With BioMarin Data, Gene Therapy Finally Shows Impact on Hemophilia A

Xconomy San Francisco — 

It’s too early to call it a breakthrough, but for the first time, a gene therapy has been shown to have a real impact on patients with hemophilia A, the most common form of the chronic blood disease. The early data, which come with plenty of caveats, were reported today by BioMarin (NASDAQ: BMRN), of San Rafael, CA.

Other gene therapy developers have produced encouraging early clinical results with hemophilia B treatments. But BioMarin is the first in hemophilia A, with a preliminary look at an early-stage study of its gene therapy BMRN-270.

“About 15 years ago there were some attempts, but this is the first clinical data that shows that we’re having an impact” on hemophilia A, says Barrie Carter, BioMarin’s VP of vector biology and a gene therapy veteran.

Here’s where the caveats come in. The trial has not run its course, and the data are from eight patients, a very small sample. What’s more, doses for the patients have ranged from low to medium to high, and the patients are on different timelines, anywhere from five to 20 weeks after treatment.

Such data from other kinds of therapies would probably not be worth noting. But this is a noteworthy milestone for gene therapy, which has been on a roller coaster ride for more than two decades, and has been battling hemophilia—long seen as its ideal application—for much of that time.

BioMarin said in a statement that six of the eight patients in the trial are producing meaningful amounts of Factor VIII, the blood-clotting protein that the livers of hemophilia A don’t produce enough of. All six of them are taking the highest of three doses of BMRN-270 tested by BioMarin. The other two patients, given a low or medium dose, haven’t produced enough to see a meaningful benefit.

In some patients, the production number has been particularly high. Two patients at a high dose were producing 57 percent and 60 percent of the Factor VIII that a normal person would produce, eight and 16 weeks post-treatment, respectively.

Patients with severe hemophilia produce less than 1 percent of normal levels. Bumping that number up even just a little, to five or 10 percent, turns a severe case to a mild one. That wouldn’t cure a person of hemophilia, but it could potentially eliminate the risk of dangerous, spontaneous bleeds that hemophilia patients suffer. Reacting to the data, ISI Evercore analyst Mark Schoenebaum wrote in a research note that there might be a path forward both for BMRN-270 “and potentially for hemophilia A gene therapy in general.”

About 80 percent of the 20,000 people in the U.S. with hemophilia have hemophilia A, compared to roughly 3,000 to 4,000 for hemophilia B. And roughly 60 percent of hemophilia A patients have the severe form, according to the National Hemophilia Foundation. They would be among the biggest candidates to benefit from gene therapy.

RBC Capital Markets analyst Michael Yee estimated in a note today, for instance, that a successful gene therapy product for hemophilia A could address around half of the $4 billion market for Factor VIII replacement products. BioMarin’s shares climbed 3 percent after the data release.

In addition to the caveats about early data and small sample sizes, however, there are other hurdles a gene therapy for hemophilia must surmount. Hemophilia is a chronic disease, but it’s manageable. Patients can get infusions of the clotting factors that they lack to prevent bleeds. These infusions can be as often as two or three times a week, depending on how severe the hemophilia is. While they’re stressful and expensive, some $2,500 a dose, they’re effective.

Because of that precedent, gene therapy for hemophilia will have to produce meaningful levels of clotting factor for a large number of patients, it will have to erase bleeds or the need for preventative treatment, and of course it will have to be safe.

One dose will also have to last a long time, although a one-shot lifetime cure is probably too much to expect. “I don’t think it’s resolved how long we need it to last,” says BioMarin’s Carter.

If it succeeds on all those fronts, BioMarin’s gene therapy will make a good economic case in hemophilia, despite a likely sticker stock-inducing price tag.

So far, it’s more a learning experience than an investable moment. The responses to BMRN-270 vary at this point, for instance. Two patients who are seven weeks out are producing 4 and 8 percent of normal Factor VIII, while another patient is producing 21 percent after six weeks.

Carter says so far that there appears to be a spike in Factor VIII expression around nine weeks after treatment, which means BioMarin’s numbers could look better soon. Still, it’s an unknown. “The only way we can really assess the variability is to follow all of these people out longer,” he says.

The trial’s lead investigator John Pasi, a professor at Barts and The London School of Medicine and Dentistry, says all six patients on high doses have been off preventative treatment since achieving “measurable” levels of Factor VIII. One of those patients had a bleed early on in the trial, but that was before the gene therapy kicked in, he said.

Like other companies developing gene therapies for hemophilia, BioMarin is reporting a rise in patients’ liver enzyme levels, a sign of an immune system response to the treatment.

The potential problem is alleviated with steroids, but it’s worth watching going forward. In BioMarin’s trial, according to Pasi, steroids haven’t temporarily caused the expression of the clotting factor to drop, as they have in some other hemophilia B studies.

Biomedical researchers and drug developers have wrestled for decades to turn gene therapy—a method of using viruses to shuttle genetic fixes into patients—into a weapon against hemophilia, as I wrote last year.

But the technology has advanced faster for hemophilia B and its smaller population than hemophilia A. Researchers at St. Jude Children’s Research Hospital in Memphis, TN, and University College London published a study in the New England Journal of Medicine in 2011 that many consider proof that the method can work. Baxalta and UniQure (NASDAQ: QURE) have already produced early clinical data in hemophilia B, and several others like Spark Therapeutics (NASDAQ: ONCE) and Dimension Therapeutics (NASDAQ: DMTX) are following closely behind.

Hemophilia A has been a tougher challenge because the gene for the Factor VIII protein is larger than the gene for Factor IX, the protein that hemophilia B patients lack. The larger the gene, the harder it is to pack into a virus and deliver to patients. Carter says BioMarin has taken out part of the gene to make it small enough to fit. So far, that’s given BioMarin the chance to be the first to the finish line with a gene therapy in hemophilia A. No one else has reached clinical testing.

“It’s a really steep learning curve,” Pasi says. “But it’s a very exciting learning curve to be on.”