A return to health

Targeting Inflammation in Duchenne Muscular Dystrophy:Non-mutation specific approaches in developing therapies for DMD

Joanne M. Donovan, M.D., Ph.D.Chief Medical OfficerCatabasis Pharmaceuticals

Forward Looking Statements

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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 Quarterly Report Form 10-Q for the three months ended June 30, 2015, 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.

Preventing Disease Progression in Duchenne

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Kinali, 2011

Muscle intact

Muscle replacement by fat and fibrosis

Progressive functional impairment

Absence of Dystrophin plus Mechanical Stress Results in DMD Disease Progression

Drives Muscle Degeneration

Promotes Inflammationand Fibrosis

Inhibits Muscle Regeneration

satellite stem cell

myoblasts

ABSENCE OF DYSTROPHIN

MECHANICAL STRESS

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Inflammation Toll-like receptors NF-kB

Drugs primarily targeting inflammation:

Steroids: prednisone, deflazacort

CAT-1004

Verolone (VB-15)

IMO-8400

NEMO peptides

‣ 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

In Duchenne, Inflammation (NF-kB) Is Present at an Early Age and During Symptomatic Disease

Muscle biopsies from infants with DMD show activated nuclear NF-κB (red)

Chen et al, 2005

NF-κB nuclear staining

Control

NF-κB Activation in Muscle in Infancy in DMD:

Activated NF-kB Inhibits Muscle Regeneration

Lu et al., 2012

8-week-old mdx/SCID mice in which p65+/– and wild-type (wt) MDSCs were implanted. Engraftment was determined by immunostaining for dystrophin (red)

WT MDSCs transplanted into mdx mice p65+/- MDSCs transplanted into mdx mice

WT MDSCs transplanted into mdx mice p65+/- MDSCs transplanted into mdx mice

Dystrophin production (red) in engrafted stem cells:

Intact NF-κB levels

Reduced NF-κB levels

‣ 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.

‣ 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

Lack of Dystrophin is Necessary but Not Sufficient for DMD Disease Progression

Sources:Akima et al Neuromuscul Disord 2012 22(1):16-25Hu et al., 2015

Control DMD

Cross section of mid-thigh muscle in boys age 12 - 14

MRI shows replacement of muscle with fat and fibrosis

Gracilis muscle

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CAT-1004 Modulates the NF-ĸB Pathway and HasPotential to be Disease-Modifying in DMD

ActivatedNF-B

Drives Muscle Degeneration

Promotes Inflammationand Fibrosis

Inhibits Muscle Regeneration

satellite stem cell

myoblasts

ABSENCE OF DYSTROPHIN

MECHANICAL STRESS

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CAT-2000 Series

CAT-1004

**

***

‣ 25-week mdx mouse study

CAT-1004 Analog Demonstrated Significant Improvements in Muscle Function, Running Wheel Activity and Diaphragm Function

Specific Force

(N/cm

2)

10

8

6

4

2

0Control CAT-1041

CAT-1041 Activity on Diaphragm Function in the mdx Mouse Model

*p=0.02

Cumulative Revolutions

800000

600000

400000

200000

0Control CAT-1041

CAT-1041 Activity on Muscle Endurance in the

mdx Mouse Model

*p=0.01

% Specific Force (N/cm

2)

80

60

40

20

0Control CAT-

1004CAT-1041

Activity on Extensor Digitorum Longus Muscle

Function After 5 Contractions

**p=0.001 *p=0.02

Study conducted by Prof. Lee Sweeney 9

*

*

Muscle

Mass

(mg)

300

250

200

150

100

50

0Gastrocnemius Quadriceps Heart

‣ 6-month mdx mouse study

CAT-1004 Analog Demonstrated Significant Improvements in Muscle Fibrosis and Muscle Mass

Treated

Untreated

CAT-1041 Activity on Muscle Mass in the mdx Mouse Model

*

*p<0.05

CAT-1041

Control

CAT-1041 Activity on Fibrosis in Quadriceps in the mdx Mouse Model

10Study conducted by Prof. Lee Sweeney

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Study Population: All mutations, ages 4 – 7, steroid naïve or off steroids for ≥6 months

CAT-1004 MoveDMD Trial Design

Part A7-day, open-label dose ranging trial

Part B12-week, randomized, double-blind

placebo-controlled trial

N = 6 per arm N = 6-8 per arm

CAT-1004 Dose 1

CAT-1004 Dose 2

Placebo*

33 mg/kg per day

67 mg/kg per day

100 mg/kg per day

Safety, tolerability and exposure data

Efficacy data

* 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

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Phase 1 Phase 2 Phase 3 Approved

Prednisone/ prednisolone

Deflazacort

CAT-1004

Verolone (VB-15)

IMO-8400

NEMO peptides

▸ 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.

Targeting NF-kB in Duchenne: The Future

Thank you!