Fred Kadiddlehopper
5月前
Re VERTEX current strruggles (From the Boston Globe 2/5/26)
https://www.bostonglobe.com/2026/02/05/business/vertex-crispr-sickle-cell/
Vertex’s CRISPR treatment for sickle cell disease hits unexpected roadblock
By Jason Mast STAT,Updated February 5, 2026, 2 hours ago
Vertex executives warned that Casgevy, its curative treatment for sickle cell disease, would be slow to reach patients. But few expected it to be this slow.
More than two years after its approval, only about 60 patients across the US, Middle East, and Europe have been treated with the gene-editing therapy. Specialists at four sickle centers told STAT they’ve been surprised by one of the key stumbling blocks to faster rollout: They can’t collect enough cells to create the treatment.
The problem comes at a crucial time for Vertex, which is trying to establish Casgevy even as it fights off rival therapies and braces for a major competitor next year.
To make Casgevy, doctors need to retrieve blood stem cells from patients and send them off to Vertex to be gene edited with CRISPR and then returned for re-infusion. But retrieval, that first, seemingly routine step, has been among the hardest.
Some patients have had to come in for five different hospital stays. A small percentage have given up during the journey or been told by physicians that they are unlikely to ever have enough cells to be treated, devastating news for patients who were hoping to be cured. In some cases, doctors have sent off what they believe to be enough cells, only for Vertex to say the company was able to edit only a small percentage of them.
“I would say if collection wasn’t a problem, you could almost get to double the number of patients,” said John Manis, a Boston Children’s Hospital physician who led a National Institutes of Health working group on cell collection for sickle cell disease.
These hurdles have not changed many patients’ desire for treatment. Casgevy, while not always a cure, offers a potential lifetime free of the excruciating pain crises and other complications of a condition that often kills in mid-life. But the collection changes have lengthened and complicated what was already expected to be an arduous treatment journey — requiring a battery of health exams, insurance approvals, months waiting for the therapy to be manufactured, intensive chemotherapy to clear out unedited cells, and four to six weeks in the hospital to receive the final infusion.
The process can exceed a year. The wait time for a slot at Vertex’s facilities fluctuates with demand but can stretch up to six months, doctors said, and it can take another six months to send back the finished therapy.
Because they can’t predict how long it will take to collect sufficient cells, doctors say they can’t give firm timelines to patients on when they’ll be treated. Christopher McKinney, a hematologist at Children’s Hospital Colorado, described an adolescent with sickle cell who started the process early last year, which should have put him on track to be treated over the summer and not miss school for the hospital stay.
He is instead being treated this week, after he needed five different collections. Each collection can last two to five days, and they have to be spaced weeks apart.
“So, yeah, it’s been quite disruptive,” he said. “And we can’t tell any of the patients how to plan that at this point.”
For Vertex, cell collection difficulties pose both an operational and business challenge. The company manufactures serially, so if a patient requires four collections, it takes up to four different manufacturing slots at the company’s factories, limiting Vertex’s ability to treat more patients.
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The company is also competing with Genetix — formerly known as Bluebird Bio — which had a different gene therapy, Lyfgenia, approved at the same time. Although the pathology of sickle cell disease can make collecting cells from any patient difficult, some doctors say they’ve encountered fewer challenges with Genetix. The company uses a gene-replacement technology that is gentler on cells and thus requires fewer of them.
Alexis Thompson, head of hematology at Children’s Hospital of Philadelphia, said she sometimes asks families who come in wanting Casgevy, because they’ve seen Vertex’s ads or are excited about CRISPR, to consider Lyfgenia.
“We’re at a point now where we’re very concerned about the reliability of timing for the Vertex product,” said Thompson, who helped run trials for Genetix and has consulted for Vertex. “If a family says, I really want and need this to be done by next summer, we say to them, ‘then we can’t honestly recommend this product for you right now.’”
Other doctors cautioned they’ve seen challenges with both. It’s “so bad for both of them,” said Manis.
A Genetix spokesperson declined to share detailed commercial numbers but claimed the company has treated more sickle cell and beta thalassemia patients — for whom these treatments are also approved — in the US than Vertex has treated around the world. He said 70 percent of sickle cell patients were treated after one collection and 89 percent were treated after two. (Beta-thalassemia patients don’t face the same collection challenges for either product.)
In an interview, Vertex Chief Commercial Officer Duncan McKechnie acknowledged the company had collection challenges early on but said its staff has been working to help centers collect better and to improve its manufacturing process.
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McKechnie said the number of collections per patient is now “essentially the same” as it was in trials, when the median patient needed two.
“So I think there’s a lot of learning,” McKechnie said, adding that, despite the complexities of gene therapy, 150 patients have already had their first collection “and 60 or so of them have now, frankly, had their lives transformed.”
A spokesperson added that Vertex tells centers to expect roughly 24 weeks from the first collection to finished product and that, “In the vast majority of cases, this target is hit” and “the turnaround is usually shorter.” But the company declined to share actual data.
For Vertex, time is of the essence. In addition to Genetix, Beam Therapeutics could have a new, potentially more effective and easier to manufacture gene-editing treatment approved next year. If so, Vertex has a limited window to establish Casgevy and recoup the billions it and its partner CRISPR Therapeutics invested in a transformative treatment.
