LAURA UNGAR
Updated Thu, December 14, 2023
Sickle Cell Therapy Inequity
Gautam Dongre, of the National Alliance of Sickle Cell Organizations, sits for a portrait with his daughter, Sumedha, 13, at their residence in Nagpur, India, Wednesday, Dec. 6, 2023. Dongre recalls how his newborn son, Girish, cried constantly from stomach and leg pain. Doctors couldn’t figure out what was wrong and didn’t diagnose him with sickle cell for 2 1/2 years. When Sumedha was born, he and his wife had her tested immediately and learned she had the disease too. (AP Photo/Ajit Solanki)
Gautam Dongre’s two children in India and Pascazia Mazeze’s son in Tanzania live with an inherited blood disorder that turns blood cells into instruments of pain.
Now that new gene therapies promise a cure for their sickle cell disease, Dongre says he's "praying the treatment should come to us.”
But experts say the one-time treatment is out of reach in India and Africa — places where the disease is most common. Vast inequities cut much of the world off from gene therapy in general.
While access to all sorts of medicine is limited in developing countries, the problem is especially acute with these therapies, which are among the most expensive treatments in the world.
Beyond their sky-high prices, these therapies are extremely complex to give patients because they require long hospitalizations, sophisticated medical equipment and specially trained doctors and scientists. So far, the two gene therapies for sickle cell have only been approved in wealthier countries: both of them in the U.S., and one in Britain and Bahrain as well.
“The vast, vast majority of patients live in an area where they have no access to this kind of therapy,” said Dr. Benjamin Watkins, who treats sickle cell in New Orleans and is also involved in pediatric work internationally. “We as medical professionals, and as a society, have to think about that.”
Access to gene therapies was a major focus of this year’s international summit on human genome editing in London. A subsequent editorial in the journal Nature said high prices leave low- and middle-income countries “entirely in the lurch” and could stymie progress across the field.
Some scientists worry that new cures won’t reach their potential, future treatments may never be invented and the prospect of wiping out diseases like sickle cell will remain a distant dream.
STRUGGLING FOR BASIC TREATMENT
For gene therapy to even be an option, people in developing nations must stay alive long enough to get it. There, sickle cell disease is more likely to disable or kill than in wealthy regions. Late diagnosis is common and basic care can be hard to come by.
While gene therapy "is a huge leap forward … we can’t forget about those patients,” said Watkins, of Children’s Hospital New Orleans.
Sickle cell disease begins its assault on the body at birth, affecting hemoglobin, the protein in red blood cells that carries oxygen. A genetic mutation causes the cells to become crescent-shaped, which can block blood flow and cause problems such as excruciating pain, organ damage and stroke.
The only other cure is a bone marrow transplant, which must come from a closely matched donor and brings a risk of rejection.
Global estimates of how many people have the disease vary, but some researchers put the number between 6 million and 8 million. It’s more common in malaria-prone regions because carrying the sickle cell trait helps protect against severe malaria. More than 1 million people with sickle cell disease live in India, studies show, and more than 5 million are in sub-Saharan Africa.
Dongre, who lives in Nagpur in central India, has seen the struggles in his own family and among people he’s met as a leader in the National Alliance of Sickle Cell Organizations in India. For many years, awareness of the disease has been lacking, he said, even among some health professionals.
Dongre recalled how his newborn son Girish cried constantly from stomach and leg pain. Doctors couldn’t figure out what was wrong and didn’t diagnose him with sickle cell for 2 1/2 years. When their daughter Sumedha was born, he and his wife had her tested immediately and learned she had the disease too.
Other patients go undiagnosed for a decade or more. Lalit Pargi, who lives in Udaipur in northern India, said he wasn’t diagnosed until he was 16 despite having the tell-tale yellow eyes and skin of jaundice, a common sign of sickle cell. That meant a childhood filled with inexplicable pain.
‘GOD AND GOOGLE’
Available treatments can reduce the bouts of pain known as “crises." Dongre’s children, now 19 and 13, take a medicine called hydroxyurea, a decades-old chemo drug that helps prevent the formation of sickle-shaped red blood cells and control the disease. Both have been hospitalized for pain episodes, especially when they were younger.
