Exhibit 99.2
Deep InsightsAdvancingImpactful Medicines Company Overview | June 2023
© Scholar Rock, Inc. All rights reserved. 2023. Forward-Looking
Statements Various statements in this presentation concerning the future expectations, plans and prospects of Scholar Rock, Inc. (“Scholar Rock”), including without limitation, Scholar Rock’s expectations regarding its strategy, its product
candidate selection and development timing, including timing for the initiation of and reporting results from its clinical trials for apitegromab, SRK-181, and other product candidates and indication selection and development timing, its cash
runway, the ability of any product candidate to perform in humans in a manner consistent with earlier nonclinical, preclinical or clinical trial data, and the potential of its product candidates and proprietary platform. The use of words such
as “may,” “could,” “might,” “will,” “should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “project,” “intend,” “future,” “potential,” or “continue,” and other similar expressions are intended to identify such forward-looking
statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. All such forward-looking statements are based on management's current expectations of future events and are subject to a
number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, without limitation, that
preclinical and clinical data, including the results from the Phase 2 trial of apitegromab or Part A of the Phase 1 trial of SRK-181, are not predictive of, may be inconsistent with, or more favorable than, data generated from future clinical
trials of the same product candidate, including the Phase 3 clinical trial of apitegromab in SMA and Part B of the Phase 1 clinical trial of SRK-181, respectively, Scholar Rock’s ability to provide the financial support, resources and
expertise necessary to identify and develop product candidates on the expected timeline, the data generated from Scholar Rock’s nonclinical and preclinical studies and clinical trials, information provided or decisions made by regulatory
authorities, competition from third parties that are developing products for similar uses, Scholar Rock’s ability to obtain, maintain and protect its intellectual property, the success of Scholar Rock’s current and potential future
collaborations, Scholar Rock’s dependence on third parties for development and manufacture of product candidates including, without limitation, to supply any clinical trials, Scholar Rock’s ability to manage expenses and to obtain additional
funding when needed to support its business activities and establish and maintain strategic business alliances and new business initiatives, and the impacts of current macroeconomic and geopolitical events, hostilities in Ukraine, increasing
rates of inflation and rising interest rates, on business operations and expectations, as well as those risks more fully discussed in the section entitled "Risk Factors" in Scholar Rock’s Quarterly Report on Form 10-Q for the quarter ended
March 31, 2023, as well as discussions of potential risks, uncertainties, and other important factors in Scholar Rock’s subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent Scholar Rock’s
views only as of today and should not be relied upon as representing its views as of any subsequent date. All information in this press release is as of the date of the release, and Scholar Rock undertakes no duty to update this information
unless required by law. Apitegromab and SRK-181 are investigational drug candidates under evaluation. Apitegromab and SRK-181 have not been approved for any use by the FDA or any other regulatory agency and the safety and efficacy of
apitegromab and SRK-181 have not been established.
Scholar Rock: Transforming Patient Lives, Addressing High Unmet Medical
Need 3 Global leader in TGFβ superfamily biology Targeting the latent forms of growth factors Exquisite selectivity to deliver differentiated therapies Revolutionary Platform Rich preclinical pipeline focused on high unmet patient
needs Phase 3 SAPPHIRE study underway, enrollment completion expected in Q3 2023; data readoutexpected in 2024 Phase 1 proof-of-concept DRAGON study underway in immuno-oncology Neuromuscular and Beyond Compelling proof-of-concept TOPAZ
data informed Phase 3 SAPPHIRE study design Seasoned leadership team with track record of clinical and commercial success Anticipated cash runway into 2025 Positioned for Success Commercial planning underway for apitegromab (SMA) in US
and Europe Broad platform, including promising early-stage assets, provides opportunities to advance alone or in partnership Strategic Optionality
Revolutionary Approach to Regulating TGFβ Superfamily Implicated in Devastating
Diseases 4 Scholar Rock’s R&D Platform Transforming Medical Practice Selectively target the latent form of growth factors in the microenvironment of cells and tissues with uniquely designed antibodies Overcome the challenges that
plague traditional approaches that target the “mature” growth factor or its receptors, which are difficult to differentiate and lead to unintended negative effects Scholar Rock’s TargetLatent Growth Factor Traditional Target“mature” growth
factor TGFβ Superfamily: Highly Sought-After Targets Dysregulation plays a role in devastating diseases that have a high unmet need, including: Neuromuscular disorders Fibrosis Oncology Recognized by the industry as important targets
given their fundamental roles in regulating a variety of biological processes
DISCOVERY/PRECLINICAL PHASE 1 PHASE 2 PHASE 3 ANTICIPATED 2023
MILESTONES SPINAL MUSCULAR ATROPHYApitegromab (selective anti- pro and latent myostatin) 36-month TOPAZ data SAPPHIRE: last patient enrolled expected in Q3 IMMUNO-ONCOLOGYSRK-181 (selective context-independent, anti-latent
TGFβ-1) Rolling clinical data updates ANEMIASelective anti-RGMc IND-enabling studies FIBROSIS Selective context-dependent (LTBP1 & LTBP3) anti-latent TGFβ-1 IND-enabling studies Robust Pipeline of Novel Product Candidates
5 Potential to transform the lives of people living with awide range of serious diseases, including neuromuscular disorders, oncology, and fibrosis LTBP3=latent transforming growth factor beta binding protein 3; LTBP1=Latent Transforming
Growth Factor Beta Binding Protein 1; RGM=Repulsive guidance molecule; TGFβ-1 =Transforming Growth Factor Beta-1
Leadership Team: Experienced in Drug Development and Commercialization 6 Jay
Backstrom, MD, MPH President & CEO 30 years of clinical R&D experience, leading multiple successful regulatory approvals Ted Myles, MBA Chief Operating Officer & CFO 25 years of progressive experience in clinical and
commercial-stage companies 25 years of experience leading HR, culture transformation, leadership development, DEI, and talent management Caryn Parlavecchio Chief Human Resources Officer 15 years of experience leading and advising life
sciences companies in areas of legal and compliance Junlin Ho, JD General Counsel &Corporate Secretary Mo Qatanani, PhD SVP, Research 15 years of industry experience on the strategic and operational sides of research &
development Tracey Sacco Chief Commercial Officer 20 years of commercial leadership experience, including product launch and global commercial strategy Jing Marantz, MD, PhD Chief Medical Officer 20 years of development and medical
leadership experience across neurology, hematology/oncology, and rare diseases
Apitegromab: The Next Potential Transformative Therapy for Patients with Spinal
Muscular Atrophy (SMA)
Apitegromab: Transformative Potential to Change the Standard of
Care 8 Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy (SMA). Apitegromab has not been approved for any use by the FDA or any other regulatory agency, and its safety and efficacy
have not been established. Phase 2 TOPAZ TrialDemonstrated substantial and sustained functional improvements in Type 2 and nonambulatory Type 3 SMA patients Apitegromab at a Glance First and only muscle-targeted investigational treatment
to demonstrate clinical proof-of-concept in SMA Phase 3 SAPPHIRE TrialRegistrational trial with topline 12-month data readout expected in 2024 ONYX Open-Label Extension Study Evaluating the long-term safety and efficacy of apitegromab in
patients who have completed TOPAZ or SAPPHIRE
There is further potential to regain vital muscle function by also addressing
the progressive muscle atrophy and associated weakness of SMA SMN therapies slow further degeneration of motor neurons1 Hallmarks of SMAProgressive Motor Neuron Loss and Muscle Atrophy Leading to Progressive Muscle Weakness 9 SMA,
spinal muscular atrophy; SMN, survival motor neuron.1. Hua Y, et al. Nature. 2011;478(7367):123-6. 2. Figure adapted from: SMA Foundation Overview. http://www.smafoundation.org/wp-content/uploads/2012/03/SMA-Overview.pdf.; Accessed April 18,
2021. ...but do not directly address muscle atrophy Muscle fiber atrophy Motor neuron degeneration2
10 *TOPAZ Phase 2 trial evaluated patients with Type 2 and 3 SMA (did not
include Type 1) ** 2/3 of overall patient population has type 2 or 3 SMA, including ambulatory and nonambulatory patients. Percentages reflected here do not add up to 100% because the prevalences of Types 0, 4, and unknown are
excluded. Percentages represent percent of prevalent patients. 1. Lally et al, Orphanet Journal of Rare Diseases, 2017; 2. SMA Europe. SMATracker. About SMA. Accessed January 24, 2022. https://smatracker.eu/what-is-spinal-muscular-atrophy;
3. National Organization for Rare Disorders. Spinal muscular atrophy. Accessed January 24, 2022. https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/. 4. Cure SMA. Care Series Booklet. Accessed September 19, 2021. 2020.
https://www.curesma.org/wpcontent/uploads/2020/08/08262020_Understanding_SMA_vWeb.pdf. 5. Cure SMA. State of SMA 2022. May 31, 2022. https://www.curesma.org/wp-content/uploads/2022/06/9042022_State-of-SMA_vweb.pdf Apitegromab is an
investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been
established. Severe, progressive disabilities; unable to walk independently Significant, progressive motor function impairment; many lose ambulation Infant onset; unable to sit up independently Type 3 25% Type 2 39% Type
1 25% TOPAZ* 12-month results showed transformative potential in nonambulatory Types 2 and 3 patients ~2/3 of overall patient population5** GLOBAL DISEASE: 30,000-35,000 affected in US and Europe1, 2, 3,4 Cure SMA. State of SMA 2022.
May 31, 2022 ALMOST 70% OF INDIVIDUALS WITH SMA IN THE U.S. HAVE RECEIVED AN FDA-APPROVED TREATMENT
Motor Function With SMN Therapies as Assessed by HFMSE HFMSE appears to Plateau
After Initial Gains 1. Mercuri E, et al. Presented at: World Muscle Society Congress 2020, P. 257 2. Oskoui M, et al. Presented at: 2021 Muscular Dystrophy Association Clinical & Scientific Conference; March 15-18, 2021. Poster 80.
