CD18

Rocket Pharmaceuticals will have to wait another three months for an FDA decision on its investigational gene therapy for severe leukocyte adhesion deficiency-I (LAD-I). The US regulator is now expected to determine whether to approve Kresladi (marnetegragene autotemcel) by June 30 to allow more time to review "clarifying" information about the company's chemistry, manufacturing, and controls (CMC) process."We remain confident and focused on making this therapy available for patients as quickly as possible," stated CEO Gaurav Shah. According to Rocket, the FDA has also confirmed that it does not intend to convene an advisory committee meeting to discuss the filing, which was granted a priority review last October.The gene therapy, also known as RP-L201, contains patient-derived haematopoietic stem cells modified with a lentiviral vector to deliver a functional ITGB2 gene, which encodes human CD18 receptor to facilitate leukocyte adhesion and ability to move out of blood vessels to fight infection.In September, Rocket completed a global Phase I/II trial of the treatment in nine paediatric patients with severe LAD-I, according to ClinicalTrials.gov. The company says all primary and secondary endpoints were met with Kresladi demonstrating 100% overall survival at one-year post-infusion, as well as for the entire 12 to 24 months of follow-up.Compared with pre-treatment history, it said Kresladi also showed "large decreases" in the incidence of significant infections, and there was evidence of resolution of LAD-I-related skin lesions and restoration of wound repair capabilities. The gene therapy was "very well tolerated" in all patients, none of whom suffered serious adverse events related to treatment.Company shares soared last September announced plans to raise $175 million in an upsized public offering. Around the same time, it initiated a pivotal Phase II to support accelerated approval of its RP-A501 gene therapy for Danon disease, a rare X-linked inherited disorder caused by mutations in the LAMP-2 gene.

Pictured: Entrance to the FDA's office in Maryland/iStock, Grandbrothers New Jersey-based Rocket Pharmaceuticals announced on Tuesday that the FDA is extending its review period by three months for the investigational gene therapy Kresladi (marnetegragene autotemcel), being proposed for the treatment of the rare disease leukocyte adhesion deficiency-I. The regulator has pushed back its target action date on Kresladi to June 30, 2024, giving it more time to go through Rocket’s additional submissions regarding the therapy’s Chemistry, Manufacturing and Controls. The FDA has confirmed that it will not hold an advisory committee meeting to discuss Kresladi’s Biologics License Application (BLA). CEO Gaurav Shah said in a statement that Rocket remains confident in its application for Kresladi. The company will continue to work closely with the FDA “and together share a deep sense of responsibility in the rigorous process” of reviewing novel and “potentially curative gene therapies.” Leukocyte adhesion deficiency-I (LAD-I) is a rare and autosomal recessive blood disorder that most often arises during childhood. LAD-I is caused by mutations in the ITGB2 gene leading to a faulty CD18 protein, which is key to leukocyte adhesion and facilitates their escape from blood vessels into tissues to combat infections. Children with LAD-I typically suffer from recurrent and life-threatening bacterial and fungal infections that are resistant to antimicrobial treatment. For patients who survive infancy, LAD-I can then manifest as pneumonia, gingival ulcers and septicemia. Without a bone marrow transplant, survival beyond childhood is unlikely. Kresladi, an investigational and autologous gene therapy, addresses the underlying pathology of LAD-I by using the patient’s own hematopoietic stem cells and causing them through genetic modification to deliver a functional copy of the ITGB2 gene. This mechanism of action has won Kresladi the FDA’s Regenerative Medicine Advanced Therapy, Rare Pediatric and Fast Track designations. Kresladi’s BLA, which the FDA accepted in October 2023, is backed by topline Phase I/II data, which enrolled nine LAD-I patients and demonstrated a 100% overall survival at 12 months after infusion. The study also detected a steep decline in the incidence of significant infections, as well as resolution of LAD-I skin lesions. Patients who were treated with Kresladi also recovered their ability to repair wounds. If approved, Kresladi would be among the first gene therapies clearing the FDA’s regulatory hurdle this year. According to advocacy group Alliance for Regenerative Medicine (ARM), 2024 could witness a large jump in the number of cell and gene therapy approvals. In ARM’s annual Cell & Gene State of the Industry briefing last month, the group noted that the sector could see up to 17 approvals in in the U.S. and European Union, including more hemophilia A therapies as well as the first allogeneic T-cell therapy in the U.S. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

The U.S. FDA has extended the priority review period by three months for Rocket Pharmaceuticals' autologous gene therapy for a rare pediatric immunodeficiency disorder. The investigational therapy, branded Kresladi (marnetegragene autotemcel), originally had a PDUFA date of March 31 for leukocyte adhesion deficiency-I (LAD-I). The FDA pushed the date to June 30, to allow additional time to review clarifying chemistry, manufacturing and controls information submitted by Rocket in response to the agency's information requests. According to Rocket, the FDA confirmed no advisory committee meeting will be needed. LAD-1 is caused by mutations in the ITGB2 gene encoding for the beta-2 integrin component CD18, a key protein needed to combat infections. Rocket'sKresladi contains autologous hematopoietic stem cells that have been genetically modified with a lentiviral vector to deliver a functional copy of the ITGB2 gene, which encodes for the beta-2 integrin component CD18. The NJ-based biotech is hopeful that the therapy has the potential to change the treatment paradigm for patients living with severe LAD-I — one of the most aggressive and highly fatal immunodeficiencies ever characterized. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2 and survival beyond the age of 5 is uncommon, according to Rocket. Back in 2022 , Rocket revealed promising phase 2 trial results: 3-24 months after Kresladi (then RP-L201) infusion, all nine trial patients sustained stable CD18 expression with no therapy-related serious adverse events. Furthermore, among all participants, the overall survival at one year was 100% — and patients are reporting a statistically significant reduction in all hospitalizations.