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Rocket Pharmaceuticals' Gene Therapies Show Early but Durable Efficacy in Fanconi Anemia, PKD


LOS ANGELES – Lentiviral-mediated gene therapies for two rare blood cell disorders being developed by Rocket Pharmaceuticals safely conferred durable effects on clinical trial patients for more than a year, data shared at the American Society of Gene and Cell Therapy's annual meeting has shown.

Agnieszka Czechowicz, an assistant professor of pediatric stem cell transplantation at Stanford University, presented data on a Phase I trial evaluating the clinical efficacy and safety of RP-L102 in treating patients with Fanconi anemia complementation group A (FA-A), an inherited condition in which the body cannot make a protein that protects against DNA damage and the bone marrow cannot produce blood cells. Rocket's RP-L102 is a hematopoietic gene therapy that comprises FA-A patients' autologous CD34-positive cells transduced ex vivo with a lentiviral vector carrying a functional FANCA gene.

In the Phase I trial, investigators wanted to see if RP-L102 would result in phenotypic correction of patient cells and increased resistance to the DNA damaging agent mitomycin-C. Of 12 patients between 2 and 6 years old, seven demonstrated sustained engraftment for one year or longer. Furthermore, bone marrow colony forming cells showed increasing mitomycin-C resistance in all seven of those patients, and six patients also demonstrated genetic correction and hematologic stabilization over that time period. All 12 patients have at least one year of follow-up observations and nine have over two years of follow-up.

Czechowicz noted that in the original Fancolen-1 trial of RP-L102, two participants had more than seven years of follow-up and showed long-term hematologic stability.

RP-L102 represents a potentially curative therapy for FA-A-related bone marrow failure, Czechowicz said, which can be administered without transplant-conditioning related toxicities. In addition to this Phase I trial ongoing in the US, Rocket is studying the hematopoietic gene therapy in another Phase I study in Europe and in a Phase II study in the US.

At the ASGCT meeting, Ami Shah, a pediatric hematologist/oncologist also at Stanford, presented results from an ongoing study evaluating the safety and toxicity of another Rocket gene therapy, RP-L301, in treating severe anemia associated with pyruvate kinase deficiency (PKD), an inherited disorder in which a lack of the pyruvate kinase enzyme causes the breakdown of red blood cells. RP-L301 inserts a functional copy of the PKLR gene into patients' autologous stem cells in order to normalize peak insulin production, and to improve red blood cell function and lifespan.

Analyzing data from six participants who received RP-L301, Shah reported that two adults achieved stable normal hemoglobin levels and didn't need red blood cell transfusions and had hematopoietic reconstitution within two weeks of administration. Both patients had maintained that status for two years as of October 2022, with no serious adverse events reported. These patients had a minor transaminase elevation but neither developed any severe complications such as veno-occlusive disease, a condition where blood flow in the veins of the liver are blocked and can cause liver damage.

Additionally, insertion site analysis of both patients showed highly polyclonal patterns, Shah reported, with no dominant clone evident in either case. 

Shah also presented new and "very early" data on a female pediatric patient enrolled in this trial, who, like the two adult patients, tolerated RP-L301 well, with engraftment occurring at day 15 post-treatment. Her hemoglobin normalized at six weeks post-treatment. As with the adult patients, she has not yet needed a red blood cell transfusion.

"The clinical efficacy and safety data indicate that RP-L301 is a potential treatment for patients with severe pyruvate kinase deficiency," Shah said, noting that it also worked on patients who did not benefit from available therapies, such as Agios' pyruvate kinase activator Pyrukynd (mitapivat).

Shah commented that investigators have finished enrolling patients to the Phase I trial of RP-L301 and that a Phase II trial of the gene therapy will launch later this year.