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FDA poised to approve first gene-editing therapy, made by local drug firms

The landmark treatment from Vertex and CRISPR Therapeutics targets sickle cell disease

FDA approves first gene-editing therapy
WATCH: The breakthrough treatment, made by local drug firms, targets sickle cell disease. Reporter Jonathan Saltzman breaks down the life-changing medicine.

Marie Tornyenu missed more than 100 days of high school while hospitalized repeatedly for sickle cell disease, an inherited blood disorder that causes crippling pain. Somehow, she still managed to complete at least eight advanced placement courses, play clarinet in the school band, and get admitted to Boston University.

Then in December 2021, after transferring to Cornell University, she received an experimental medicine that used a revolutionary gene-editing technology to treat inherited diseases. It freed her from excruciating bouts of pain and the frequent blood transfusions that are a mainstay of sickle cell treatment.

“It’s kind of surreal,” said Tornyenu, 22, who grew up in Bethlehem, Pa., and participated in a clinical trial at Children’s Hospital of Philadelphia. “I’m, like, wait, I don’t have sickle cell anymore.”

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The life-changing drug, developed by Boston-based Vertex and its Swiss partner CRISPR Therapeutics, is expected to be approved by the Food and Drug Administration by Friday for people with severe cases of the disease. Called Casgevy, it would usher in a new era not only for those with sickle cell but also for medicine: The drug would be the first gene-editing therapy authorized by US regulators, and uses a tool called CRISPR.

The likely approval — Casgevy was cleared by British regulators last month — raises both the promise of cures for diseases as well as the ethical concerns that come with the power to manipulate the building blocks of human life. With an expected price tag in the seven figures, it also touches on issues of equity in medicine.

Sickle cell primarily afflicts people of African descent. Research on the disease languished for decades, which many experts blame on structural racism, particularly in funding.

For Tornyenu, Casgevy has meant an end to the searing pain crises that caused her to miss a week of classes every month as a high school senior. After getting the treatment, she took the spring semester off from Cornell to recover from the debilitating effects of chemotherapy that made room in her blood marrow for gene-edited cells.

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Marie Tornyenu at Children's Hospital of Philadelphia the day she got her genetically edited stem cells back on Dec. 28, 2021. Family Photo

But now she no longer dreads the arrival of cold weather, which would often induce excruciating pain in her hips and legs. A senior at Cornell, she has a job lined up as a consultant at PricewaterhouseCoopers in Boston after graduation.

“I’m very hopeful [Casgevy] will be approved,” she said, “because I don’t know what I would have done otherwise.”

The gene-editing method that became known as CRISPR was first reported in a landmark 2012 paper by American biochemist Jennifer Doudna of the University of California, Berkeley, and French microbiologist Emmanuelle Charpentier of the Max Planck Institute for Infection Biology. They would share the 2020 Nobel Prize in chemistry for their work on the tool.

Sickle cell was an obvious choice for scientists to tackle with CRISPR. It was the first human disorder understood on a molecular level, its underpinnings explained in a landmark 1949 paper written by the future two-time Nobel laureate Linus Pauling. Yet progress against the disease was slow for decades afterward.

Sickle cell affects hemoglobin, the oxygen-carrying protein in red blood cells. It causes the round, flexible blood cells to deform into a sickle shape and stick to vessel walls. That deprives tissues of oxygen, causing crushing pain that can often only be relieved with opioids and blood transfusions.

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Sickle cell can also lead to strokes, damage organs, and cause early death. A 2019 study in JAMA Network Open estimated the life expectancy of adults with sickle cell in the US is 54 years, about 20 years shorter than the general population.

In a clinical trial, Casgevy demonstrated remarkable results. The medicine completely relieved 29 of 30 sickle cell patients of debilitating episodes of pain for at least one year among trial participants who were followed for at least 18 months, according to Vertex. The patients received a one-time intravenous infusion of edited stem cells that flipped a genetic switch to restore their blood cells’ ability to carry oxygen throughout their bodies.

The headquarters of Vertex Pharmaceuticals in Boston on Nov. 4.JOSEPH PREZIOSO/AFP via Getty Images

“This is what a potential cure looks like,” said Dr. Stephan Grupp, chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia. He was the principal investigator at the trial site where Tornyenu got Casgevy and was paid by Vertex to help organize the study at locations across the US.

About 100,000 Americans, most of them Black or Hispanic, are believed to have sickle cell. The Vertex-CRISPR treatment was geared for those with severe and repeated pain crises, roughly 20,000 people in the US. As of 2021, almost 8 million people around the world live with sickle cell, according to the Institute for Health Metrics and Evaluation at the University of Washington in Seattle.

The FDA has approved four medicines for the disorder, but none has been remotely as effective as Casgevy, which is expected to cost more than $1 million for a one-time infusion in the US, according to experts. (No price has been announced in the United Kingdom.) Sickle cell can be cured with a bone-marrow transplant, but few patients have compatible donors.

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Patients are already inquiring about Casgevy, said Dr. Sharl Azar, a hematologist at Massachusetts General Hospital and medical director of its Comprehensive Sickle Cell Disease Treatment Center. He said he is eager to see whether the FDA clears it, how broad the approval would be, and whether Medicare and Medicaid would cover it.

“There’s a lot of unknowns that we’re looking forward to working out in the coming months,” he said. “But I think everyone, from patients to providers, recognizes that this is a big deal.”

Rahman Oladigbolu, a 52-year-old Harvard-educated filmmaker in Brockton, is among local patients interested in Casgevy. He has had six joints — his hips, shoulders, and knees — surgically replaced since 2000 because of damage from sickle cell. He walks with a cane at times, often gets lightheaded, and takes opioids to relieve persistent pain.

