Saturday, October 1, 2022

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Biotechnology News Magazine

Reduced Nicotine Content Cigarettes: A Bridge to Somewhere: By James A Mish Chief Executive Officer 22nd Century Group

Addiction to nicotine products is a global health problem costing nations and communities hundreds of billions of dollars in medical costs and lost productivity yearly, plus millions of lives. Tobacco use is the leading preventable cause of disease and death in the United States.

According to the U.S. Department of Health and Human Services, smoking has been responsible for more than  20 million people dying from tobacco-related diseases in the fifty years between 1965 and 2014. During that study period smoking was responsible for the deaths of 6.5 million Americans from smoking-related cancers, 7.7 million from cardiovascular and metabolic diseases, 3.8 million from pulmonary illnesses, 108,000 from pregnancy-related disorders, and 86,000 from residential fires. An additional 2.2 million additional Americans have died from smoking-related heart disease, and 260,000 from lung cancer caused by second-hand smoke. Note that these figures were collected over 50 years. The latest reliable figures estimate the premature and preventable death toll from smoking in the U.S. at around 480,000 per year.

In addition to this devastating toll in human suffering, smoking-related illness in the United States costs more than $400 billion each year, including more than $225 billion in direct medical costs and $180 billion in lost productivity.

Worldwide figures are equally sobering. The World Health Organization (WHO) estimates that globally, more than 7 million deaths occur each year as a direct result of smoking, with an additional 1.2 million people dying from the effects of second-hand smoke.

Is willpower the answer?

Mark Twain stated that “giving up smoking is the easiest thing in the world. I know because I’ve done it thousands of times.” Anyone who has tried to quit and stay quit, or knows someone who has tried, immediately recognizes the irony in that statement.

Around 70% of smokers want to quit, but no more than 20% who are trying at any given time succeed, regardless of the method they use. Strategies based on willpower alone do not cost anything, but their success rate is depressingly low — just 3% quit for good the first time they try this way. Regardless of their method, most smokers require several attempts before they stop once and for all. While difficult, the good news is that with access to good support and appropriately regulated alternative products or medication, eventually, many successfully break their addiction to cigarettes. A 2018 study found that nearly 62% of adult Americans who had ever smoked cigarettes had quit; this is positive, though there is much more to be done to end this public health disaster.

All aspects of tobacco use are big business, including the global market for smoking cessation, valued at $21 billion with annual growth of around 10%. This highly fragmented market that includes services (psychotherapy, counseling, plus computer- and phone-based reminders), pharmaceuticals, dietary supplements, nicotine replacement products (gums, lozenges, patches, and reduced-nicotine tobacco products).

Pharmacologic interventions

The U.S. Food and Drug Administration (FDA) has approved two oral, non-nicotine-containing prescription-only drugs specifically for smoking cessation: Chantix (varenicline tartrate), and Zyban (buproprion hydrochloride).

While Pfizer’s production of Chantix is on hold, when available it competed with nicotine for receptors in the brain, thereby diminishing smoking’s biochemical “reward.” Many studies of pharmacologic agents for smoking cessation use, as a comparator treatment, nicotine replacement therapy (NRT), a strategy involving tobacco-free nicotine-containing gums, lozenges, patches, vapes, etc. Compared with NRT, Chantix is associated with gastrointestinal side effects (nausea, constipation, gas, vomiting) plus insomnia and vivid, unusual dreaming. For drinkers, Chantix may increase the likelihood of intoxication. Chantix is contraindicated in smokers under the age of 18.

Zyban, whose mechanism of action is unknown, is the same chemical entity as Wellbutrin, a non-SSRI-type antidepressant which, like Chantix, is not approved for individuals under age 18. It is presumed that Zyban also works by acting on sites in the brain affected by nicotine.

Where NRT supplies a substance already known to be well-tolerated in this patient group and available over the counter in many places, smokers considering either Chantix or Zyban are Rx only and require consultation with health providers on their suitability for individual smokers p.

A retrospective study of patients entering one smoking cessation clinic over a three-and-a-half year period compared the effectiveness of varenicline (166 patients), bupropion (148 patients) and NRT (108 patients). Although the clinic’s overall success rate was a respectable 35%, the interventions showed markedly different effectiveness at one year. Smoking cessation rates were 32.5% for varenicline (Chantix), 23% for bupropion (Zyban), and 52.8% for NRT.

Several other medications, approved for conditions other than smoking cessation, have been tried with varying degrees of success. These include the tricyclic antidepressant nortriptyline, the blood pressure agent clonidine, anxiolytics, and the opioid antagonist naltrexone. None of these agents enjoy broad acceptance and all, particularly clonidine, are associated with potentially serious side effects.

