MoveDMD: Phase 1/2 Trial of Edasalonexent, an NF- B Inhibitor, in 4 - - PowerPoint PPT Presentation

Richard Finkel, MD1,; 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

1Nemours Children’s Health System, Orlando, FL; 2University of Florida Health, Gainesville, FL; 3Oregon Health Sciences

University, Portland, OR; 4The Children's Hospital of Philadelphia, Philadelphia, PA; 5University of California, Los Angeles, Los Angeles, CA; 6Catabasis Pharmaceuticals, Cambridge, MA

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

March 22, 2017

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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

• perating 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

• f 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

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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

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Positive Effects of NF-κB Inhibitors, CAT-1041 and Edasalonexent (CAT-1004), Observed in mdx Mice

CAT-1041 has positive effects on:

Hammers et al, JCI Insights (2016) *p<0.05

Edasalonexent increases dystrophin expression in combination with exon skipping

M23D: exon skipping specific for mdx; Nelsa Estrella, Sarepta (Unpublished observations)

Muscle mass Fibrosis Muscle specific tension

wild type/saline mdx/saline mdx/edasa mdx/M23D mdx/M23D/edasa Merge Laminin Dystrophin *p<0.05

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MoveDMD Trial Design

• Assess the safety

and PK of edasalonexent in ~18 boys with Duchenne

• Showed positive PK,

NF-κB biomarker effects, safety and tolerability

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

Edasalonexent 67 mg/kg/day

33 mg/kg/day

Edasalonexent 67 mg/kg/day Edasalonexent 100 mg/kg/day

67 mg/kg/day

• Measure the same safety and efficacy parameters as

in Part B of the trial to assess treatment effects over a longer time

Placebo

100 mg/kg/day

Edasalonexent 100 mg/kg/day or 67 mg/kg/day Edasalonexent 100 mg/kg/day

• 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

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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:

33 mg/kg n=5 67 mg/kg n=6 100 mg/kg n=6 Total n=17 Diarrhea 4 4 Soft feces 1 1 1 3 Abdominal pain upper 1 1 2 Edasalonexent 100mg Edasalonexent 250mg Tic-Tac M&M

Key Study Metrics

• 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

Primary Efficacy End Point

• 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) Additional Efficacy End Points

• 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)

Part B Key Study Metrics and Efficacy End Points

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MRS: Magnetic Resonance Spectroscopy

MoveDMD Trial Part B Patient Disposition

• All 31 patients completed the study and were included in the per protocol

population.

Treatment Groups From Part A

Screened n=33 Randomized n=31 PBO 67 mg/kg n=5 n = 2 Edasa 67 mg/kg n=10 n = 6 PBO 100 mg/kg n=6 n = 2 Edasa 100 mg/kg n=10 n = 6 Screen Failed n=2 Discontinuations n=0

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MoveDMD Trial Part B Baseline Demographics and Values

1Patient randomization was stratified for baseline age and 10-meter walk/run 2On 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

Values shown are means Patients were all male and steroid-naive and predominantly Caucasian

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)1 6.3 6.0 6.0 6.0 Age at Symptom Onset (years)2 3.7 3.0 2.0 2.5 Age at Diagnosis (years) 2 4.6 3.5 3.0 3.3 Weight at randomization (kg) 21.4 22.1 22.0 22.1 10-meter walk/run (10MWR in seconds)1 6.9 6.3 6.8 6.6 4-stair climb (4SC in seconds)2 5.0 4.5 6.3 5.4 Time to stand (TTS in seconds)2 6.5 7.0 12.0 9.4

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MoveDMD Trial Part B Results Primary Efficacy End Point

• 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.

P = NS Change in MRI T2 (milliseconds)

Change in MRI T2 from Baseline to Week 12 in Composite of 5 Lower Leg Muscles

Error bars in chart denote SEM

Smaller increase in MRI T2 correlates with less muscle inflammation

P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d

0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0

E d a s a l o n e x e n t

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MoveDMD Trial Part B Results 10-meter Walk/Run Speed and Time to Stand Speed

Change in Speed (units / second) Change in 10-meter Walk/Run Speed from Baseline to Week 12 Change in Speed (units / second) Change in Time to Stand Speed from Baseline to Week 12

• 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 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

Faster vs. baseline Faster vs. baseline Error bars in chart denote SEM

P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 0 . 0 2 0
• 0 . 0 1 5
• 0 . 0 1 0
• 0 . 0 0 5

0 . 0 0 0 0 . 0 0 5 0 . 0 1 0 E d a s a l o n e x e n t

P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 0 . 0 6
• 0 . 0 4
• 0 . 0 2

0 . 0 0 0 . 0 2 E d a s a l o n e x e n t

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MoveDMD Trial Part B Results 4-Stair Climb Speed

• Change in 4-stair climb Speed was numerically better for edasalonexent 100 mg/kg/day
• vs. placebo, although not statistically significant

Change in Speed (4-Stairs / second) Change in 4-Stair Climb Speed from Baseline to Week 12

Faster vs. baseline Error bars in chart denote SEM

P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 0 . 0 4
• 0 . 0 2

0 . 0 0 0 . 0 2 0 . 0 4

E d a s a l o n e x e n t

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MoveDMD Trial Part B Results North Star Ambulatory Assessment (NSAA)

