CAP-1002 for Advanced DMD: A New Treatment Option

CAP-1002 for Advanced DMD: A New Treatment Option

October 24, 2019NASDAQ: CAPR

Forward-Looking Statements

2

Statements in this press release regarding the efficacy, safety, and intended utilization of Capricor's product candidates; the initiation,conduct, size, timing and results of discovery efforts and clinical trials; the pace of enrollment of clinical trials; plans regardingregulatory filings, future research and clinical trials; regulatory developments involving products, including the ability to obtainregulatory approvals or otherwise bring products to market; plans regarding current and future collaborative activities and theownership of commercial rights; scope, duration, validity and enforceability of intellectual property rights; future royalty streams,revenue projections; expectations with respect to the expected use of proceeds from the recently completed offerings and theanticipated effects of the offerings, and any other statements about Capricor's management team's future expectations, beliefs, goals,plans or prospects constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.Any statements that are not statements of historical fact (including statements containing the words "believes," "plans," "could,""anticipates," "expects," "estimates," "should," "target," "will," "would" and similar expressions) should also be considered to be forward-looking statements. There are a number of important factors that could cause actual results or events to differ materially from thoseindicated by such forward-looking statements. More information about these and other risks that may impact Capricor's business is setforth in Capricor's Annual Report on Form 10-K for the year ended December 31, 2018 as filed with the Securities and ExchangeCommission on March 29, 2019, and as amended by its Amendment No. 1 to Annual Report on Form 10-K/A filed with the Securitiesand Exchange Commission on April 1, 2019, in its Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2019, asfiled with the Securities and Exchange Commission on August 8, 2019, and in its Registration Statement on Form S-3 as filed with theSecurities and Exchange Commission on October 24, 2018, and as amended by its Amendment No. 1 to Form S-3 filed with theSecurities and Exchange Commission on July 17, 2019, together with prospectus supplements thereto. All forward-looking statementsin this press release are based on information available to Capricor as of the date hereof, and Capricor assumes no obligation toupdate these forward-looking statements.

CAP-1002 is an Investigational New Drug and is not approved for any indications. CAP-2003 has not yet been approved for clinicalinvestigation.

‒ Craig McDonald, M.D., is professor and chair of the Department of Physical Medicine and Rehabilitation and Director of the Neuromuscular Disease Clinics at the University of California, Davis. Dr. McDonald is an internationally recognized expert in the clinical management and rehabilitation of neuromuscular diseases including DMD. He is the national PI of the Capricor HOPE-2 Trial.

‒ Linda Marbán, Ph.D. – Chief Executive Officer, Capricor Therapeutics, Inc.

‒ AJ Bergmann, Chief Financial Officer, Capricor Therapeutics, Inc.

Call Participants

3

Dystrophin Deficient Muscular Dystrophy: Diagnosis, Natural History and Current Therapies

Craig McDonald, MD Professor and Chair of PM&R

Professor of PediatricsStudy Chair CINRG Duchenne Natural History Study

University of California Davis HealthSacramento, CA

4

Disclosures

‣ Consulting work on Duchenne muscular dystrophy clinical trials for – Capricor Therapeutics, Inc.– Catabasis Pharmaceuticals, Inc.– PTC Therapeutics– Sarepta– Prosensa– GSK– Pfizer– Eli Lilly– Bristol Myers Squib– Italfarmaco– Mitobridge– Cardero Therapeutics

5

Duchenne Muscular Dystrophy The most common muscular dystrophy of childhood

1 in 3500-5500 boys BMD is about 1 in 18000-35000

X-linked recessive inheritance (Xp21.2) males affected & females carriers However, 1/3 cases are de novo mutation

Caused by mutation of dystrophin gene

Dystrophin gene is the largest gene in genome: 2.4 mb 14 kb mRNA coding sequence 3685 amino acid 427kDa protein 6

Duchenne Muscular Dystrophy Is a Devastating Progressive Disease with Significant Unmet Need

‣ Rare recessive x-linked disorder caused by mutation in the DMDgene

‣ Leads to dystrophin deficiency in muscle tissue and subsequently chronic activation of NF-kB

‣ Progressive disease that leads to devastating deteriorating muscle strength and early death

