Very Low Nicotine Cigarettesand

Low-Tar-to-Nicotine Cigarettesas

Potential Reduced Exposure Tobacco Products

Michael R. Moynihan22nd Century Group, Inc.69th Tobacco Science Research ConferenceSeptember 2015

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Cigarettes and the Risk Continuum

• Cigarettes are recognized as occupying one end of the tobacco product risk continuum, at quite a distance from other products

• However, cigarettes still dominate tobacco use• Many who have tried alternative tobacco

products, even many who use other products regularly, continue to smoke

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Cigarettes and the Risk Continuum

• 2104 U.S. National Health Interview Survey (NHIS) – 30 million U.S. adults have tried e-cigarettes– 8.9 million use some days or daily– 71% of e-cigarette users are also smoking

cigarettes– Only 2.3 million are using e-cigarettes and not

smoking, compared to about 40 million who are smoking cigarettes

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Cigarettes and the Risk Continuum

• Why do cigarettes still dominate tobacco use?– Matching the nicotine delivery of cigarettes with

non-combustible products may be possible, but is not easy

– Cigarettes are nicotine delivery devices, but not just nicotine delivery devices

– For many current smokers, the behavioral aspects of smoking are very significant

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Cigarettes and the Risk Continuum

Alternative products cannot reduce risk in those who will not use them.

Are there combustible products that can reduce smoke intake by those that continue to smoke?

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Reduced Nicotine Cigarettes• Reducing the nicotine content of cigarettes is not a

new idea– Early interest may have been driven by recognition of

nicotine’s efficacy as an insecticide and potential direct toxicity, but also in part to provide less “harsh” smoke

– More recently, proposed as regulatory strategy to reduce tobacco use

– May have a role in reducing nicotine exposure and smoking in a subgroup of smokers who choose to use such products

• Challenging to reduce nicotine to very low levels while retaining “tobacco” aroma and flavor

• A number of different approaches have been used– “Sweating” or extraction to produce “denicotinized”

tobacco– Use of tobacco with low alkaloid tobacco content

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Reduced Nicotine Tobacco and Cigarettes“Denicotinized” Tobacco

Sano, O-Nic-O, Sackett, Dormy Bailey et al ., 1928

Finnegan,1945

Valleau,1949

Legg et al ., 1969

Legg et al ., 1970

Chaplin, 1975

Diana and Vaught, 1990

Pickworth et al, 1999

Next, Merit Free, Benson & Hedges De-Nic Dunsby and Bero, 2004

Research Cigarettes Pickworth et al ., 2002

Quest 3 Xie et al. 2004

Xodus, Magic, MAGIC 0

Research Cigarettes Hatsukami et al ., 2013

Lopez, 2011 (MS Thesis)

Dewey TWC 2014

Genome editing

Non-transgenic VLA Tobacco

Sequence-guided mutant selection

Low Alkaloid (LA) Tobacco Varieties

nic1, nic2 genes (A, B loci) Research Cigarettes

“Denicotinized” Tobacco Redux

Supercritical CO2

extraction

Genetically Engineered VLA Tobacco

Suppression of nicotine biosynthesis genes

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VLN Cigarettes and Smoking Behavior• Published studies including VLN Cigarette Smoking for >1 week

– Donny et al., 2007, Addiction 102:324–334– Donny and Jones, 2009, Drug Alcohol Depend. 104:23–33– Hatsukami et al., 2010, Addiction 105:343–355– Hatsukami et al., 2013, Cancer Epidemiol. Biomarkers Prev. 22:1015–

1024– Walker et al., 2012, Addiction 107:1857–1867– Hammond D, O'Connor RJ 2014, Cancer Epidemiol Biomarkers Prev

23:2032-40• X-22 Cessation Trial, 22nd Century (NCT01400815)

– 234 smokers intending to quit within next 3 months – Randomized to VLN or control cigarettes for 6 weeks prior to quit date

• Investigating the Impact of Nicotine Using SPECTRUM Cigarettes, CENIC (NCT01681875)– 840 smokers not intending to quit within 30 days– Randomized to one of 6 research cigarettes with different nicotine

content or usual brand for 6 weeks 8

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22nd Century X-22 Smoking Cessation TrialCigarette Consumption Prior to Quit Date

