Spark Therapeutics saw its share price tumble about 30% in early-morning trading after it reported mixed preliminary data this morning from a Phase I/II trial of its hemophilia A gene therapy candidate SPK-8001.

Shares of Spark fell 29%, to $55.03, as of 10:28 a.m., from yesterday’s closing price of $77.61. The selloff was touched off after Spark released second-quarter results in an announcement that included updates on its clinical programs.

“Based on the totality of the data in our Phase I/II clinical trial of investigational SPK-8011 for hemophilia A, we are pleased to announce our plans to initiate a Phase III run-in study in the fourth quarter of 2018,” Spark CEO Jeffrey D. Marrazzo said in a statement.

Following completion of the run-in study, Phase III participants are expected to receive 2×1012 vector genomes (vg)/kg of SPK-8011. Spark said additional details on the Phase III trial design will be determined following continued discussions with FDA and EMA, which are expected in the fourth quarter.

In the Phase I/II study, 12 participants received a single administration of investigational SPK-8011 as of the July 13, 2018, data cutoff. The 12 included two at a dose of 5×1011 vg/kg body weight, three at a dose of 1×1012 vg/kg and seven at a dose of 2×1012 vg/kg.

Spark emphasized positive results from the trial showing a 97% reduction in annualized bleeding rate (ABR) and a 97% reduction in annualized infusion rate (AIR) across all participants, at all three doses, beginning four weeks after vector infusion. The company also cited evidence of a dose-dependent increase in mean FVIII activity levels across the three dose cohorts.

The first two trial participants, who have been followed for greater than one year, showed stable FVIII activity levels since reaching plateau for up to 66 weeks, with follow-up ongoing, Spark said. And five of the seven participants in the 2×1012 vg/kg cohort showed FVIII activity levels between 16% and 49%, with follow-up ranging from 12 to 30 weeks. Mean FVIII activity for these five participants was 30%, based on average FVIII levels post-12 weeks after vector infusion.

The five participants reduced their overall ABR by 100% and reduced their overall AIR by 100%, based on data after week four, the company added.

Immune Response in 2 Patients

However, the other two participants in the 2×1012 vg/kg cohort experienced an immune response that caused their FVIII levels to decline to less than 5%, Spark acknowledged.

“Both participants have moved from prophylactic to on-demand treatment and have seen meaningful reductions in their bleeding and infusion rates,” Spark disclosed. “One of these participants did not rapidly respond to oral steroids and he elected to be admitted to the hospital to receive two intravenous (IV) methylprednisolone infusions rather than have the infusions on an outpatient basis. The event was subsequently resolved.”

“The admission to hospital for the infusions met the criteria for a serious adverse event,” the company added.

Seven of the 12 participants received a tapering course of oral steroids in response to an alanine aminotransferase (ALT) elevation above patient baseline, declining FVIII levels and/or positive IFN-g enzyme-linked immunospots (ELISPOTs), Spark added. “For these seven participants, steroids led to normalization of ALT and ELISPOTs. For all but the two above mentioned 2×1012 vg/kg cohort participants, oral steroids led to stabilization of target FVIII levels.”

Marrazzo stated that Phase III plans will include dosing of patients with steroids to suppress immune responses such as those experienced by the two patients in the 2×1012 vg/kg cohort: “We know exactly what's happening in these two patients, and we have a plan that we're confident in to correct it.”

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