‣ Only supportive treatments are available– Physical therapy– Orthopedic Surgery for contractures and scoliosis– Assisted ventilation– Heart failure management (e.g., afterload reduction) – Off-label / labeled use of corticosteroids– Eteplirsen in the US for exon-51 mutations – Ataluren in the EU for nonsense mutations

7

Disease Progression Is Characterized by Muscle Damage and Replacement of Muscle Fibers with Fat Infiltration and Sclerosis, Resulting in Loss of Function

Normal muscle tissue Muscle tissue 19 year old DMD patient Post-Mortem

Fat infiltration, sclerotic changes and loss of muscle

fibers

Lack of dystrophin cause shearing of the sarcolemma and activation of NF-kB,

increasing cellular damage and muscle fiber loss

Progressive loss of muscle fibers and replacement of functional muscle units by

fat infiltration and sclerosis

Loss of function; walking capacity preserved in spite of significant loss of

muscle strength due to ‣ Reserve capacity in muscle function‣ Biomechanical compensations

8

Pathophysiology of DMD

Gene abnormality at Xp21 loci ↓

Absence of dystrophin↓

Muscle membrane injury↓

Cascade of events leading to muscle fiber injury and degradation↓

Cycles of degeneration ←→ regeneration↓

Cell death (replacement by fat & connective tissue)

9

DMD pathomechanism

Adapted fromEngvall & Wewer (2003) FASEB 17:1579

Structural defect

Membrane instability

Apoptosis / Necrosis

Inflammation

Fibrosis Fiber Death

10

From: physrev.physiology.org

Dystrophin Gene & Protein

• 8 different promoters• Differential tissue expression of dystrophin isoforms

• 79 exons (0.6% of gene) and most of the gene composed of non-coding introns

• Dystrophin protein organization:• N-terminal actin binding domain• 24 spectrin like repeats in the rod domain• Cysteine rich and c-terminal

• Dystrophin is an important component of DAG complex at muscle membrane• Muscle membrane stability• Cell signalling pathway

11

Duchenne dystrophy =Absence of dystrophinComplete loss of function

Becker dystrophy = Present, but abnormalPartial loss of function

Large in-frame deletionsCan be clinically very mild, asymptomatic BMD (hyperCKemia)

12

Types of mutations in Dystrophinopathies Deletions account for majority of mutations

~65-72% of DMD~85 % of BMDmost in “hotspot” region of exon 45-53

Point mutations and splicing region mutations~25-30%most result in nonsense/frameshift (stop); rare missense

Duplications~5-10%in minor “hotspot” region of exon 2-20

Premature stop codon mutation~13-15% 13

Reading Frame Rule

Out-of-frame mutations result in disruption of ORF→ premature stop codon→ truncated dystrophin/non-functional protein→ Absence of dystrophin→ DMD

In-frame mutations that preserve the ORF→ replacements of amino acids in dystrophin→ partially functional protein→ BMD

Majority of DMD and BMD follow this rule 14

15

51 5352 54 5655 57 58 59 60 61

504948474645444342414039

62 63 64 65 66 67 68 69 70 71 72 73

77 78 79

27 28 29 30 31 32 33 34 35 36 37 38

26252423

74 75 76

22

8765431

21201918171615

9 10 11 12 13 14

DP427 muscle, neurons

DP260 retina

DP140 neurons, kidney

DP116 Schwann cells

DP71 - 45 universal

Deletions that disrupt the codon reading frame produce severe Duchenne dystrophy2

16

51 5352 54 5655 57 58 59 60 61

504948474645444342414039

62 63 64 65 66 67 68 69 70 71 72 73

77 78 79

27 28 29 30 31 32 33 34 35 36 37 38

26252423

74 75 76

22

8765431

21201918171615

9 10 11 12 13 14

DP427 muscle, neurons

DP260 retina

DP140 neurons, kidney

DP116 Schwann cells

DP71 - 45 universal

Deletions that do not disrupt the codon reading frame produce

mild Becker dystrophy2

DMD ↔ outlier DMD ↔ BMDAbsent/nonfunctional dystrophin proteinsevere phenotype: DMD

