Hemophilia Gene Therapy Looks Like a Winner

An investigational gene therapy for hemophilia A showed good results in 16 of 18 patients treated in a phase I/II study and followed for up to 4 years, researchers said.

Levels of factor VIII (the clotting factor missing in hemophilia A) were boosted rapidly after administration of the vector-delivered agent, called SPK-8011, and remained elevated in these responders, according to Lindsey A. George, MD, of the University of Pennsylvania in Philadelphia, and colleagues.

Clinical outcomes were also excellent, the group reported in the New England Journal of Medicine. Annualized rates of bleeding events fell by an average of 91.5% from pretreatment baseline (95% CI 88.8%-94.1%) in the 16 responders. Clinicians determined that all 16 no longer needed prophylactic factor VIII infusions, and these were discontinued.

However, the other two patients fell victim to immune responses to the adeno-associated virus (AAV) capsid that served as the vector. These patients showed increases in factor VIII levels initially that dropped off within a few months. George and colleagues were prepared for this possibility and administered glucocorticoids to some participants, either to prevent this immune attack or to shut it down. In these two patients, however, the steroids showed no effect.

Significantly, perhaps, both of these patients also experienced the worst short-term reactions to the treatment. One suffered vomiting, muscle and back pain, and fever shortly after receiving the infusion, which took 3 days to resolve; the other experienced an alanine aminotransferase (ALT) elevation above three times the upper limit of normal and was hospitalized (at the patient's request) for intravenous steroid treatment. This latter reaction was the only one the investigators rated as serious.

Six other patients had transient and mostly milder ALT elevations. George and colleagues attributed these events as signs of cellular immune responses to the AAV capsid protein, which resolved with steroid treatment. Yet the steroids, too, caused problems in four participants, with symptoms including weight gain, edema, irritability, and adrenal insufficiency. Some patients with anti-therapy immune responses received other immunosuppressants such as azathioprine, which the researchers suggested might be the better way to go in the future.

Overall, the researchers determined that SPK-8011 posed "no major safety concerns." The investigators were reserved, though, in their conclusions regarding efficacy, calling the findings "support" for the treatment as "a viable approach for long-term stable phenotypic amelioration of hemophilia A."

Data came from two ongoing studies: one, with recruitment still underway, with an eventual target enrollment of 30 patients; and another with recruitment by invitation, for which the treatment's developer, Spark Therapeutics, hopes to include 100 patients. Spark expects to complete both studies by December 2022, according to the Clinicaltrials.gov listings.

The 18 patients in the study were adult men, ranging in age from 18 to 52, with factor VIII activity below 2% of normal (it was less than 1% in 17 patients). More than a dozen different hemophilia A genotypes were represented. Thirteen were receiving factor VIII infusions on a regular schedule, while the other five took them as deemed necessary.

Four doses were tested in the trial, from 5×10¹¹ to 2×10¹² vector genomes per kg of body weight. The vector was an engineered AAV3 capsid plus a liver-specific enhancer and promoter intended to concentrate the factor VIII genetic payload's expression in hepatocytes.

After dosing, all participants showed substantial factor VIII expression, at least initially. Follow-up ranged from 5.5 to 50.3 months, for a mean of 36.6 months. Mean factor VIII activity at 1 year was 11.0% of normal (range 3.2%-24.8%) among the 15 participants evaluated at that time, using a one-stage assay. With a chromogenic assay, factor VIII activity averaged 6.9% (range 3.0%-14.3%). Higher peak levels were seen with the higher doses, but no dose-response was seen after 1 year.

Twelve patients had follow-up of more than 2 years, and substantial factor VIII in these individuals was maintained, George and colleagues reported. Bleeding events were drastically reduced from baseline: prior to enrollment, annualized rates were 8.5/year, which fell to 0.3/year after dosing. Most had no bleeding events from year 1 onward. Rates of factor VIII infusion showed similar large decreases.

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