PowerPoint Presentation · 2019-06-18 · Leukocyte Adhesion Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD), Infantile Malignant Osteopetrosis (IMO) and Danon disease and

June 2019

Important InformationCautionary Statement Regarding Forward-Looking StatementsVarious statements in this release concerning Rocket’s future expectations, plans and prospects, includingwithout limitation, Rocket’s expectations regarding the safety, effectiveness and timing of product candidatesthat Rocket may develop, including in collaboration with academic partners, to treat Fanconi Anemia (FA),Leukocyte Adhesion Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD), Infantile Malignant Osteopetrosis(IMO) and Danon disease and the safety, effectiveness and timing of related pre-clinical studies and clinicaltrials, may constitute forward-looking statements for the purposes of the safe harbor provisions under thePrivate Securities Litigation Reform Act of 1995 and other federal securities laws and are subject tosubstantial risks, uncertainties and assumptions. You should not place reliance on these forward-lookingstatements, which often include words such as "believe", "expect", "anticipate", "intend", "plan", "will give","estimate", "seek", "will", "may", "suggest" or similar terms, variations of such terms or the negative of thoseterms. Although Rocket believes that the expectations reflected in the forward-looking statements arereasonable, Rocket cannot guarantee such outcomes. Actual results may differ materially from thoseindicated by these forward-looking statements as a result of various important factors, including, withoutlimitation, Rocket’s ability to successfully demonstrate the efficacy and safety of such products and pre-clinical studies and clinical trials, its gene therapy programs, the preclinical and clinical results for its productcandidates, which may not support further development and marketing approval, the potential advantagesof Rocket’s product candidates, actions of regulatory agencies, which may affect the initiation, timing andprogress of pre-clinical studies and clinical trials of its product candidates, Rocket’s and its licensors ability toobtain, maintain and protect its and their respective intellectual property, the timing, cost or other aspectsof a potential commercial launch of Rocket’s product candidates, Rocket’s ability to manage operatingexpenses, Rocket’s ability to obtain additional funding to support its business activities and establish andmaintain strategic business alliances and new business initiatives, Rocket’s dependence on third parties fordevelopment, manufacture, marketing, sales and distribution of product candidates, the outcome oflitigation, and unexpected expenditures, as well as those risks more fully discussed in the section entitled“Risk Factors” in Rocket’s Annual Report on Form 10-K for the year ended December 31, 2018. Accordingly,you should not place undue reliance on these forward-looking statements. All such statements speak only asof the date made, and Rocket undertakes no obligation to update or revise publicly any forward-lookingstatements, whether as a result of new information, future events or otherwise.

3

Gene Therapy: A Multi-Platform Approach

In Vivo (In Body)AAV Gene Therapy

Ex Vivo (Outside Body)Lentiviral Gene Therapy

Remove cells &isolate patient HSCs

Laboratory-produced LV

Laboratory-produced AAV

Direct intravenous injection

Gene-modifyHSCs

Infusion of modified HSCs

TherapeuticLVVTherapeutic

AAV

4

About Rocket Pharma

Multi-Platform Gene Therapy (GTx) Company Targeting Rare Diseases1st-in-class with direct on-target mechanism of action (MOA) and clear clinical endpoints

Ex-vivo Lentiviral vectors (LVV) Fanconi Anemia (FA)

Leukocyte Adhesion Deficiency-I (LAD-I)

Pyruvate Kinase Deficiency (PKD)

Infantile Malignant Osteopetrosis (IMO)

In-vivo adeno-associated virus (AAV) Danon Disease

Multiple Near- & Medium-term Company Value Drivers

Near-term Milestones (2019) Four programs in the clinic (FA, LAD-I, PKD, Danon)

Additional clinical data for FA and LAD-I (Next 12-18 months)

FA and LAD-I advance to potential registration trial stage

Medium-term Milestones (2020-2021) Registrational studies ongoing in four programs

First global submission (BLA/MAA)

Platform establishment and pipeline expansion

Currently planned programs eligible for Pediatric Priority Review Vouchers

Strong Precedents and World-Class Expertise

Strong Precedents and Sound Strategy Precedents for LVV- & AAV-based therapies

Clearly-defined product metrics across indications

Experienced company leadership

Leading research and manufacturing partners

5

Gaurav Shah, M.D.President & Chief Executive Officer

Jonathan Schwartz, M.D.CMO & SVP, Clinical Development

Kinnari Patel, Pharm.D., MBACOO & EVP, Development

Annahita Keravala, Ph.D.AVP,

AAV Platform

Gayatri R. Rao, M.D., J.D.

VP, Reg Policy & Patient Advocacy

Raj Prabhakar, MBASVP, Bus Operations &

Bus Development

Claudine Prowse, Ph.D.

