Treatment of Young Boys with Duchenne Muscular Dystrophy with the NF- - PowerPoint PPT Presentation

Treatment of Young Boys with Duchenne Muscular Dystrophy with the NF- κB Inhibitor Edasalonexent Showed a Slowing of Disease Progression as Assessed by MRI and Functional Measures Richard Finkel, MD 1 ; Krista Vandenborne, PT, PhD 2 , H Lee Sweeney, PhD 2 , Erika Finanger, MD 3 , Gihan Tennekoon, MBBS, MRCS, LCRP 4 , Perry Shieh, MD, PhD 5 , Rebecca J. Willcocks, PhD 2 , Glenn Walter PhD 2 , William Rooney PhD 3 , Sean C Forbes, PhD 2 , William T. Triplett, BSc 2 , Sabrina W. Yum, MD 4 , Maria Mancini, MHP 6 , James MacDougall, PhD 6 ; Angelika Fretzen, PhD 6 , Pradeep Bista, PhD 6 ; Andrew Nichols, PhD 6 ; Joanne Donovan, MD, PhD 6 1 Nemours Children’s Health System, Orlando, FL; 2 University of Florida Health, Gainesville, FL; 3 Oregon Health Sciences University, Portland, OR; 4 The Children's Hospital of Philadelphia, Philadelphia, PA; 5 University of California, Los Angeles, Los Angeles, CA; 6 Catabasis Pharmaceuticals, Cambridge, MA Abstract O.42, World Muscle Society, Copenhagen, October, 2019

Disclosures ‣ The clinical trial was sponsored by Catabasis Pharmaceuticals, Inc. ‣ Richard Finkel, Krista Vandenborne, H. Lee Sweeney, Erika Finanger, Gihan Tennekoon, Perry Shieh, Rebecca Willcocks, Sean Forbes, William Triplett, and Sabrina Yum received research support from Catabasis. Richard Finkel, H. Lee Sweeney, Erika Finanger, and Perry Shieh received honoraria from Catabasis ‣ Maria Mancini, James MacDougall, Pradeep Bista, Andrew Nichols, Angelika Fretzen and Joanne Donovan are employees or consultants of Catabasis and may hold stock in Catabasis ‣ Edasalonexent is an investigational agent that is not approved in any territory 2

Activation of NF- κ B in Duchenne Muscular Dystrophy is a Key Factor in Disease Progression in Skeletal and Cardiac Muscle No Dystrophin + Mechanical Stress Inflammation in Infancy Degeneration MuRF1/MAFbx Control DMD Inflammation Cross section of mid-thigh muscle in Cytokines 12-14 YO boys Fibrosis Activated NF- κ B Regeneration Dystrophin and Membrane Stability Cyclin D1 MMP-9 β -Dystroglycan NF- κ B decreases dystrophin Satellite Cell production, suggesting Myoblasts inhibition could increase MyoD miRNA dystrophin with dystrophin- targeted therapies Dystrophin Myotube Actin Disease Progression Chen et al., Neurology 2005 65: 826 Kumar et al., FASEB J 2003 17:386 Fiorillo et al., Physiol Genomics 2018 50:735 Akima et al., Neuromuscul Disord 2012 22: 16 3

Edasalonexent Inhibits NF- κ B, A Key Driver of Muscle Disease in DMD ‣ Edasalonexent is an orally- administered small molecule that is ‣ Inhibiting NF- κ B slowed disease progression in animal models of DMD not a steroid – Oral administration of edasalonexent analog (CAT-1041) reduced muscle inflammation and improved function in mdx mice and GRMD dog Reduced Inflammation in mdx Increased Diaphragm Specific Force in mdx 2.5 Control 10 Control p=0.02 CAT-1041 Relative Protein Content (AU) CAT-1041 p=0.04 2 8 p=0.01 Specific Force (N/cm 2 ) p=0.02 1.5 6 1 4 0.5 2 ‣ Being developed as foundational 0 0 therapy for patients with DMD OPN IL-6 IL-4 Control CAT-1041 regardless of mutation, both as monotherapy and potentially to be combined with dystrophin-targeted therapies Hammers, et al. JCI Insight 2016 1(21): e90341 Means + SEM 4

Design of MoveDMD, a Phase 1/2 Trial with Open-Label Extension ‣ Study Objectives – Safety and PK in pediatric patients with DMD – Proof of concept using MRI to assess changes in muscle health – Long-term safety and effects on age-appropriate functional measures to enable design of Phase 3 study ‣ Study Population – Age 4 up to 8 th birthday not currently being treated with corticosteroids – Able to perform timed function tests and MRI ‣ Design – Phase 1: 1-week open-label to assess safety and PK, with initial assessments of function and MRI – Off-treatment period of ~6 months prior to Phase 2 – Phase 2: 12-week placebo-controlled period of 67 mg/kg and 100 mg/kg doses of edasalonexent – Open-label extension >72 weeks Open-Label Phase 1 Off-Treatment Period Phase 2 Extension n=17 n=16 n=31 n=31 ‣ Prespecified Analysis Plan – 12-week placebo controlled period evaluated MRI, T2, North Star Ambulatory Assessment, timed-function tests, and safety – Additional comparison of rates of change during off-treatment control period versus on edasalonexent treatment 5