Other patients in rural areas are dying at very young ages without getting the right treatments, Dongre said.
In July, Indian Prime Minister Narendra Modi launched a sickle cell “elimination mission” that combines awareness, education, screening, early detection and treatment. Dongre lauded the effort but said the country faces huge obstacles to meet its goals.
The situation is much the same in East Africa's Tanzania, where the health ministry has partnered with drug company Novartis, which makes sickle cell medicine, to improve access to diagnosis and treatment.
Mazeze scrambled for information after her son, Ian Harely, was diagnosed.
“I Googled and Googled and I couldn’t sleep,” said Mazeze, executive director of the Tanzania Sickle Cell Warriors Organization. “After that, I was praying. It was God and Google.”
Her son is now 10 and takes hydroxyurea and folic acid for anemia. They’ve helped, but haven’t eliminated pain episodes like the one that put him in the hospital for two weeks earlier this year.
Still, Mazeze counts herself lucky she can afford treatment at all.
“We have people in Tanzania who can’t even manage folic acid,” she said. “Folic acid for a month is 1,000 Tanzanian shillings – less than a dollar,” while out-of-pocket costs for hydroxyurea can be more than 35 times that.
‘SIGNIFICANT CHALLENGES'
Such stark realities make the cost of gene therapies an insurmountable obstacle, experts say. The price tags for the two sickle cell therapies in the U.S. are $3.1 million and $2.2 million although the cost for gene therapies can vary by country.
The process of giving the therapies is just as big a hurdle.
Patients must go to the hospital, where stem cells are removed from their blood in a process that requires specialized equipment. One treatment, made by Vertex Pharmaceuticals and CRISPR Therapeutics, involves sending the cells to a lab as quickly as possible to keep them fresh and using a gene-editing tool called CRISPR to knock out a gene. The cells must be sent back in liquid nitrogen so they stay frozen until they’re ready to use.
The other therapy, made by Bluebird Bio, doesn't use CRISPR but involves the same process for patients. In both cases they must undergo chemotherapy before they get back their altered cells by IV, and spend weeks in the hospital. The process can stretch on for months.
“The infrastructure doesn’t exist to make it possible in many parts of the world,” said Dr. David Altshuler, chief scientific officer at Vertex. “There’s great unmet need, but there are also significant challenges.”
Not only do many medical centers lack things like specialized equipment, but health care systems themselves are comparatively skeletal. For example, World Health Organization data shows India and Tanzania both have less than a quarter of the per-capita hospital beds the U.S. has.
Scientists say one possible solution — though not an immediate fix — is to develop easier-to-administer versions of the new therapies. Altshuler said Vertex is trying to find ways to provide the same benefits without requiring chemo, which comes with serious risks such as infertility. His team is working on making a pill that wouldn’t edit genes but would have the same goal: helping the body produce a fetal form of hemoglobin since the adult form is defective in people with sickle cell.
Other scientists are also working on simpler potential cures, including Dr. Stuart Orkin, one of the scientists whose work led to the development of the Vertex therapy.
Orkin said he's not sure if next-generation treatments like pills will necessarily be affordable.
“Someone's going to want to be compensated for the development of that pill,” although foundations could help bring it to the developing world, said the Harvard Medical School pediatrics professor, who is paid by the Howard Hughes Medical Institute, which also supports The Associated Press' Health and Science Department. Experts said governments will likely also be instrumental in getting cures to patients.
Dongre said he hopes gene therapy for sickle cell eventually makes it to India. If it does, he’d like his children to be among the first to get it. Mazeze said she may wait to see how other patients fare but will consider it for her son too.
Both agreed that patients in all countries — rich or poor — should have the option.
“We all are part of one single planet,” Dongre said.
___
The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.
FDA approves gene-editing treatment for sickle cell
Talia Naquin
Wed, December 13, 2023
(WJW) – Breakthrough treatments for sickle cell disease have been approved by the U.S. Food and Drug Administration (FDA).
On Dec. 8, the FDA approved Casgevy and Lyfgenia. They’re the first cell-based gene therapies for the treatment of sickle cell patients 12 and older.
See the research here
Casgevy is also the first FDA-approved treatment to use a novel genome editing technology.
