New Data Starts Stretch Run for UniQure’s Upgraded Hemophilia Gene Therapy

Xconomy Boston — 

The race to treat hemophilia with gene therapy, a one-time, long-lasting infusion, is entering its final stages. And with new data released this morning, Dutch and Lexington, MA, firm UniQure has finalized its plans to be among the top finishers.

UniQure (NASDAQ: QURE) today disclosed preliminary results from a tiny mid-stage study of a gene therapy called AMT-061. The treatment is one of several gene therapies in clinical testing for hemophilia. And it’s one of two specifically for hemophilia B—the less common form of the disease—that have begun enrolling patients in their final tests before potential approval.

Today UniQure reported that all three patients in the Phase 2 trial are producing an average of 31 percent of normal levels of Factor IX (FIX), the clotting protein they lack, an average of six weeks after getting AMT-061. One patient had 37 percent FIX at ten weeks; a second had 23 percent at eight weeks; and a third had 30 percent at six weeks. At least as of yet, none of them have had the dangerous bleeds hemophilia patients can suffer, or needed other preventative drugs to stave them off. The treatment hasn’t begun to wear off for any of the three patients.

No safety problems have emerged either; one patient had a “mild” increase in liver enzymes that quickly dissipated without additional treatment, UniQure says in a statement. (Similar immune responses have been seen in several tests of hemophilia gene therapies and are typically alleviated with steroids. None have yet led to significant issues.)

These results are from a very small number of patients, and after just a short period of time (UniQure will track them for years), so several caveats apply. But the data are nonetheless noteworthy because they are the first results with AMT-061, a newer version of UniQure’s hemophilia gene therapy. And they show that AMT-061, which is heading into late-stage testing, has the potential to compete with a rival treatment, SPK-9001, from Pfizer (NYSE: PFE) and Spark Therapeutics (NASDAQ: ONCE).

UniQure shares surged 40 percent, to $32 apiece, in pre-market trading Thursday.

The earlier version of UniQure’s gene therapy, AMT-060, couldn’t keep up with competition. The treatment produced average FIX levels of about 7 percent in ten patients in early testing, results which were once thought to be good enough. As other experimental gene therapies have advanced, the bar is now higher. A minimum of 12 percent of normal FIX should erase the bleeds that patients report and are treated for, while above 20 percent of normal should reduce the “subclinical” bleeds that patients may not even be aware of, but can still lead to health problems like joint damage, UniQure CEO Matt Kapusta says. In initial results from an early test, patients who got SPK-9001 averaged 35.5 percent of normal FIX 12 weeks after getting treated.

Last year, UniQure tweaked the treatment to boost its effectiveness. The new product, AMT-061, uses a mutant therapeutic gene that clots blood more strongly than normal—as does SPK-9001. Importantly, the FDA didn’t force UniQure to start over despite that change. So UniQure outlined a late-stage trial of AMT-061, HOPE-B, in which patients are observed for six months before getting treatment. And while enrolling patients, it decided to test AMT-061 in three test subjects at the same dose as its previous gene therapy, hoping for better results. UniQure believed three patients “would be sufficient” given it only made one change to the product and had amassed both preclinical and human data with AMT-060, Kapusta says.

UniQure is trying to show its treatment is at least as effective as Pfizer/Spark’s, but is less likely to provoke an immune response that could neutralize the treatment—and thus, potentially, be an option for more patients with hemophilia B. The key reason why is the two are delivered with different types of gene therapy delivery tools, known as viral “vectors.” UniQure will have to prove its potential advantage with further testing, though the company notes that two of its three responders were screened out of another gene therapy trial. Their immune system would have shut down the vector used in that study, UniQure says.

Before the data were released, Leerink analyst Joseph Schwartz estimated that if UniQure could show FIX levels for the three patients ranged between 20 and 35 percent, it would put the company “on-track to matching SPK-9001’s profile.”

“The big question in my mind, from investors, is can these guys get FIX levels up to be competitive?” Kapusta says. “And I believe we’ve now answered that question even with these early data.”

Given the results, UniQure will use the dose it has tested in the HOPE-B study when patients begin getting treated next year. Kapusta won’t say what the company’s expected timelines are after that, but he is talking up at least the possibility that the FDA is open to an “accelerated” approval of the gene therapy based on its ability to boost FIX levels. That puts its path in line with Pfizer, which began its pivotal program in July but hasn’t provided more details. A Pfizer spokesperson said the company “does not have an update at this time.” But the database shows that the company is recruiting patients for a six-month “lead-in” study that would serve as the control group for a subsequent Phase 3 trial. Kapusta says there’s a chance UniQure may reach the finish line first.

It’s important to note that while gene therapy has shown, in some cases, a stunning ability to help people with severe hemophilia produce enough clotting protein to prevent bleeds, several crucial questions remain unanswered. Responses to the gene therapies have varied—in some cases, significantly—patient to patient. It’s unclear how to tell who will respond the best, and at what point each patient will still need supplemental clotting factor on top of the gene therapy. Will some patients’ bodies neutralize the treatment? Will treatment effects wear off—especially with children—and if so, will anyone be eligible for a second dose?

These unanswered questions are why, for instance, Mark Skinner, the former president of the World Federation of Hemophilia, told Xconomy this week that he expects gene therapy, when it arrives, to “launch with a limited profile of patients.”  Variables from price point to coverage decisions to peoples’ personal preference—some may stick with existing treatments and take a wait and see approach with gene therapy, Skinner says—will all determine who will get treated.

“It may not be every patient is waiting on line as soon as this product is approved,” Kapusta says. “But I do think over time you will see a substantial migration of the hemophilia community to gene therapies as they’re demonstrated to be durable and safe.”

The most advanced treatment is a hemophilia A gene therapy from BioMarin Pharmaceutical (NASDAQ: BMRN), which could head for an FDA review next year. The hemophilia B programs from UniQure and Pfizer/Spark could be next.

Here’s more on the shifting landscape of hemophilia treatments, and the race to treat it with gene therapy.