HFMSE, Hammersmith Functional Motor Scale–Expanded; SE, standard error. *MFM was primary efficacy endpoint of SUNFISH. HFMSE was a secondary endpoint. This third-party information is provided for background only and is not intended to
convey or imply a comparison to the TOPAZ clinical trial results. Overall population age 2-25 Change in HFMSE* Over Four Years with Risdiplam2
Risdiplam n= 120 120 119 117 109 106 89 99 101 97 Placebo n= 60 60 58 58 Risdiplam Placebo (months 0-12) Mean (+/-SE) Change in HFMSE Total Score From Baseline* 0 30 48 6 12 18 24 36 42 Visit,
months 11 Change in HFMSE Over Four Years with Nusinersen1 Overall population age 2-12 Mean (+SE) Change in HFMSE Total Score From Baseline Analysis Visit, days Initial Treatment CHERISH Chronic Maintenance
Phase SHINE 1 92 169 253 350 450 690 930 1170 1410 1650 Nusinersen n= 84 82 84 84 83 76 83 83 79 61 20 Placebo n= 42 41 41 42 42 39 Nusinersen in CHERISH and SHINE Sham control in CHERISH
Patients and caregivers want new therapies to address the following unmet
needs2* : Improving and Sustaining Muscle Function Remains an Unmet Need 12 HFMSE=Hammersmith Functional Motor Scale-Expanded *Percentages represent percent of patients who named these unmet needs when asked “What are your most
significant current unmet needs that you hope new therapies would address”? 1. Mercuri E et al.; N Engl J Med 2018; 378:625-635; DOI: 10.1056/NEJMoa1710504; cherish trial results. 2. 2022 Community Update Survey, Cure SMA.This third-party
information is provided for background only and is not intended to convey or imply a comparison to the TOPAZ clinical trial results. Mean improvement in HFMSE experienced by patients with nonambulatory Types 2/3 SMA in nusinersen Phase 3
CHERISH trial1 3.9-point increase in HFMSE from nusinersen(4.9 point increase relative to sham control) HFMSE Score at Month 15 Total Possible HFMSE Score of 66 Unmet need remains substantial Increase muscle strength Improve daily
activities Stabilize or gain new motor function Reduce fatigue 97% 92% 89% 83%
Apitegromab Offers Significant Potential to Address Unmet Needs 13 * Based on
Animal Model Data; 1. Long KK, et al. Hum Mol Genet. 2019;28(7):1077-1088; 2. Pirruccello-Straub M, et al. Sci Reports. 2018;8(1):2292. doi:10.1038/s41598-018-20524-9 3. Figure adapted from: SMA Foundation Overview.
http://www.smafoundation.org/wp-content/uploads/2012/03/SMA-Overview.pdf.; Accessed April 18, 2021. For illustrative purposes only Apitegromab is a MUSCLE-TARGETED APPROACH designed to improve motor function*1,2 Myostatin is a negative
modulator of muscle growth Strong preclinical evidence indicates upstream targeting of structurally differentiated pro- and latent myostatin avoids undesirable off-target effects Apitegromab Muscle fiber atrophy Apitegromab selectively
inhibits myostatin and has the potential to build muscle and strength to improve certain patient outcomes Motor neuron degeneration3
Phase 2 TOPAZ Trial: Safety and Efficacy Data from First Muscle-Targeted
Treatment Candidate in SMA
Phase 2 Trial Design1,2 15 Ambulatory Patients (Revised Hammersmith
Scale) Safety RHS mean change from baseline at 12 months Ages 5-21 Type 3 SMA Open-label, single-arm Apitegromab 20 mg/kg IV q4w Receiving nusinersen Apitegromab monotherapy Nonambulatory Patients (Hammersmith Functional Motor Scale
Expanded) Safety HFMSE mean change from baseline at 12 months COHORT 2 N=15 Ages 5-21 Type 2 or Type 3 SMA Apitegromab 20 mg/kg IV q4w Open-label, single-arm Receiving nusinersen (initiated ≥ 5 years of age) Safety HFMSE mean
change from baseline at 12 months COHORT 3 N=20 Ages ≥ 2 Type 2 SMA Apitegromab 2 mg/kg IV q4w Apitegromab 20 mg/kg IV q4w R1:1 Double-blind, randomized (1:1) Receiving nusinersen (initiated< 5 years of age) TREATMENT (12
months) PRIMARY ENDPOINTS All SMA Types 2/3, cohorts defined by age and present ambulatory status at time of enrollment. HFMSE, Hammersmith Functional Motor Scale Expanded; IV, intravenous; q4w, every 4 weeks; SMA, spinal muscular atrophy;
SMN, survival motor neuron. 1. Place A, et al. Eu J Neurol. 2021;28(Suppl1):207-334 (EPR-184). 2. Crawford T, et al. TOPAZ Extension: 24-month Efficacy and Safety of Apitegromab in Patients With Later-onset SMA (Type 2 and Type 3 SMA).
Presented at CureSMA Annual Conference; June 16-19, 2022. COHORT 1 N=23
Motor Function Outcomes by HFMSE Over 36 Months Improvements Were Substantial
and Sustained 16 For the 36-month evaluation, an observed case analysis was conducted, which pooled all the nonambulatory patients (Cohorts 2 and 3) and was based upon the available data for given timepoints. This analysis population
included patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). This analysis excludes data post scoliosis surgery from seven
patients. One patient did not conduct HFMSE at time of database lock for 24 months, however, this patient had an unscheduled HFMSE score one month prior to their scheduled visit. In the most recent analysis, this result was included in the
24-month analysis. Error bars represent SE. CI represents confidence interval. SMN Rx=SMN therapy. In the age 2-21 group, 18/28 patients achieved ≥ 1-pt gains, and 11/28 patients ≥ 3-pt gains at 36 months. Data cutoff date as of March 13,
2023. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have
not been established. n= 35 29 32 29 28 95% CI= (1.4, 4.1) (1.2, 6.0) (1.9, 6.6) (1.0, 6.9) n= 29 23 26 23 23 95% CI= (1.8, 5.0) (1.8, 7.4) (2.3, 8.0) (1.3, 8.3) Pooled Nonambulatory Patients Mean Change from Baseline
(+SE) Baseline mean age=7.3 | Time on SMN Rx=24.1m Age 2-21 YearsAll Doses (N=35) Baseline mean age=5.5 | Time on SMN Rx=24.6m Age 2-12 YearsAll Doses (N=29) Mean Change from Baseline (+SE)
Motor Function Outcomes by RULM Over 36 Months Improvements Were Substantial and
Sustained 17 For the 36-month evaluation, an observed case analysis was conducted, which pooled all the nonambulatory patients (Cohorts 2 and 3) and was based upon the available data for given timepoints. This analysis population included
patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). This analysis excludes data post scoliosis surgery from seven patients. One
patient did not conduct RULM at month 24, however, had an unscheduled RULM score one month prior to their scheduled visit. In the most recent analysis, this result was included in the 24-month analysis. Error bars represent standard error
(SE). CI represents confidence interval. SMN Rx=SMN therapy. In the age 2-21 group, 15/27 patients achieved ≥ 1-pt gains, and 18/27 patients ≥ 3-pt gains at 36 months. Data cutoff date as of March 13, 2023. Apitegromab is an investigational
drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. Baseline mean
age=7.3 |Time on SMN Rx=24.1m Baseline mean age=5.5 |Time on SMN Rx=24.6m Pooled Nonambulatory Patients Mean Change from Baseline (+SE) Age 2-21 YearsAll Doses (N=35) Age 2-12 YearsAll Doses (N=29) n= 35 28 31 31 27 95%
CI= (-0.2, 1.4) (0.2, 2.3) (1.2, 3.3) (1.1, 3.7) n= 29 22 25 25 22 95% CI= (-0.7, 1.1) (0.1, 2.4) (1.0, 3.5) (1.4, 4.2)
Time (weeks) No. of observations Time (weeks) No. of observations Year
3 Year 2 Year 1 Pooled Nonambulatory Patients | Age 2 – 21 | All Doses | Over 36 Months Improvements in PRO Measures Were Consistent with Motor Function IMPROVEMENT PEDI-CAT Daily Activities IMPROVEMENT IMPROVEMENT N = 35; Baseline
mean age=7.3 |Time on SMN Rx=24.1m HFMSE Change from baseline (±SE) IMPROVEMENT Year 2 Year 3 Year 1 RULM Year 3 Year 2 Year 1 PROMIS Fatigue (Proxy) Change from baseline (±SE) Year 2 Year 3 Year
1 34 34 34 28 27 29 31 32 32 31 27 27 27 35 35 34 29 28 29 32 32 32 29 27 28 27 31 29 30 21 23 25 25 22 27 23 16 17 15 25 23 22 19 19 22 16 19 18 19 16 14 14 HFMSE=Hammersmith Functional
Motor Scale Expanded; OC=observed case; PEDI-CAT=Pediatric Evaluation of Disability Inventory Computer Adaptive Test; PROMIS=Patient Reported Outcome Measurement Information System; RULM=Revised upper limb module; SE=standard error of the
mean. SMN Rx=SMN therapy. Data on File. Scholar Rock, Inc. Cambridge, MA. Data cutoff date as of March 13, 2023. The updated PEDI-CAT analysis included additional records (2 at 12 months and 1 at 24 months) that were not available at the time
of previous analysis. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and
efficacy have not been established.
