Stopping the bleeding

The first time Terence Blue understood he was different was during a kindergarten kickball game.

The other team fielded his kick and threw the big rubber ball at him to get him out. Blue tripped over the ball and hit his head on the ground, which didn’t rattle him much. What did was the reaction of the adults watching, who gasped and rushed over. Luckily, the 5-year-old had recently received clotting factor as part of his regular treatment for hemophilia. The factor did its job, stopping any bleeding from the tumble’s cuts and scrapes.

“I’d seen other kids take falls and remember thinking, ‘What’s all the fuss?’ Then I realized I really do need to be extremely careful about those things,” Blue said. “I realized then that I had to pay attention.”

For the next 27 years, Blue paid attention. Diagnosed at just months old, for years he visited the hospital two to three times a week for shots of the clotting factor missing from his blood. Eventually his mother learned to give him the shots and, when he was 8, a nurse taught him to do the task himself.

Over time, medical technology made living with hemophilia easier. Synthetic factors eliminated the risk of HIV, hepatitis C, and other pathogens that might lurk in donated blood. New factors last longer, allowing Blue to stretch the interval between shots to two weeks. Still, the idea he might go two months without a shot was more dream than reality.

“I remember being told ‘Within your lifetime, there may be a cure,’” Blue said. “It always seemed like a magic bullet or wishful thinking, a genie-in-a-bottle situation. But it’s starting to prove true. This is one step closer. So science, let’s keep making it happen.”

“I remember being told ‘Within your lifetime, there may be a cure.’ It always seemed like a magic bullet or wishful thinking.”

Terence Blue

In early February, Blue was the first patient in New England to receive a relatively new gene therapy for hemophilia B, at Harvard-affiliated Brigham and Women’s Hospital. Called Hemgenix, it was developed by drug maker CSL Behring and granted FDA approval in November 2022. It is part of surge of gene and cell therapies finally emerging from the long discovery pipeline that leads from the lab to patients’ hospital rooms.

Market reality vs. scientist and patient dreams

While that surge promises an expanding menu of gene and cell therapies — which are targeting more common conditions, have improved safety profiles, and improved vectors to carry them into the body — it also means the new treatments must face another force: the market. An implacable attention to balance sheets can negate both scientists’ long labors and patients’ fervent dreams.

“We’re seeing many more gene therapies coming into the clinic but the field is adjusting to the fact that not only does it matter that you can bring the gene therapies to the clinic and get them approved by the FDA, but there are market pressures and patient acceptance that has to be put into the equation,” said Roger Hajjar, head of Mass General Brigham’s Gene and Cell Therapy Institute. “So if the pricing is too high and too few patients actually benefit from the therapies, certain approved drugs in gene therapy are actually being withdrawn because there’s not enough payers to pay for them and not enough patients to benefit.”

Part of gene therapies’ difficulty is that they offer fewer opportunities to recoup research and development costs. Unlike medications for chronic diseases like diabetes, high cholesterol, and high blood pressure, which are taken regularly over a lifetime, gene therapies are typically given in a single dose that aims to correct disease-causing mutations and provide long-lasting benefits. That means eye-watering prices. Blue’s treatment, for example, lists for $3.5 million, though insurance companies typically negotiate lower rates, said his physician, Nathan Connell, associate director of the Boston Bleeding Disorders Center and vice chair of the Department of Medicine at Brigham and Women’s Hospital.

That can mean little room for a market to grow and mature as patients and physicians learn about a treatment, according to Nathan Yozwiak, head of research for Mass General Brigham’s Gene and Cell Therapy Institute. The learning curve is often gradual, he said, and patients sometimes aren’t as enthusiastic as expected. Drugmaker Pfizer is already pulling its own hemophilia B gene therapy, Beqvez, from the market less than a year after its FDA approval, citing limited interest among patients and their doctors. In 2021, Bluebird Bio withdrew its beta thalassemia therapy Zynteglo from the market after a dispute with German regulators over its $1.8 million price. Even a groundbreaking treatment like Glybera, a treatment for a rare dysfunction in fat digestion and the world’s first gene therapy, was withdrawn in 2017 after treating just a single patient in five years.

But enthusiasm for gene therapy’s potential to transform patients’ lives, perhaps permanently, ensures that work continues. Today, the field is gathering additional steam as new treatments emerge from the pipeline connecting basic research to the hospital clinic, according to Hajjar, a pioneer in cardiac gene therapy for heart failure. An FDA tally of gene and cell therapies — in which healthy cells or those altered in the lab are given to the patient — shows 44 therapies have been approved in the U.S. Two were approved in 2022, five in 2023, and 18 in 2024 for conditions including multiple myeloma, invasive bladder cancer, sickle cell disease — which employed CRISPR gene editing technology for the first time — and cartilage defects in the knee, among others.

“Within the research side of things, there’s enormous, enormous optimism that’s reflected in the fact that the catalog of diseases for which researchers are pursuing a gene or cell therapy is growing every year,” Yozwiak said. “At the end of the day, I think we’re going to have a number of therapies that are actually very effective. Aligning that with the economic realities can be frustrating for researchers sometimes.”

