Two new therapies for hemophilia A aim to eliminate bleeding events entirely, significantly changing the sometimes daily treatment regimens for severe disease.
Positive data for Roche Holding AG's Hemlibra, approved in the U.S. in November 2017, and BioMarin Pharmaceutical Inc.'s experimental gene therapy valoctocogene roxaparvovec, also known as BMN 270, were presented Dec. 9 at the American Society of Hematology conference in Atlanta. Both focus on hemophilia A, the most common form of the disease, but target markedly different patient populations — for now.
Roche's Hemlibra is designed to be a once-weekly preventive injection for patients with inhibitors, or a built-up resistance to typical coagulant therapies that replace factor VIII, the clotting protein missing in hemophilia A patients. About 20% of the hemophilia A population develops these inhibitors, according to the U.S. Centers for Disease Control and Prevention, though it is more common in severe cases. Patients with inhibitors use medicines called bypassing agents to control bleeding.
In a phase 3 trial among children dubbed HAVEN 2, 95% of the trial participants experienced no bleeding events requiring treatment.
"That's honestly, truly remarkable," Guy Young, the lead author on the study and the director of the hemostasis and thrombosis program at Children's Hospital Los Angeles, said in a press briefing. "Most of the time, these patients are bleeding at least on a monthly basis, sometimes more often than that."
Importantly for Roche, no serious side effects related to the drug were reported, a key departure from the HAVEN 1 trials among adolescents and adults. Deaths in a phase 3 trial combining Hemlibra with Shire's bypassing agent Feiba have been hotly debated between the two companies, with Roche originally pinning the fatalities and other serious side effects on Feiba's impact.
Young again attributed these events to other factors, saying in a statement alongside the presentation that these problems did not happen in HAVEN 2 because the patients rarely used bypassing agents due to their relatively sparse bleeding events.
"There were six serious adverse events, but these were really related either to the disease, [such as] bleeding and hemorrhage, or to the use of catheters," Young said at the press briefing. There were three bleeding events that were all safely treated, and the medicine's 10 related side effects were nearly all injection site reactions, he added.
Roche recently shared positive data from another phase 3 trial for patients who have not developed inhibitors, and days before the conference it posted solid interim results for once-monthly dosing regimens in HAVEN 4.
Prior to the recent positive HAVEN 3 data, Cowen analyst Steven Scala had forecast Hemlibra revenue of CHF 250 million next year, reaching CHF 2 billion by 2024. If Roche can expand to non-inhibitor patients, there is likely upside to these forecasts, Scala said in a Nov. 20 note.
'Way more than we ever expected'
Yet these non-inhibitor patients are the key cohort for BioMarin's gene therapy, a virus-attached infusion designed to be a one-time treatment to indefinitely raise factor VIII levels, effectively removing the need for treatment.
In a phase 1/2 study, 13 patients in two dosing groups maintained normal or near-normal factor VIII levels for up to 19 months, with the patients in the higher-dose section keeping up normal levels that eventually plateaued, and patients in the lower range showing near-normal levels that appeared to steadily rise.
Prior to this study, these participants received up to 185 infusions a year and still had breakthrough bleeds despite preventive care, K. John Pasi, the presenting researcher and a professor of hematology at Barts and the London School of Medicine and Dentistry, said in the press briefing. After the gene therapy, all patients on both dosing regimens were able to completely discontinue preventive factor VIII infusions, and 10 – or 76% of the trial participants – had no bleeding episodes requiring treatment.
The safety profile is promising too, with no patients showing evidence of an adverse response, something that has posed a problem in other gene therapy trials. No patients showed evidence of inhibitor development, a constant anxiety in hemophilia A, Pasi said.
"We've found that this has been an amazing experience – the data here is way more than we ever expected," Pasi said.
BioMarin's therapy has only been tested in non-inhibitor patients, and it is unlikely that they will include those with resistance anytime soon, according to Pasi's comments. However, he said the company will broaden its patient group in phase 3 studies, including people with other risks, such as HIV infections and past, but treated, hepatitis C infections.
"Gene therapy for hemophilia has long been regarded as potentially a holy grail," Pasi said. "It's an ideal candidate."
