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SAN DIEGO -- Results from a small single-center study showed that treatment with a gene therapy involving the use of lentiviral vector-transduced autologous hematopoietic stem cells (HSCs) increased factor VIII levels in patients with severe hemophilia A.

Among five patients, the median factor VIII activity level from 4 weeks until the last follow-up visit increased to 5.2 and 1.7 IU/dL with a peripheral-blood vector copy number of 0.2 and 0.1 copies/cell, respectively, in the two participants in group 1 (who did not receive a transduction enhancer), and 37.1, 19.3, and 39.9 IU/dL with a peripheral-blood vector copy number of 4.4, 3.2, and 4.8 copies/cell, respectively, in the three participants in group 2 (who received a transduction enhancer), reported Alok Srivastava, MD, of St. John's Research Institute in Bengaluru, India, at the American Society of Hematology annual meeting.

In addition, over a cumulative period of 81 months, all participants had a median annualized bleeding rate of zero, the researchers noted in the , where the study was concurrently published.

Srivastava and colleagues said their study validated a new approach to gene therapy in severe hemophilia A -- through transplantation, after myeloablative conditioning, of autologous HSCs transduced with a lentiviral vector encoding a novel factor VIII transgene driven by a CD68 promoter.

"The safety and feasibility of this approach to gene therapy for hemophilia A has been established," said Srivastava. "The regimen-related toxicities, both conditioning and the procedure, are mild and well tolerated, and there is a highly significant and sustained expression of factor VIII activity, with excellent clinical response in all participants."

"However, it is still a complex procedure for gene therapy requiring individualized product manufacturing and hemopoietic stem cell transplantation," he added. "And the long-term safety and efficacy need to be evaluated in larger numbers."

In an , Johnny Mahlangu, MB, BCh, MMed, of the University of the Witwatersrand in Johannesburg, noted that "in four of the five patients in this study, factor VIII levels were in the mild-to-moderate hemophilia range. If these findings are reproduced and factor VIII levels are consistent and stable over time, these results may be superior to outcomes of current gene therapies involving AAV [adeno-associated virus]-delivered factor VIII and replacement of factor VIII."

In explaining the rationale behind their gene therapy approach, Srivastava noted that valoctocogene roxaparvovec (Roctavian) -- a liver-directed AAV vector-based gene therapy -- has been approved for the treatment of hemophilia A, as have two other AAV vector-based gene therapies, fidanacogene elaparvovec (Beqvez) and etranacogene dezaparvovec (Hemgenix), for hemophilia B.

"This approach has shown high initial levels of factor activity, and a good safety profile," Srivastava observed. "However, there are several limitations, as well." These include unpredictable initial levels of expression, a progressive drop of expression after 6 to 12 months -- particularly in hemophilia A -- which is associated with transaminitis that requires immunosuppression, and exclusion of patients due to pre-existing anti-AAV antibodies, as well as children under the age of 12 due to liver immaturity.

"So, there is a need for an alternative approach to gene therapy in hemophilia," Srivastava said.

In his editorial, Mahlangu noted that "the use of lentiviral vector to deliver the factor VIII gene therapy not only overcomes the barrier with respect to pre-existing anti-AAV antibodies but also opens the door for many more patients, including pediatric patients, to receive gene therapy. This breakthrough could remove other barriers, such as liver health and maturity, unpredictable transaminitis, and the need for immunosuppressive therapy with lentiviral vector-delivered factor VIII gene therapy."

The study included five participants with severe hemophilia A (<1% measurable factor VIII activity), who ranged in age from 22 to 41. Each received CD68-ET3-LV-transduced autologous CD34+ HSCs at doses of 5.0 × 10⁶ to 6.1 × 10⁶ per kg of body weight. The vector copy numbers in the final drug product were 1.0 and 0.6 copies/cell for the two participants in group 1 and 1.5, 0.6, and 2.2 copies/cell for the three participants in group 2.

The median follow-up after gene-modified hematopoietic stem cell transplantation was 14 months. Srivastava reported that evidence of endogenous factor VIII expression was observed as early as day 18 after infusion of the drug product in one participant.

No spontaneous bleeding events occurred in any participant during transplant or after gene therapy, whereas all participants had reported an annualized bleeding rate of at least 20 events before gene therapy. Srivastava and colleagues said the lack of bleeding after gene therapy in the participant who had the lowest level of factor VIII activity is "notable."

All participants in the study were able to increase their duration and intensity of physical activities without fear of bleeding, and two patients maintained hemostasis even after experiencing trauma in motor vehicle accidents.

Severe cytopenia was observed in all five participants. The duration of severe neutropenia was 7 to 11 days, and was 1 to 7 days for severe thrombocytopenia. No other adverse events greater than grade 2 occurred in any participant. The most common adverse event was nausea with or without vomiting.