Smaller/partially functional/reduced amount of dystrophinmild phenotype: BMD

Mutations can result in phenotype within the spectrum Genotype (mutation characterization)/phenotype

correlation is not perfect nor easy Clinical picture is better at predicting prognosis and

disease progression; and immunochemical analysis of dystrophin rarely necessary

17

DMD vs. BMD• Immunostaining using Antibodies to different dystrophin

epitopes

• Antibody to C-terminus:• Absent staining: DMD• Present staining: BMD

Antibody to Rod domain may be positive in DMD

• Western Blot Analysis (using C-terminal):• < 2-3% quantity → Duchenne phenotype• 5 – 20% quantity → “Outlier” phenotype• 20 –80% quantity → Becker phenotype• or 90 – 100% &

abnormal structure/size from Novocastra18

DMD vs. BMDDuchenne Becker

Clinical Onset 2 – 6 years 4 – 12 (or later)

Age to wheelchair 7-13 years (no steroids)(-) steroids 10 years(+) steroids 13.5 years

> 16 years(often in 3rd

decade)

Restrictive Lung Disease

Progresses to severe RLD(2nd decade)

Mild severity RLD

Cardiomyopathy Severe (mid to late 2nd

decade)

Severe (in 3rd to 4th

decade)Scoliosis Severe in 80-90% Rare

Life Expectancy 17 – 25 (non-vent)30’s (vent)

4th to 6th decade19

Interventions that have impacted the natural history of disease progression and survival in DMD

1. Glucocorticoids (GC, still off-label in EU despite proven efficacy)

2. Management of spine deformitya) Glucocorticoids

b) Timely spine surgery for curves >30–40 degrees

3. Respiratory managementa) Airway clearance strategies / Mech. cough assistance

b) Non-invasive ventilation

4. Cardiac managementa) Early afterload reduction (e.g. ACE inhibitors)

b) Recognition and management of heart failure

5. Novel disease-modifying therapies20

0 5 10 15 20 25 30Years

Stages of DMD are captured with the use of multiple clinical endpoints

Loss of Ambulation

Death

Impaired ability toHop Run Jump Rise from Floor

Loss of Rise from

Floor

Loss of Stair Climb

Stages of DMD Disease Progression

Loss of Upper Limb

Overhead reach

21

Late Ambulatory Stage (Rapid Functional decline)

Delayed & Impaired Acquisition of Milestones / Motor Skills

Early Ambulatory Stage (Modest functional decline)

Late Non-Ambulatory Stage

Early Non-Ambulatory Stage

Loss of Upper LimbHand to Mouth

Non-invasive Ventilation (Nocturnal)

Loss of Upper LimbDistal Hand

Non-invasive Ventilation (Diurnal)

AGE

BayleyNSAA

TFTs____________NSAA TFTs6MWT100 m. QMT

NSAATFTs. 6MWT. PUL100 m. PFTs QMT

PFTsPUL

EK Scale. QMT

PFTsPUL

EK Scale

ExampleClinical Endpoints

0 5 10 15 20 25 30Years


Impaired ability toHop Run Jump Rise from Floor


22

Delayed & Impaired Acquisition of Milestones / Motor Skills

AGE

BayleyNSAA

TFTs____________


Motor and Cognitive Assessment of Infants and Young Boys with Duchenne Muscular Dystrophy:

Results from the Muscular Dystrophy Association DMD Clinical Research Network. Connolly et al. (n=25; 1.8±0.8 years)

23

NSAA Latent Class Trajectory (UK NSAA)(Muntoni et al.

25

Maturation, stability, and decline on hop and jump

• Maturation phase is similar across cluster classes • Proportion of patients who can hop and jump is highest in patients with milder trajectories • Decline phrase is separated by cluster class Muntoni et al. submitted

26

Performance on rise from floor and run NSAA items by latent trajectory class

A

Proportion of patients with NSAA item score > 0

27

Mean of individual patient fitted curves with

higher and lower quartiles

Muntoni et al, WMS, 2018Signorovitch et al, ISPOR, 2018

NSAA Score at

mean peak

AGE (years)

50% of mean peak NSAA

27

23

30

30

20

10

1086 12 1614

6.8

7.85.9

Age at mean peak NSAA score

Upper quartile

Lower quartileN

SAA

Scor

e

28

0 5 10 15 20 25 30Years


Loss of Ambulation

Loss of Rise from

Floor

Loss of Stair Climb


29

Late Ambulatory Stage (Rapid Functional decline)

