New medications such as emicizumab (Hemlibra) are transforming the lives of patients with hemophilia A, and more treatments are in the pipeline.
"It's an amazing time to be a hemophilia provider," Alice D. Ma, MD, University of North Carolina at Chapel Hill hematologist and bleeding disorder specialist, said in an interview. "There are real options, and it's very exciting."
But the drugs come with quirks that hematologists must understand, hemophilia specialists cautioned, and stubborn insurers pose significant obstacles to appropriate care. Also, new generations of medications in development offer both hope and more questions.
By far, the biggest game changer in hemophilia A is a monoclonal antibody called emicizumab (Hemlibra), first approved by the Food and Drug Administration for hemophilia A patients with factor VIII inhibitors and then in 2018 for those without factor VIII inhibitors.
"It's just been getting a bigger and bigger slice of market share as patients and parents really buy in to how great that product is," Ma said. "I do not have any hemophilia A patients with factor VIII inhibitors who aren't on it. That's just kind of a no-brainer, no ifs, ands, or buts."
About 50%-60% of her noninhibitor patients with hemophilia A take the drug, she said.
According to its manufacturer, Genentech, the drug "acts like a bridge, bringing factor IXa and factor X together to allow the blood coagulation process to continue without needing to replace factor VIII."
Since emicizumab is not a blood factor, Ma said, it doesn't cross-react with antibodies or inhibitors. "The other thing that is pretty amazing is that it's given subcutaneously as opposed to intravenously. It's given under the skin, kind of like an insulin shot, rather than into a vein."
Prophylaxis treatments did exist for patients with hemophilia A prior to emicizumab, University of North Carolina at Chapel Hill hematologist and blood disorder specialist Nigel S. Key, MB, ChB, said in an interview. But the treatments didn't stop all bleeding. "We never really kept them under control," he said, adding that patients needed to get infusions several times a week. "It was cumbersome and took a lot of compliance, a lot of effort to do it.
Thanks to emicizumab, adult patients don't have to put on tourniquets and stick butterfly needles into their own veins anymore, and parents no longer need to regularly give factor infusions to their children every 2-3 days, Ma said. Instead, doses may be required just once a week.
Not Every Patient Is Eager to Embrace Emicizumab
Emicizumab isn't necessarily an easy sell. Home-care company pharmacies don't get reimbursed as much for providing emicizumab, compared with factor infusions, Ma said, and some of these companies are urging parents to not accept the drug for their kids.
Prior experience can also make people wary. According to Ma, one of her patients – a 62-year-old man – was reluctant to take factor because he'd gotten infected with HIV from an infusion. "For guys of that certain age, factor was death. It was poison, so you tried really hard not to take it."
The patient now regrets not taking emicizumab earlier. He told Ma that his joints "do feel better than when I took factor regularly," and "he really thinks that it has made his hemophilia recede into the background of his life, which is pretty, pretty nice."
In fact, Ma said, he dropped a 7-pound rock on his foot but did not need to take factor or be hospitalized because of bleeding. Instead, he simply "watched a bruise form and then get better."
As for challenges beyond convincing patients to take emicizumab, Ma said that insurers can may still refuse to pay for it in noninhibitor patients. "Some of them say you have to fail a regular clotting factor to be able to take Hemlibra," she said, noting that she finds this viewpoint intolerable.
Hemlibra is remarkably expensive, but treatment of bleeds is also pricey. A 2021 study found that median 6-month hemostatic treatment costs in hemophilia A patients fell from more than $176,000 to barely $128,000 after they started taking the drug.
There's another hitch. Some hematologists don't realize that the drug can throw off certain coagulation readings. Ma recalled that a patient with hemophilia A went to a different healthcare facility for a gall bladder operation, and hematology fellows there failed to adjust his factor VIII level – an extraordinarily high 400%, suggesting high coagulation – to reflect his use of emicizumab.
"My patient bled severely and could have lost his life," Ma said.
Despite Gains, Hemophilia B Remains Hard to Treat
The much rarer hemophilia B (the type that affected members of European royal families who descended from Queen Victoria) has proved more difficult to treat than hemophilia A. An estimated 1 in 5,600 males in the United States are born with hemophilia A, compared with 1 in 19,300 males born with hemophilia B. The conditions rarely affect females.
Recombinant factor IX products that replace a missing protein have been improved and can now be given every 7 or 14 days, instead of twice a week, Key said. As for the future, so-called rebalancing therapies are in phase 3 trials and look promising: "Instead of trying to beef up the proclotting proteins, you're trying to knock down the anticlotting proteins. 'Rebalancing' is a good way to think of it."
These treatments are also agnostic – like Hemlibra – to the presence of inhibitors, he said.
These drugs could be available within a few years, Key said. "The major concern is always going to be a risk of thrombosis or clotting. Some of that has only become apparent through clinical trials and require a return to the drawing board to redesign the dosing to hit the safe, sweet spot that prevents bleeds but doesn't cause clots."
Ma agreed that clots are a significant risk from rebalancing agents. "I don't know that I would put a factor IX patient without an inhibitor on a rebalancing therapy, because we already have pretty darn good therapies for them," she said. However, factor IX patients with inhibitors do need better treatments, "and we're all looking forward to the next approved drugs there."
Hoopla for Gene Therapy, With Questions, as Well
The prospect of gene therapy for hemophilia, meanwhile, continues to draw attention as phase 3 trials continue. Potentially, gene therapy could be given just once to patients with hemophilia A or hemophilia B and provide bleeding control indefinitely, Ma said.
However, Key wondered whether gene therapy may be useful in hemophilia A, since emicizumab has worked so well. "I just don't see the tsunami of patients who are wanting to undergo gene therapy in the first few years. I think there'll be relatively slow uptake due to a lot of factors, including reimbursement."
Hematologist Amar H. Kelkar, MD, of Dana-Farber Cancer Institute in Boston, is also skeptical that a groundswell of patients will embrace gene therapy, even if one-time treatment lasts for years. Current treatments are working well for many patients, Kelkar said in an interview, "and comfort with novel therapies may be slow within the community, especially if the treatment effect is expected to be transient. This is the same community that was hit hard by contaminated blood products during the HIV crisis, so it may be hard to convince a large number of patients to adopt a new type of therapy. There's also the issue of the projected high upfront cost of gene therapies. Of course, I'd love to be wrong, especially if cost issues for the patients can be mitigated."
Moving forward, both Ma and Key urged hematologists to send their hemophilia patients to Hemophilia Treatment Centers so they can get specialized care. There are about 140 of these federally funded centers around the country, according to the National Hemophilia Foundation. Many are located in children's hospitals.
Hemophilia treatment now requires a subspecialty degree of knowledge that's difficult for a hematologist in general practice to master, Ma said. "If you have a patient with hemophilia, and you're in private practice for general hematology/oncology, please send them to a Hemophilia Treatment Center for something like a once-a-year check-in to make sure that the patient is getting comprehensive care."
Ma discloses relationships with Takeda (research funding and consultation). Key discloses relationships with BioMarin and Takeda (advisory board), Novo Nordisk (grants review committee), and Uniqure (steering committee). Kelkar has no disclosures.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Cite this: 'It's an Amazing Time to Be a Hemophilia Provider' - Medscape - May 27, 2022.