provides general information regarding cytisine

Quit Smoking with Tabex
Sopharma Shop

By John Vandermosten, CFA



On September 18, 2020, two presentations related to Achieve Life Sciences (NASDAQ:ACHV) were given at the Society for Research on Nicotine and Tobacco European (SRNT-E) Annual Meeting. The first presentation addressed Achieve’s smoking cessation candidate cytisine’s (cytisinicline’s) lower binding affinity to the 5-HT3 receptor and the second detailed final results from RAUORA, presented by study leader Dr. Natalie Walker. Press releases for the two announcements are here: 5-HT3 / Non-inferiority trial. The two presentations were entitled:

‣ Cytisine’s Lower Potency at 5-HT3 Receptors May Explain its Lower Incidence of Nausea and Vomiting than Varenicline

‣ Is Cytisine At Least as Effective as Varenicline for Smoking Cessation? Findings from a Non-Inferiority Trial in Indigenous New Zealanders and their Extended Family

The first piece shed light on the favorable lower side-effect profile of cytisinicline vs varenicline (Chantix) and the second updated final results in the RAUORA study comparing the two for smoking cessation.

5-HT3 Receptor

The “5-HT3 Receptor” piece 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. The receptor pharmacology study conducted by Professor Sarah Lummis and Dr. Kerry Price at the University of Cambridge Department of Biochemistry evaluated in vitro binding characteristics of cytisinicline and its competitor varenicline to the human 5-HT3 receptor. These receptors in the brain stem, when activated by an agonist, are known to directly lead to nausea and vomiting. The study was done using a radioligand antagonist displacement design. Human embryonic kidney (HEK) 293 cells were first cultured under controlled conditions, transfected with cDNA coding for the 5-HT3A receptor subunit and then later incubated with the radioligand before displacing with either cytisinicline or varenicline. 1uM quipazine was used as a control. Results reported an IC50 of 0.50 mM for cytisinicline and 0.25 µM for varenicline, representing a 2000-fold greater agonist binding affinity to the 5-HT3 receptor for varenicline compared to cytisinicline. More cytisinicline was required to displace the radioligand compared to varenicline indicating cytisinicline’s weaker bond with 5-HT3. Cytisinicline’s weaker bond explains the lack of nausea and vomiting-related side effects versus varenicline.

Exhibit I – Displacement Curves for Cytisine (Cytisinicline) vs Varenicline1


Dr. Natalie Walker, who led the RAUORA trial, presented “Is Cytisine At Least as Effective as Varenicline…” which reported favorable results. In June, topline results for the New Zealand RAUORA study were made available without quantification. The trial achieved statistical significance in demonstrating that cytisinicline and behavioral support were at least as effective as varenicline plus behavioral support at six months. Cytisinicline showed significantly fewer reported adverse events compared with varenicline in the study. Adding to the topline announcement in June, final results showed that the trial met its pre-specified, non-inferiority endpoint of no less than 10% lower quit rate compared to varenicline. Not only did the trial meet its endpoint, but the trend was toward superiority with an Absolute Risk Difference of 4.29. Cytisinicline’s 4.29% improvement in quit rates fell within a 95% confidence interval of -0.22 to 8.79. If the lower end of the confidence interval had not fallen below zero, the trial would have demonstrated superiority. We think that if a larger population size was enrolled in the trial, that cytisinicline could have generated statistical superiority. Trial highlights include:

‣ Cytisinicline subjects were 55% more likely to quit smoking at 6 months compared to varenicline subjects

‣ Cytisinicline treated subjects presented significantly fewer overall adverse events

Continuous abstinence at 6 months, verified by exhaled carbon monoxide, was 12.1% for cytisinicline compared to 7.9% for varenicline. Subjects in the cytisinicline arm were approximately 1.5x more likely to have quit smoking and maintain this status by 6 months compared to those in the varenicline arm as evidenced by 1.55 Relative Risk on an intent to treat basis. Equally noteworthy were the significantly fewer adverse events in cytisinicline-treated subjects (p <0.001). 111/337 cytisinicline subjects compared to 138/342 experienced adverse events with less nausea and fewer vivid dreams in those treated with cytisinicline versus varenicline at 22.5% vs 39.1% and 7.2% vs 17.4%, respectively.

Achieve’s two presentations at SRNT-E bode well for cytisinicline, which is expecting to start the first of two Phase III trials in the early part of 4Q:20. Quantification of topline results from the RAUORA trial provide solid footing, featuring the drug’s relative strength against its main competitor varenicline. Pharmacological studies also provided insight into cytisinicline’s superior side-effect profile.

Achieve is one of our favorite companies and on a risk-adjusted basis is very attractive given the magnitude of the need, eight million deaths reported each year2 and the $1.1 billion in revenues generated by Chantix in 2019. The market cap of around $40 million is only a fraction of what the company could be worth if the two Phase III trials generate statistically significant results. We think that with the Phase II data that has already been produced, the long period of use of the product in Europe and the additional support for non-inferiority compared to market leader Chantix in RAUORA, there is an even stronger rationale for owning Achieve Life Sciences. Please see our latest report for an update as of the second quarter report.

SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to receive our articles and reports emailed directly to you each morning. Please visit our website for additional information on Zacks SCR. 

DISCLOSURE: Zacks SCR has received compensation from the issuer directly, from an investment manager, or from an investor relations consulting firm, engaged by the issuer, for providing research coverage for a period of no less than one year. Research articles, as seen here, are part of the service Zacks provides and Zacks receives quarterly payments totaling a maximum fee of $40,000 annually for these services. Full Disclaimer HERE.


1. Lummis SCR, Price KL, Clarke A, Cytisine’s lower potency at 5-HT3 receptors may explain its lower incidence of nausea and vomiting than varenicline, September 28, 2020, SRNT-E Annual Meeting

2. World Health Organization. WHO Report on the Global Tobacco Epidemic, 2019. Geneva: World Health Organization, 2017