When Simone Day was in the ambulance taking her to the Maryland Shock Trauma Center in 2016, she looked into the bright lights and thought “I had died.”
Like other patients with sickle cell disease, the 27-year-old Baltimorean had made many trips to the emergency room for pain crises and worsening organ damage. This time, she ended up in a hospital bed for more than a month and hooked up to a life-saving ECMO machine that was circulating blood through her body.
Now, seven years after receiving a new type of bone marrow transplant that can cure many more people than was previously possible, Day, now 33, feels “blessed” to be cured of the disease.
“Sickle cell was really tough thing to live with,” said Day. “I had to have my hip replaced when I was 25. I was afraid to go to the gym or go out of town far away from my doctors.”
Day was born one of 100,000 people in the U.S. suffering from sickle cell disease, a painful and debilitating condition caused by a genetic mutation affecting red blood cells that primarily shows up in Black patients. Those suffering from the disorder have faced widespread discrimination and mistreatment in health care settings as well as neglect in scientific research.
That’s finally changing. Last month, two groundbreaking gene therapies thought to cure sickle cell were approved by the Food and Drug Administration, and one will be available locally starting in a few weeks. Both come with price tags in the millions, and it’s not clear yet who will pay.
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But other recent advances could put a cure — or at least relief — within reach for many more people with the disease. Bone marrow transplants like the kind Day received are likely to become more routine. And a large international study headquartered at the University of Maryland is investigating a treatment that could help the sickest sickle cell patients with disease too advanced for a cure.
The promise of gene therapy
Sickle cell disease is caused by a genetic mutation that alters hemoglobin, the protein in red blood cells that captures oxygen and carries it throughout the body. While red blood cells are normally round and flexible, the hemoglobin in sickle cell patients clumps together when it releases oxygen, forming a long, stiff rod inside the cell, distorting it into a sickle, or crescent, shape.
These odd-shaped cells can slow down or block blood flow, which causes intermittent, severe pain and long-term damage to organs that don’t receive enough oxygen when red blood cells can’t reach them. The sickled cells also break apart and die much sooner than normal cells — in 10 to 20 days instead of 120 — and their debris damages blood vessels while their early death creates a blood cell shortage, also known as anemia.
Most people in the U.S with sickle cell are of African descent. The gene mutation evolved to protect its carriers against malaria, an endemic disease in some African countries, as it is harder for the malaria-infected parasites carried by mosquitoes to attach to those cells. About 1 in 13 Black babies born in the U.S. carry the mutation, and 1 in 365 inherit two copies — one from each parent — and will develop the disease.
Over time, sickle cell disease can cause infections, organ damage and failure, tissue and bone damage, high blood pressure in the lungs, vision problems, stroke, as well as other serious or fatal complications. Even now, with many promising treatments on the horizon, the median life expectancy for patients with sickle cell is still “stubbornly stuck” at about 45 years in the United States, said Dr. Mark Gladwin, vice president for medical affairs and dean of the school of medicine at University of Maryland Medicine.
Though the genetic cause for sickle cell was discovered nearly 65 years ago, until recently, there was just one drug that partially treats the disease.
That’s one reason why the newly approved gene therapies for sickle cell have generated so much buzz. Another reason is that one therapy, Casgevy, represents the first-ever use of the revolutionary gene-editing technique CRISPR, which won its discoverers the Nobel prize in 2020. Casgevy won’t be offered in Maryland initially.
In a few weeks, though, the University of Maryland Medical Center will begin to offer the other gene therapy, called Lyfgenia.
Lyfgenia uses a technique that’s been FDA-approved to treat other blood disorders, where a healthy gene hitches a ride on an inactive virus that will penetrate and alter a defective gene, ideally curing whatever ailment it causes. The sickle cell therapy introduces a modified gene that produces an anti-sickling hemoglobin.
The process takes about six months. A patient’s stem cells are harvested from their bone marrow by a machine and sent to a Texas laboratory to be genetically modified over the course of three to four months, said Dr. Jennie Law, hematologist-oncologist at the UM Greenebaum Comprehensive Cancer Center and associate professor of medicine at the UM School of Medicine. Prior to getting the altered cells infused back into their body, the patient is hospitalized to get high-dose chemotherapy, which kills existing bone marrow cells. They stay in the hospital for 4 to 6 weeks to recover and to make sure the stem cells take root in the bone marrow and start to produce the genetically modified hemoglobin.
