Achieve Life Sciences (NASDAQ:ACHV) hosted a web conference last week featuring company management, equity analysts and key opinion leaders (KOLs) in the tobacco and nicotine addiction space. The group presented recent data from Achieve’s ORCA-1 trial, data from the RAUORA study, highlighted some of the features of cytisinicline that reduce the side effect profile, examined the relationship between COVID and smoking and gave a preview of the ORCA-2 trial which launched in October.
Representatives from Achieve Life Sciences included:
• John Bencich, Chief Executive Officer
• Cindy Jacobs, Ph.D., M.D., President and Chief Medical Officer
• Dr. Anthony Clarke, Chief Scientific Officer
The panel was moderated by:
• Michael Higgins, MBA – Ladenburg Thalmann
• Thomas Flaten – Lake Street Capital Markets
The panel consisted of:
• Nancy Rigotti, M.D. – Professor of Medicine, Harvard Medical School, Director of Tobacco Research & Treatment, Massachusetts General Hospital, and ORCA-2 Principal Investigator
• Mitchell Nides, Ph.D. – President, LA Clinical Trials LLC, ORCA-1 Principal Investigator
• Neal Benowitz, M.D. – Professor of Medicine, Emeritus, University of California, San Francisco
• Judith Prochaska, Ph.D., MPH – Professor of Medicine, Stanford University
• Scott Leischow, Ph.D. – Professor and Director, Clinical and Translational Science, Arizona State University, Former Senior Advisor for Tobacco Policy at HHS
The virtual event began with a welcome from Achieve’s CEO, John Bencich, who introduced the panelists and the event. Mr. Bencich gave an overview of Achieve, cytisinicline and the pre-existing work confirming safety and product usage in central and eastern Europe. He noted that cytisinicline is sourced naturally and has yet to be commercialized in the US.
Dr. Nides kicked off the key opinion leader segment with a presentation and review of the ORCA-1 trial and its results. Prior to Achieve’s efforts, Dr. Nides had been aware of cytisinicline’s long-popular status in Europe, eager to see its efficacy proven to the FDA. This was achieved through a Phase II proof of concept study conducted to optimize the Phase III study design. ORCA-1 evaluated the safety and efficacy of two doses, 1.5 mg and 3 mg of cytisinicline vs placebo over a treatment period of 25 days, with standardized behavioral support and follow-up out to eight weeks. The enrolled population included individuals who smoke 10 cigarettes a day or more with expired air carbon monoxide of greater than 10 ppm. The endpoints for the study were biochemically verified abstinence and self reported reduction in cigarettes smoked during treatment.
Exhibit I – ORCA-1 Study Arms (1)
Subject demographics included those who had been smoking, on average, for 30+ years, who smoked about one pack per day, who had attempted to quit, on average, about 4-5 times and had used, to varying degrees, varenicline, bupropion, nicotine patches and other replacement therapies and e-cigarettes. All active arms demonstrated statistically significant quit rates at the end of treatment. Thrice daily (TID) administration outperformed downward titration groups both at end of treatment and after discontinuation. Based on the results, the 3 mg dose was selected with TID administration for use in the Phase III. This dosage showed statistically significant quit rates both at end of and after treatment, confirmed by expired CO, with high treatment adherence.
Exhibit II – ORCA-1 Results (2)
Cytisinicline was well tolerated across all treatment groups, with a low incidence of adverse events and no serious adverse events reported, comparing favorably to available smoking cessation products.
Next, Dr. Anthony Clarke, Chief Scientific Officer for Achieve, presented recent data from the Society for Research on Nicotine and Tobacco European (SRNT-E) Annual Meeting, both results from the RAOURA trial and experiments that helped explana cytisinicline’s superior side-effect profile compared to varenicline. Study principal investigator, Dr. Natalie Walker designed and executed the study and Achieve provided the drug. The study was designed to evaluate, head-to-head, cytisinicline and varenicline and was performed in the Māori population in New Zealand. The study targeted enrollment of 2,140 subjects, and eventually enrolled 679 after curtailing enrollment due to budget constraints. It was designed as a non-inferiority study, assuming varenecline was the gold standard and that cytisinicline would be inferior in efficacy and dictated a non-inferiority margin of 10%. Treatment was for 12 weeks and varenicline dosing was conducted according to package insert while cytisinicline was 1.5 mg according to European packaging insert to day 24, then 1.5 mg twice daily for maintenance. The primary outcome was biochemically verified smoking cessation after 6 months. The trial achieved statistical significance demonstrating that cytisinicline and behavioral support were at least as effective as varenicline (3) plus behavioral support at six months. Not only did the trial meet its endpoint, but the trend was toward superiority with an Absolute Risk Difference of 4.29. Carbon monoxide verified quit rates at six months narrowly missed statistical significance in demonstrating cytisinicline superiority to varenicline. Cytisinicline showed significantly fewer reported adverse events compared with varenicline in the study with nausea, insomnia and abnormal dreams experienced statistically less than varenicline.
