Targeting Inflammation in Duchenne Muscular Dystrophy: Non-mutation specific approaches in developing therapies for DMD Joanne M. Donovan, M.D., Ph.D. Chief Medical Officer Catabasis Pharmaceuticals

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Preventing Disease Progression in Duchenne Muscle replacement by fat and fibrosis Muscle intact Progressive functional impairment Kinali, 2011

Absence of Dystrophin plus Mechanical Stress Results in DMD Disease Progression Drugs primarily targeting inflammation: Steroids: prednisone, deflazacort CAT-1004 Verolone (VB-15) IMO-8400 NEMO peptides Inflammation Toll-like receptors NF-kB satellite stem cell myoblasts Drives Muscle Degeneration Promotes Inflammation and Fibrosis Inhibits Muscle Regeneration

In Duchenne, Inflammation (NF-kB) Is Present at an Early Age and During Symptomatic Disease NF-κB Activation in Muscle in Infancy in DMD: What are the earliest changes that are seen in Duchenne? Eric Hoffman’s group looked at gene expression changes before birth, in infancy and in boys aged 5 to 12 Dystrophin is absent at all ages Changes in gene expression related to inflammation – TLR7, NF-kB were present in muscle soon after birth and in symptomatic boys aged 5 to 12 NF-κB nuclear staining Control Muscle biopsies from infants with DMD show activated nuclear NF-κB (red) Chen et al, 2005

Activated NF-kB Inhibits Muscle Regeneration Dystrophin production (red) in engrafted stem cells: Repair of muscle damage occurs in response to injury in normal muscle and dystrophic muscle Stem cell proliferation and differentiation into mature muscle cells is key to muscle repair However, the local environment around stem cells has a major impact on their ability to regenerate, and inflammatory mediators inhibit muscle regeneration. Intact NF-κB levels Reduced NF-κB levels 8-week-old mdx/SCID mice in which p65+/– and wild-type (wt) MDSCs were implanted. Engraftment was determined by immunostaining for dystrophin (red) Lu et al., 2012

Cross section of mid-thigh muscle in boys age 12 - 14 Lack of Dystrophin is Necessary but Not Sufficient for DMD Disease Progression MRI shows replacement of muscle with fat and fibrosis Muscles with less evidence of muscle edema and inflammation in younger boys show less disease at older ages Muscles exposed to less mechanical stress are relatively protected from degradation Control DMD Cross section of mid-thigh muscle in boys age 12 - 14 Gracilis muscle Sources: Akima et al Neuromuscul Disord 2012 22(1):16-25 Hu et al., 2015

CAT-1004 Modulates the NF-ĸB Pathway and Has Potential to be Disease-Modifying in DMD ABSENCE OF DYSTROPHIN MECHANICAL STRESS CAT-1004 Activated NF-B CAT-2000 Series satellite stem cell myoblasts Drives Muscle Degeneration Promotes Inflammation and Fibrosis Inhibits Muscle Regeneration

CAT-1004 Analog Demonstrated Significant Improvements in Muscle Function, Running Wheel Activity and Diaphragm Function Activity on Extensor Digitorum Longus Muscle Function After 5 Contractions CAT-1041 Activity on Muscle Endurance in the mdx Mouse Model CAT-1041 Activity on Diaphragm Function in the mdx Mouse Model * ** % Specific Force (N/cm2) 80 60 40 20 Control CAT- 1004 CAT- 1041 Cumulative Revolutions 800000 600000 400000 200000 Control CAT-1041 Specific Force (N/cm2) 10 8 6 4 2 Control CAT-1041 * * **p=0.001 *p=0.02 *p=0.01 *p=0.02 25-week mdx mouse study Study conducted by Prof. Lee Sweeney

CAT-1004 Analog Demonstrated Significant Improvements in Muscle Fibrosis and Muscle Mass CAT-1041 Activity on Fibrosis in Quadriceps in the mdx Mouse Model CAT-1041 Activity on Muscle Mass in the mdx Mouse Model Muscle Mass (mg) 300 250 200 150 100 50 Gastrocnemius Quadriceps Heart * CAT-1041 Control Untreated * Treated *p<0.05 6-month mdx mouse study Study conducted by Prof. Lee Sweeney

CAT-1004 MoveDMD Trial Design Part A 7-day, open-label dose ranging trial Part B 12-week, randomized, double-blind placebo-controlled trial N = 6 per arm N = 6-8 per arm 33 mg/kg per day CAT-1004 Dose 1 67 mg/kg per day CAT-1004 Dose 2 100 mg/kg per day Placebo* Safety, tolerability and exposure data Efficacy data Study Population: All mutations, ages 4 – 7, steroid naïve or off steroids for ≥6 months * placebo followed by cross-over to 12 weeks CAT-1004 Objectives Assess safety, tolerability and pharmacokinetics Key Endpoints Primary efficacy: changes in MRI of muscles Secondary efficacy: 10 meter walk/run, 4-stair climb, time to stand Additional efficacy assessment: muscle strength

Current Status in the Clinic Phase 1 Phase 2 Phase 3 Approved Prednisone/ prednisolone Deflazacort CAT-1004 Verolone (VB-15) IMO-8400 NEMO peptides

Targeting NF-kB in Duchenne: The Future Multiple pathophysiologic process including activated NF-kB are key to the process of muscle damage in Duchenne, and will be a key component of future treatments. Treatment with glucocorticoids demonstrates that targeting inflammation has benefits in preserving ambulation and positive effects on pulmonary and cardiac function; however, these effects come with significant side effects. Combination therapy of dystrophin / utrophin targeted therapies and NF-kB targeted therapies offer potential benefits because of differing mechanisms of action Therapies currently in development offer the potential to inhibit the inflammation seen at all stages of Duchenne without the negative effects of steroids.

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