Alexander M. Castellino, PhD

December 09, 2017

ATLANTA — Patients with hemophilia A who received a single infusion of an investigational gene therapy called valoctocogene roxaparvovec showed substantially increased levels of the essential blood clotting factor VIII. Of the 13 patients who took part in the study, 11 achieved normal or near-normal factor VIII levels.

Self-reported bleeding and external use of factor VIII were profoundly reduced in cohorts of participants given a high dose of valoctocogene roxaparvovec, an adeno-associated virus serotype 5 (AAV5) vector containing the B-domain-deleted F8 gene (AAV5-VIII), which replaces the gene missing in hemophilia A, factor VIII.

The new data were reported here at the American Society of Hematology (ASH) 2017 Annual Meeting, and simultaneously published online December 9 in the New England Journal of Medicine.

"The clinical data to date for this investigational gene therapy exceeded our expectations, in terms of increasing factor VIII levels and reducing the annualized bleed rate," said lead researcher K. John Pasi, MD, professor of hemostasis and thrombosis at Barts and the London School of Medicine and Dentistry and haemophilia clinical director at Barts Health NHS Trust, London, United Kingdom.

At a press conference, Dr Pasi explained that replacement products for hemophilia A are expensive and are demanding for users, who have to infuse themselves regularly.

"Hemophilia A is a single gene disorder with a clear cause-and-effect relationship and, with a wide therapeutic window, is an ideal candidate for gene therapy," he said.

"Many clinical trial participants have seen factor VIII levels at or close to normal. This clinical result has the potential to improve the lives of subjects who now must infuse themselves with factor VIII as often as every other day. With this experimental treatment, we are researching whether it may be possible for hemophilia A subjects to reduce or eliminate factor VIII treatment over an extended timeline," Dr Pasi said.

Moderating the press conference, Margaret Ragni, MD, professor of medicine at the University of Pittsburgh, Pennsylvania, and ASH expert on hemophilia, said that these patients have the opportunity to be "phenotypically cured."

"A Cure for Hemophilia Within Reach," was the title of an accompanying New England Journal of Medicine editorial, authored by H. Marijke van den Berg, MD, PhD, from the PedNet Hemophilia Research Foundation, Baarn, the Netherlands, and the Blood Center of Wisconsin, Milwaukee. Dr van den Berg was writing about two studies published: the one on gene therapy for hemophilia A, and another on gene therapy for hemophilia B.

"These...landmark studies are leading the way to a cure for hemophilia," she writes. "Gene therapy for hemophilia A, seen as the ultimate grail, was not expected to be feasible soon," she noted.

Factor VIII Gene Therapy

At a press conference, Dr Pasi reported on efficacy results with AAV5-VIII for two cohorts of patients with severe hemophilia A. Seven participants received 6 × 1013 vector genomes (vg)/kg, and 6 participants received 4 × 1013 vg/kg. Participants received a single intravenous injection of valoctocogene roxaparvovec.

In participants receiving the higher dose, prophylactic corticosteroid use was initiated after the first patient had alanine aminotransferase elevation 1.5 times above baseline. No prophylactic corticosteroids were given to participants with the lower dose. The trigger for corticosteroids was set at an alanine aminotransferase elevation of 1.5 times upper limit of normal.

Valoctocogene roxaparvovec was well tolerated across all doses, and no patient developed inhibitors to factor VIII. Two participants developed serious adverse events: one had pyrexia with myalgia and headache at the time of infusion, and the other a planned total knee replacement for chronic arthropathy.

Treatment of alanine aminotransferase elevations with steroids was well tolerated. All participants receiving the higher vector dose remain off steroids; one patient treated with the lower dose of vector remains on steroids.

After infusion, antibodies to AAV5 were detected in all the participants; however, T-cell-mediated immune responses to AAV5 capsid proteins were not seen, nor were neutralizing antibodies to factor VIII.

"The absence of factor VIII inhibitors during more than 1 year of follow-up underscores the safety of AAV5-hFVIII-SQ [valoctocogene roxaparvovec]," the study authors noted in their article.

In participants receiving the higher dose, factor VIII activity plateaued by week 20, with median levels seen in the normal range (86 - 122 IU/dL) between weeks 20 and 64. At week 64, median factor VIII activity was 86 IU/dL.

