Potential Gene Therapy SPK-8011 Fares Well in Hemophilia A Study

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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A single dose of Spark Therapeutics’ investigational gene therapy SPK-8011 increased the levels of factor VIII (FVIII) — the missing clotting protein in hemophilia A — and, in 16 of 18 male patients, those levels were sustained for up to four years, according to results from a Phase 1/2 clinical trial and its extension study.

Notably, the sustained FVIII levels allowed the discontinuation of prophylaxis, or preventive FVIII therapy, and resulted in a pronounced reduction or complete elimination of bleeding episodes.

Also, this FVIII level stability stands out from results of previous trials of Roctavian, another experimental gene therapy for hemophilia A, showing that, following a sharp increase, FVIII levels started to decline after a year and up to four years.

This raised the possibility that gene therapy for hemophilia A, which typically works by delivering a working version of the disease-causing faulty F8 gene to cells, may not be able to provide sustained FVIII production. F8 is the gene that provides instructions for making FVIII.

These findings “offer compelling data to support the current approach to hemophilia A gene transfer can indeed confer stable factor VIII [production] over multiple years for near disease ameliorating effect,” Lindsey A. George, MD, said in a press release. George is the trial’s principal investigator at the Children’s Hospital of Philadelphia (CHOP).

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“These data build on the decades-long history of hemophilia gene therapy research at Children’s Hospital of Philadelphia, which has sought to bring curative therapies to these patients,” added George, who also is director of CHOP’s clinical in vivo gene therapy. Of note, Spark Therapeutics originally was spun off from CHOP in 2013.

“Future research will aim to further improve on this work to safely achieve sustained, stable, and predictable FVIII levels in all hemophilia A patients,” George said.

Trial findings were detailed in the study, “Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A,” published in The New England Journal of Medicine.

SPK-8011 is designed to increase the production of FVIII by providing a healthy copy of F8 specifically to liver cells, the body’s main producers of clotting factors. A modified and harmless version of an adeno-associated virus (AAV) is used to carry and deliver the gene.

By restoring FVIII production, the therapy, administered through a single infusion directly into the bloodstream, is expected to reduce, or possibly eliminate, bleeding events and the need for lifetime FVIII replacement therapies.

SPK-8011 was granted orphan drug status in both the U.S. and Europe, as well as breakthrough therapy designation in the U.S., for the treatment of hemophilia A. These designations are meant to speed the therapy’s clinical development and regulatory review.

The ongoing Spark-funded Phase 1/2 trial (NCT03003533) is assessing the one-year safety and effectiveness of different doses of SPK-8011 in up to 30 men with hemophilia A.

After completing the trial, participants can choose to enter a long-term extension study (NCT03432520), in which they will be monitored for four years, totaling five years of follow-up post-dosing.

The newly published data, with a cut-off date of May 3, concerned the 18 participants (ages 18–52 years) who received one of four doses of SPK-8011, ranging from 5×1011 vector genomes per kilogram (vg/kg) to 2×1012 vg/kg.

Men were followed for a median of 36.6 months, or about three years (range, 5.5 months to four years). One patient was lost to follow-up 32.6 months after dosing. Prior to the study, 13 participants (72%) were on preventive FVIII therapy, while the remaining five were receiving replacement therapy on demand.

Most men (72%) were given standard immunosuppressive treatment (steroids) within one year after SPK-8011 to prevent or treat a presumed immune response against the therapy’s viral carrier. This response is a common adverse side effect of virus-based gene therapies that can limit their effectiveness.

Results showed the therapy was generally safe and well-tolerated, with no deaths or detection of antibodies against FVIII, which, in worst cases, can render treatment useless.

A total of 33 SPK-8011-related adverse events were reported in eight men: 17 were linked to immune reactions against the viral carrier, including one serious adverse event that was resolved with appropriate care; and 16 were associated with steroid treatment.

While the suspected immune response did not result in major safety concerns, it limited SPK-8011’s efficacy in two men given the highest dose, who stopped producing FVIII within one year, despite steroid treatment. One of them re-initiated preventive treatment and the other was started on Hemlibra (emicizumab).

This highlighted that immune responses against SPK-8011’s viral carrier are not “universally sensitive” to steroids, the team wrote.

The remaining 16 men showed sustained FVIII levels throughout follow-up. Among the 12 who were followed for more than two years, mean FVIII activity was 12.9% of the normal value between six and 12 months post-dosing, and 12% after one year, suggesting there is no decline in FVIII levels over time.

All of these 16 men became free from prophylaxis.

Overall, SPK-8011 treatment reduced the annualized bleeding rate by 91.5% and the annualized FVIII usage by 96.4%, both reaching median values below 1. That means patients experienced less than one bleed or used FVIII less than one time per year.

These findings “support our hypothesis that liver-directed AAV gene therapy is a viable approach for long-term treatment of hemophilia A,” George said.

The data also “began to answer questions that have emerged from previous trials of AAV-mediated gene transfer for hemophilia A” regarding their long-term effects, the team wrote, adding that “close monitoring of participants to determine safety and efficacy and to confirm initial multiyear observations of durable [effects] are ongoing.”

“The safe achievement of sustained, stable, and predictable factor VIII levels in all participants, even in the presence of immune responses, remains an unrealized goal of gene therapy for hemophilia A,” the researchers wrote.

“Potential solutions are under investigation,” they added, noting that these may include the use of AAVs that are less likely to promote immune reactions, modified versions of F8 that promote stronger FVIII production, or improved immunosuppressive regimens, “or all of these.”