The good news from the three-year update on Biomarin’s haemophilia A gene therapy: in patients who responded to valoctocogene roxaparvovec (valrox) bleeding rates remain impressively low, while enough subjects have hit a pre-specified regulatory criterion to allow the project to be filed for approval.
The not-so good news: effectiveness in the phase I/II trial has continued to wane, and early data from a phase III trial seem to suggest an even weaker response. These results seem to confirm concerns about the product’s durability and, further out, ability to compete with rival gene therapies.
First to the phase I/II data, which was a three-year look at patients’ progress. The study tested two doses of valrox, 4x1013vg/kg and 6x1013vg/kg, though only the latter brought patients’ factor VIII level into a normal range, so is the major focus.
For the higher dose, the median annualised bleed rate (ABR) remained at zero, with a mean ABR of 0.7 in the third year. Factor VIII levels measured with the chromogenic substrate assay produced a median 19.9% of normal, a fall from 26.2% at the end of year two.
This was expected to drop, and while this level might have disappointed some, it was probably the minimum required for valrox to be considered a viable product.
Biomarin believes that Factor VIII expression is “nearing” a plateau, and says that its statistical models imply that valrox should be able to control bleeding for at least eight years. That might be enough for regulators, but with other haemophilia gene therapies in the offing valrox could struggle to remain competitive.
The company also provided a glimpse at the ongoing Gener8-1 phase III trial, which uses the 6x1013vg/kg dose. At the April 30, 2019 data cut-off, among the 16 subjects who had reached 26 weeks, seven had mean factor VIII levels above 40% of normal during weeks 23-26, while an eighth subject met this standard after April 30. Hitting this 40% threshold is the target agreed with regulators on both sides of the Atlantic for Biomarin to seek accelerated approval.
The sellside tried to spin the data as positive, but the phase I/II data in particular missed – albeit narrowly – the 20% of normal factor VIII target that had been mooted as a possible definition of success (Biomarin hopes long-term valrox data can stem the bleeding, May 22, 2019).
Valrox might still have a chance of approval – Biomarin said it would set out a timeline for going to the regulators in the coming months. But the project does not seem capable of living up to gene therapy’s once-and-done promise.