued, are expected to expire in 2039, excluding any patent term adjustments or patent term extensions.
For
 
our
 
product
 
candidates
 
targeting
 
cholesterol
 
and
 
cardiovascular
 
disease,
 
including
 
our
 
anti-PCSK9
 
product
 
candidate
 
targeting
PCSK9
 
and
 
formulations
 
thereof
 
for
 
prevention
 
and
 
treatment
 
of
 
PCSK9-mediated
 
disorders,
 
we
 
are
 
in
 
the
 
process
 
of
 
acquiring
 
a
pending patent application in Taiwan and a pending PCT patent application. This Taiwanese
 
patent application, if issued, and any U.S.
or non-U.S. patent issuing from this PCT
 
patent application, if such patent is issued,
 
is expected to expire in 2041, excluding
 
any patent
term adjustment or patent term extension.
For our product
 
candidates targeting SARS-CoV-2,
 
including UB-612 for
 
COVID-19, we have
 
pending patent applications
 
in Brazil,
Pakistan and Taiwan,
 
one pending PCT patent
 
application and three provisional
 
patent applications in the
 
United States. These patent
applications, if issued, and any U.S. or
 
non-U.S. patent issuing from this PCT or
 
provisional patent application, are expected to expire
between 2041 and 2042, excluding any patent term adjustments or patent term extensions.
For each product candidate utilizing
 
the Vaxxine
 
platform, additional patent rights directed
 
to artificial T helper
 
cell epitopes and to a
CpG delivery system are provided by
 
patents and patent applications, the majority
 
of which are being prosecuted in
 
the United States,
Australia, Austria,
 
Belgium, Brazil,
 
Canada, Chile,
 
China, Colombia,
 
Denmark, the
 
EPO, France,
 
Germany,
 
Hong Kong,
 
Indonesia,
India, Ireland, Israel, Italy, Japan, Mexico, the Netherlands, New Zealand, Peru, Philippines, the Republic of Korea, Russia, Singapore,
South
 
Africa,
 
Spain,
 
Sweden,
 
Switzerland/Liechtenstein,
 
Taiwan,
 
Thailand,
 
the
 
United
 
Arab
 
Emirates,
 
the
 
United
 
Kingdom
 
and
Vietnam. These
 
issued patents and patent
 
applications, if issued, are
 
expected to expire between
 
2023 and 2039, excluding
 
any patent
term adjustments or patent term extensions.
The term of
 
individual patents
 
depends on the
 
countries in which
 
they are obtained.
 
The patent
 
term is 20
 
years from the
 
earliest effective
filing date of a
 
non-provisional patent application in most
 
of the countries in
 
which we file, including the
 
United States. In the United
States, a
 
patent’s
 
term may
 
be lengthened
 
by patent
 
term adjustment,
 
which compensates
 
a patentee
 
for administrative
 
delays by
 
the
USPTO in
 
examining and granting
 
a patent, or
 
may be shortened
 
if a patent
 
is terminally disclaimed
 
over an earlier
 
filed patent. The
term of a patent that
 
covers a drug or biological product
 
may also be eligible for patent
 
term extension when FDA approval is
 
granted
for a
 
portion of
 
the term
 
effectively lost
 
as a
 
result of
 
the FDA
 
regulatory review
 
period, subject
 
to certain
 
limitations and
 
provided
statutory and regulatory requirements are met.
In addition to our reliance on patent protection for our inventions, products and technologies, we also seek to protect
 
our brand through
the procurement of trademark rights.
 
We
 
own registered trademarks and pending
 
trademark applications for our brands,
 
including our
“Vaxxinity”, “United Neuroscience” and “COVAXX” brands and
 
other related names
 
and logos, in
 
the United States
 
and certain
 
foreign
jurisdictions.
39
Furthermore, we
 
rely upon
 
trade secrets
 
and know-how
 
and continuing
 
technological innovation
 
to develop
 
and maintain
 
our competitive
position. However, trade
 
secrets and know-how can be
 
difficult to protect. We
 
generally control access to and
 
use of our trade
 
secrets
and know-how, through
 
the use
 
of internal
 
and external
 
controls, including
 
by entering
 
into nondisclosure
 
and confidentiality
 
agreements
with
 
our
 
employees
 
and
 
third
 
parties.
 
