In September 2021, we completed an underwritten follow-on public offering of 10,781,250 shares of our common stock, including the full exercise of the underwriters’ option to purchase additional shares, at a price to the public of $8.00 per share. The total net proceeds from the offering were approximately $80.6 million, after deducting underwriting discounts, commissions and offering expenses payable by us.

In February 2020, we completed an underwritten follow-on public offering of 4,235,294 shares of our common stock at a price to the public of $4.25 per share. In March 2020, the underwriters fully exercised their over-allotment option for the issuance of an additional 635,294 shares of common stock. The total net proceeds from the offering were approximately $18.8 million, after deducting underwriting discounts, commissions and offering expenses payable by us.

In March 2021, we entered into a Capital on Demand^TM Sales Agreement with JonesTrading Institutional Services LLC (JonesTrading) for an at-the-market offering (ATM Offering Program), pursuant to which we can sell from time to time, at our option, up to an aggregate of $25.0 million of shares of our common stock through JonesTrading, as sales agent or principal. JonesTrading is entitled to a commission at a fixed rate equal of up to 3% of the gross proceeds. For the year ended December 31, 2021, we sold an aggregate of 986,267 shares of common stock at an average price of $4.75 per share for net proceeds of $4.4 million under the JonesTrading ATM Offering Program.

In May 2019, we entered into a sales agreement with H.C. Wainwright & Co., LLC (Wainwright) with respect to an ATM Offering Program under which we could offer and sell shares of our common stock having an aggregate offering price of up to $10.0 million. Wainwright was entitled to a commission at a fixed rate equal to 3% of the gross proceeds. In November 2020, we amended our sales agreement with Wainwright to increase the amount of the ATM Offering Program up to $20.0 million. In March 2021, the ATM Offering Program with Wainwright automatically terminated upon the issuance and sale of all of the shares of common stock having an aggregate offering price of $20.0 million. Under the ATM Offering Program with Wainwright, during 2020, we sold an aggregate of 1,657,075 shares of common stock at an average price of $4.07 per share for net proceeds of $6.4 million. Prior to the termination of the sales agreement with Wainwright, in 2021, we sold an aggregate of 1,988,254 shares of common stock at an average price of $4.99 per share for net proceeds of $9.6 million under the Wainwright ATM Offering Program.

In September 2020, we entered into a common stock purchase agreement (Purchase Agreement) with Aspire Capital Fund, LLC (Aspire Capital), which provides that, upon the terms and subject to the conditions and limitations set forth therein, Aspire Capital is committed to purchase up to an aggregate of $20.0 million of shares of our common stock at our request from time to time during the 30 month term of the Purchase Agreement. Concurrently with entering into the Purchase Agreement, we also entered into a registration rights agreement with Aspire Capital, in which we agreed to file one or more registration statements, as permissible and necessary to register under the Securities Act of 1933, as amended, for the resale of the shares of our common stock that have been and may be issued to Aspire Capital under the Purchase Agreement. For the year ended December 31, 2021, we sold an aggregate of 3,000,000 shares of common stock at an average price of $5.09 per share for net proceeds of $15.2 million under this Purchase Agreement. We did not sell any shares of common stock to Aspire Capital under this Purchase Agreement for the year ended December 31, 2020.

We adopted a stock option plan in 2007 (the 2007 Plan), which was subsequently amended, restated and renamed in July 2014 (the 2014 Plan) to provide for the incentive stock options, nonstatutory stock options, stock and rights to purchase restricted stock to eligible recipients. Recipients of incentive stock options are eligible to purchase shares of our common stock at an exercise price equal to no less than the estimated fair market value of such stock on the date of grant. The maximum term of options under the 2014 Plan is ten years. Options granted generally vest over four years. Shares underlying any awards under the 2014 Plan that are forfeited, canceled, reacquired by us prior to vesting, satisfied without the issuance of stock or otherwise terminated (other than by exercise) will be added to shares available for issuance under the 2015 Plan.

In April 2015, our board of directors adopted, and our stockholders approved, the 2015 Stock Plan (the 2015 Plan). The 2015 Plan became effective on May 6, 2015 and we ceased granting any new awards under our 2014 Plan. Awards granted under the 2014 Plan prior to our IPO that are forfeited, canceled, reacquired by us prior to vesting satisfied without the issuance of stock or otherwise terminated (other than by exercise) will be added to shares available for issuance under the 2015 Plan. At our 2020 Annual Meeting of Stockholders and at our 2021 Annual Meeting of Stockholders, our stockholders approved an amendment to increase the number of shares of common stock reserved under the 2015 Plan by 350,000 shares and 750,000 shares, respectively. Total shares available for issuance under the 2015 Plan as of December 31, 2021 were 420,896. Shares underlying any awards under the 2015 Plan that are forfeited, canceled, reacquired by us prior to vesting, satisfied without the issuance of stock or otherwise terminated (other than by exercise) will be added to shares available for issuance under the 2015 Plan.

The maximum term of options granted under 2015 Plan is ten years. For an initial grant to an employee, 25% of the options generally vest on the first anniversary of the original vesting date, with the balance vesting monthly over the remaining three years. For subsequent grants to an employee, the options generally vest monthly over a four-year term.

Options under inducement grants vest over a period of four years, with 25% vesting on the one year anniversary of the grant date and the remaining 75% vesting on a monthly basis over three years thereafter, subject to continuous employment. These options were inducement grants issued outside of the 2015 Plan in accordance with Nasdaq Listing Rule 5635(c)(4). In addition, from time to time, we may make inducement grants of stock options to new employees.