Rahman Oladigbolu has had six joints — his hips, shoulders, and knees — surgically replaced since 2000 because of damage from sickle cell disease.Jonathan Wiggs/Globe Staff

When Oladigbolu was growing up in Nigeria, his grandmother would take him to traditional medicine men and medicine women who prescribed herbs and potions, some of which they rubbed into his aching limbs after cutting him with a razor blade. He moved to the US when he was 28 and currently takes a sickle cell drug called crizanlizumab, which reduces his pain but doesn’t eliminate it.

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“Pursuing a cure has been like a side job all my life,” said Oladigbolu, who receives treatment at Boston Medical Center.

CRISPR-based treatments will likely be approved for other disorders in the coming years, experts say, although its hard to predict for what and when. Researchers, including scientists at multiple biotech companies and hospitals in Massachusetts, are studying the potential of gene editing for a variety of diseases, from ALS to forms of cancer.

“There will be other gene-editing therapies, certainly, but each disease is different,” said Dr. Stuart Orkin, a researcher at Dana-Farber Cancer Institute and Boston Children’s Hospital who in 2008 helped identify the gene that Casgevy snips to treat sickle cell. “For some diseases, it’s not clear what to edit. People will argue about what’s the right target. Each one is a special case.”

Gene editing has also raised ethical concerns. In 2018, a Chinese scientist, He Jiankui, was widely condemned when he announced that he used CRISPR to edit DNA in human embryos to try to make them immune to HIV. The experiment sparked fears that He had opened the door to creating so-called designer babies — children whose genetic makeup is altered to produce desired traits.

Dr. George Q. Daley, dean of Harvard Medical School, was among those who said He’s experiment raised the specter of a Brave New World of eugenics. Casgevy, he said recently, is completely different. The modifications it makes to DNA only helps sickle cell patients and cannot be passed on to their children.

Daley’s bigger worry concerns access to Casgevy. While wealthy countries like the US have hospitals and doctors capable of preparing patients for the treatment and administering it, he said, millions of people with sickle cell in sub-Saharan Africa don’t have those options.

“This is a triumph of modern biomedicine,” he said. “The major ethical concerns now are issues of cost and equitable distribution.”

Casgevy isn’t the only gene-based medicine on the horizon for sickle cell. The Somerville biotech Bluebird Bio hopes the FDA approves a so-called gene therapy, lovo-cel, by Dec. 20. It also proved remarkably effective in clinical trials.

Unlike Casgevy, which cuts a gene, lovo-cel adds a modified gene into a patient’s DNA to enable blood cells to deliver oxygen. The FDA has approved at least eight gene therapies for mostly rare diseases since 2017.

This microscope photo provided on Oct. 25 by the Centers for Disease Control and Prevention shows crescent-shaped red blood cells from a sickle cell disease patient in 1972. F. Gilbert/Associated Press

Both Casgevy and lovo-cel are expected to be breathtakingly expensive. That has renewed questions about whether the health care system can afford such cutting-edge medicines.

Still, the Institute for Clinical and Economic Review, or ICER, an independent Boston-based drug-pricing watchdog, estimates that either drug could cost nearly $2 million and be worth it, given the cumulative costs of treating sickle cell over a lifetime and the benefits the new approaches would bring to patients and families.

Casgevy, which was called exa-cel in clinical trials, works by editing a patient’s bone marrow stem cells to make high levels of fetal hemoglobin — the healthy, oxygen-carrying form of hemoglobin produced during fetal development that is replaced by adult hemoglobin soon after birth.

Unlike adult hemoglobin, fetal hemoglobin resists forming a crescent shape in sickle cell patients, and scientists have long searched for a way to restart it. The researchers behind Casgevy solved the problem by editing a gene called BCL11A, which regulates fetal hemoglobin.

The treatment involves multiple steps over several months. Patients must donate stem cells to be modified at a laboratory. Then donors have to undergo a grueling regimen of chemotherapy to make room in their bone marrow for the genetically altered cells. Finally, the patients get the cells back through a single infusion.

Dr. David Altshuler, Vertex’s chief scientific officer, acknowledged that the gene-editing treatment is “extremely complex and resource intensive.” He said Vertex is researching the possibility of developing a pill that could do what Casgevy does without gene editing. (Vertex’s business partner for Casgevy, CRISPR Therapeutics, is based in Zug, Switzerland, but has most of its workforce in Boston.)

FDA officials have raised concerns about the possibility that Casgevy could inadvertently change patients’ DNA beyond the targeted disease — so-called off-target editing. Dr. Daniel E. Bauer, a staff physician at Dana-Farber Cancer Institute and Boston Children’s Hospital, told an FDA advisory panel on Oct. 31 that Casgevy contains hundreds of millions of edited cells and one could undoubtedly go off target and cause leukemia. But he described the risk as “modest” given the benefits of the treatment.

Altshuler said recently that “there is no evidence to date of off-target editing, but it is important to be humble and to continue to follow patients.” Vertex and CRISPR have pledged to follow trial participants for 15 years to make sure they stay healthy.

Tornyenu, the Cornell student, says she considers Casgevy a miracle and would celebrate Dec. 8 every year if the FDA approves the drug that day.

“For lack of a better term,” she said, “it’s a big FU to sickle cell.”

Marie Tornyenu in November 2022 in Boston's Seaport District. Helen Meckstroth

Jonathan Saltzman can be reached at jonathan.saltzman@globe.com.