MoveDMD: A Phase 1/2 Clinical Trial with CAT-1004 in Boys with Duchenne Muscular Dystrophy

Transcription

1 MoveDMD: A Phase 1/2 Clinical Trial with CAT-1004 in Boys with Duchenne Muscular Dystrophy Joanne M. Donovan, MD, PhD Chief Medical Officer Catabasis Pharmaceuticals A return to health

2 About Catabasis Pharmaceuticals Located in Cambridge, MA Founded in 2008 Focused on bringing important medicines for patients with rare diseases and serious lipid disorders Philosophy of Patients and Science First Working with PPMD and MDA since

3 CAT-1004, an Investigational Drug Candidate Being Developed for DMD Why CAT-1004? In DMD, lack of dystrophin and mechanical stress activate NF-ĸB in muscles, leading to muscle degeneration, inflammation, fibrosis and inhibition of muscle regeneration and ultimately loss of function Steroids suppress inflammation but have significant side effects 3

4 CAT-1004 Modulates the NF-ĸB Pathway and Has Potential to be Disease-Modifying in DMD ABSENCE OF DYSTROPHIN MECHANICAL STRESS Activated NF-ĸB CAT-1004 satellite stem cell Drives Muscle Degeneration Promotes Inflammation and Fibrosis myoblasts Inhibits Muscle Regeneration 4

5 Central Role of NF-ĸB: Lack of Dystrophin is Necessary but not Sufficient for DMD Disease Progression MRI shows replacement of muscle with fat and fibrosis Muscles in DMD boys that are mechanically stressed and have activated NF-kB show replacement of muscle by fat and fibrosis characteristic of DMD Cross section of mid-thigh muscle in boys age Control DMD Muscles with less mechanical stress and hence less activated NF-kB are relatively protected even in the absence of dystrophin It is believed that muscle degeneration may be slowed if levels of activated NF-kB can be decreased. Sources: Akima et al Neuromuscul Disord (1):16-25 Muscles with no dystrophin but less mechanical stress are relatively protected from degradation 5

6 Outside cell Outside cell CAT-1004 May Act via the Same Pathway as Corticosteroids, but Without the Side Effects CAT-1004 Prednisone Inside cell Inside cell Inhibits NF-κB GR Salicylate DHA NF-κB Inhibits NF-κB NF-κB Inhibits NF-κB pgre GR GR ngre Hormonal GRE transaction Nucleus Nucleus Potential Efficacy Reduce muscle degeneration Inhibit inflammation and fibrosis Enable muscle regeneration Efficacy Inhibits inflammation Side Effects Muscle damage Immune system compromise Reduction in bone strength Growth suppression Source: EMBO Molecular Medicine, : GR: Glucocor*coid Receptor GRE: Glucocor*coid Response Element 6

7 Pre-Clinical (Animal) Studies: CAT-1004 Analog Demonstrated Significant Improvements in Muscle Fibrosis and Muscle Mass Fibrosis in Quadriceps in the mdx Mouse Model Muscle Mass in the mdx Mouse Model 300 * Control Untreated Treated Muscle Mass (mg) 250 CAT * * Gastrocnemius Quadriceps Heart *p< month mdx mouse study Study conducted by L. Sweeney University of Pennsylvania mdx mice treated for 25 weeks 7

8 Phase 1 Trials: Significant Reduction in Activated NF-κB Observed with CAT-1004 Objectives: Safety and tolerability Pharmacokinetics NF-κB biomarker activity Design: Three trials Single and multiple ascending dose trials Biomarker trial 79 adult subjects treated with CAT-1004 Results: No safety signals and good tolerability Significant reductions in NF-κB biomarker signal compared to placebo or the combination of the bioactives The effect seen with CAT-1004 is not seen when salicylate and the omega-3 DHA are taken at the same time NF-κB p65 (% reduction) Phase 1 Clinical Data Inhibition of Activated NF-κB * Placebo CAT-1004 DHA / Salicylate Dose group 3-way crossover design, 9 subjects * p<

9 MoveDMD Trial Approach: Targeting Early Intervention in DMD 2 years 5 years 9 years Late-stage Infancy Early Ambulatory Young Ambulatory Late Ambulatory Non- Ambulatory 4-7 year old boys Key ways of evaluating: Time to stand from supine Time to run / walk 10 meters Time to climb 4 stairs Initial focus for Catabasis Potential to expand over time 9