Early Ambulatory Stage (Modest functional decline)

AGE

____________NSAA TFTs6MWT100 m. QMTNSAA

TFTs. 6MWT. PUL100 m. PFTs QMT


CINRG Data: Loss of Ambulation(all mutation subtypes and steroid use, N = 309)

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20Age (years)

<30 days cumulative GC exp1 year or greater cumulative GC exposure

Kaplan-Meier survival estimates

> 1 year steroids:• Median LOA = 13.3 ± 0.3 yrs• 95% CI = 12.5 – 14 yrs

< 1 month steroids:• Median LOA = 9.8 ± 0.2 yrs• 95% CI = 9.3-10.1 yrs• (n=309)

30

There Has Been a Changing Natural History in DMD Over the Last 4 Decades Affecting Survival1960s

No Treatment

Passamano, et al. Acta Myol. 2012;31(2):121-125. Eagle, et al. Neuromuscul Disord. 2007;17(6):470-475.

1970-1990 Spine Surgery & Ventilation

31

DMD Survival Affected Primarily by Ventilation

• Ventilation was recognized as a main intervention affecting survival

• Ventilated median survival = 27.0 yr

• Without ventilation = 19.0 yr

Passamano, et al. Acta Myol. 2012;31(2):121-125.

• Ventilation was recognized as a main intervention affecting survival

• Ventilated mean survival = 27.9 yr(range, 23 - 38.6 yr)

• Without ventilation = 17.7 yr(range, 11.6-27.5 yr)

Rall and Grimm: Acta Myol. 2012 Oct;31(2):117-20.

32

There Has Been a Changing Natural History in DMD Over the Last 4 Decades Affecting Survival

1980s – Present Glucocorticoids/Steroids

Schram, et al. J Am Coll Cardiol. 2013;61(9):948-954. Duboc D, et al. Am Heart J. 2007;154(3):596-602.

2000 – PresentAfterload Reduction With

ACE Inhibitors

33

Glucocorticoids target NF-κB which is Chronically Activated in DMD

• miRNAs in muscle microenvironments cause variable dystrophin in muscular dystrophy

• miRNAs are elevated in dystrophic myofibers and increase with disease severity

• Inflammatory cytokines induce miRNAs, and antiinflammatories block their expression

• miRNAs provide a precision medicine target in dystrophy and exon skipping

34

8 Milestones that are clinically meaningful in DMD (based on PODCI Transfer / Basic Mobility)

Standfrom supine < 5 sec

Stand from supine 5-10 sec

Stand from supine > 10 sec or Lost Risefrom Floor

Lost4-StairClimb

Still Amb

Non-AmbFull Overhead reach

Lost Full Overhead Reach(Retains hand to mouth)

Lost Hand to Mouth(RetainsHand Function)

Lost Lost Hand Function(Brooke 6) 36

0 5 10 15 20 25 30Years


Death


Loss of Upper Limb

Overhead reach

40

Late Non-Ambulatory Stage

Early Non-Ambulatory Stage

Loss of Upper LimbHand to Mouth

Non-invasive Ventilation (Nocturnal)

Loss of Upper LimbDistal Hand

Non-invasive Ventilation (Diurnal)

AGE

PFTsPROM PUL

EK Scale. QMT

PFTsPROM PULEK Scale


PPMD Patient and Caregiver

Survey

41

Loss of Key Upper Limb Milestones prolonged with steroids by 3-5 years (McDonald et al. Lancet 2018)

42

McDonald et al. Lancet, 201843

DMD survival is impacted primarily by ventilation

1. Rall S, Grimm T. Acta Myol, 2012;31:117-1202. Passamano L, et al. Acta Myol, 2012;31:121-125

StudyMedian survival, years (range)

Ventilated Not ventilatedRall & Grimm1 27.0 (20.2-33.8) 19.0 (17.7-20.3)Passamano et al 2 27.9 (23-38.6) 17.7 (22.6-27.5)

0 5 10 15 20 25 30 35 400.0

0.2

0.4

0.6

0.8

1.0

Age (years)

Prop

ortio

n su

rviv

ing

Ventilated (n = 44)Non-ventilated (n = 22)

44

Despite advances in care, respiratory and cardiac complications remain the leading causes of death in DMD

#From the total pool of 340 eligible patients (minus Indian cohort due to differences in standard of care) 32 died over the 8 year study period.Unpublished CINRG data.47%

25% 28%

0

10

20

30

40

50

Respiratoryfailure

Cardiac failure Other

Perc

enta

ge o

f dea

ths n = 32

Causes of death in CINRG-DNHS

#From the total pool of 340 eligible patients (minus Indian cohort due to differences in standard of care) 32 died over the 8 year study period.Unpublished CINRG data.