We
 
cannot
 
guarantee,
 
however,
 
that
 
we
 
have
 
executed
 
such
 
agreements
 
with
 
all
 
applicable
counterparties, that such agreements will not be breached or that these agreements will afford us adequate protection of our intellectual
property and
 
proprietary rights.
 
Furthermore, although
 
we take
 
steps to
 
protect our
 
proprietary information
 
and trade
 
secrets, third
 
parties
may independently develop
 
substantially equivalent proprietary
 
information and techniques
 
or otherwise gain
 
access to our trade
 
secrets
or disclose our technology. As a result, we may not be able to meaningfully protect our trade secrets. For further discussion of the risks
relating to intellectual property, see “Risk Factors—Risks Related to Our Intellectual Property Rights.”
Platform License Agreement
In August 2021, Vaxxinity
 
entered into a license
 
agreement (the “Platform License
 
Agreement”) with UBI and
 
certain of its affiliates
(collectively, the “Licensors”) that
 
expanded intellectual
 
property rights previously
 
licensed under
 
the Original
 
UBI Licenses (as
 
defined
below). Pursuant
 
to the
 
Platform License
 
Agreement, Vaxxinity
 
obtained a
 
worldwide, sublicensable
 
(subject to
 
certain conditions),
perpetual, fully paid-up, royalty-free (i) exclusive license (even as to the Licensors) under all patents owned or otherwise controlled by
the Licensors or their affiliates
 
existing as of the effective
 
date of the Platform License
 
Agreement, (ii) exclusive license (except
 
as to
the Licensors) under all patents owned or otherwise controlled by the Licensors or their affiliates arising after the effective
 
date during
the term of the Platform License Agreement, and (iii) non-exclusive
 
license under all know-how owned or otherwise controlled by the
Licensors or their affiliates existing as of the
 
effective date or arising during the term of
 
the Platform License Agreement, in each of
 
the
foregoing
 
cases,
 
to
 
research,
 
develop,
 
make,
 
have
 
made,
 
utilize,
 
import,
 
export,
 
market,
 
distribute,
 
offer
 
for
 
sale,
 
sell,
 
have
 
sold,
commercialize or otherwise exploit peptide-based vaccines in the field of all
 
human prophylactic and therapeutic uses, except for such
vaccines related to human
 
immunodeficiency virus (HIV), herpes
 
simplex virus (HSE) and
 
Immunoglobulin E (IgE). The
 
patents and
patent applications licensed
 
under the Platform
 
License Agreement inclusde
 
claims directed to
 
a CpG delivery
 
system, artificial T
 
helper
cell
 
epitopes
 
and
 
certain
 
designer
 
peptides
 
and
 
proteins
 
utilized
 
in
 
UB-612.
 
As
 
partial
 
consideration
 
for
 
the
 
rights
 
and
 
licenses
 
we
received pursuant to the Platform License Agreement, we granted UBI a warrant to purchase 1,928,020 shares of our Class A common
stock (“UBI Warrant”). The UBI
 
Warrant is exercisable at an
 
exercise price of
 
$12.45 per share
 
(subject to adjustment
 
pursuant thereto),
is not subject to vesting, and has a term of five years.
Vaxxinity
 
has the first right to control the filing, prosecution, maintenance and enforcement of the licensed patents
 
at Vaxxinity’s
 
own
expense, subject to the
 
Licensors’ right to comment on
 
and review any patent filings.
 
The Platform License Agreement shall
 
continue
until the parties mutually consent in writing to terminate the agreement. Upon such termination, all licenses granted
 
under the Platform
License Agreement shall
 
terminate and Vaxxinity
 
will assign any
 
regulatory documentation previously
 
assigned to Vaxxinity
 
back to
the Licensors.
Coverage and Reimbursement
Sales of
 
our product
 
candidates in
 
the United
 
States will
 
depend, in
 
part, on
 
the extent
 
to which
 
third- party
 
payors, including
 
government
health programs such
 
as Medicare and
 
Medicaid, commercial insurance
 
and managed health
 
care organizations provide
 
coverage and
establish
 
adequate
 
reimbursement levels
 
for
 
such
 
product
 
candidates.
 
