MoveDMD: Phase 1/2 Trial of Edasalonexent, an NF-κB Inhibitor, in 4 to 7-Year Old Patients with Duchenne Muscular Dystrophy

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Camilla Skinner
5 years ago
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2, Erika Finanger, MD 3, Gihan Tennekoon, MBBS, MRCS, LCRP 4, Perry Shieh, MD, PhD 5, Sabrina Yum, MD 4, Maria Mancini,

Orlando, FL; 2 University of Florida Health, Gainesville, FL; 3 Oregon Health Sciences University, Portland, OR; 4 The

1 MoveDMD: Phase 1/2 Trial of Edasalonexent, an NF-κB Inhibitor, in 4 to 7-Year Old Patients with Duchenne Muscular Dystrophy 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, Sabrina Yum, MD 4, Maria Mancini, MHP 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 March 22, 2017

2 Forward Looking Statements This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, including statements regarding our expectations and beliefs about our business, future financial and operating performance, clinical trial plans, product development plans and prospects. The words believe, anticipate, plans, expect, could, should, will, would, may, intend and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The forward-looking statements contained in this presentation and in remarks made during this presentation and the following Q&A session are subject to important risks and uncertainties that may cause actual events or results to differ materially from our current expectations and beliefs, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of our product candidates; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products; availability of funding sufficient for our foreseeable and unforeseeable operating expenses and capital expenditure requirements; other matters that could affect the availability or commercial potential of our product candidates; and general economic and market conditions. These and other risks are described under the caption Risk Factors in our Annual Report on Form 10-K for the year ended December 31, 2016, which is on file with the Securities and Exchange Commission, and in other filings that we may make with the Securities and Exchange Commission in the future. In addition, the forward-looking statements included in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this presentation. Conflict of interest: Joanne Donovan, Maria Mancini, Pradeep Bista and Andrew Nichols are employees of Catabasis 2

3 Background and Objective NF-κB is activated from infancy in DMD, driving inflammation, muscle degeneration and inhibiting muscle regeneration. Edasalonexent, an oral small molecule that inhibits NF-κB, has shown positive preclinical effects on skeletal muscle, including the diaphragm, and heart in DMD models. Objective of the study: To assess safety and efficacy of edasalonexent (CAT-1004) in boys with Duchenne muscular dystrophy (DMD) not yet on steroids 3

05 Edasalonexent increases dystrophin expression in combination with exon skipping mdx/saline mdx/edasa mdx/m23d

4 Positive Effects of NF-κB Inhibitors, CAT-1041 and Edasalonexent (CAT-1004), Observed in mdx Mice CAT-1041 has positive effects on: Muscle mass Fibrosis Muscle specific tension Hammers et al, JCI Insights (2016) *p<0.05 Edasalonexent increases dystrophin expression in combination with exon skipping mdx/saline mdx/edasa mdx/m23d mdx/m23d/edasa Merge Laminin Dystrophin wild type/saline M23D: exon skipping specific for mdx; Nelsa Estrella, Sarepta (Unpublished observations) *p<0.05 4

5 MoveDMD Trial Design Study Population: All DMD mutations, ages 4 7, steroid naïve or off steroids for 6 months Part A 7-day, open-label dose-ranging trial N ~ 6 per arm Part B 12-week, randomized, double-blind placebo-controlled trial N ~ 10 per arm Part C 36-week, open-label treatment period N ~ 10 per arm 100 mg/kg/day Edasalonexent 67 mg/kg/day Edasalonexent 67 mg/kg/day 67 mg/kg/day Edasalonexent 100 mg/kg/day Edasalonexent 100 mg/kg/day 33 mg/kg/day Placebo Edasalonexent 100 mg/kg/day or 67 mg/kg/day Assess the safety and PK of edasalonexent in ~18 boys with Duchenne Showed positive PK, NF-κB biomarker effects, safety and tolerability Assess the safety and efficacy of edasalonexent versus placebo using MRI as an early biomarker; trial was powered only for the primary end point of change from baseline in MRI T2 of composite of lower leg muscles Other measures: timed function tests (10-meter walk/run, 4-stair climb, time to stand), NSAA, muscle strength, PODCI and MRI fat fraction Measure the same safety and efficacy parameters as in Part B of the trial to assess treatment effects over a longer time 5

safety issues in liver, renal, hematology Physical exam, EKG, vitals: no safety issues Adverse events over 7 days: Edasalonexent 100mg

