Giroctocogene fitelparvovec for hemophilia

Last updated Jan. 11, 2024, by Margarida Maia, PhD
Fact-checked by Inês Martins, PhD

What is giroctocogene fitelparvovec for hemophilia?

Giroctocogene fitelparvovec, formerly known as SB-525 or PF-07055480, is a gene therapy being developed to reduce the risk of bleeding episodes in people with hemophilia A.

Given as a single intravenous or into-the-vein infusion, the medication is designed to provide a functioning copy of the F8 gene, which is mutated in hemophilia A patients, leading to blood-clotting problems.

It initially was developed by Sangamo Therapeutics in collaboration with Pfizer, though in 2020, Pfizer became responsible for leading the gene therapy’s Phase 3 clinical development.

Giroctocogene fitelparvovec has been granted orphan drug, fast track, and regenerative medicine advanced therapy designations in the U.S., all designed to speed the regulatory process. It also has been granted orphan medicinal product designation in Europe.

Therapy snapshot

How does giroctocogene fitelparvovec work in hemophilia?

Hemophilia A is caused by mutations in the F8 gene, which provides instructions for making a blood clotting protein called factor VIII (FVIII). As a result of these mutations, FVIII is either missing or defective, and patients are unable to form blood clots to stop bleeding. Thus, people with hemophilia A may experience heavy, prolonged bleeding episodes, either spontaneously or following an injury or surgery, that are difficult to control.

Giroctocogene fitelparvovec is designed to deliver a shorter but working version of the F8 gene to liver cells, which are the main producers of clotting factors in the body. The gene is packaged inside a viral vector that is more specific to the liver and acts as a delivery vehicle to those cells.

The viral vector used in giroctocogene fitelparvovec is derived from the adeno-associated virus serotype 6, known as AAV6, which does not cause disease in humans. Once the genetic cargo is unloaded from the vector, liver cells can start producing FVIII on their own. This is expected to increase FVIII levels in the bloodstream, thus helping to prevent and control bleeding episodes in people with hemophilia A.

How will giroctocogene fitelparvovec be administered in hemophilia?

In clinical trials, giroctocogene fitelparvovec has been given as a single intravenous infusion. Its doses ranged from 9×10¹¹, or 0.9 trillion vector genomes per kilogram of body weight (vg/kg), to 3×10¹³, or 30 trillion.

Giroctocogene fitelparvovec in hemophilia clinical trials

Giroctocogene fitelparvovec is being investigated in two studies: a Phase 1/2 clinical trial (NCT03061201), called Alta, and the AFFINE Phase 3 clinical trial (NCT04370054).

Alta Phase 1/2 trial

The Alta clinical trial, ongoing at multiple sites in the U.S., is testing the safety and efficacy of giroctocogene fitelparvovec over five years in 11 men with severe hemophilia A. For each patient, FVIII activity was below 1% of normal.

The participants, ages 19 to 47, had all previously received preventive or on-demand replacement therapy to temporarily supply the missing FVIII.

As part of the clinical trial, each was given a one-time intravenous infusion of the gene therapy at one of four doses. Specifically, two patients each received doses of 0.9 vg/kg, 2 vg/kg, or 10 vg/kg, while five patients were given a dose of 30 vg/kg. Some patients received corticosteroids after dosing if they had any signs of liver damage, indicating a possible immune response against the vector.

An initial analysis six months later showed giroctocogene fitelparvovec was generally well tolerated and resulted in dose-dependent increases in FVIII activity levels across all doses.

The strongest results were seen in participants given the 30 trillion dose, all of whom reached steady-state levels of FVIII (median 56.9% of normal) after nine weeks. These levels were sustained for up to 1.5 years, at 48.9% of normal.

While none of these patients experienced bleeding episodes or needed replacement therapy for at least one year, their FVIII levels dropped to 25.4% of normal at two years, and two patients experienced bleeds that required FVIII infusions after 16 months.

The latest analyses were conducted after patients had been followed for up to 214 weeks, or about 4.1 years. These results indicated that, among the entire group of patients, bleeding rates dropped from 7.5 bleeds per year prior to the gene therapy to 2.7 bleeds per year during the follow-up.

That reduction was again particularly stronger in the group given the highest dose, who had experienced a mean of 8.8 bleeds in the year before treatment and had 0.7 bleeding episodes per year after receiving the gene therapy.

The trial is still following patients to continue assessing the therapy’s long-term safety and efficacy. It’s expected to conclude in June 2024.

AFFINE Phase 3 trial

After promising six-month data from Alta were released, Pfizer launched a lead-in Phase 3 clinical trial (NCT03587116) ahead of a registrational trial to collect safety and efficacy data with usual treatment with FVIII prophylaxis replacement therapy, prior to treatment with giroctocogene fitelparvovec.

The lead-in study enrolled 213 people, ages 18-65, with moderately severe to severe hemophilia A, defined as FVIII activity levels of 1% of normal or lower. As in the previous trial, all were required to have received FVIII therapy for at least 150 days prior to enrollment.

Participants who completed six months of routine prophylaxis therapy during this study could then enter the AFFINE trial, where all received a single infusion of giroctocogene fitelparvovec. A total of 68 men, ages 18 to 64, are taking part in this trial and will be monitored for five years.

The trial’s primary goal is to compare the annualized bleeding rate, or the number of bleeds per year, in the 15 months following treatment with that observed during the lead-in study. Secondary measures include FVIII levels, need for replacement therapy, joint health, and patient-reported quality of life. Safety also will be monitored for up to five years.

Patient screening and dosing was voluntarily paused by Pfizer in 2021 after some patients showed FVIII levels higher than 150% of normal, which may increase the risk of blood clots. While no side effects related to increased FVIII levels were reported, the company implemented a protocol amendment to provide guidance on how to manage patients with elevated FVIII levels.

As a result, U.S. Food and Drug Administration (FDA) placed on a clinical hold on the trial, forcing a pause on recruitment and dosing in AFFINE while the agency reviewed changes to the protocol.

Enrollment resumed about one year later with an updated protocol, after the FDA lifted the clinical hold. Top-line data from the trial are expected in late 2024, and the study is slated to conclude in 2028.

Common side effects of giroctocogene fitelparvovec

In the Phase 1/2 Alta trial, the most common treatment-related side effect was an elevation in the level of certain liver enzymes, a sign that the liver may be damaged, which was treated with corticosteroids.

Other side effects that emerged after giroctocogene fitelparvovec treatment during this trial included:

• respiratory tract infections
• fever
• ear infection (otitis media)
• headache
• joint pain
• skin laceration
• falls
• throat pain
• low levels of immune cells
• elevated heart rate
• low blood pressure.

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