The
 
process
 
for
 
determining whether
 
a
 
third-party payor
 
will
provide coverage for a pharmaceutical
 
or biological product is typically separate
 
from the process for setting
 
the price of such a
 
product
or for establishing the reimbursement rate
 
that the payor will pay for
 
the product once coverage is
 
approved, and we may also
 
need to
provide
 
discounts
 
to
 
purchasers,
 
private
 
health
 
plans
 
or
 
government
 
healthcare
 
programs,
 
as
 
increasingly,
 
third-party
 
payors
 
are
requiring that
 
drug companies provide
 
them with
 
predetermined discounts from
 
list prices and
 
are challenging the
 
prices charged
 
for
medical products.
 
As a
 
result, a
 
third-party payor’s
 
decision to
 
provide coverage
 
for a
 
pharmaceutical or
 
biological product
 
does not
imply that the reimbursement rate will be adequate for commercial viability, and inadequate reimbursement rates, including significant
patient
 
cost
 
sharing
 
obligations,
 
may
 
deter
 
patients
 
from
 
selecting
 
our
 
product
 
candidates.
 
Obtaining
 
coverage
 
and
 
reimbursement
approval of a
 
product from a
 
third-party payor is
 
a time-consuming and
 
costly process that
 
could require us
 
to provide to
 
each payor
supporting scientific, clinical
 
and cost-effectiveness data
 
for the use
 
of our product
 
on a payor-by-payor
 
basis, with no
 
assurance that
coverage and adequate reimbursement will
 
be obtained. Third-party payors may limit
 
coverage to specific products on an
 
approved list,
also known as a formulary, which might not include all of the approved products for a particular indication.
Further,
 
no uniform
 
policy for
 
coverage and
 
reimbursement exists
 
in the
 
United States,
 
and coverage
 
and reimbursement
 
can differ
significantly from
 
payor to payor. In
 
general, factors
 
a payor
 
considers in
 
determining coverage
 
and reimbursement
 
are based
 
on whether
the product is a covered benefit under its health plan; safe, effective,
 
and medically necessary, including its regulatory approval
 
status;
medically appropriate for the specific
 
patient; cost-effective; and neither experimental
 
nor investigational. Third-party payors
 
often rely
upon Medicare coverage policy and payment limitations in setting their own reimbursement
 
rates, but also have their own methods and
approval process apart from
 
Medicare determinations. As such,
 
one third-party payor’s
 
decision to cover a
 
particular medical product
or service does not ensure that other payors will also
 
provide coverage for the medical product or service, and the level
 
of coverage and
reimbursement can differ significantly from payor to payor. Even if favorable coverage and reimbursement status is attained for one or
40
more products for which
 
we receive regulatory approval,
 
less favorable coverage
 
policies and reimbursement
 
rates may be implemented
in the future.
Product Approval and Government Regulation
Government authorities in the United States, at the
 
federal, state and local level, and other countries extensively
 
regulate, among other
things,
 
the
 
research,
 
development,
 
testing,
 
manufacture,
 
quality
 
control,
 
approval,
 
labeling,
 
packaging,
 
storage,
 
record-keeping,
promotion, advertising, distribution,
 
post-approval monitoring and
 
reporting, marketing and
 
export and import
 
of products such as
 
those
we are
 
developing. Any
 
product candidate
 
that we
 
develop must
 
be approved
 
by the
 
FDA before
 
it may
 
be legally
 
marketed in
 
the
United States and by the appropriate foreign regulatory agency before it may be legally marketed in foreign countries.
U.S. Drug Development Process
In the United States,
 
the development, manufacturing and marketing
 
of human drugs and vaccines
 
are subject to extensive
 
regulation.
The FDA
 
regulates drugs
 
under the
 
Federal Food,
 
Drug and
 
Cosmetic Act
 
(“FDCA”) and
 
implementing regulations,
 
and biological
products, including vaccines, under provisions of the FDCA and the
 
Public Health Service Act. Drugs and vaccines are also subject
 
to
other federal, state
 
and local statutes
 
and regulations. The
 
process of obtaining
 
regulatory approvals and
 
the subsequent compliance
 
with
appropriate federal, state, local and foreign statutes and regulations
 
require the expenditure of substantial time and financial resources.
Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after
approval, may
 
subject an
 
applicant to
 
administrative or
 
judicial sanctions.
 
