A gene therapy for hemophilia could be on the market by the end of next year, according to its developer BioMarin Pharmaceutical, if regulators agree that a tiny amount of data show enough promise.
San Rafael, CA-based BioMarin (NASDAQ: BMRN) said this morning that a single dose of the therapy, valoctocogene roxaparvovec—known in shorthand as valrox—should stop the spontaneous bleeding of people with hemophilia A for at least eight years. However, that estimate is largely based on a small group of patients who have been on the therapy for three years, at most.
In that long-term Phase 1/2 study, according to BioMarin data presented today, valrox’s power to produce the blood-clotting protein called factor VIII starts to decline after peaking around the four-month mark. But in the third year, it “appears to be approaching a plateau,” President of Worldwide Research & Development Hank Fuchs said during a conference call.
It’s important to note that, even at the lowest levels in the third year, most patients on valrox still produced much more factor VIII than the level, 5 international units per deciliter, that is considered the border between moderate and mild hemophilia.
Hemophilia affects an estimated 20,000 people in the US and 400,000 worldwide, and hemophilia A is the most common form. It is typically treated with two or three self-injections a week of recombinant factor VIII to replace what the patient’s liver cells cannot produce due to a genetic mutation. These drugs help prevent dangerous bleeding events that can lead to joint damage and other health problems.
“We don’t see the rate of decline [in Factor VIII] at year three as highly concerning,” wrote RBC Capital Markets analyst Kennen MacKay in a note to investors. MacKay pointed to another measure of the therapy’s success: The number of bleeds that occurred remained steady, even as factor VIII levels waned.
In a note to investors, Stifel analyst Paul Matteis agreed that the reduction in bleeds remained “very significant” after three years and that benefit “should likely last for multiple more years.” But he wasn’t convinced that factor VIII levels would stabilize over time, as BioMarin argued. “We do not think the durability debate for ValRox is over,” Matteis wrote.
The small number of patients involved present a notable caveat. The three-year data come from seven patients. BioMarin estimated valrox’s effectiveness at a minimum of eight years by combining those data with two years of results from a lower dose given to six more patients, as well as short-term results from the 20-patient Phase 3 study, dubbed GENEr8-1.
The Phase 3 Surprise
BioMarin revealed interim data today from GENEr8-1, which surprised observers who were not expecting data until later this year. BioMarin has yet to dose 96 more patients. The surprise was not necessarily a good one, even though BioMarin said the data were positive and would form the basis of its request for an accelerated market approval.
BioMarin shares were down $2.03, or 2.8 percent, in midday trading Tuesday.
The company will make its case to US and European regulators in the hopes of having a product on the market by the end of 2020. Fuchs said during the conference call that the Phase 3 GENEr8-1 study met the main goal that regulators agreed upon beforehand: Eight patients in the study reached or exceeded the desired 40 international units per deciliter level of factor VIII at the half-year mark. That’s out of 17 patients so far. The final three patients in the 20-patient cohort have not been evaluated, so the number meeting the threshold could rise to 11.
One reason for the negative reaction from investors today: The eight patients meeting the 40 IU/dl bar so far comprised a lower percentage than the long-term Phase 1/2 study at that same half-year mark. Three of the 17 evaluated patients were considered “nonresponders,” in that they did not even reach the 5 international units per deciliter minimum. One was “bleeding a lot” and had to go back to taking traditional factor VIII drugs, but the other two have not, according to Fuchs.
“The interim data from the Phase 3 study is raising questions since the overall response curve is less than” the Phase 1/2 study, wrote SVB Leerink analyst Joseph Schwartz in a note to investors.
Fuchs said regulators will go meticulously through each patient’s data. “I expect FDA to conduct a lot of sensitivity analysis,” he said. “If you want to get a novel gene therapy approved [based on data from] a couple dozen patients, the level of effectiveness has to be pretty darn high.”
Approval by regulators is only one hurdle. BioMarin will also have to convince insurers to pay for what’s likely to be a very expensive medicine. “They’re going to want to see tangible evidence of clinical benefit,” Fuchs said.
They’ll also want to see at least some savings over the current standard treatment of weekly drug injections, which can add up to hundreds of thousands of dollars a year. A drug made by Roche and approved for all hemophilia A patients last year has a list price of $482,000 for the first year. It requires less frequent doses; it also carries safety concerns.
BioMarin Chariman and CEO Jean-Jacques Bienaimé used last week’s approval of another gene therapy, Zolgensma, as a point of comparison. Like BioMarin’s valrox, Novartis’s Zolgensma will go head-to-head with an established standard of care. Novartis (NYSE: NVS) set a $2.1 million list price but is working on various plans, including five annual payments of $425,000.
“It might be difficult for payers to pay more” than the equivalent cost of five years of current hemophilia care, Bienaimé said during today’s call. “But based on our analysis, I think there’s a pretty solid argument that valrox will last at least five years.”
Across the long-term study and the Phase 3 study, there were no serious safety problems.
A comment Fuchs made toward the end of the conference call deserves to be highlighted: “We need more data to understand the phenomenon.” He was referring to statistical differences; there was a notable gap between the mean and median levels of factor VIII in the third year of the long-term study. But his caveat about small sample size could apply to just about everything related to the results from valrox, or any gene therapy to date.