Sickle cell affects about 100,000 people in the U.S. Sickle cell disease is a group of inherited blood disorders.
It causes red blood cells to develop a crescent or ‘sickle’ shape, which limits the delivery of oxygen to the body.
“Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” said Nicole Verdun, M.D., director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research. “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.”
Casgevy is the first FDA-approved therapy utilizing CRISPR/Cas9, a type of genome editing technology. Patients’ hematopoietic (blood) stem cells are modified by genome editing using CRISPR/Cas9 technology.
CRISPR/Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut.
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The modified blood stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery.
With Lyfgenia, the patient’s blood stem cells are genetically modified to produce a gene-therapy derived hemoglobin that functions similarly to hemoglobin A, which is the normal adult hemoglobin produced in persons not affected by sickle cell disease. These modified stem cells are then delivered to the patient.
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Both products are made from the patients’ own blood stem cells, which are modified and are given back as a one-time, single-dose infusion as part of a blood stem cell transplant.
“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.
Only 1 Michigan hospital to initially offer new sickle cell gene editing treatment
Wed, December 13, 2023
(WJW) – Breakthrough treatments for sickle cell disease have been approved by the U.S. Food and Drug Administration (FDA).
On Dec. 8, the FDA approved Casgevy and Lyfgenia. They’re the first cell-based gene therapies for the treatment of sickle cell patients 12 and older.
See the research here
Casgevy is also the first FDA-approved treatment to use a novel genome editing technology.
Sickle cell affects about 100,000 people in the U.S. Sickle cell disease is a group of inherited blood disorders.
It causes red blood cells to develop a crescent or ‘sickle’ shape, which limits the delivery of oxygen to the body.
“Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” said Nicole Verdun, M.D., director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research. “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.”
Casgevy is the first FDA-approved therapy utilizing CRISPR/Cas9, a type of genome editing technology. Patients’ hematopoietic (blood) stem cells are modified by genome editing using CRISPR/Cas9 technology.
CRISPR/Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut.
Actor Andre Braugher of ‘Brooklyn 99’ dead at 61
The modified blood stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery.
With Lyfgenia, the patient’s blood stem cells are genetically modified to produce a gene-therapy derived hemoglobin that functions similarly to hemoglobin A, which is the normal adult hemoglobin produced in persons not affected by sickle cell disease. These modified stem cells are then delivered to the patient.
Ohio village voted as one of America’s most ‘Christmassy’ towns
Both products are made from the patients’ own blood stem cells, which are modified and are given back as a one-time, single-dose infusion as part of a blood stem cell transplant.
“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.
Only 1 Michigan hospital to initially offer new sickle cell gene editing treatment
Kristen Jordan Shamus, Detroit Free Press
Thu, December 14, 2023
When 17-year-old Gabriella Ngang dreams about the future, she envisions one without the debilitating pain that sometimes renders her unable to walk, the pain that forced her to quit cheerleading, the pain that keeps her from swimming.
Swimming is too risky for Gabriella, who goes by Gabby, because a dip in water can send her sickle cell disease into a crippling pain crisis that could trigger a weekslong hospitalization.
“If it’s too cold or it's too hot, it might trigger the pain,” said Gabriella, a senior at Farmington High School. “Or if I don't have enough oxygen or if I’m already in pain, it might trigger it. ... It's kind of hard to describe the waves of pain that just keep hitting you."
Gabby Ngang, 17, of Farmington Hills, sits at the dining room table in her home alongside her mother Vivian Ngang, 53, on Dec. 7, 2023. The Farmington Hills High School senior has sickle cell anemia. The FDA is poised to approve two gene editing treatments for sickle cell disease that could be a cure for Gabriella.
But now there's hope for Gabby and the roughly 100,000 Americans like her who suffer from the inherited blood disorder. Two new, blockbuster gene therapy treatments for sickle cell disease were approved last week by the U.S. Food and Drug Administration for Americans ages 12 and older.
However, getting swift treatment might not be easy for the vast majority of patients, given that the manufacturers have authorized only 36 U.S. hospitals to begin using the therapies in the near future. And the price tag is extremely high — $2 million to $3 million per treatment.
