Gene Therapy SPK-8016 Shows Early Promise for Severe Hemophilia A

A single dose of the experimental gene therapy SPK-8016 showed promising safety and efficacy in lowering the frequency of bleeds and the need for infusions in men with severe hemophilia A.

These preliminary findings from an ongoing Phase 1/2 trial (NCT03734588) were presented by Spencer Sullivan, MD, a researcher at the Mississippi Center for Advanced Medicine, at the European Association for Haemophilia and Allied Disorders 2021 Virtual Congress, held online Feb. 3–5.

SPK-8016 is an investigational gene therapy, developed by Spark Therapeutics, that is specifically designed to restore the production and activity of factor VIII (FVIII) in patients with FVIII inhibitors.

FVIII is the clotting factor missing or defective in patients with hemophilia A, causing them to experience spontaneous bleeds. Replacement therapies that provide patients with artificial forms of FVIII are often used as standard treatments for the condition. Yet, around 30% of patients receiving these treatments end up developing inhibitors (neutralizing antibodies) against FVIII, rendering them useless.

The Phase 1/2 trial is currently investigating the safety and efficacy of a single intravenous (into-the-vein) dose of SPK-8016 in adult men with severe hemophilia A, meaning FVIII activity levels lower than 1%, or levels from 1%–2% with more than 10 bleeding events per year or while receiving prophylaxis treatment.

In the first part of the study, the investigators will focus on assessing the safety and efficacy of the therapy in patients without FVIII inhibitors. Based on findings from this part, the investigators will then adjust the study’s design and therapy’s dosage for the second part of the study, where SPK-8016 will be given to patients with FVIII inhibitors.

Spark has now presented preliminary data from the first four patients who received a single SPK-8016 dose of 5×10¹¹ vector genomes per kilogram (vg/kg) in the first part of the study.

As of Oct. 26, 2020, patients saw their FVIII activity levels increase to 5.9%–21.8% and remain stable for more than a year, without experiencing serious side effects or starting to develop FVIII inhibitors.

Within a period of 15–18 months, SPK-8016 also lowered the annual rate of FVIII infusions by 98% and the annual rate of bleeds by 85%.

“Preliminary data from part one of the Phase 1/2 study of SPK-8016, on four participants who have no history of FVIII inhibitors, are very encouraging as we observe stable and durable FVIII activity with a safety profile supporting further evaluation at a very low vector dose,” Gallia Levy, MD, PhD, chief medical officer of Spark Therapeutics, said in a press release. “We are critically evaluating these data to plan the second part of the SPK-8016 study.”

The patient achieving the highest level of FVIII activity (21.8%) had never received treatment with an immunomodulatory agent. Three participants received oral corticosteroids three to six weeks following SPK-8016 administration due to a suspected immune response against liver cells. Two of these patients were also started on azathioprine and/or tacrolimus (two medications that lower the activity of the immune system) to spare their exposure to steroids.

No patient saw his liver enzymes persistently rise to an unhealthy level. However, one of the study participants experienced a temporary episode of transaminitis (high levels of liver enzymes) associated with azathioprine toxicity, which was resolved after this treatment was discontinued.

Mild-to-moderate side effects associated with the use of steroids were observed in the three patients who received immunomodulatory agents.