Latest News in Gene Therapy for Rare Disease Day 2023


In observance of Rare Disease Day, held annually on February 28, catch up on some of the latest data updates from clinical trials for rare diseases.

Over the past few weeks, CGTLive has covered news and updates from clinical trials of cell and gene therapies in development for patients with a number of rare diseases, including data that were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida; and at the 2023 Tandem Meetings, held the week prior, February 15-19, also in Orlando, Florida.

For Rare Disease Day, which is observed annually on February 28, the CGTLive team has gathered some of the latest updates on rare disease research below:

Infantile GM1 Gangliosidosis Gene Therapy Demonstrates Safety and Dose-dependent Biomarker Changes

Passage Bio’s PBGM01, an investigational adeno-associated virus (AAV) vector-based gene therapy currently being evaluated in the phase 1/2 Imagine-01 clinical trial (NCT04713475) for the treatment of infantile GM1 gangliosidosis, was shown to have a favorable safety profile and demonstrated dose-dependent changes in biomarkers.1 PBGM01 is intended to provide a functional copy of GLB1, the disease-targeted gene, via AAVhu68, and is administered to the central nervous system (CNS) with an intra-cisterna magna injection. Following treatment with PBGM01, participants in the trial showed stabilization of MRI severity scores, in contrast to increases seen in natural history data from untreated patients.

Gene Therapy Yields Neurodevelopmental Improvements in Children With MPSI

RGX-111, REGENXBIO’s investigational gene therapy for the treatment of mucopolysaccharidosis type 1 (MPSI), was shown to be well-tolerated and showed signs of efficacy in children enrolled in a phase 1/2 trial (NCT03580083) as well as 1 child treated under a single-patient nvestigational new drug (IND) application.2 RGX-111 is an AAV9 gene therapy that delivers the gene for the IDUA enzyme to the central nervous system. Most treated participants were within 2 SDs of normative mean in acquiring cognition, expressive language and fine motor skills.

MPSII Gene Therapy Shows Some Signs of Durable Efficacy

REGENXBIO’s gene therapy RGX-121 has demonstrated safety and efficacy in improving development in children with mucopolysaccharidosis type 2 (MPSII), according to interim data from the phase 1/2 CAMPSIITE trial (NCT03566043).3 Promising signs of efficacy were observed in the treated patients, with most participants (n = 14) having dose-dependent reductions in CSF heperpan sulfate from baseline at week 48.

Late-Onset Pompe Disease Gene Therapy Shows Promise in Phase 1/2 Study

Astellas Pharma’s AT845, an investigational AAV vector-based gene replacement therapy intended to treat late-onset Pompe disease has demonstrated encouraging efficacy in interim data from the phase 1/2 FORTIS clinical trial (NCT04174105).4 AT845 is intended to deliver a functional copy of the acid alpha-glucosidase gene with a muscle-specific promotor via an AAV8 vector with tropism to muscle tissue. Among the 4 patients treated with AT845 in the FORTIS trial so far, 3 have ceased treatment with their prior standard of care treatment, enzyme replacement therapy.

HSC Gene Therapy Demonstrates Improvements in Type 3 Gaucher Disease Case Study

AVROBIO’s AVR-RD-02, an investigational hematopoietic stem cell (HSC) gene therapy, has demonstrated sustained improvements in a 12-year-old male patient with type 3 Gaucher disease.5 Following myeloablative conditioning with busulfan, the patient received AVR-RD-02, which is comprised of autologous CD34+ cells that have been modified ex-vivo to express functional glucocerebrosidase, the disease-targeted enzyme, in 2 infusions lots. Within 6 weeks of AVR-RD-02 infusion, GCase activity increased to the healthy control range (1 to 5 nmol/mg/hr) and has stayed within that range since, reaching 3.5 nmol/mg/hr at the 13-month timepoint.

Arsa-cel Shows Favorable Risk/Benefit Profile in up to 11 Years of Follow-up Data

Long-term data of up to 11 years of follow-up on the gene-edited cell therapy atidarsagene autotemcel (arsa-cel; Orchard Therapeutics) has demonstrated a continued favorable risk/benefit profile in patients with pre-symptomatic (PS) late-infantile and early-juvenile (EJ), and early-symptomatic (ES) EJ metachromatic leukodystrophy (MLD).6 The investigators analyzed data from 39 patients (PSLI, 18; PSEJ, 8; ESEJ, 11) across studies compared to an untreated natural history cohort of 43 patients (LI, 26; EJ, 17) with early-onset MLD at the same center. All patients achieved hematological recovery, stable engraftment, and restoration of arylsulfatase A enzyme to normal or supranormal levels by 3 months in peripheral blood mononuclear cells and by 3 to 12 months in cerebrospinal fluid.