45

Changes in ambulatory milestones correlate to severity of respiratory function decline

FVC%p 80%= Lower limit of

normal1-4

FVC%p50%FVC%p40%FVC%p30%

Loss of ambulation1

Loss of overhead reach1,8#

Loss of self-feeding1,8#

Complete loss of hand function1,8#

Start of respiratory function decline1

Severe respiratory Insufficiency1,5,6

Insufficient cough

Moderate respiratory insufficiency1,5,6

Respiratory function decline (FVC%p)1

Respiratory clinical milestone

Lower limb clinical milestone

Upper limb clinical milestone

#Brooke score of upper limb function = 3, 5 and 6, respectively.6%p: percent predicted; FVC: forced vital capacity.1. Mayer OH, et al. US Neurology 2017;13:35–41; 2. Finder JD, et al. Am J Respir Crit Care Med 2017;196:512-9; 3. Finder JD, et al. Am J Respir Crit Care Med 2004;170:456-65;4. Johnson JD and Theurer WM. Am Fam Physician 2014;89:359-66; 5. Humbertclaude V, et al. Eur J Paediatr Neurol 2012;16:149-60; 6. Mayer OH, et al. J Neuromuscul Dis 2017;4:189-98; 7. Bushby K, et al. Lancet Neurol 2010;9:177-89; 8. Brooke MH, et al. Neurology 1989;39475-481.

46

Clinical thresholds of respiratory function can guide patient management

1. Mayer OH et al. US Neurology 2017;13:35-41; 2. Bushby K, et al. Lancet Neurol 2010;9:177-89; 3. Birnkrant DJ, et al. Lancet Neurol 2018;17:347-61. 4. Sawnani, H. et al. J Pediatr 2015;166:640-5.

5 10 20 25 3015Age (years)

Resp

irato

ry fu

nctio

n te

st

100

80

60

40

0

50

30

Daily in-exsufflator / airway clearanceNight time ventilation

Mouthpiece ventilation

Raised volume Rx in-exsufflator

Continuous ventilation

For every 10% reduction in FVC, odds of hypoventilation increase by 20%

n = 334

Change in PEF%p and FVC%p with age

PEF%pFVC%p

47

Progressive muscle weakness in DMD leads to a sequential loss of function

• 1. Mayer OH, et al. US Neurology 2017;13:35–41; 2. Finder JD, et al. Am J Respir Crit Care Med;Article in Press 2017; 3. Finder JD, et al. Am J Respir Crit Care Med 2004;170:456-65; 4. Johnson JD and Theurer WM. Am Fam Physician 2014;89:359-66; 5. Humbertclaude V, et al. Eur J Paediatr Neurol 2012;16:149-60; 6. Mayer OH, et al. J Neuromuscul Dis 2017;4:189-98; 7. Bushby K, et al. Lancet Neurol 2010;9:177-89; 8. McDonald CM, et al. Neuromuscular Disorders 2016;26:473-80; 9. Brooke MH, et al. Neurology 1989;39475-481.

Respiratory muscle weakness

Low lung volumes

Nocturnal hypoventilation

Poor airwayclearance

Loss of ambulation

Diurnalhypoventilation

Overhead motion

No overhead motion

Hand to mouth

No hand to mouth

Respiratory Lower extremityUpper extremity

48

Clinical management of respiratory function decline in DMD

• Mayer OH, et al. US Neurology 2017;13:35–41.


Low lung volumes


Poor airway clearance

Diurnal hypoventilation

49


• 1. Mayer OH, et al. US Neurology 2017;13:35–41; 2. Birnkrant DJ, et al. Lancet Neurol 2018;17:347-61.


Low lung volumes




Hyperinsufflation Rx

Cough assist / Airway clearance

50


• 1. Mayer OH, et al. US Neurology 2017;13:35–41; 2. Birnkrant DJ, et al. Lancet Neurol 2018;17:347-61.