Just one Michigan hospital has authorization to begin gene therapy to treat sickle cell disease patients in the first quarter of 2024. That's Children's Hospital of Michigan in Detroit, which is among 27 U.S. hospitals that can use lovo-cel, which has the brand name Lyfgenia. The other newly FDA-approved gene therapy, exa-cel, which has the brand name Casgevy, isn't initially being offered at any Michigan site.
Doctors hope the treatments last a lifetime
Sickle cell disease affects the shape of red blood cells, making them crescent or sickle shaped. The misshapen cells can cluster together and get stuck in blood vessels, impairing their ability to carry oxygen. The disease can cause strokes, organ damage, severe pain and early death.
The genetic disorder is most prevalent among people of African descent, occurring in 1 in every 365 births among Black Americans and about 1 in every 16,300 Hispanic American births, according to the U.S. Centers for Disease Control and Prevention.
About 4,000 Michiganders suffer from it, said Dr. Alexander Glaros, medical director of the Comprehensive Sickle Cell Center at Children’s Hospital of Michigan in Detroit.
“About 2,500 live in the city of Detroit,” he said. “We, at Children's, have about 800 patients from ages 0 to 25, and we're one of the biggest sickle cell centers in the country.”
The new gene-editing treatments alter a patient's own stem cells, allowing the body to make healthy, round red blood cells rather than sticky, sickle-shaped cells. Although the treatments haven't been researched long enough to describe them as curative, doctors are hopeful a single treatment will last a lifetime for patients like Gabby.
She's eager to try it.
“I'm happy about the new gene therapy and the new treatments that are coming out for sickle cell," she said. "I want to just live out my life the way I want to live it out, and advocate more for people with sickle cell, too, and gene therapy, if I get the treatment."
How gene editing works against sickle cell
That's a big if.
Gabby's mother, Vivian Ngang, is trying to find a way to get gene therapy for Gabby, but she knows that, at least for now, only lovo-cel is likely to be available in Michigan by the end of the first quarter of 2024, according to bluebird bio, the pharmaceutical company that developed the treatment.
Gabby Ngang, 17, of Farmington Hills, holds her family dog alongside her mother Vivian Ngang, 53, at their home on Dec. 7, 2023. The Farmington Hills High School senior has sickle cell anemia. The FDA is poised to approve two gene editing treatments for sickle cell disease that could be a cure for Gabriella.
Lovo-cel reengineers a patient’s own stem cells by adding a functional beta hemoglobin gene.
Those stem cells first are extracted from the patient and altered in a lab using a virus as a carrier for the modified beta hemoglobin gene. The person then undergoes high-dose chemotherapy, which wipes out the immune system. Doctors then reintroduce the genetically repaired stem cells, rebooting the person’s immune system so it can begin to produce red blood cells without sickling.
“Centers will be onboarded to deliver Lyfgenia on a rolling basis," bluebird said in a news release issued Friday. "Today, 27 (qualified treatment centers) are ready to receive patient referrals and we anticipate the full network will be fully activated by the end of Q1 2024,”
Children’s Hospital of Michigan didn’t provide details to the Free Press about the timing of when treatments will begin for its patients, but Glaros issued the following statement: “As the first medical center in Michigan to offer patients the option of a similar gene therapy for beta-thalassemia earlier this year, we are pleased to see the FDA’s decision. … We look forward to reviewing the details and moving ahead from there as expeditiously as possible on behalf of our patients.”
The University of Michigan Health told the Free Press it, too, is "actively engaged" in efforts to "introduce gene therapy for sickle cell disease and other inherited disorders that affect red blood cells." It said it is "strategically planning" to make both gene therapies available within the next year.
Corewell Health Helen DeVos Children’s Hospital in Grand Rapids issued a statement to the Free Press on Wednesday, saying its goal is to work through the logistics to be able to offer gene therapy "in the future" to its roughly 100 children and adolescent patients with sickle cell disease.
Treatment requires long hospital stays
Although lovo-cel is the treatment that's likely to be available first in Michigan, Ngang would prefer that her daughter undergo the exa-cel gene therapy treatment instead.
"The cancer risk is my concern with lovo-cel," Ngang said of the black-box warning the FDA issued along with its approval of the treatment. In clinical trials, two of the patients who were treated in lovo-cel later developed leukemia.
