Vamorolone: A novel side effect-mitigating for the treatment of DMD

Disclosures: All under venture philanthropy models CEO, co-founder, ReveraGen BioPharma VP, co-founder, AGADA BioSciences President, co-founder, TRINDS LLC

Academic: Assoc Dean for Research, SUNY Binghamton Disclaimer

• This presentation does not provide medical advice, diagnosis or treatment. • This presentation is not intended to be a substitute for professional medical advice, diagnosis, or treatment. • Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. • Never disregard professional medical advice or delay in seeking it because of something you have seen or heard in this presentation. Goal of vamorolone program

• work well in DMD • Mechanism of action may be anti-inflammatory • Corticosteroids are complicated – remain standard of care for hundreds of conditions, despite extensive side effects

• Department of Defense CDMRP: Understand why corticosteroids work • Figure out how to make them better • Peel away layers (subactivities) • Keep, enhance and/or add efficacy aspects • Reduce or remove the safety aspects Chemist John McCall: Revisit the molecular structure Tweak chemistry to reduce safety concerns, increase efficacy in DMD

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9 9 Tirilizad Head and spinal cord trauma vamorolone Membrane stabilizer

The delta 9,11 double bond is the key to the enhanced safety profile of VBP Compounds 4 ‘Classic’ Efficacy: Anti-inflammatory via NFkB inhibition Novel Efficacy: Membrane stabilization

NF-kB inhibition – myogenic cells Membrane stabilization - myogenic cells Vamorolone is a potent anti-inflammatory Vamorolone stabilizes cell membranes

Prednisone makes fragile membranes worse

VBP15 stabilizes myofiber membranes

Heier et al. 2013 5 CONFIDENTIAL What are the different layers of the onion?

• • Known efficacy Novel efficacy – Membrane stabilizing effects (may – Anti-inflammatory action via help compensate for dystrophin NFkB inhibition (suppresses deficiency and unstable membranes) innate immunity ‘danger signals’) – New to vamorolone – Vamorolone retains this • Novel safety-turned-efficacy • Known safety – Cross-reaction with mineralocorticoid – Interaction with hundreds of receptor (regulates kidney function) genes, and turning them on – Corticosteroids agonist (turns on) – – Vamorolone reduces this 100-fold safety concern – Vamorolone antagonist (turns off) –

new efficacy (epleronone) 6 How does vamorolone do in a mdx mouse?

• Kanneboyina Nagaraju DVM PhD • TREAT-NMD standard operating procedures • Blinded, larger #’s mice • Multiple trials

7 Safety: Vamorolone does not show stunting of growth and bone side effects

8 8 CONFIDENTIAL Heier et al. 2013 : small, strong mouse Vamorolone: large, strong mouse

9 9 CONFIDENTIAL Heier et al. 2013 VAMOROLONE AND PREDNISONE IMPROVE HEART FUNCTION (PRED HYPERTROPHIC HEART; VAMOROLONE NORMAL SIZE HEART)

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• Blinded pre-clinical trial in mdx/DBA model

n=9-10 for DBA/2J group and DBA mdx groups, ****P < 0.0001 Efficacy: Retention of transrepression - NF-kB inhibition

Ø Can increase dose, potential upside

Efficacy: Gain of membrane stabilization

Ø Changes pred damage to vamorolone protection

Safety: 100-fold loss of transactivation

Ø Loss of muscle atrophy pathways and many others

Safety-turned-efficacy: MR antagonist (instead of agonist)

Ø Loss of growth stunting

Ø Gain of heart efficacy Vamorolone developed under a venture philanthropy model

De-risking (if a fail, fail early in program, not later in larger clinical trials)

NIH NCATS Therapeutics for Rare and Neglected Disease program – • Brings government drug development team to help • Validate work done previously, promote program through ‘in kind’ help

TREAT-NMD TACT (TREAT-NMD Therapeutics Advisory Committee) • Reviews program, helps de-risk

