Spark’s hemophilia A data causes investor jitters

The company is trying to allay fears about variability in factor VIII levels.

Just over a week ago, Spark Therapeutics was riding high on positive data for its hemophilia B gene therapy. It’s now fallen back to earth after spooking investors with the results of a trial in hemophilia A.

Shares in the company fell more than a third after the results of the phase 1/2 trial of SPK-8011 in seven hemA patients were presented at the American Society of Hematology (ASH) meeting in Atlanta—and suggested that the gene therapy may not be as potent as a rival in development at BioMarin when it comes to increasing levels of factor VIII in patients.

Presenting data on four of seven patients treated in the trial at ASH, Spark highlighted a 100% reduction in annualized bleeding rates beginning four weeks after the gene therapy was delivered via infusion, as well as an annualized infusion rate reduction of 98%.

The trial is still trying to establish the best dose of SPK-8011, and two patients in the lower dose group saw levels of factor VIII—the missing clotting factor in hemA—rise to 10% and 37% respectively at the data cutoff on Dec. 6. Two patients on a midrange dose showed ranges of 7% to 24%, and there is no data yet on the highest dose tested.

Spark CEO Jeffrey Marazzo said that the results show there is some way to go with the program, but so far they include some positive findings.

“The factor levels are not yet where we'd like them to be,” he acknowledged on a conference call with analysts, but added: “We have a potent vector and a product candidate that works at generating therapeutic levels at low doses.”

Overall, the factor VIII levels seemed to be lower than those reported in the BioMarin trial of its candidate valoctocogene roxaparvovec, reported in the New England Journal of Medicine over the weekend. And questions have been raised about the variability of the factor VIII response observed with both therapies.

It’s worth noting that the jury is out just yet on what level of expression will translate into clinical efficacy in hemA, particularly as there tends to be a lot of variation in factor VIII levels between individuals and even in the same patient on different days.

That’s thought to be less of an issue in hemB, where Spark’s SPK-9001 candidate was able to achieve median increases to around 12% of circulating factor IX levels, which is considered high enough to ensure control of bleeds. There was however a threefold difference in expression levels even in this study, according to Katharine High, M.D., Spark’s head of R&D, suggesting this sort of variation between patients is a natural phenomenon.

Marazzo said it is important that the dose of SPK-8011 is scaled up slowly in the study to reduce the risk of blood clots, and a clearer picture of the therapy—including dose response—will be evident once the results are in for the remaining three patients.

“From a clinical outcome perspective, we're not seeing variability … in both the B and the A experience, albeit the A is earlier, we are seeing consistent results in terms of nearly eliminating bleeds and nearly eliminating need for infusions,” he stressed. “Ultimately the goal does need to be focused on the clinical outcome.”