SVP, Strategy & Corporate Dev

Christopher Ballas, Ph.D.

VP, Manufacturing

Brian C. Beard, Ph.D.

AVP, CMCLenti & AAV

Leadership Team: Expertise in GTx & Rare Diseases Clinical Development

Spearheaded Kymriah (CART-19) development at Novartis towards approval

Led multiple biologics approvalsLed Opdivo and six rare disease indication

approvals

~20 years cell and gene therapy development &

manufacturing

7-Year Former Director of FDA’s Office of Orphan

Products Development

~17 years cell, gene and biotech

business development

~20 years capital markets, strategy,

corporate development

20+ years gene therapy expertise

15+ years cell and gene therapies expertise

6

Discovery Preclinical Phase 1 Phase 2 Designations

Fast Track, Orphan Drug (U.S.)

RMAT, ATMP, Fast Track, Rare Pediatric, Orphan Drug (U.S./E.U.)

ATMP, Fast Track, Rare Pediatric, Orphan Drug (U.S./E.U.)

Orphan Drug (U.S./E.U.)

Rare Pediatric, Orphan Drug (U.S.)

Rocket’s Expanding Pipeline: Potential for Significant Value Creation Near and Long Term

RP-A501Danon Disease

RP-L102Fanconi Anemia

RP-L201Leukocyte Adhesion

Deficiency-I

RP-L301Pyruvate Kinase

Deficiency

RP-L401Infantile Malignant

Osteopetrosis

AAV LVV

Process B (U.S.)

Process A (E.U.)*

*Phase 1/2

Process B (E.U.)

7


Deficiency-I




Deficiency


Osteopetrosis

Danon Disease Monogenic Heart Failure Syndrome

Overview:

• Background: Devastating multisystemic disorder caused by highly penetrant and X-linked dominant LAMP2 mutations

• Currently available treatments: Non-curative heart transplants associated with considerable morbidity and mortality

• Addressable Market: Estimated US+EU prevalence of 15,000-30,000

• RP-A501: AAV9 gene therapy product that elicits improvements in survival, cardiac function, and liver enzymes in preclinical studies

• Regulatory Designations: Orphan Drug & Fast Track designations in the US

8

Danon Disease: An Impairment in Autophagy Caused by LAMP2B Mutations

9

0

2000

4000

6000

8000

10000

dP

/dt

max (

mm

Hg

/s)

WT PBS 1e13 5e13 1e14 2e14

LAMP2 KO

AAV9.LAMP2B

-8000

-6000

-4000

-2000

0

dP

/dt

min

(m

mH

g/s

)WT PBS 1e13 5e13 1e14 2e14

LAMP2 KO

AAV9.LAMP2B

Cardiac Contractility Cardiac Relaxation

P<0.0001P<0.0001

P<0.0001P<0.0001

P=0.0018P=0.0093

P=0.011P=0.045

P=0.005

P=0.005

**

*PBS = Phosphate Buffered Saline (Negative Control)

Lower dP/dt max indicates impaired contractility; Higher (less negative) dP/dt min indicates impaired heart relaxation

RP-A501 Restores Cardiac Function in KO Mice

Dose-Dependent Improvements in Systolic and Diastolic Function in LAMP2 KO Mice

10

RP-A501 Shows Survival Benefit at Higher Doses

Note: All mice were sacrificed at Month 10

11

RNA: RP-A501 Elicits Expression of hLAMP2B mRNA in Cardiac Tissue of KO Mice

*hLAMP2B = Human LAMP2B

hLAMP2B mRNA*

12

Protein: RP-A501 Elicits Durable Expression of LAMP2B Protein and Autophagic Flux in Heart1

LAMP2 Protein Expression

1Data are Mean ± SEM. N=5-8 per group. Untx = Untreated, PBS = Phosphate buffered salineNote: Mouse LAMP2 and Human LAMP2 data are from separate Western blots.

LC3-II Protein Expression

Untx PBS 1e13 5e13 1e14 2e14 0

1

2

3

4

5

LA

MP

2 In

ten

sit

y

(No

rmalized

to

GA

PD

H)

AAV9.LAMP2B

LAMP2 KO

Mouse

LAMP2

Human

LAMP2

WT

P = 0.002

P = 0.0001

P = 0.0001

Untx PBS 1e13 5e13 1e14 2e14 0.0

0.5

1.0

1.5

LC

3-I

I In

ten

sit

y

(N

orm

alized

to

GA

PD

H)