Dietary supplements have also been used directly or to support other strategies for smoking cessation. Clinical evidence to support their use, however, is slim even though some (e.g., S-adenosyl methionine, melatonin) have been extensively studied.

Nicotine replacement therapy

Nicotine replacement therapy (NRT) uses low doses of nicotine to reduce withdrawal symptoms and ease smokers into a smoke- and nicotine-free life. NRT may be self-directed — “on the fly” — or incorporated, with or without other cessation strategies, into a formal smoking cessation program under guidance from a healthcare professional or coach.

Numerous NRT products are available, most of them over the counter, including nicotine-containing gums, lozenges, sprays, patches, tobacco-free vapes, etc.

A review of the effectiveness of various NRTs suggests that all may improve a user’s chances to quit successfully by 50% to 70%, and that success is “largely independent of the intensity of additional support.”

The study analyzed results from 150 trials; many with more than 50,000 participants. Investigators calculated the risk ratio for abstinence vs. non-NRT control as 1.0 (95% confidence interval). Risk ratios and confidence intervals were similar for NRTs studied but some were clearly superior, for example nicotine gum (1.49; 95%), nicotine patch (1.64, 95%), oral tablets/lozenges (1.95; 95%); nicotine inhaler (1.90; 95%), and nicotine nasal spray (2.02, 95%). Five studies directly comparing NRT to non‐nicotine bupropion treatment showed no difference, but combining NRT with bupropion was more effective than bupropion alone (1.24; 95%). Adverse events were rare and mild.

Counseling, etc.

Many quit-smoking programs incorporate some form of counseling, coaching, or psychotherapy. Counseling is attractive because it does not contribute to nicotine exposure, does not interfere with pharmacotherapies, and may help with coexisting behavioral issues (e.g., overeating). A systematic review of studies combining counseling plus pharmacotherapy, however, revealed that these benefits were less achievable than was previously assumed.

Another review assessed the effectiveness of counseling to prevent relapse among smokers who had quit by any means, including on their own, through forced abstinence, or through drug treatment programs. The authors concluded that “there is insufficient evidence to support the use of any specific behavioral intervention to help smokers who have successfully quit for a short time to avoid relapse.”

Reduced nicotine content cigarettes

In July, 2017, FDA announced plans to “begin a public dialog” on lowering nicotine levels in cigarettes to non-addictive levels. The objective was to offer new smokers a less addictive alternative to conventional cigarettes (with the intention of making quitting easier Reducing tobacco dependence through the introduction of new cigarette products may seem counterintuitive but it makes sense when smoking is viewed as a complex behavior which, in addition to nicotine, involves taste, smell, respiratory tract sensations, and behavioral factors.

In December, 2019, FDA authorized the marketing  of two products manufactured by 22nd Century Group, Inc., a plant biotechnology company focusing on tobacco harm reduction. Where conventional U.S. cigarettes contain between 10 mg and 14 mg of nicotine per smoke the 22nd Century reduced nicotine cigarettes contain between 0.2 mg and 0.7 mg of nicotine per cigarette.

As part of the Agency’s scientific review, it considered scenarios in which reduced-nicotine cigarettes would harm rather than help. For example, would users smoke more or inhale more deeply to achieve nicotine doses similar to those of conventional cigarettes? Research available at the time suggested this would not occur, that individuals who began smoking these products would not become addicted, and that these products might also help smokers addicted to other brands to quit.

Subsequently, in late 2021, the FDA authorized two of  22nd Century products, with the brand name of VLN® King and VLN®  Menthol King, under the Agency’s “modified risk tobacco products” (MRTP) designation. These are the first “combustible” cigarettes thus authorized. In addition, some  smokeless MRTPs have also been approved, for example Philip Morris’s IQOS product (which heats tobacco but does not burn it), and several smokeless oral tobacco products.

Research on reduced nicotine content cigarettes

FDA’s decision to explore the potential benefits of reduced nicotine content cigarettes was based on a range of comprehensive clinical studies and other research. A 2007 study found, for example, that treating patients with Quest 3 denicotinized (containing about 0.05 mg of nicotine) cigarettes in addition to a standard 21-mg patch resulted in lower cravings and facilitated quitting, compared with a Quest 1 product (6 mg of nicotine). A 2008 trial compared three conditions: NRT patch plus Quest, NRT plus standard cigarettes, and Quest plus placebo patch. The primary endpoint was four weeks of continuous abstinence, which was reached by 32.8% of subjects in the Quest + patch arm vs. 21.9% in the active control + patch group. Just 16.4% of those using Quest + placebo patch met this endpoint. A third early piece of evidence, comparing 0.05-mg cigarettes, 0.3mg cigarettes, and 4mg lozenges concluded that “The 0.05 mg cigarette led to a significantly higher rate of cessation than the 0.3 mg cigarette and a similar rate as nicotine lozenge.”