FDA sanctions
 
could include
 
refusal to
 
approve pending
applications, withdrawal of
 
an approval, clinical
 
hold, warning
 
letters, product recalls,
 
product seizures, total
 
or partial suspension
 
of
production or distribution, injunctions, fines,
 
refusals of government contracts, debarment,
 
restitution, disgorgement or civil or criminal
penalties. Any agency
 
or judicial enforcement
 
action could have
 
a material adverse
 
effect on us.
 
The process required
 
by the FDA
 
before
a drug or biological product may be marketed in the United States generally involves the following:
 
completion
 
of
 
nonclinical
 
laboratory
 
tests,
 
animal
 
studies
 
and
 
formulation
 
and
 
stability
 
studies
 
according
 
to
 
GLP
 
or
 
other
applicable regulations;
 
submission to the FDA of an application for an IND, which must become effective before human clinical trials may begin;
 
performance of adequate
 
and well-controlled human
 
clinical trials according
 
to the FDA’s
 
regulations commonly referred
 
to
as GCPs to establish the safety and efficacy of the proposed drug for its intended use;
 
submission to the FDA of an NDA or BLA for a new drug;
 
satisfactory completion of
 
an FDA inspection
 
of the manufacturing
 
facility or facilities
 
where the drug
 
is produced to
 
assess
compliance
 
with
 
the
 
FDA’s
 
cGMP,
 
to
 
assure
 
that
 
the
 
facilities,
 
methods
 
and
 
controls
 
are
 
adequate
 
to
 
preserve
 
the
 
drug’s
identity, strength, quality and purity;
 
potential FDA audit of the nonclinical and clinical trial sites that generated the data in support of the NDA or BLA; and
 
FDA review and approval of the NDA or BLA.
The
 
lengthy process
 
of
 
seeking required
 
approvals and
 
the continuing
 
need for
 
compliance with
 
applicable statutes
 
and
 
regulations
require the expenditure of substantial resources and approvals are inherently uncertain.
Before testing any compounds
 
with potential therapeutic value
 
in humans, the product
 
candidate enters the pre-clinical
 
study stage. Pre-
clinical tests, also
 
referred to as
 
nonclinical studies, include
 
laboratory evaluations of
 
product chemistry,
 
toxicity and formulation,
 
as
well as
 
animal studies
 
to assess
 
the potential
 
safety and
 
activity of
 
the product
 
candidate. The
 
conduct of
 
the pre-clinical
 
tests must
comply with federal regulations and requirements including GLP. The sponsor must submit the results of the pre-clinical tests, together
with manufacturing information, analytical data, any available clinical data
 
or literature and a proposed clinical protocol, to the FDA as
part of the
 
IND. The IND
 
automatically becomes effective
 
30 days after
 
receipt by the
 
FDA, unless the
 
FDA imposes a
 
clinical hold
within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical
trial can begin. The FDA may also impose clinical holds on
 
a product candidate at any time before or during clinical trials due to safety
concerns or non-compliance. Accordingly,
 
we cannot be sure that
 
submission of an IND will result
 
in the FDA allowing clinical trials
to begin, or that, once begun, issues will not arise that suspend or terminate such trial.
Clinical trials
 
involve the
 
administration of
 
the product
 
candidate to
 
healthy volunteers or
 
patients under
 
the supervision
 
of qualified
investigators,
 
generally
 
physicians
 
not
 
employed
 
by
 
or
 
under
 
the
 
trial
 
sponsor’s
 
direct
 
control.
 
Clinical
 
trials
 
are
 
conducted
 
under
protocols detailing, among other
 
things, the objectives of
 
the clinical trial, dosing
 
procedures, subject selection and
 
exclusion criteria,
and the parameters to be used to monitor subject safety. Each protocol must be submitted to
 
the FDA as part of the IND. Clinical trials
must be conducted in accordance
 
with the FDA’s regulations comprising the good clinical practices requirements. Further, each
 
clinical
41
trial must be reviewed and approved by
 
an independent IRB at or servicing each
 
institution at which the clinical trial will
 
be conducted.
An IRB is charged
 
with protecting the
 
welfare and rights
 
of trial participants
 
and considers such
 
items as whether
 
the risks to
 
individuals
participating in the clinical trials
 
are minimized and are reasonable
 
in relation to anticipated benefits.
 