P = 0.033

AAV9.LAMP2B

LAMP2 KO

P = 0.0072P = 0.019

WT

Western Blot

13

Structural: RP-A501 Reduces Autophagic Vacuoles in All Examined Organs

Wild Type KO Control 5e13 vg/kg 1e14 vg/kg 2e14 vg/kg

AAV9.LAMP2B

LAMP2 KO

Heart

Liver

SkeletalMuscle

14

Dose-dependent Widespread LAMP2 Expression in Cardiac Tissue

15

AAV9 Vector Shows Consistent & Strong Cardiac Tropism in Several Studies Across Different Species

Disorder &Vector

Dose Species Results Sponsor Reference

LGMD2AAAV9.hCAPN3

3E+13 vg/kg NHP 8-80-fold higher transduction in cardiac vs. skeletal muscle

Genethon Lostal(ASGCT 2018)

Non-specificAAV9.Luc

3E+12 vg/kg NHP ~ 10-fold higher transduction in cardiacvs. diaphragm; and comparable to other muscle

UNC Tarantal 2016

PompeAAV9.hGAA

1E+11 vg/mouse Mouse ~ 10-fold higher transduction in cardiacvs. diaphragm

U. Florida Falk 2015

DMDAAV9.mDys

1.9 - 6.2E+14vg/kg

Dog 2-3 fold higher transduction in cardiac vs. skeletal muscle

U. Missouri Yue 2015

SMAAAV9.SMN

3E+14 vg/kg & 1E+13 vg/kg

Mouse & NHP

~ 100-fold higher transduction in cardiacvs. skeletal muscle (mouse)

Nationwide Children’s

Meyer 2014

MPSIIIBAAV9.hNAGLU

1 - 2E+13 vg/kg NHP ≥ 10-fold higher transduction in cardiac vs. skeletal muscle in majority of animals

Nationwide Children’s

Murrey 2014

Non-specificAAV9.Luc

5E+10 vg/mouse Mouse 5-10-fold higher transduction in cardiac vs. skeletal muscle

UNC Pulicherla 2011

PompeAAV9.hGAA

4E+05 - 4E+08vg/mouse

Mouse ~ 8-12-fold higher transduction in cardiac vs. skeletal muscle or diaphragm

U. Florida Pacak 2006

SMAAAV9.SMN

2E14 vg/kg Human Heart VCN ~3-4, Muscle & CNS ~1 AveXis Kaspar 2019 (ASGCT 2019)

16

VCN in Non-Human Primates at Day 102 High in Cardiac Tissues

Differential distribution of vector genomes was observed, with highest levels seen in liver followed by heart

• 30 mg tissue • 20 ng DNA template • Primer/probe to WPRE

• qPCR (40 cycles)

Tissue Type NHP ID 366 NHP ID 690 NHP ID 2750 NHP ID 4247

Brain Cerebellum 0.12 0.06 0.00 0.00

Brain Frontal 1.65 0.63 0.00 0.00

Brain Hipp. 0.50 0.27 0.00 0.00

Brain Medulla 12.26 1.34 0.00 0.00

Brain Occ. Cortex 0.73 0.09 0.00 0.00

Brain Parietal 0.35 0.50 0.00 0.00

Brain Temporal 0.59 0.48 0.00 0.00

Diaphragm 3.25 1.03 0.00 0.00

EYE 0.03 0.56 0.00 0.00

Heart LA 35.74 58.07 0.00 0.00

Heart LV 8.41 11.90 0.00 0.00

Heart RA 57.57 201.58 0.00 0.00

Heart RV 10.82 19.76 0.00 0.00

Kidney Left 4.71 1.55 0.00 0.00

Kidney Right 5.83 1.70 0.00 0.00

Liver Caudate 2536.51 2373.70 0.02 0.00

Liver Left Lobe 2334.43 1862.57 0.00 0.00

Liver Middle Lobe 2447.59 2010.33 0.00 0.00

Liver Right Lobe 2248.60 2168.30 0.00 0.00

Lung Left 4.82 4.93 0.00 0.00

Lung Right 6.74 5.17 0.00 0.00

Lymph Node Inguinal 19.01 10.01 0.00 0.00

Lymph Node Mand. 8.25 7.60 0.00 0.00

Lymph Node Mesen. 1.91 0.87 0.00 0.00

Muscle Gastroc. 0.07 0.52 0.00 0.00

Muscle Quad. 0.61 0.28 0.00 0.00

Pancreas 1.11 1.69 0.00 0.00

Spleen 2.54 1.96 0.00 0.00

Testes Left 1.16 0.24 0.00 0.00

Testes Right 0.94 0.27 0.00 0.00

Vector Genome Copies per Diploid Nuclei

VCN in NHPs Dosed with 3x1014 vg/kg

17

Protein Expression in Non-Human Primates Highest in Cardiac Tissues

Western Blot Analysis GAPDH (housekeeping gene)

LAMP2

LAMP2 Assessment Based on Total Protein1 Loaded on Gel

• Higher levels of transgenic human LAMP2 protein detected over endogenous NHP LAMP2 in most tissues tested, specifically the heart

1Normalized to total protein instead of GAPDH, as housekeeping protein levels were variable.