Pooled Nonambulatory Patients New WHO Development Milestones Achieved Over 36
Months 19 Proportion of patients gaining new milestones in TOPAZ Cohort 2: BL (0%),12m (20%), 24m (7%), 36m (0%) Cohort 3 (all doses): BL (0%,) 12m (24%), 24m (26%), 36m (30%) Cohort 3: Randomized to 20mg/kg dose: 12m (25%), 24m (33%),
36m (40%) *Includes patients who crossed over from 2 mg/kg to 20mg/kg starting week 68 through week 104. SMN Rx=SMN therapy. Data cutoff date as of March 13, 2023. Apitegromab is an investigational drug candidate being evaluated for the
treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. Age (years) Hands & kneescrawling Standing
with assistance Walking with assistance Standing alone Walking alone SMN Rx (≥ age 5) 8 9 19 SMN Rx (< age 5) 2* 4* 5* 2 2 4 5 WHO MILESTONE X X X X X X X X X X X X
X X X X X X X X X X X X X X X Key Takeaways Patients receiving nusinersen ≥ age 5 mostly maintained WHO milestones Patients receiving nusinersen < age 5 improved overall: 6 out of 20 gained new milestones over 36
months BL 12M 24M 36M Able X Unable No record
TOPAZ Safety Summary Over 36 Months 20 Treatment-Emergent Adverse Events
(TEAEs)* 2 mg/kg dose (N=10) n (%) 20 mg/kg dose (N=48) n (%) Total (N=58) n (%) Any TEAE 10 (100) 46 (95.8) 56 (96.6) Any serious TEAE 5 (50) 16 (33.3) 21 (36.2) Any TEAE leading to study drug discontinuation 0 1
(2.1) 1 (1.7) Any Grade 3 (severe) or higher TEAE 4 (40) 16 (33.3) 20 (34.5) *Defined as AEs that start after the first dose of study drug or start prior to the administration of study drug and worsen in severity/grade or relationship
to investigational medication after the administration of study drug. % = 100 x n/N; % at 12 month. AE, adverse event; TEAE, treatment emergent adverse events. Data cutoff date as of March 13, 2023. Apitegromab is an investigational drug
candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. TEAEs were consistent
with previous reports with no new findings after 198 patient-years of exposure Most frequently reported TEAEs*: headache (38%), pyrexia (38%), COVID-19 (36%), nasopharyngitis (36%), & upper respiratory tract infection (33%) TEAEs were
mostly mild to moderate in severity and generally consistent with the underlying patient population and nusinersen therapy No deaths or suspected unexpected serious adverse reactions or hypersensitivity reactions to apitegromab were
reported No patients displayed positive titers for apitegromab antibodies (ADA)
Summary of TOPAZ Data Substantial and Sustained Improvement Over 36
MONTHS 21 PRO=Patient Reported Outcome Data to date has shown substantial clinical benefit that is dose-dependent TOPAZ data suggest that apitegromab has the potential to transform care in SMA by directly addressing progressive muscle
weakness Benefit continued to improve or was sustained over 36 months Consistency across functional scales and patient-reported outcomes Well tolerated profile and low discontinuation rate supports durability of treatment
Sapphire Phase 3 Pivotal Trial
SAPPHIRE Phase 3 Design is Optimized by Insights from TOPAZ 23 Substantial
HFMSE gains observed in the nonambulatory Type 2/3 SMA cohorts Exploratory age 2-12 analysis in nonambulatory Type 2/3 showed transformative potential HFMSE gains substantial by 12 months of treatment Dose response seen (greater effect
observed with 20 mg/kg over 2 mg/kg) Study population: nonambulatory Type 2/3 SMA Primary efficacy endpoint: HFMSE Age 2-12 main efficacy population 12-month treatment duration 20 mg/kg apitegromab dose Also evaluating 10 mg/kg arm (to
explore potential that dose between 2 and 20 mg/kg may be comparable to 20 mg/kg) TOPAZ Learnings SAPPHIRE Design Elements HFMSE=Hammersmith Functional Motor Scale Expanded
Ongoing SAPPHIRE Phase 3 Trial Overview 24 Randomized, double-blind,
placebo-controlled, parallel arm design (n=204) Enrolling patients who are on SMN-directed therapy (nusinersen or risdiplam) Anticipate completing enrollment in 3Q 2023 TREATMENT (52 weeks) Apitegromab (20 mg/kg IV q4w) + SMN-directed
therapy Apitegromab (10 mg/kg IV q4w) + SMN-directed therapy Placebo (IV q4w) + SMN-directed therapy SCREENING MAIN POPULATION (n=156) Ages 2-12 With nonambulatory Types 2 and 3 SMA N=52 N=52 N=52 R Stratified to ensure balanced
allocation across the three arms: Age at SMN therapy initiation(age < 5 vs age ≥ 5) SMN therapy (nusinersen vs. risdiplam) ENDPOINTS Primary Efficacy: Mean HFMSE change from baseline at 12 months Additional Efficacy
Measures: RULM, WHO, other outcome measures Safety, PK/PD, ADA Additional Data Opportunities Exploratory population (age 13-21), in patients using SMN therapy Focused upon safety & exploratory efficacy (n=48; 2:1 randomization
between apitegromab 20 mg/kg vs placebo) Separate open-label extension study (after patients complete 12-month treatment period) Focused upon safety & exploratory long-term efficacy ClinicalTrials.gov Identifier:
NCT05156320 HFMSE=Hammersmith Functional Motor Scale Expanded; RULM=Revised Upper Limb Module; R=randomization; SMA=spinal muscular atrophy; SMN=survival motor neuron.
Executing on the Promise: Apitegromab SMA Trials 25 SMA=Spinal Muscular
Atrophy *Subject to regulatory approval WHERE WE AREPhase 3 12-Month IN PROCESS Long-term EXTENSION 3Q 2023 enrollment 2024 data 2025 launch* ANTICIPATED MILESTONES WHERE WE WERE Phase
2 12-Month COMPLETE 24-Month EXTENSION COMPLETE 36-Month EXTENSION COMPLETE WHERE WE PLAN TO GO Ambulatory patients Under 2 Years of Age (including those treated with gene therapy)
26 Potential first muscle-targeted therapy in SMA Robust body of data
supports therapeutic potential Differentiation Strong pre-clinical evidence indicates upstream targeting of structurally differentiated latent myostatin avoids undesirable off-target effects Phase 2 TOPAZ trial demonstrated the
therapeutic potential of inhibiting the latent forms of growth factors Strong Scientific Rationale TOPAZ has demonstrated sustained motor function gains to date in patients with nonambulatory Types 2 and 3 SMA Pivotal Phase 3 SAPPHIRE
trial: enrollment completion expected in Q3 2023 FDA has granted Fast Track, Orphan Drug, and Rare Pediatric Disease designations European Medicines Agency (EMA) has granted Priority Medicines (PRIME) and Orphan
designations Clear Clinical Pathway SMN therapies prevent further degeneration of motor neurons but do not directly address muscle atrophy Apitegromab is a muscle-targeted approach and has the potential to address this unmet medical
need Global SMA treatment market expected to grow in the next five years High Unmet Medical Need & Significant Commercial Opportunity ApitegromabSummary
SRK-181: Potential Transformative Backbone for a New Era ofCancer Immunotherapy
Resistance to Checkpoint Inhibitor (CPI) Therapies Remains a Significant
Clinical Challenge 28 1. Source: Gores, M. (2022). In the eye of the storm: PD-(L)1 inhibitors weathering turbulence [White paper].
IQVIA. https://www.iqvia.com/library/white-papers/in-the-eye-of-the-storm-pd-l-1-inhibitors-weathering-turbulence 2. Source: Carretero-Gonzalez et al. (2018) Oncotarget 9:8706-8715 Meta-analysis of twelve randomized trials with control
arm or adequate safety profile (includes nivolumab, pembrolizumab, and atezolizumab) Clinically derived rationale points to significant opportunity to increase checkpoint therapy responses by targeting TGFβ-1 7.9-10.41MILLION US patients
on CPI therapies First-lineCPI therapy Second-line(or later) CPI therapy DID NOT respond 63% 2 78% 2
Strong Scientific Rationale for the Role of TGFβ Inhibition in
Immuno-Oncology 29 “Bristol Myers Squibb Enters Agreement to Acquire Forbius TGF-beta Program” August 2022. “Merck to Acquire Tilos Therapeutics: Merck Gains Portfolio of Investigational Antibodies Modulating TGFβ” $773 million total
potential deal value June 2019. Selective inhibition of TGFβ-1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape Science Translational Medicine, March 25, 2020. Constance J. Martin,
et al. Vol 12, Issue 536. DOI: 10.1126/scitranslmed.aay8456 Nature (online), February 14, 2018. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Sanjeev Mariathasan1*, Shannon J. Turley1*, Dorothee
Nickles1*, Alessandra Castiglioni1, Kobe Yuen1, Yulei Wang1, Edward E. Kadel III1, Hartmut Koeppen1, Jillian L. Astarita1, Rafael Cubas1, Suchit Jhunjhunwala1, Romain Banchereau1, Yagai Yang1, Yinghui Guan1, Cecile Chalouni1, James Ziai1,
Yasin Şenbabaoğlu1, Stephen Santoro1, Daniel Sheinson1, Jeffrey Hung1, Jennifer M. Giltnane1, Andrew A. Pierce1, Kathryn Mesh1, Steve Lianoglou1, Johannes Riegler1, Richard A. D. Carano1, Pontus Eriksson2, Mattias Höglund2, Loan
Somarriba3, Daniel L. Halligan3, Michiel S. van der Heijden4, Yohann Loriot5, Jonathan E. Rosenberg6, Lawrence Fong7, Ira Mellman1, Daniel S. Chen1, Marjorie Green1, Christina Derleth1, Gregg D. Fine1, Priti S. Hegde1, Richard Bourgon1
& Thomas Powles8 Willy Hugo, Jesse M. Zaretsky, Lu Sun, Douglas B. Johnson, Antoni Ribas, Roger S. Lo Volume 165, Issue 1, 24 March 2016, Pages 35-44 Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic
Melanoma July 24, 2020: https://doi.org/10.1038/ s41571-020-0403-1 Nature Reviews , July 24, 2020 NATURE REVIEWS | CLINICAL ONCOLOGY TGFβ: biology in cancer progression and immunotherapy Rik Derynck1,2,3, Shannon J. Turley4 and Rosemary
J. Akhurst2,3
SRK-181: Unique Latent TGFβ-1 Selective Approach Designedto Overcome Checkpoint
Inhibitor Resistance 30 Traditional Target“Mature” growth factor 1. Wakefield LM, Winokur TS, Hollands RS, Christopherson K, Levinson AD, Sporn MB. Recombinant latent transforming growth factor beta 1 has a longer plasma half-life in rats
than active transforming growth factor beta 1, and a different tissue distribution. J Clin Invest. 1990 Dec;86(6):1976-84. doi: 10.1172/JCI114932. PMID: 2254455; PMCID: PMC329834. SRK-181: Latent TGFβ-1 Inhibitor Targets TGFβ-1 Potential
to overcome CPI resistance SRK-181 inhibits the TGFβ-1 implicated in check point inhibitor resistance Selective to β-1 isoform Highly selective to β-1 isoform vs. 2 and 3 Increases therapeutic window and potentially avoids toxicities
associated with non-selective TGFβ inhibition Other programs target multiple isoforms of TGFβ Context-independent Inhibits all sources of TGFβ-1 SRK-181 targets all TGFβ-1 sources (LRRC33, GARP and LTBP1 and 3) Some programs only target
one source Targets the latent form of TGFβ-1 Selectively targeting the latent form shuts off the growth factor before activation Increases opportunity to inhibit TGFβ-1 Most other programs target the mature form of TGFβ-1
SRK-181-mIgG1 + Anti-PD1 Overcomes Immune Exclusion 31 Anti-PD1/
SRK-181-mIgG1 Anti-PD1 Overcoming immune exclusion Tumor micro-environment Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med. 2020 Mar 25;12(536):eaay8456.
https://scholarrock.com/platform/publications. Data from MBT-2 syngeneic tumor model. Dose 10mg/kg QW for 4 weeks. Overcome Exclusion SRK-181-mIgG1 combination therapy led to influx and amplification of cytotoxic CD8+ cells in preclinical
bladder tumor model Immune Exclusion
DRAGON Phase 1 POC Trial to Evaluate SRK-181’s Ability to Overcome Primary
Resistance to Checkpoint Inhibitors 32 * A cohort of 2000 mg Q2W (n=3) was also evaluated. **The clear cell RCC and HNSCC cohorts will also explore the effects of SRK-181 in patients with relapsed response after anti-PD-1 treatment. 1.
