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

Richard Finkel, MD1; Krista Vandenborne, PT, PhD2, 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

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

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

Abstract O.42, World Muscle Society, Copenhagen, October, 2019

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• 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

Disclosures

Chen et al., Neurology 2005 65: 826 Fiorillo et al., Physiol Genomics 2018 50:735 3

Activation of NF-κB in Duchenne Muscular Dystrophy is a Key Factor in Disease Progression in Skeletal and Cardiac Muscle

No Dystrophin + Mechanical Stress Disease Progression Activated NF-κB

Kumar et al., FASEB J 2003 17:386 Akima et al., Neuromuscul Disord 2012 22: 16

Degeneration

MuRF1/MAFbx Control DMD Cross section of mid-thigh muscle in 12-14 YO boys

Dystrophin and Membrane Stability

β-Dystroglycan Actin Dystrophin MMP-9 miRNA NF-κB decreases dystrophin production, suggesting inhibition could increase dystrophin with dystrophin- targeted therapies

Inflammation in Infancy

Cytokines Fibrosis Inflammation

Regeneration

Satellite Cell Myoblasts Myotube Cyclin D1 MyoD

Edasalonexent Inhibits NF-κB, A Key Driver of Muscle Disease in DMD

• Inhibiting NF-κB slowed disease progression in animal models of DMD

– Oral administration of edasalonexent analog (CAT-1041) reduced muscle inflammation and improved function in mdx mice and GRMD dog

• Edasalonexent is an orally-

administered small molecule that is not a steroid

• Being developed as foundational

therapy for patients with DMD regardless of mutation, both as monotherapy and potentially to be combined with dystrophin-targeted therapies

Reduced Inflammation in mdx

Relative Protein Content (AU) 2.5 2 1.5 1 0.5

OPN IL-6 IL-4

p=0.02 p=0.01 p=0.04 Control CAT-1041

Increased Diaphragm Specific Force in mdx

Specific Force (N/cm2) 10 8 6 4 2

Control CAT-1041

Control CAT-1041 p=0.02

Hammers, et al. JCI Insight 2016 1(21): e90341 Means + SEM 4

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• 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 8th 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

• 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

Design of MoveDMD, a Phase 1/2 Trial with Open-Label Extension

Phase 1

n=17

Off-Treatment Period

n=16

Phase 2

n=31

Open-Label Extension

n=31

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In Phase 2 MoveDMD Trial and Open-Label Extension:

Range of Endpoints to Demonstrate Proof of Concept and Support Design of Phase 3

NF-κB Target Engagement Biomarkers Muscle MRI Functional

▸ Inhibition of

NF-κB targeted gene set in peripheral blood

▸ CRP

, biomarker of inflammation

▸ Muscle enzymes ▸ MRI T2 of upper

and lower leg

▸ MRS muscle fat ▸ North Star

Ambulatory Assessment and Timed Function Tests

NCT02439216

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• In MoveDMD trial, during the off-treatment control period, levels of NF-κB target genes were increased

– Consistent with increased NF-κB activity during disease progression in DMD

• Treatment with edasalonexent decreased the levels of individual NF-κB target genes in the blood

– Demonstrates target engagement

Edasalonexent Inhibits NF-κB Target Genes in DMD Boys

• Changes in aggregated NF-κB 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

• 6 0
• 4 0
• 2 0

2 0 4 0 4 0 8 0 1 2 0

N F K B IA

(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 )

T im e (w e e k s ) R P K M

O ff-tre a tm e n t p e rio d 1 0 0 m g /k g e d a s a lo n e x e n t

• 6 0
• 4 0
• 2 0

2 0 4 0 5 1 0 1 5 2 0

N F K B 2

(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)

T im e (w e e k s ) R P K M

O ff-tre a tm e n t p e rio d 1 0 0 m g /k g e d a s a lo n e x e n t

Off-treatment period 100 mg/kg edasa NFKB2

4.60 0.74

NFKBIA

2.50 0.97

Mean fold change in NF-κB target gene abundance in blood (relative to start of treatment)

