A Phase 1/2 Study of Lentiviral-mediated Ex-vivoGene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I): Initial

Results from the First Treated Patient.

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Donald B. Kohn, M.D., ProfessorDepartments of Microbiology, Immunology & Molecular Genetics;

Pediatrics; and Molecular & Medical PharmacologyUniversity of California, Los Angeles

ASGCT 2020

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The UC Regents have licensed intellectual property on ADA SCID gene therapy to Orchard Therapeutics on which I am an inventor.

I am a paid member of the Scientific Advisory Boards of Orchard Therapeutics and Allogene Therapeutics.

Conflict of Interest Statement

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• In LAD-I, mutations in the common chain (CD18) of the beta2-integrin family (ITGB2 gene) prevent expression of CD18/CD11 heterodimers on cell surface essential for cell migration and adhesion.

• Disorder characterized by recurring and ultimately fatal infections due to inability of leukocytes to leave bloodstream to get to sites of tissue infection

• Severe inflammatory complications include omphalitis, gingivitis and ulcerative skin lesions.

• Current Treatment Option: Allogeneic HSCT limited by availability of suitable donor, GvHD, infections, and mortality

Leukocyte Adhesion Deficiency-I (LAD-I)Monogenic Immunodeficiency Disorder

Integrin

CD18CD11

ß2α

ITGB2 gene

Qasim W et al. Pediatrics 2009; 123: 836-40Almarza Novoa E et al. J Allergy Clin Immunol Pract. 2018 July-August (6) 1418-1420.

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Clinical Pathogenesis of LAD-I

Almarza Novoa E et al. J Allergy Clin Immunol Pract. 2018 July-August (6) 1418-1420.

Kaplan-Meier Survival Estimates by Neutrophil CD18 ExpressionLAD-I Disease Spectrum

Moderate:2-30%

CD18+ PMN

Severe: <2%

CD18+ PMNPMN = polymorphonuclear leukocytes

• Patients suffer from recurrent infections; fatal in majority• 60-75% with severe LAD-I

die prior to age 2• >50% with moderate LAD-I

die before age 40

LAD-I Clinical Prognosis

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

Patients with severe & moderate LAD-I not receiving allogeneic HSCT

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Ex-vivo lentiviral vector gene therapy consists of autologousCD34+ cells transduced with a lentiviral vector (Chim-CD18-WPRELV) encoding for the CD18 (β-subunit) component of β2-integrin

RP-L201: Gene Therapy for LAD-I

• CD34+ cells are mobilized to PB with G-CSF and plerixafor• Cells are collected via apheresis• Following transduction & cryopreservation, TDM-Busulfan conditioning is

administered prior to infusion of RP-L201

Developed at CIEMAT, in partnership with UCL

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RP-L201 LAD-I Clinical Trial and Outcome Measures1

1 https://clinicaltrials.gov/ct2/show/NCT03812263?cond=Leukocyte+Adhesion+Deficiency&rank=5

Trial Design – Non-Randomized Phase 1/2 Study

N=9 patients across Phase 1/2 global study w/US & EU centersPhase 1: Assess safety and preliminary efficacy (n=2)

Phase 2: Global study (U.S. and EU) w/ efficacy endpoints including overall survival (n=7)

Primary Outcomes • Phase 1:

• Safety & preliminary efficacy• Phase 2:

• Survival: proportion of patients alive at age 2 and at least 1-year post infusion (& not requiring alloHSCT)

• Safety

• Percentage of pts w/neutrophil CD18 expression at least 10% of normal

• Percentage of pts w/neutrophil VCN of at least 0.1 copies/cell at 6m post-rx

• Incidence and severity of infections• Improvement/normalization of

neutrophilia• Resolution (partial or complete) of any

underlying skin rash or periodontal abnormalities

Secondary Outcomes Secondary Outcomes

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RP-L201 Clinical Trial Status

Phase 1 (n=2) : Enrollment Complete

L201-003-1001: Treated with RP-L201 on 8/20196 Month Follow-up Completed

L201-003-1004: Treated with RP-L201 on 5/2020Data Pending

UCLA Mattel Children’s Hospital Data December 2019LAD-I program has received CIRM Funding

