SELECTIVE RECEPTOR MODULATORS (SARMS): A NEW CLASS OF MUSCLE BUILDING AGENTS

James T Dalton, PhD Dean and Professor of Pharmaceutical Sciences

November 28, 2018 Disclosures

• Inventor on enobosarm and other SARM patents • Receive royalty distributions on SARM inventions through University of Tennessee Research Foundation Anabolic/androgenic SARMs are anabolic in muscle and prostate-sparing

MUSCLE SARM Testosterone = SARM Brain

Skin

PROSTATE Muscle Testosterone >> SARM Prostate

Bone Stimulation Inhibition Enobosarm Dose Response and Tissue Selectivity

Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT. J Pharmacol Exp Ther. 304(3):1334, 2003;Kim J, Wu D, Hwang DJ, Miller DD, Dalton JT. J Pharmacol Exp Ther. 315(1):230, 2005 Tissue selectivity

130 SARM 120

110

100 Soleus muscle Levator Ani 90 strength 80 weight Control Intact of % 70

60 0.5 1 5 10 25 Dose (mg/kg/day)

100

90 Hydroxyflutamide 80

70 Prostate SARM Bone 60

50 weight Control Intact of % μCT

40

30 0.5 1 5 10 25 Dose (mg/kg/day) Gao, W., Kearbey, J.D., Nair, V.A., Chung, K., Parlow, A.F., Miller, D.D., and Kearbey JD, Gao W, Narayanan R, Fisher SJ, Wu D, Miller DD, Dalton JT. Dalton, J.T. Endocrinology, 145(12): 5420-5428, 2004. Pharmaceutical Research, 24(2):328-335, 2007. Gao W, Reiser PJ, Coss CC, Phelps MA, Kearbey JD, Miller DD, and Dalton JT. Kearbey JD, Gao W, Fisher SJ, Wu D, Miller DD, Dalton JT. Endocrinology, 146(11):4887-4897, 2005. Pharmaceutical Research, 26(11):2471-2477, 2009. Molecular mechanisms of selectivity

SARM-LBD Ligand-specific differences in: E897 Q738M734 . AR conformation (x-ray) K720 I898 . M894 Tissue accumulation E893 L712 V716 K717 . Lack of 5α-reductase E709W741 V713 amplification X-Ray: DHT, SARM, AF-2 . Gene regulation Bohl et al. Proc Natl Acad Sci U.S.A. 2005;102(17):6201.Bohl et al. J Biol Chem. 2005;280(45):37747.Bohl et al. J Biol Chem. 2007;282:13468. . N/C interactions 3.5 . Non-genomic signaling 3.0 ProstateProstate 2.5 . Coactivator/corepressor 2.0 SARM Tissue interactions 1.5 Concentrations 1.0 Skeletal Muscle after Oral Dosing 0.5 Muscle 0.0 Concentration (ug S-4/g tissue) S-4/g (ug Concentration

0 5 10 15 20 25 30 Time (hour) SARMs in Development

Compound Clinical status Enobosarm (GTx) Phase III (NCT01355497 and NCT01355484) GSK2849866 (GSK) Phase I (NCT01696604) MK-0773 (Merck) Phase I (NCT00529659) GLPG0634 (Galapagos) Phase I (NCT01820806) LGD-4033 (Ligand) Phase I S-101479 (Kaken) Phase I BMS-564929 (BMS) Phase I LY2452473 (Eli Lilly) Phase I PF-05314882 (Pfizer) Phase I NC O

F3C N N O OH Galapagos

7 SARM Clinical Applications

• Hormonal therapy for breast cancer – Phase II (ongoing): ER+ and AR + metastatic breast cancer – Phase II (ongoing): triple negative, AR+ metastatic breast cancer

• Chronic Muscle Wasting – Phase II (complete): Sarcopenia (age-related muscle wasting) – Phase II (complete): Stress Urinary Incontinence – Duchenne Muscular Dystrophy

• Acute Muscle Wasting – HIV – End-stage renal disease – Burns – Phase III (complete): Cancer cachexia Enobosarm Clinical Trial Overview (27 completed/ongoing trials, > 2200 subjects)

Study # Title Subjects G100401 Single ascending dose study in healthy, young male volunteers (0,1, 3, 10, 30 and 100 mg) 96 G100402 Multiple ascending dose study in healthy, young males and elderly males (14 days) 71 G100503 Divided dose study in healthy elderly male and female volunteers (14 day) 36 G100506 Relative bioavailability and food effect study in healthy male volunteers 27 G100507 Phase I Study to Assess the Pharmacokinetics and Absolute Oral Bioavailability of GTx-024 in Caucasian and 48 African American Men and Postmenopausal Women G100508 Phase I Study to Assess the Effect of Mild and Moderate Hepatic Impairment on Pharmacokinetics of GTx-024 24