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In Phase 2 MoveDMD Trial and Open-Label Extension:

Muscle Enzymes Significantly Decreased on Edasalonexent, Supporting a Positive Drug Effect

Weeks on 100 mg/kg Edasalonexent IU/mL

• 5000
• 10000
• 15000
• 20000
• 25000

IU/mL

• 50
• 100
• 150
• 200

Alanine Aminotransferase

12 36 72 48 24 60 IU/mL

• 50
• 100
• 150
• 200
• 250

Aspartate Aminotransferase

12 36 72 48 24 60 IU/mL

• 200
• 400
• 600
• 800

Lactate Dehydrogenase

12 36 72 48 24 60

Creatine Kinase

*

12 36 72 48 24 60

* * *

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

• Early and sustained

biomarker response

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• 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

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 Not Receiving Steroids or Edasalonexent MRI Shows Disease Progression

Finkel et al., World Muscle Society, 2018; Vandenbourne et al., World Muscle Society, 2018

Lower Leg Composite MRI T2 Soleus Fat Fraction Vastus Laterals Fat Fraction 10-meter walk/run 4-stair climb Time to stand

Non-Steroid Cohort: Natural History ImagingDMD Off-treatment: MoveDMD

Means + SEM; side by side comparison from ImagingDMD and MoveDMD datasets Annualized Rate of Change (tasks/s/year) 0.00

• 0.05
• 0.10
• 0.15

Annualized Rate of Change (ms/year) 6 4 2 Annualized Rate of Change (%/year) 4 3 2 1 Annualized Rate of Change (%/year) 20 15 10 5

10

• MRI T2 is tightly correlated with fat

fraction and functional measures

• Composite of 5 lower leg muscles MRI T2

(soleus, gastrocnemius, anterior and posterior tibialis, peroneals) used to encompass muscles at various stages of disease progression and minimize variability

• Following 72 weeks of edasalonexent, the

rate of increase in the composite MRI T2 decreased as compared to the rate of increase during the off-treatment control period

• Early and sustained response in

annualized rate of change

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: Composite of 5 Lower Leg Muscles

Weeks on Edasalonexent

12 48 36 24

* * * *

Edasalonexent 100 mg/kg

Off-treatment control

*

72 Better

Annualized Rate of Change (m sec/year)

6 4 2

• 4

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

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In Phase 2 MoveDMD Trial and Open-Label Extension:

All Assessments of Function Stabilized on Edasalonexent Compared to Off-Treatment Control

North Star Ambulatory Assessment

NSAA Score

25 20 15 10 5

• 36
• 24
• 12

12 24 36 48 60 72

Edasalonexent 100 mg/kg Control Period Speed (1/Seconds)

0.4

Edasalonexent

0.3 0.2

• 36
• 24
• 12

12 24 36 48 60

100 mg/kg Control Period

0.1

4-Stair Climb

72

Time (Seconds)

5 10 15

10-Meter Walk/Run

Speed (1/Seconds) Time (Seconds)

0.20 0.18 0.16 0.14 0.12 5 10

• 36
• 24
• 12

12 24 36 48 60 72

Edasalonexent 100 mg/kg Control Period Weeks Weeks Weeks

Time to Stand

Speed (1/Seconds)

Time (Seconds) 0.3

• 36
• 24
• 12

12 24 36 48 60 72

Edasalonexent 100 mg/kg

0.2 0.1 5 10

Control Period

15

Weeks Means ± SEM shown. Includes data of all boys initially started on 100 mg/kg dose (n=16) with 11 boys participating through 72 weeks.

