Fidanacogene elaparvovec for hemophilia
What is fidanacogene elaparvovec for hemophilia?
Fidanacogene elaparvovec, previously known as SPK-9001 or PF-06838435, is an experimental gene therapy being developed for treating hemophilia B.
The medication is given one time as an intravenous (into-the-vein) infusion to reduce the risk of bleeding episodes in patients. It’s approved in Canada under the name Beqvez for adults with moderately severe to severe hemophilia B who are negative for antibodies against the therapy’s viral vector.
Fidanacogene elaparvovec is being developed by Pfizer. Roche subsidiary Spark Therapeutics was codeveloping it, but transferred full responsibility to Pfizer in 2018.
The gene therapy has received the designations of breakthrough therapy, regenerative medicines advanced therapy, and orphan drug in the U.S. for treating hemophilia B. It also won orphan drug and priority medicines (PRIME) status in the European Union (EU). These designations are expected to accelerate its development via a number of incentives.
Fidanacogene elaparvovec is being reviewed for approval in the U.S. and EU. A decision by the U.S. Food and Drug Administration is expected in the second quarter of 2024. The European Medicines Agency should announce its decision in January 2024.
Therapy snapshot
Treatment name: | Fidanacogene elaparvovec |
Administration: | Being tested in hemophilia B as a one-time intravenous infusion |
Clinical testing: | Previously tested in a Phase 1/2 trial; Phase 3 study ongoing |
How does fidanacogene elaparvovec work in hemophilia?
Hemophilia B is caused by mutations in the F9 gene, which carries instructions to produce factor IX (FIX), a clotting factor needed to form blood clots to stop bleeding. Mutations in the gene result in a faulty or missing FIX protein, which causes clotting problems. As a result, people with hemophilia B may have recurrent bleeding episodes that can be difficult to control.
Fidanacogene elaparvovec is a gene therapy candidate designed to deliver a highly functional version of F9 to liver cells, the main producers of clotting factors. The working gene is packaged inside an engineered delivery vector called adeno-associated virus (AAV)-Spark 100.
The F9 gene in this therapy is called Padua and occurs naturally. It contains a single mutation that makes an FIX protein with 8-12 times greater clotting activity than the normal protein, enabling a lower dose to achieve a therapeutic effect.
When given as an infusion into the bloodstream, the vector heads toward the liver and delivers its payload to liver cells, which will use the gene’s instructions to make FIX on their own. This is expected to raise the levels of working FIX and reduce the risk of bleeding events.
How will fidanacogene elaparvovec be administered in hemophilia?
In clinical trials, fidanacogene elaparvovec has been administered as a single intravenous infusion at a dose of 5×1011, or 0.5 trillion, vector genomes per kilogram of body weight (vg/kg).
Fidanacogene elaparvovec in clinical trials
The safety and pharmacological properties of fidanacogene elaparvovec were initially investigated in an open-label Phase 1/2a study (NCT02484092) involving 15 men with hemophilia B. The participants were required to have at least four bleeds a year, on average, that required on-demand or preventive treatment with FIX products.
All received a single administration of the gene therapy, given at a dose of 0.5 trillion vg/kg, but the last five participants were treated with an improved version. They were then followed for up to a year.
The participants are continuing to be followed in a long-term observational study (NCT03307980). This study includes a subgroup of patients who didn’t participate in the earlier trial and received a higher dose of the therapy.
Results announced in 2018, with a follow-up time of 5-121 weeks after treatment, showed average bleeding rates decreased by 98% within four weeks. Participants went from an average of 8.9 bleeds a year before receiving the gene therapy to only 0.2 bleeding episodes a year after treatment.
Participants also stopped taking their preventive FIX infusions and the need for infusions to control or prevent bleeds was reduced by 99%.
BENEGENE-2 Phase 3 trial
After the promising results from the Phase 1/2a trial, a Phase 3 clinical trial called BENEGENE-2 (NCT03861273) was launched to study the gene therapy in a larger population of hemophilia B patients. Pfizer’s applications for approving fidanacogene elaparvovec in the U.S. and Europe are based on data from this trial.
The study, which is still ongoing, is designed to enroll about 50 men with moderately severe to severe hemophilia B, meaning an FIX activity that’s 2% of normal or lower.
Participants first took part in a lead-in study (NCT03587116) where they were monitored for at least six months on standard replacement therapy prophylaxis (preventive treatment). They then received a single intravenous infusion of fidanacogene elaparvovec at a dose of 0.5 trillion vg/kg.
The trial’s main goal was to assess the gene therapy’s effect on bleeding rates. Bleeding rates during the six month lead-in study were compared with those observed from months three to 15 after the gene therapy, allowing three months for the therapy to take full effect.
Top-line results from the first 45 participants showed the average bleeding rate was 71% lower after the gene therapy treatment compared with the lead-in period (1.3 vs. 4.43 bleeds a year). The rate of bleeds that required treatment decreased by 78%, while the rate of replacement therapy infusions declined by 92%.
At two years after treatment, the average FIX activity in the treated patients was 25% of normal. For context, FIX activity between 5% and 40% is considered mild hemophilia B. Patients with these values usually don’t have spontaneous bleeds and only have noteworthy bleeding with an injury or during surgery.
The participants will be evaluated for up to 15 years to assess long-term safety outcomes.
Common side effects of fidanacogene elaparvovec
The most common side effect in clinical trials related to fidanacogene elaparvovec was an elevation of liver enzymes, which is generally indicative of damage to the liver.
In the Phase 3 BENEGENE-2 clinical trial, two serious side effects related to fidanacogene elaparvovec were reported. One patient who was also taking corticosteroids at the time experienced bleeding in the digestive tract and anemia, and another had elevated liver enzymes. Increased liver enzymes were also reported in two patients who took part in the Phase 1/2 study.
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