SPK-8011 for hemophilia

Last updated Aug. 1, 2024, by Margarida Maia, PhD
Fact-checked by Joana Carvalho, PhD

What is SPK-8011 for hemophilia?

SPK-8011, also known as dirloctocogene samoparvovec, is an experimental gene therapy for hemophilia A. Given as a one-time intravenous, or into-the-vein, infusion, it aims to reduce the risk of bleeding in patients.

The therapy is being developed by Spark Therapeutics, now part of Roche.

SPK-8011 has been granted orphan drug designation in the U.S. and Europe for the treatment of hemophilia A. It also received breakthrough therapy designation in the U.S. for the same indication. These designations are expected to accelerate the therapy’s development via a number of incentives including, in the case of orphan drug status, a period of market exclusivity if it’s approved by regulators.

Therapy snapshot

How does SPK-8011 work in hemophilia?

Hemophilia A is caused by mutations in the F8 gene, which provides instructions for making factor VIII (FVIII), a clotting protein found in the bloodstream. When FVIII is faulty or missing, the blood cannot clot properly to stop bleeding. As a result, people with hemophilia A may experience heavy, longer-than-usual bleeding episodes that can be difficult to control.

SPK-8011 is designed to deliver a shorter, but functional version of the F8 gene to liver cells — the body’s main producers of clotting factors. This alternative version of the F8 gene is packaged inside a delivery vehicle called a vector. The vector used in SPK-8011 is derived from a virus called adeno-associated virus 3 (AAV3), which is harmless to humans. 

When given as an infusion directly into the bloodstream, SPK-8011 is designed to target the liver. Once there, the working gene is unloaded from the vector, and liver cells use its instructions to make FVIII on their own. This is expected to increase FVIII levels in the blood, helping to prevent and control bleeding episodes in hemophilia A patients.

How will SPK-8011 be administered in hemophilia?

In clinical testing, SPK-8011 has been given as a single intravenous infusion at doses ranging from 5×10¹¹, or 0.5 trillion, vector genomes per kilogram of body weight (vg/kg) to 2×10¹² vg/kg, or 2 trillion.

SPK-8011 in hemophilia clinical trials

A Phase 1/2 clinical trial (NCT03003533) tested the safety and efficacy of SPK-8011 in about 30 men with hemophilia A. The men’s FVIII activity levels were no greater than 2% of normal. All had previously received preventive or on-demand replacement therapy, a standard hemophilia treatment, to supply the faulty or missing FVIII.

As part of the clinical trial, participants were given a one-time intravenous infusion of SPK-8011 at one of four doses, ranging from 0.5 to 2 trillion vg/kg. Some patients received corticosteroids within 52 weeks, or one year, after dosing to prevent or treat a possible immune response against the vector.

Those who completed the 52-week clinical trial could then roll over into a long-term extension study (NCT03432520), where they are being followed for an additional four years.

An interim analysis of the first 18 men who received the gene therapy, with a data cut-off of May 2021, showed that FVIII levels increased and remained elevated in 16 of the evaluable patients. All 16 men with sustained FVIII levels stopped their routine prophylaxis (preventive) treatment.

Among these men, 12 were followed for more than two years; their FVIII levels increased from no greater than 2% to an average of 12% after one year.

The median annualized bleeding rate was reduced by 91.5% — from 8.5 bleeds per year before treatment to 0.3 bleeds per year after the infusion of SPK-8011. The median annualized number of FVIII infusions also was reduced, by 96.4%, specifically from 57.5 to 0.6 infusions per year.

At a median follow-up of 36.6 months, or about three years, 33 treatment-related side effects were reported in eight men. Of these, 17 were deemed related to an immune response against the vector and 16 were related to treatment with corticosteroids. Two men given the highest dose of SPK-8011 stopped producing FVIII within one year due to an immune response against the vector, which occurred despite immunosuppressive treatment with corticosteroids.

Five-year results involving 23 men who received SPK-8011 in the trial and then entered its extension study showed that 21 of them had sustained, elevated FVIII levels. The annualized bleeding rate was reduced by 92%, and most of the men (90%) had less than one spontaneous bleeding episode per year requiring treatment.

Ongoing trials

Roche has launched a Phase 3 clinical trial, called KEYSTONE 1 (NCT06297486), that is recruiting up to 85 men with severe or moderately severe hemophilia A, whose FVIII levels are no greater than 3% of normal. Enrollment is open at a number of study centers across the U.S., with more sites expected to open. To be eligible, patients must have been treated with FVIII replacement therapies for at least 150 days, or about five four months, and test negative for FVIII inhibitors — neutralizing antibodies that may limit the efficacy of the clotting protein.

The main goal of the clinical trial, which is sponsored by Spark, is to test how well a one-time intravenous infusion of SPK-8011 prevents bleeding episodes in patients who were previously receiving either on-demand or prophylactic replacement therapy, or prophylaxis with Hemlibra (emicizumab), an approved antibody-based therapy marketed by Genentech, a subsidiary of Roche.

The primary outcome measure, the annualized bleeding rate, is being measured for up to 66 weeks, or about 15 months, in patients who have previously received prophylactic replacement therapy. Secondary outcome measures include assessing median FVIII levels, the proportion of patients with zero bleeding episodes, and annualized bleeding rate for spontaneous, joint, and target joint bleeding episodes for up to 10 years after infusion of SPK-8011. Other measures include evaluating the proportion of patients who receive intravenous methylprednisolone, a corticosteroid, in the first eight weeks after infusion of SPK-8011, and the proportion of patients who develop FVIII inhibitors. Side effects will be monitored for up to 10 years.

Common side effects of SPK-8011

The most common side effects that have been reported with SPK-8011 during clinical trials include:

• elevated liver enzymes, a sign that the liver may be damaged or inflamed
• fever
• muscle pain
• back pain
• vomiting.

Hemophilia News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.