From the Journals

Gene therapy found promising in patients with hemophilia B


Key clinical point: A single intravenous dose of the adeno-associated viral vector SPK-9001 produced sustained expression of factor IX coagulant activity, virtually eliminating bleeding and use of clotting factors in patients with hemophilia B.

Major finding: A mean functional clotting-factor activity of 33.7% of the normal value (median, 29.8% of the normal value) was achieved among study participants.

Data source: An open-label, nonrandomized, multicenter phase 1-2a study including 10 men with hemophilia B and factor IX coagulant activity 2% or less of normal value.

Disclosures: Spark Therapeutics and Pfizer funded the study. Lead author Lindsey A. George, MD, reported support from Spark Therapeutics for the study, and personal fees from Pfizer outside the submitted work. Full author disclosures were published on the New England Journal of Medicine website.

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A cure within reach?

The positive results seen in this trial of the adeno-associated viral vector SPK-9001 represent “an important milestone for the community of patients with hemophilia B and their caregivers and advocates, who now are within touching distance of having an ideal cure for this terrible disease,” Matthew Porteus, MD, PhD, wrote in an editorial.

To reduce spontaneous bleed risk in patients with hemophilia, the current standard of care is transitioning from prophylactic intravenous infusions of clotting factor multiple times per week to longer-acting agents that can be given every 7-10 days.

However, an “ideal therapy” according to Dr. Porteus, would be one that can be delivered once with minimal toxicity and last a lifetime, and be affordable for patients anywhere in the world.

“Gene therapy in which a sufficient number of cells are modified by the delivery of a gene with prolonged or even permanent expression to produce the missing clotting factor has the potential to be such an ideal therapy for hemophilia,” he wrote.

The findings regarding SPK-9001 are “striking” but are limited due to short follow-up, he said, although investigators have started a longer-term study to better investigate safety and efficacy.

Future research on hemophilia gene therapy should focus on broadening the number of patients who could benefit from it, including children, patients with preexisting antibodies, and the 80% of hemophilia patients with hemophilia A, he added.

Dr. Porteus is with the department of pediatrics at Stanford (Calif.) University. These comments are derived from his editorial (N Engl J Med. 2017;377[23]2274-5). Dr. Porteus reported receiving personal fees from CRISPR Therapeutics outside of his submitted editorial.



A one-time intravenous infusion of a single-stranded recombinant adeno-associated viral vector is safe and results in a sustained level of factor IX coagulant activity, according to results of a recent phase 1-2a study including 10 men with hemophilia B.

The treatment, known as SPK-9001, prevented bleeding and virtually eliminated the need for exogenous factors, said authors of the study, published online Dec. 6 in the New England Journal of Medicine.

“This early success requires confirmation in a larger cohort and long-term monitoring of safety and efficacy,” wrote Lindsey A. George, MD, of the division of hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at Children’s Hospital of Philadelphia, and her coauthors (N Engl J Med. 2017;377[23]:2215-27).

The 10 men enrolled in the study had factor IX coagulation activity 2% or less of normal value. Within a week of treatment with SPK-9001, patients exhibited vector-derived factor IX coagulant activity, according to Dr. George and her colleagues.

For all participants, the mean vector-derived factor IX coagulant activity was 33.7% of normal value, they noted in the report.

Moreover, the bleeding rate was significantly reduced over follow-up, which ranged from 28 to 78 weeks. Annualized bleeding rate was 11.1 events per year before treatment and 0.4 events per year afterward (P = .02), with 9 of 10 patients experiencing no bleeds over the follow-up period, they reported.

Factor use also dropped substantially, from a mean dose of 2,908 IU/kg before vector administration to 49.3 IU/kg afterward, the researchers said, noting that 8 of 10 patients used no factor at all.

No serious adverse events were observed during vector infusion or afterward, but the long-term safety of adeno-associated viral gene transfer will require further study, the researchers said. “However, to date, no genotoxic or gene-silencing events have been noted in human participants, including those who have been followed since the first [adeno-associated virus] trials were reported in 1998,” Dr. George and her colleagues wrote.

Spark Therapeutics and Pfizer funded the study. Dr. George reported support from Spark Therapeutics for the study, and personal fees from Pfizer outside the submitted work. Some of the authors are employees of Spark or had other financial relationships with Spark and/or Pfizer.

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