ACHV: The Final Phase III Begins
NASDAQ:ACHV
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Since Our Last Update
Since our last update, Achieve Life Sciences, Inc. (NASDAQ:ACHV) announced several milestones. In January, Achieve’s pivotal, Phase III ORCA-21 trial had its last subject, last follow up, and the confirmatory Phase III ORCA-3 trial was initiated. In addition, Achieve hosted a key opinion leader panel on smoking and e-cigarette cessation, established a $25 million loan facility with Silicon Valley Bank, and presented at the BIOCONNECT Virtual Conference. With multiple important milestones including the read out of ORCA-2, the start of ORCA-3 and ORCA-V1 and potentially the conclusion of ORCA-V1 in 2022, Achieve had added three new team members to its roster including a Director of Clinical Operations.
Highlights since our last update include:
➢ ORCA-2 clears final DSMC review - November 2021
➢ KOL panel on smoking and e-cigarette cessation - December 2021
➢ $25 million loan facility from Silicon Valley Bank - December 2021
➢ ORCA-2 last subject, last follow up - January 2022
➢ HC Wainwright BIOCONNECT Virtual Conference - January 2022
➢ Initiation of ORCA-3 - January 2022
➢ Expansion of clinical operations team - February 2022
Cytisinicline Clinical Milestones
Shortly after our November update, Achieve announced that in its fifth and final review the Data Safety Monitoring Committee (DSMC) held no concerns with cytisinicline safety or trial conduct for ORCA-2. Additionally, the DSMC noted excellent compliance with drug administration procedures and that the study has progressed well despite the impact from the COVID-19 pandemic. On January 4, 2022, Achieve announced completion of the last follow up visit for the last subject for the ORCA-2 trial. The study randomized 810 subjects across 17 clinical sites in the US. Topline data from ORCA-2 is expected in 2Q:22. On January 25th, Achieve initiated screening subjects for the ORCA-3 confirmatory Phase 3 trial required for registrational approval of cytisinicline in the United States. The press release went on to provide details for the grant-funded Phase II ORCA-V1 study in nicotine e-cigarette cessation. Enrollment of 150 subjects in this trial is expected to begin in 2Q:22.
ORCA-2
Achieve announced the start of its Phase III ORCA-2 trial on October 7, 2020, targeting enrollment of 750 smokers at 15 clinical sites throughout the United States. The trial was a multi-center, double-blind, randomized, placebo-controlled Phase III study that will enroll adult cigarette smokers who intend to quit smoking. 810 subjects were randomized into one of three arms: 12 weeks of placebo, six weeks of cytisinicline then six weeks of placebo or 12 weeks of cytisinicline. Dosing will be 3.0 mg, three times daily (TID) in each of the treatment cohorts. This dosing regimen is expected to be effective against even high nicotine use prior to cessation as cytisinicline efficiently binds nicotinic acetylcholine receptors. The trial began with a slower than expected enrollment rate due to disruptions related to the coronavirus and severe winter weather in the South; however, the enrollment rate accelerated and ORCA-2 reached its enrollment target. A six-month follow up period occurred after the measurement at week 12, and last patient, last visit was completed in late December 2021. The data analysis portion is the next order of business and topline results are anticipated to be available by 2Q:22.
On August 13, 2021, Achieve announced that it had expanded its Clinical Operations Team with the hiring of a Director of Clinical Operations, a Senior Manager of Clinical Trials, and a Senior Director of Biometrics. The additions supported Phase III ORCA-2 and will continue to support cytisinicline development. On February 3, 2022, Achieve announced the hiring of a Director of Clinical Operations. Achieve’s Board approved the issuance of incentive stock options for 15,000 shares of Achieve common stock with grant date of January 31, 2022.
ORCA-3
ORCA-3 is similar in trial design, safety and efficacy evaluations, and statistical criteria as ORCA-2. The trial will target enrollment of 750 subjects across 15 clinical trial sites, randomized into three arms. Dosing will be 3mg TID. As per FDA requirements, it will be conducted at new sites from ORCA-2 to ensure the statistical robustness of the data. As with the first Phase III trial, the primary outcome measure for ORCA-3 will be biochemically verified continuous abstinence during the last 4 weeks of treatment in the 6 and 12-week cytisinicline treatment arms compared to placebo. Each treatment arm will be compared independently to the placebo arm, and the trial will be determined to be successful if either or both of the cytisinicline treatment arms show a statistical benefit compared to placebo. Secondary outcome measures will be conducted to assess continued abstinence rates through 6 months from the start of study treatment. We anticipate that the diminishing impacts of COVID, the alignment of the start of the trial with New Year’s resolutions to stop smoking and Achieve’s extensive experience conducting this type of trial, the enrollment of the planned 750 patients will be at a materially faster pace than in previous studies. On January 25, 2022, Achieve announced that it had initiated ORCA-3.