G100509 Phase I Mass Balance Study to Determine the Metabolism and Excretion of Radiolabeled GTx-024 6 G100510 A Single-dose, Randomized, Double-Blind, Comparative, Positive and Placebo-Controlled, Four-Period 54 Crossover Study to Define the ECG Effects of GTx-024: A Thorough ECG Trial G100511 Phase I Study to Assess the Effect of Severe Renal Impairment on Pharmacokinetics of GTx-024 16 G100512 Phase I Study to Assess the Effects of on the Pharmacokinetics of GTx-024 24 G100513 Phase I Study to Assess the Effects of Rifampicin on the Pharmacokinetics of GTx-024 24 G100514 Phase I Study to Assess the Effects of GTx-024 on the Pharmacokinetics of Celecoxib 24 G100515 Phase I Study to Assess the Effects of Probenecid on the Pharmacokinetics of GTx-024 24 G100516 Phase I Study to Assess the Effects of GTx-024 on the Pharmacokinetics of Rosuvastatin 50 Enobosarm clinical trial overview

Study Design Duration Total Treatment Study 003 Head-to-head comparison of GTx-024 to MK-3984 12 weeks 88 3 mg (Phase Ib) in postmenopausal women Study 006 Pharmacokinetic study in postmenopausal 10 days 12 1, 3, 10 mg (Phase Ib) Japanese women G200501 Proof of concept study in healthy older men & 12 weeks 120 0.1, 0.3, 1, 3 mg (Phase II) postmenopausal women G200502 Cancer cachexia study in males ≥45 & post- 16 weeks 159 1, 3 mg (Phase II) menopausal women with cancer G300504 Effect of GTx-024 on Muscle Wasting in Patients 21 weeks 330 0, 3 mg (Phase III) With Non-Small Cell (NSCLC) on First Line Platinum + Taxane G300505 Effect of GTx-024 on Muscle Wasting in Patients 21 weeks 330 0, 3 mg (Phase III) With Non-Small Cell Lung Cancer (NSCLC) on First Line Platinum + Non-Taxane G200517 Efficacy and Safety of GTx-024 in Patients With 24 weeks 88 9, 18 mg (Phase II) ER+/AR+ Breast Cancer G200518 Efficacy and Safety of GTx-024 in Patients With 24 weeks 55 18 mg (Phase II) AR +Triple Negative Breast Cancer (AR+ TNBC) G200519 GTx-024 as a Treatment for Stress Urinary 12 weeks 35 3 mg (Phase II) Incontinence in Women Clinical proof of concept

• Protocol #G200501 completed in 2006 • Randomized, double-blind, placebo-controlled, multicenter trial in men > 60 years and postmenopausal women • 3 months of dosing (n=21-24 group) with Placebo or Enobosarm 0.1, 0.3, 1, or 3 mg • Subjects were not given a prescribed diet or exercise regimen

LBM Power

• No significant changes in PSA, sebum production, skin biopsy for virilization gene panel • No significant changes in hair growth in females (modified Ferriman-Gallwey Model) • No significant changes in bleeding diaries or endometrial biopsies Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, Morton RA, Steiner MS. Journal of Cachexia Sarcopenia and Muscle. 2(3):153-161, 2011 Safety in men and PMW

• Pattern of Adverse Effects suggest that particular drug- related events are few • Overall adverse events rates are generally comparable between studies and between men and women • Skin biopsies, sebum production, endometrial biopsies, and bleeding diaries indicative of tissue selcetivity • Transient but mild dose-dependent increases in ALT are observed – Very few instances of clinically significant elevations in ALT by end of trial, and discontinuations due to ALT were rare – ALT is androgen-regulated gene Coss CC, Bauler M, Narayanan R, Miller DD, Dalton JT. Pharmaceutical Research. 29(4):1046-1056, 2012 • Lipids – Total Cholesterol, VLDL, HDL (15-30%) and Triglycerides decreased as function of dose. – LDL/HDL ratio for all doses remain in the low cardiovascular risk category.

J Cachexia Sarcopenia Muscle. 2011 Sep;2(3):153-161.; Lancet Oncol. 2013 Apr;14(4):335-45; Invest New Drugs. 2016 Aug;34(4):458-67; Enobosarm increased LBM and improved physical function

1.6 LEAN BODY MASS 30% PHYSICAL FUNCTION 1.4 Placebo 25% Placebo Enobosarm 3 mg 1.2 Enobosarm 3 mg 20% 15% Phase IIb cancer 1 10% 0.8 cachexia trial: 5% 0.6 0% 0.4 159 subjects with cancer -5% 0.2 STAIR CLIMB cachexia, Change from baseline (%) -10% 0 Time Power 4 months tx Change from baseline (kg) -0.2 25% 1.4 20% Placebo 1.2 Placebo 15% Enobosarm 3 mg 1 Enobosarm 3 mg 10% Phase II POC clinical 0.8 5% trial: 0.6 0% 0.4 -5% 120 elderly men and 0.2 -10% STAIR CLIMB 0 postmenopausal women, Change from baseline- (%) 15% Time Power -0.2 3 months tx Change from baseline (kg) 40 1.6 Placebo 1.4 Placebo 30 Enobosarm 3 mg 1.2 Enobosarm 3 mg 1 20 Phase Ib sarcopenia 0.8 0.6 10 trial: 0.4 0 0.2 88 postmenopausal 0 -10 -0.2

women, 3 months tx Change from baseline (lbs)

