UPDATED July 27, 2022 // Editor's note: This story has been updated with additional comments from Dr Pratima Chowdary, the lead author of the study.
Patients with hemophilia B face a lifelong need for regular factor IX injections. But in 9 of 10 patients treated with a novel gene therapy, this need was eliminated.
"Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life," commented lead author Pratima Chowdary, MD, of the Royal Free Hospital, University College London Cancer Institute, UK in a press statement.
The team reported new results with the investigational gene therapy FLT180a in a study published July 20 in the New England Journal of Medicine.
"We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a," the authors reported.
"In all but one patient, gene therapy led to durable factor IX expression, eliminated the need for factor IX prophylaxis, and eliminated spontaneous bleeding leading to factor IX replacement."
FLT180a (Freeline Therapeutics) is a liver-directed, adeno-associated virus (AAV) gene therapy designed to normalize levels of the factor IX protein that is needed for coagulation; however, it is produced in dangerously low levels in people with hemophilia B as a result of gene mutations.
Under the current standard of care, patients with hemophilia B require lifelong prophylaxis of regular intravenous injections with recombinant factor IX replacement therapy, and they commonly continue to experience potentially severe joint pain.
While factor-replacement therapies with longer half-lives have emerged, the prophylaxis is still invasive and extremely expensive, with the average price tag in the US of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
Novel Gene Therapy
Hemophilia B is a rare and inherited genetic bleeding disorder caused by defects in the gene responsible for factor IX protein, which is needed for blood clotting.
AAV gene therapy delivers a functional copy of this gene directly to patient tissues to compensate for one that is not working properly. It leads to the synthesis of factor IX proteins and a one-time gene therapy infusion can achieve long-lasting effects, the team explained in a press release.
The results they report come from the phase 1/2 multi-center B-AMAZE open label trial. It involved 10 patients (all age 18 and older) with severe or moderately severe hemophilia B, defined as having a factor IX level of 2% or less that of normal values.
All patients received one-off gene therapy infusion, at one of four FLT180a doses.
All patients also received immunosuppression to prevent the body from rejecting the vector gene therapy. This consisted of glucocorticoids with or without tacrolimus for a period of ranging from several weeks to several months.
Following the FLT180a infusion, all patients showed dose-dependent increases in factor IX levels. After a median follow-up of 27.2 months (range 19.1 - 42.4 months), nearly all the patients (9 of 10) continued to show sustained factor IX activity.
Steady production of factor IX activity started at month 12, with low bleeding frequency that allowed these nine patients to no longer require weekly injections of the protein.
Five of the patients had factor IX levels in the normal range, from 51%–78%; three patients had lower increases of 23%–43% of the normal range, and one patient who had received the highest dose, had a level that was 260% of normal.
The exception was one patient who required a return to factor IX prophylaxis. He had experienced a failure in the immunosuppression regimen due to a delay in the recognition of an immune response at approximately 22 weeks after treatment, the authors report.
The therapy was generally well tolerated, with no infusion reactions or discontinuations of infusions. As of the study cutoff, no inhibitors of factor IX were detected.
"[Development of inhibitors] is not much of a concern with gene therapy, as continuous expression results in tolerance," Chowdary told Medscape Medical News.
Of the adverse events, about 10% were determined to be related to the gene therapy. The most common event associated with the gene therapy was increases in liver aminotransferase, which is a concern with AAV gene therapies, the authors comment.
Otherwise, 24% of adverse events were determined to be related to the immunosuppression, and were consistent with the known safety profiles of glucocorticoids and tacrolimus.
Late increases in aminotransferase levels were reported among patients who had received prolonged tacrolimus beyond the tapering of glucocorticoid treatment.
The one serious adverse event that was reported involved an arteriovenous fistula thrombosis, which occurred in the patient who had received the highest dose of gene therapy and who showed the highest factor IX levels.
The current findings, along with data from another recent study involving gene therapy for patients with hemophilia A, emphasize that "immune responses can occur later than previously expected and may coincide with the withdrawal of immunosuppression," the authors caution.
"Consistent best practices for monitoring aminotransferase levels and deciding when ALT increases warrant intervention remain a critical topic for the field," they note.
That being said, the future looks bright for the brave new approach in hemophilia treatment, Chowdary said.
"Gene therapy is here to stay!" she told Medscape. "We are now looking at [the] development of new techniques to facilitate the transfer of the transgene and increase the pool of eligible patients and children and adolescents."
In the meantime, the patients in the current B-AMAZE trial all remain enrolled in a long-term follow-up study to assess the safety and durability of FLT180a over 15 years.
The trial was sponsored by University College London and funded by Freeline Therapeutics. Chowdary has disclosed various relationships with industry. The full list of author disclosures can be found here.
N Engl J Med. Published July 20, 2022. Abstract
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Cite this: No More Injections After One-Off Gene Therapy in Hemophilia B - Medscape - Jul 22, 2022.