NCT04291079 on www.clinicaltrials.gov. PART B SRK-181 + pembrolizumab; non-responders to prior anti-PD-1 SRK-181 + pembrolizumab Non-small cell lung cancer SRK-181 + pembrolizumab Urothelial carcinoma SRK-181 +
pembrolizumab Cutaneous melanoma SRK-181 + pembrolizumab Clear cell renal cell carcinoma** SRK-181 + pembrolizumab Head and neck squamous cell** carcinoma COHORT TREATMENT PART A SRK-181 80 mg (n=1) SRK-181 240 mg (n=1) SRK-181
800 mg (n=3) SRK-181 1600 mg (n=3) SRK-181 2400 mg (n=3) SRK-181 3000 mg (n=3)* SRK-181 all-comers A1 A2 SRK-181+anti-PD-(L)1; non-responders to prior anti-PD-(L)1 SRK-181 240 mg (n=3) SRK-181 800 mg (n=3) SRK-181 1600 mg
(n=3) SRK-181 2400 mg (n=3)
DRAGON Part A: Safety PART A1 Monotherapy Treatment-Emergent AEs Related to
SRK-181, All Grades >10% PART A2 Combination Treatment Treatment-Emergent AEs Related to SRK-181 or Anti-PD(L)1, All Grades >10% Dose
(MG) 80N=1 240N=1 800N=3 1600N=4 2400N=3 3000N=3 2000N=4 AllN=19 Fatigue 0 1 0 0 1 0 1 3 (15.8%) Decreased Appetite 1 0 1 0 0 0 0 2 (10.5%) Nausea 1 0 0 0 0 0 1 2 (10.5%) Dose (MG) 240N=3 800
N=3 1600N=6 2400N=3 AllN=15 Rash maculo-papular 1 1 1 2 5 (33.3%) Pruritus 1 1 1 1 4 (26.7%) Rash 0 1 0 2 3 (20.0%) Diarrhea 0 0 2 0 2 (13.3%) Pemphigoid 0 0 0 2 2 (13.3%) All dose levels were administered
q3w except 2000 mg, which was administered q2w. Treatment-related Grade 3 AEs: Alanine aminotransferase increased (1 patient) Treatment-related SAEs: None No DLTs were observed up to 3000 mg q3w and 2000 mg q2w No Grade 4 or 5
treatment-related AEs occurred Treatment-related Grade 3 AEs: Pruritus (2 patients), blister, immune-mediated lung disease, pemphigoid, rash, rash maculo-popular and rash vesicular (1 patient each) Treatment-related SAEs: Blister,
pruritus, and rash (all in 1 patient) and immune-mediated lung disease (1 patient) No DLTs were observed up to 2400 mg q3w No Grade 4 or 5 treatment-related AEs occurred Yap T et al. Safety and Efficacy Results of SRK-181, a latent TGFβ1
inhibitor, from a Phase 1 trial (DRAGON Trial); Presented at ESMO-TAT; March 7, 2023. *Clinical cutoff date: December 2, 2022. Response is assessed using RECIST v1.1 by PI; the scan is performed during screening, 6 weeks after first dose,
every 9 weeks for the next 6 months of treatment, and every 12 weeks thereafter. SRK-181 is an investigational drug candidate that is being evaluated for the treatment of cancer. SRK-181 has not been approved by the US FDA or any other health
authority, and its safety and efficacy have not been established. 33
Duration of Treatment DRAGON Part A: Preliminary Efficacy Data* 34 Part A1
(n=19) Part A2 (n=15) 8 patients had a best response of stable disease (SD) All 3 patients with ovarian cancer were stable for 6-10 months Yap T et al. Safety and Efficacy Results of SRK-181, a latent TGFβ1 inhibitor, from a Phase 1
trial (DRAGON Trial); Presented at ESMO-TAT; March 7, 2023. *Clinical cutoff date: December 2, 2022. Response is assessed using RECIST v1.1 by PI; the scan is performed during screening, 6 weeks after first dose, every 9 weeks for the next 6
months of treatment, and every 12 weeks thereafter. SRK-181 is an investigational drug candidate that is being evaluated for the treatment of cancer. SRK-181 has not been approved by the US FDA or any other health authority, and its safety
and efficacy have not been established. At 800 mg q3w, 1 partial response (PR) was observed in patient with anti-PD-1-resistant clear cell renal cell carcinoma (ccRCC) 9 patients had best response of SD 6 patients (green highlight) were
stable beyond the 16-week cutoff 1 ongoing patient with head and neck cancer had a 29.4% tumor reduction
Preliminary Efficacy Data in Combination with Pembrolizumab: Best Response in
Target Lesions 35 Best Response in Target Lesions Best Response of PR Best Response of SD Best Response of PD Ongoing Percent Change from Baseline 800 mg q3w 800 mg q3w 1600 mg q3w 1600 mg q3w 1600 mg q3w 1600 mg q3w 2400 mg
q3w 2400 mg q3w 2400 mg q3w 240 mg q3w 240 mg q3w 800 mg q3w Head and Neck Head and Neck Head and Neck Uveal Melanoma NSCLC Melanoma Melanoma Liver RCC RCC TNBC Squamous Cell Skin Carcinoma Part A2 Yap T et al. Safety and
Efficacy Results of SRK-181, a latent TGFβ1 inhibitor, from a Phase 1 trial (DRAGON Trial); Presented at ESMO-TAT; March 7, 2023. *Clinical cutoff date: December 2, 2022. Response is assessed using RECIST v1.1 by PI; the scan is performed
during screening, 6 weeks after first dose, every 9 weeks for the next 6 months of treatment, and every 12 weeks thereafter. SRK-181 is an investigational drug candidate that is being evaluated for the treatment of cancer. SRK-181 has not
been approved by the US FDA or any other health authority, and its safety and efficacy have not been established. Part B (as of 12/2/22) 20 patients dosed across multiple cohorts Two confirmed PRs ongoing patients with anti-PD-1 resistant
clear cell renal cell carcinoma All dose levels were generally well tolerated SRK-181 dose of 1500 mg q3w or 1000 mg q2w in combination with anti‑PD-(L)1 for Part B
36 Summary of ccRCC Patients on Combination Treatment (Part A2 and Part
B) 11 ccRCC patients enrolled n=2 in Part A2 (all discontinued from study) and n=9 in Part B (5 pts remain on study) enrollment in Part B continues 3 confirmed PRs observed in ccRCC patients Patients are anti-PD-1 resistant patient (no
response on prior anti-PD-1 therapy and disease progress on the most recent prior anti-PD-1 therapy) ORR: 27% (3/11) Yap T et al. Safety and Efficacy Results of SRK-181, a latent TGFβ1 inhibitor, from a Phase 1 trial (DRAGON Trial);
Presented at ESMO-TAT; March 7, 2023. *Clinical cutoff date: December 2, 2022. Response is assessed by investiogator using RECIST v1.1 by PI; the scan is performed during screening, 6 weeks after first dose, every 9 weeks for the next 6
months of treatment, and every 12 weeks thereafter. SRK-181 is an investigational drug candidate that is being evaluated for the treatment of cancer. SRK-181 has not been approved by the US FDA or any other health authority, and its safety
and efficacy have not been established. As of clinical cutoff date of Dec 2, 2022
Summary of ccRCC Patients with PR in Dragon (Part A2 and Part B,
Combination Treatment) Responded Pts SRK-181 Dose (mg, Q3W) Age (Year)/ Gender Lines of Prior Therapy IMDC Score at Screening Metastatic Sites at Screening Pt Status Duration of Treatment (wks) Best % Change in SOD*
from Baseline Pt #1 Part A2, 800 56/M Sunitinib Nivolumab/Ipilimumab Cabozantinib Lenvatinib/Everolimus Pembrolizumab/Axitinib 3 (Poor risk) Lung/ Lymph Nodes/ Pleural/ Pancreas/ Bone Off study 30 -57% Pt #2 Part B,
1500 58/M Nivolumab/Ipilimumab Cabozantinib 3 (Poor risk) Lung/ Lymph Nodes/Liver Ongoing 32+ (by Dec 2, 2022) -67% Pt #3 Part B, 1500 63/M Nivolumab/Ipilimumab Nivolumab Cabozantinib 2 (Intermediate risk) Lung/ Lymph
Nodes Ongoing 16+ (by Dec 2, 2022) -50% Pt#2: Screening Common hepatic lymph node 4.0 × 3.0 (cm) Pt#2: C7D8 Common hepatic lymph node 3.2 × 1.7 (cm) Pt#1: Screening Liver nodule segment II 1.7 × 1.4 (cm) Pt#1: C8D1 Liver
nodule segment II 0.0 × 0.0 (cm) Yap T et al. Safety and Efficacy Results of SRK-181, a latent TGFβ1 inhibitor, from a Phase 1 trial (DRAGON Trial); Presented at ESMO-TAT; March 7, 2023. *Clinical cutoff date: December 2, 2022. Response is
assessed using RECIST v1.1 by PI; the scan is performed during screening, 6 weeks after first dose, every 9 weeks for the next 6 months of treatment, and every 12 weeks thereafter. *SOD: sum of diameters in target lesions. SRK-181 is an
investigational drug candidate that is being evaluated for the treatment of cancer. SRK-181 has not been approved by the US FDA or any other health authority, and its safety and efficacy have not been established. 37
SRK-181: Encouraging Early Clinical Data Consistent with Hypothesis 38 TGFβ
pathway evaluation (PD) Target engagement (blood) TGFβ-1 signaling (tumor p-SMAD2 & RNAseq) Immunophenotyping, including immune exclusion status Tumor immune contexture (e.g., tumor CD8+ T cells) Immune cell contexture (tumor &
blood MDSCs) Immune response markers (e.g., IO gene signature) Therapeutically relevant dose Drug exposure needed for efficacy Objective response Anti-tumor response and survival benefits TGFβ pathway evaluation (PD) Target engagement
(blood) TGFβ-1 signaling (tumor p-SMAD2 & RNAseq) Immunophenotyping, including immune exclusion status Tumor immune contexture (e.g., tumor CD8+ T cells) Immune cell contexture (tumor & blood MDSC’s) Immune response markers
(e.g., IO gene signature) Therapeutically relevant dose Dosing regimens achieved target steady state levels Objective response Anti-tumor response observed (partial responses) Preclinical Data Phase 1 DRAGON proof-of-concept trial
39 *(PD-1/PD-L1) First in class monoclonal antibody targeting latent and
context-independent binding to TGFβ1 Differentiated from other TGFβ inhibitors by its novel selectivity Offers potential to avoid toxicity and dose-limiting challenges of non-selective TGFβ inhibition approaches Differentiation Emerging
evidence implicates TGFβ1 as driving resistance to checkpoint inhibitor therapies Potent and selective inhibitor of latent TGFβ1 activation in preclinical studies Strong safety and preclinical efficacy
data Strong Scientific Rationale DRAGON Part A demonstrated ability to escalate to high doses of SRK-181 at levels exceeding the anticipated efficacious drug exposure level Advanced to DRAGON Part B: Evaluating SRK-181 in 5 parallel
tumor-specific cohorts, with efficient path towards early POC for each Early efficacy signals have been observed Clear Clinical Pathway PD-(L)1* becoming a standard of care therapy in many tumor types; the market for synergistic
combination product would be vast SRK-181 could potentially be used in many tumor types, potentially both in patients resistant to PD-(L)1 and in CPI naïve patients, as well as other therapeutic applications High Unmet Medical Need &
Large Commercial Opportunity SRK-181Summary
Next Horizon: Fibrosis
TGFβ is Established as Key Driver of Fibrosis Across Multiple Diseases
41 Nature Reviews , April 25, 2016 NATURE REVIEWS | NEPHROLOGY TGF-β: the master regulator of fibrosis Xiao-ming Meng1, David J. Nikolic-Paterson2 and Hui Yao Lan3 Nature Reviews. August 19, 2014 NATURE REVIEWS |
RHEUMATOLOGY Transforming growth factor β―at the centre of systemic sclerosis Robert Lafyatis Int. J. Mol. Sci. August 27, 2018 Targeting TGF-β Signaling in Kidney Fibrosis Yoshitaka Isaka J. Am. Soc. Nephrol. December 3,
2017 Targeting Anti-TGF-β Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach Steve McGaraughty,* Rachel A. Davis-Taber,† Chang Z. Zhu,* Todd B. Cole,* Arthur L. Nikkel,* Meha Chhaya,† Kelly J. Doyle,* Lauren M. Olson,*
Gregory M. Preston,† Chrisine M. Grinnell,† Katherine M. Salte,* Anthony M. Giamis,* Yanping Luo,* Victor Sun,† Andrew D. Goodearl,† Murali Gopalakrishnan,* and Susan E. Lacy† J Pathol, July 25, 2021 TGF-β as a driver of fibrosis:
physiological roles and therapeutic opportunities Erine H Budi1, Johanna R Schaub1, Martin Decaris1, Scott Turner1, Rik Derynck2 J Receptors Sign Trans, Feb 13, 2020 Inevitable role of TGF-β in progression of nonalcoholic fatty liver
disease Bhagyalakshmi Nair and Lekshmi R. Nath PNAS, February 24, 1986 Transforming growth factor type β: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro ANITA B. ROBERTS* MICHAEL B.