"My preference is exa-cel. If it means us waiting or going somewhere else to get that treatment, we'll do that. If they roll it out and (Children's Hospital of Michigan) is not among the hospitals, I am looking into Ohio and/or Chicago."
Exa-cel works differently and has not been associated with leukemia or other blood cancers. Instead of adding a new functioning beta hemoglobin gene, exa-cel disrupts the malfunctioning BCL11A gene that causes the sickling of red blood cells after a baby with the genetic disorder is born. Once that faulty gene is disrupted, the body then reverts back to the use of fetal hemoglobin to produce healthy red blood cells.
Both exa-cel and lovo-cel require high-dose chemotherapy and potentially long hospital stays.
Vertex Pharmaceuticals and CRISPR Therapeutics co-created exa-cel. The companies have authorized only nine U.S. medical centers to be among the first to offer exa-cel therapy. They are:
Boston Medical Center in Boston
Children’s National Hospital in Washington, D.C.
City of Hope Children’s Cancer Center in Los Angeles
Medical City Children’s Hospital in Dallas
Methodist Children’s Hospital in San Antonio
Nationwide Children’s Hospital in Columbus, Ohio
The Children’s Hospital at TriStar Centennial in Nashville, Tennessee
The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute in Columbus
University of Chicago/Comer Children’s Hospital in Chicago
“The administration of Casgevy requires specialized experience in stem cell transplantation; therefore, Vertex is engaging with experienced hospitals to establish a network of independently operated, authorized treatment centers throughout the U.S. to offer Casgevy to patients,” the company said in a statement.
“Additional (authorized treatment centers) will be activated in the coming weeks.”
'Everyone deserves access to this treatment'
Though there's hope in these new treatments, access is a big concern, said Melissa Creary, an assistant professor in health management policy and global public health at the University of Michigan's School of Public Health.
"Who's going to actually be able to get access to this gene-editing technology?" asked Creary, who also has sickle cell disease. "When these innovative therapies come to market, but it's not going to be necessarily widely available, that there is more burden for folks to get to where the technology is being offered.
"Everyone deserves access to this treatment. I think everyone deserves access to a great quality of life. ... And therein lies the issue. There will not be enough options for all the people who deserve therapy to get it."
For many people living with the disease, uprooting their lives to temporarily move to a city where the treatment is available simply isn't an option.
"What does it mean to pack up a patient and a support system to go to that place, to be able to afford to live in that place, to step away from a job for three to six months?" Creary asked. "There are a lot of questions of how people are going to actually be able to benefit from this therapy."
Patient share of costs unknown
Cost is a concern, too.
Bluebird set its pricing for lovo-cel at $3.1 million per person “in recognition of the value the therapy may deliver through robust and sustained clinical benefits and the estimated lifetime impact” that could come by eliminating or reducing the number of pain crises that patients face, the number of hospitalizations and other medical treatments they require over a lifetime and its impact on future earnings and opportunities.
The Cambridge, Massachusetts-based pharmaceutical company said people with sickle cell disease face lifetime medical costs that can amount to $4 million-$6 million. In addition, 1 in 4 will have a stroke by age 45, and the average person with the disease will lose as much as $1.3 million in lifetime earnings because of how their illness limits job opportunities.
Vertex and CRISPR estimate their exa-cel therapy will cost about $2 million.
"How do we begin to wrap our mind around the cost?" Creary asked. "I think we can assume that no one's going to be responsible for paying the full $2 (million) to $3 million, but there is still going to be a very heavy responsibility of cost. We don't know what that is yet.
"We do know that the majority of people living with sickle cell disease are on Medicaid, which means that we're going to have to depend on CMS (the Centers for Medicare and Medicaid Services) and the federal government to be able to offer a level of financial support. Given the ways that health policy has worked out around Medicaid in terms of expansion on the federal level, and in terms of how it actually gets operationalized internally state by state, there's still a lot of questions to figure out how Medicaid programs are going to be able to afford to support a really expensive therapy like this. "
Creary is concerned that although these therapies could be transformative for so many people, affordability and access hurdles will further deepen health inequities and pile on to an already heavy history of medical neglect and injustice for Black and brown Americans.
