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Gene Therapy For Hemophilia B Significantly Outperforms Factor IX Prophylaxis
Gene therapy for hemophilia B allowed almost three-fourths of patients to discontinue prophylactic factor IX therapy with no increase in bleeding, results of the pivotal BENEGENE-2 trial showed.
The annualized rate of bleeding for total bleeding episodes decreased by 71% after treatment with fidanacogene elaparvovec (Beqvez), while the mean annualized rate of bleeding for treated bleeding episodes was reduced by 78%, reported Adam Cuker, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and co-authors in the New England Journal of Medicine.
The results met prespecified criteria for noninferiority compared with factor IX prophylaxis and provided the basis for FDA approval of the therapy earlier this year.
"In this study, factor IX levels after fidanacogene elaparvovec therapy, as compared with prophylaxis, were associated with an amelioration of the bleeding phenotype and a significant reduction in the annualized bleeding rate and the annualized total factor IX consumption," the authors wrote. "These findings offer additional evidence that transduction of the FIX-R338L variant can produce hemostatic competence at the reported factor IX activity level."
"The majority (>80%) of the participants had factor IX activity in the mild-hemophilia range for a sustained period of 15 to 24 months, a finding that shows durable efficacy similar to that observed in other trials of gene therapy for hemophilia B," they added.
Standard of care for hemophilia B is episodic intravenous administration of factor IX replacement, Cuker and co-authors noted in their introduction. Current prophylactic therapies do not provide a cure, eliminate symptoms, or prevent joint damage.
Other non-factor IX agents that reduce antithrombin synthesis and monoclonal antibodies that neutralize the inhibitory activity of tissue factor pathway inhibitors have either been approved or are in advanced stages of clinical development, the authors noted. However, those agents still require regular administration.
Gene therapy can eliminate the need for ongoing treatment and the burden of regular disease management. The FDA approved etranacogene dezaparvovec (Hemgenix) as the first gene therapy for hemophilia B in 2022. Administered as a single infusion, the therapy consists of an adeno-associated virus (AAV) serotype 5 vector expressing FIX-R338L.
Fidanacogene elaparvovec delivers transgene production of FIX-R338L. In a phase I-IIa trial with long-term follow-up, the gene therapy led to sustained factor IX activity in the range of mild hemophilia to normal, associated with few episodes of bleeding and reduced factor IX prophylaxis. Results of the 15-patient study provided the basis for the phase III BENEGENE-2 trial that led to the therapy's approval.
BENEGENE-2 included men ages 18-65 with hemophilia B, defined as a factor IX level ≤2%, with at least a 6-month history of factor IX prophylaxis. After screening and exclusions (primarily for anti-AAV antibodies), 45 patients received a single infusion of fidanacogene elaparvovec, and 44 completed at least 15 months of follow-up.
The primary endpoint was the annualized rate of treated and untreated bleeding episodes from 12 weeks to 15 months after treatment, as compared with the factor IX prophylaxis lead-in period.
The results showed that the annualized bleeding rate decreased from 4.42 episodes at baseline to 1.28 at 15 months, a difference that not only met noninferiority but also superiority versus factor IX prophylaxis (P=0.008). At 15 months, the mean factor IX activity was 26.9%.
A total of 28 patients received glucocorticoid treatment for increased liver enzymes or decreased factor IX levels between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, or malignancies occurred, as well as no development of factor IX inhibitors.
"The findings from this phase III study showed that fidanacogene elaparvovec had a favorable benefit-risk profile providing efficacy at one of the lowest doses of AAV-based gene therapy studied for hemophilia B," the authors concluded. "An ongoing extended follow-up study to 15 years after gene therapy will provide further insights regarding the effects of fidanacogene elaparvovec."
Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow
Disclosures
The study was supported by Pfizer.
Cuker disclosed relationships with MingSight Pharmaceuticals, the New York Blood Center, Pfizer, Sanofi, and Synergy Research, as well as a patent/royalty/intellectual property interest.
Primary Source
New England Journal of Medicine
Source Reference: Cuker A, et al "Gene therapy with fidanacogene elaparvovec in adults with hemophilia B" N Engl J Med 2024; DOI: 10.1056/NEJMoa2302982.
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Gene Therapy For Hemophilia B Could Lower Health Plans' Budget Over Time
Health plans would see savings faster if they switched to etranacogene dezaparvovec sooner, the investigators found.
The use of gene therapy for people with hemophilia B can result in overall cost savings for US health plans, according to a new analysis, but it may take several years for the savings to be realized.
The report, which was published in the Journal of Managed Care Pharmacy, comes nearly 2 years after the Food and Drug Administration (FDA) first approved etranacogene dezaparvovec (Hemgenix) for the treatment of hemophilia B.
The analysis is important because etranacogene dezaparvovec comes with an estimated price tag of $3.5 million, but it has the potential to eliminate the need for a lifetime of prophylactic therapy.
Switching patients with hemophilia B to gene therapy may compound immense health care savings in the long termimage credit: Saiful52 - stock.Adobe.Com
Corresponding author Songkai Yan, MS, of CSL Behring, noted that the current standard of care for people with severe or moderately severe hemophilia B is routine prophylactic administration of blood clotting factor IX (FIX), which is deficient in people with hemophilia B.1
"Although FIX prophylaxis is effective at reducing the risk of bleeds, the treatment is costly, with annual prophylaxis costs of more than $600,000 per year in the United States," they wrote.
CSL Behring is the distributor of Hemgenix. The study was conducted by RTI Health Solutions and funded by CSL Behring.