The IRB also approves the
 
form
and content
 
of the
 
informed consent
 
that must
 
be signed
 
by each
 
clinical trial
 
subject or
 
his or
 
her legal
 
representative and
 
provide
oversight for the clinical trial until completed.
Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:
Phase 1
. The drug is initially introduced into healthy human subjects and tested for safety, dosage
tolerance, absorption, metabolism, distribution and excretion. In the case of some products for severe or life-threatening diseases,
especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing may
 
be
conducted in patients;
Phase 2
.
The
 
drug is evaluated in a limited patient population to identify possible adverse effects and safety
risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal
dosage and dosing schedule; and
Phase 3
. Clinical trials are undertaken to further evaluate dosage, clinical efficacy and safety in an
expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish
 
the overall
risk/benefit ratio of the product and provide an adequate basis for product labeling. Generally, a well-controlled Phase 3 clinical trial is
required by the FDA for approval of an NDA or BLA.
Post-approval clinical trials, sometimes referred
 
to as Phase 4
 
clinical trials, may be
 
conducted after initial marketing approval.
 
These
clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
During all
 
phases of
 
clinical development,
 
regulatory agencies
 
require extensive
 
monitoring and
 
auditing of
 
all clinical
 
activities, clinical
data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA and
written IND safety reports must
 
be promptly submitted to the
 
FDA and the investigators for
 
serious and unexpected adverse events or
any finding from
 
tests in laboratory
 
animals that suggests
 
a significant risk
 
for human subjects.
 
Phase 1, Phase
 
2 and Phase
 
3 clinical
trials may
 
not be
 
completed successfully
 
within any
 
specified period,
 
if at
 
all. The
 
FDA or
 
the sponsor
 
or its
 
data safety
 
monitoring
board may
 
suspend a clinical
 
trial at
 
any time on
 
various grounds, including
 
a finding that
 
the research subjects
 
or patients
 
are being
exposed to
 
an unacceptable
 
health risk.
 
Similarly,
 
an IRB
 
can suspend
 
or terminate
 
approval of
 
a clinical
 
trial at
 
its institution
 
if the
clinical trial
 
is not being
 
conducted in accordance
 
with the IRB’s requirements
 
or if the
 
drug has been
 
associated with
 
unexpected serious
harm to patients.
Concurrently with clinical
 
trials, companies usually
 
complete additional animal
 
studies and must
 
also develop additional
 
information
about the chemistry and
 
physical characteristics of the drug
 
as well as finalize
 
a process for manufacturing
 
the product in commercial
quantities in
 
accordance with
 
cGMP requirements.
 
The manufacturing
 
process must
 
be capable
 
of consistently
 
producing quality
 
batches
of the product candidate and, among other things, must
 
develop methods for testing the identity, strength, quality and purity of the final
drug. Additionally,
 
appropriate packaging must be selected and
 
tested, and stability studies must
 
be conducted to demonstrate that
 
the
product candidate does not undergo unacceptable deterioration over its shelf life.
U.S. Review and Approval Processes
Assuming successful completion of all required
 
testing in accordance with all applicable
 
regulatory requirements, the results of product
development, nonclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical
 
tests conducted on
the
 
chemistry
 
of
 
the
 
drug,
 
proposed
 
labeling
 
and
 
other
 
relevant
 
information
 
are
 
submitted
 
to
 
the
 
FDA
 
as
 
part
 
of
 
an
 
NDA
 
or
 
BLA
requesting approval to market the product.
 
The submission of an NDA or BLA
 
is subject to the payment of substantial
 
fees; a waiver of
such fees may be obtained under certain limited circumstances.
In addition, under the Pediatric Research Equity Act (“PREA”), an NDA or
 
BLA or supplement to an NDA or BLA must contain data
to assess
 
the safety
 
and effectiveness
 
of the
 
drug for
 
the claimed
 
indications in
 
all relevant
 
pediatric subpopulations
 
and to
 
support
dosing and administration for each
 
pediatric subpopulation for which
 
the product is safe and
 
effective. The FDA may grant
 
deferrals for
submission of data
 
or full or
 
partial waivers. Unless
 
otherwise required by
 
regulation, PREA does
 
not apply to
 
any drug for
 
an indication
for which orphan designation has been granted.
The FDA reviews all NDAs or
 