"While I want to be excited about innovation, I want to still move toward an acknowledgment that we still have to treat people with great dignity outside of offering access to technology," Creary said.
Gene-editing therapy for people with sickle cell disease is an important advance, but those who need treatment also deserve equitable care, she said.
"It doesn't address the ways in which people are treated when they enter the health care system. It doesn't address the lower quality of health care because the patients are Black and brown. It doesn't address the limited opportunities that many people with sickle cell disease have access to because of these systems," she said.
'I knew one day something would come up'
Winter is the hardest season for Gabby. The cold, blustery air almost always brings a stint in the hospital because of a pain crisis, her mother said.
Every trip to the hospital means Gabby misses school, misses work, misses hanging out with friends and family, misses singing in the Detroit Youth Choir and doing all the other things she loves.
Neither her twin sister nor her older brother have the disease.
Gabby Ngang, 17, of Farmington Hills, stops to look at photos of her and her twin sister and other family members at her home on Dec. 7, 2023. The Farmington Hills High School senior has sickle cell anemia. The FDA is poised to approve two gene editing treatments for sickle cell disease that could be a cure for Gabriella.More
"Sometimes, she gets really angry with that," Ngang said. "'Why me? Why me? Why me?' she asks. I say, 'You are the privileged one.' I usually tell her 'You're the chosen one. I don't have an answer for that. I didn't ask for you to get it. They didn't ask me to choose who should have it, but God chose you. So we have got to deal with it. It's been a family trauma.'"
Still, the Ngangs have never given up hope that an innovation like gene therapy would come along and take Gabby's pain away.
"With all the medical research, I knew one day something would come up," Ngang said. "They're doing it for cancer and other illnesses. Why not sickle cell?"
Contact Kristen Shamus: kshamus@freepress.com. Subscribe to the Free Press.
This article originally appeared on Detroit Free Press: Only 1 Michigan hospital to initially offer new sickle cell gene editing treatment
At ASH, doctors acclaim new sickle cell gene therapies, but are cautious on details
Gwendolyn Wu and Ned Pagliarulo
Wed, December 13, 2023
The Food and Drug Administration’s approval Friday of two gene therapies for sickle cell disease opens up their use by as many as 20,000 people in the U.S.
But in their first year on the market, and maybe for a year or two after that, physicians expect the uptake of the powerful, but complex treatments to be gradual at best.
“I think it'll be a slow ramp up,” said Akshay Sharma, a pediatric hematologist at St. Jude Children’s Research Hospital who was an investigator in testing. “Most of us clinicians are taking a very cautious approach, because many of us are looking for long-term data before we start saying, ‘Hey, everybody should get it.’”
The reasons are many. Fewer than 100 people received the therapies in clinical testing, the earliest treated of whom have now been followed for four or five years. While the data show dramatic benefit — treatment eliminated the pain crises associated with sickle cell — there are still outstanding questions on safety and on their use in sicker individuals, such as those who have a history of stroke.
The personalized treatments are also cumbersome to manufacture and require “conditioning” chemotherapy beforehand that carries risks of its own, particularly infertility. They’ll be among the most expensive medicines sold, too, priced at $3.1 million for Bluebird Bio’s Lyfgenia and $2.2 million for Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy. Working out payment and getting insurers onboard may take time.
"I anticipate very few patients that first year for both products, maybe for the first couple of years,” said Alexis Leonard, also a pediatric hematologist at St. Jude’s.
Who should receive gene therapy?
While sickle cell is considered a rare disease, it still affects an estimated 100,000 people in the U.S., a figure President Joe Biden cited in a statement hailing Lyfgenia and Casgevy as “major breakthroughs.”
The indications approved by the FDA — 12 years or older with recurrent sickle cell crises — significantly shrink the number of people who could receive treatment. Vertex estimates about 16,000 people will be eligible, while Bluebird believes that number to be higher than 20,000.
Notably, the FDA did not restrict use of either Lyfgenia or Casgevy in people who have matched stem cell donors, the only other curative therapy for the blood disease. (Regulators in the U.K., where Casgevy was approved weeks prior, chose to exclude these individuals from the drug’s approved labeling.)
People with matched stem cell donors were not enrolled in testing of either treatment, so insurers might balk at paying for gene therapy in these individuals.