6 MoveDMD Part A Results: Safety and Tolerability Generally well tolerated No serious adverse events, no discontinuations All patients able to take edasalonexent capsules Adverse events (AE) predominantly mild, most common AE was diarrhea Assessments: Laboratory: no trends or safety issues in liver, renal, hematology Physical exam, EKG, vitals: no safety issues Adverse events over 7 days: Edasalonexent 100mg Edasalonexent 250mg Tic-Tac M&M 33 mg/kg n=5 67 mg/kg n=6 100 mg/kg n=6 Total n=17 Diarrhea Soft feces Abdominal pain upper

Part B Key Study Metrics and Efficacy End Points Key Study Metrics Primary Efficacy End Point Additional Efficacy End Points Enrolled total of 31 boys at 5 sites for Part B of the trial, 16 of whom

7 Part B Key Study Metrics and Efficacy End Points Key Study Metrics Primary Efficacy End Point Additional Efficacy End Points Enrolled total of 31 boys at 5 sites for Part B of the trial, 16 of whom also participated in Part A. In Part B, patients were randomized to: Edasalonexent 67 mg/kg/day given as twice per day dosing Edasalonexent 100 mg/kg/day given as three times per day dosing Placebo All 31 patients who enrolled completed the trial Average change from baseline to week 12 in MRI T2 relaxation time (milliseconds) for the composite of lower leg muscles: Soleus (Sol) Medial gastrocnemius (MG) Tibialis posterior (TP) Tibialis anterior (TA) Peroneals (Per) Speeds and times for timed function tests (TFTs): Completing the 10-meter walk/run (10MWR) Climbing 4 stairs (4SC) Standing from supine (time to stand: TTS) North Star Ambulatory Assessment (NSAA) Other MRI/MRS measures in lower and upper leg muscles Muscle strength testing Knee extension Plantar flexion Pediatric outcomes data collection instrument (PODCI) MRS: Magnetic Resonance Spectroscopy 7

MoveDMD Trial Part B Patient Disposition Screened n=33 Screen Failed n=2 Discontinuations n=0 Randomized n=31 Treatment Groups PBO 67 mg/kg n=5 Edasa 67 mg/kg

8 MoveDMD Trial Part B Patient Disposition Screened n=33 Screen Failed n=2 Discontinuations n=0 Randomized n=31 Treatment Groups PBO 67 mg/kg n=5 Edasa 67 mg/kg n=10 PBO 100 mg/kg n=6 Edasa 100 mg/kg n=10 From Part A n = 2 n = 6 n = 2 n = 6 All 31 patients completed the study and were included in the per protocol population. 8

9 MoveDMD Trial Part B Baseline Demographics and Values Treatment Group Placebo Edasalonexent 67 mg/kg/day Edasalonexent 100 mg/kg/day Overall Edasalonexent (n =11) (n =10) (n =10) (n =20) Age at Week 0 (years) Age at Symptom Onset (years) Age at Diagnosis (years) Weight at randomization (kg) meter walk/run (10MWR in seconds) stair climb (4SC in seconds) Time to stand (TTS in seconds) Values shown are means Patients were all male and steroid-naive and predominantly Caucasian 1 Patient randomization was stratified for baseline age and 10-meter walk/run 2 On average, patients in the edasalonexent 100 mg/kg/day group were symptomatic at a younger age and did not perform as well on the 4-stair climb and the time to stand function tests at baseline; characteristics consistent with more advanced disease 9

MoveDMD Trial Part B Results Primary Efficacy End Point Change in MRI T2 from Baseline to Week 12 in Composite of 5 Lower Leg Muscles Change in MRI T2 (milliseconds) 1. 0 0. 8 0. 6 0.

10 MoveDMD Trial Part B Results Primary Efficacy End Point Change in MRI T2 from Baseline to Week 12 in Composite of 5 Lower Leg Muscles Change in MRI T2 (milliseconds) P = NS Smaller increase in MRI T2 correlates with less muscle inflammation P l a c e b o 6 7 m g / k g m g / k g P o o l e d E d a s a l o n e x e n t No significant change in the primary end point, average change from baseline to Week 12 in the MRI T2 measure for a composite of lower leg muscles for the pooled edasalonexent treatment groups vs. placebo. Error bars in chart denote SEM 10

11 MoveDMD Trial Part B Results 10-meter Walk/Run Speed and Time to Stand Speed Change in 10-meter Walk/Run Speed from Baseline to Week 12 Change in Speed (units / second) P l a c e b o 6 7 m g / k g m g / k g P o o l e d E d a s a l o n e x e n t Faster vs. baseline Change in timed function test Speed at Week 12 was a pre-defined end point Speed is the reciprocal of the time to perform the function test. In contrast to Time, Speed allows for accounting for boys who are unable to perform tests Change in Speed (units / second) Change in Time to Stand Speed from Baseline to Week 12 Faster vs. baseline Change in 10-meter walk/run Speed and change in time to stand Speed numerically better for edasalonexent 100 mg/kg/day vs. placebo although neither was statistically significant P l a c e b o 6 7 m g / k g m g / k g P o o l e d Error bars in chart denote SEM 11 E d a s a l o n e x e n t