BLAs submitted to determine if they
 
are substantially complete before it accepts
 
them for filing. If the
FDA determines that an
 
NDA or BLA is
 
incomplete or is found
 
to be non-navigable, the
 
filing may be refused
 
and must be re-submitted
for consideration. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA or BLA. Under the goals
and policies agreed to by the FDA under
 
the Prescription Drug User Fee Act (“PDUFA”),
 
the FDA has 10 months from acceptance of
filing in which to complete its initial review of a
 
standard NDA or BLA and respond to the applicant, and
 
six months from acceptance
of filing for a priority
 
NDA or BLA. The FDA does
 
not always meet its PDUFA
 
goal dates. The review process
 
and the PDUFA
 
goal
42
date
 
may
 
be
 
extended
 
by
 
three
 
months
 
or
 
longer
 
if
 
the
 
FDA
 
requests
 
or
 
the
 
NDA
 
or
 
BLA
 
sponsor
 
otherwise
 
provides
 
additional
information or clarification regarding information already provided in the submission before the PDUFA goal date.
After the NDA or BLA submission
 
is accepted for filing, the
 
FDA reviews the NDA or BLA
 
to determine, among other things,
 
whether
the proposed product is
 
safe and effective for
 
its intended use, and
 
whether the product is
 
being manufactured in accordance
 
with cGMP
to assure and preserve the product’s identity,
 
strength, quality and purity. The FDA may
 
refer applications for novel drug or biological
products or drug
 
or biological products
 
which present difficult
 
questions of safety
 
or efficacy to
 
an advisory committee,
 
typically a panel
that includes clinicians
 
and other experts,
 
for review, evaluation and
 
a recommendation as
 
to whether the
 
application should be
 
approved
and
 
under
 
what
 
conditions.
 
The
 
FDA
 
is
 
not
 
bound
 
by
 
the
 
recommendations
 
of
 
an
 
advisory
 
committee,
 
but
 
it
 
considers
 
such
recommendations carefully when making decisions.
 
During the drug approval
 
process, the FDA also
 
will determine whether a
 
REMS
is necessary to assure the safe use of the drug. If the FDA concludes a REMS
 
is needed, the sponsor of the NDA or BLA must submit
 
a
proposed REMS; the FDA will not approve the NDA or BLA without a REMS, if required.
Before approving an NDA or BLA, the FDA
 
will inspect the facilities at which the product
 
is manufactured. The FDA will not approve
the product unless
 
it determines that
 
the manufacturing processes
 
and facilities are
 
in compliance with
 
cGMP requirements and
 
adequate
to assure consistent
 
production of the
 
product within required
 
specifications. The FDA requires
 
vaccine manufacturers to
 
submit data
supporting
 
the
 
demonstration
 
of
 
consistency
 
between
 
manufacturing
 
batches,
 
or
 
lots.
 
The
 
FDA
 
works
 
together
 
with
 
vaccine
manufacturers to develop
 
a lot release
 
protocol, the tests
 
conducted on each
 
lot of vaccine
 
post-approval. Additionally, before approving
an NDA
 
or BLA, the
 
FDA will
 
typically inspect
 
the sponsor
 
and one
 
or more
 
clinical sites
 
to assure that
 
the clinical
 
trials were conducted
in
 
compliance
 
with
 
IND
 
study
 
requirements.
 
If
 
the
 
FDA
 
determines
 
that
 
the
 
application,
 
manufacturing
 
process
 
or
 
manufacturing
facilities are not acceptable it will outline the deficiencies in the submission and often will request additional testing or information.
The NDA
 
or BLA
 
review and
 
approval process
 
is lengthy
 
and difficult
 
and the
 
FDA may
 
refuse to
 
approve an
 
NDA or
 
BLA if
 
the
applicable regulatory criteria
 
are not satisfied
 
or may require
 
additional clinical data
 
or other data
 
and information. Even
 
if such data
and information
 
is submitted,
 
the FDA
 
may ultimately
 
decide that
 
the NDA
 
or BLA
 
does not
 
satisfy the
 
criteria for
 
approval. Data
obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.
 
The
FDA will issue a complete response letter if the agency decides not to approve the NDA or BLA. The complete
 
response letter usually
describes
 
all of
 
the
 
specific deficiencies
 
in the
 
NDA or
 
BLA
 
identified by
 
the FDA.
 
The deficiencies
 
identified may
 
be minor,
 
for
example, requiring
 
labeling changes,
 
or major,
 
for example,
 
requiring additional
 
clinical trials.
 