Another study also found, surprisingly, that the 0.05-mg dose resulted in less “compensatory smoking behavior” than either the higher-dose smoke or the lozenge. This term refers to smoking more or taking more or deeper draws to compensate for the lower nicotine dosage. This finding was confirmed in a major 2018 study which found that, compared with a tapered nicotine dose, an “Immediate reduction in nicotine content of cigarettes provided the greatest reduction in biomarkers of smoke exposure over time.” It is important to note that prior to granting its MRTP authorization, the FDA and NIH had invested more than $120 million studying reduced nicotine cigarettes.

Unhealthy compensatory behavior is always a concern when treating addiction. In addition to reducing nicotine cravings as noted above, the use of reduced nicotine content cigarettes is not associated with increased reliance on either alcohol or cannabis products.

Discussion

“The FDA should quickly move to reduce nicotine levels in cigarettes to non-addictive levels. If we reduce the level of the stimulus, we reduce the craving. It is the ultimate harm reduction strategy.”

— David Kessler, MD, Former FDA Commissioner, speaking on the Impact of the Family and Smoking Prevention and Tobacco Control Act, June 16, 2010

Dr. Kessler’s comments reflect a desire, based in science, to break the connection between a set of behaviors (smoking) and an inherently addictive substance (nicotine). Because they use actual tobacco in combustible form, reduced-nicotine cigarettes are the uniquely capable of achieving this. Ignoring such human factors is perhaps one reason why patches, lozenges, vapes, and sprays enjoy an aggregate success rate of just 17% (endpoint: six month-long abstinence), just 7 percentage points better than the self-quit route.

Like other approached to smoking reduction or cessation, adult smokers need to be made aware of the products, either through responsible marketing practice or by healthcare professionals. A survey conducted on behalf of 22nd Century Group queried 501 smokers, averaging about four unsuccessful  quit attempts, about their preferences for smoking cessation products. 89% of those surveyed identified a very low-nicotine cigarette as their top choice to help them quit, and 88% said they would have tried to quit sooner had such a product been available (the survey was conducted in 2017, two years before the 22nd Century authorization).

Prescribers understand smoking’s behavioral components as well. In a survey of 101 U.S. primary care doctors and twenty pulmonologists, 73% recognized that the familiar use modality of low-nicotine cigarettes as the most desirable for patients trying to quit. 78% of respondents said they would prescribe low-nicotine cigarettes. A similar query of European physicians found that 100% would prescribe very low-nicotine cigarettes, and 73% would prescribe them to replace or augment regimens already underway. While all combusted products are damaging to health and can be deadly, the prospect of increasing quit attempts in the smoking population, while reducing cigarette consumption with a product that also has a low abuse liability is a compelling basis for considering such products as an option by healthcare professionals.

Conclusion

All tobacco or nicotine products available today, including pharmaceuticals, smokeless tobacco, vapes, and reduced nicotine cigarettes, carry some degree of risk, albeit much lower than cigarette addition. NRTs, despite being less harmful than smoking, carry some risk of addiction to the very substance the user is trying to quit.

What makes these products attractive, from the perspective of individual and public health, is that despite their clear short term risks these products benefit patients in the long term by helping them to smoke much less, increase their quit attempts, have more smokefree days and all with no or minimal withdrawal or craving. FDA has estimated that 8 million lives would be saved over the next 80 years if nicotine levels in all cigarettes were reduced “to minimally addictive levels.”

Reduced nicotine content cigarettes with 95% less nicotine represent a fresh approach to an ages-old problem, and a new alternative for smokers for whom NRT has not been effective. Where nicotine patches, gums, lozenges, and other nicotine replacement products provide the addictive substance but not the complex sensations involved with smoking — the experience — reduced nicotine content cigarettes work by preserving the behavioral and sensory factors, but with a nicotine dose that facilitates smoking less and increased quitting attempts.

Editor’s Note: Appointed Chief Executive Officer of 22nd Century Group in June 2020, Mish has a track record of delivering profitable growth at both privately-held and publicly-traded science-driven companies with a focus on pharmaceutical and consumer products commercialization.