By John Vandermosten, CFA
Achieve Life Sciences, Inc. (ACHV) reported topline results from its Phase IIb Ongoing Research of Cytisinicline for Addiction (ORCA)-1 trial which was launched in October 2018. The study enrolled 254 subjects, employing six arms: four with active drug and two with placebo. The primary goal of the study was to identify the proper dose for the Phase III study which we anticipate will launch in late 2019 and begin enrolling in earnest in January 2020.
View Exhibit I - ORCA-1 Study Design
The primary endpoint for the ORCA-1 study was the self-reported reduction in daily smoking. Three of the active arms demonstrated a statistically significant (p < 0.05) improvement in daily smoking and the fourth active arm was only slightly behind the target threshold (p = 0.052). For all cohorts, subjects averaged about 20 cigarettes at baseline and experienced a 74 to 80% decline in median cigarettes smoked. This compares to a 62% reduction in the placebo arms.
ORCA-1’s secondary endpoint was the four week continuous abstinence rate. This will be the primary endpoint for the upcoming Phase III trials. Achieve noted that there were significant improvements in all cohorts; and quantified the benefit in the 3 mg TID group, which demonstrated a 54% abstinence rate at week four compared to placebo at 16% or a 38 percentage point difference. During weeks 5 to 8, abstinence for the 3.0 mg TID arm was 30% as compared to placebo at 8% which is a 22 percentage point difference. It is important to note that the observations of abstinence for Cytisinicline are all after the completion of the 25 day treatment.
For reference, we provide abstinence data for Chantix; however, the duration of treatment was 12 weeks and the abstinence measure takes place while the subjects are on therapy. It is also important to note that comparing data from disparate trials is imprecise due to different trial design and other factors. With this in mind, we note that Chantix abstinence during weeks 9 – 12 of 40% to 51% and placebo of 12% to 18%, yielding a 26 to 39 percentage point difference.
Another important measure to use for comparison is the odds ratio, which demonstrates the likelihood of quitting as compared to placebo. The ratio for the 3.0 mg TID arm was 6.3 vs placebo at four weeks and compares to Chantix vs. placebo at four weeks which was 4.0 calculated with data taken from Oncken, et al.1
Reduction in expired carbon monoxide (CO) was also measured and is used to confirm self-reported changes in cigarettes smoked. For the four active arms of the trial, CO levels declined by a median of 71 to 80% compared to the placebo arms which declined 38%. This produces a 33 to 42 percentage point reduction in CO levels between active arms and placebo. All arms were statistically significant at the 5% level.
Adherence to treatment was 98.5% and also a strong point of the study. We note that one of the contributing factors to lower adherence in competing therapies is a difficult side effect profile, most notably nausea, but also insomnia, abnormal dreams and headache. While the results of the EAGLES study is not directly comparable to the ORCA-1 study, we do want to point out that side effects were materially higher for Chantix vs. Cytisinicline.
No serious adverse events were reported in the ORCA-1 study. Adverse events greater than 5% across the active arms included abnormal dreams, insomnia, upper respiratory tract infections, and nausea. In the 3 mg TID treatment arm, the most common adverse events were abnormal dreams, insomnia, and constipation (each 6% vs 2%), upper respiratory tract infections (6% vs 14%), and nausea (6% vs 10%). This compares to 1 mg BID Chantix results vs. placebo of nausea (30% vs 10%), insomnia (18% vs 13%), abnormal dreams (13% vs 5%), headache (15% vs. 13%) and upper respiratory tract disorder (5% vs. 4%).
ACHV shares declined sharply following the report of what we felt were solid data and in our opinion this was incrementally positive information supportive of successful Phase III trials. The trial was not powered to generate a statistically significant result for the endpoints but rather to identify the dose to be used for the larger Phase III study. Despite the small population size, there were statistically significant results for number of cigarettes smoked in three of the four cohorts. Abstinence rates and CO levels were also very favorable and statistically significant as well.
Next steps for Achieve are to conduct another end of Phase II meeting with the FDA to finalize Phase III trial protocol which we anticipate will take place in the September or October timeframe. This will enable the launch of the first of two Phase III trials before the end of the year and allow rapid enrollment as 2020 begins. Below we include the latest timeline for Achieve from the April presentation. After yesterday’s results there should now be a check to the “Top line results P2b” row.
View Exhibit II - Cytisinicline Planned Development Program and Milestones
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1. Oncken, Cheryl, MD; et al. Efficacy and Safety of the Novel Selective Nicotinic Acetylcholine Receptor Partial Agonist, Varenicline, for Smoking Cessation. Arch Intern Med. 2006;166:1571-1577
By John Vandermosten, CFA