Hurdles in Treating Aging as a Disease for Drug Development February 9, 2018 Second Annual Workshop on Healthspan Extension Policy and Regulation Gary Marchant, Ph.D., J.D. Regents’ Professor and Lincoln Professor of Emerging Technologies, Law & Ethics

FDA Definition of “Drug” The term "drug" means: articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals (by chemical action); or articles (other than food) intended to affect the structure or any function of the body of man or other animals (also by chemical action).

Defining the Disease of “Aging” for Drug Development? Premature, accelerated or “degenerative” aging could be the defined disease condition just like premature balding, loss of memory, or visual deterioration Or define new disease intervention “age delaying” “delaying multiple morbidities relating to aging”

Defining Clinical Endpoints of Premature Aging Ideal – follow large cohort of individuals on anti-aging intervention (blinded) and compare their lifespan and healthspan with placebo controls Reality – such a study would require many thousands or tens of thousands of subjects followed for two or more decades Economically and practically infeasible Therefore need surrogate biomarker to measure rate of aging

FDA’s Perspective: Regulatory Pathways FDA presentation recognized two potential regulatory pathways for anti-aging treatment: “The treatment can be evaluated for the ability to prevent or delay conditions that may not yet have a rigorously defined pathophysiology, but occur with age and have adverse outcomes.” e.g., loss of muscle mass and function (sarcopenia) e.g., loss of balance leading to morbidity and mortality from fractures resulting from falls “The treatment can be evaluated for its ability to improve outcomes in an optimally-treated patient with a distinct chronic disease that progresses over time when there are no known effects of the treatment on the pathophysiology of that disease.” Most persuasive if there were >1 such disease or conditions (TAME study)

Possible Study Design Solutions to Surrogate Endpoint Hurdle Use multi-morbidity as biomarker (e.g., TAME study) Use resilience to stresses as biomarker e.g., falls, immunizations, surgery, chemotherapy, cold/flu infections Various fragility indexes (FI) and multi blood biomarker signatures have been proposed Conduct study in highly enriched patient pool e.g., patients with premature aging conditions e.g., Alzheimer’s Prevention Initiative

Possible Emerging Technology Molecular Biomarkers Use senescent cell numbers as biomarker Transcriptomics Epigenetics Big data Artificial intelligence Combine multiple molecular and physiological markers for aging score?

Daniel W. Belski et al, Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing, Am. J. Epidemiology (in press) “The implication of this analysis is that several methods proposed to quantify biological aging in fact appear to quantify different ‘things.”

Hallmarks of Aging López-Otín et al., 2013 Functional Interconnections between the Hallmarks of Aging The proposed nine hallmarks of aging are grouped into three categories. (Top) Those hallmarks considered to be the primary causes of cellular damage. (Middle) Those considered to be part of compensatory or antagonistic responses to the damage. These responses initially mitigate the damage, but eventually, if chronic or exacerbated, they become deleterious themselves. (Bottom) Integrative hallmarks that are the end result of the previous two groups of hallmarks and are ultimately responsible for the functional decline associated with aging. López-Otín et al., 2013 Cell 2013 153, 1194-1217DOI: (10.1016/j.cell.2013.05.039) Copyright © 2013 Elsevier Inc. Terms and Conditions

Other Hurdles: Inter-Individual Heterogeneity People have different genetic, epigenetic, environmental, disease, and age factors that affect rate of aging This heterogeneity may also influence response to anti-aging interventions E.g., caloric restriction extends lifespan on some inbred strains of mice, but reduces lifespan in others

Risk-Benefit Analysis FDA conducts risk-benefit analysis in approving drugs and biologics Greater tolerance for risk if benefits of treatment substantial, and vice versa With anti-aging interventions, will be treating “healthy” people Claim that anti-aging drugs would have to be as safe as drinking water But this argument fails to frame premature aging as a disease Very substantial potential health benefits from slowing aging

“We must draw aside the rosy veil of tradition and face ageing for what it is, and in all its horror; the greatest disease of them all.” David Gems, The aging-disease false dichotomy: understanding senescence as pathology. Front Genet, 6. (2015)