#ISTH2020 – Gene Therapy SPK-8011 Lowers Bleeding Rate in Hemophilia A for up to 3 Years, Trial Shows

A single dose of the investigational gene therapy SPK-8011 is safe and leads to durable production of factor VIII (FVIII) for up to three years, effectively lowering the frequency of spontaneous bleeds in men with hemophilia A, preliminary data from a Phase 1/2 trial show.

The findings were presented by Lindsey George, MD, from the University of Pennsylvania and Children’s Hospital of Philadelphia, at the 2020 Congress of the International Society on Thrombosis and Haemostasis, which is being held virtually this week. Her oral presentation was titled “Phase I/II Trial of SPK-8011: Stable and Durable FVIII Expression for >2 Years with Significant ABR Improvements in Initial Dose Cohorts Following AAV-Mediated FVIII Gene Transfer for Hemophilia A.”

SPK-8011 is an experimental gene therapy for hemophilia A currently being developed by Spark Therapeutics. It uses a harmless, modified version of an adeno-associated viral vector (AAV) to deliver the genetic information required for producing FVIII — the blood clotting protein missing in people with hemophilia A — in the liver.

By doing so, SPK-8011 aims to restore the production of FVIII in the body, reducing or eliminating the need for repeated infusions of FVIII throughout the patient’s life.

A Spark-sponsored Phase 1/2 trial (NCT03003533) is investigating the safety and efficacy of a one-time intravenous administration (directly into the bloodstream) of three different doses of SPK-8011 — 5×10¹¹ vector genomes (vg)/kg, 1×10¹² vg/kg, and 2×10¹² vg/kg — in men with hemophilia A, whose FVIII activity levels are up to 2% of normal levels.

After completing one year of follow-up, patients will enroll in a long-term extension study (NCT03432520) to be monitored for an additional period of four years.

Earlier data from the first 12 participants indicated that SPK-8011 was safe, reducing the frequency of annual bleeding episodes by 94%, and the need for FVIII infusions by 95% across all doses, four weeks after treatment.

New findings from the study and its long-term extension included data from 14 men (ages 18 to 52) who received one of the three doses of SPK-8011 and were followed for 14–40 months. Results showed that none of the participants experienced treatment-related adverse events or serious adverse events since the last study update.

Likewise, none of the patients developed neutralizing antibodies against FVIII, which may render the therapy ineffective. No deaths have been reported in the study.

An early analysis performed in the five men who received SPK-8011 at a dose of 5×10¹¹ vg/kg or 1×10¹² vg/kg showed treatment led to a durable and stable production of FVIII in the liver that lasted up to 3.3 years.

“This to me is a very important observation in the field because it suggests that hepatocyte expression [liver cell production] of factor VIII after AAV gene transfer can be stable and durable over time, and supports that this is a viable approach for hemophilia A gene transfer efforts,” George said in an interview following her presentation.

From the nine patients who received the highest dose of SPK-8011, seven showed sustained production of FVIII in the liver. Also, five of these men experienced no bleeding episodes during follow-up.

Two patients in this group, who received steroids to prevent immune response against the outer shell (capsid) of the therapy’s viral vector, showed abnormally high activity of FVIII, which was resolved by gradually tapering of steroids.

In addition, from the five men in the highest dose group who received steroids, two stopped producing FVIII and had to re-initiate prophylactic treatment with FVIII or Hemlibra (emicizumab). The other three continued producing FVIII after stopping steroids.

Data from the 12 patients, whose levels of FVIII remained stable over the course of the study and were eligible for efficacy analyses, demonstrated that SPK-8011 lowered the frequency of annual bleeds by 91%, and the rate of annual FVIII infusions by 96%.

The investigators added that “optimal vector dose and immune suppression regimens, including alternatives to daily steroid use,” are being explored in the study “to optimize predictable, safe, effective, and durable FVIII expression.”