Low lung volumes




Hyperinsufflation Rx

Cough assist / Airway clearance

Nasal non-invasive ventilation

Mouthpiece “Sip” ventilation

51

Key Learnings from Natural History in DMD

There is linkage of the timing of functional deterioration and loss of milestones with later disease course in DMD

52

Age at loss of ambulation is linked to age at loss of hand to mouth function

53

Age at Loss of Ambulation Predicts Age at Onset of 1 liter FVC (CINRG Data)

FVC < 1 liter increases risk of death

HR (95% CI)

4.1(1.3, 13.1)

0.00

0.25

0.50

0.75

1.00

0 10 20 30Age (years)

Proportion Reaching FVC of 1L

Ambulatory patients age 9-18 at study entry

Number at RiskLOA <10 years 53 53 46 22 3 1 0 0LOA 13 years or still walking 208 208 132 71 27 7 0 0

LOA <10 years

LOA 13 years or still walking

McDonald et al. Lancet, 2018 54

Median Absolute FVC (Liters) by Age and GC use. Peak in median FVC is shown and

the point at which the median absolute FVC value drops below 1 liter.

McDonald et al. Neuromuscular Disorders, 201855

Steroid use and all-cause mortality in DMD

• Forty-five deaths occurred over almost 10 years of follow-up

• The odds ratio for death for those on GC treatment ≥ 1 year showed a reduced death risk by over 50%

• (odds ratio 0.47, 95% CI 0.22-1.00, p = 0.05).

McDonald et al. Lancet, 201856

0 1 2 3 4 5 6

No useful function of hands.

Can use hands to hold pen or pick up a coin ordrive a powered Chair

Can raise 1 or 2 hands to mouth but cannot raise a cup with a 200g weight in it to mouth

Can raise standardized plastic cup with 200g weight in it to mouth using both hands if necessary

Can raise both arms to shoulder height simultaneously w/ or w/o compensation

Can raise both arms simultaneously above head only by flexing the elbow

Full overhead reach without compensation

Performance of the Upper Limb (Entry Items)

Target Population

57

Primary Efficacy Endpoint: PUL Assessment to Assess Skeletal Muscle Primary Efficacy Endpoint:

Performance of the Upper Limb (PUL: v1.2) to Assess Skeletal Muscle

58

PUL v.2.0:• 3-point response scale - more robust and reproducible than v1.2• Compensatory strategies allowed to achieve tasks (not allowed in v1.2)• V2.0: better able to detect change at 12 months at all levels of ability*

*Mayhew et al, 2019; Pane et al, 2018

Static positioning leads to contractures in DMD

59

Scoliosis in DMD

Without steroids80-90% require fusion

With steroids20-30% require fusion

60

Cardiomyopathy in DMD• Clinically significant cardiomyopathy rare before age 10; MRI changes

common• Fibrosis posterior wall left ventricle• Myocardium exhibits abnormal contractility• Arrythmias

• Treatment: Early ACE Inhibitors; Evidence Class Ia• enalapril, lisinopril, perindopril

• ARBs (Losartan)• Beta Blockers (metoprolol, carvedilol)• Aldosterone receptor antagonists (Spironolactone, eplerenone)• Diuretics (Furosemide, Thiazides)

61

Potential for Combination Treatments in DMD

‣ Six main categories for therapeutic targets for DMD

‣ One addresses primary genetic defect; rest address downstream aspects of the pathogenesis

‣ Targeting any single pathway may be an approvable mono-therapy

‣ Future treatment paradigm may involve targeting multiple pathways to have greater patient impact

62

Increasing muscle mass

and regeneration

Decreasing inflammation and fibrosis

Correcting perturbations

in Calcium handling

Mitochondria dysfunction

Replacement of dystrophin/

utrophin

Correcting blood flow regulation

DMD Therapeutic

Development

Development of State-of-the-Art Combination Therapies for Duchenne Muscular Dystrophy


63


and regeneration



in Calcium handling



utrophin


DMD Therapeutic

Development

‣ NF-κB Is Chronically Activated in DMD

‣ Prednisone / Prednisolone‣ Deflazacort (Emflaza, PTC)

‣ Current Trials:‣ Vamorolone (ReveraGen)

