Ash 2017 – Spark extinguished by Biomarin haemophilia data

Biomarin’s lead in haemophilia A gene therapy has been confirmed by rival Spark Therapeutics, which disappointed investors on Monday with underperforming data for SPK-8011.

The duelling presentations at Ash revealed that Biomarin’s high-dose strategy has helped haemophilia patients achieve normal levels of factor VIII expression, while Spark’s more cautious approach has delivered some mixed results. Shares went in opposite directions: Biomarin ended the day up 7%, while Spark closed down 35%, losing $1bn of its valuation.

Good, but not good enough

Biomarin’s data for valoctocogene roxaparvovec were previewed to the press over the weekend, and Ash was waiting to hear updated data from Spark – its submitted abstract only contained data from three patients with a maximum of five months’ follow-up. Seven patients have now been infused with SPK-8011, and some follow-up has been completed for four, out to a maximum of 40 weeks.

It was clear that Spark’s agent improved clotting factor VIII expression over baseline. However, patients were only typically reaching levels that prevent spontaneous bleeds, as opposed to the normal expression achieved by Biomarin, and an unexplained variability in expression and lack of clear dose response raised questions over SPK-8011’s effectiveness.

The third and fourth patients enrolled – who received the higher of two doses – saw their factor VIII levels drop, prompting a round of prednisone therapy in order to try to rectify this. Both saw their expression levels decline as they were weaned from the prednisone.

The second patient, on the lower dose, saw a surprising and rapid rise in factor VIII levels after 24 weeks, and at data cutoff had the highest levels of any of the patients.

Leerink analyst Joseph Schwartz wrote that Spark had indicated that the patients on the higher dose had seen a doubling in their factor VIII expression, but now the data show that initial response “has been followed by an early plateauing effect and/or week-to-week variability for unknown reasons”.

Two of the three that have undergone SPK-8011 treatment, but for whom Spark did not present data, received a dose double that of patients three and four.

Threading the needle

Spark had made a decision to try to reach a factor VIII expression level that prevented spontaneous bleeds, but not the normal level sought by Biomarin, reasoning that the odds of thrombosis rise when factor VIII levels exceed 100IU/dl.

Many of Biomarin’s patients taking the highest dose of valoctocogene roxaparvovec, or valrox, reached factor VIII levels above that 100IU/dl threshold, though those at a lower dose did not (Ash 2017 – Biomarin breaks away in haemophilia A gene therapy chase, December 9, 2017).

That could be because patients treated with valrox were dosed at 20 to 30 times the number of vector genomes as those given the highest dose of SPK-8011. This, of course, means it runs the risk of being a much costlier treatment, and payers could argue that the higher level of factor VIII expression achieved by valrox is not necessary to improve outcomes.

Moreover, while the Biomarin presentation did not reveal any thrombotic events, this side effect will be worth watching, especially as the same two doses will be tested in phase III.

Achieving normal levels of factor VIII expression now appears to be the expectation in haemophilia A. It will be interesting to see how followers like Spark, Sangamo and Shire begin to adjust the clinical strategies for their gene therapy candidates as they attempt to match valrox.

This story has been updated to reflect the closing share prices for Spark and Biomarin.

To contact the writer of this story email Jonathan Gardner in Atlanta at or follow @ByJonGardner on Twitter

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