The Role of Non- Combusted Products in Harm Reduction September, 2018

Jason Flora, Maria Gogova, Mohamadi Sarkar

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 : A Significant Public Health Problem

Cigarette smoking Cigarette Smokers’ life causes about smoking causes expectancy one of every an estimated is about five deaths 480,000 deaths 10 years shorter annually annually than nonsmokers’ in the U.S.

Source: http://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/tobacco_related_mortality/index.htm#cigs

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 2

Our Focus Reducing the harm caused by tobacco products is a strategic focus for our companies and an important step in achieving our Mission Developing and marketing lower-risk products

Helping reduce underage tobacco use

Supporting cessation

Combusted Continuum of Risk Non-combusted Tobacco Products Tobacco Products Communicating about the health effects of Most Harmful Least Harmful tobacco use

http://www.altria.com/Responsibility/Tobacco-Harm-Reduction/Pages/default.aspx?src=topnav 3/22/16

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 3

Public Health Recognizes a Continuum of Risk

Hatsukami et. al. 2009 Shields et. al. 2011 Benowitz 2014

Frank et. al. 2016 El-Toukhy & Choi 2016

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 4

Family Smoking Prevention and Act (FSPTCA)

Regulatory Oversight of Reduced Risk Products One of the purposes of the FSPTCA is “to provide new and flexible enforcement authority to ensure that there is effective oversight of the 's efforts to develop, introduce, and promote less harmful tobacco products”

Note: Third party trademarks and images are the property of their respective owners and are used for illustrative purposes only. Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 5

FDA Recognizes Continuum of Risk

“We must recognize the potential for innovation to lead to less harmful products, which, under FDA’s oversight, could be part of a solution. While there’s still much research to be done on these products and the risks that they may pose, they may also present benefits that we must consider.” Dr. Scott Gottlieb FDA Commissioner Continuum of Risk Combusted Tobacco Products Non-combusted Tobacco Products

MOST LEAST HARMFUL HARMFUL July 28, 2017: Protecting American Families: Comprehensive Approach to Nicotine and Tobacco https://www.fda.gov/NewsEvents/Speeches/ucm569024.htm

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 6

Harm Reduction Opportunities – U.S.

~5 MM Adult Smokeless Consumers

~40 MM Adult Cigarette ~10 MM Smokers Adult E-Vapor Consumers

*Source: 18+ATCT 12MM ending December 2017 Numbers may not foot due to rounding

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 7

Pathways to Market for New Tobacco Products

Product Pathway Reduced Exposure or Reduced Risk Claim

Substantial Equivalence Premarket Tobacco Modified Risk Tobacco Substantial Equivalence Exemption Request Product Application Product Application “SE” or “905” “905(j)(3)” “PMTA” or “910” “MRTPA” or “911”

For reduced risk claims, manufacturers must demonstrate: . Significant reduction in harm and risk of tobacco-related disease to individuals . Benefit to the health of the population as a whole taking into account both users of the tobacco products and persons who do not currently use tobacco products

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 8

Evidence to Support Reduced Risk

Constituent Risk Reduction Harm Reduction Reduction Individual Population

Risks and Product Chemical Toxicology Studies in Perception Benefits to Design and and Physical and Risk Adult Human and Behavior Health of the Control Characterization Assessment Subjects Assessment Population

The Product Exposure and Health Risk Impact on the Population

The science and evidence necessary for a MRTPA is different for new products (e.g., e-vapor and heated tobacco products) where decades of exposure data do not exist compared to traditional products (e.g., smokeless tobacco) where epidemiological data is available.

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 9

Potential Product Platforms

Oral Tobacco/ Heated Tobacco E-Vapor Nicotine Products Products

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 10

Potential Tobacco Harm Reduction Product Platforms

Oral Tobacco/ Nicotine Products

USSTC Submitted a MRTP Application (MRTPA) for Copenhagen Snuff Fine Cut on March 20, 2018

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 11

Harm Reduction Opportunities – Smokeless Tobacco

~5 MM Adult Smokeless Consumers 2.3 Million Adult Dual Users1

Over 20% of adult ~40 MM smokers are Adult Cigarette interested in Smokers smokeless tobacco alternatives to cigarettes2

*Source: 18+ATCT 12MM ending December 2017 Numbers may not foot due to rounding

1 Based on ALCS analysis of PATH Wave 1 data Sep 12, 2013 – Dec 14, 2014 2 Based on internal ALCS research Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 12

Perceptions of Smokeless Tobacco Two U.S. Government studies show the public generally considers smokeless tobacco use to have the same or greater risk than cigarette smoking. Population Assessment of NCI Health Information National Tobacco and Health Survey1 Trends Survey2 Overall, about 90% the population “Do you think that some smokeless tobacco thinks smokeless tobacco has the ST products are less harmful to a person's 2 same or greater risk than health than cigarettes?”

