Rocket Pharmaceuticals: RP-102 Gene Therapy for Fanconi Anemia Subtype A

About Fanconi Anemia
Fanconi Anemia (FA) is a rare pediatric disease characterized by bone marrow failure, malformations and cancer predisposition. The primary cause of death among patients with FA is bone marrow failure, which typically occurs during the first decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT), when available, corrects the hematologic component of FA, but requires myeloablative conditioning. Graft-versus-host disease, a known complication of allogeneic HSCT, is associated with an increased risk of solid tumors, mainly squamous cell carcinomas of the head and neck region. Approximately 60-70% of patients with FA have a Fanconi Anemia complementation group A (FANCA) gene mutation, which encodes for a protein essential for DNA repair. 

Mutation in the FANCA gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Increased sensitivity to DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is a ‘gold standard’ test for FA diagnosis. Somatic mosaicism occurs when there is a spontaneous correction of the mutated gene that can lead to stabilization or correction of a FA patient’s blood counts in the absence of any administered therapy. Somatic mosaicism, often referred to as ‘natural gene therapy’ provides a strong rationale for the development of FA gene therapy because of the selective growth advantage of gene-corrected hematopoietic stem cells over FA cells.

Title of Clinical Study
A Phase II Clinical Trial to Evaluate the Efficacy of the Infusion of Autologous CD34+ Cells Transduced With a Lentiviral Vector Carrying the FANCA Gene (Orphan Drug) in Patients With Fanconi Anemia Subtype A

Brief Summary:
This is an open-label Phase II clinical trial to evaluate the efficacy of a hematopoietic cell-based gene therapy for pediatric patients with Fanconi Anemia, subtype A (FA-A).
ematopoietic stem cells from mobilized peripheral blood of patients with FA-A will be transduced ex vivo (outside the body) with a lentiviral vector carrying the FANCA gene. After transduction, the corrected stem cells will be infused intravenously back to the patient with the goal of preventing bone marrow failure

Detailed Description:
This is a pediatric open-label Phase II clinical trial to assess the efficacy of a hematopoietic gene therapy consisting of autologous CD34+ enriched cells transduced with a lentiviral vector carrying the FANCA gene in pediatric subjects with FA-A.
Enriched CD34+ hematopoietic stem cells will be transduced ex vivo with the therapeutic lentiviral vector and infused via intravenous infusion following transduction without any prior conditioning

Study Design
Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Experimental Drug: RP-L102
RP-L102 is CD34+ enriched cells from subjects with Fanconi anemia subtype A transduced ex vivo with lentiviral vector carrying the FANCA gene

Primary Outcome Measures:
  • Phenotypic correction of bone marrow colony-forming units after infusion of RP-L102 [ Time Frame: 3 years ]. During months 12-36 post-infusion, the survival of bone marrow colony-forming units to 10nM mitomycin C (MMC) increases to over or equal to 10% with respect to values determined at baseline (pretreatment evaluation).
Secondary Outcome Measures:
  • Phenotypic correction of T-lymphocytes in peripheral blood after infusion of RP-L102 [ Time Frame: 3 years ]. Assessment of the percentage of peripheral blood T-cells with diepoxybutane (DEB)-induced chromosomal aberrations that decreases from over or equal to 50% at baseline (defined as the interval between the pre-treatment evaluation and 2 months post-infusion) to less than 50% during the interval between 12 and 36 months post-infusion.
  • Engraftment of gene-corrected hematopoietic cells after infusion of RP-L102 [ Time Frame: 3 years ]. The level of gene marking of the FANCA-lentiviral vector (LV) provirus in total peripheral blood cells is at least 0.1 vector copy number (VCN) in peripheral blood cells during months 6-36 post-infusion.
  • Prevention or rescue of bone marrow failure after infusion of RP-L102 [ Time Frame: 3 years ].  Assessment of the need for treatment of bone marrow failure 6-36 months post-infusion. During the 3rd year post-infusion, peripheral blood parameters: hemoglobin levels, neutrophils, and platelets will be assessed and considered stable if they remain at over or equal to 80% of values determined at pre-treatment evaluation visit or immediately prior to mobilization before the administration of granulocyte-colony stimulating factor.

Results from Phase I/II Study
The data presented are from seven of the nine patients treated as of the cutoff date of October 2020 in both the U.S. Phase 1 and global Phase 2 studies of RP-L102 for FA. Seven patients had follow-up data of at least 2-months, and three of the seven patients had been followed for 12-months or longer. Key highlights from the presentation include:
  • RP-L102 was generally well tolerated with no significant safety issues reported with infusion or post-treatment
  • Evidence of preliminary engraftment was observed in five out of seven total patients with bone marrow (BM) vector copy numbers (VCNs) from 0.16 to 0.22 (long-term follow up only) and peripheral VCNs ranging from 0.01 (2-month follow up) to 0.11 (long-term follow up)
  • Two of the three patients with greater than 12-months follow up showed evidence of increasing engraftment, mitomycin-C (MMC) resistance and stable blood counts
  • One patient’s course was complicated by Influenza B resulting in progressive BM failure. The patient received a successful bone marrow transplant

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