Gene Therapy SPK-8011 Prevents Bleeds Up to 4 Years

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A single dose of Spark Therapeutics’ investigational gene therapy SPK-8011 safely and effectively prevented bleeding episodes and the use of clotting factor VIII (FVIII) for up to four years in men with hemophilia A, according to the latest data from a Phase 1/2 trial and its extension study.

These benefits, observed so far in 16 of the 18 treated patients, were associated with sustained production of FVIII, the clotting factor missing in people with hemophilia A, the new data show.

“We are encouraged by the results from the phase 1/2 trial for investigational SPK-8011, which has been evaluated in the largest phase 1/2 gene therapy trial in this disease to date, and demonstrates continued response over time, a critical measure of a therapy’s potential to transform lives for people living with this chronic condition,” Gallia Levy, MD, PhD, Spark’s chief medical officer, said in a press release.

“We remain focused on optimizing the dose and immunomodulatory regimen in the phase 1/2 study and look forward to continuing our evaluation of this therapy in a Phase 3 study,” Levy added.

These findings were shared by Lindsey A. George, MD, the trial’s principal investigator, in an oral presentation at the International Society on Thrombosis and Haemostasis 2021 Virtual Congress, hosted in Philadelphia and held online July 17–21.

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The presentation by George, of the Perelman School of Medicine at the University of Pennsylvania, and the Children’s Hospital of Philadelphia, known as CHOP, was titled “Phase I/II Trial of SPK-8011: Stable and Durable FVIII Expression After AAV Gene Transfer for Hemophilia A.”

SPK-8011 uses a modified and harmless version of an adeno-associated virus (AAV) to deliver a working copy of the F8 gene — which provides instructions for making FVIII — to liver cells, the main producers of clotting factors in the body.

Given through a single infusion directly into the bloodstream, the therapy is expected to restore FVIII production, thereby reducing or eliminating bleeding episodes and the need for lifetime FVIII replacement therapies.

Both the U.S. and European regulatory agencies have granted SPK-8011 orphan drug status, and it also has received breakthrough therapy designation in the U.S. for the treatment of hemophilia A. These designations are meant to accelerate the therapy’s development and regulatory review.

The ongoing Phase 1/2 trial (NCT03003533) is evaluating the one-year safety and effectiveness of different doses of SPK-8011 in up to 30 men with hemophilia A. The trial is still recruiting at sites in the U.S. and Australia; more information can be found here.

After completing the one-year follow-up, participants can choose to enroll in a long-term extension study (NCT03432520), in which they will be monitored for four additional years.

Previous three-year data from the first 14 men treated in the Phase 1/2 trial, all of whom entered its extension study, showed the therapy was generally well-tolerated and sustainably raised FVIII activity levels.

Two participants stopped producing FVIII due to a presumed immune response against the therapy’s viral carrier that could not be prevented with standard immunosuppressive treatment. These patients had to re-initiate preventive FVIII treatment or Hemlibra (emicizumab).

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Emerging From the ‘Longest Bleed Ever’

In the 12 patients who achieved steady FVIII production, SPK-8011 reduced the annualized bleeding rate (ABR) by 91% and the annualized FVIII usage by 96%.

The newly presented data concerned results from 18 men who received one of four doses of SPK-8011 — ranging from 5×1011 vector genomes per kilogram (vg/kg) to 2×1012 vg/kg — and who were followed for up to four years post-dosing.

As of May 3, no additional participants stopped producing FVIII, and the single dose of SPK-8011 resulted in sustained FVIII levels in 16 of the 18 patients.

These 16 patients also experienced a 91.2% drop in ABR and a 97% reduction in annualized FVIII infusions.

SPK-8011 continued to be generally safe and well-tolerated with longer follow-up, with no deaths or detection of antibodies against FVIII reported.

In addition to the immune reactions against AAV in two men, other side effects were detected in seven participants. These men experienced temporary mild-to-moderate increases in liver enzymes, a potential sign of liver damage that often occurs with gene therapy.

None of these seven patients showed symptoms of liver damage, but one man with moderate increases in one liver enzyme had to be hospitalized to receive intravenous (into-the-vein) immunosuppressive treatment, therefore qualifying as a serious adverse event.

One participant had a mild-to-moderate, non-serious infusion reaction, with fever, vomiting, and muscle and back pain, which also was resolved.

These findings emphasize that SPK-8011 results in sustained FVIII production, controlling bleeds and reducing FVIII usage for up to four years post-dosing in men with hemophilia A. According to investigators, these results support the therapy’s long-term favorable safety and effectiveness profile.