Getting control of bleeding

Hemophilia B is a rare, genetic bleeding disorder, most commonly affecting males, that causes the blood to take longer to clot than normal. This can cause excessive and recurrent bleeding, often into the muscles and joints, and carries the potential to be life-threatening. Patients with hemophilia B have a deficiency of a protein in the blood, clotting factor IX, which is currently treated with intravenous infusions of either plasma-derived or recombinant factor IX to control and prevent bleeding episodes.

As of Nov. 30, 2016, all nine infused patients experienced a reduction of the total clotting factor IX concentrates consumption by 1.13 million international units when compared to their factor IX concentrates usage in the year before vector administration. Seven of those nine experienced consistent and sustained factor IX activity levels, with a mean steady-state level greater than 28 percent. So far, no participants have developed factor IX inhibitors or experienced thrombotic events after the vector administration, and no other serious adverse effects have been reported after SPK-9001 administration.

The first patient to reach the one-year earmark has reduced his number of intravenous factor IX infusions to zero without having any bleeds, and his steady-state factor IX activity level was reported at 33 percent of normal. By comparison, in the year prior to participation in the trial, he infused factor IX concentrates as a precaution a total of 98 times and still experienced four traumatic bleeds.

To date, eight of the patients have required no factor IX concentrates to prevent or control bleeding events since the day after vector administration, though one participant with severe joint disease self-administered two precautionary infusions on separate occasions for suspected bleeds.

Two of the nine participants experienced asymptomatic, transient elevation in liver enzymes associated with an immune response to the Spark100 vector capsid during the first four to eight weeks following administration. In one case, this response was accompanied by a decline in factor IX activity level from 32 to 12 percent. With the other patient, steroids were administered more promptly, experiencing a decline from a peak factor IX activity level of 71 to 68 percent. Both participants were put on a tapering course of corticosteroids, and, to date, neither participant has experienced any bleeds nor has required infusion of replacement factor IX concentrates.

“We will monitor these two participants carefully as we continue to taper the corticosteroids,” said Dr. Katherine A. High, president and chief scientific officer at Spark Therapeutics. “It’s important to remember that the immune response to the capsid typically is transient, and in both cases, seems to have been arrested by corticosteroids. Once corticosteroids have been discontinued altogether, levels of expression will be the best measure of the efficacy of this approach. The experience we have gained in immuno-monitoring and in clinical management of the immune response in the hemophilia B trial will further inform our upcoming hemophilia studies.”

Thus far, six of the nine patients have reported increased physical activity and improved quality of life based on the Haemophilia Quality of Life Questionnaire for Adults, a validated instrument that measures health-related quality of life in adults with hemophilia. Two of the remaining participants received the gene therapy product too recently to evaluate quality-of-life measures.

Spark Therapeutics and Pfizer entered into a collaboration in 2014 for the SPK-FIX program, including SPK-9001, but Spark’s founding team carries history of hemophilia gene therapy research and clinical development that goes back almost 30 years.

SPK-9001, a novel investigational bio-engineered adeno-associated virus capsid expressing a codon-optimized, high-activity human factor IX variant enabling endogenous production of factor IX, has received Breakthrough Therapy status and Orphan Drug designation from the U.S. Food and Drug Administration. Per the terms of the collaboration, Spark is responsible for conducting all Phase 1/2 studies for any product candidates, while Pfizer assumes responsibility for pivotal studies, any regulatory activities and potential global commercialization of any products that may result from the collaboration.

“Giving people living with hemophilia B treatment options that potentially minimize or eliminate the need for infusions of factor concentrates is one of the main goals of conducting clinical studies of investigational gene therapies,” said High. “While continued observation and larger cohorts are needed, these updated preliminary data continue to be encouraging and suggest the potential of investigational SPK-9001 to deliver a consistent, sustained and therapeutically meaningful level of factor IX activity through a one-time intravenous administration.”