Lots of grant applications, lots of reviewers, $24M to date Many foundation grants: 400% return on investment base on later drug sales FDA, EMA multiple rounds of great advice Vamorolone clinical program

• Phase 1 clinical trials in adult volunteers: Complete – 80 healthy adults

• Major goals: – pharmacokinetics (how long drug is around in the body): 3 hr half-life – safety (2 weeks daily treatment to 30-times prednisone dose)

• Cannot test efficacy in healthy adults

• Can test safety in healthy adults - biomarkers BRIDGED PHARMACODYNAMIC SAFETY BIOMARKERS CORTICOSTEROIDS

¡ Secondary outcomes: Bridged safety biomarkers Corticosteroids: • Clinical side effects months of ¡ Adrenal suppression: treatment ¡ Chronic measures: first-in-morning 24 hrs after last drug dose - Dramatic biomarker changes within hours of first dose ¡ Acute measures: Cortisol and ACTH 8 hours after initial drug dose - Dramatic chronic changes ¡ Insulin resistance within 7 days treatment ¡ Chronic measures: fasting insulin, glucose ¡ Acute measures: insulin 8 hours after initial drug dose ¡ Bone turnover markers ¡ Chronic measures: after weeks and months of treatment: osteocalcin, P1NP, CTX ¡ Acute measures: Osteocalcin, P1NP 8 hours after initial drug dose Eur J Endocrinol. 2012 Mar;166(3):459-67. Prednisone affects inflammation, glucose tolerance, ¡ Immune suppression and bone turnover within hours of treatment in healthy individuals. ¡ Chronic measures: White blood cell differentials throughout Kauh E1, Mixson L, Malice MP, Mesens S, Ramael S, Burke J, Reynders T,Van Dyck K, Beals C, Rosenberg E, Ruddy M. ¡ Acute measures: Neutrophils up, lymphocytes down ADRENAL SUPPRESSION

¡ The adrenal cortex is the steroid hormone factory of the body ¡ Steroid hormones: Cortisol (), testosterone, estrogen, aldosterone, others ¡ Treatment with corticosteroid drugs suppressed activity of adrenal cortex ¡ All steroid hormones drop acutely, and long term ¡ Side effects: ¡ Diurnal sleep/wake cycles, growth stunting, delay of puberty ¡ Risk of adrenal crisis (surgery, injury, illness) Adrenal suppression - steroid hormones

Duchenne muscular dystrophy n=4 Pediatric inflammatory bowel disease n=11 Pre-treatment Pre-treatment 4 months post-treatment 2 months post-treatment

Corticosterone 17-OH-

11-deoxycortisol Testosterone PHASE 1 ADULTS: MORNING CORTISOL FOR ADRENAL SUPPRESSION ~100-FOLD IMPROVEMENT OVER PREDNISONE PHASE 1 ADULTS: BONE TURNOVER - CTX1 MARKER VAMOROLONE SHOWS NO INCREASE IN CTX1 – AGREES WITH MOUSE DATA

Single dose PREDNISONE IN ADULT VOLUNTEERS

0 mg/kg/day (placebo) 0.14 mg/kg/day 0.35 mg/kg/day 0.85 mg/kg/day

7 doses

Bone resorption

Bone formation

Kauh et al. 2012 PHASE 1 ADULTS: INSULIN RESISTANCE VAMOROLONE SHOWS NO EVIDENCE OF INSULIN RESISTANCE

Vamorolone shows no evidence of hyperglycemia Prednisone causes hyperglycemia SUMMARY OF PHASE 1 DATA

¡ PK data: “well-behaved” drug ¡ Short half-life (similar to corticosteroids) (e.g. pulsed daily dose) ¡ Food effect ¡ Safety: Liver primary target organ (as in pre-clinical data) ¡ No severe adverse events to 20 mg/kg/day (2 wks treatment; fasted) ¡ One subject halted dosing due to mild elevations of ALT ¡ Pharmacodynamic biomarkers – all consistent with pre-clinical data ¡ 100-fold Improvement in adrenal suppression (but seen at high doses) ¡ No evidence of insulin resistance ¡ No evidence of immune suppression ¡ No evidence of abnormal bone turnover