– Dissociative steroids (decreased Aes)

‣ Edasalonexent (Catabasis)– covalently linked salicylic acid (ASA) and

docosahexaenoic acid (DHA), – synergistically leverages the ability of both

compounds to intracellularly inhibit activated NF-κB

‣ Givinostat (Italfarmaco)‣ ? CAP 1002


64


and regeneration



in Calcium handling



utrophin


DMD Therapeutic

Development

‣ Therapeutics targeting dystrophin restoration

‣ Antisense Oligonucleotides‣ PMOs‣ PPMOs‣ AAV microdystrophin gene

therapy


‣Myostatin Inhibitors

‣ Investigational

‣Pfizer (IV Q month)

‣Roche (SQ Q week)

65


and regeneration



in Calcium handling



utrophin


DMD Therapeutic

Development

Development of State-of-the-Art Combination Therapies for Duchenne Muscular Dystrophy


66


and regeneration



in Calcium handling



utrophin


DMD Therapeutic

Development

‣ Therapeutics targeting mitochondrial health

‣ Idebenone (Santhera)‣ PPAR𝛅𝛅 agonist (Astellas)‣ (+)-epicatechin (Cardero)

‣ ? CAP-1002

Acknowledgments

UC Davis Neuromuscular Medicine & Rehabilitation Research Center and CINRG Network

67

Linda Marbán, Ph.D.Capricor CEO

68

Treatment Options for DMD are Limited

69

Challenges EXONDYS 51 –13% of

DMD population Gene therapy Steroids have adverse

side-effects NF-kB inhibition may

not be enough

Exon Skipping Gene therapy Utrophin NF-kB Steroids

Immunomodulatory Anti-fibrotic Pro-regenerative Cellular Energy

We believe CAP-1002 may be used synergistically with other therapeutics aimed to treat DMD

Capricor’s Regulatory Designations - DMD

Rare Pediatric Disease Designation

Orphan Drug Designation

RMAT Designation

Goal: to facilitate efficient development and expedite review of a drug

Similar to breakthrough therapy designation: RMAT provides benefits that include more

frequent meetings with FDA to discuss the development plan for the product candidate

eligibility for rolling review and priority review Products may also be eligible for accelerated

approval on the basis of a surrogate or intermediate

endpoint reasonably likely to predict long-term clinical benefit

reliance upon data obtained from a meaningful number of sites

70

December 2018 RMAT Meeting Summary

71

Interdisciplinary meeting with FDA (CBER)

FDA suggested using PUL v2.0 as primary efficacy endpoint– Interim analysis was positive for PUL 2.0

FDA stated that the trial would need to show:– Evidence of clinically meaningful changes in the PUL– Stabilization or improvement in other measures of skeletal, respiratory

and/or cardiac function Interim analysis for HOPE-2 shows all of these improving in treated

patients over placebo

FDA advised CAPR to request an end of phase meeting after completion of the trial to determine whether HOPE-2 could serve as the registration study.

– Discussions with FDA are ongoing regarding CAP-1002 and DMD

‒ CAP-1002 is a biologic consisting of allogeneic cardiosphere-derived cells (CDCs)

Manufactured from donated heart muscle

Does not act by “stemness” – the cellsdo not engraft into host tissue

MOA: cells secrete exosomes: Contain miRNA, non-coding RNAs and proteins Internalized by target cells Stimulate diverse and lasting changes in cellular behavior 3 known miRNAs drive CAP-1002 potency

CAP-1002 has been investigated in multiple independent clinical trials and more than 150 human subjects

Capricor’s CAP-1002 Technology

72

73

CAP-1002 Manufacturing

CSps CDCs Wash Formulate Fill CAP-1002

‒ CAP-1002 is manufactured from donor hearts via a proprietary process

‒ Clinical trial material currently produced at Capricor facility

‒ High-yield process in advanced development

‒ Previous 3-year collaboration with Janssen Biotech focused on chemistry, manufacturing and controls (CMC)

Design: Phase II, randomized, double-blind, placebo-controlled trial in participants with DMD and reduced skeletal muscle function

Objective: Evaluate safety and efficacy of CAP-1002

Dosing Regimen: 150M cells delivered every 3 months

Delivery: Intravenous infusion Sites: approximately 9 sites (USA)