SPORN*, RICHARD K. ASSOIAN*, JOSEPH M. SMITH*, NANETTE S. ROCHE*, LALAGE M. WAKEFIELD*, URSULA I. HEINE*, LANCE A. LIOTTA*, VINCENT FALANGA†, JOHN H. KEHRL‡, AND ANTHONY S. FAUCI‡ Proc Am Thorac Soc, July 3, 2006 Transforming Growth Factor
β A Central Modulator of Pulmonary and Airway Inflammation and Fibrosis Dean Sheppard
GARP Presents TGFβ on Tregs LRRC33 Presents TGFβ on Macrophages LTBP1 & 3
Present TGFβ in Connective Tissue Targeting Presenting Molecule/TGFβ-1 Complexes Provides Context Specificity Targeting Latent TGFβ-1 Complexes Creates Multiple “Handles” For Selectivity 42 Latent TGF-β GARP Treg Integrin expressing
cell avb8 Integrin Latent TGF-β LRRC33 Macrophage Integrin expressing cell avb8 Integrin Latent TGF-β binding protein (LTBP) Extracellular matrix Fibrillin Latent TGF-β Epithelial Cell avb6 Integrin Latent TGFβ-1
LTBP-49247 Reduced TGFβ Signaling and Fibrosis in Preclinical Models of Kidney
Fibrosis 43 LTBP-49247 reduced a TGFβ PD biomarker in kidneys of Col4a3 KO mice (Alport Syndrome model) LTBP-49247 reduced fibrosis in kidneys of Alport model ** p < 0.01 One way ANOVA vs. IgG HYP=hydroxyproline Efficacy also seen
in rat model of kidney fibrosis No observed toxicity in mouse 13-week non-GLP repeat dose study Favorable PK in cynomolgus monkeys (t1/2 ~28 days) suggests LTBP-49247 is amenable to clinical subcutaneous dosing with promising
developability profile
Significant Opportunities to Address High Unmet Need Across Multiple Fibrotic
Indications 44 Alport Syndrome (AS) Focal Segmental Glomerulosclerosis (FSGS) IgA Nephropathy (IgAN) Primary Sclerosing Cholangitis (PSC) Diffuse Cutaneous Systemic Sclerosis (dcSSc) Idiopathic Pulmonary Fibrosis (IPF) Collectively,
significant commercial potential given large patient population with clear high unmet need given poor outcomes and lack of effective therapeutics Significant impact to delay or stop progression to end-stage disease and organ transplant
Expansion opportunities via other indications given shared etiologies
Next Horizon: Iron-Restricted Anemia
BMP6/RGMc Pathway is a Well Validated Regulator of Systemic Iron Homeostasis
46 Fig: Muckenthaler, M.U., Rivella, S., Hentze, M.W. and Galy, B. (2017) A Red Carpet for Iron Metaboism. Cell, 168(3): 344-361 1: Kuns-Hashimoto R, et al. (2008) Selective binding of RGMc/hemojuvelin, a key protein in systemic iron
metabolism, to BMP-2 and neogenin. Am J Physiol Cell Physiol 294(4):C994-C1003 2: Constante M, et al.. (2007) Repression of repulsive guidance molecule C during inflammation is independent of Hfe and involves tumor necrosis factor-alpha. Am
J Pathol 170(2):497-504 3: Core A.B., et al. (2014) Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front Pharmacol. 5:104. 4. Wang CY and Babitt JL. (2016) Hepcidin Regulation in the Anemia of Inflammation.
Curr Opin Hematol 23(3): 189-197. Elevation of proinflammatory cytokines drives increased hepcidin expression and results in anemia due to functional iron deficiency4 Anemia of Inflammation/ Chronic Disease Hepcidin Serum
iron Untreated Hepcidin Serum iron Ab treated Human mutations in HJV/RGMc establish it as a central player in hepcidin regulation1 Knockout phenotypes and tissue-specific expression pattern demonstrate that its predominant role is in
iron homeostasis2 Member of repulsive guidance molecule (RGM) family (RGMa, RGMb, RGMc/HJV) that act as BMP co-receptors to modulate BMP signaling3 HJV/RGMc is a key player in the regulation of hepcidin expression
HJV-35202: An Investigational High-Affinity Antibody Demonstrating Selective
Inhibition of HJV/RGMc and Robust PK/PD in Cynos 47 Potent in vitro binding affinity (KD=3.9E-11) Highly specific to RGMc/HJV with well understood mechanism Sustained PD effect in single dose Cyno study Specific to RGMc over other RGM
family members Nicholls S.B., et al. Poster: RGMc-selective antibodies modulate iron homeostasis in vivo, 12th International BMP Conference, Tokyo, October 2018 Scholar Rock, Data on File High-affinity antibody Specific to RGMc, with
mechanism of specificity understood Cross-reactive to human, mouse, rat and cyno Sustained PD observed in healthy rats and cynos, with clear PK/PD relationship Highly manufacturable framework with no sequence liabilities Formulatable into
a subcutaneous format (150 mg/mL) HJV-35202 (mg/mL) Serum Iron and UIBC (mg/dL) PK: HJV-35202 (10mg/kg, IV) PD: UIBC: HJV-35202 (10mg/kg, IV) PDF: Serum Iron: HJV-35202 (10mg/kg, IV) Octet Response
Units RGMa RGMb RGMc/HJV RGMa RGMb RGMc/HJV Key Attributes of HJV-35202:1,2
Significant Opportunities to Target Iron-Restricted Anemias Across Multiple
Indications 48 Chronic Kidney Disease (CKD) Anemia of Chronic Inflammation (AI) Myelofibrosis (MF) Targeting RGMc/HJV for anemia is well validated and relatively de-risked High levels of hepcidin, the main regulator of systemic iron
metabolism, are associated with anemia across various diseases Safe and convenient RGMc inhibitor has promise of improving patient outcomes across multiple indications as stand alone or in combination with SoC Significant and clear unmet
need given lack of approved treatments or severe limitations of current treatments Well defined patient population Collectively, sizeable commercial opportunity given relatively large population Potential for rapid POC with clear
regulatory path Opportunity to build an anemia franchise with initial POC and indication expansion in the future
Scholar Rock Summary
50 Key Investment Highlights Revolutionary Platform Overcome the
Challenges targeting the latent forms of growth factors Discover and Develop monoclonal antibodies with extraordinary selectivity Positioned For Success Upcoming Data Readouts for both clinical programs $205M financing in June
2022 Cash balance of $275M as of March 31, 2023; anticipated runway into 2025 Robust Clinical Pipeline SRK-181 (Phase 1) Potential to shift current treatment landscape for cancer patients with CPI resistance Apitegromab (Phase
3) Potential first-in-class Significant market opportunity Program on track Clear path to approval Discovery-stage Pipeline Fibrosis and iron-restricted anemia Strategic optionality
Appendix
TOPAZ Baseline Characteristics1,2 52 *Patients on average received ~2 years of
nusinersen treatment at baseline and ~3 years of nusinersen treatment by the end of the TOPAZ study (12-months). SMN2 copy numbers were not available for all patients. †12-month baseline characteristics recorded in the table, 1-cohort 1
patient and 1- cohort 2 patient discontinued during 24M Extension Period A. All discontinuations were for reasons unrelated to study drug. HFMSE, Hammersmith Functional Motor Scale–Expanded; max, maximum; min, minimum; RHS, Revised
Hammersmith Scale; SMN, survival motor neuron. 1. Crawford T, et al. Neuromuscul Disord. 2022;32(Suppl1):S86-S87. P102. 2. Crawford T, et al. TOPAZ Extension: 24-month Efficacy and Safety of Apitegromab in Patients With Later-onset Spinal
Muscular Atrophy (Type 2 and Type 3 SMA). Presented at CureSMA Annual Conference; June 16-19, 2022. N (dosed) Mean age (min, max) Mean RHS (min, max) Mean HFMSE (min, max) Prior Nusinersen, Months Mean (min, max)* No. of patients
with 2,3, or 4 SMN2 copies Discontinuation(s) Ambulatory COHORT 1: Age 5-21 20 mg/kg monotherapy 11 12 (7, 19) 48 (26, 63) N/A 1, 4, 4 0 20 mg/kg + nusinersen 12 13 (7, 21) 51 (43, 62) 20 (12, 28) 0, 9,
1 1† Pooled 23 13 (7, 21) 50 (26, 63) N/A 1, 13, 5 1† Nonambulatory COHORT 2: Age 5-21 20 mg/kg + nusinersen 15 12 (8, 19) 23 (13, 39) 25 (12, 39) 0, 11, 2 0 COHORT 3: Age 2+ 20 mg/kg + nusinersen 10 4 (2,
6) 24 (14, 42) 24 (10, 34) 1, 8, 0 0 2 mg/kg + nusinersen 10 4 (2, 6) 26 (12, 44) 1, 8, 1 0 Pooled 20 4 (2, 6) 25 (12, 44) 2, 16, 1 0
TOPAZ Patient Disposition Over 36 Months a. Patients stratified based on
previous treatment with approved SMN therapy. b. Patients randomized to receive 2 or 20 mg/kg apitegromab. *Includes patients who crossed over from 2 mg/kg to 20mg/kg starting week 68 through week 104 ** Excludes patients on
monotherapy SMN Rx=SMN therapy. SMN Rx ≥ 5 ENROLLMENT n=58 YEAR 1: Thx Period n=57 YEARS 2-4: ExtensionN=50 ONYX Study NONAMBULATORY N=20 Ages ≥ 2 Type 2 SMA n=20 Apitegromab 20 mg + nusinersen* SMN