Additionally,
 
the complete
 
response
letter may include recommended actions that the applicant might take to place the application in a condition for approval. If a complete
response letter is issued,
 
the applicant may either
 
submit new information, addressing
 
all of the deficiencies
 
identified in the letter,
 
or
withdraw the application.
If a product receives regulatory
 
approval, the approval may be
 
significantly limited to specific diseases
 
and dosages or the
 
indications
for use may otherwise be
 
limited, which could restrict the commercial
 
value of the product. Further,
 
the FDA may require that
 
certain
contraindications, warnings or
 
precautions be included
 
in the product
 
labeling. In addition,
 
the FDA may
 
require post-marketing clinical
trials, sometimes referred to as Phase 4 clinical trials, which are
 
designed to further assess a product’s safety and effectiveness and may
require testing and surveillance programs to
 
monitor the safety of approved
 
products that have been commercialized. In
 
addition, new
government requirements, including those
 
resulting from new legislation,
 
may be established, or
 
the FDA’s
 
policies may change, which
could impact the timeline for regulatory approval or otherwise impact ongoing development programs.
Expedited Development and Review Programs
The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that meet
certain criteria. Specifically, new drugs and biologics are eligible for fast track designation if they are intended to treat a serious or life-
threatening condition and preclinical
 
or clinical data
 
demonstrate the potential to
 
address unmet medical needs
 
for the condition.
 
Fast
track designation
 
applies to
 
the combination of
 
the product and
 
the specific indication
 
for which
 
it is
 
being studied. The
 
sponsor can
request the FDA to designate the
 
product for fast track status any
 
time before receiving NDA or BLA
 
approval, but ideally no later than
the pre-NDA or pre-BLA meeting.
Additionally,
 
a
 
drug
 
or
 
biologic
 
may
 
be
 
eligible
 
for
 
designation
 
as
 
a
 
breakthrough
 
therapy
 
if
 
the
 
product
 
is
 
intended,
 
alone
 
or
 
in
combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and
 
preliminary clinical evidence
indicates
 
that
 
the
 
product
 
may
 
demonstrate
 
substantial
 
improvement
 
over
 
currently
 
approved
 
therapies
 
on
 
one
 
or
 
more
 
clinically
significant endpoints.
 
The benefits
 
of breakthrough
 
therapy designation
 
include the
 
same benefits
 
as fast
 
track designation,
 
plus intensive
guidance from the FDA to facilitate an efficient drug development program.
Any product
 
submitted to
 
the FDA for
 
marketing, including under
 
a fast track
 
or breakthrough therapy
 
designation program,
 
may be
eligible for
 
other types
 
of FDA
 
programs intended
 
to expedite
 
development and
 
review, such as
 
priority review
 
and accelerated
 
approval.
Any product is eligible
 
for priority review if
 
it treats a serious or
 
life-threatening condition and, if
 
approved, would provide a
 
significant
improvement
 
in
 
safety
 
and
 
effectiveness
 
compared
 
to
 
available
 
therapies.
 
Priority
 
review
 
reduces
 
the
 
review
 
time
 
for
 
an
 
initial
 
or
supplemental marketing application by four months.
43
A product may be
 
eligible for accelerated
 
approval if it
 
treats a serious
 
or life-threatening condition
 
and generally provides
 
a meaningful
advantage over available therapies based on an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a
clinical endpoint that
 
can be measured
 
earlier than irreversible
 
morbidity or mortality
 
("IMM") that is
 
reasonably likely to
 
predict an
effect on IMM
 
or other clinical
 
benefit. As a
 
condition of accelerated approval,
 
the FDA requires
 
that a sponsor of
 
a drug or
 
biologic
receiving
 
accelerated
 
approval
 
subsequently
 
provide
 
additional
 
data
 
confirming
 
the
 
anticipated
 
clinical
 
benefit,
 
for
 
example
 
by
performing adequate and well-controlled post-marketing clinical
 
trials. If clinical benefit is not confirmed,
 
accelerated approval may be
revoked. If the FDA concludes that a drug
 
or biologic shown to be effective can be safely
 
used only if distribution or use is restricted,
 
it
may require such post-marketing restrictions, as it deems necessary to assure safe use of the product.
Fast
 