HOPE-2 Clinical Trial Design

https://www.clinicaltrials.gov/ct2/show/study/NCT03406780 74

https://www.clinicaltrials.gov/ct2/show/study/NCT03406780

HOPE-2 Interim Analysis Safety Results

75

A total of 57 infusions were performed in HOPE-2 as of July 31, 2019 With the exception of two serious adverse events1,2 in the form of

immediate allergic reactions, no safety signals were identified To reduce the risk of future adverse events, Capricor initiated a

commonly used pre-medication regimen including oral steroids and antihistamines Since initiation of the pre-treatment regimen, approximately

40 infusions of CAP-1002 or placebo have been administered with only one serious adverse event1 reported that required an overnight observation of the patient.

1Assessed as related to either CAP-1002 or placebo administration2One SAE each in HOPE-2 and HOPE-OLE

HOPE-2 Interim Analysis Data Summary

76

Skeletal: Mid-Level PUL 2.0 at 6 months (p=0.0612) Shoulder + Mid + Distal Level PUL 2.0 at 6 months (p=0.0299) and strong

signal at 3 months (p=0.0549) Mid + Distal Level PUL 2.0 at 6 months (p=0.0177) Tip to Tip strength (independent skeletal measure) at 6 months (p=0.0111)

Respiratory Trends towards improvements in PEF (% predicted) and IFR (absolute)

Cardiac Improvements in wall thickening (similar to positive changes seen in

HOPE-Duchenne) LV myocardium mass

Improvements in PUL 2.0 ObservedMid + Distal

‒ Δ 1.6 difference in CAP-1002 vs. placebo at 6-months

‒ Skeletal muscle function improved in non-ambulant patients with DMD

‒ Could help patients maintain independence if function is improved or decline attenuated

77

p= 0.0177

Comparisons treated vs. placebo using mixed model repeated measures ANOVA with covariatesAnalysis done in Sept. ITT PopulationColored boxes heights, either positive or negative, represent mean change from baselineBars represent ± one standard deviation from the meanP-values are nominal without adjustment for multiple testing or claims of statistical significance

n=10n=8

n=8

n=6

Conclusions and Future DirectionsConclusions:

First placebo-controlled trial in DMD to use PUL 2.0 for evaluation of efficacy First placebo-controlled trial

showing upper limb functional improvements in non-ambulant DMD patients Directionally consistent

improvements in function, strength, pulmonary and cardiac endpoints

Moving Forward:

Meet with FDA to determine if CAP-1002 potentially qualifies for accelerated approval based on RMAT standards

– Based on Guidance for Industry: Expedited Programs for Regenerative Medicine Therapies for Serious Conditions

78

Duchenne Market Statistics and Projections

79

Patient Population Est. US DMD population: 15,000 Est. non-ambulant patient population*: 50% Est. addressable patients*: 7,500

Estimated Target Price* CAP-1002 Target Price: $150,000 per dose

Current dosing estimate: 4 doses per year = $600,000

Revenue Projections* Est. Annual Revenue (10% market penetration): $450M Est. Annual Revenue (50% market penetration): $2.25B

*Based on internal projections and estimates

World-Class DMD Advisory BoardCraig McDonald, M.D. (National PI) University of California at Davis (USA)

Michelle Eagle, Ph.D., M.Sc., MCSP Atom International Ltd (UK)

Richard Finkel, M.D. Nemours Children's Hospital (USA)

Pat Furlong Parent Project Muscular Dystrophy (USA)

Kan Hor, M.D. Nationwide Children's Hospital (USA)

John Jefferies, M.D. Cincinnati Children's Hospital Medical Center (USA)

Oscar Henry Mayer, M.D. Children's Hospital of Philadelphia (USA)

Eugenio Mercuri, M.D., Ph.D. Catholic University of the Sacred Heart (Italy)

Francesco Muntoni, M.D. University College London (UK)

Thomas Voit, M.D. University College London (UK)

Lee Sweeney, Ph.D. University of Florida (USA)

Michael Taylor, M.D., Ph.D. Cincinnati Children's Hospital Medical Center (USA)

80

Thank you

Questions and Answer

81

CAP-1002 for Advanced DMD: A New Treatment Option

Documents

Transcript of CAP-1002 for Advanced DMD: A New Treatment Option