Benefits of RP-L201 in LAD-I Persist With Additional Follow-Up

Jonathan Schwartz, MD

RP-L201 continued to show promising preliminary efficacy in 100% of pediatric patients with severe leukocyte adhesion deficiency-I (LAD-I) treated in a phase 1/2 study, according to updated findings presented at a virtual poster session at the Clinical Immunology Society (CIS) 2021 Annual Meeting.

Follow up for the first 2 patients treated with RP-L201 had reached 9 and 18 months at the February 2021 data cutoff. Data from 2 additional patients with 3 months of follow-up were also presented at the CIS meeting (N = 4). Promising responses were seen in all patients in the study. In the 2 patients with the longest follow-up, CD18+ polymorphonuclear neutrophil (PMN) expression remained stable with additional follow-up and all patients remained alive, despite entering the study with CD18+ PMN of <2%. Additionally, there were improvements in skin lesions and consistent peripheral vector copy number (VCN) findings.

“Today’s positive updates on our LAD-I program add to the growing body of encouraging evidence that RP-L201 may provide durable clinical benefit for patients with severe LAD-I who face recurrent, life-threatening infections from birth,” Jonathan Schwartz, MD, chief medical officer and senior vice president of Rocket, the company developing the gene therapy, said in a statement. “We are very pleased to report that a second patient is nearing survival at 1-year post-treatment, the primary outcome measure for the phase 2 portion of the study."

The patient with 18 months' follow-up post treatment was 9 years old and treated with RP-L201 at a dose of 4.2 x 10⁶ cells/kg. In this patient, the CD18+ PMN expression at the follow up was approximately 40% and there was resolution of pre-existing skin lesions and no new lesions detected. The second patient was a 3-year-old treated with a 2.8 x 10⁶ cells/kg dose. At 9 months of follow-up post-infusion of RP-L201, the CD18+ PMN expression was 28%.

“These updates move us 1 step closer towards BLA [biologic license application]/MAA [marketing authorization application] filings in the United States and Europe and eventual commercialization of a potentially curative option for the children facing this truly devastating disease,” Jonathan Schwartz, MD, chief medical officer and senior vice president of Rocket, the company developing the gene therapy, said in a statement. “We look forward to providing more comprehensive phase 2 results in the second half of 2021.”

RP-L201 consists of autologous CD34+ enriched cells transduced ex vivo with a lentiviral vector to add the ITGB2 gene, which encodes the CD18 receptor (beta 2 integrin subunit). Once manufactured and cryopreserved, the transduced autologous cells are infused into the patient at a target dose of at least 2 x 106 total CD34+ cells/kg, following myeloablative conditioning with intravenous busulfan.

In the phase 1/2 study, 2 patients were treated with RP-L201 in the phase 1 portion and an additional 5 were treated in the phase 2 cohort, with data presented for 2 of these patients. For the 4 patients presented at the meeting, 75% were female. The age at enrollment was 9 years, 3 years, 2 years, and 7 months. The CD34+ cell dose ranged from 2.8 x 106 to 6.5 x 106 cells/kg.

Prior to entering the study, patients had an extensive history of severe and/or persistent infections, including some that required surgery, antibiotics, or anti-inflammatory therapy. The primary end point for phase 1 was safety and efficacy and the phase 2 portion is focused on the number of patients alive at age 2 and those alive at least 1-year post-infusion without requiring a bone marrow transplant.

The follow up was 3 months for both patients treated in the phase 2 portion of the study. In the first patient, a 2-year-old female treated with a 6.5 x 106 cells/kg dose, the CD18+ PMN expression was approximately 51%. In the second patient, who was a 7-month-old male patient treated with 4.3 x 106 cells/kg, the CD18+ PMN expression was 70%. Peripheral blood VCN kinetics were similar to the first 2 patients enrolled in the study.

Following hematopoietic reconstitution with RP-L201, there were no severe infections reported in any of the patients. Moreover, infusions of the gene therapy were well tolerated, with no signs of product-related serious or severe adverse events.

"In all patients treated, CD18 expression has substantially exceeded the 4%-10% threshold associated with survival into adulthood, with consistent peripheral blood VCN levels," said Schwartz. "Improved disease-related skin lesions, absence of new infections post-treatment, and no further requirements for prophylactic anti-infectives were also observed in both phase 1 patients with prolonged follow-up."

Earlier findings from the phase 1/2 study were presented at the ASH Annual Meeting in December 2020 and were the basis for a regenerative medicine advanced therapy (RMAT) designation from the FDA in early March 2021. Additional findings from the study are anticipated before the end of the year.