ASH Annual Meeting and Exposition

ASH Annual Meeting and Exposition

Perspective from Margaret V. Ragni, MD, MPH
December 03, 2016
4 min read

Gene transfer sustains stable Factor IX levels in hemophilia B

Perspective from Margaret V. Ragni, MD, MPH
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SAN DIEGO — Gene transfer via SPK-9001 achieved sustained mean Factor IX levels greater than 30% without immunosuppression in patients with hemophilia B, according to study results scheduled for presentation during the plenary session of the ASH Annual Meeting and Exposition.

This treatment led to the termination of prophylaxis, bleeding prevention and nearly complete cessation of Factor use in patients on study.

Katherine A. High

“We manage hemophilia B by giving recurrent IV infusions of clotting factor,” Katherine A. High, MD, president and chief scientific officer of Spark Therapeutics, as well as a HemOnc Today Editorial Board member, said during a press conference. “This is a medically demanding regimen for patients, and it also results in peaks and troughs of Factor level, and patients are at risk for breakthrough bleeding when they hit the trough.”

Gene therapy can provide individuals with a normal copy of the Factor VIII or Factor IX gene in their liver cells, when then directs the expression of adequate levels of clotting factor to prevent bleeds.

However, achieving higher levels of Factor IX (FIX) with dose escalation has been difficult because the vector capsids often elicit dose-dependent immune responses that prevent sustained expression and efficacy.

“Our goal is to get long-term expression of levels of at least 12% to get consistent results across every subject enrolled, and to do that at the lowest possible dose, not only because it’s always important to use the lowest effective dose of any medication, but also because there is risk for immune response directed against the AAV vector that will destroy the efficacy if it’s not controlled,” High said.

Thus, High and colleagues sought to develop a highly efficient vector capsid and expression cassette that can be administered at low doses to achieve hemostatic FIX expression without immunosuppression.

SPK-9001 (Spark Therapeutics) uses a bioengineered AAV capsid (Spark100) with liver-specific trompism. Researchers used a codon-optimized, single-stranded transgene encoding FIX Padua for the expression cassette.

Seven men aged 18 to 52 years with hemophilia B were infused with 5 x 1011 vg/kg SPK-9001. Patients had baseline FIX coagulant activity of 2% or lower and had Spark100 neutralizing antibody titer of less than or equal to 1:1. Researchers observed no vector- or procedure-related adverse events after infusion.

Follow-up interval was at least 2 weeks to 34 weeks after infusion. During this time, researchers evaluated laboratory values, bleeding frequency, FIX consumption, and changes in activity and quality of life.

By 12 weeks, patients reached a steady-state FIX expression, with a mean FIX activity level of 28.4% (median, 30%; range, 13-38). All nine patients achieved at least 12% activity levels.

For example, the first patient infused in the trial demonstrated a rise in clotting Factor level over about 10 weeks until he reached a plateau around 30%.

“What this has meant for him is that, the year before gene therapy, he had 98 infusions and he still had four breakthrough bleeds. Over the last year, he had no infusions, no bleeding episodes, he went off prophylaxis and he didn’t require any steroid courses to do that,” High said. “This is the power of dropping the dose. We had six more patients with results just like him.”

Two patients required steroids for immunosuppression. One of these patients received steroids and achieved stabilized levels around 12% to 14%. Despite the immune response and decline in FIX activity level, the two patients have not experienced any bleeds or required replacement FIX.

One patient was infused with FIX concentrate for a suspected ankle bleed 2 days after the infusion. There were no other bleeding events on study.

Researchers reported that at the time of the analysis — 724 days postinfusion — total Factor consumption among patients was reduced by 99%, or 543,589 IU, which would equate to $1,182,298 in savings.

Six of the patients reported increased physical activity and improved quality of life.

“At the Factor IX levels seen in this study, most normal activities of daily living should be open to people with hemophilia,” High said in a press release. “It could be a potential paradigm shift in the treatment of hemophilia.” – by Alexandra Todak


George LA, et al. Abstract 3. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosure: High reports employment with Spark Therapeutics and equity ownership in SPK-9001. Please see the abstract for a list of all other researchers’ relevant financial disclosures.