Single dose of Roctavian effective over 7 years, per new trial update
Gene therapy reduces yearly bleeding rates up to 96% in hemophilia A
That’s according to an update on a Phase 1/2 clinical trial (NCT02576795), launched in the U.K. in 2015, that’s testing the safety and efficacy of increasing doses of the gene therapy, which was approved in the U.S. in June 2023.
The new data is being presented by BioMarin Pharmaceutical, Roctavian’s developer, at the 2024 European Association for Haemophilia and Allied Disorders (EAHAD) Congress, being held Feb. 6-9, in Frankfurt, Germany. The poster is titled “Seven-year follow-up of valoctocogene roxaparvovec gene therapy for haemophilia A.”
“We are pleased to present data showing the impact of one-time treatment with Roctavian over seven years following the infusion, underscoring the potential of gene therapy to make a meaningful and long-lasting impact for people living with severe hemophilia A,” Hank Fuchs, MD, BioMarin’s president of worldwide research and development, said in a company press release.
No new safety issues were found during the seven years of follow-up, according to the company. The therapy is now available commercially in the U.S. and in certain countries in the European Union, where Roctavian is conditionally approved.
2 patients resumed FVIII replacement therapy after bleeds last year
In hemophilia A, mutations in the F8 gene result in the lack or malfunction of a blood clotting protein called factor VIII (FVIII), causing patients to experience excessive and prolonged bleeding. Recurrent bleeds in the joints also can lead to irreversible damage, pain, and limited mobility.
Standard treatment for patients involves the administration of regular, lifelong infusions of FVIII to replace the missing or faulty clotting protein and prevent bleeding episodes. Yet, many patients end up developing neutralizing antibodies, or inhibitors, against the delivered FVIII that can lower treatment efficacy and even render it useless.
“People living with severe hemophilia A face a lifelong treatment burden, including frequent injections or infusions and a high risk of health complications like uncontrolled bleeding and irreversible joint damage, which may persist despite good adherence to prophylactic [preventive] therapy,” Fuchs said.
Roctavian is an approved one-time gene therapy that uses a harmless adeno-associated virus (AAV5) to deliver a shorter, but functional version of the F8 gene to liver cells, where most clotting factors are produced. Its goal is to restore FVIII levels, reduce bleeds, and minimize or even eliminate the need for conventional replacement therapies.
This ongoing Phase 1/2 study enrolled men with severe hemophilia A, defined as FVIII levels of 1 international unit per deciliter (IU/dL) or less — far below the normal range of 50-150 IU/dL.
Eligible participants were previously receiving FVIII replacement therapy, had no inhibitors against FVIII or AAV5, and showed no signs of significant dysfunction, fibrosis (scarring), or cirrhosis in the liver.
Seven patients received a higher dose of Roctavian — 6e13 vector genomes per kilogram, or vg/kg — and six were given a lower dose, of 4e13 vg/kg. Six-year data from the study showed that bleeding events and the use of FVIII replacement therapy were substantially reduced after treatment with Roctavian.
At the most recent seven-year follow-up, now being reported, all seven patients who received the higher dose remained in the study, as did five of the six treated with the lower dose. One lower-dose participant was lost to follow-up after week 287, or around 5.5 years.
Median FVIII activity remained in the mild hemophilia range, at 10.3 IU/dL in the high-dose group at the seventh year of follow-up, and at 7.2 IU/mL in the low-dose group at the sixth year of follow-up.
During follow-up, the mean annualized bleeding rate (ABR) for bleeds that required treatment dropped by 96% in patients given the higher dose of Roctavian and by 88% among those given the lower dose.
The mean FVIII replacement infusion rate dropped by 95% among individuals treated with the higher dose of the gene therapy and by 93% in those given the lower dose. In year seven, two high-dose participants resumed FVIII replacement therapy after experiencing bleeds.
Over the past year, one participant in each dose group had a mild (grade 1) treatment-related adverse event: enlargement of the liver in one and of the spleen in the other.
BioMarin also sharing updates on other Roctavian trials at conference
At the EAHAD conference, BioMarin also is presenting data on Roctavian from another Phase 1/2 study, called GENEr8-INH (NCT04684940), that will run until 2029.
This international study is assessing the gene therapy’s safety and efficacy when given at a dose of 6e13 vg/kg in up to 20 men with severe hemophilia A who have current or prior inhibitors against FVIII, but no anti-AAV5 antibodies.
So far, Roctavian has showed a similar safety profile regardless of inhibitor status. In two participants with active inhibitors, FVIII inhibitor levels peaked 12 weeks, or about three months, after the single-dose treatment. Inhibitor levels fell in one patient and rose in the other, who had been treated with corticosteroids. In two participants with prior inhibitors, FVIII activity reached 26.2 and 247.8 IU/dL, and inhibitors did not recur.
According to researchers, these “interim efficacy results are encouraging.”
The company also is presenting the latest data from the Phase 3b GENEr8-3 trial (NCT04323098) in an oral presentation at the congress. GENEr8-3, slated to run through 2027, is evaluating the safety and efficacy of Roctavian when given at a dose of a 6e13 vg/kg alongside corticosteroids.
This trial, with study sites in Australia, Brazil, Taiwan, and the U.S., involves a total of 22 men with severe hemophilia A.
After one year, mean FVIII activity increased to 1-16.1 IU/dL, the yearly use of FVIII replacement therapy dropped by 91.6%, and the mean ABR for treated bleeds fell by 67.1%. A total of 20 patients had treatment-related side effects and saw their levels of liver enzyme increase, while 19 had steroid-related side effects, and 14 used on-demand corticosteroids.
The researchers noted that compared with previous trials using on-demand corticosteroids, the use of preventive corticosteroids in this trial “yielded lower FVIII activity and conferred no benefit for safety or [corticosteroid] burden.”
In all, BioMarin is conducting three poster presentations and three oral presentations at the EAHAD congress.