12 MoveDMD Trial Part B Results 4-Stair Climb Speed Change in 4-Stair Climb Speed from Baseline to Week Change in Speed (4-Stairs / second) Faster vs. baseline P l a c e b o 6 7 m g / k g m g / k g P o o l e d E d a s a l o n e x e n t Change in 4-stair climb Speed was numerically better for edasalonexent 100 mg/kg/day vs. placebo, although not statistically significant Error bars in chart denote SEM 12

13 MoveDMD Trial Part B Results North Star Ambulatory Assessment (NSAA) Change in Total NSAA Score from Baseline to Week 12 Change in NSAA Score (units) Better vs. baseline P l a c e b o 6 7 m g / k g m g / k g P o o l e d E d a s a l o n e x e n t Change in NSAA was numerically better for edasalonexent 100 mg/kg/day vs. placebo although not statistically significant Error bars in chart denote SEM 13

14 MoveDMD Trial Part B Results Muscle Strength Change in Plantar Flexion Strength from Baseline to Week 12 Change in Knee Extension Strength from Baseline to Week C h a n g e i n P e a k T o r q u e ( f t. l b s ) 0 C h a n g e i n P e a k T o r q u e ( f t. l b s ) 2 Better vs. baseline M e a n 6 7 m g / k g m g / k g P o o l e d - 4 M e a n 6 7 m g / k g m g / k g P o o l e d E d a s a l o n e x e n t E d a s a l o n e x e n t Assessed by Biodex at Baseline and Week 12 in 26 of 31 boys Changes not statistically significant Error bars in chart denote SEM 14

15 MoveDMD Trial Part B Results Pediatric Outcomes Data Collection Instrument C h a n g e i n P O D C I B L P a r t B t o W e e k 1 2 ( t r a n s f e r & b a s i c m o b i l i t y ) C h a n g e i n P O D C I B L P a r t B t o W e e k 1 2 ( u p p e r e x t r e m i t y & p h y s i c a l f u n c t i o n ) S c o r e 0 S c o r e P l a c e b o 6 7 m g / k g m g / k g P o o l e d 0 P l a c e b o 6 7 m g / k g m g / k g P o o l e d Better vs. baseline E d a s a l o n e x e n t E d a s a l o n e x e n t S c o r e C h a n g e i n P O D C I B L P a r t B t o W e e k 1 2 ( g l o b a l f u n c t i o n ) P l a c e b o 6 7 m g / k g m g / k g P o o l e d E d a s a l o n e x e n t Better vs. baseline Of the PODCI subscores, the Transfer and Basic Mobility Score generally correlates best with loss of milestones over time (McDonald, 2010). For all PODCI subscores, there were numerical improvement for the treatment groups compared with placebo, although not statistically significant. Error bars in chart denote SEM 15

16 MoveDMD Trial Design Study Population: All DMD mutations, ages 4 7, steroid naïve or off steroids for 6 months Part A 7-day, open-label dose-ranging trial N ~ 6 per arm Part B 12-week, randomized, double-blind placebo-controlled trial N ~ 10 per arm Part C 36-week, open-label treatment period N ~ 10 per arm 100 mg/kg/day Edasalonexent 67 mg/kg/day Edasalonexent 67 mg/kg/day 67 mg/kg/day Edasalonexent 100 mg/kg/day Edasalonexent 100 mg/kg/day 33 mg/kg/day Placebo Edasalonexent 100 mg/kg/day or 67 mg/kg/day Assess the safety and PK of edasalonexent in ~18 boys with Duchenne Showed positive PK, NF-κB biomarker effects, safety and tolerability Assess the safety and efficacy of edasalonexent versus placebo using MRI as an early biomarker; trial was powered only for the primary end point of change from baseline in MRI T2 of composite of lower leg muscles Other measures: timed function tests (10-meter walk/run, 4-stair climb, time to stand), NSAA, muscle strength, PODCI and MRI fat fraction Measure the same safety and efficacy parameters as in Part B of the trial to assess treatment effects over a longer time 16