Right Left

Diaph

ragm

Muc

le Q

uad.

Mus

cle

GA.

Hea

rt RA

Hea

rt LA

Hea

rt RV

Hea

rt LV

Live

r Middle

Live

r Cau

date

Live

r Right

Live

r Lef

t0.0

0.1

0.2

0.3

ng L

AM

P2 p

er

mg o

f Tota

l Pro

tein

(norm

aliz

ed b

ased o

n B

CA

)

**

**

**

*

Vehicle

RP-A501

*p<0.05, **p<0.01

18

Summary of Preclinical Data

• Shows Phenotypic Improvements as Low as 5e13 vg/kg:

- Survival benefit at higher doses

- Dose-dependent restoration of cardiac function

- Improvement in liver enzymes

• RP-A501 Reduces Autophagic Vacuoles in All Examined Organs: Heart, Liver, Skeletal Muscle

• RP-A501 Elicits dose-dependent increase in LAMP2 mRNA and protein

• RP-A501 Preclinical Safety, Tox and Biodistribution Summary:

- No therapy-related deaths

- No significant hematologic changes

- No significant biochemical changes

- No significant clinical chemistry changes

- Mild and transient ALT elevation that self-resolved after one week in a single NHP

- In both mouse and NHPs, VCN detection in Danon disease organs include high concentrations in heart tissue (for NHP, ~10x higher on average than in skeletal muscle and CNS)

19

RP-A501 Clinical Trial and Endpoints

Design1

• Enroll ~12-24 pediatric and young adult male patients• Two dose levels investigated in 4 distinct cohorts (n=3-6 patients)

‐ Cohort 1: Adult and age 15 and older: Low Dose

‐ Cohort 2: Adult and age 15 and older: High Dose

‐ Cohort 3: Pediatric age 8-14: Low Dose

‐ Cohort 4: Pediatric age 8-14: High Dose

Primary Endpoints1

• Evaluation and assessment of safety at both dose levels• Assessment of target tissue transduction • Assessment of effect on cardiomyocyte histology• Assessment of clinical stabilization or improvement via cardiac imaging,

serology and exercise testing

Non-Randomized

Dose-Escalation

Phase 1 Study

1Source: https://clinicaltrials.gov/ct2/show/NCT03882437?cond=danon&rank=2

20

RP-A501 Clinical Development Plans

Adaptive Study (Prelim./Pivotal) Confirmatory Study

Natural History Study/Registry (3 year)

Phase 1Phase 2 / Registrational Study for Accelerated/Conditional Approval

2019 2020

2019• U.S. Phase 1 Study with clinical GMP AAV9 RP-A501 in patients with Danon disease• Continue registry & patient education/identification • Clinical retrospective database in progress• Prospective natural history study ongoing1

2020• Phase 2/Registration-enabling Study for global submission seeking Accelerated Approval

1Natural History ClinicalTrials.gov Identifier: NCT03766386

21

Danon Disease Prevalence: ~15-30K in the US+EU

US+EU Prevalence: ~15-30,000

Hypertrophic Cardiomyopathy (HCM)● US HCM Prevalence: 600K-1MM+ 1

● 1-4% of HCM patients consistently identified with LAMP2 mutations in multiple studies with >1000 subjects evaluated2

● Danon Disease Patients with HCM3

o 85% of males o 30% of females

Dilated Cardiomyopathy (DCM)● Danon Disease Patients with DCM3

o 15% of maleso 50% of females

Hypertrophic Cardiomyopathy

Dilated Cardiomyopathy

Other

1Source: J Am Coll Cardiol. 2015 Mar 31;65(12):1249-1254. 2Sources: Heart. 2004 Aug;90(8):842-6. N Engl J Med. 2005 Jan 27;352(4):362-72. Genet Med. 2015 Nov;17(11):880-8. Gene. 2016 Feb 15;577(2):227-35. J Cardiovasc Transl Res. 2017 Feb;10(1):35-46 3Sources: Neurology. 2002 Jun 25;58(12):1773-8. Genet Med. 2011 Jun;13(6):563-8. Rev Esp Cardiol (Engl Ed). 2018 Aug 11.

22

Author& Year

Age nHCM

n Danon

%Danon

Note

Charron2004

N.A. 197 2 1.0% Studied LAMP2 mutations in 197 HCM patients at a general hospital in Paris

Arad 2005

12-75 75 2 2.7% Studied glycogen storage diseases in 75 consecutive pts diagnosed with HCM (multicenter US/EU). No cases of Pompe or Fabry were detected.