Increased Motor Development Seen in First 2 Patients With Infantile Krabbe Treated With FBX-101

FBX-101 (Forge Biologics) gene therapy restored galactocerebrosidase (GALC) activity and supported normal white matter development in the first 2 patients with infantile Krabbe disease dosed in the phase 1/2 RESKUE clinical trial (NCT04693598).7 Efficacy signals included GALC levels 174-fold above normal controls in plasma and 3-to-10 fold above normal in cerebrospinal fluid.

Gene Therapy Yields 100% 1-Year Survival in LAD-1

The gene therapy RP-L201 (Rocket Pharma) was well-tolerated and yielded genotypic and phenotypic corrections in children with leukocyte adhesion deficiency-1 (LAD-1) according to updated data from a global phase 1/2 study (NCT03812263).8 All 9 patients met the primary end point of survival at 1 year. These participants achieved neutrophil engraftment and sustained CD18 PMN expression of at least 10% (range, 15.4-88.6; median, 51.2) as well as sustained CD11 expression with less than 0.1 vector copy number integration.

Hematopoietic Cell-based Gene Therapy Shows Durable Response in Fanconi Anemia

Patients with Fanconi anemia who received treatment with an investigational hematopoietic cell-based gene therapy carrying the FANCA gene saw durable responses through more than 12 months of follow-up.9 Although hematopoietic stem cell transplant typically results in over an 80% survival rate, the therapy is associated with serious adverse effects, including 100-day mortality and an increased risk of malignancies. To address this, investigators are evaluating a gene therapy that utilizes autologous Fanconi anemia Group A CD34+ enriched hematopoietic stem and progenitor cells that engraft without the use of antecedent conditioning.

1. Jarnes JR, Hatings CA, Ficicioglu C, et al. Updated interim safety, biomarker, and efficacy data from Imagine-1: A phase 1/2 open-label, multicenter study to assess the safety, tolerability, and efficacy of a single dose, intra-cisterna magna (ICM) administration of PBGM01 in subjects with type I (early onset) and type IIA (late onset). Presented at WORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #186
2. Wang RY, Ficicioglu CH, Giugliani R, et al. RGX-111 gene therapy for the treatment of severe mucopolysaccharidosis type I (MPS I): Interim analysis of data from the first in human study. Presented at: WORLDSymposium, February 22-26, 2023; Orlando, Florida. Abstract #371.
3. Ficicioglu C, Giugliani R, Harmatz P, et al. RGX-121 gene therapy for the treatment of neuronopathic mucopolysaccharidosis type II (MPS II): interim analysis of data from the first in human study. Presented at: WORLDSymposium 2023, February 22-26; Orlando, Florida. Abstract #LB-21
4. Diaz-Manera J, Mozaffar T, Longo N, et al. AT845 gene replacement therapy for late onset Pompe disease: An update on safety and preliminary efficacy data from FORTIS, a phase I/II open-label clinical study. Presented at WORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #95
5. Donald A, Potter JE, Church HJ, et al. Sustained improvement of clinical CNS and somatic features of Type 3 Gaucher disease after haematopoietic stem cell (HSC) gene therapy: A first in world report. Presented at WORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #100
6. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy [HSC-GT] for metachromatic leukodystrophy) with up to 11 years follow-up. Presented at: WORLDSymposium2023, February 22-28; Orlando, Florida. Abstract #125
7. Escolar ML, Vander Lugt M, Poe M, et al. First-in-human phase 1/2 trial of intravenous FBX-101 following hematopoietic stem cell transplantation increases GALC activity, supports brain development, and improves motor function in patients with infantile Krabbe disease: RESKUE clinical trial. Presented at: WORLDSymposium 2023, February 22-26; Orlando, Florida. Abstract #108.
8. Booth C, Sevilla J, Rao G, et al. Lentiviral-mediated ex-vivo gene therapy for pediatric patients with severe leukocyte adhesion deficiency-I (LAD-I): Interim results from an ongoing phase 1/2 study. Presented at: 2023 Tandem Meetings. Abstract #3
9. Czechowicz A, Sevilla J, Agarwal R, et al. Lentiviral-Mediated Gene Therapy for Patients with Fanconi Anemia [Group A]: Updated Results from Global RP-L102 Clinical Trials. Presented at: 2023 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. February 15-19, 2023; Orlando, FL. Abstract 113
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