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Medical History of Patient L-201-003-1001

1 2 3 4 5 6 7 8 9Age (Years)

10

IV Abx, Steroids

Hosp

italiz

ed

Multiple Abscesses Buttocks

Enbrel, Abx

Ulcer R-Leg

Suspected Nocardia Pneumonia

Severe Anemia

IV Abx, Transfusion

Hosp

italiz

ed

Pyoderma GangrenosumLower Back (BM Bx site)

IV Abx, Ustekinumab

Hosp

italiz

ed

IV Abx, PO Steroids, Multiple Wound DebridementHo

spita

lized

Pseudomonas Skin InfectionEcthyma/Pyoderma

Gangrenosum

IV Abx, IV Steroids, Daily Wound Care, Enbrel

Skin Lesions L-flank & Buttocks

Hosp

italiz

ed

Lesion on ThighHumira

Partial Lung Resection, Antifungal, Abx

Aspergilloma(Pulmonary)

Hosp

italiz

ed IV Abx, Ustekinumab

Pyoderma Gangrenosum Abdomen

Recurrent URI, UTI, Otitis Media, Asthma

Prophylactic Antifungal and Antibiotic Rx

Historical patient records collected by UCLA Mattel Children’s Hospital LAD has received CIRM Funding

9-y.o. female diagnosed with

severe LAD-I at age 7

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RP-L201: Drug Product Metrics and Clinical Results

Key Drug Product Metrics

CD34+ Cell Dose: 4.2 x 106 cells/kgDrug Product VCN: 3.8

Months Post-GT

% C

D11a

% C

D11b

0 3 60

10

20

30

40

50

0 3 60

10

20

30

40

50

6-mo PB CD18 expression post-GT: 47%Pre-tx CD18 expression: <1%

Clinical Results

% CD18 Expression in PB

% C

D18

Months Post-GT

0 3 60

10

20

30

40

50

UCL GOSH Data March 2020LAD-I program has received CIRM Funding

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RP-L201: Flow Cytometry 6-Months Post-Treatment

Healthy Donor Control L201-003-1001

Neutrophils Neutrophils

CD18 Expression99%

CD18 Expression47%

UCL GOSH Data March 2020LAD-I program has received CIRM Funding

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RP-L201: VCN

VCN in PBMCs VCN in PB Subsets

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RP-L201: Visible Improvements Post-Treatment

Spontaneous Abdominal Lesion

UCLA Mattel Children’s Hospital Data December 2019LAD has received CIRM Funding

3-mos post-infusion 6-mos post-infusionBaseline (Pre-Treatment)

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Prior to Gene Therapy: BM Bx Site

BM Bx Site 2 Days After 3-Month Marrow Bx

UCLA Mattel Children’s Hospital Data December 2019LAD has received CIRM Funding

Lower Back Lesion(after BM aspirate)

Lower Back(after BM aspirate)

RP-L201: No Infection/Inflammation After 3-Month Bone Marrow Biopsy

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• Severe LAD-I is a very rare, life-threatening PID with 60-75% mortality by age 2- < 2% CD18+ PMN expression in Severe LAD-I

• Allogeneic HSCT as a treatment option is limited by donor availability, significant GVHD, infections, and mortality

• First patient successfully treated with RP-L201, an ex-vivo LV gene therapy, with durable CD18+ PMN expression > 47% at 6 months, and visible signs of improvement in existing skin lesions- Infusion was well-tolerated with no safety issues- Results from second patient treatment pending

• Preliminary evidence demonstrates that RP-L201 enables ITGB2genetic correction with robust CD18+ PMN expression

Conclusions

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• LAD-I patients have been identified globally for the gene therapy trial including in the US, Europe, Turkey, India, Sri Lanka, Pakistan and the Middle East

• Active enrollment of severe LAD-I patients underway:

• For patient referral or consultation, please contact:

RP-L201 LAD-I Gene Therapy Trial Actively Enrolling Patients

DRTerrazas@mednet.ucla.edu LADclinicaltrial@rocketpharma.com

Clinical trials.gov: NCT03812263

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Acknowledgements