17 MoveDMD Trial: Observations During Control Period from Baseline of Part A to Baseline of Part B s p e e d ( m e t e r s / s e c ) meter 0 M W T - v ewalk/run l o c i t y b aspeed r * 5.9 s P a r t A P a r t B B a s e l i n e Time to stand speed T T S v e l o c i t y s p e e d ( s t e p s / s e c o n d ) Faster vs. baseline 4-stair 4 S climb C - v espeed l o c i t y 4.0 s P a r t A B a s e l i n e P a r t B North Star Ambulatory Assessment N S A A * The period from Baseline of Part A to Baseline of Part B was defined as the control period. During this period of approximately 8 months, patients were off-treatment except for the initial week of dosing in Part A. s p e e d ( 1 / s e c o n d s ) s P a r t A * P a r t B s c o r e P a r t A * P a r t B Declines in TFTs and NSAA were evident during the control period. Muscle strength was stable. B a s e l i n e B a s e l i n e *p<0.05 For reference, shown for Baseline of Part A are the times corresponding to the average speed. Error bars in chart denote SEM 17

18 Comparison of Rate of Change During Control and Active Treatment Periods 1 0 M e t e r W a l k / r u n S p e e d T i m e t o S t a n d S p e e d W e e k l y C h a n g e W e e k l y C h a n g e S t e p C l i m b S p e e d P O D C I - B a s i c M o b i l i t y a n d T r a n s f e r S c o r e 0. 6 W e e k l y C h a n g e W e e k l y C h a n g e N o r t h S t a r A m b u l a t o r y A s s e s s m e n t M u s c l e s t r e n g t h 0. 2 P l a n t a r f l e x i o n K n e e E x t e n s i o n For the 12 boys who crossed over to edasalonexent in Part B, there was numerical improvement in the rate of decline in timed function tests, NSAA and PODCI when comparing the active treatment period to the control period, although these changes were not statistically significant. The time periods for the control period between Part A and Part B differ, so weekly rates of change are shown. W e e k l y C h a n g e Control O f f - t r e a t m e n t O n - t r e a t m e n t W e e k l y C h a n g e Better vs. baseline For perspective, during the control period there was at least an 8% decline in the timed function tests. 18

19 MoveDMD Trial Part B Results Adverse Events: No Safety Signals and Well Tolerated No safety signals Well tolerated with majority of adverse events being mild in nature Most common treatment-related adverse events were mild diarrhea and vomiting No serious treatment-related adverse events No dose reductions No discontinuations 19

20 MoveDMD Trial Part B Results Adverse Events Treatment Group Placebo Edasalonexent 67 mg/kg/day Edasalonexent 100 mg/kg/day Overall Edasalonexent Adverse events in >10% of edasalonexent patients (n =11) (n =10) (n =10) (n =20) Subjects with any TEAEs 10 (90.9) 9 (90.0) 8 (80.0) 17 (85.0) Gastrointestinal disorders Diarrhea 0 (0.0) 3 (30.0) 4 (40.0) 7 (35.0) Vomiting 1 (9.1) 1 (10.0) 3 (30.0) 4 (20.0) Abdominal Pain Upper 0 (0.0) 2 (20.0) 2 (20.0) 4 (20.0) Nausea 0 (0.0) 1 (10.0) 2 (20.0) 3 (15.0) General disorders Pyrexia 3 (27.3) 0 (0.0) 0 (0.0) 0 (0.0) Injury, poisoning and procedural complications Fall* 3 (27.3) 4 (40.0) 2 (20.0) 6 (30.0) Skin abrasion 0 (0.0) 2 (20.0) 1 (10.0) 3 (15.0) Metabolism and nutritional disorders Decreased appetite 0 (0.0) 1 (10.0) 2 (20.0) 3 (15.0) Respiratory, thoracic and mediastinal disorders Rhinorrhoea 1 (9.1) 2 (20.0) 2 (20.0) 4 (20.0) *Falls were specifically recorded as an exploratory measure. 20

21 MoveDMD Trial Part B Conclusions No significant change was observed in the primary end point of change from baseline in MRI T2 of the composite of lower leg muscles for pooled edasalonexent doses vs. placebo. In functional exploratory endpoints, edasalonexent treatment groups generally showed numerical improvement vs. placebo across multiple measures although the changes were not statistically significant: 3 age-appropriate timed function tests: 4-stair climb, 10-meter walk/run and time to stand NSAA, PODCI and muscle strength For the 12 boys who crossed over to edasalonexent in Part B, there was numerical improvement in the rate of decline in timed function tests, NSAA and PODCI when comparing the active treatment period to the control period, although these changes were not statistically significant. No safety signals were seen and edasalonexent was well tolerated with an adverse event profile consistent with prior findings. There were no dose reductions or discontinuations. The open-label extension portion (Part C) of the MoveDMD trial is ongoing to assess effects in patients on edasalonexent over a longer time period. 21

22 Thank you Patients and families Patient groups ImagingDMD Staff Catabasis team 22

This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform

This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, as amended. These forward-looking statements