20 DMD clinical program • 4-7 year old boys, steroid-naïve

• Phase 2a – Multiple ascending dose – 2 wk acute safety/tolerability, pediatric pharmacokinetics – 4 dose groups, ~10 boys/dose; ~40 total; 0.25, 0.75, 2.0, 6.0 mg/kg/day – Begins: June 2016 • Phase 2a extension – dose finding (lowest efficacious dose) – 6 month, Open label – DNHS CINRG Natural history vs. CINRG prednisone trial • Sample size calculations for safety and efficacy of prednisone • Phase 2b – pivotal study – Blinded, randomized, placebo- and prednisone-controlled – Four arms through Europe, Israel, Australia; ~100 boys – Begins: June 2017 21 How will we measure clinical efficacy?

• Move away from six minute walk • As we are benchmarked against corticosteroids, what timed function tests improve with prednisone/?

• Cooperative International Neuromuscular Research Group (24 sites) • Timed function, quantitative strength measures; ~400 patients ~8 years – McDonald et al. 2013; :Henricson et al. 2013; Bello et al. 2013; Bello et al. 2015a, 2015b • CINRG corticosteroid trial – Escolar et al. 2011

22 Corticosteroid effect: Measure at 6 months, many tests work well

Change seen in Change seen in Correlation Parents feel prednisone untreated DNHS calculated treated group group after 6 between Sample size time to after 6 months months screening and required per Measurement +6 mo. group stand most Treatment in (power=0.8) relevant to N Mean SD N Mean SD the treated group QOL TTRW velocity 28 0.257 0.284 25 -0.136 0.413 0.856 4 TTCLIMB velocity 28 0.069 0.087 24 -0.002 0.069 0.839 6 TTSTAND velocity 26 0.057 0.083 25 -0.008 0.058 0.675 11

Grip QMT 27 1.930 2.697 12 1.580 2.049 0.541 520

Elbow extensor 10 27 0.850 2.092 -0.630 1.071 0.691 11 QMT

Elbow flexor QMT 27 1.397 1.507 11 -0.237 0.773 0.791 4 Manual muscle 26 5.7 19.4 10 11.6 41.5 0.641 N/A testing total

23 What will we measure for clinical safety? • Safety – Side effects of corticosteroids are profound – But they generally take a long time to develop – What to measure? – CINRG prednisone trial 12 month 12 month Deceleration Change in BMI of linear growth

24 Need only 3 patients on corticosteroids vs. off drug to see change in BMI at 3 months

Untreated – Natural Treated – Prednisone N needed per history study trial group to Time P-value between Outcome detect a (months) treated and N Mean ± SD N Mean ± SD significant untreated difference participants 3 41 -0.1 ± 0.8 13 1.0 ± 0.9 5 <0.001 BMI 6 40 -0.2 ± 0.8 13 1.1 ± 1.4 7 <0.001 (kg/m2) 12 26 -0.3 ± 0.9 13 1.6 ± 1.2 3 <0.001 3 42 1.1 ± 2.1 13 1.1 ± 0.8 1000+ 0.97 Height 6 40 3.2 ± 2.0 13 2.3 ± 2.0 55 0.17 (cm) 12 26 6.0 ± 2.0 13 5.2 ± 2.7 70 0.34

25 Primary clinical outcome measures

• Clinical efficacy: Time to Stand

• Clinical safety: Change in BMI

• Multiple secondary outcomes – Timed function tests; quantitative muscle testing; NSAA

• But can we glean more information from a limited number of patients? – Blood biomarkers for safety and efficacy

26 Showed that blood biomarkers are predictive of later safety concerns. Are there biomarkers that are predictive of efficacy?