“I don't know if I would be as enthusiastic in recommending this over a matched sibling donor transplant,” said Sharma. “But the label clearly doesn't say that.”
Physicians also expressed uncertainty about treating sickle cell patients with a history of stroke with either therapy. Bluebird did enroll five such people in its trial before changing its study criteria, while Vertex excluded them.
“Stroke is a major indication for transplant so that should change,” said John Tisdale, a branch chief at the National Institutes of Health who specializes in sickle cell research, at a Monday session during the American Society of Hematology’s annual meeting. “The companies have been reluctant to accept the risk of [central nervous system] bleeding while trying to figure out if the approach works.”
Vertex’s study also capped the age of participants at 35, meaning physicians wanting to prescribe Casgevy won’t have data on its use in older individuals with sickle cell, who may have more organ damage as a result of their disease. They may also be unable to tolerate the chemotherapy conditioning.
How quickly can centers get up to speed?
Initially, only a handful of treatment centers around the country will offer Casgevy or Lyfgenia.
Vertex will make its drug available at nine sites across six states and Washington, D.C., while Bluebird said that 27 centers in 12 states are now ready to receive patient referrals. Both companies envision a broader network, but discussions at ASH made clear that the process for onboarding new hospitals will take time.
“We got approval [Friday], but that doesn't mean that all these centers are ready to provide the therapy,” said Leonard, of St. Jude’s, who presented at ASH Saturday on the topic. She noted a survey of 50 hospitals by the National Alliance of Sickle Cell Centers. Only 32 had participated in a gene therapy clinical trial, which Leonard described as an experience gap.
Prospective treating centers need comprehensive care teams that can include pain specialists, pulmonologists, infectious disease doctors and social workers. They also need access to a blood bank, space to draw and collect patient stem cells, cell processing facilities and fertility preservation services.
“The first step to getting these therapies is you have to be a qualified treatment center,” said Leonard. “We actually went to the Vertex and asked them, ‘What's your definition?’ And we got a very wishy-washy, no answer.”
In an email, a Vertex spokesperson said the company has been in “close dialogue” with all of its targeted authorized treatment centers. Many of these prefer to complete contracting discussions until after Casgevy’s approval, the spokesperson added.
Are there alternative treatments?
Matched bone marrow transplants can be a curative option for sickle cell. But only a small minority of patients, about 15% or so, have a donor who’s a suitable genetic match. Even then, the transplants still require patients to be healthy enough to undergo preconditioning with the toxic chemotherapy busulfan.
Research presented at ASH Monday suggested haploidentical, or half-match, transplants could be used in more patients, and with a gentler conditioning regimen. Haploidentical transplants use stem cells from family members such as parents, aunts, uncles or cousins, greatly broadening the pool of people who may be donors for a person with sickle cell.
The study, which was funded by the NIH, found that haploidentical transplants with a modified, less toxic regimen still led to good outcomes.
Adetola Kassim, director of Vanderbilt University's adult sickle cell disease program and an investigator, described how the studied procedure boosted hemoglobin levels as well as gene therapy. He noted, too, that transplants are about one-fifth the cost of the new therapies.
“The ideal curative therapy profile should offer protection from sickle cell related complications,” Kassim said during a Monday presentation at ASH. “[But] it also must be accessible and available to most patients.”
More broadly, researchers are looking at other ways to prepare patients for gene therapy, such as by using medicines known as antibody-drug conjugates for conditioning. Not only could these drugs be gentler on older people or those with organ damage, they could also preserve fertility. Further out, gene therapies involving an inside-the-body, or “in vivo” approach, could sidestep preconditioning altogether.
Ultimately, gene therapy offers new promise for treating sickle cell, said Tisdale. The NIH scientist included in his presentation a nod to Rodrick Murray, an early volunteer to receive sickle cell gene therapy in the U.S.
Murray was declared sickle cell-free two years after therapy, but died in 2020 from complications of leukemia he developed from preconditioning. The data recorded while tracking his treatment effects helped doctors adjust the treatment for later clinical trial participants.
“He told me he wanted to do this not for himself, but for other patients with sickle cell disease,” Tisdale said. “I was really happy to be in communication with his wife … on Friday to let her know he succeeded.”
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