Therapy Yes No n=10 n=10 Apitegromab 2 mg + nusinersen Apitegromab 20 mg + nusinersen NONAMBULATORY N=15 Ages 5-21 Type 2 or Type 3 SMA n=15 Apitegromab 20 mg + nusinersen n=15 Apitegromab 20 mg + nusinersen 1 withdrew consent
(COVID concern) 57 ENROLLED 7 discontinued 2 due to concerns with COVID-19 5 on monotherapy due to lack of benefit >90% of patients on combination therapy remained in study** TOPAZ patient retention PRIMARY
TREATMENT: EXTENSION: 58 ENROLLED 57 completed primary treatment period and enrolled in the extension study 1 withdrew consent due to fatigue & weight gain SMN Therapy AMBULATORY N=23 Ages 5-21 Type 3 SMA 1 withdrew consent
(fatigue /weight gain) 1 withdrew consent (COVID concern) Yes No n=11 n=12 Apitegromab 20 mg monotherapy Apitegromab 20 mg + nusinersen n=11 n=11 Apitegromab 20 mg monotherapy Apitegromab 20 mg + nusinersen 4 withdrew consent
(lack of benefit) 1 withdrew consent (lack of benefit) 53 SMN Rx < 5
Time (weeks) No. of observations Year 3 Year 2 Year 1 Year 3 Year 2 Year
1 PROMIS Fatigue (Proxy) Year 2 Year 3 Year 1 Year 2 Year 3 Year 1 Pooled Nonambulatory Patients | Age 2 – 12 | All Doses | Over 36 MonthsImprovements in PRO Measures Consistent With Motor Function 54 Time (weeks) No. of
observations IMPROVEMENT PEDI-CAT Daily Activities IMPROVEMENT IMPROVEMENT N = 29.; Baseline mean age=5.5 |Time on SMN Rx=24.6m HFMSE 29 29 29 23 24 26 26 26 26 23 22 23 22 Change from baseline
(±SE) 25 23 24 16 18 20 20 18 23 19 14 15 13 IMPROVEMENT RULM 28 28 28 22 23 26 25 26 26 25 22 22 22 Change from baseline (±SE) 21 19 18 15 15 18 12 17 16 16 13 12 11 HFMSE=Hammersmith Functional
Motor Scale Expanded; OC=observed case; PEDI-CAT=Pediatric Evaluation of Disability Inventory Computer Adaptive Test; PROMIS=Patient Reported Outcome Measurement Information System; RULM=Revised upper limb module; SE=standard error of the
mean. SMN Rx=SMN therapy. Data on File. Scholar Rock, Inc. Cambridge, MA. Data cutoff date as of March 13, 2023. Error bars represent standard error (SE). Data cutoff date as of March 13, 2023. The updated PEDI-CAT analysis included
additional records (2 at 12 months and 1 at 24 months) that were not available at the time of previous analysis. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has
not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established.
PEDI-CAT Daily Activities Over 36 Months Improvements Were Substantial and
Sustained 55 For the 36-month evaluation, an observed case analysis was conducted, which pooled all the nonambulatory patients (Cohorts 2 and 3) and was based upon the available data for given timepoints. This analysis population included
patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). Error bars represent SE. CI represents confidence interval. SMN Rx=SMN
therapy. Data cutoff date as of March 13, 2023. The updated analysis included additional records (2 at 12 months and 1 at 24 months) that were not available at the time of previous analysis. Apitegromab is an investigational drug candidate
being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. Baseline mean age=7.3 | Time on
SMN Rx=24.1m Baseline mean age=5.5 | Time on SMN Rx=24.6m n= 35 21 25 23 17 95% CI= (-0.0, 2.6) (-0.1, 2.6) (0.9, 3.5) (-0.1, 4.5) Mean Change from Baseline (+SE) n= 29 16 20 19 15 95%
CI= (-0.1, 2.0) (-0.5, 2.1) (0.5, 3.2) (-0.8, 4.2) Pooled Nonambulatory Patients Age 2-21 YearsAll Doses (N=35) Age 2-12 YearsAll Doses (N=29)
PEDI-CAT Daily Activities Over 36 Months Improvements Were Substantial and
Sustained 56 For the 36-month evaluation, an observed case analysis was conducted, which pooled all the nonambulatory patients (Cohorts 2 and 3) and was based upon the available data for given timepoints. This analysis population included
patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). Error bars represent SE. CI represents confidence interval. SMN Rx=SMN
therapy. Data cutoff date as of March 13, 2023. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health
authority, and its safety and efficacy have not been established. Baseline mean age=7.3 | Time on SMN Rx=24.1m Baseline mean age=5.5 | Time on SMN Rx=24.6m n= 35 21 25 23 17 95%
CI= (-0.0, 2.6) (-0.1, 2.6) (0.9, 3.5) (-0.1, 4.5) Mean Change from Baseline (+SE) n= 29 16 20 19 15 95% CI= (-0.1, 2.0) (-0.5, 2.1) (0.5, 3.2) (-0.8, 4.2) Pooled Nonambulatory Patients Age 2-21 YearsAll Doses (N=35) Age
2-12 YearsAll Doses (N=29)
PROMIS Fatigue (Proxy) Over 36 Months Improvements Were Substantial and
Sustained 57 For the 36-month evaluation, an observed case analysis was conducted, which pooled all the nonambulatory patients (Cohorts 2 and 3) and was based upon the available data for given timepoints. This analysis population included
patients receiving either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab (inclusive of patients in Cohort 3 who switched from 2 mg/kg to 20 mg/kg in Year 2). Error bars represent SE. CI represents confidence interval. SMN Rx=SMN
therapy. Data cutoff date as of March 13, 2023. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health
authority, and its safety and efficacy have not been established. Mean Change from Baseline (+SE) Pooled Nonambulatory Patients n= 35 19 17 20 14 95%
CI= (-4.3, 1.4) (-5.7, 0.8) (-6.0, -0.3) (-8.7, -0.5) n= 29 15 13 17 12 95% CI= (-3.7. 2.8) (-6.0, 0.2) (-6.0. 0.1) (-8.9, 0.4) Baseline mean age=7.3 | Time on SMN Rx=24.1m Baseline mean age=5.5 | Time on SMN Rx=24.6m Age
2-21 YearsAll Doses (N=35) Age 2-12 YearsAll Doses (N=29)
TOPAZ Topline 12-Month Data Showed Apitegromab’s Transformative Potential in
Patients with Type 2/3 SMA 58 Crawford T et al. TOPAZ topline results; Presented at CureSMA, 2021 Virtual SMA Research & Clinical Care Meeting; June 9-11, 2021 * Pooled cohorts of nonambulatory patients treated with apitegromab 20
mg/kg and 2 mg/kg **Nonambulatory patients who initiated background nusinersen at a young age of <5 years and treated with apitegromab 20 mg/kg dose. Apitegromab is an investigational drug candidate being evaluated for the treatment of
spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. HFMSE change from baseline Majority of nonambulatory patients*
experienced HFMSE increases from apitegromabduring chronic maintenance phase of SMN therapy Apitegromab led to HFMSE improvements in both nonambulatory cohortsincluding patients started on nusinersen at age ≥ 5 Initiated background
nusinersen Age < 5** Age ≥ 5 Mean HFMSE Increase +7.1 points +0.6 points ≥ 1-point Increase % (n/N) 88% (7/8) 64% (9/14) ≥ 3-point Increase% (n/N) 63% (5/8) 29% (4/14)
TOPAZ Age 2-12 Analysis* in Pooled Nonambulatory Cohorts (20mg/kg) at 12 Months
Mean Increase of Motor Function Outcomes by HFMSE was Significant 59 Mean HFMSE Increase OF 4.4 POINTS with majority experiencing ≥ 3-point increases on top of background SMN therapy HFMSE Gains Also Notable in subset of individuals in
this analysis who had started background nusinersen at age ≥ 5: 75% (6/8) with ≥ 1-point increase 50% (4/8) with ≥ 3-point increase Nonambulatory Types 2/3 SMA (Apitegromab 20 mg/kg; Intent-to-Treat Population) Age 2-12
years (n=16†) Mean HFMSE change from baseline, (95% CI) +4.4 (1.3, 7.4) Patients with ≥ 1-pt increase in HFMSE, n (%) 13 (81%) Patients with ≥ 3-pt increase in HFMSE, n (%) 9 (56%) TOPAZ results showed HFMSE improvement from baseline
or RHS stabilization across all three pre-specified cohorts.1 No safety signals for apitegromab were identified through month 12 of TOPAZ; the five most frequently reported treatment-emergent adverse events were headache, pyrexia, upper
respiratory tract infection, cough, and nasopharyngitis *Exploratory, post hoc analysis. †For 12-month endpoint, if participants skipped three consecutive doses due to site restrictions caused by COVID-19, records after dose skipping were
excluded from analysis. The last observation carried forward was used for other missing data. 1. Crawford T et al. TOPAZ topline results. Presented at Muscular Dystrophy Association, 2023 Clinical & Scientific Conference, March 22, 2023.