Change Change from baseline (kg) BILATERAL LEG PRESS -0.4 -20 J Cachexia Sarcopenia Muscle 2(3):153-161, 2011; Lancet Oncology, in press, 2013; Endocrine Reviews 31(3):(suppl 1)S872, 2010. Anabolic Agents in Doping

• Adverse analytical findings and atypical findings of all World Anti-Doping Agency (WADA) accredited laboratories in 2012 reported via Anti-Doping Administration and Management System (ADAMS)

Geyer H, et al. Br J Sports Med 2014;48:820–826. doi:10.1136/bjsports-2014-093526 Lab Bench to Bench Press?

Also known as: ostarine, GTx-024, MK-2866, enobosarm, S-22 • Not approved for human use by FDA or others • Increasing numbers of positive tests in athletes - Purposeful consumption of illegal products - Unexpected consumption in dietary supplements (creatine) • Currently 36 products on High Risk List • FDA Office of Criminal Investigations initiated prosecutions of companies Internet Availability 2018 USADA Sanctions

• Reyes, Polo (cycling) 11/7/18 – 4 yr suspension • Francis, Victoria (wrestling) 8/31/18 – 1 yr suspension • Palicka, Megan (weightlifting) 4/6/18 – 3 yr suspension • Volrath, Frank (weightlifting) 4/5/18 – 4 yr suspension • Raymond, Abby (weightlifting) 3/29/18 – 3 month suspension • Barnett, Josh (MMA) 3/23/18 – public warning • Tukhugov, Zubaira (MMA) 2/15/18 – 2 yr suspension • Magomedov, Rusian (MMA) 2/15/18 – 2 yr suspension • Wallhead, Jim (MMA) 2/15/18 – 9 month suspension • Ribas, Amanda (MMA) 1/10/18 – 2 yr suspension

• Track&Field, Paralympics, Triathalon, NCAA basketball & hockey • WADA reported 28 cases globally in 2015 • USADA reported 17 suspensions since 2014 Enobosarm Detection Methods

388 [M-H]-

135 269 2nd diagnostic 118 used for detection Metabolites Identified

Plasma Urine (major, 87% of radioactivity)

Urine (trace) Plasma Plasma Urine (trace) Feces (6.8% of radioactivity) (in only 2 subjects) Feces (trace, 0.34%)

Urine (trace) Doping example

Original result

After being notified & suspended 12 days later

Days • Athlete suspended based on positive urine result. • Reported “unintentionally” ingesting a single large dose to speed recovery • Urine remained positive for M-11 (118 m/z) 41 days after suspension • Reported no additional ingestion of enobosarm • Urine data suggests half-life > 3 weeks? • Additional intentional exposure after informed of result seems unlikely • Unknown exposure from dietary supplement? • Other sources of 4-cyanophenol? Reportedly used as antiseptic in cosmetics. US laws likely to toughen

• Senate Bill 2742 sponsored by Orrin Hatch (Utah) • Classify SARMs as DEA Schedule III like testosterone • Criminal penalties would be associated with illegal sale or use Reducing your risk

• https://www.usada.org/wp-content/uploads/Reduce-Your- Risk_Red-Flags.pdf

Advice from other athletes or anyone based on word of mouth is risky!! SPOILER ALERT! Not everything that you read on the internet is true. Watch out for “secret formula”, “for research purposes only”, “prescription alternative” Third party certification

• National Sanitation Foundation (NSF International) http://www.nsf.org/consumer-resources/health-beauty/supplements- vitamins/supplement-vitamin-certification

• Neither FDA not WADA nor USADA “approve” dietary supplements. If you see language suggesting it, it is bogus. DO use the internet to look for warnings! Read the label! USADA Supplement 411

• https://www.usada.org/wp- content/uploads/Reduce-Your- Risk_Red-Flags.pdf

• Drug Free Sport Axis (www.dfsaxis.com)

• None of the SARMs or other anabolic agents can be legally included in a dietary or food supplement!

• Screening tests are highly sensitive.

• Be wary of products available only on online! Summary

• Enobosarm (aka ostarine, GTx-024, MK-2866, S-22) and other SARMs increase lean mass and muscle strength but none are approved for human use yet • The prevalence of SARM doping is increasing despite their presence on WADA prohibited list • High sensitivity assays are available to detect SARM doping. Users will be caught. • SARMs are being found unexpectedly in dietary and food supplements (creatine) • Avoiding supplements is the only guanranteed way to avoid problems. Following USADA’s 411 will significantly reduce risk. Questions?

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