Clinical: Individual Risk

17 September 2024

CHAPTER 4 . OUR SMOKELESS SCIENCE

**Clinical: Individual Risk^*†**

How the product may impact consumers

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Our clinical exposure studies have shown that adult smokers who switch completely to our Smokeless Products reduce their exposure to a number of harmful chemicals as compared to continued smoking.^*† Using the same methods, our clinical risk studies focus on biomarkers that reflect unfavourable changes within the body known to occur with smoking.

Referred to as ‘Biomarkers of Potential Harm’ (BoPH) or ‘Biomarkers of Biological Effect’ (BoBE), we monitor those that are known to occur with smoking. These BoPH are markers of physiological processes in the body such as inflammation, oxidative stress, and DNA damage. These processes can be indicators of potential disease pathways: chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and lung cancer.

As these physiological changes take time to occur, our clinical risk studies focus on product use for at least six months. This gives a reasonable time for changes to occur. However, it should be noted that by their very nature these effects can be caused by other lifestyle choices and not just smoking (e.g. obesity also affects cardiovascular disease risk).

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In our clinical risk studies, we monitor seven BoPH and one physiological measure associated with disease endpoints:

Unfavourable Changes and Disease

Oxidative Stress

Oxidative stress is a significant factor in the development of CVD, COPD and cancer.^[1,2,3]Oxidants produced as a result of cigarette smoking can cause damage to DNA and affect arteries and lung tissue. We measure 8-epiprostaglandin F2α Type III (8-epi-PGF2а Type III) as a biomarker for oxidative stress. Levels have been shown to be higher in smokers compared to never-smokers.

Inflammation

We monitor white blood cell count (WBC) as a biomarker for inflammation. White blood cells are part of the immune system and increased levels occur with bacterial and viral infections. Levels also increase with various cancers, inflammatory disorders (e.g. arthritis) and COPD, as well playing a prominent role in CVD.^[4,5,6]Levels have also been shown to be higher in smokers compared to never-smokers.

CVD

We measure several biomarkers for CVD:

Carbon monoxide
Carbon monoxide attaches to red blood cells and therefore prevents the attachment of oxygen which places stress on the heart to deliver oxygen to the body. Smoking leads to higher carbon monoxide levels in the blood compared to never-smokers. It is measured in exhaled breath (COex) or Carboxyhemoglobin the blood (COHb).^[7,8]
Soluble intercellular adhesion molecule (sICAM)
sICAM is part of the blood vessel inflammatory system. It contributes to CVD with levels in blood greater for smokers compared to never-smokers.^[6]
High-density lipoprotein (HDL) cholesterol
HDL cholesterol or ‘good cholesterol’ plays a protective role in CVD, levels tend to be lower in smokers compared to never-smokers.^[6]
Thromboxane (11-dTx-B2)
Thromboxane is a molecule produced in the blood to help it clot, generally after an injury. Levels measured in urine are greater for smokers compared to neversmokers.^[6]

Lung Cancer

Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK) has been shown to be associated with lung cancer development in smokers. Measured as total NNAL in the urine, levels in smokers are greater compared to never-smokers.^[9]

Potential Detrimental Health Outcomes

Inclusive of measuring BoPH/BoBE, we assess potential detrimental health outcomes through physiological measures for all our participants such as blood pressure monitoring. We have also used spirometry, a simple test to help diagnose and monitor certain lung conditions.^[10,11]

"BOPH could serve as more intermediate endpoints for assessing potential health risk of new and novel tobacco products in the absence of long-term epidemiological evidence."

Scientists from the Office of Science

Center for Tobacco Products, Food and Drug Administration^[14]

Smokers who completely switch to our Smokeless Products can achieve favourable changes in biomarkers of potential harm.

Like our clinical exposure studies, our clinical risk studies can be either Longitudinal or Cross-Sectional in design.

Longitudinal (Journey)

Cross-Sectional (Snapshot)

Vuse Users and Former Smokers: %Difference vs. Smokers

Our cross-sectional clinical studies have proven that adult consumers of Vuse and Velo have favourable differences in BoPH compared to adult smokers with some comparable to former smokers.*^†[12,13]

Velo Users and Former Smokers: %Difference vs. Smokers

Standard deviations have been omitted from charts for ease of reading, Full figures are available in references: ^{[10], [11] and [12]}

Our longitudinal clinical study has proven that switching completely to glo can have favourable changes in BoPH compared to smokers with some comparable to former smokers.*^†[11]

glo Users and Former Smokers: %Change vs. Smokers

"In all of our clinical studies when switching completely to our Smokeless Products we observed statistically significant reductions in exposure to a number of harmful chemicals and favourable changes in biomarkers of potential harm when compared to continued smoking. The results of our studies demonstrate that reduction in the studied biomarkers of those switching to our Smokeless Product approach that of those quitting smoking.*^†"

Dr Michael McEwan

Head of Health Outcomes

Footnotes

* Based on the weight of evidence and assuming a complete switch from cigarette smoking. These products are not risk free and are addictive.

† Our products as sold in the U.S., including Vuse, Velo, Grizzly, Kodiak, and Camel Snus, are subject to FDA regulation and no reduced-risk claims will be made as to these products without agency clearance

^Not a BoPH but physiological measure

References

[1] Lowe, F.J., et al., Lung cancer biomarkers for the assessment of modified risk tobacco products: an oxidative stress perspective. Biomarkers, 2023. 18(3): p. 183-195. DOI: 10.3109/1354750x.2013.777116

[2] Yao, H. and Rahman, I., Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. Toxicol Appl Pharmacol, 2011. 254(2): p. 72-85. DOI: 10.1016/j.taap.2009.10.022

[3] Siti, H.N., et al., The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vasc Pharmacol, 2015. 71: p. 40-56. DOI: 10.1016/j.vph.2015.03.005

[4] Ross, R., Atherosclerosis is an inflammatory disease. Am Heart J, 1999. 138(5): p. S419-S420. DOI: 10.1016/S0002-8703(99)70266-8

[5] Rader, D.J. and Daugherty, A., Translating molecular discoveries into new therapies for atherosclerosis. Nature, 2008. 451: p. 904-913. DOI: 10.1038/nature06796

[6] Scherer, G., Suitability of biomarkers of biological effects (BOBEs) for assessing the likelihood of reducing the tobacco related disease risk by new and innovative tobacco products: a literature review. Regul Toxicol Pharmacol, 2018. 94: p. 203-233. DOI: 10.1016/j.yrtph.2018.02.002

[7] Scherer, G., Carboxyhemoglobin and thiocyanate as biomarkers of exposure to carbon monoxide and hydrogen cyanide in tobacco smoke. Exp Toxicol Pathol, 2006. 58(2-3): p. 101-124. DOI: 10.1016/j.etp.2006.07.001

[8] Peck, M.J., et al., Review of biomarkers to assess the effects of switching from cigarettes to modified risk tobacco products. Biomark, 2018. 23(3): p. 213-244. DOI: 10.1080/1354750X.2017.1419284

[9] Hecht, S.S., et al., Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai cohort study. Cancer Lett, 2013. 334(1): p. 34-38. DOI: 10.1016/j.canlet.2012.07.016

[10] MacIntyre, N.R., Spirometry for the diagnosis and management of chronic obstructive pulmonary disease. Respiratory care, 2009. 54(8): p. 1050-1057.