AT ASH 2016

SAN DIEGO (FRONTLINE MEDICAL NEWS) – Patients with hemophilia B who received a single 1-hour infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.

All nine patients treated to date have exceeded the 12% steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, said during a press briefing at the annual meeting of the American Society of Hematology. One patient infused himself once with factor IX after developing a suspected ankle bleed 2 days after treatment, Dr. High and her associates reported in the accompanying abstract.

But there have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product, they reported.

This therapy works at a lower dose than previous factor IX gene transfer products and therefore has not caused the hepatotoxicity that halted their development, according to Dr. High, president and chief scientific officer of Spark Therapeutics, which makes SPK-9001. Two of nine patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels, but the immune response was halted by tapering doses of corticosteroids, and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor, she said.

Because the virus capsid breaks down over time, a transient immune response to it “is not really a safety issue, but is an efficacy issue,” Dr. High emphasized. “If it is not caught in time, and patients are not given steroids promptly, they can lose the donated gene. Therefore, quick recognition is key.” Patients who develop an immune response to the viral capsid show sharp declines in factor IX activity levels, rises in baseline AST and ALT, and mononuclear cell reactivity, she explained during an interview.

The current standard of care for hemophilia B involves the cost and treatment burden of intravenous factor IX injections given one to three times weekly. Previous work evaluated factor IX gene transfer mediated by adeno-associated virus, but long-term factor IX activity levels did not reach the trough levels typically achieved with long-acting factor IX prophylaxis. Simply escalating the vector dose did not work because the viral capsid triggered immune-mediated hepatotoxicity, Dr. High noted.

To develop a more efficient product that works at lower doses, she and her associates created a recombinant vector containing a bioengineered adeno-associated virus capsid and a DNA sequence with a promoter designed to drive hepatic expression of a highly active variant of factor IX. To test the product, researchers in Mississippi, Pennsylvania, and California enrolled men aged 18-52 years with a confirmed diagnosis of hemophilia B (no more than 2 IU/dL or 2% endogenous factor IX) who had received at least 50 days of exposure to factor IX products and averaged at least four bleeding events per year requiring factor IX treatment or prophylaxis. Patients had no measurable inhibitory antibodies but otherwise represented the “general hemophilia B population,” Dr. High said. Five of nine patients had multiple target joints, liver disease associated with hepatitis C virus infection, or both. Each patient received a 1-hour infusion of 5 x 1011 vector genomes per body weight and was followed for 7-52 weeks.

Among seven patients who, by Nov. 30, 2016, had surpassed the 12 weeks needed to reach steady state factor IX expression levels, median steady-state level was 30% (range, 13%-38%), Dr. High reported. “Now we can give one quarter the dose [of adeno-associated virus vector] that was given before, and its driving factor IX expression levels five to eight times higher,” she concluded. Results for the first seven treated patients prompted Food and Drug Administration to give the product orphan drug designation in July 2016. Plans for phase III trials are underway, and researchers also are planning to investigate this approach to gene therapy in hemophilia A, Dr. High said.

Spark Therapeutics Inc. and Pfizer sponsored the study. Dr. High is president and chief scientific officer of Spark. Dr. George had no relevant financial disclosures.