Uptake of new hemophilia gene therapies slow as field assesses options
People with hemophilia have a fault in a gene that regulates production of proteins called clotting factors.
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NEW YORK: High cost, logistical issues and the prospect of potential treatment advances are holding back adoption of the first gene therapies for hemophilia, experts said this week during the American Society of Hematology's (ASH) annual meeting. Experimental options discussed at the San Diego meeting included personalized treatments and next-generation gene therapies, many still in the earliest stages of testing.
People with hemophilia have a fault in a gene that regulates production of proteins called clotting factors. This can cause spontaneous bleeding as well as severe bleeding following injuries or surgery. Since the gene is carried on the X chromosome, hemophilia is almost entirely a male disease.
U.S. regulators over a year ago approved the first one-time gene therapy for hemophilia B, CSL's Hemgenix. Its list price of $3.5 million makes it the world's most expensive drug. BioMarin's Roctavian, the first gene therapy for the more common hemophilia A, was approved in June and has a U.S. list price of $2.9 million.
"The problem is nothing is perfect with gene therapy," said Dr. Margaret Ragni, professor at the University of Pittsburgh's hematology/oncology division. She said many patients are not great candidates due to underlying conditions such as having antibodies to blood factors, antibodies to the virus used as a vector to deliver the new gene, liver disease, HIV infection or obesity. The durability of the replacement genes and risks of long-term side effects are also open questions.
Dr. Michael Recht, chief medical and scientific officer at the National Bleeding Disorders Foundation, said gene therapies can be "transformative" for the right patient, but large medical systems have been stymied by their expense and logistics. "Three and a half million bucks is a lot to have sitting on your books, waiting for an insurance company to get around to cutting that check," he said. "In the entire Northeast region so far there hasn't been a single vector delivered yet."
BioMarin declined to comment on timing for commercial use of Roctavian in the United States, but said many hemophilia treatment centers have begun site preparation. The first commercial patient was treated with Hemgenix in June. CSL declined to comment on use to date, but has said it expects around 50 commercial patients globally by next June.
Bob Lojewski, CSL's North America general manager, said "a lot of patients" have been referred for Hemgenix and are waiting to get the therapy administered. Sources said the hemophilia community has been hesitant to embrace gene therapy in part because in the 1970s and 1980s thousands of patients became infected with hepatitis C or HIV from donated blood.
A major advance came in the early 1990s, when bioengineered clotting factors replaced those derived from blood plasma. About 10 years ago, long-acting factor replacements were developed, greatly reducing the number of infusions needed to prevent traumatic bleeding. Both Hemgenix and Roctavian deliver replacement genes by an infusion to the liver using a modified virus. Afterward, patients develop antibodies to the virus, making them ineligible for any future gene therapies that use the same delivery system.
'INCREDIBLE INNOVATION' Hemgenix data presented at ASH showed that after three years, 51 out of 54 trial participants remained free from the need for regular factor replacement infusions, although nine needed treatment for liver enzyme issues.
Roctavian trial results showed that after three years, 46 out of 134 patients had factor VIII levels within the range classified as moderate or severe disease, and eight of them had resumed other treatments. Currently, the most widely-used hemophilia A treatment is Roche's antibody Hemlibra, which won U.S. approval in 2017. Given as a weekly injection, it works by bridging other factors in the blood to restore clotting.
Unlike the gene therapies, which are approved only for adults, Hemlibra can be given to all ages, including infants. Pfizer on Monday said it is seeking U.S. approval for its experimental antibody marstacimab after showing positive Phase 3 data at ASH for both hemophilia A and B.
Pfizer and Roche are also developing gene therapies for hemophilia. Other hemophilia researchers are looking to genetically modify a patient's own stem cells and re-introduce them, but without need for harsh transplantation conditioning regimens. Others are looking at ways to engineer a patient's B cells to produce blood factors; and to use gene editing to correct clotting factor production.
"There is some incredible innovation," Recht said.