Yang2005

1m-15y 50 2 4.0% Studied LAMP2 mutations in 50 pts with ped./juvenile onset HCM (single US center). Additional DD identified in relatives of the n=2 probands were not included in this analysis.

Cheng 2012

N.A. 50 3 2.3% Studied LAMP2 mutations in 50 consecutive pts diagnosed with concentric LVH at a general hospital in Peking. (Concentric LVH is seen in appx. 38% of HCM). DD incidence higher (3/36) when n=14 w/ cardiac amyloidosis were removed from n=50 cohort.

Charon et al. Heart 2004; 90:842-6. Arad et al. N Engl J Med 2005; 352;362-72.Yang et al. Circulation 2005; 112:1612-17. Cheng et al. Eur Heart J 2012; 33:649-56.

Danon Disease Causes 1-4% of Hypertrophic Cardiomyopathy:Consistent Presence in Multiple Series Published 2004-Present

23

• Current available treatments: Allogeneic hematopoietic stem cell transplant associated with 100-day mortality, GVHD, and additional increased cancer risk

• Addressable Market2: Estimated US+EU target population of approximately 2,000 patients, 400-500 patients/year

• RP-L102: LVV gene therapy that elicits phenotypic correction of blood cells and stabilization of previously declining blood counts

• Regulatory Designations: Fast Track, Regenerative Medicine Advanced Therapy (RMAT) and Rare Pediatric Disease designations in the US; Advance Therapy Medicinal Product (ATMP) classification in EU; Orphan Drug designation in the US/EU

Fanconi Anemia (FA)

Monogenic DNA-repair disorder

1 Alter Br J Hametol 2010.2 CIBMTR and EBMT registries 2009-2013.

Disease Sequelae:Birth DefectsSkin DiscolorationDevelopmental Issues80% Bone Marrow Failure by Age 10Acute Myeloid Leukemia Head and Neck Cancer1

( risk 30-50x)


Deficiency-I




Deficiency


Osteopetrosis

Platelets

RBCs

WBCs

Bone Marrow

FANC-A Gene Mutation

Chromosomal breakage

Overview:DNA

double-strand break

CHEK2

BRCA1

PALB2

BRAC2RAD51

RAD51B-RAD51C-RAD51D-XRCC2

DNA repairedA

E

B

F

GL

MC

Fanconi anemia complex

ATM FANCD2

FANCI

24

Potential to Correct Bone Marrow Defect without Conditioning to Prevent Hematologic Failure

Gene Therapy Value Proposition:

• Potential to correct blood & bone marrow defect without conditioning

• GTx implemented as preventative measure to avert bone marrow failure; BMT is indicated for patients in whom marrow failure has occurred.

REL

ATI

VE

VA

LUE

(%)

Age (months) J.Surralles

Rationale for GTx in FA:

• Somatic mosaicism demonstrates that a modest number of gene-corrected hematopoietic stem cells can repopulate a patient’s blood and bone marrow with

corrected (non-FA) cells.1,2

1 Soulier, J., et al. (2005) Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway.Blood 105: 1329-1336; 2Data on file: Showing a single patient with a spontaneous correction of blood counts, no therapy administered.

25

FA Path to Product Registration

• Clinical trial with ~12 patients with sites at the Stanford (US), Niño Jesús Hospital (Spain), and other leading centers in the U.S./E.U.

• No conditioning required

Rocket-Sponsored

Process B

(Higher cell doses, transduction enhancers, commercial-grade vector

and modified cell processing)

• Interim data (>12-month follow-up) showed durable engraftment, continued improvement in phenotypic markers and stabilization of previously-declining blood counts

• No conditioning required

CIEMAT-Sponsored Fancolen 1 Study

Process A

Optimization

BLA/MAA

26

Updated Data from Phase 1/2 Gene Therapy Trial of RP-L102 in Patients with Fanconi Anemia

Key Efficacy Measurements:

● Genetic correction of bone marrow cells (engraftment): measured by peripheral blood VCN

● Functional and phenotypic correction of bone marrow cells: measured by resistance to mitomycin-C (MMC)

● Functional and phenotypic correction of blood cells: measured by chromosomal stability of T-lymphocytes in the presence of diepoxybutane (DEB)

● Hematologic correction: measured by changes in previously declining pre-treatment blood count trajectories

27

Bone Marrow Engraftment: Increasing Blood Cell VCNs Provide Evidence of Survival Advantage of Gene-Corrected FA Cells

First Demonstration of Engraftment Without Conditioning (“Process A”—non-optimized—RP-L102)

Ciemat Data Presented at ASGCT May 2019 cCFU = Corrected Colony Forming Units; pVCN: Product VCN *Minimally Acceptable Dose