10 What can MRI Show? Magnetic Resonance Imaging (MRI) allows investigators to understand more about natural history of DMD, to assess muscle health, and to assess potential effects of investigational drugs on muscle without need for biopsy No radiation exposure or injections MRI shows that different areas of the same muscle can be affected differently, so the whole muscle can be looked at instead of a small biopsy sample The same muscles with inflammation go on to develop fibrosis and replacement of muscle tissue by fat MoveDMD will include MRI to understand the effects of CAT-1004 in boys with DMD 10

11 The MoveDMD Study The MoveDMD trial is a two-part clinical trial investigating the safety and effects of CAT-1004 in DMD. Part A: Enrolling Goal is to evaluate the safety and pharmacokinetics of 7 days of treatment with CAT-1004 in boys with DMD Additionally to collect data at baseline (before any drug is administered) on the muscles of the lower and upper legs using magnetic resonance imaging (MRI), physical function (including timed function tests), and muscle strength. Part B to follow: Goal is to evaluate the safety and effects of CAT-1004 or placebo for a 12 week period in boys with DMD Placebo group to cross-over to CAT-1004 after 12 weeks 11

12 CAT-1004 The 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 Dose 1 Dose 2 Dose 3 N = 6-8 per arm CAT-1004 Dose 1 CAT-1004 Dose 2 Placebo Enrollment: All mutations, ages 4 7, steroid naïve or off steroids for 6 months Safety: Monitored by investigators and Sponsor and overseen by Data Safety and Monitoring Committee Key Endpoints Changes in Magnetic Resonance Imaging (MRI) of muscles Changes in appropriate Timed Function Tests 10 meter walk/run, 4 step climb, time to stand Assess safety, tolerability and pharmacokinetics 12

13 What are the Eligibility Requirements for the Trial? In order to participate, boys must meet the following criteria: Between 4 and 7 years old and have a diagnosis of DMD Able to walk independently Adequate immunization for influenza (the flu) and varicella infection (chickenpox) Must not have used corticosteroids within the last 6 months or plan to start steroid therapy within the next 6 months Must not have any medical conditions that would prevent study assessments to be completed, or heart or liver problems, or an allergy to fish or shellfish Must not have participated in another investigational drug study within the last 28 days 13

14 How Will the Drug be Given? CAT-1004 is given as soft gel capsules in two sizes, depending upon the boys ability to swallow capsules TicTac CAT mg These are the capsules compared to a Tic Tac and an M&M CAT-1004 will be taken with food M&M CAT mg 14

15 What Other Tests will be Performed in the Trial? Blood tests to monitor safety and measure the amount of CAT-1004 in the blood Timed function tests: 10 meter walk / run Time to climb 4 steps Time to rise from lying down Limited muscle strength testing North Star Ambulatory Assessment (NSAA) and a questionnaire about health and well-being. All of these tests have been studied in boys with DMD of this age Each test takes a relatively short time, allowing us to keep the attention of boys of this age 15

16 Where Will the Study be Conducted? University of Florida, Gainesville Dr. Krista Vandenborne Dr. Peter Kang Dr. S.H. Subramony Shriners Childrens Hospital -- Portland Dr. Erika Finanger Dr. Barry Russman Dr. William Rooney Children s Hospital of Philadelphia Dr. Gihan Tennekoon Dr. Sabrina Yum Travel support is being provided by a grant from Parent Project Muscular Dystrophy 16

17 What is the Current Status of the Trial? Current Status of MoveDMD Trial Sites are actively recruiting and the first patient has received CAT-1004 The future: Consider discussing the trial with your child s physician, a participating site, or contact us If you know another parent or guardian of a child with DMD who may be interested in this trial, please make them aware of it 17

18 Summary Why CAT-1004? In DMD, lack of dystrophin and mechanical stress activate NF-ĸB in muscles, leading to muscle degeneration, inflammation, fibrosis and inhibition of muscle regeneration and ultimately loss of function Steroids suppress inflammation but have side effects CAT-1004 and a closely related analog have demonstrated positive effects in preclinical (animal) models of DMD CAT-1004 may be effective regardless of mutation type Catabasis has completed Phase 1 program in adults No safety signals identified Inhibition of activated NF-ĸB observed CAT-1004 has been granted orphan drug designation by the FDA for the treatment of DMD The MoveDMD study in young boys with DMD is actively enrolling 18

19 Thank You! Parent Project Muscular Dystrophy Muscular Dystrophy Association ImagingDMD Investigators and Staff Professor Lee Sweeney and Lab (U. Pennsylvania) Professor Kristen Vandenborne Professor Richard Finkel 19

20 Questions? ClinicalTrials.gov Catabasis.com 20