• Sustained stabilization

through 72 weeks

• n edasalonexent

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NF-κB Inhibition Showed Potential for Cardiac Benefits in DMD

Beats per minute

• 5
• 10
• 15

Heart Rate: Change from Baseline

20 40 Weeks on Edasalonexent 80 60

*

p<0.01

Thomas, et al. Pediatr Cardiol. 2012 33(7):1175-9. Hammers, et al. JCI Insight 2016 1(21): e90341 Fleming, et al., Lancet 2011 377: 1011-18 Means ± SEM shown;

Baseline 99 beats/min

• Elevated resting heart rate is initial

manifestation of cardiac disease in DMD – Cardiac failure is a leading cause of mortality in DMD – Elevated heart rate triples the risk of cardiomyopathy several years later

• Edasalonexent analog had positive effects on

fibrosis in mdx and GRMD models

12 month-old GRMD Untreated CAT-1041 Masson’s Trichrome Staining

• On edasalonexent, mean resting heart rate

significantly decreased, approaching age-normative heart rate ~92 beats per minute – Decreases in heart rate noted to be more pronounced in patients with higher resting heart rates

In Phase 2 MoveDMD Trial and Open-Label Extension:

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• 55+ patient years of exposure
• Well tolerated, with majority of adverse events mild in nature

– Most common related adverse event was diarrhea, generally mild and transient – No serious adverse events on treatment (one on placebo) – No adverse trends in chemistry, hematology, or measures of adrenal function (cortisol and ACTH)

In Phase 2 MoveDMD Trial and Open-Label Extension:

Safety: Edasalonexent was Well-Tolerated

Weeks on Edasalonexent

Treatment-Related Adverse Events >5% Edasalonexent Overall (N=31) System Organ Class/ Preferred Term n % Gastrointestinal disorders Diarrhoea 16 (51.6%) Abdominal pain upper 7 (22.6%) Nausea 3 (9.7%) Vomiting 3 (9.7%) Abdominal discomfort 2 (6.5%) Abdominal pain 2 (6.5%) Faecal incontinence 2 (6.5%) Faeces soft 2 (6.5%) Metabolism and nutrition disorders Decreased appetite 4 (12.9%)

100 75 50 25 14

• Boys on edasalonexent grew similarly to growth curves for unaffected boys

– Weight increased by mean 1.3 kg/year – Height increased by mean 5.3 cm/year – BMI decreased toward 50th percentile

In Phase 2 MoveDMD Trial and Open-Label Extension:

Safety: Growth Continues as Expected Compared to Standard Growth Charts

Percentiles Compared to CDC Growth Charts

BMI

100 75 50 25

Weight

100 75 50 25

Height

Percentile Weeks on Edasalonexent Means ± SEM shown Comparison with CDC growth charts: https://www.cdc.gov/growthcharts/clinical_charts.htm 12 24 36 48 60 72 12 24 36 48 60 72 12 24 36 48 60 72 Weeks on Edasalonexent Weeks on Edasalonexent Percentile Percentile

• Edasalonexent, an oral NF-κB inhibitor, showed:

– Clinically meaningful slowing of disease progression on edasalonexent compared to off-treatment control period

• North Star Ambulatory Assessment and all timed function tests stabilized

– MRI measures supportive of positive edasalonexent treatment effects

• Muscle MRI T2 rate of change improved with edasalonexent treatment versus off-treatment control period

progression – Well tolerated

• Supportive of Phase 3 clinical trial – PolarisDMD is fully enrolled at 40 sites globally

– Enrollment: 4 to 7 year-old (up to 8th birthday) boys not on steroids for 6 months – Primary endpoint NSAA, secondary timed function tests – Additional assessments of growth, cardiac and bone

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Conclusions from Phase 2 MoveDMD Trial and Open-Label Extension:

Edasalonexent Substantially Slowed DMD Disease Progression on Edasalonexent

12-month, randomized, double-blind placebo-controlled trial, n~125 Open-label extension

Edasalonexent

Primary Endpoint

Placebo Edasalonexent 100 mg/kg

NCT03703882 and NCT03917719