According to a 2021 analysis, FIX prophylaxis accounts for more than 90% of the overall cost of treating patients with hemophilia B.2 Yan and colleagues added that, despite its general efficacy, prophylaxis does not eliminate the risk of bleeding episodes. One study found 9% of people with hemophilia B experienced a bleed-related hospitalization over a 12-month period, despite being treated with FIX prophylaxis.3
Etranacogene dezaparvovec is a gene therapy designed to provide a more durable solution by delivering a gene for FIX to the liver, resulting in an increase in FIX activity and ideally an ability for patients to cease taking FIX prophylaxis. A phase 3 trial of the therapy found that at 24 months there was a 64% reduction in the annualized bleed rate (ABR) of patients receiving the therapy (mean ABR 1.51; P = 0.0002) in months 7 through 24 post-administration.4
Still, the high price tag of etranacogene dezaparvovec raises questions about how the therapy's introduction might affect the overall cost of healthcare.
To find out, Yan and colleagues developed a budget impact model to estimate the impact of the therapy on a hypothetical million-member health plan's 5-year budget. They used published reports of the cost of existing FIX therapy prophylaxis to estimate the cost of traditional prophylaxis, and $3.5 million for the gene therapy. In addition, they used estimates based on published literature to calculate the costs of disease monitoring, bleed management, and adverse events.
Uptake of etranacogene dezaparvovec was estimated using 2 different analyses. In the first, eligible patients were switched to the new therapy over the course of the 5-year model; in the second, the authors assumed all eligible patients received the therapy in the first year of the model.
Given the rarity of the disease, the investigators estimated that the million-member health plan would have 1.8 patients with hemophilia B who would be eligible for etranacogene dezaparvovec.
The investigators found that a gradual uptake of the gene therapy would add a cumulative total of $848,509 to the plan's budget over the course of 5 years, compared to a scenario in which no patients took the new therapy. When that analysis was expanded to 10 years, though, the newer therapy would lead to cumulative savings of about $1.3 million, the investigators found.
Conversely, if etranacogene dezaparvovec were given to all eligible patients in the first year of the analysis, savings would begin in the second year, and the health plan would save $754,844 over the course of 5 years, and nearly $8 million over 10 years.
Yan and colleagues said one difficult part of the analysis is the time horizon. Using a 5-year horizon might underestimate the long-term savings to a health plan. However, health plans must also factor in the possibility that a patient leaves the health plan after receiving the therapy, thus depriving the health plan of the full savings associated with paying for the high-cost gene therapy.
Yet, the authors said their data show that health plans can realize savings more quickly by moving patients to etranacogene dezaparvovec sooner.
"Faster uptake of etranacogene dezaparvovec will lead to greater up-front costs but may result in greater long-term budget savings if these individuals remain with the same health plan," they wrote.
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Marstacimab Recommended For EU Approval For Hemophilia A And B
A European Medicines Agency (EMA) committee has issued a positive opinion recommending the approval of marstacimab in the European Union for preventing bleeding episodes in people with severe hemophilia A or hemophilia B without inhibitors.
The European Commission will now review the recommendation, made by the EMA's Committee for Medicinal Products for Human Use (CHMP), with a final decision on the therapy's approval expected in the coming months.
If approved, the treatment, developed by Pfizer, should be available under the brand name Hympavzi, as a 150 mg solution for subcutaneous, or under-the-skin, injection, according to the EMA. The company also has submitted a request to the U.S. Food and Drug Administration asking for the therapy's approval, with a decision expected in that country this year.
"The benefit of Hympavzi is the prevention of bleeding in severe haemophilia A or severe haemophilia B patients when given as prophylaxis," or preventive treatment, the EMA's overview states.
Marstacimab shown in BASIS trial to reduce bleed ratesHemophilia A and B are caused by mutations that disrupt the activity of blood clotting proteins: factor VIII in type A and factor IX in type B. Standard treatment usually involves replacement therapy, in which a functional version of the faulty or missing clotting factor is delivered to patients.
However, these treatments usually involve frequent intravenous, or into-the-vein, infusions, which imposes a treatment burden on patients. Further, some individuals with hemophilia may develop antibodies against the delivered clotting proteins — known as inhibitors — which reduce the treatment's efficacy.
Marstacimab is an antibody-based therapy designed to block the activity of tissue factor pathway inhibitor, a protein that normally helps prevent the formation of blood clots. Given as a preventive treatment once a week, marstacimab is expected to promote blood clotting and reduce or prevent bleeding in people with hemophilia.
CHMP's positive opinion, which specifically applies to hemophilia A or B patients weighing at least 35 kg (about 77 pounds) with no preexisting antibodies against clotting factors, was supported by data from the Phase 3 BASIS trial (NCT03938792). The results showed that marstacimab significantly reduced bleed rates in adults and adolescents without inhibitors, compared with standard therapies.
In this first part of the trial, patients without inhibitors received their current replacement therapy for six months, followed by marstacimab, given at a 300 mg loading dose and then 150 mg weekly, for about one year. Marstacimab was found to reduce annualized bleed rates by 35% relative to preventive replacement therapy, and by 92% compared with on-demand replacement treatment.
The therapy was generally safe and well tolerated, with the most common side effects including injection site reactions, headache, high blood pressure, and itching.
Results from patients with inhibitors are expected by the year's end.
Patients who complete this trial may enroll in an open-label extension study (NCT05145127) to continue receiving marstacimab for up to seven years. Available data so far indicate consistent benefits for up to 1.5 years.
Another Phase 3 clinical trial, called BASIS KIDS (NCT05611801), is investigating the safety and efficacy of marstacimab in children with severe hemophilia A and moderately severe to severe hemophilia B, with or without inhibitors. That trial is expected to be completed in 2028.
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