To stem the bleeding Spark's pivotal trial needs to catch fire

Lower factor expression and immune reactions hand big lead to rival Biomarin.

Perhaps if Biomarin had not already blazed a trail on a haemophilia A gene therapy Spark’s emerging data with a rival project would be seen as a breakthrough. As it is, SPK-8011 looks like a less effective alternative with a vanishingly small therapeutic window owing to an immune response.

This has not dissuaded Spark from forging ahead with a phase III trial later this year relying on a prophylactic steroid regimen to counter adverse events and perhaps counting on Biomarin to trip up on the way to its own pivotal readout. Investors put more faith in the latter company, however, pushing its shares up 8% yesterday as Spark’s fell 28%.

Proactive, not reactive

An update on the phase I/II trial of SPK-8011, which came as Spark announced its second-quarter earnings yesterday, revealed that five of seven patients taking the highest dose tested, 2x1012vg/kg, achieved factor VIII expression of 30% of normal, on average.

Had it not been for the two other patients in this group the result would probably have been viewed positively, as it exceeded the minimum bar of 12%, the level above which spontaneous bleeds do not occur. But the two remaining subjects experienced an immune response that dropped factor expression to less than 5%, and one ended up in hospital to receive intravenous methylprednisolone infusions after he did not respond to oral steroids.

Across the total 12 patients in the trial's three dose cohorts, a 97% reduction in annualised bleeding and infusion rates was achieved. However, seven patients had to take a tapering course of oral steroids in response to liver enzyme elevations, declining factor VIII levels or positive IFN-g enzyme-linked immunospots, a measure of cytokine releasing cells.

Katherine High, Spark’s president and R&D head, said these immune responses had been triggered by the viral capsid, not the gene itself, and that they declined as the virus was cleared from the liver. It is difficult to detect this problem before factor VIII expression drops, however, so as a precaution the company plans to administer steroids prophylactically in phase III, much as it does with the approved gene therapy Luxturna.

Race to the market

Annualised bleeding and infusion rates shrank drastically in SPK-8011 patients who saw increases in factor VIII expression. However, it is hard to escape the conclusion that Biomarin’s valoctocogene roxaparvovec (valrox) has a better-looking profile, and has the advantage of already having started phase III trials.

Valrox has achieved much higher factor VIII expression and its pivotal trials do not involve steroid prophylaxis. Patients in valrox’s early-stage trials, who received more than 10 times the amount of vector than is used in SPK-8011, reached near-normal, or sometimes above normal levels of factor VIII expression, although this appears to wane over time, raising questions about durability (Snippet roundup: Biomarin gets a double dose of doubt, May 25, 2018).

High vector levels could raise the risk of thromboembolic events, which Spark claims it is trying to avoid. “From autopsy data we know that men with haemophilia develop atherosclerosis,” Ms High told EP Vantage. However, haemophiliacs are protected from cardiovascular events by suppressed clotting, and higher factor VIII expression increases the cardiovascular risk.

“I think there’s a differential risk here around [vector] levels that are too high,” she said. “To me the risk of levels that are too high is greater than the risk around levels that are too low.”

Spark now needs its project to storm forward with no further hiccups. Importantly, the US FDA still needs to signal its comfort with the company's pivotal programme – the immune reactions seen could easily prompt further questions from the regulator.

A Stifel analyst, Paul Matteis, acknowledged that Biomarin’s programme, despite its lead, was not without risk because of the unclear durability and the risk of thrombotic events. Forecasts for haemophilia A gene therapies push $2bn in 2024. While the data so far flatter valrox, this race is far from over.

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