Given everything he’s been through, Bobby Wiseman says he should have been dead instead of celebrating the birth of his first grandchild several days ago.
Wiseman, 51, who lives near Sacramento, was diagnosed as an infant with hemophilia, the rare genetic disease that prevents blood from clotting. He tested positive for HIV and hepatitis C when he was 11 after catching the viruses from contaminated blood-clotting products. As a teenager, he spent 45 days hospitalized in a coma from massive gastrointestinal bleeding.
But Wiseman’s HIV is undetectable now because of medication he takes monthly. His hepatitis, he said, was cured by another breakthrough drug. Perhaps most remarkably, he hasn’t had to regularly inject a protein to make his blood clot since 2018. That’s when he became the first patient in a study to receive an experimental gene therapy for his form of the bleeding disorder, hemophilia B. The one-time intravenous infusion was developed by UniQure, a Dutch biotech with operations in Lexington.
Called Hemgenix, the gene therapy was cleared by the Food and Drug Administration in November, but has yet to be given to patients outside of a clinical trial. It uses a modified virus to deliver a gene to liver cells to produce a missing blood-clotting protein called factor IX. Hemgenix is the first approved gene therapy in the United States for hemophilia. At $3.5 million per patient, it’s also the world’s most expensive drug.
Wiseman says he volunteered to receive it partly because he remembers how HIV and hepatitis C from tainted blood-clotting proteins killed friends with hemophilia in the 1980s, before better screening methods for donated blood emerged.
“I did not want the folks who would be coming up to have to go through some of the things that I had to go through living with hemophilia B,” said Wiseman, financial services director for a San Francisco nonprofit.
CSL Behring, a drug company headquartered in King of Prussia, Pa., paid UniQure $450 million in 2020 for the global rights to Hemgenix. The firm plans to begin treating patients with severe hemophilia B in the United States by March 31. William Mezzanotte, CSL’s head of research and development, said that “maybe a third” of the roughly 6,000 hemophilia B patients will be eligible for Hemgenix. He said “multiple” insurers have pledged to cover the cost of the treatment but declined to name them.
There are as many as 33,000 people in the United States with hemophilia, according to the Centers for Disease Control and Prevention. Predominantly male, they lack one of two key proteins needed for blood to clot. About 15 to 20 percent have hemophilia B while the rest have hemophilia A, which is caused by low levels of another protein known as factor VIII.
Hemgenix was approved based on two clinical trials of 57 men with severe or moderately severe hemophilia B. In one study with 54 volunteers, a single infusion led to an increase in clotting factor levels, reduced the rate of annual bleeding episodes, and enabled 94 percent of patients to stop injecting clotting factor.
Despite those impressive results, several hemophilia doctors, advocates for patients, and patients themselves report widely varying interest in Hemgenix and in another potential gene therapy for hemophilia A called Roctavian. BioMarin Pharmaceutical, a San Francisco area drug firm, hopes the FDA will approve Roctavian this year.
Dr. Steven Pipe, a professor of pediatrics and pathology at the University of Michigan who served as principal investigator in the clinical trials for Hemgenix and Roctavian, said he has already spoken with two young men with hemophilia B who want to receive Hemgenix soon. Both had relatives in the trials.
“It’s very telling when you have family members of guys who have gone through this procedure who are now clamoring and calling and saying, ‘I want what he had,’ ” said Pipe.
But Dr. Stacy Croteau, a pediatric hematologist and clinical researcher at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, said no one has asked her for Hemgenix, although some patients are curious. The FDA approved Hemgenix for males 18 and older; some of Croteau’s patients are as old as 24.
Many of her patients, she explained, lead relatively normal lives by injecting one of the two clotting factors a few times a week or month. Some had relatives with hemophilia who were infected with HIV and hepatitis C a generation ago and don’t want to take a chance on a new technology, particularly because it’s uncertain how long the benefits of gene therapy will last.
“Some are interested in learning more, but no one has said, ‘Dr. C, I’m going to bust down your door to get it,’ ” she said. “It’s not a slam dunk.”
Garrett Hayes is among those in no rush. A 24-year-old medical scribe for a cardiologist in the Dallas area, Hayes has severe hemophilia A ― the form that the experimental gene therapy Roctavian targets ― and injects himself with factor VIII three times a week. He has been doing it since he was eight years old and says it takes about 10 minutes.
Without the injections, Hayes said, his body produces less than 1 percent of the normal amount of factor VIII. But with them, he has run five marathons without fear of hemorrhages (his fastest time is three hours and 36 minutes), earned a master’s degree in public health, and plans to attend medical school in the fall.