0.5

0.00

0.02

0.04

0.06

0.08

2.0

4.0

6.0

8.0

1 1.5 2 4 6 9 12 15 18 21 24

0.00

* *

28Ciemat Data Presented at ASGCT May 2019

Functional Correction of Bone Marrow

MMC assay identifies cells resistant to Mitomycin-C (MMC), a DNA damaging agent toxic to (uncorrected) FA blood and bone marrow cells

Progressive Phenotypic Correction of BM Cells (MMC-Resistance)

MM

Csu

rviv

al(%

)

MM

Cre

sist

ance

% Corrected CD34+ cells

Months Post-GT

29

Gene Therapy Confers a Phenotype Similar to

Somatic Mosaicism

Ciemat Data Presented at ASGCT May 2019

Months Post Gene Therapy Months Post Gene Therapy

Months Post Gene Therapy Months Post Gene Therapy

% A

ber

ran

tce

lls%

Ab

erra

nt

cells

% A

ber

ran

tce

lls%

Ab

erra

nt

cells

30

Increases of Corrected Leukocytes Support Restoration of Normal Bone Marrow Function Consistent with Mosaic Phenotype

Kinetics of Corrected and Uncorrected PB Leukocytes Prior to and After Gene Therapy

Uncorrected leukocytes/µL Corrected leukocytes/µL

FA-02002 FA-02006 FA-02005 FA-02004

Months Post Gene Therapy Months Post Gene Therapy Months Post Gene Therapy Months Post Gene Therapy


Leu

kocy

tes/

µl

31

Gene Therapy Stabilizes Previously Declining Blood Counts. Most Encouraging Stability When BM Gene Correction Exceeds 50%*


*

BM = Bone Marrow; cCD34+ = Corrected CD34+ cells; cCFU = Corrected Colony Forming Units

32

~2,000 US+EU RP-L102 Addressable Patients

• Fanconi anemia occurs in one in every 160,000 individuals worldwide1

‐ Most commonly inherited bone marrow failure syndrome2

‐ Approximately one in every 181 people in the US is a carrier of Fanconi Anemia3

‐ More common among people of Ashkenazi Jewish descent, the Roma population of Spain, and black South Africans.1

• Fanconi anemia incidence:

‐ Approximately one in every 130,000 births in the US3

• 30-40% of patients undergo HSCT2

1Source: https://ghr.nlm.nih.gov/condition/fanconi-anemia#statistics3Source: Haematologica. 2018 Jan;103(1):30-392Source: https://www.stjude.org/disease/fanconi-anemia.html

33

Overview:

• Background: Disorder characterized by recurring and ultimately fatal infections caused by ITGB2 gene mutations

- >50% patients with severe variant: 60-75% mortality by age 2

• Current Available Treatments: Allogeneic hematopoietic stem cell transplant associated with significant GVHD

• Addressable Market: Estimated 25-50 pts treatable per year for severe population; up to 100 for potential expansion into moderate population in the US+EU with effective gene therapy

• RP-L201: Preclinical studies show stable engraftment and phenotypic correction in murine models, with restored neutrophil migration capability

• Regulatory Designations: Fast Track and Rare Pediatric Disease designations in the US; Advance Therapy Medicinal Product (ATMP) classification in EU; Orphan Drug designation in the US/EU

Leukocyte Adhesion Deficiency-I (LAD-I)

Monogenic Immunodeficiency Disorder


Deficiency-I




Deficiency


Osteopetrosis

Tissue infiltration

Leukocyte

ß2 Integrin

CD11CD18

1

1 Defective expression of ß2 integrin on leukocytes limits their extravasation to inflamed sites.

ß2α

34

LAD-I Program Summary

Ultra-rare Disease = Streamlined Regulatory Approach

Potential design & clinical endpoints Target Patient Population: Severe LAD-I patients (CD18<2%), ~2/3 mortality by 2y

Control: Lit review of ~300 pts. (Rocket/academic collaborative publication1)

Potential Clinical Endpoints: Modest correction of CD18 expression, Survival

Efficacy Trials & Registration Status – Ahead of Schedule

Registration & study planning on-schedule Orphan Drug (U.S./E.U.) and Pediatric Rare Disease (U.S.) designations granted

IND & Phase 1/2 cleared by FDA Spain IMPD cleared US PI (UCLA Dr. Don Kohn) 3 global sites planned in the US/EU Recruitment underway from around the globe

Product/Manufacturing Optimization

Process now optimized VCN using GMP vector with transduction enhancers consistently ~3 (Target VCN >1)

1Almarza Novoa E, Kasbekar S, Thrasher AJ, Kohn DB, Sevilla J, Nguyen T, Schwartz JD, Bueren JA. Leukocyte adhesion deficiency-I: A comprehensive review of all published cases. J Allergy Clin Immunol Pract. 2018 Jan 20. pii: S2213-2198(17)31026-7. doi: 10.1016/j.jaip.2017.12.008.

