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A Phase 1/2 Study of Lentiviral-mediated Ex-vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I): Results From Phase I Donald B. Kohn, M.D., Professor Departments of Microbiology, Immunology &

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

Donald B. Kohn, M.D., Professor Departments of Microbiology, Immunology & Molecular Genetics; Pediatrics; and Molecular & Medical Pharmacology University of California, Los Angeles 19th Biennial Meeting of the European Society for Immunodeficiencies (ESID), 2020 Lecture #216

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I am a paid member of the Scientific Advisory Boards of Orchard Therapeutics, Allogene Therapeutics and MyoGene Bio The UC Regents have licensed intellectual property on ADA SCID gene therapy on which I am an inventor to Orchard Therapeutics

Conflict of Interest Statement – D.B. Kohn

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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

LAD characterized by recurring and ultimately fatal infections due to inability
f 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. May be limited by availability of

suitable donor, GvHD, infections.

Leukocyte Adhesion Deficiency-I (LAD-I)

Monogenic Immunodeficiency Disorder

Integrin CD18 CD11

ß2

α

ITGB2 gene

Qasim W et al. Pediatrics 2009; 123: 836-40 Almarza 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 Expression LAD-I Disease Spectrum Moderate: 2-30% CD18+ PMN Severe: <2% CD18+ PMN

PMN = 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 autologous CD34+ cells transduced with a lentiviral vector (Chim-CD18-WPRE LV) encoding for the CD18 (β-subunit) component of β2-integrin

Gene Therapy for LAD-I - RP-L201

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 Global Phase 1/2 Study Phase 1 (n=2): COMPLETED Phase 2 (n=7): Currently Enrolling

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
% of pts w/neutrophil CD18 expression at least

10% of normal

% 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 underlying

skin rash or periodontal abnormalities

Secondary Outcomes

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Phase 1: Subject L201-003-1001 12 Months Follow-up

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Medical History of Subject L-201-003-1001

1 2 3 4 5 6 7 8 9 Age (Years) 10 IV Abx, Steroids Hospitalized Multiple Abscesses Buttocks Enbrel, Abx Ulcer R-Leg Suspected Nocardia Pneumonia Severe Anemia IV Abx, Transfusion Hospitalized Pyoderma Gangrenosum Lower Back (BM Bx site) IV Abx, Ustekinumab Hospitalized IV Abx, PO Steroids, Multiple Wound Debridement Hospitalized Pseudomonas Skin Infection Ecthyma/Pyoderma Gangrenosum IV Abx, IV Steroids, Daily Wound Care, Enbrel Skin Lesions L-flank & Buttocks Hospitalized Lesion on Thigh Humira Partial Lung Resection, Antifungal, Abx Aspergilloma (Pulmonary) Hospitalized 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

Dx with LAD

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Subject L201-003-1001: 12 Month Follow-Up

Key Drug Product Metrics CD34+ Cell Dose: 4.2 x 106 cells/kg Drug Product VCN: 3.8

% CD18 Expression (PMN) PBMC VCN

PMN: neutrophil PBMC: peripheral blood mononuclear cell

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RP-L201: Visible Improvements Post-Treatment

Spontaneous Abdominal Lesion

UCLA Mattel Children’s Hospital Data Sep 2020 LAD has received CIRM Funding

3M 6M Baseline (Pre-Treatment) 12 M

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Phase 1: Subject L201-003-1004 4 Months Follow-up

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Medical History of Subject L-201-003-1004

Birth Hospitalized Fever

Historical patient records collected by UCLA Mattel Children’s Hospital

Hospitalized Fever/RSV/perianal rash B/L PET Tympanoplasty B/L Tympanic Perforation Recurrent Cellulitis Recurrent Otitis Media 12/2015 1 12/2016 2 12/2017 3 12/2018 URI Gingivitis/Periodontiis Keflex Keflex

3-y.o. female

Delayed umbilical cord separation
Diagnosed with LAD-I at age 3
2 younger siblings diagnosed LAD-I