Conference Coverage

Gene therapy normalized or near-normalized factor VIII in hemophilia A



– A single infusion of valoctocogene roxaparvovec normalized or nearly normalized factor VIII levels in 11 of 13 adults with severe hemophilia A, eliminated spontaneous bleeds and the need for factor VIII infusions, showed durable effects for up to 72 weeks of follow-up, K. John Pasi, MD, said at the annual meeting of the American Society of Hematology.

Dr. John Pasi of Barts and The London School of Medicine and Dentistry. Amy Karon/Frontline Medical News

Dr. John Pasi

This is the first report of a successful study of gene therapy for hemophilia A in humans. Nicknamed valrox and designated as a breakthrough therapy by the Food and Drug Administration in October 2017, valoctocogene roxaparvovec uses an adenoviral vector to deliver a functional copy of the factor VIII gene to patients with hemophilia A, said Dr. Pasi of Barts and The London School of Medicine and Dentistry.

Gene therapy has long been the “holy grail” for managing hemophilia because it is a single-gene disorder with a clear relationship between clotting factor level and bleeding severity, Dr. Pasi said. In a mouse model of hemophilia A, valrox restored factor VIII plasma concentrations to levels thought to be adequate to support normal clotting in humans.

Accordingly, the phase 2/3 enrolled 13 patients with severe hemophilia A whose baseline factor VIII levels were less than 1 IU/dL. Patients started at the lowest dose of gene therapy (4 x 1013 vector genomes/kg) and then received a higher dose ( 6 x 1013 VG/kg) if their factor VIII level remained under 5 IU/dL at week 3. Six patients received the lower dose and seven received the higher dose.

At 78 weeks, median factor VIII level in the higher-dose cohort was 90 IU/mL, as Dr. Pasi and his associates reported simultaneously in the New England Journal of Medicine (2017 Dec 9. doi: 10. 1056/NEJMoa1708483).

Before undergoing gene therapy, study participants had endured up to 41 breakthrough bleeds per year despite often receiving more than 150 infusions of factor VIII annually. Median annualized bleeding rates, which at baseline were 16.5 in the higher dose group and 8 in the lower dose group, zeroed out in both groups after factor VIII activity rose above 5%. Quality of life was evaluated in five patients, who reported substantial improvements across all domains.

All patients began producing factor VIII several weeks after infusion. Median levels plateaued within normal range by 20 weeks in the higher-dose group. At the lower dose, median levels rose steadily to a median of 34 IU/dL by 20 weeks. Additionally, three recipients of the lower dose who were followed for 32 weeks achieved factor VIII levels within normal range (median 51 IU/dL). Levels of factor VIII remained within normal range for up to 78 weeks of posttreatment follow-up, Dr. Pasi said.

No patients developed inhibitors or signs of immune-related adverse effects, nor were adverse events qualitatively different between dose groups, Dr. Pasi said. The most common adverse effects were transient increases in alanine transaminase (ALT), which peaked between 44 IU/L and 141 IU/L and lasted anywhere from several days to 15 weeks. Patients whose ALT rose 1.5-fold above baseline received short-term corticosteroids with no adverse effects. All but one was tapered off. There were two serious adverse events – one elective knee surgery and one case of transient fever, headache, and myalgia at time of infusion.

So far, valrox appears to be long lasting, but “durability is a huge question for any gene therapy approach,” Dr. Pasi said. “The only way to answer it is to follow patients through.”

In hemophilia B, studies indicate that some patients continue expressing factor IX years after a single infusion of gene therapy (N Engl J Med. 2017 Dec 7;377:2215-27).

Two phase 3 trials will further evaluate safety and optimal dosing of valrox, Dr. Pasi said. The GENEr8-1 trial will use the 6 x 1013 VG/kg dose and the GENEr8-2 trial will use the 4 x 1013 VG/kg dose. Like the pilot study, these trials will exclude patients with inhibitors, but they may include patients with comorbidities such as liver disease, he said.

Valrox was previously known as BMN 270.

The study was sponsored by BioMarin. Dr. Pasi disclosed research funding, consultancy fees, and speaker and advisory relationships with BioMarin. He disclosed ties to many other companies that develop hemophilia therapies.

SOURCE: Pasi KJ et al. ASH 2017 Abstract 603

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