10.3 13.2 Yes 29.5 27.1 . 27.6% of the population think smokeless No tobacco is more harmful than cigarettes 70.7 Don't 69.6 know . 8.6% of the population think smokeless 60.0 71.8 tobacco is less harmful than cigarettes 19.0 17.1 10.5 1.2 ST users Smokers Dual users Total users

1 1 Data excerpted from Highlighted Findings From Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study presented at the 2016 annual meeting of the Society for Research on Nicotine and Tobacco 2 2 Data from ALCS analysis of the 2015 National Cancer Institute Health Information National Trends Survey (HINTS)

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 13

Public Health Perspectives on Smokeless Tobacco

. Many global public health organizations accept the scientific fact that smokeless tobacco is far less hazardous than cigarette smoking. For example:

- Royal College of Physicians (RCP): “The consumption of non-combustible tobacco is of the order of 10-1,000 times less hazardous than smoking, depending on the product.” 1

- World Health Organization (WHO): “[U]sers of smokeless tobacco products generally have lower risks for tobacco-related morbidity and mortality than users of combustible tobacco products such as cigarettes.”2

- Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR): “…in relation to the risks of the above major smoking-related diseases, and with the exception of use in pregnancy, STP [smokeless tobacco products] are clearly less hazardous, and in relation to respiratory and cardiovascular disease substantially less hazardous, than cigarette 3 smoking.” 1 Royal College of Physicians of London, Tobacco Advisory Group of the Royal College of Physicians, Protecting Smokers, Savings Lives (London: RCP 2002) 2 WHO, (2008) Scientific basis of tobacco product regulation. Second report of a WHO study group. WHO Technical Report Series 951. http://www.who.int/tobacco/global_interaction/tobreg/publications/ 9789241209519.pdf (accessed June 22, 2018). 3 European Commission, Health & Consumer Protection Directorate-General, Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), Health Effects of Smokeless Tobacco Products 115 (2008).

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 14

Data Sources for Epidemiological Evidence Two nationally representative public health surveys linked to the National Death Index (2011 update)

National Health Interview Survey National Longitudinal (NHIS) Mortality Study (NLMS) Survey years: . Based on the Current Population 1987, 1991, 1992, 1998, 2000, 2005 Survey Follow-up: . Survey years: 1993-2005 6-24 years . Follow-up: 5 years 154,391 total respondents, including 3,006 . 210,090 total respondents, current smokeless tobacco users including 3,492 current smokeless tobacco users These data sources enable a direct comparison of the relative risk of smokeless tobacco use to cigarette smoking

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 15

Summary: Smokeless Tobacco

. U.S. Government data show a substantial risk differential between smokeless tobacco (ST) use and cigarette smoking. . ST presents an opportunity to reduce the risks from cigarette smoking by correcting widely held misperceptions of the risk differential between ST and cigarettes, thereby helping consumers make more informed tobacco product use decisions. . Our MRTPA on Copenhagen Snuff Fine Cut has the potential to reduce the harm of cigarette smoking by: . Correcting widely held misperceptions between smokeless tobacco and cigarettes. . Helping consumers make more informed tobacco product use decisions.

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 16

Potential Tobacco Harm Reduction Product Platforms

Heated Tobacco Products

Philip Morris Through our agreement International (PMI) with PMI, Altria has the Submitted a MRTPA for exclusive commercial iQOS on December 5, rights to the iQOS system 2016 in the United States.

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 17

Application Overview: Introduction . The MRTPA for the iQOS Tobacco Heating System (THS) with three tobacco Heatsticks (PMTA submitted March 2017) - HeatSticks (THS) - Marlboro Smooth Menthol HeatSticks (low menthol)(lmTHS) - Marlboro Fresh Menthol HeatSticks (mTHS)

Source: May 2017 “Philip Morris International Summary of Modified Risk Tobacco Product Application”

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 18

Underlying Principles

. More than 6,000 constituents identified in cigarette smoke

. About 100 of these constituents are categorized as harmful or potentially harmful constituents ("HPHCs")

. Most of the HPHCs are formed when the tobacco burns

. The highest observed temperature of the tobacco in the iQOS Tobacco Stick is approximately 300ºC and cannot exceed 350ºC

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 19

Aerosol Chemistry and Physics . Cigarette total particulate matter (TPM) compared with THS aerosol composition (Health Canada Intense (HCI) machine-smoking conditions).

. The photographs of the Cambridge glass-fiber filter pads after the collection of cigarette smoke (left) and THS aerosol (right) are also shown.

Schaller J-P, Keller D, Poget L, Pratte P, Kaelin E, McHugh D, Cudazzo G, Smart D, Tricker AR, Gautier L, Yerly M, Pires RR, Le Bouhellec S, Ghosh D, Hofer I, Garcia,E, Vanscheeuwijck P and Maeder S (2016) Reg Tox Pharm, 81 Suppl 2:S27-S47

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 20

Relative Yield Ratios of THS on per Tobacco Stick/Cigarette Basis

. Data supports the hypothesis that the controlled heating of tobacco in THS resulted in a significant reduction in the pyrosynthesis of HPHCs.