‘I’m tired of needles’

Blue began talking about gene therapy with Connell two years ago after Hemgenix was approved by the Food and Drug Administration. Blue said it took several months to examine study data on his own, get used to the idea of introducing foreign genes into his body, and decide to move ahead. The idea that he might be able to unhitch his life from the needles that have been a daily reality, that he might be able to travel without needing an emergency supply of factor IX — just in case — and that he might escape the very real social pressures that have cost him friends grew on him.

“I’m tired of needles. They’ve been a part of my life forever,” Blue said. “It’s a small thing but it gets to you.” 

After he decided to move forward, it took months more for the hospital to develop its own scientific review, internal approvals, and protocols before, finally, ordering the drug and administering the treatment.

The therapy takes advantage of viruses’ natural ability to home in on a particular organ and insert viral DNA into cells’ genetic code. In this case, bioengineers picked a virus that targets the liver — where the body makes clotting factor — and replaced the virus’ DNA with a corrected copy of the mutated gene that causes hemophilia B. Once in the liver, the virus inserts its payload into liver cells, jump-starting production of clotting factor IX, which is deficient or missing in hemophilia B, the rarer of hemophilia’s two forms and affecting about 15 percent of patients.

“You basically have a bit of a Trojan horse,” Connell said. “You want to get it into the liver and you use this mechanism to get it there. Patients come into the infusion center and it’s all done as an outpatient.”

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Because the genes causing hemophilia reside on the X chromosome, the condition is more common among men than women. Women have two copies of the X chromosome and even one normal gene usually allows their blood to clot normally. Men, with XY chromosomes, have only one chance: If their single X chromosome contains the mutation, they develop hemophilia. The U.S. Centers for Disease Control and Prevention says exact figures for those living with hemophilia are unknown, but a recent survey showed about 33,000 American males living with the condition.

Hemophilia care has come a long way, greatly aided by recent decades’ standardization of prophylactic injection of clotting factor for severe cases like Blue’s. Life expectancy was under 30 before the advent of modern hemophilia care but today approaches that of the average male population, according to a recent study by Canadian researchers.

“I called him and I think he was in a meeting at work. He didn’t know what to expect. I was really excited to tell him that it’s working.”

Nathan Connell

Though better, care remains imperfect, Connell said. Spontaneous bleeds are part of life, can be difficult to predict or control, and are often internal, affecting different parts of the body, including the brain. It’s not unusual for patients to experience spontaneous bleeds and wake up with a stiff elbow, knee, or other joint, a sign that blood has pooled within. The situation can be managed with an extra dose of clotting factor, but over time the bleeds damage the joints’ smooth, slippery cartilage, causing pain as well as making them prone to additional bleeding. Blue, today 33, has an ankle with an arthritis-like condition called hemophilic arthropathy because of trauma that began with an injury when he was young.

“Before we used prophylaxis, many people with severe hemophilia wound up in wheelchairs or using crutches because they would have frequent bleeds and then lose their ability to walk,” Connell said.

After decades managing the condition, Blue said the physical aspects of living with hemophilia have become routine, though never far from his consciousness. The social aspects are still difficult, however, and can be disheartening. He regularly must explain to companions why he can’t do certain activities and says that revealing his condition has cost him friends. Today, unless he’s engaged in an activity for which he believes companions need to know, he keeps silent.

Even with its limitations, Blue’s been able to live an active life. He got his black belt in tae kwon do when he was 14 — wearing extra pads when sparring — and outside of his work as an IT security engineer, enjoys bachata, a type of Latin social dancing, several times a week.

For something so cutting-edge and potentially impactful, receiving the therapy was fairly routine, if not dull. Blue’s infusion occurred on Feb. 6 and took about two hours. Watched closely by Connell and other members of his care team, Blue reported few side effects. After another four hours of observation, he was able to go home after reporting nothing amiss. In the weeks that followed, he began steroid treatment after enzymes in his liver became elevated. On. Feb. 20, he received his last injection of clotting factor IX, and as of mid-March, was tapering off steroids as liver function improved. By then, his factor IX levels, which had been less than 1 percent, had risen to 32 percent, in the mild hemophilia to low normal range.

“We hope it works. We have data that it works, but until you see it start to do something, you always have a little fear that maybe it’s not going to work out right,” Connell said. “I called him and I think he was in a meeting at work and he stepped out when he saw the number. He didn’t know what to expect. I said, ‘It’s working.’ And I was really excited to tell him that it’s working.”

Though physicians are hesitant to describe these therapies as “cures,” there is the prospect of yearslong or decadeslong effects. Ninety-four percent — 51 of 54 — of those treated with Hemgenix during the clinical trial still do not require factor IX prophylaxis three years later, according to the drugmaker’s website. Blue, who got a painful cut under his thumbnail in March, is still getting used to the healing journey he’s embarked on.

“I’ve had this happen many times before, so after I freaked out for a moment, I went to treat it,” Blue said. “My wife was sitting there looking at me, watching, and within seconds I realized that it was starting to resolve. This is abnormal for me. I’m ‘severe’ and am used to seeing bleeding happen for longer. In that moment I thought, ‘Wow, this is real. This is working. I haven’t had factor in ages, but here I am actually healing faster than I ever have in my life.’”