Cytisinicline Promising for Vaping Cessation
A recent study is the latest to suggest that a drug long available overseas could be effective at helping people stop using nicotine.
Cytisine is an alkaloid naturally derived from the Fabaceae family of plants, including the genera Laburnum and Cytisus. Pictured here is Laburnum anagyroides, also known as Cytisus laburnum.
Getty Images/iStock/Reimphoto
Cytisinicline, a novel formulation of the plant-based alkaloid cytisine, may help adults stop vaping, a study in JAMA Internal Medicine has found. Cytisine, long available overseas as a smoking-cessation aid, is a partial agonist for nicotinic acetylcholine receptors and is thought to work much like varenicline to reduce nicotine cravings. In July, the Food and Drug Administration (FDA) granted Breakthrough Therapy designation to cytisinicline for the treatment of nicotine e-cigarette or vaping dependence. The FDA’s Breakthrough Therapy designation expedites the development and review of drugs for serious conditions.
Nancy Rigotti, M.D., a professor of medicine at Harvard Medical School, and colleagues examined data from the Phase II, placebo-controlled ORCA-V1 trial, sponsored by cytisinicline developer Achieve Life Sciences Inc. The ORCA-V1 trial included 160 adults with a mean age of 33.1 years who vaped nicotine daily, wanted to quit, and did not smoke traditional cigarettes.
Participants were randomized into two groups, with 107 taking 3 mg of cytisinicline three times per day and 53 taking placebo for 12 weeks. Participants also had weekly visits with a counselor who offered 10 minutes of brief vaping-cessation support. The primary endpoint was continuous vaping abstinence during the last four weeks of treatment as reported by the participants and verified through saliva tests.
Studies have shown that cytisine has fewer side effects than varenicline, said Nancy Rigotti, M.D.
Stanley Rowin
From week nine to week 12, 31.8% of participants in the cytisinicline group had continuous vaping abstinence, compared with 15.1% in the placebo group. At a follow-up visit four weeks after the study concluded, 23.4% of participants in the cytisinicline group had sustained vaping abstinence for eight weeks.
The most common adverse events among participants in the cytisinicline group were abnormal dreams, insomnia, anxiety, headache, fatigue, and upper respiratory tract infection.
Designing the First Trial
Achieve’s ORCA (Ongoing Research of Cytisinicline for Addiction) program has conducted previous trials showing that cytisinicline is effective at promoting smoking cessation. One example is ORCA-2, which Rigotti and colleagues published in JAMA last year. In that trial, which included 810 adults who smoked at least 10 traditional cigarettes per day, 32.6% of participants who took cytisinicline did not smoke during weeks nine to 12, compared with 7% in the placebo group.
But as the first trial to test cytisinicline for vaping cessation, ORCA-V1 had to be carefully designed, said study researcher Neal Benowitz, M.D., an emeritus professor of medicine at the University of California, San Francisco and Zuckerberg San Francisco General Hospital.
“There are so few trials for vaping cessation that this was a gamble,” Benowitz said. “We had to develop counseling specifically for vaping. While the general [aim of] behavioral counseling is the same as for smoking cessation, counseling for vaping cessation is more product specific.” Benowitz added that the relative youth of the ORCA-V1 trial participants is also notable, given the way vaping products are marketed to young people.
The relative youth of ORCA-V1 participants is notable, given how vaping products are marketed to young people, said Neal Benowitz, M.D.
University of California, San Francisco
Smita Das, M.D., Ph.D., M.P.H., former chair of APA’s Council on Addiction Psychiatry, said she was encouraged by the study and its findings, especially because there are currently no medications approved by the FDA specifically for vaping cessation. Das, who was not involved in the research, is an addiction psychiatrist at the Dual Diagnosis Clinic and a clinical associate professor of psychiatry and behavioral sciences at Stanford University School of Medicine.
“When it comes to vaping, in practice clinicians have been using general tobacco guidelines and medications, [so] it is exciting that a potential medication is being studied specifically for [vaping] cessation in a well-designed approach,” Das said. “I am hopeful to have one more tool in in our toolbox for nicotine cessation and hope that in general there is renewed interest in using all of our tools given that tobacco use disorder is still the leading preventable cause of death in this country.”
The prospect of a medication specifically for vaping cessation is promising because health professionals currently have to use general tobacco-cessation guidelines, Smita Das, M.D., Ph.D., M.P.H.
Cytisine’s Long History
Generic cytisine, derived from seeds of plants such as the golden rain acacia, has been used as an over-the-counter smoking-cessation aid in Eastern European countries for nearly 50 years. In 2017, Health Canada approved cytisine as an over-the-counter natural health product. However, cytisine is currently an investigational product in the United States and is not FDA approved.
“Getting FDA approval for a new smoking-cessation medication in the U.S. requires a lengthy and expensive regulatory process,” Rigotti told Psychiatric News. “A company that does so for a generic drug that it has not patented will not have exclusive rights to sell the drug.” She added that Achieve Life Sciences spent the last decade developing cytisinicline as a novel (and patentable) formulation for smoking cessation and gathering the evidence needed to submit a New Drug Application (NDA) to the FDA.
According to a company announcement, Achieve hopes to submit its NDA in the first half of 2025, once it has the required long-term safety exposure data from its ORCA-OL open-label study of cytisinicline in people who currently smoke or vape nicotine. The NDA would apply to the smoking cessation indication, while a separate NDA for vaping cessation under the breakthrough designation will follow if the smoking cessation indication is achieved, according to Rigotti.
An unrelated Australian noninferiority trial published in JAMA in 2021 compared cytisine to varenicline in 1,452 adults who smoked cigarettes daily and wanted to quit. Participants in the cytisine group took 1.5 mg of cytisine six times per day for three days, then gradually tapered off the drug until day 25 (this is the duration used in Eastern Europe). Participants in the varenicline group took 1 mg of varenicline twice per day for 84 days. The primary outcome was six-month continuous abstinence as verified via a carbon monoxide breath test at a seven-month follow-up.
Among the 1,108 participants who completed the trial, six-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group. In addition, self-reported adverse events occurred less frequently in the cytisine group compared with the varenicline group.
Although the trial did not show that cytisine was noninferior to varenicline, that does not mean cytisine is inferior, according to Rigotti. “In that trial, 25 days of cytisine was compared to 12 weeks of varenicline,” she said. “A comparison of 12 weeks of both medications using the new cytisine dosing regimen might have different results. What was clear in that study was that cytisine has fewer side effects than varenicline, which has been a consistent finding in several other studies.”
The ORCA-V1 study in JAMA Internal Medicine was supported by the National Institute of Drug Abuse and Achieve Life Sciences. The ORCA-2 study in JAMA was supported by Achieve Life Sciences. The noninferiority trial in JAMA was supported by the Australian National Health and Medical Research Council. ■
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Published online: 29 August 2024
Published in print: September 1, 2024 – September 30, 2024
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