“Will Beam become the leading cell therapy quite quickly just based on this merit alone?” said Eric Schmidt, a biotechnology analyst at Cantor Fitzgerald. “Yes, I think it will be.”
Not designed for sickle cell patients
Hospitals routinely collect stem cells from patients for transplants to treat cancer and certain genetic conditions. But it is uniquely challenging to do in sickle cell patients.
Doctors can safely use only one drug, rather than the typical two, to “mobilize” stem cells out of their niche in the bone marrow and into peripheral blood. These cells are then collected using an apheresis machine, a chaotic bedside console of tubes, knobs, and blood bags that probably “was designed for patients that don’t have sickle cell disease,” said Manis.
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The machine centrifuges blood to separate its component parts, creating a color band from the red of red blood cells to the yellow of plasma. Technicians draw stem cells from the clearish band in the middle. In sickle cell, though, the misshapen blood cells “throws off your color,” said Manis. “So all the visual cues that you ordinarily use aren’t there.”
The gene therapies, meanwhile, require far more stem cells than doctors typically collect from non-sickle cell patients. And Vertex’s process, in particular, is less efficient because it uses CRISPR gene editing, in which cells are opened with a zap of electricity to allow in DNA-cutting enzymes. Both the zaps and the DNA cuts kill some cells, leaving fewer for treatment.
Production became more inefficient when Vertex switched to a commercial manufacturing process that required more cells for quality control tests, McKechnie said.
“It is a small part of the equation,” he said.
These factors amounted to a rude introduction to gene editing for many doctors. They knew that the chemotherapy would make gene therapy a poor fit for most patients — Vertex estimated around 20 percent of the 150,000 sickle cell and beta-thalassemia patients in the US and Europe might be eligible, though some specialists think it’s less — and that manufacturing would take time. Cell collection wasn’t high on the list of concerns.
Sharl Azar, head of the sickle cell clinic at Massachusetts General Hospital, said collection for his first patient, a man in his 30s, took three visits. The last visit stretched for two weeks as the man had a sickle cell pain crisis — possibly related to the collection — and developed an infection.
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Azar was ultimately able to collect enough cells, and Vertex made the drug quickly. The patient has no regrets, Azar said. But another patient, a woman, had to stop after they became convinced they would never get enough cells. It’s harder, he learned, to collect cells from adults over 30.
“She was very devastated by the whole thing,” said Azar. “She ended up having actually a very nasty crisis on the tail end of it, and was in the hospital for six weeks and was super depressed and just absolutely devastated.”
Most confusing for centers has been cases where they’ve sent off what they believe to be enough cells — say 30 million per kilogram — and are told they need to collect more, because Vertex was only able to edit around 10 percent.
“We’ve not been able to get great answers from them on exactly what’s going on that they lose so many cells,” said Thompson.
McKechnie said such cases are “outliers” in a variable manufacturing process and that Vertex has started sharing more information with doctors.
“We’ve become much more transparent,” he said.
Jailbreaking the machine
With the right approach, doctors say they’ve been able to collect more cells. Jeffrey Glassberg, director of the sickle cell center at Mt. Sinai Hospital in Manhattan, said he struggled to collect any cells from the first patient he tried to treat with Lyfgenia. Genetix staff suggested various tips, like trying exchange transfusions — essentially replacing all of a patient’s red blood cells with a donor’s — before collecting.
The first patient still wasn’t able to give enough cells, but transfusions have helped subsequent patients.
“There’s a lot of stuff that is not written in the books,” he said.
Manis, who consulted with both Genetix and Vertex, has been giving advice to hospitals around the country on transfusions, medications, forming coordinated collection teams, and manipulating the machine to work for sickle cell patients. “You have to override the instrument,” he said.
Michele Wang, a hematologist at City of Hope, said the advice helped them collect cells on a third visit from a patient with combined sickle cell-thalassemia who produced barely any cells before.
“We still have more collections,” Wang cautioned. “And we still have more new things to try.”
In a few cases for sickle cell and beta-thalassemia, patients have given cells but the product Vertex or Genetix produced didn’t pass quality control. Such manufacturing failures occurred in five out of 33 patients treated commercially with either product, according to data presented this week from a multi-center consortium. The same study found that nine out of 18 sickle cell patients needed at least three collection cycles.
With more experience, doctors said, the process is likely to get smoother. Azar, the Mass General physician, said he’s been discouraged watching the toll these medicines take on patients and is likely to be conservative. But at Children’s National Hospital, David Jacobsohn said he expects to treat 10 sickle cell and beta-thalassemia patients this year between Vertex and Genetix, after treating 10 patients over the last two years.
Vertex opened a new manufacturing facility in New Hampshire last quarter and is instructing doctors to collect cells from patients for an additional day per hospital visit. McKechnie disputed that Beam Therapeutics, which uses a form of gene editing that is gentler on cells, has better data and noted Vertex is working on other improvements, such as alternatives to chemotherapy, that could expand the number of eligible patients.
For now, Manis and other doctors remain enthusiastic about gene therapies’ ability to transform their patients’ lives for the better — but they understand why many patients decline to pursue them.
“Right now it’s just overwhelming,” he said. If “you’re navigating a job and a family while you’re trying to do this — you’re like forget it, it’s not worth it.”
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