CI, confidence interval; HFMSE, Hammersmith functional motor scale expanded; SMA, spinal muscular atrophy. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been
approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established.
TOPAZ 12-Month Data | Nonambulatory Type 2 High Dose CohortInitiated nusinersen
age <51,2 60 Increases in HFMSE observed in patients already treated with chronic maintenance nusinersen Improved: 88% (7/8) ≥ 5-point increase: 63% (5/8) > 10-point increase: 38% (3/8) Continuous and durableimprovements observed
through12-months of treatment Apitegromab (20 mg/kg) + nusinersen n=8* Mean change from baseline in HFMSE (95% CI) +7.1 (1.8, 12.5) # (%) patients achieving: ≥ 1-pt increase in HFMSE 7/8 (88%) ≥ 3-pt increase in HFMSE 5/8 (63%) ≥
5-pt increase in HFMSE 5/8 (63%) Baseline characteristics: mean (min, max) n=10 Age 3.8 (2, 6) HFMSE score 23.5 (14, 42) # of nusinersen maintenance doses 5.4 (3, 8) *This was a primary intent-to-treat (ITT) analysis that, as
prespecified, excluded 2 patients who missed 3 doses due to COVID-19 related site access restrictions. An all-patients sensitivity analysis that included those 2 patients had similar results as this primary ITT analysis. Crawford T et al.
TOPAZ topline results; Presented at CureSMA, 2021 Virtual SMA Research & Clinical Care Meeting; June 9-11, 2021. 2. Data on file; Scholar Rock. 2022. Apitegromab is an investigational drug candidate being evaluated for the treatment of
spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established.
TOPAZ 12-Month Data | Nonambulatory Type 2/3 CohortInitiated nusinersen age
≥51,2 61 Majority of patients improved in HFMSE (despite initiating background nusinersen age ≥ 5) ≥ 1-point increase: ~67% ≥ 3-point increase: ~30% Durability of effect observed through 12-months of treatment *Intent-to-treat analysis
excluded 1 patient (per prespecified approach) who missed 3 doses due to COVID-19 related site access restrictions; 1 patient who had inadvertently been enrolled who was receiving (and continued to receive) an acetylcholinesterase inhibitor
was removed, which is not permitted per the trial protocol; 1. Crawford T et al. TOPAZ topline results; Presented at CureSMA, 2021 Virtual SMA Research & Clinical Care Meeting; June 9-11, 2021. 2. Data on file. Scholar Rock,
Inc. Apitegromab is an investigational drug candidate being evaluated for the treatment of spinal muscular atrophy. Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have
not been established. Apitegromab (20 mg/kg) + nusinersen Per Protocol Population* (n=13) Intent-to-Treat Population (n=14) Mean change from baseline in HFMSE (95% CI) +1.2 (-0.5, 2.9) +0.6 (-1.4, 2.7) # (%) patients
achieving: ≥ 1-pt increase in HFMSE 9/13 (69%) 9/14 (64%) ≥ 3-pt increase in HFMSE 4/13 (31%) 4/14 (29%) ≥ 5-pt increase in HFMSE 2/13 (15%) 2/14 (14%) Baseline characteristics: mean (min, max) n=15 Age 11.7 (8, 19) HFMSE
score 22.7 (13, 39) # of nusinersen maintenance doses 5.1 (2, 9)
TOPAZ 12-Month HFMSE Changes and Duration of Prior Nusinersen 62 Patients
enrolled were already in the chronic maintenance phase of nusinersen Lack of clear correlation between 12-month HFMSE & duration of prior nusinersen exposure in patients aged 2 – 21 suggests motor function improvement mainly attributable
to apitegromab Post hoc analysis: Scatter plot of prior nusinersen treatment duration vs change in HFMSE from baseline; in nonambulatory Types 2 and 3 participants in TOPAZ, there was no clear relationship between duration of nusinersen
treatment and change in motor function. Patients skipped 3 or more doses due to COVID-site restrictions excluded; apitegromab is an investigational product candidate under development. HFMSE, Hammersmith Functional Motor Scale–Expanded
1. Mercuri E, et.al. Nusinersen versus sham control in later-onset spinal
muscular atrophy. N Engl J Med. 2018;378:625-635. 2. Efficacy and safety of risdiplam (RG7916) in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA) Roche/PTC Therapeutics This third-party information is provided for
background only and is not intended to convey or imply a comparison to the TOPAZ clinical trial results Nusinersen CHERISH Trial in Later-Onset SMA1 In patients with later-onset SMA who were age >5 at screening: Primary benefit of
nusinersen: stabilization of motor function Majority of patients do not experience HFMSE increases Nonambulatory Type 2/3 SMA Majority of Patients Started on SMN Therapy After Age 5 Do Not Experience Motor Function Increases 63 Risdiplam
SUNFISH Trial in Later-Onset SMA2 Low percentage of patients over the age of 5 achieved ≥3-point increase on MFM32 scale, even with risdiplam treatment HFMSE secondary endpoint showed a mean 0.58-point improvement over placebo (not
statistically significant) Change From Baseline to 15 Months in HFMSE Score Age, year 2 4 6 8 Nusinersen (N=66) Control (N=34) % of patients with > 3 change in MFM32 total at Month 12 Change in MFM32 total score 2-5
Years 6-11 Years 12-17 Years 18-25 Years Risdiplam Placebo
Significance of Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised
Upper Limb Module (RULM) 64 HFMSE Assesses the physical abilities of patients with Types 2/3 SMA ABLE TO: Touch Head Above Ear Level whilst maintaining stable trunk and head Roll From Supine to Prone over the right side without
pulling/ pushing on hands 33 Items Graded on scale 0 to 2 0 = unable 1 = performed with modification or adaptation 2 = without modification or adaptation Item scores are summed to give a total score The higher the total score, the
greater the patient’s motor function Maximum score: 66 Examples of items: One hand to head in sitting Rolls supine to prone Lying to sitting Four–point kneeling Supported standing Stepping Ascends 4 stairs with
railing RULM Evaluates Motor Performance in Upper Limbs ABLE TO: Bring Token to Cup placed vertically at shoulder height Bring Weight at Eye Level using two hands 19 Items Graded on scale 0 to 2(Except for 1 activity with a binary
score) 0 = unable 1 = able with modification 2 = able with no difficulty Evaluated upper limb tasks correspond to ability to perform everyday activities Maximum score: 37 Examples of items: Putting a coin into a cup Elevating a cup to
mouth Picking up a coin Bringing hand to shoulder Lifting up weighted objects Opening a zip lock bag Drawing a line on paper O’Hagen et al. 2007; Glanzman et al. 2011; Hammersmith Functional Motor Scale Expanded for SMA (HFMSE) Manual,
2019 Mazzone et al. 2017; Pierzchlewicz et al. 2021; Revised Upper Limb Module for SMA Manual, 2014
PEDI-CAT: Measure of activities of daily living PROMIS (Fatigue): Measure of
Patient Fatigue ESBBT (Fatigability): Measure of how fast a patient fatigues 1 2 3 PRO measurement tool4 Muscle endurance measurement tool6 4-point scale (1=unable to 4=easy) assessment of various activities, higher scores reflect
improved abilities1,2 PEDI-CAT has been validated in SMA, but alone cannot identify small changes in function across all types of SMA3 Measures mild subjective feelings of tiredness to debilitating and sustained feelings of exhaustion, with
lower scores reflecting less fatigue4,5 Has been utilized to assess fatigue and fatigability in the Cure SMA database, but has not been fully validated in SMA5 Part of a series of endurance shuttle tests that include: nine-hole peg test,
box and block test, and walk test (ESNHPT, ESBBT, and ESWT)6 Patients are asked to move blocks individually from one box to another in one minute, with higher numbers of blocks suggesting higher muscle endurance6 The endurance shuttle tests
have been validated for use in patients with SMA7 Measures pediatric abilities through 3 functional domains, daily activities, mobility, and social cognitive1 Activities of Daily Living and Fatigue: Assessed by Three Measures 65 ADL,
activities of daily living; ESBBT, endurance shuttle box and block test; ESNHPT, endurance shuttle nine-hole peg test; ESWT, endurance shuttle walk test; PEDI-CAT, pediatric evaluation of disability inventory computer adaptive test; PROMIS,
patient-reported outcomes measurement information system; PRO(s), patient-reported outcome(s); SMA, spinal muscular atrophy. 1. Cre Care. PEDI-CAT. Accessed April 26, 2022. https://www.pedicat.com/. 2. Data on file; Scholar Rock. 2022. 3.