. When compared with 3R4F, the formation of the majority HPHCs was reduced by more than 90% under the HCI machine- smoking conditions.

Schaller J-P, Keller D, Poget L, Pratte P, Kaelin E, a) Aerosol collection with Intense Health Canada’s Smoking Regime: 55 mL puff volume, 2-second puff duration, 30-second interval puff. Comparison on a per-stick basis. Reduction calculations exclude Nicotine, Glycerin and Total Particulate Matter McHugh D, Cudazzo G, Smart D, Tricker AR, Gautier L, (b) The PMI 58 list includes the FDA 18 and (c) the 15 carcinogens of the IARC Group 1 Yerly M, Pires RR, Le Bouhellec S, Ghosh D, Hofer I, Note: These data alone do not represent a claim of reduced exposure or risk Garcia,E, Vanscheeuwijck P and Maeder S (2016) Reg Tox Pharm, 81 Suppl 2:S27-S47; and PMI, M. Gilchrist Global Forum on Nicotine Presentation 2017

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 21

90 -Day Clinical Studies: BoE . % Reduction in Biomarkers of Exposure (BoE) after switching for three months iQOS Smoking Abstinence 100% 80% Cigarettes 60% 40% 20%

0%

Exposure Percent Percent ofCigarette

100% 80% Cigarettes

60% 40% 20%

0%

Exposure Percent Percent ofCigarette

. Levels of exposure to HPHCs when smokers switch to THS approach the levels observed in those who quit smoking during the study. Philip Morris Products S.A., PMI Research and Development. THS 2.7 Executive Summary 2016: Available on FDA CTP Website. ZRHM-REXA-08-US page 83

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 22

IQOS – Independent Research German Federal Institute of Risk Assessment “Our study confirms that levels of major carcinogens are markedly reduced in the emissions of the analyzed HNB [heat-not- burn] product in relation to the conventional tobacco cigarettes ....”

Mallock et al, Archives of Toxicology, 2018

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 23

Potential Tobacco Harm Reduction Product Platforms

E-Vapor

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 24

HPHCs in MarkTen® Aerosol Are Substantially Lower Than Reference Cigarettes Volatile Aromatic Organic Percentage Carbonyls B(a)P Aromatic Amines VOCs TSNAs Carbonyls B(a)P Amines Compounds TSNAs Change 100%0 Compared to Reference Cigarette 3R4F (mass/puff)

> 99% ~100% ~100% ~100% ~99.9% reduction reduction reduction reduction reduction

100 0% 55mL, 5 second duration, 30 second inter-puff interval

ALCS Internal Report LIQUID 16241 – MarkTen® XL Classic 3.5% nicotine, Official Stability Study – PMT1, 3, 6 and 9 months. Average of 140 intense puffs (55mL, 5 second duration, 30 second inter-puff interval). Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 25

Significant Differences in BOE and BOPH Between E- vapor Users and Cigarette Smokers1

1 Data shared at Society for Research on Nicotine and Tobacco 2018 Annual Meeting. Oliveri et al., Cross-Sectional Study Comparing Biomarkers of Exposure to Select Harmful and Potentially Harmful Constituents and Biomarkers of Inflammation and Oxidative Stress Between Adult E-vapor Users and Conventional Cigarette Smokers. Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 26

Royal College of Physicians (UK)

“Although it is not possible to quantify the long-term health risks associated with e- cigarettes precisely, the available data suggest that they are unlikely to exceed 5% of those associated with smoked tobacco products, and may well be substantially lower than this figure.”

2016

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 27

American Cancer Society Position on E-Cigarettes

. “Some smokers, despite firm clinician February 2018 advice, will not attempt to quit smoking cigarettes and will not use FDA approved cessation medications.”

. “These individuals should be encouraged to switch to the least harmful form of tobacco product possible; switching to the exclusive use of e-cigarettes is preferable to continuing to smoke combustible https://www.cancer.org/healthy/stay-away-from- products.” tobacco/e-cigarette-position-statement.html

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 28

Continuing the Advancement of Tobacco Harm Reduction

. As manufacturers, it is critical to develop a variety of innovative reduced harm tobacco products that are acceptable alternatives to conventional cigarettes for adult smokers, transparently provide extensive science and evidence about these products, and, with FDA authorization, bring them to market.

. FDA and the broader public health must provide reasonable regulatory pathways, unbiased scientific assessments, collaborative research, and science and evidence based differential risk communications about these products.

. A diverse market of FDA-authorized, non-combustible products with accompanying modified risk claims will enable informed decisions for adult cigarette consumers to choose products proven to be lower on the continuum of risk and thus is an extremely important step in advancing tobacco harm reduction in the U.S.

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 29

Altria’s Center for Research & Technology (CRT)

Questions?

Altria Client Services l Scientific Strategy and Analysis I Sr. Principal Scientist I 72nd TSRC, Memphis, Tennessee l September 2018 I 30