In October 2021, we granted a non-qualified option to purchase 70,000 shares of our common stock at an exercise price of $8.73 per share as an inducement award in connection with the hiring of our Vice President, Regulatory Affairs, and in December 2021, we granted a non-qualified option to purchase 70,000 shares of our common stock at an exercise price of $7.77 per share as an inducement award in connection with the hiring of our Vice President, Human Resources.

We intend to file a registration statement on Form S-8 to register the shares of common stock underlying the options granted under the inducement grants prior to the time at which this option becomes exercisable.

In April 2015, our board of directors adopted, and our stockholders approved, our 2015 Employee Stock Purchase Plan (the 2015 ESPP). The 2015 ESPP became effective on May 6, 2015. As of December 31, 2021, total shares reserved for issuance under the 2015 ESPP were 71,933.

	Number of Outstanding Stock Options			Weighted Average Exercise Price		Weighted Remaining Contractual Term		Aggregate Intrinsic Value
Outstanding as of December 31, 2020		576,534		$	23.33
Granted		892,239		$	5.08
Exercises		(10,751	)	$	5.78
Canceled/forfeited/expired		(45,472	)	$	22.38
Outstanding as of December 31, 2021		1,412,550		$	12.01		8.46	$	3,134,377
Options vested and expected to vest as of December 31, 2021		1,412,550		$	12.01		8.46	$	3,134,377
Options exercisable as of December 31, 2021		472,553		$	25.55		7.10	$	763,461

The assumptions used in the Black-Scholes option pricing model to determine the fair value of the employee stock option grants were as follows:

Years Ended December 31,

2021

2020

2019

Expected term (in years)

5.50 – 6.08

5.51 – 6.07

Risk-free interest rate

0.6% – 1.3%

0.3% – 1.5%

1.4% – 2.6%

Expected volatility

86.3% – 104.8%

102.2% – 109.7%

97.2% – 105.4%

Expected dividend yield

0.0%

The assumptions used in the Black-Scholes option pricing model to determine the fair value of the ESPP offering were as follows:

	Years Ended December 31,
	2021		2020		2019
Expected term (in years)		0.50		0.50		0.50
Risk-free interest rate	0.04% – 0.12%		0.1% – 1.6%		1.6% – 2.5%
Expected volatility	89.7% – 108.12%		89.7% – 143.2%		99.7% – 141.7%
Expected dividend yield		0.0%		0.0%		0.0%

Expected term. The expected term represents the period of time that options are expected to be outstanding. Because we do not have sufficient history of exercise behavior, we determine the expected life assumption using the simplified method, which is an average of the contractual term of the option and its vesting period.

Risk-free interest rate. We base the risk-free interest rate assumption on the U.S. Treasury’s rates for U.S. Treasury zero-coupon bonds with maturities similar to those of the expected term of the award being valued.

Expected volatility. The expected volatility assumption is based on our historical volatility as well as the volatilities of a peer group of similar companies whose share prices are publicly available. The peer group was developed based on companies in the biotechnology industry.

Expected dividend yield. We base the expected dividend yield assumption on the fact that we have never paid cash dividends and have no present intention to pay cash dividends.

Occasionally, we grant restricted stock units to employees. The fair value of restricted stock is determined by the closing price of the Company's common stock reported on the Nasdaq Global Select Market on the date of grant. Restricted stock unit activity is summarized as follows:

	Number of Outstanding Restricted Stock Units			Weighted Average Grant Date Fair Value
Balance as of December 31, 2020		7,677		$	5.32
Granted		4,000		$	3.89
Released		(4,177	)	$	6.18
Balance as of December 31, 2021		7,500		$	4.08

The allocation of stock-based compensation for all options, including performance options with market condition and restricted stock units is as follows (in thousands):

	Years Ended December 31,
	2021		2020		2019
Research and development	$	295	$	254	$	354
General and administrative		1,319		1,211		1,429
Total stock-based compensation expense	$	1,614	$	1,465	$	1,783

The weighted-average grant date fair value per share of stock options granted by us, during the years ended December 31, 2021, 2020 and 2019 was $3.82, $3.39 and $5.67, respectively. The total grant date fair value of restricted stock units granted by us during the years ended December 31, 2021, 2020, and 2019 was approximately $16,000, $21,000 and $39,000, respectively. The aggregate intrinsic value of stock options exercised during the year ended December 31, 2021 was approximately $80,000. We did not have any options exercised during the years ended December 31, 2020 and 2019. The aggregate intrinsic value of restricted stock units released during the years ended December 31, 2021, 2020 and 2019 was approximately $31,000, $34,000 and $31,000, respectively. As of December 31, 2021, total unrecognized share-based compensation expense related to unvested stock options and restricted stock units was approximately $3.5 million and $20,000, respectively. These unrecognized costs for options and restricted stock units are expected to be recognized ratably over a weighted-average period of approximately 3.0 years and 2.6 years, respectively.

Warrants outstanding for the purchase of common stock as of December 31, 2021 were as follows:

Number		Exercise Price		Expiration
Outstanding		Per Share		Date
	1,066	$	281.50	July 2023
	6,830	$	43.93	November 2023
	2,978	$	50.37	June 2024
	2,886	$	51.98	December 2024
	13,760

	December 31, 2021
Common stock warrants		13,760
Common stock options and restricted stock units		1,420,050
Shares available under the 2015 equity incentive plan		420,896
Shares available under the employee stock purchase plan		71,933
		1,926,639