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Gene transfer therapy leads to stable factor IX levels in hemophilia B

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December 6, 2017

Lindsey A. George
Katherine A. High

A one-time IV infusion of gene therapy with SPK-9001 appeared associated with sustained level of factor IX coagulant activity of approximately 30% among adult men with hemophilia B, according to results from an open-label, nonrandomized phase 1/phase 2a clinical study.

The therapy allowed for termination of prophylaxis, prevented bleeding and almost eliminated the need for exogenous factor use among study participants.

“A one-time therapy sufficient to prevent bleeding without further medical intervention is the ideal treatment goal for patients with hemophilia,” lead investigator Lindsey A. George, MD, attending physician in the division of hematology at Children’s Hospital of Philadelphia and a member of HemOnc Today’s Next Gen Innovators, said in a press release. “I am optimistic this study is just the beginning of a true paradigm shift in the treatment of hemophilia.”

Inherited gene mutation limits the ability of a person with hemophilia B to produce normal levels of a blood clotting factor, which can result in disabling or life-threatening bleeding.

Gene therapy can provide a normal copy of the factor VIII or factor IX gene in a patient’s liver cells, which then directs the expression of adequate levels of clotting factor to prevent bleeding.

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

“People who live with hemophilia face a lifelong need for vigilant monitoring and recurrent factor concentrate infusions to prevent spontaneous, potentially life-threatening bleeds, and to protect their joints,” senior investigator Katherine A. High, MD, president and chief scientific officer of Spark Therapeutics, as well as a HemOnc Today Editorial Board member, said in the release. “The discipline required to execute the usual prophylactic regimen can exact a heavy toll on quality of life that most people take for granted, and those regimens result in significant costs to patients, families and the health care system.”

High and colleagues developed a highly efficient vector capsid and expression cassette that can be administered at low doses to achieve hemostatic factor IX expression without immunosuppression.

SPK-9001 (Spark Therapeutics) uses a bioengineered adeno-associated viral capsid (Spark100) with liver-specific tropism. Researchers used a codon-optimized, single-stranded transgene encoding factor IX Padua (factor IX-R338L) for the expression cassette.

The analysis included 10 men (age range, 18 to 53 years) with hemophilia B and factor IX coagulant activity of 2% or less, with AAV-Spark 100 neutralizing antibodies of 1:5 or less.


The men received IV infusions of SPK-9001 administered at 5 x 1011 vector genomes per kg of body weight.

As HemOnc Today previously reported, researchers presented initial results at ASH Annual Meeting and Exposition in 2016.

The current analysis is based on cumulative follow-up of 492 weeks among all participants. Mean follow-up among individual participants was 49 weeks (range, 28-78).

During this time, researchers assessed vital signs, performed physical examinations and tracked adverse events. They also performed laboratory testing that included the following: factor IX coagulant activity, factor IX inhibitor, liver-function tests, and cellular/humoral immune response against the capsid.

Researchers observed sustained vector-derived factor IX coagulant activity in all participants, with a mean steady-state factor IX coagulant activity of 33.7±18.5% (range, 14-81).

Annualized bleeding rate declined from a mean rate of 11.1 (range, 0-48) events per year prior to vector administration to 0.4 (range, 0-4) events per year after vector administration (P = .02).

Factor use also decreased from a mean dose of 2,908 IU per kg (range, 0-8,090) prior to vector administration to 49.3 IU per kg (range, 0-376) after vector administration (P = .004).

Eight patients did not use external factor, and nine of 10 did not experience bleeding after vector administration.

No serious adverse events occurred during or after infusion. Two patients developed increased liver enzyme levels. One other patient with significant joint damage at baseline administered factor for bleeding but used 91% less factor than prior to vector infusion.

“This cohort of 10 patients all safely experienced sustained clinical benefit after one infusion,” George said. “We look forward to continuing the development of this therapy in a phase 3 trial.”

The study by George and colleagues is another clinical success for patients with hemophilia B, according to Matthew Porteus, MD, PhD, associate professor of pediatrics in the division of pediatric stem cell transplantation at Stanford University School of Medicine.

“This study represents an important milestone for the community of patients with hemophilia B, their caregivers and advocates, who now are within touching distance of having an ideal cure for this terrible disease,” Porteus wrote in a related editorial.

Despite “striking” findings, there were some limitations, Porteus added. They included short follow-up and the fact patients with pre-existing humoral immunity to adeno-associated vector are excluded from receiving this type of therapy.

“A key future direction for hemophilia gene therapy is to broaden the number of patients for whom gene therapy would be safe and effective,” Porteus wrote. “This broadening includes finding methods to use gene therapy safely and effectively in patients with pre-existing antibodies, finding methods for use in children, developing gene therapy approaches for the 80% of patients with hemophilia A — a patient population with a much higher frequency of inhibitors — and finding ways to reduce the costs.” – by Melinda Stevens


Disclosures: George reports no relevant financial disclosures. High reports employment with Spark Therapeutics and equity ownership in SPK-9001. Please see the full study for all other authors’ relevant financial disclosures. HemOnc Today was unable to confirm Porteus’s relevant financial disclosures at the time of reporting.