In Phase 2 MoveDMD Trial and Open-Label Extension: Range of Endpoints to Demonstrate Proof of Concept and Support Design of Phase 3 NF- κ B Target Engagement Biomarkers Muscle MRI Functional ▸ Inhibition of ▸ CRP , biomarker of ▸ MRI T2 of upper ▸ North Star NF- κ B targeted inflammation and lower leg Ambulatory gene set in Assessment and ▸ Muscle enzymes ▸ MRS muscle fat peripheral blood Timed Function Tests NCT02439216 6

Edasalonexent Inhibits NF- κ B Target Genes in DMD Boys ‣ In MoveDMD trial, during the off-treatment control period, levels of NF- κ B target genes were increased – Consistent with increased NF- κ B activity during disease progression in DMD ‣ Treatment with edasalonexent decreased the levels of individual NF- κ B target genes in the blood – Demonstrates target engagement N F K B 2 N F K B IA Mean fold change in NF - κ B target gene ( 6 κ B s ite s in p r o m o te r r e g io n : -3 7 7 , -9 5 , -6 8 , + 7 01 , + 9 5 5 , + 1 1 0 8) ( 3 κ B s ite s in p r o m o te r r e g io n : -3 1 9 , -2 2 5 , -6 3 ) abundance in blood 2 0 1 2 0 O ff-tre a tm e n t p e rio d 1 0 0 m g /k g O ff-tre a tm e n t p e rio d 1 0 0 m g /k g (relative to start of treatment) e d a s a lo n e x e n t e d a s a lo n e x e n t 1 5 8 0 Off -treatment 100 mg/kg R P K M R P K M period edasa 1 0 NFKB2 4 0 4.60 0.74 5 NFKBIA 2.50 0.97 0 0 -6 0 -4 0 -2 0 0 2 0 4 0 -6 0 -4 0 -2 0 0 2 0 4 0 T im e (w e e k s ) T im e (w e e k s ) ‣ Changes in aggregated NF- κ B target gene-sets (HALLMARK and BIOCARTA) were also seen with treatment – Expression of genes in these sets were increased during off-treatment control period and decreased after edasalonexent treatment 7

In Phase 2 MoveDMD Trial and Open-Label Extension: Muscle Enzymes Significantly Decreased on Edasalonexent, Supporting a Positive Drug Effect Creatine Kinase Aspartate Aminotransferase 0 0 -5000 -50 -10000 -100 IU/mL IU/mL -15000 -150 * * -20000 -200 -25000 -250 12 24 36 48 60 72 12 24 36 48 60 72 ‣ Early and sustained Alanine Aminotransferase Lactate Dehydrogenase biomarker response 0 0 -50 -200 IU/mL IU/mL -100 -400 -150 -600 * * -200 -800 12 24 36 48 60 72 12 24 36 48 60 72 Weeks on 100 mg/kg Edasalonexent Plasma muscle enzymes are elevated 10 to 100 fold in DMD, indicative of leakage from damaged myocytes Means ± SEM shown; * p<0.05 for mean change from baseline after 12 weeks 8

Both Functional Decline and MRI Disease Progression Were Similar in Untreated Patients in MoveDMD and ImagingDMD Natural History Studies Functional Declines in Velocity for Patients MRI Shows Disease Progression Not Receiving Steroids or Edasalonexent Lower Leg Vastus Laterals 10-meter walk/run 4-stair climb Time to stand Composite MRI T2 Soleus Fat Fraction Fat Fraction 0.00 6 4 20 Annualized Rate of Change (tasks/s/year) Annualized Rate of Change (ms/year) Annualized Rate of Change (%/year) Annualized Rate of Change (%/year) 3 15 -0.05 4 2 10 -0.10 2 1 5 -0.15 Non-Steroid Cohort: Natural History Off-treatment: MoveDMD ImagingDMD ‣ Off-treatment, steroid-naïve patients enrolled in the MoveDMD study with same data collection protocols had declines consistent with observations in the ImagingDMD natural history study. – Declines in function in natural history study at ages 4-7 were similar to those observed in the MoveDMD trial off-treatment – Decreases in function correlate with increases in 5 composite lower leg MRI T2 as well as muscle fat fraction Means + SEM; side by side comparison from ImagingDMD and MoveDMD datasets 9 Finkel et al., World Muscle Society, 2018; Vandenbourne et al., World Muscle Society, 2018

In Phase 2 MoveDMD Trial and Open-Label Extension: Edasalonexent Improved Rate of Change of MRI T2 Compared to Off-Treatment Control Period ‣ MRI T2 is tightly correlated with fat MRI T2: Composite of 5 Lower Leg Muscles fraction and functional measures 6 ‣ Composite of 5 lower leg muscles MRI T2 Edasalonexent (soleus, gastrocnemius, anterior and 100 mg/kg Annualized Rate of Change (m sec/year) posterior tibialis, peroneals) used to 4 encompass muscles at various stages of Better disease progression and minimize variability 2 * * * * * ‣ Following 72 weeks of edasalonexent, the rate of increase in the composite MRI T2 0 Off-treatment 12 24 36 48 72 decreased as compared to the rate of control increase during the off-treatment control Weeks on Edasalonexent period -4 ‣ Early and sustained response in annualized rate of change Means + SEM; mixed model comparison with off-treatment period * Week 12: p=0.002, n=16; Week 24: p=0.004, n=14; Week 36: p=0.032, n=13; Week 48: p=0.018, n=12; Week 72: p=0.052, n=9 10