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

No adverse events related to RP-L201 have been reported to date.

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).

These data, from all 9 participants with follow-up ranging from 12 to 36 months, were presented by Donald Kohn, MD, Distinguished Professor of Microbiology, Immunology & Molecular Genetics, Pediatrics and Molecular & Medical Pharmacology, and Director, University of California – Los Angeles (UCLA) Human Gene and Cell Therapy Program, and member, Broad Stem Cell Research Center, Jonsson Comprehensive Cancer Center and UCLA Children’s Discovery and Innovation Institute, at the 2023 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held February 15-18 in Orlando, Florida.

“Severe LAD-1 is characterized by recurrent disseminated infections, the majority of which are fatal, and in fact, in severe LAD-1, 60-70% of patients die before the ageof 2 [years]. Even in the more moderate form, there’s accelerated mortality, with 50% of patients dying before the age of 40. The current treatment is allogeneic hematopoietic stem cell transplantation (HSCT), but it can be limited by the availability of donors, infections, and it’s also associated, in this disease especially, with frequent graft-versus-host disease and graft failure,” Kohn said during his presentation.

Enrolled participants had to have severe LAD-1, be at least 3 months of age, and have had at least 1 prior significant bacterial or fungal infection. The study primarily evaluated safety and preliminary efficacy in its phase 1 portion and survival and safety in its phase 2 portion. Secondary outcomes included reductions in significant infections and related hospitalizations, CD18 expression, vector copy number (VCN) in the peripheral blood, and improvements in leukocytosis, neutrophilia, skin rash, and periodontal abnormalities.

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Kohn and colleagues observed efficacy signals and all 9 patients met the primary endpoint 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 VCN integration. They also observed genotypic and phenotypic correction, durable for up to 36 months of follow-up. RP-L201 yielded a 100% overall survival rate in patients for at least 1 year of follow-up and up to 2 years of age without HSCT. Furthermore, these participants experienced spontaneous resolution of skin rash related to LAD-1 as well as a restoration of wound repair capabilities and have not experienced infections typical of LAD-1 since treatment.

RP-L201 has been well-tolerated, with no treatment-related adverse events (AEs) reported and no serious infusion-related AEs. AEs that did occur were consistent with study procedures such as busulfan conditioning, which was determined to be related to 1 case of veno-occlusive disease which resolved without subsequent complications. Another serious AE of grade 4 pulmonary arterial hypertension (PAH) was considered related to conditioning and underlying disease. The AE was considered secondary to busulfan due to severe pre-treatment pneumonia. This participant also had a double aortic arch associated with tracheal compression and, after PAH resolved, they underwent a successful surgical correction of their double aortic arch. Investigators also performed sequencing analysis and observed highly polyclonal patterns without any evidence of proximal oncogenic loci integrations.

“In this phase 1/2 study in pediatric patients with severe LAD-1, RP-L201 gene therapy resulted in functional immune reconstitution, phenotypic correction and survival with a favorable safety profile in all 9 patients. RP-L201 lentiviral gene therapy represents a highly promising alternative for the treatment of severe LAD-1,” Kohn concluded his presentation.

For more coverage of the 2023 Tandem Meetings, click here.

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
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