News Release Details
Rocket Pharmaceuticals Presents Updated Data from Phase 1/2 Gene Therapy Trial of RP-L102 in Patients with Fanconi Anemia at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting
May 18, 2018
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- Continued Clinical Evidence Demonstrates RP-L102 Can Restore Bone Marrow Function of Fanconi Anemia Patients Without Conditioning -
- Increases in Gene-Corrected Leukocytes Demonstrate Bone Marrow Rescue Leading to Hematologic Stabilization -
- All Four Patients Followed for Six Months or Longer Demonstrate Mixed Chimerism; Two Patients with Higher Product Doses Exhibit Sustained Mosaic Phenotype -
- First Patient Treated with Transduction-Enhanced RP-L102 Shows Highest Transduction Efficiency and Earliest Engraftment to Date -
“Several important observations are emerging from our ongoing Phase 1/2 trial in FA. First, even without myeloablative conditioning, there are increasing levels of bone marrow engraftment following administration of RP-L102. Second, the improvement of chromosomal stability in corrected FA cells indicates that RP-L102 is reversing the FA phenotype. Third, the natural progression of bone marrow failure in these patients is reversed. In fact, the bone marrow cells of the two patients who received higher doses demonstrate conversion to a somatic mosaic status that is sustained over the course of several months. Finally, the progressive increases of corrected, versus non-corrected, peripheral blood leukocytes indicate that RP-L102 is restoring functionality of bone marrow hematopoietic stem cells. This translates to a stabilization in peripheral blood cell counts which would otherwise continue to decline in the absence of treatment. Based on these encouraging results, I believe that RP-L102 has the potential to be a transformative and minimally toxic prevention of bone marrow failure for FA,” said Dr. Bueren.
This Phase 1/2 study is an ongoing, open-label, single-center study
designed to evaluate the safety and efficacy of RP-L102 in FA type A
without the use of myeloablative conditioning. Julian Sevilla, M.D.,
Ph.D., of the hospital of Niño Jesús in
Key efficacy measurements include:
- Genetic correction of bone marrow cells (engraftment): measured by peripheral blood vector copy number (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
Other measured parameters include safety, vector integration profile, and clonal repertoire.
Updated Results Presented at ASGCT 2018:
Data presented today includes all five patients treated to date with RP-L102 under academic protocol:
- All patients demonstrated continued improvement in engraftment following administration of RP-L102. In patient 02002—the first patient treated with higher doses—peripheral blood VCN increased to 44% at 24 months, from 34% at 19 months and 17% at 12 months.
- Sustained phenotypic reversals and earlier evidence of gene correction were seen in higher-dosed patients (02002 and 02006) within months of treatment. Notably, based on MMC and DEB assays, these two patients showed durable improvements consistent with somatic mosaicism that has persisted over the course of several months. Somatic mosaicism is an FA phenomenon where patients largely do not develop the typical FA manifestations of bone marrow failure and leukemia1. Moreover, in patient 02002, the bone marrow resistance to MMC increased to 70% at 24 months (up from ~20% at 12 months), approaching the phenotype of a healthy donor.
- Patients 02004 and 02005 received non-optimized and lower doses of RP-L102. Nonetheless, evidence of gene-corrected and phenotypically-normalized cells was seen, but after longer durations.
- One patient (01003) received RP-L102 manufactured in the presence of transduction enhancers. Based on early data, RP-L102 transduction efficiency (drug product VCN) was the highest to date—more than five-fold higher compared to the best previously achieved (0.53 for patient 2006 and 0.43 for patient 2002). Additionally, early engraftment accelerated more than three-fold compared to earlier patients.
- No serious drug-related adverse events have been observed to date.
“We are very pleased by the trajectory of progressively increasing gene
markings and reversion to a phenotype where the blood and bone marrow
cells are resistant to DNA damaging agents. Moreover, it appears that
the stabilization of blood counts, which previously were declining,
resulted from an increase in gene-corrected peripheral blood cell
lineages,” said
“The value creation we seek, relative to standard transplant, is to enable intervention soon after diagnosis as a preventative measure. Therefore, stability of blood counts is going to be an important indicator of the potential benefit of our FANCA-focused LVV gene therapy programs for this life-threatening disease,” continued Dr. Shah. “Rocket remains committed to advancing the standard of care in FA, and to the continued advancement of our pipeline of five LVV and AAV-based gene therapy programs. We will continue to innovate and aspire to create new options for patients with devastating diseases.”
Additional patient data from the FA program is expected over the next 12-18 months. Based on these promising preliminary results, Rocket will engage with regulatory authorities to progress RP-L102 towards a potential global registrational study in 2019.
Presentations from ASGCT will be posted on Rocket’s website at: www.rocketpharma.com/pipeline/. Updated data from the ongoing Phase 1/2 trial in FA will be submitted for publication.
About RP-L102 (LVV-based gene therapy for Fanconi Anemia):
RP-L102 is Rocket’s lentiviral vector (LVV)-based gene therapy in
development for patients with FA with Rocket’s collaboration partners at
Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas
(CIEMAT) in
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, which is highly toxic for the patient. HSCT is frequently complicated by graft versus host disease and also increases the risk of many solid organ malignancies. Approximately 60-70% of patients with FA have a FANC-A gene mutation, which encodes for a protein essential for DNA repair. Mutation in the FANC-A gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Chromosome fragility induced by DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is the ‘gold standard’ test for FA diagnosis. The DEB assay can further differentiate FA patients from somatic mosaic patients. Somatic mosaicism occurs when there is a spontaneous reversion mutation that can lead to a mixed chimerism of corrected and uncorrected bone marrow cells leading to stabilization or correction of an FA patient’s blood counts in the absence of any administered therapy. Somatic mosaicism provides strong rationale for the development of FA gene therapy and demonstrates the selective advantage of gene-corrected hematopoietic cells in FA1.
About
Cautionary Statement Regarding Forward-Looking Statements
Various statements in this release concerning Rocket’s future
expectations, plans and prospects, including without limitation,
Rocket’s expectations regarding the safety, effectiveness and timing of
product candidates that Rocket may develop, including in collaboration
with academic partners, to treat Fanconi Anemia (FA), Leukocyte Adhesion
Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD) and Infantile
Malignant Osteopetrosis (IMO), and the safety, effectiveness and timing
of related pre-clinical studies and clinical trials, may constitute
forward-looking statements for the purposes of the safe harbor
provisions under the Private Securities Litigation Reform Act of 1995
and other federal securities laws and are subject to substantial risks,
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"expect", "anticipate", "intend", "plan", "will give", "estimate",
"seek", "will", "may", "suggest" or similar terms, variations of such
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expectations reflected in the forward-looking statements are reasonable,
Rocket cannot guarantee such outcomes. Actual results may differ
materially from those indicated by these forward-looking statements as a
result of various important factors, including, without limitation,
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 product
candidates, which may not support further development and marketing
approval, Rocket’s ability to commence a registrational study in FA
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10-K for the year ended
1Soulier, 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
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Source:
Claudine Prowse, Ph.D.
SVP Corporate Development and IRO
Rocket
Pharmaceuticals, Inc.
The Alexandria Center for Life Science
430
East 29 Street, Suite 1040
New York, NY 10016
cp@rocketpharma.com