Exhibit III – Risk Difference at Six Months (4)
Varenicline nausea side effect is a major driver of lack of treatment adherence in those attempting to quit. Experiments measured cytisinicline’s lower binding affinity to the 5-HT3 receptor. The 5-HT3 receptor report provided insight into a potential explanation for cytisinicline’s lack of nausea and vomiting side effects compared to varenicline. Varenicline had been confirmed to be a potent and full agonist for the 5-HT3 receptor, which, when activated by an agonist, are known to directly lead to nausea and vomiting.
Dr. Nancy Rigotti, ORCA-2 Principal Investigator, then provided an overview of the in-progress ORCA-2 Phase III cilinical trial.
Exhibit IV – ORCA-2 Phase III Trial Design (5)
The study is intended to evaluate safety and efficacy of 3 mg cytisinicline vs placebo administered TID over six and 12 weeks in addition to standardized behavioral support and followup up to 24 weeks. The population enrolled will target 750 smokers at greater or equal to 10 cigarettes smoked a day and expired carbon monoxide greater than 10 ppm. The enrollees also must intend to quit smoking immediately, have failed at least one previous quit attempt and agree to participate in behavioral support throughout the study.
The primary endpoints are biochemically verified continuous abstinence during the last four weeks of treatment, with a comparison at weeks 3-6 and weeks 9-12 between arms. Secondary endpoints included biochemically verified continuous abstinence through week 24 or the follow up period, and reduction in risk of relapse at week 24 comparing 6-week and 12-week dosing duration arms.
Dr. Rigotti also provided an update on the current status of ORCA-2 which had been delayed due to the pandemic. The ORCA-2 final protocol was reviewed by the FDA in September 2020, and the study began initiating screening in October 2020 with 15 sites now actively enrolling. The risk of the pandemic is ongoing, and ORCA-2 has risk mitigatiion strategies including having only one study site in each state, with strategies for dealing with any spikes in COVID-19 cases, potential closures, and any resulting data loss.
Dr. Neal Benowitz followed, presenting on the relationship between smoking and COVID-19. He began with an overview of the coronavirus and the progression of COVID-19 infection. Next, he presented an epidemiology overview tracking smokers and COVID-19 in meta-analysis. Findings varied significantly. One study found that smokers were less likely to become infected, while another found that smokers were more likely to become infected depending on socioeconomic status. One study found that smokers were less likely to be hospitalized and yet another found no differences in hospitalization. Another piece of research observed that current and former smokers were more likely to die from COVID-19, if hospitalized.
Dr. Benowitz also presented data related to the impact of COVID-19 on smoking behaviors. A study by Jackson based on the Smoking Toolkit, data collected monthly by interviewing smokers, before and after the pandemic. There was no change in prevalence of smoking, but the effort found increased serious quit attempts, increased quit success, and increased cessation in general. The Klemperer study, based on a web-based survey of users of tobacco and electronic cigarettes, found that if participants were concerned about the effect of smoking on their susceptibility to COVID-19, motivation to quit increased in 36% of people but decreased in 16% of people. 23% attempted to quit to reduce harm, 28% reduced use and 30% increased use, showing varying effects of risk perception and stay-at-home trends. Conclusions were that cigarette smoking is deadly regardless of COVID-19 infection, that smokers hospitalized perform worse, the benefits of e-cigarette use unclear, and smokeless tobacco use likely not a concern, though no explicit data is available.
The event then proceeded to a panel discussion, hosted by Thomas Flaten and Michael Higgins. Questions centered on smoker patient experience, the continued, vast and unmet need for treatments for the cessation of smoking, the role of behavioral support in therapy and cytisinicline quit rates compared to current therapies among other topics. An important note made during the discussion by Dr. Anthony Clarke was that smoking cessation as a drug class differs from a disease state such as hypertension, where a new drug entrant must be considered against the current therapies of the patient, and if stabilized, there is limited incentive to switch. However, the majority of those who have attempted to quit smoking have failed, even with professional assistance. This reality supports the development of new solutions, and even multiple solutions in the market.
In summary, the event featured highly esteemed individuals with a stake in the success of new tobacco and nicotine addiction medicine, and Achieve’s cytisinicline was at its centerpoint, a potential win in a battle with an addiction that has plagued human health for hundreds of years. The drug’s efficacy and improved side effect profile compared to alternatives is a material benefit that may be proven out in the ongoing Phase III trial. For more details on Achieve, please access our most recent report here.
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1. Achieve Life Sciences Cytisinicline – Smoking Cessation Virtual Roundtable
2. Achieve Life Sciences Cytisinicline – Smoking Cessation Virtual Roundtable
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4. Achieve Life Sciences Cytisinicline – Smoking Cessation Virtual Roundtable
5. Source: Achieve Life Sciences S-1 Filed November 6, 2019.