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22nd Century X-22 Smoking Cessation TrialCigarette Consumption Prior to Quit Date

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CENIC Study- Smokers Not Intending to Quit

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VLN Cigarettes and Smoking Behavior

• Fewer cigarettes per day• Decreased nicotine exposure• Decreased abstinence-induced withdrawal• Increased quit attempts

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Next Generation VLN Tobacco

• Available palette of VLN tobaccos is limited• Advances in molecular genetics of tobacco provide alternative

approaches• Nicotiana Berberine Bridge-Like (BBL) Enzyme

– Catalyzes final steps in nicotine synthesis (Kajikawa et al., 2011, Plant Physiol 155(4):2010-22)

– Six loci in N. tabacum– Knockouts

• Sequence-guided selection (Lopez, 2011, MS Thesis, North Carolina State University)

• Genome editing (in progress, Dewey lab, NCSU)• Advantages over current VLN Tobacco

– Absence of nic loci, which affect maturation and quality– Absence of non-tobacco DNA– Greater reduction in nicotine and total nicotinic alkaloid content

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Low-Tar-to-Nicotine Cigarettes

• In the 1970s, Russell argued for significantly reducing “tar” yield while maintaining the nicotine yield (Br Med J 1:1430-3)

• Russell and others maintained this position for an extended period (Kozlowski et al. 1975; Goldfarb et al., 1976; Fagerström, 1982; Gori and Lynch, 1985; Armitage et al., 1988; Russell 2000; McKinney et al., 2014), but empirical evidence that LTN cigarettes can substantially reduce smoke intake is limited

• Interpretation of studies with cigarettes fortified with nicotine or with nicotine salts is complicated by uncertainty as to how differences in sensory characteristics and palatability of the experimental cigarettes may have affected smoking behavior

• The range in nicotine concentration and tar-to-nicotine ratio in many studies is limited– Recent study by McKinney et al. (Nicotine Tob Res 16:948) is a notable

exception in terms of range in nicotine content, but higher nicotine cigarettes were “usual tar – high nicotine” rather than “low tar –medium nicotine”

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Higher Nicotine Flue Cured Tobacco• Nicotiana with significantly higher nicotine content are

known, but attempts to produce higher nicotine varieties useful for cigarette manufacturing have faced technical and non-technical difficulties

• Advances in the understanding of molecular mechanisms responsible for the upregulation of nicotine biosynthesis in tobacco in response topping has provided a surprisingly simple approach to genetic engineering of higher nicotine levels in flue-cured tobacco.– A number of genes encoding transcription factors regulating

gene expression of nicotine biosynthesis enzymes were identified (Todd et al., 2010)

– Constitutive expression of a single transcription factor in a flue-cured tobacco variety resulted in more than 1.5 times the nicotine of the parent variety (Wang, PhD Thesis, NCSU, 2011)

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Topped

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HNFC Tobacco2014 Comparative Trial

Total Reducing Cwt Grade Nicotine Alkaloids Sugars Yield Value Index

Genotype (%) (%) (%) (lbs/A) ($)NC95/MYC2AOE-3 4.7 5.3 11.06 2130 136.79 81.20NC95/MYC2AOE-6 4.8 5.5 11.49 2113 138.61 82.56NC95 3.3 3.7 15.12 2597 129.68 77.47K346 2.9 3.1 14.20 2585 138.95 83.15K326 2.6 2.8 15.80 3048 134.24 80.27

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Is There a Place for Combustible Reduced Exposure Tobacco Products?

• VLN and LTN cigarettes would be positioned much higher on the risk continuum than non-combustible tobacco products

• However, higher acceptance by current smokers might result in substantial reductions in total smoke exposure

• With VLA and HN tobacco varieties, no substantial changes in tobacco production, tobacco processing, or cigarette manufacturing would be required to produce VLN or LTN products

• VLN and LTN approaches can be easily combined with other reduced exposure strategies

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Is There a Place for Combustible Reduced Exposure Tobacco Products?

Yes,if they are assessed by comparison to

products in actually in wide use, and can be differentiated in the marketplace.

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