“I do think gene therapy is the most promising thing I’ve seen in my lifetime,” he said. “But I kind of approach it with the if-it-ain’t-broken-don’t-fix-it mentality. There’s too many unknowns for me to want to jump aboard that ship at this point.”
Although hemophilia is rare, it has played an outsized role in history.
The first cases of abnormal bleeding were documented in the 2nd century AD, according to the National Hemophilia Foundation. The Talmud, a collection of Jewish rabbinical writings on laws and traditions, said baby boys did not have to be circumcised if two of their brothers bled to death from the procedure.
Hemophilia was sometimes known as “the royal disease” because it afflicted the royal families of England, Germany, Russia, and Spain in the 19th and 20th centuries. Queen Victoria, who ruled England from 1837 to 1901, is believed to have been a carrier of hemophilia B.
Her great-grandson, Alexei Nikolaevich, the only son of the last czar of Russia and heir to the throne, was afflicted with hemophilia B. To stanch his bleeding, his mother, Empress Alexandra Feodorovna, turned to the notorious Siberian mystic and faith healer Rasputin. His growing influence on the empress, some historians say, contributed to the czar’s unpopularity and helped precipitate the Russian Revolution of 1917.
In the late 1950s and much of the 1960s, fresh frozen plasma transfused in patients was the mainstay of hemophilia treatment. But because the plasma contained only tiny amounts of clotting factors, it required great volumes. Children often had to be hospitalized to stop bleeding, particularly into joints such as a knee or elbow. By the early 1970s, technological advances enabled patients to infuse themselves using bottles of freeze-dried factor concentrates made from pooled plasma.
The emergence of HIV in the early 1980s took a devastating toll on people with hemophilia. About half of them in the United States eventually became infected through contaminated blood products, and thousands died, according to the National Hemophilia Foundation.
In the 1990s, scientists developed genetically engineered clotting factors that don’t come from human blood. The standard of care for treating hemophilia has also changed from stanching bleeding to preventing it with regular infusions of factors, a regimen called prophylaxis.
Given that clotting factor levels in the blood fall between infusions, some patients schedule them before activities that can cause bleeding, such as playing sports or undergoing surgery.
A gene therapy that provides lasting benefits would make that unnecessary, one of the reasons it has tantalized patients and scientists for 30 years. Although the first patients in the Hemgenix studies received it only five years ago, trial data suggest that it will protect people with moderate to severe hemophilia from uncontrolled bleeding for eight years, and maybe longer.
Matt Kapusta, chief executive of UniQure, developer of Hemgenix, said the vast majority of patients in the trial stopped needing replacement therapy and that for most of them, the gene therapy was “functionally curative.” UniQure plans to manufacture Hemgenix in Lexington.
Although the $3.5 million price is eye-popping, CSL, which licensed the gene therapy, said that patients with moderate to severe hemophilia B can cost health care systems more than $20 million over their lifetimes, so it could actually save money in the long run.
Still, the price tag exceeded the $2.93 million to $2.96 million that the Institute for Clinical and Economic Review, an independent nonprofit drug-pricing watchdog in Boston, said would be fair.
Earlier this month, BioMarin, located in the San Francisco Bay area, unveiled encouraging data about Roctavian. It showed that over three years, 92 percent of 134 adults with hemophilia A who received the gene therapy no longer needed to inject clotting factor, and that annual bleeding episodes dropped by 80 percent.
BioMarin originally hoped the FDA would approve the gene therapy by the end of March, but Dr. Henry Fuchs, the company’s president, said that deadline could get pushed to the end of June to give regulators more time to evaluate the latest data. “We’re encouraged that those data will be viewed favorably by the FDA,” he said.
But Dr. Leonard Valentino, chief executive of the National Hemophilia Foundation, said he was underwhelmed by the data because factor levels rose after infusions but then declined before stabilizing.
“If this were approved by the FDA and was available in the US, I think the uptake would be relatively minimal,” said Valentino, who worked on a rival potential hemophilia gene therapy at Spark Therapeutics in Philadelphia before joining the foundation in 2020.
For his part, Wiseman has no regrets that he received the first approved gene therapy, for hemophilia B. He said he hopes it eases his 75-year-old mother’s worries about his health.
“My momma can see where I’m at, and I’m doing good,” he said.
Ryan Cross of the Globe staff contributed to this report.
Jonathan Saltzman can be reached at firstname.lastname@example.org.