A new gene therapy for hemophilia B appeared to override a genetic defect critical for clotting in a combined phase I and II clinical trial involving six patients with severe disease phenotype.
Hemophilia B is an X-linked disorder resulting from a defect in the gene encoding human factor IX (FIX).
In the study, a single intravenous injection of an adenovirus-associated virus (AAV) vector that expresses FIX improved the bleeding phenotype in all six patients, Dr. Amit C. Nathwani of the University College London Cancer Institute and his colleagues report online in the Dec. 10 New England Journal of Medicine.
The findings, which represent a critical step toward the goal of eliminating the need for long-term intravenous infusions of recombinant clotting factor concentrates in hemophilia patients, were presented simultaneously at the annual meeting of the American Society of Hematology.
Patients with a severe hemophilia B disease phenotype have functional FIX levels less than 1% of normal, leading to frequent life-threatening bleeding episodes and crippling joint disease, and are typically treated with expensive prophylactic injections of FIX protein concentrate two to three times weekly.
After injection with the AAV vector (scAAV2/8-LP1-hFIXco), all patients in the study achieved expression of FIX at 2%-12% of normal levels, allowing four of the patients to discontinue FIX prophylaxis. Those patients remained free of spontaneous hemorrhage at up to 16 months of follow-up, even when they undertook activities – such as training for a marathon – that had caused bleeding in the past, the investigators said (N. Engl. J. Med. 2011, Dec. 10 [doi:10.1056/NEJMoa11108046]).
In the other two patients, the interval between FIX prophylaxis injections was increased to one injection every 2 weeks, except in cases of upcoming sporting or other events that required prophylaxis or that resulted in trauma.
The patients were enrolled into one of three cohorts (two patients in each) and were treated with either a high dose (2x1012 vector genomes/kg), intermediate dose (6x1011 vg/kg), or low dose (2x1011 vg/kg) of vector. Response was generally dose-dependent, with the high dose mediating peak expression at the highest levels in the study (8%-12% of normal values). However, one of the two patients treated with the high dose experienced a transient, asymptomatic increase in serum aspartate and alanine aminotransferase levels caused by AAV8-capsid-specific T cells in the peripheral blood, and the other patient in the high-dose group experienced a slight increase (though still below the upper limit of normal) in liver enzyme levels. Short-course glucocorticoid therapy was effective in both patients, normalizing aminotransferase levels without reducing FIX transgene expression levels, the investigators said.
None of the study participants had an immunologic response to the FIX transgene product, they noted.
It is "very important" to determine the frequency of "clinically significant elevations in aminotransferase levels after gene transfer," the investigators wrote, adding that this will require a larger number of participants treated at the high-dose level.
Follow-up of larger numbers of patients and for longer period of time will be required to fully characterize the benefits and risks of this gene therapy, as well as to optimize dosing, but the findings of this study suggest that it has the potential to convert severe hemophilia B into a mild form of disease, and to possibly reverse the disease process entirely, they concluded.
The study was funded by the U.K. Medical Research Council. Dr. Nathwani reported receiving grant funding from the Katharine Dormandy Trust for Haemophilia and Allied Disorders, the U.K. Department of Health, and the National Health Service Blood and Transplant, as well as serving as a consultant for Amsterdam Molecular Therapeutics. The complete list of disclosures for Dr. Nathwani and the other study authors is available with the full text of the article at NEJM.org.