Gene therapy offers encouraging possibilities for hemophilia care

The 2016 WFH World Congress has seen incredible enthusiasm and excitement about the topic of gene therapy, said David Lillicrap, Canada, when he chaired “Medical Free Papers – Gene Therapy” yesterday afternoon.

Lindsey George, Pennsylvania, USA, spoke first about rAAV mediated gene transfer for hemophilia B.

She said that in 2011, research showed success for AAV8 vector for FIX, as there was no evidence of late toxicity sustained expression with circulating FIX activity levels of 1% to 6%. “The goal of gene transfer is sustained long term expression,” said George. “We want consistent and predictable results to subsequently build upon.”

In her team’s research, they used SPK-9001 investigational vector. Those that did not have neutralizing antibodies to this vector were eligible for the trial. The transgene was a single strain. “The study enrolled adult males with FIX > 2% and no underlying HBV or HCV. The vector administrated intravenously over one hour, outpatient.”

“The 4 subjects treated all have negative rAAV neutralizing antibodies with SPK-9001 at a dose of 5 x 1011 vg/kg. We followed for 532 days and to date no subject required immunosuppression, there was no inhibitor development, we saw a marked reduction in factor use and bleeding events. 5 x 1011 vg/kg confers sustained FIX expression without need for immunosuppression,” she said. “To our knowledge these data represent the highest levels of sustained FIX expression at the lowest dose. Additional subjects and continued observation are needed to confirm initial results.”

John Pasi London, UK, said we have a completely new generation of therapies. “These require single infusion eliminating the dependency on repeated FVIII injections over a lifetime.”

Pasi told of research done with an AAV5 capsid vector, using a single stranded DNA. “This has been tested extensively in preclinical animal models. In this study we enrolled nine patients; eight were on prophylaxis and three had previous HCV infection. No participant had HIV or inhibitor to FVIII.”

Pasi said liver function elevation was relatively mild. FVIII expression on low dose had no change in baseline, while mid-dose showed stable FVIII activity for over 28 weeks. “In seven patients on high dose (BMN 270 at 6E13 vg/kg), all had FVIII activity levels and six showed > 50 IU/dl. Bleeding essentially ceased after two weeks.”

Wolfgang Miesbach, Germany, also addressed hemophilia B with the premise that factor level determines phenotype. “We used the molecule AMT-060, which was prepared in the pharmacy, infused over 30 minutes by IV with 24 hour observation in the hospital.”

He said the gene cassette was same as used in the St. Jude/UCL study and corresponded to a meaningful reduction in FIX usages.

Adult patients with severe or moderate hemophilia B were included. Excluded from study were those with preexisting neutralizing AAV5 antibodies, FIX inhibitors, active HB, active HCV and uncontrolled HIV.

No evidence of sustained AAVS capsid specific T cell activation was found. As expected all patients developed anti AAV5 antibodies. “A single treatment of 5 x 1012 gc/kg AMT in 5 patients was generally well tolerated after 30 weeks,” he said. “Results were stable with durable FIX activity and a mean of 5.4%. In 4 of 5 patients we saw discontinuation of FIX prophylaxis. This supports a wide application of AAV5 based gene transfer approach.”