track designation,
 
breakthrough therapy
 
designation, priority
 
review,
 
and accelerated
 
approval do
 
not
 
change the
 
standards for
approval but may expedite the development or approval process.
EUA Approval
The Commissioner
 
of the
 
FDA, under
 
delegated authority from
 
the Secretary of
 
the U.S. Department
 
of Health
 
and Human
 
Services
(“DHHS”) may,
 
under certain circumstances,
 
issue an EUA
 
that would permit
 
the use of
 
an unapproved drug
 
product or unapproved
use of an approved
 
drug product. Before
 
an EUA may be
 
issued, the Secretary
 
must declare an emergency
 
based on one of
 
the following
grounds:
 
a
 
determination
 
by
 
the
 
Secretary
 
of
 
the
 
Department
 
of
 
Homeland
 
Security
 
that
 
there
 
is
 
a
 
domestic
 
emergency,
 
or
 
a
significant potential for a domestic
 
emergency, involving a heightened risk of attack with
 
a specified biological, chemical,
radiological or nuclear agent or agents;
 
a determination by the
 
Secretary of the Department
 
of Defense that there
 
is a military emergency, or a significant
 
potential
for a military
 
emergency, involving a heightened
 
risk to U.S.
 
military forces
 
of attack with
 
a specified
 
biological, chemical,
radiological or nuclear agent or agents; or
 
a determination by the Secretary of the DHHS that a
 
public health emergency that affects, or has
 
the significant potential
to affect, national security and that involves a
 
specified biological, chemical, radiological or nuclear agent or agents, or
 
a
specified disease or condition that may be attributable to such agent or agent.
In order to be the subject of an EUA, the FDA Commissioner must conclude that, based on the totality of scientific evidence available,
it is
 
reasonable to
 
believe that
 
the product
 
may be
 
effective in
 
diagnosing, treating
 
or preventing
 
a disease
 
attributable to
 
the agents
described above, that the
 
product’s potential
 
benefits outweigh its potential
 
risks and that
 
there is no adequate
 
approved alternative to
the product.
Although an EUA cannot
 
be issued until after
 
an emergency has been
 
declared by the Secretary
 
of DHHS, the FDA
 
strongly encourages
an entity with a
 
possible candidate product,
 
particularly one at an
 
advanced stage of
 
development, to contact the
 
FDA center responsible
for the candidate
 
product before a determination
 
of actual or potential
 
emergency. Such an entity may submit
 
a request for consideration
that includes data to
 
demonstrate that, based on
 
the totality of scientific
 
evidence available, it is
 
reasonable to believe that
 
the product
may be
 
effective
 
in diagnosing,
 
treating or
 
preventing the
 
serious or
 
life-threatening disease
 
or condition.
 
This is
 
called a
 
pre-EUA
submission and
 
its purpose
 
is to
 
allow FDA
 
review considering
 
that during
 
an emergency,
 
the time
 
available for
 
the submission
 
and
review of an EUA request may be severely limited.
Post-Approval Requirements
Any drug or
 
biological products for
 
which we or
 
our collaborators receive
 
FDA approvals are
 
subject to continuing
 
regulation by the
FDA, including,
 
among other
 
things, record-keeping
 
requirements, reporting
 
of adverse
 
experiences with
 
the product,
 
providing the
FDA with updated safety and efficacy
 
information, product sampling and distribution requirements, complying with
 
certain electronic
records and
 
signature requirements
 
and complying
 
with FDA
 
promotion and
 
advertising requirements, which
 
include, among
 
others,
standards for
 
direct-to-consumer advertising,
 
promoting drugs
 
for uses
 
or in
 
patient populations
 
that are
 
not described
 
in the
 
drug’s
approved
 
labeling
 
(known
 
as
 
“off-label
 
use”),
 
industry-sponsored
 
scientific
 
and
 
educational
 
activities,
 
and
 
promotional
 
activities
involving the internet.
Failure to comply
 
with FDA requirements
 
can have negative
 
consequences, including adverse
 
publicity,
 
enforcement letters from
 
the
FDA,
 
mandated
 
corrective
 
advertising
 
or
 
communications
 
with
 
doctors,
 
and
 
civil
 
or
 
criminal
 
penalties.
 
Although
 
physicians
 
may
prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.
Manufacturers of
 
our product
 
candidates are
 
required to
 
comply with
 
applicable FDA
 
manufacturing requirements
 
contained in
 
the
FDA’s