• Could argue against placebo effect if open label trial – Acute, objective read outs of drug effect

• Could aid in dose selection (minimal efficacious dose) with limited number of subjects

• Could enable drug development in ages where there are no clinical outcome measures for efficacy – Newborns with DMD detected via newborn screening DEFINE CORTICOSTEROID-RESPONSIVE BIOMARKERS 3 GROUPS (TWO DMD, ONE IBD)

¡ Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children ¡ Yetri b Hathout, Laurie Conklin, Haeri Seol, Heather Gordish-Dressman, Kristy J Brown, Lauren P Morgenroth, Kanneboyina Nagaraju, Christopher R Heier, Jesse M Damsker, John N. van den Anker, Erik Henricson, Paula R Clemens, Jean K Mah, Craig McDonald and Eric P Hoffman and CINRG Investigators.

¡ Pharmacodynamic Serum Biomarker Discovery in Children with Inflammatory Bowel Disease ¡ Christopher R. Heier, Alyson A. Fiorillo, Ellen Chaisson, Heather Gordish-Dressman, Yetri b Hathout, Jesse M. Damsker, Eric P. Hoffman,Laurie S. Conklin

¡ FUNDING: Clark Charitable Foundation (ongoing); NIH Wellstone Center (1998-2013); NICHD National Center Medical Rehabilitation Research (1995-2015); Department of Defense (ongoing)

SUMMARY OF PHARMACODYNAMIC BIOMARKERS

¡ Secondary outcome: Bridged safety markers ¡ Adrenal suppression, insulin resistance, bone turnover ¡ Acute (5 hours after initial drug dose) ¡ Chronic (throughout study) ¡ Exploratory outcomes: Non-bridged safety and efficacy markers ¡ Additional safety (SOMAscan; adrenal hormones) ¡ Candidate efficacy (SOMAscan) ¡ Chronic (throughout study) Phase 2a, 2a extension: Paula Clemens and CINRG ; USA Time lines Phase 2b; Kate Bushby, Michaela Guglieri; trans-EU

Phase 1-2a Transition Phase 2b, Phase 2b Extension Phase 2a, Phase 2a Extension

Aug 2015 2016 FDA/EMA 2017 2018 FDA/EMA Parallel NDA Guidance www.clinicaltrials.gov – vamorolone Phase 2a Sites Physician www.duchenneconnect.org - vamorolone 1 Pittsburgh Mathula Thangarajh 3 Washington DC Hoda Abdel-Hamid 8 Dallas Susan Iannaconne Contact: 19 Sacramento Craig McDonald Andrea Smith, University of Pittsburgh 31 Chicago Nancy Kuntz 34 Duke Edward Smith [email protected] 36 Gainesville Barry Byrne 46 Nemours, FL Richard Finkel Acknowledgements

• Vamorolone - ReveraGen – John McCall – Kanneboyina Nagaraju – Jesse Damsker, Erica Reeves, Rahel Ketema, Suzanne Gaglianone • Biomarkers – CINRG Duchenne Natural History Study (Craig McDonald, CINRG group) – Yetrib Hathout – Laurie Conklin (Inflammatory bowel disease) • Phase 2a trial – Paula Clemens, Avital Cnaan, Andrea Smith, CINRG group • Phase 2b trial – Michela Guglieri, Kate Bushby, Becky Davis, Newcastle University VBP15 Key Organizations

September 2015 NIH NINDS $3M EU Horizons 2020 $7M (under negotiation) Department of Defense Validations, de-risking, $3M in kind Stake holder foundations USA: FED, MDA, CureDuchenne, PPMD, Clark Charitable Foundation, Michael’s Cause, Pietro’s Fight, Ryan’s Quest, DuchenneAlliance UK: Joining Jack, Duchenne Research Fund, Duchenne Children’s Trust, ActionDuchenne, TACT de-risking Alex’s Wish Australia: Save Our Sons

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