• Change in NSAA was numerically better for edasalonexent 100 mg/kg/day vs.

placebo although not statistically significant

Change in NSAA Score (units)

Change in Total NSAA Score from Baseline to Week 12

Better vs. baseline Error bars in chart denote SEM

P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 3
• 2
• 1

1 2

E d a s a l o n e x e n t

MoveDMD Trial Part B Results Muscle Strength

• Assessed by Biodex at Baseline and Week 12 in 26 of 31 boys
• Changes not statistically significant

Better vs. baseline

M e a n 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 6
• 4
• 2

2 E d a s a l o n e x e n t M e a n 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 4
• 2

2 4 E d a s a l o n e x e n t C h a n g e i n P e a k T o r q u e ( f t . l b s ) C h a n g e i n P e a k T o r q u e ( f t . l b s )

Change in Plantar Flexion Strength from Baseline to Week 12 Change in Knee Extension Strength from Baseline to Week 12

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Error bars in chart denote SEM

MoveDMD Trial Part B Results Pediatric Outcomes Data Collection Instrument

• 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.

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Better vs. baseline

P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d 5 1 0 1 5

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

E d a s a l o n e x e n t P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 5

5 1 0 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 ) S c o r e E d a s a l o n e x e n t P l a c e b o 6 7 m g / k g 1 0 0 m g / k g P o o l e d

• 1 0
• 5

5 1 0 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 ) S c o r e E d a s a l o n e x e n t

Better vs. baseline

Error bars in chart denote SEM

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MoveDMD Trial Design

• Assess the safety

and PK of edasalonexent in ~18 boys with Duchenne

• Showed positive PK,

NF-κB biomarker effects, safety and tolerability

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

Edasalonexent 67 mg/kg/day

33 mg/kg/day

Edasalonexent 67 mg/kg/day Edasalonexent 100 mg/kg/day

67 mg/kg/day

• Measure the same safety and efficacy parameters as

in Part B of the trial to assess treatment effects over a longer time

Placebo

100 mg/kg/day

Edasalonexent 100 mg/kg/day or 67 mg/kg/day Edasalonexent 100 mg/kg/day

• 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

MoveDMD Trial: Observations During Control Period from Baseline of Part A to Baseline of Part B

• 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

• ff-treatment except

for the initial week of dosing in Part A.

• Declines in TFTs and

NSAA were evident during the control period.

• Muscle strength was

stable.

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Error bars in chart denote SEM

P a r t A P a r t B 0 . 0 0 0 . 0 5 0 . 1 0 0 . 1 5 0 . 2 0

1 0 M W T - v e l o c i t y b a r

s p e e d ( m e t e r s / s e c ) B a s e l i n e P a r t A P a r t B 0 . 0 0 . 1 0 . 2 0 . 3

4 S C - v e l o c i t y

s p e e d ( s t e p s / s e c o n d ) B a s e l i n e P a r t A P a r t B 0 . 0 0 0 . 0 5 0 . 1 0 0 . 1 5 0 . 2 0 0 . 2 5

T T S v e l o c i t y

s p e e d ( 1 / s e c o n d s ) B a s e l i n e P a r t A P a r t B 5 1 0 1 5 2 0 2 5

N S A A

s c o r e B a s e l i n e

10-meter walk/run speed 4-stair climb speed Time to stand speed North Star Ambulatory Assessment

* * * * *p<0.05

◊ For reference, shown for Baseline of Part A are the

times corresponding to the average speed.

Faster vs. baseline

◊ 5.9 s ◊ 4.0 s ◊ 5.0 s

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Comparison of Rate of Change During Control and Active Treatment Periods

• For the 12 boys who

crossed over to edasalonexent in Part B, there was numerical improvement in the rate

• f 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.

• For perspective, during

the control period there was at least an 8% decline in the timed function tests.

O f f - t r e a t m e n t O n - t r e a t m e n t

• 0 . 0 0 1 0
• 0 . 0 0 0 5

0 . 0 0 0 0 0 . 0 0 0 5

1 0 M e t e r W a l k / r u n S p e e d

W e e k l y C h a n g e

• 0 . 0 0 3
• 0 . 0 0 2
• 0 . 0 0 1

0 . 0 0 0

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

• 0 . 0 0 3
• 0 . 0 0 2
• 0 . 0 0 1

0 . 0 0 0 0 . 0 0 1 0 . 0 0 2

4 - S t e p C l i m b S p e e d

W e e k l y C h a n g e

• 0 . 2
• 0 . 1

0 . 0 0 . 1 0 . 2

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

W e e k l y C h a n g e

• 0 . 2

0 . 0 0 . 2 0 . 4 0 . 6

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

W e e k l y C h a n g e

• 0 . 2

0 . 0 0 . 2

M u s c l e s t r e n g t h

W e e k l y C h a n g e P la n t a r f le x io n K n e e E x t e n s io n

Control

Better vs. baseline

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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

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.

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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.

Thank you

• Patients and families
• Patient groups
• ImagingDMD Staff
• Catabasis team

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