Cytisinicline: A Treatment To Help People Battling Nicotine Addiction

The pharmaceutical company Achieve Life Sciences is focused on addressing one of the biggest public health threats globally – tobacco use. By developing treatment options for people who are battling nicotine addiction, it hopes to reduce the number of preventable deaths caused by smoking.

Technology Networks had the pleasure of speaking with Cindy Jacobs, MD, PhD and chief medical officer at Achieve Life Sciences to learn more about cytisinicline, a plant-based alkaloid the company is currently developing as a smoking cessation treatment.

Laura Lansdowne (LL): Tobacco use is one of the biggest public health threats globally. Could you elaborate on the current global tobacco and nicotine addiction epidemic, what strategies can be used to address this?

Cindy Jacobs (CJ): Smoking is the number one cause of preventable death and is responsible for 8 million premature deaths each year worldwide. Reducing these deaths requires a two-pronged approach. The first is educational outreach and implementation of policies that discourage people from starting to smoke. The second is making it easier for current smokers to quit, which in itself comprises multiple approaches. One of those is encouraging and facilitating candid and productive discussions between smokers and their healthcare providers about why they should quit and what resources are available to help them achieve their smoking cessation goals. Another is ensuring that healthcare providers themselves are educated about the importance of recommending both evidence-based pharmacotherapy and behavioral support, as this combination is more effective than either approach by itself.

Since no new treatments have been approved in over a decade, new pharmacologic therapy options are desperately needed. Currently available treatments can have side effects that lead to high rates of early discontinuation, thus reducing their overall efficacy. U.S. claims data show that 76% of those using Chantix® (varenicline), the most commonly prescribed smoking cessation therapy, fail to complete the US Food and Drug Administration (FDA)-approved three-month treatment regimen. A survey sponsored by Achieve found that the occurrence of side effects was the primary reason that 61% of survey respondents failed to complete their full prescription of Chantix or Zyban® (bupropion), the other prescription non-nicotine replacement therapy used for smoking cessation.

Achieve believes that cytisinicline, a natural, plant-based smoking cessation therapy, could be an important addition to the smoking cessation treatment landscape. Clinical data generated to date suggest that cytisinicline could have a lower incidence of troublesome side effects, which could help smokers complete their treatment regimen and lead to improved quit rates.

LL: What are the key challenges related to breaking nicotine addiction?

CJ: Nicotine usage results in dopamine release, which provides users with a sense of pleasure, and it also acts as a stimulant, which can help them focus. Stress and social situations can be triggers for smoking where these effects can be rewarding, and smokers can also become accustomed to having a cigarette in their hands or mouths. Alternatively, smoking cessation leads to nicotine withdrawal, which is associated with symptoms such as feeling irritable, having trouble sleeping, difficulty thinking clearly, hunger and weight gain. So, there are biologic, physical and psychologic obstacles to breaking nicotine addiction. Medication can help to address the biologic component of addictions, and behavioral therapy can help to address the physical and psychologic components. Unfortunately, less than 5% of smokers trying to quit use both pharmacotherapy and behavioral therapy, even though the combination of both approaches results in improved quit rates compared with either approach by itself.

LL: Could you tell us more about Achieve’s mission to help people battling nicotine addiction?

CJ: Achieve’s singular focus is to address nicotine addiction and the global deterioration of health due to smoking through the development and commercialization of cytisinicline. We are currently evaluating cytisinicline as a smoking cessation therapy in combination with behavioral support in a Phase 3 trial (ORCA-2) for adult subjects who smoke combustible cigarettes and have tried unsuccessfully to quit. We also intend to initiate a separate clinical trial designed to specifically evaluate cytisinicline as a cessation therapy for those wishing to quit e-cigarettes (vaping), pending available funding.

LL: What is cytisinicline and how does it work?

CJ: Cytisinicline is a plant-based, naturally occurring alkaloid that has a structure similar to nicotine.  It is believed to help in smoking cessation by binding to the α4β2 nicotinic receptors in the brain. This binding has a dual role: it partially stimulates a weak release of dopamine, which helps to reduce both the craving for nicotine and the severity of symptoms that occur with nicotine withdrawal symptoms, while directly inhibiting nicotine binding, which reduces the satisfaction that users of combustible cigarettes and e-cigarettes (vaping) typically associated with nicotine use.

We believe that a key advantage of cytisinicline compared with other prescription cessation therapies that target the α4β2 nicotinic receptor, such as Chantix, is that cytisinicline is much less active at other receptors that regulate serotonin. We believe this may provide a better side effect profile, especially with respect to nausea/vomiting and sleep disorder/abnormal dreams.

LL: Could you touch on the design and primary endpoints of the Ongoing Research of Cytisinicline for Addiction (ORCA) clinical studies you have been conducting and summarize key findings?

CJ: We are currently conducting ORCA-2, which is a Phase 3 double-blind, placebo-controlled study comparing cytisinicline and placebo in combination with behavioral support for smoking cessation. The primary endpoint is 4-weeks continuous smoking abstinence on treatment. The study is also looking at 6- and 12-week treatment courses of cytisinicline, which will provide insight into whether longer treatment leads to improved efficacy or if continued treatment prevents early relapse.

The dose and schedule that is being evaluated in ORCA-2 was determined based on the results of ORCA-1, which was a double-blind, randomized, placebo-controlled Phase 2b trial that evaluated various dosing schedules of cytisinicline plus behavioral support in approximately 254 smokers. Key findings from the study were that subjects in the cytisinicline arms (regardless of dose or schedule) had larger reductions in cigarettes smoked compared with placebo. All cytisinicline arms had statistically significantly higher abstinence rates at 4-weeks post-treatment compared with placebo. Both cytisinicline arms had statistically significantly higher continuous abstinence rates from Weeks 5 to 8 post-treatment compared with placebo. There were no safety concerns and cytisinicline was well tolerated, with no serious adverse events reported. Importantly, the incidence of nausea was lower than what has been publicly reported for Chantix. Based on excellent tolerability and best continued abstinence rate, the cytisinicline 3 mg three times per day dose/schedule was selected for use in the ongoing ORCA-2 Phase 3 trial.

LL: Are you able to share any further information in terms of next steps and future research?

CJ: We are currently enrolling and dosing patients in ORCA-2. We also intend to initiate a separate clinical trial designed to specifically evaluate cytisinicline as a cessation therapy for those wishing to quit e-cigarettes (vaping), pending available funding. It is estimated that about 13.7 million American adults used e-cigarettes in 2018. While there is evidence suggesting that smokers of combustible cigarettes may reduce their risk of tobacco-related disease by switching to e-cigarettes, the long-term effects of nicotine addiction or continued e-cigarette use on overall health is not yet known. Many experts and professional societies recommend that smokers who switch to e-cigarettes to reduce harm should eventually aim to stop nicotine vaping. None of the approved smoking cessation therapies have been evaluated for their ability to help people quit nicotine-vaping, creating an unmet need for an evidence-based vaping cessation therapy. Achieve believes that addressing the negative health effects of nicotine dependence encompasses both combustible and e-cigarette use, and we believe that cytisinicline could be an important new treatment option for users of these nicotine products who wish to quit.

Cindy Jacobs was speaking with Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.