35

Rationale for Gene Therapy in LAD-I:

CD18 Expression Correlative to Patient Survival

The grey diamond indicates the 39% survival to age 2 years for 66 evaluable patients with severe LAD-I not receiving HSCT

Natural history studies show the correlation between higher CD18 expression and longer patient survival, supporting gene therapy’s potential in LAD-I patients

Source: Almarza Novoa E et al. J Allergy Clin Immunol Pract. 2018 Jan 20. pii: S2213-2198(17)31026-7. [Epub ahead of print]

Kaplan-Meier Survival Estimates by Neutrophil CD18 Expression-Patients with moderate LAD-I not receiving allogeneic HSCT-

Poster Presentation at ASGCT May 2018

36

LAD-I: Mouse Study Shows LAD-I Correction

• Primary and serially transplanted LAD mice underwent CD18 lenti GTx with different promoters

• Myeloablative conditioning was used

• Rocket chose the Chimeric cFES/CTSG (myeloid-specific) promoter (Post-transplant PB VCN 0.4-0.9)

Leon-Rico D, Aldea M, Sanchez-Baltasar R, Mesa-Nuñez C, Record J, Burns SO, Santilli G, Thrasher AJ, Bueren JA, Almarza E. Hum Gene Ther. 2016 Sep;27(9):668-78. doi: 10.1089/hum.2016.016. Epub 2016 May 5.

37

RP-L201 Elicits Dose-Dependent CD18 Expression & Phenotypic Correction in KO Mice

100

80

60

40

20

0

%P

osi

tiv

ece

lls

Gr-1+ Gr-1+

CD11b- CD11b+

100

80

60

40

20

0

Gr-1+ Gr-1+

CD11b- CD11b+

LPS

100

80

60

40

20

0

Gr-1+ Gr-1+

CD11b- CD11b+

100

80

60

40

20

0

Gr-1+ Gr-1+

CD11b- CD11b+

Control Animals Treated Animals

CD18WT CD18KO CD18KO MOI 5 CD18KO MOI20

PB

S

100

80

60

40

20

0

Gr-1+ Gr-1+

CD11b- CD11b+

Untreated (Control) Treated with RP-L201

PB

SLP

S

VCN and CD18 Expression in Peripheral Blood Cells1

Ciemat Poster Presentation at ASGCT May 2019

Preferential Migration of Corrected Neutrophils

VC

N/c

ell

% h

CD

18

+ce

lls

57

0.0357

0.03

1 MOI-multiplicity of infection; CD18 measured by flow cytometry; VCN determined by QPCR

Treated animals demonstrate preferential migration of corrected neutrophils

• Likely 5-10% neutrophil CD18 expression is sufficient to enable phenotypic reversal in severe LAD-I

38

0

1

2

3

4

V C N in L iq u id C u l t u r e

VC

N/

ce

ll

N o T r a n s d u c t io n

E n h a n c e r s

W it h c o m b in a t io n o f

T r a n s d u c t io n E n h a n c e r s

10 20 50 1 0 0 M O I

O ld p ro c e s s

Im p ro v e d p ro c e s s

10 20 50 1 0 0

U tiliz in g G M P v e c to r b a tc h

LAD-I: Improved Process Produces VCN >~2-4

Source: Company data on file

VCN in Liquid Culture

No Transduction Enhancers

With Combination of Transduction Enhancers

Improved Process

Old Process

VC

N/c

ell

Utilizing GMP vector batch

39

Pyruvate Kinase Deficiency (PKD)

Monogenic Red Blood Cell Hemolytic Disorder

• Current Available Treatments: Chronic blood transfusions and splenectomy—side effects include iron overload and extensive end-organ damage

• Addressable Market2: ~250-500 patients/year

• RP-L301: Corrects multiple components in a PKD mouse model, including increases in hemoglobin, reduction in reticulocytosis, correction of splenomegaly and reduction in hepatic erythroid clusters and iron deposits

• Regulatory Designations: Orphan Drug designation in the US/EU

1One glucose molecule is metabolized into two Phosphoenolpyruvate and ultimately two Pyruvate (pyruvic acid) molecules; this final enzymatic step yields two additional ATPs from each glucose molecule 2Market research indicates the application of gene therapy to broader populations could increase the annual market opportunity from approximately 250 to 500, based on an estimated prevalence in the US/EU of approximately 3,000 to 8,000.