ORCA-V1
ORCA-V1 trial will enroll 150 subjects that are vaping but not smoking. Randomization will be divided into a 2:1 split with 100 receiving twelve weeks of cytisinicline and 50 on placebo. Dosing is expected to follow the regimen evaluated in ORCA-2: 3 mg three times daily. The Phase II study will examine vaping cessation as the endpoint at the six week and twelve week point by measuring cotinine levels.4 If the trial is successful and generates statistically significant results, it could provide support, along with a successful ORCA-2 trial, to require only one Phase III to obtain approval. On November 2, 2021, Achieve announced that cytisinicline’s investigational new drug (IND) application for e-cigarette cessation had been reviewed and accepted by the FDA. ORCA-V1 is expected to begin in 2Q:22.
NIH Vaping Grant
Last year, Achieve announced a collaboration with the FreeMind Group to identify non-dilutive funding to support the launch of a clinical trial that will evaluate the effectiveness of cytisinicline in subjects that are vaping and using e-cigarettes. On July 22, 2021, Achieve announced that it had been awarded a grant from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) for the evaluation of cytisinicline in cessation of nicotine e-cigarette use. The grant award commenced on August 1, 2021, in an amount of $320,000. This initial infusion will support the completion of regulatory and clinical activities, namely protocol finalization, clinical site identification, and submission of an IND. Upon completion of the milestones, Achieve will then be subject to NIH assessment for the next stage of grant award of $2.5 million. The second tranche of the award will enable initiation of the Phase II trial designated ORCA-V1, which will target ~150 adult nicotine e-cigarette users in the US. Grant funding is expected to cover approximately 50% of the trial cost. Primary investigators for the grant are Achieve’s CMO, Dr. Cindy Jacobs, and Dr. Nancy Rigotti, Professor of Medicine at Harvard Medical School.
$25 Million Loan Facility from Silicon Valley Bank
On December 22, 2021, Achieve announced that it has entered into a $25 million debt agreement with Silicon Valley Bank (SVB). The proceeds are expected to fund the completion of the cytisinicline smoking cessation clinical development program. SVB will fund $15 million in convertible debt on the close of December 22, 2021. Upon mutual consent, Achieve may borrow additional non-convertible term loans of up to $10 million before December 31, 2022. The outstanding loans mature December 22, 2023 (extendable to December 22, 2024) and will accrue interest at 7.0% per year compounding monthly plus the greater of 2.25% or prime minus 1.0%. SVB may convert its debt at $9.34 per share. All outstanding convertible debt will mandatorily convert when Achieve’s common stock closing price per share has been equal or greater to $24.00 for thirty consecutive trading days. Finally, Achieve has the right to extinguish its SVB debt completely prior to conversion by payment of a premium of 125% of outstanding principal including interest before 18 months after closing date. After 18 months from the closing date, the premium rises to 150%.
Key Events
➢ Launch of ORCA-2 - October 2020
➢ RAUORA Study Publication - March 2021
➢ $23.0 million gross capital raise - May 2021
➢ Completion of enrollment in ORCA-2 - June 2021
➢ NIDA (NIH) grant for ORCA-V1 - July 2021
➢ IND acceptance for ORCA-V1 - November 2021
➢ ORCA-2 last patient, last visit - December 2021
➢ ORCA-V1 IND development - 2H:21
➢ Launch of ORCA-3 - January 2022
➢ Topline readout of ORCA-2 - 2Q:22
➢ ORCA-V1 launch - 2Q:22
➢ ORCA-V1 results - 1H:23
➢ ORCA-3 results - 1H:23
Summary
Since our last update, Achieve reached multiple milestones for its pivotal Phase III ORCA-2 trial, started ORCA-3, guided toward second quarter release of ORCA-2 topline results and ORCA-V1 launch. ORCA-2’s DSMC reported no concerns with cytisinicline safety or trial conduct after its fifth and final review, and in December 2021, Achieve completed ORCA-2’s last follow-up visit for its last patient. ORCA-3 was initiated and began screening on January 25, 2022. Achieve also hosted a KOL panel on smoking and e-cigarette cessation, established a $25 million loan facility with Silicon Valley Bank, and presented at the BIOCONNECT Virtual Conference.
With the conclusion of ORCA-2 and the initiation of ORCA-3, Achieve makes progress toward the US regulatory finish line with its naturally-derived candidate in smoking cessation. Cytisinicline has a robust historical safety profile with over 10,000 participants in clinical trials to date. In Achieve-led trials, the drug has not only shown a superior side-effect profile compared with standard of care, it has also shown signs of superior efficacy. Furthermore, the leading approved product, Chantix, lost patent protection in November 2020, leaving a billion-dollar hole in its sponsor’s portfolio. With more than 34 million smokers in the US and 1.1 billion worldwide there is a substantial market for a superior smoking cessation product with fewer side effects. The rise of e-cigarette and nicotine vaping raises another concern related to addiction which also may be addressed by cytisinicline. To address this unmet need, Achieve expects to launch the grant-funded ORCA-V1 in nicotine e-cigarette cessation in the second quarter of 2022.
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1. Ongoing Research of Cytisinicline for Addiction
2. Source: Achieve Life Sciences November 2021 Corporate Presentation
3. Source: Achieve Life Sciences October 2020 Corporate Presentation
4. Cotinine is a metabolite of nicotine. Cotinine urine or blood testing is considered highly accurate for assessing nicotine use, including vaping.
5. Source: Achieve HCW BIOCONNECT Presentation