Pasternak A, et al. Muscle Nerve. 2016;54(6):1097-1107. 4. NIH. PROMIS. Accessed April 26, 2022. https://commonfund.nih.gov/promis/index. 5. Belter L, et al. Orphanet Journal of Rare Diseases. 2020;15:217. 6. Cure SMA. Best Practices for
Physical Therapists and Clinical Evaluators in Spinal Muscular Atrophy (SMA). 2021. Available at: https://www.curesma.org/wp-content/uploads/2021/09/Clinical-Evaluators-Best-Practices-13-August-2021.pdf. 7. Bartels B, et al. Orphanet Journal
of Rare Diseases. 2020;15:75. PEDI-CAT, PROMIS, and ESBBT Used to assess: ADL Fatigue Muscle Endurance
Reported Impact of Scoliosis Surgery on Motor Abilities in SMA 66 Dunaway
Young et al. 2020 Scoliosis Surgery HFMSE Total Score 3-month post-surgery assessment 14/17 Lost >3 points on the HFMSE (mean change = - 12.1, SD = 8.9) Functionally meaningful change 13/17 Minimal HFMSE changes within ± 2 points
(mean change = - 0.7) No change or stability 0/17 Improvement > 2 points post-surgery Post-Surgery HFMSE scores Type 2/3 SMApeer-reviewed study
SRK-181: Transformative Potential as the Backbone For Next Era of Cancer
Therapy 67 CPI Combination (solid tumors) Other Combinations (solid tumors) & Hematologic Other immunotherapies Chemotherapy XRT Otherapplications Myelofibrosis Liquid tumors 1st line immunotherapy First in class monoclonal
antibody targeting latent and context-independent binding to TGFB-1 CURRENT FOCUS Primary and AcquiredCPI resistance Investigation in primary (pre-existing) CPI resistance offers path to early clinical POC for SRK-181
Regulatory T cell Tumor Associated Macrophage Cancer Associated Fibroblasts
(Stromal cells) Tumor cells SRK-181 Attributes Targets latent TGFβ-1 Inhibits activation of latent TGFβ-1 across ALL compartments Turns it off at the source Context-Independent: SRK-181 Designed to Inhibit Latent TGFβ-1 Across All
Compartments of the Tumor Microenvironment 68 Latent TGFβ-1 Key driver of tumor resistance to CPIs Present in multiple compartments of the tumor microenvironment TGFβ Latent growth factor TGFβ source
presentation LRRC33 GARP LTBPs LTBPs LRRC33: leucine-rich-repeat-containing protein family member 33 | LTBPs: latent transforming growth factor β binding proteins | GARP: glycoprotein A repetitions predominant
SRK-181 Therapeutic Hypothesis: Potential Advantages of Latent TGFβ-1
Inhibitor 69 SRK-181* Bifunctional TGFβ/CPI ALK5 Inhibitor Nonselective TGFβ antibody Selectivity for TGFβ-1: potential for wider therapeutic window and improved safety Ability to combine with any anti-PD-(L)1 Ability to
optimize dosing of each component of combination therapy Activity spatially distinct from anti-PD-(L)1 in tissue Inhibits all sources of TGFβ-1 contributing to CPI resistance (Context independent) Target latent form (Blocks TGFβ-1
activation) *SRK-181 is an investigational product candidate currently being evaluated in DRAGON phase 1 clinical trial. The efficacy and safety of SRK-181 have not been established. X X X X X X X X X X
TGFβ-1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible
to Anti-PD1 Therapy 70 Days after treatment initiation Tumor volume (mm3) Anti-PD1/ SRK-181-mIgG1(3 mg/kg QW) 4/14 Anti-PD1/ SRK-181-mIgG1(10 mg/kg QW) 8/14 Preclinical data published in Science Translational Medicine. Martin CJ, et
al. Sci Transl Med. 2020 Mar 25;12(536):eaay8456. https://scholarrock.com/platform/publications/. *SRK-181-mIgG1 is the murine version of SRK-181; responder defined as tumor size <25% endpoint volume at study end. Bladder Cancer Breast
Cancer (TGFβ-1/3 co-expressing) 0/13 Anti-PD1 (10 mg/kg BIW) 0/10 SRK-181-mIgG1* (10 mg/kg QW) Anti-PD1/ SRK-181-mIgG1(10 mg/kg QW) 5/10 Responders 0/9 Control 0/9 Anti-PD1 (10 mg/kg BIW) SRK-181-mIgG1* (10 mg/kg QW) Responders
0/12 MBT-2 and EMT6 Models
SRK-181-mIgG1 Combination Treatment Led to Melanoma Tumor Regression and
Survival Benefit 71 *P<0.01. †P<0.05 Log-rank (Mantel-Cox test) vs anti-PD1. * * † Days after treatment initiation Tumor Regression Survival Benefit Anti-PD1 + SRK-181-mlgG1 (30 mg/Kg/wk) Anti-PD1 + SRK-181-mlgG1 (3
mg/Kg/wk) Anti-PD1 + SRK-181-mlgG1 (10 mg/Kg/wk) Anti-PD1 (10 mg/Kg/2xwk) SRK-181-mlgG1 (30 mg/Kg/wk) Control Melanoma (Cloudman S91) model Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med.
2020 Mar 25;12(536):eaay8456. https://scholarrock.com/platform/publications. Days after treatment initiation Monotherapy 3/12 Anti-PD1 (10 mg/kg BIW) Tumor volume (mm3) SRK-181-mIgG1 (30 mg/kg QW) Responders 0/12 Combination
Therapy Led to tumor regression and survival benefit Anti-PD1/SRK-181-mIgG1 (30 mg/kg QW) 8/11 Days after treatment initiation Anti-PD1/SRK-181-mIgG1 (10 mg/kg QW) Tumor volume (mm3) 4/9
Selectivity of SRK-181 Offers Potential to Overcome Toxicity and Dose-limiting
Challenges of Non-selective TGFβ Pathway Approaches 72 Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med 2020 Mar 25;12(536): eaay8456. *Source: Anderton MJ, et al. Induction of heart valve
lesions by small-molecule ALK5 inhibitors. Toxicol Pathol. 2011;39: 916-924.; and Stauber AJ, et al. Nonclinical safety evaluation of a transforming growth factor β Receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. J Clin
Pract. 2014: 4:3. Microscopic Observations in Heart Valvulopathy Atrium—Mixed cell infiltrate Myocardium—Degeneration/necrosis Myocardium—Hemorrhage Myocardium—Mixed cell infiltrate, base Coronary artery—Necrosis with
inflammation Cardiomyocyte—Necrosis/inflammatory cell infiltrate CONTROL Vehicle iv, qwk x 4 LY2109761 300 mg/kg po, qd x 8 PanTGFβAb 30 mg/kg Iv, 1 dose 10 mg/kg iv, qwk x 4 30 mg/kg iv, qwk x 4 100 mg/kg iv, qwk x
4 SRK-181 Selective TGFβ-1 Toxicity: Minimal Non-selective TGFβ Toxicity: Minimal, slight and moderate Unremarkable Minimal Slight Moderate Toxicology: Repeat Dose Pilot Toxicology Study Adult female Sprague Dawley rats Cardiac
findings were exhibited in animals dosed with pan-TGFβ antibody or LY2109761 (inhibitor of ALK5, common TGFβ receptor kinase) as expected based on published data† NO CARDIOTOXICITIES (valvulopathy)were noted with SRK-181 NOAEL for
SRK-181: 100 mg/kg QW(highest dose evaluated) 4-week GLP toxicology studies RATS NOAEL for SRK-181: 200 mg/kg QW (highest dose evaluated) NON-HUMAN PRIMATES NOAEL for SRK-181: 300 mg/kg(highest dose evaluated) Not test article related
Bladder urothelial carcinoma Had & neck squamous carcinoma Kidney clear
cell carcinoma Kidney papillary cell carcinoma Liver hepatocellular carcinoma Lung adenocarcinoma Skin cutaneous melanoma Stomach adenocarcinoma Acute myeloid leukemia Adrenocortical cancer Brain lower grade glioma Breast invasive
carcinoma Cervical & endocervical cancer Cholangiocarcinoma Colon adenocarcinoma Diffuse large B-cell carcinoma Esophageal carcinoma Glioblastoma multiforme Kidney chromophobe Lung squamous cell carcinoma Mesothelioma Ovarian
serous cystadenocarcinoma Pancreatic adenocarcinoma Pheochromocytoma & paraganglioma Prostate adenocarcinoma Emerging Evidence Implicates TGFβ-1 as Driving Primary Resistance to Checkpoint Inhibitors 73 Human Tumor Analyses Reveal
TGFβ-1 as Most Likely Driver of TGFβ Signaling Pathway in Cancers †Priti H, et al. Top 10 challenges in cancer immunotherapy. Immunity. 2020 Jan 14:52(1):17-35. https://doi.org/10.1016/j.immuni.2019.12.011. *Source: National Cancer
Institute - Cancer Genome Atlas Program. NSCLC TMB Low High Substantial % of Solid Tumors Exhibit Immune Exclusion Immune Excluded Immune Phenotype Inflamed Immune Desert Tumor Type Melanoma RCC UBC TNBC Gastric CRC
MSS Pancreatic SCLC HR+BC Prostate Immune Excluded Inflamed Immune Desert Cancer Genome Atlas RNAseq Analysis of >10,000 Samples Spanning 33 Tumor Types* TGFB1 TGFB2 TGFB3 Scale % of patient samples (+) for TGF-β
isoform 100 80 60 40 20 0
Biomarker Strategies Employed in DRAGON Trial 74 Multiple tissue-based and
circulating biomarker analyses to be evaluated in DRAGON study Higher resolution histochemical characterization of tumor immune contexture (e.g. CD8+) Classification of inflamed, excluded or immune desert tumors and tumor nests Ability of
SRK-181 to overcome tumor immune exclusion Analysis of immune response markers (e.g. PD-L1) Changes to intra-tumoral and/or circulating immune cell contexture (MDSC) Show evidence of the SRK-181 target engagement e.g. circulating TGFβ-1
levels TGFβ pathway modulation: e.g. Histochemical analysis of pSMAD e.g. RNA-based TGFβ gene signatures and pathway analyses Paired biopsies from the head and neck cohort allow for a potential to accelerate the development
path Immunophenotyping Assessment of immune landscape TGFβ-1 pathway evaluation Assessment of signaling pathway
Clear Evidence of Target EngagementPharmacodynamic Biomarker Results for Part A:
Circulatory TGFβ-1 75 Yap T et al. SRK-181, a latent TGFβ1 inhibitor: safety, efficacy, and biomarker results from the dose escalation portion of a phase I trial (DRAGON trial) in patients with advanced solid tumors (Poster 780); Presented
at SITC; Nov. 10-11, 2022. Circulatory TGFβ-1 and PF4 levels were quantitated by using validated ELISA kits from R&D System.12 Because platelet activation during sample processing can lead to elevated TGFβ-1 levels, samples with elevated
PF4, a platelet activation biomarker, were excluded from the analysis based on a preliminary cutoff value. Pre-infusion. SRK-181 is an investigational drug candidate that is being evaluated for the treatment of cancer. SRK-181 has not been
approved by the US FDA or any other health authority, and its safety and efficacy have not been established. Binding to latent TGFβ-1 delays maturity state allowing TGFβ-1 to accumulate in system Combination treatment with pembrolizumab did
not appear to impact circulatory TGFβ-1 levels C1D2 C1D8 C1D15 C2D1* C3D1* C3D2 C3D8 C3D15 C4D1* C5D1* Baseline Circulatory TGFβ-1 (Fold-Change from Baseline) 2 3 4 6 5 Median Circulatory TGFβ-1 Increased Post-treatment
with SRK-181 (Q3W, All Patients)
Preclinical Data Provide Scientific Rationale to Evaluate Peripheral Samples for
Evidence of SRK-181 Activity 76 MBT-2 bladder tumor model IgG, anti-PD-1 and SRK-181-mIgG1 dosed d1, d7 Analysis on day 10 Circulating MDSC Levels Correlate with Tumor Volume Both tumoral and circulatory MDSC are being evaluated in the
DRAGON study Immunophenotyping Assessment of immune landscape Measurement of MDSCs in circulation may provide indirect evidence of drug action on the tumor Myeloid-derived suppressor cells (MDSCs) have immune suppressive
functions SRK-181 plus anti-PD1 combination drive MDSC levels down significantly in the tumor microenvironment Reductions in circulating MDSC levels correlate with reduced tumor volume following SRK-181 and anti-PD1 treatment in MBT-2 tumor
model Anti-PD-1+ SRK-181 1 mpk 3 mpk 10 mpk IgG Ctrl SRK-181 Anti-PD-1