Gene Therapies Advancing in Trials Offer Hope to Hemophiliacs, But Concerns Abound

Gene therapy has the potential to stop hemophilia in its tracks. But such therapy will likely be costly, and can carry risks that have generated some apprehension among patients who could benefit most from it.

That’s the message from hemophilia patient advocates who spoke at the 2018 NORD Rare Diseases & Orphan Products Breakthrough Summit in Washington, D.C., last month.

“In the bleeding disorders community, gene therapy is not new. It is also only available in clinical trials for adults, so there’s still a lot of reservations about it,” said Carrie Koenig, the mother of a child with severe hemophilia and programs manager at the Washington-based Hemophilia Federation of America.

Compared to many rare diseases, hemophilia is generally considered a good candidate for gene therapy — and several companies have made progress in this regard. One is Philadelphia-based Spark Therapeutics, which won approval from the U.S. Food and Drug Administration for Luxturna (voretigene neparvovec) in December 2017 to cure a rare, genetic form of blindness.

Luxturna is the first approved one-time therapy of its kind that targets a disease caused by mutations in a specific gene. At $850,000 for both eyes, it’s also the most expensive treatment in the United States.

Building on that success, Spark, together with Pfizer, is now investigating fidanacogene elaparvovec (formerly, SPK-9001) to treat hemophilia B. The latest results of its open-label Phase 1/ 2 trial (NCT02484092) — underway at sites in the U.S., Canada, and Australia — show that the overall annualized bleeding rates of all 15 treated patients dropped by 98 percent four weeks after the therapy’s infusion.

A Phase 3 study (NCT03587116), sponsored by Pfizer, will enroll up to 110 adults with moderate to severe hemophilia B for six months of factor IX prophylaxis replacement therapy (standard care) prior to testing fidanacogene elaparvovec, which using a harmless virus to deliver the human factor IX gene to liver cells where this factor is normally produced. Sites in four U.S. states are, or soon will start, enrolling patients; information is available here.

Jumping on the bandwagon

In May, BioMarin released updated data from its Phase 1/2 trial of valoctocogene roxaparvovec (formerly, BMN 270) for hemophilia A, which is caused by missing or defective factor VIII, a clotting protein. About 30 percent of patients with severe hemophilia A develop an inhibitor that neutralizes factor VIII activity.

Data from the California-based company’s study showed continued and substantial reductions in bleeding requiring factor VIII infusions, no spontaneous bleeds, and elimination of bleeds in target joints in the second year. Two global Phase 3 trials — one testing this gene therapy at a 6E13 vg/kg dose (NCT03370913), and the other at a  4E13 vg/kg dose (NCT03392974) — are now getting underway; more information is available by clicking on their respective trial numbers.

Meanwhile, Dutch biotech firm uniQure is developing a gene therapy candidate called AMT-180 with the potential to treat all hemophilia A patients, according to the company.

AMT-180 contains a modified factor IX gene known as Super9, which has shown ability to bypass inhibitors to factor VIII in preclinical studies and may therefore help patients previously excluded from gene therapy approaches.

Recently, uniQure announced that patient enrollment for its global Phase 3 trial (NCT03569891) of the potential hemophilia B gene therapy AMT-061 is ongoing. It also said that three patients included in a Phase 2b study (NCT03489291) of AMT-061 have already been treated.

“We’re now at the stage where gene therapies are going to be completely transformative,” uniQure’s chief scientific officer, Sander van Deventer, said at the World Orphan Drug Congress in Barcelona on Nov. 7. “If you speak to hemophilia patients who have been treated with gene therapy, they say their lives have been completely transformed.”

Gene therapy ‘not a cure’

A resident of Maryland, Koenig is all too familiar with the disease; both her father and son have severe hemophilia B.

“I personally watched my father live without any viable treatment option,” Koenig said. “But my son is a fairly active, well-managed 8-year-old with hemophilia. There are still a lot of unknowns for us, but if we can manage his disorder and he can live a normal life, why rock the boat? I’m not unique in that perspective. Even a lot of older guys with severe hemophilia have that view as well.”

Koenig, who graduated Penn State in 2004 and McDaniel College in 2013 with a master’s degree in curriculum and instruction, says there’s a misperception in the hemophilia community that gene therapy is a cure.

“That’s not really what it is. It’s a transformation, a pause in the disease,” she said. “It doesn’t reverse the damage, but stops it from continuing.”

Asked how to explain gene therapy to people who know nothing about it, Koenig said she has a hard enough time explaining hemophilia.

“Hopefully we can save our kids and change the story for patients who have had very little hope for many years,” she said. “We need to partner with industry and push for education for patients and families, so they can know what questions to ask and understand the risks. Education is really important when it comes to gene therapy — especially with bleeding disorders.”

‘Unprecedented growth’ and challenges

Brendan Hayes is government relations specialist at the New York-based National Hemophilia Foundation. She’s also the mom of two sons with hemophilia.

Hayes says that while medicine is “in an era of unprecedented growth” for hemophiliacs, treatment prices — including those likely for gene therapies, should they be approved —must come down significantly so that patients, and the companies that employ them, can afford such innovations.

“Patients across the country are demanding safe, effective and affordable treatments. There’s a misconception that patients aren’t really concerned with price, they just want a cure,” she said. “But we are concerned. I’m in awe of these parents of rare-disease children who are raising money to fund biotech firms to cure their child’s illness.”

In the U.S., 60 percent hemophiliacs are on commercial insurance plans — most of them self-funded.

“You’d think that if you have advances in therapy, you’d see the cost of existing therapies go down,” she said. “But right now, you have people who can barely afford their premiums but can’t afford to use their insurance. There’s something wrong with that.

“I live in Texas, and we have the highest uninsured rate in the country,” Hayes added. “If you have a bleeding disorder and you’re a man over 18 without insurance, you go to the ER. And the infusion you could have done at home for $3,000 now costs about $20,000.”

Potential one-time gene therapies for hemophilia, meanwhile, may end up costing anywhere between $1 million and $2 million.

“The question is, how long will that person need to be employed for the employer to see some sort of payback?” she said. “Current therapies for hemophilia typically cost $300,000 to $500,000 a year, so we have to come up with creative solutions. We don’t want to slow down progress, but we must look at alternative payment strategies.”