Deficiency-I




Deficiency


Osteopetrosis

Energy Deficit

Hemolysis

PKLR Mutation

2 ADP

PK

C O

CH3

C

O O-

C-O-PO3H2

CH2

C

O O-

Phosphoenolpyruvate1 Pyruvate1

2ATP

Overview:

40

• PKD correction observed when at least 20-30% of bone marrow cells are genetically corrected

• PKD correction was achieved when ≥0.3 copies of the vector were detected in peripheral blood mononuclear cell populations

• Spleen size and weight correlated to vector copy number

Mouse Model Indicates Correlation Between Genetic Correction and Reversal of Hemolytic Phenotype Including Normalization of Splenomegaly

Spleen Size

Spleen Weight


41

PKD Program Summary

Product/Manufacturing Optimization

Positive outlook for near term optimization PoC Target engraftment of 30-40% Optimization of vector manufacturing

+ transduction process VCN now 2-4 range with TDx Enhancers

Clinical Efficacy/Registration Status

Registration & study planning on-schedule Registry efforts underway US site identified as Stanford University Plan to treat 2 adults, then 2 older and then 2

younger pediatric patients 18 post-splenectomy, transfusion-dependent

patients pre-identified in EU

42

RPL301 Addressable Market: Approximately 250-500 Patients per Year

• Published Prevalence:

‐ PKD in non-Hispanic Caucasians calculated to be 51 per million1

‐ Conservative estimates conclude a number from 3,000 to 8,000 in the US+EU combined

• Addressable PKD market estimated to be between 250-500 patients per year in the US+EU

• ~50% non-response rate reported in one targeted therapy in development2

1Source: Blood. 2000 Jun 1;95(11)-3585-8.2https://www.sec.gov/Archives/edgar/data/1439222/000119312517366278/d443156dex991.htm

43

Infantile Malignant Osteopetrosis (IMO)

Monogenic bone resorption disorder

Overview:• Background: Dysfunctional osteoclast disease

characterized by bone marrow failure, skeletal deformities, and neurologic abnormalities caused by TCIRG1 mutations in >50% of cases1

– Frequent mortality before age 10

• Current Available Treatments: Hematopoietic stem cell transplants associated with GVHD and limited efficacy

• Addressable Market: >50 patients/year2

• RP-L401: In vitro restoration of osteoclast resorptivefunction observed

• Regulatory Designations: Rare Pediatric Disease and Orphan Drug designations in the US


Deficiency-I




Deficiency


Osteopetrosis

1Source: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=6672Estimated incidence of one in 200,000 live births; Source: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=667

44

Growing IP Portfolio

Multiple in-licensed patent families for GTx products and related technology platforms

Supporting current pipeline efforts Four In-licensed pending international patent applications filed under Patent Cooperation Treaty (PCT):

‐ FA (2)‐ LAD-I‐ PKD

One pending PCT application:‐ Danon (exclusive world-wide license from UCSD)

Multiple patent families licensed from REGENXBIO:‐ Danon – AAV9 (exclusive world-wide license)‐ Danon – 2 undisclosed capsid serotypes (exclusive

world-wide option to license)Multiple cell and gene therapy platform technologies

licensed for pipeline product improvements

Rocket Proprietary Filed IP

Extensive patent portfolio across multiple platforms

Multiple pending patent applications for ex-vivo LVV programs

Multiple pending patent applications for in-vivo AAV

45

World-Class Research and Development Partners

• CIBER

• CIEMAT

• Fred Hutchinson Cancer Research Center

• IIS FJD

• Lund University

• Memorial Sloan Kettering Cancer Center

• REGENXBIO

• Stanford Medical School

• University of California, San Diego

• University of California, Los Angeles

46

FA (RP-L102): Updated Data from Four Patients Treated Under “Process A”

Danon (RP-A501): FPI for Phase 1 Study

LAD-I (RP-L201): Phase 1/2 Study Enrolling

FA (RP-L102): Additional Data

FA (RP-L102): PRIME Designation “Process B”

Danon (RP-A501): Initial Phase 1 Data

LAD-I (RP-L201): RMAT Designation

IMO (RP-L401): FPI for Phase 1 Study

Near and Long-Term Value Drivers

Potential for Five Gene Therapy Products to be Approved by 2025

2Q19 2H19 2020

FA (RP-L102): EU Phase 2 Study

FA (RP-L102): Regulatory Alignment on Final Endpoints for Registration

FA (RP-L102): Initial Phase 1 Data Under “Process B”

LAD-I (RP-L201): Initial Phase 1 Data

PKD (RP-L301): IMPD

PKD (RP-L301): FPI for Phase 1 Study

Documents

PowerPoint Presentation · 2019-06-18 · Leukocyte Adhesion Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD), Infantile Malignant Osteopetrosis (IMO) and Danon disease and