Dr Pasi reported that participants administered a single infusion of 6 × 1013 vg/kg valoctocogene roxaparvovec demonstrated sustained, clinically relevant factor VIII activity levels 1.5 years after gene transfer.

At the lower dose, median factor VIII levels continued to rise toward the normal range: median factor VIII level was 34 IU/dL at week 20 and 51 IU/dL at week 32.

Dr Pasi noted that in these participants, factor VIII activity levels rose steadily toward the lower end of the normal range up to 1 year after gene transfer.

Dramatic decline in annualized bleeding rates were also reported. For example, participants receiving the higher dose had a preinfusion annualized bleeding rate of 16.5; this dropped to 0 after a single infusion of valoctocogene roxaparvovec.

Four weeks after infusion of valoctocogene roxaparvovec and through the last follow-up, median annualized factor VIII infusions simultaneously declined from 138.5 to 0 in cohort A and from 155.5 to 0 in cohort B.

Both doses appeared to provide long-term normalization of factor VIII activity in participants with severe hemophilia A.

An ASH news release noted that before this study, participants received up to 185 factor VIII infusions per year to prevent bleeds, resulting in up to 41 breakthrough bleeding episodes per year, despite prophylactic treatment.

After receiving the gene therapy, all participants from both dose cohorts were able to completely discontinue prophylactic factor VIII infusions. No participant showed evidence of an adverse response by the immune system, an adverse effect that has posed concern in trials for other gene therapies, the news release noted.

Dr Pasi noted that two separate single-group, phase 3 studies have been initiated with the goal of achieving clinically meaningful increases in factor VIII in hemophilia A.

Is Factor VIII Gene Therapy Ready for Clinical Practice?

Valoctocogene roxaparvovec has been granted orphan drug status from the US Food and Drug Administration. This designation is provided to drugs and biologics that are intended for the treatment of rare diseases (those affecting fewer than 200,000 people in the United States).

When asked at the press conference whether this therapy provided durable responses, Dr Pasi suggested that in contrast to standard care, which requires multiple intravenous therapy infusions per week, this gene therapy appears to have long-lasting effects after a single infusion. "Only time will tell whether the responses seen are durable," he said.

Dr Ragni suggested that not all patients with hemophilia A will benefit from valoctocogene roxaparvovec: Half the adults have antibodies to AAV, and children with liver disease will not be eligible for factor VIII gene therapy, she noted.

Dr van den Berg noted that although the levels of the missing factor are impressive, the large variation seen among participants needs clarification. She said several questions remain, including whether it will be possible to predict who can be treated with lower doses, and whether or not a preconditioning regimen could reduce the vector dose.

"Because subjects who have been recruited for the current trials had to be AAV negative, without active hepatitis, and inhibitor negative, most subjects with hemophilia cannot yet benefit from gene therapy," she said.

"The adoption of gene therapy in subjects with hemophilia will depend on the safety profile and the persistence of therapeutic levels.... If it could be perfected, children born with this devastating disease could benefit from a life without bleeding and other sequelae of the disease," Dr van den Berg noted.

"As we work toward this goal, primary prophylaxis for all subjects with severe hemophilia should be the standard of care," she concluded.

The study was sponsored by Biomarin Pharmaceuticals Inc. Details of conflict-of-interest disclosures are listed in the article. Dr. Pasi reports grant support, personal fees and nonfinancial support from BioMarin during the conduct of the study; grant support, personal fees, and nonfinancial support from Biogen and Octapharma, personal fees and nonfinancial support from Sobi, Pfizer, and Genzyme, grant support and personal fees from Baxalta/Shire and Alnylam, and personal fees from Novo Nordisk outside the submitted work. Other coauthors also report conflicts of interest as detailed in the paper. Dr. van den Berg reports grants and personal fees from Bayer, grants from CSL, grants from NovoNordisk, grants from Pfizer, grants from Grifols, grants from Sobi, grants from Bioverativ, non-financial support from Blood Products Working Party - European Medicines Agency, nonfinancial support from World Federation of Hemophilia, outside the submitted work.

American Society of Hematology (ASH 2017) Annual Meeting: Abstract 603. To be presented December 11, 2017.

New Engl J Med. Published online December 9, 2017. Full text, Editorial

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