The therapy costs an eye-popping $3.1 million.
Data shows the price tag is actually cost-effective, Law said, “when it’s balanced against the lifetime cost of having sickle cell” — including hospitalizations, emergency room visits, and other costly care. The therapy can “give people back their lives, allow them to work and function, have a much better quality of life,” she said.
All of that was taken into account in determining Lyfgenia’s price, said Jess Rowlands, a spokesperson for the company that developed the therapy, Bluebird Bio.
Still, consolidating a lifetime’s worth of costs into a single payment is daunting, no matter who foots the bill. The University of Maryland Medical Center is not receiving any research funding or help from the manufacturer to cover the cost of Lyfgenia, Law said, and most of her patients are covered by Medicaid, a public health insurance program jointly funded by federal and state governments. The same is true for half of people with sickle cell disease nationwide, Rowlands said.
“Bluebird is in advanced discussions with the largest commercial payers in the U.S. and Medicaid agencies representing 80% of individuals with sickle cell disease,” Rowlands said.
To incentivize coverage, Bluebird is working on contracts with state governments and private insurance companies that agree to refund a significant portion of Lyfgenia’s cost if it does not work as expected over a three-year period.
In the meantime, providers can still make a case for insurers to cover Lyfgenia for individual patients under their “medical exceptions policies,” Rowlands said.
The half-match option
There’s another sickle cell cure at a fraction of Lyfgenia’s cost that until recently wasn’t an option for most patients. It’s the type of bone marrow transplant that cured Day.
“It can be done now, today, at most major hospitals that perform transplants,” said Dr. Robert Brodsky, director of hematology at the Johns Hopkins University School of Medicine and Vanderbilt Health.
The transplant used to require a bone marrow donor who was a perfect match for a patient, almost always a sibling. Only about 10% of patients can find a perfect match.
But a new study co-led by Brodsky offers solid evidence to support the use of partial donor matches. The study of 42 patients with sickle cell were presented last month at the American Society of Hematology, showing 95% of participants were alive and 88% were disease-free after two years.
“The bottom line is the average person has a half-match donor in the family,” Brodsky said, which means many more people can be cured. Day, for example, was able to get bone marrow from her mother.
Brodsky said the new half-match, or haploidentical, transplants have other benefits. The prep time is four to six weeks, rather than six months. There is no need for the high-dose chemotherapy regimen required for gene therapy, known as myeloablative conditioning, to prepare for the procedure — which is too risky for adults already weakened by organ damage.
Day said the haploidentical transplant was still pretty harsh. The low-dose chemo she had made her lose her hair, and radiation made her nauseated. It was five months before she was well enough to return to work at a local biotechnology company. Transplant patients also must take immunosuppressive medications for about a year afterward, which is not necessary with gene therapies.
Brodsky said there is still a lot of excitement for CRISPR and gene therapies generally, which he said will only improve over time. They will also be available for those who do not have a half-match donor or can’t have a transplant for another reason.
For patients, there are finally options
Dr. Mark Gladwin, vice president for medical affairs and dean of the school of medicine at University of Maryland, is leading an international study that will test a treatment for sickle cell patients whose bodies are too damaged to withstand the conditioning regimen needed for a cure.
The study will test a type of transfusion called red blood cell exchange on sickle cell patients with chronic kidney disease or pulmonary hypertension (high blood pressure in the lungs) to see if it improves their survival and quality of life while decreasing hospitalizations. Patients are hooked up to a machine that exchanges some of their own blood for healthy blood, reducing the share of sickled red blood cells in the body, allowing better oxygen circulation and fewer pain crises.
“We don’t have any treatments that try to arrest the development of end organ damage or any treatments that improve survival in adults,” Gladwin said. He hopes red blood cell exchange can do both for the sickest patients.
The treatment is used for other groups with sickle cell, such as kids who’ve had strokes or are at risk for them. Red blood cell exchange has been shown to help them gain weight, perform better in school and suffer fewer complications, Gladwin said.
The transfusions may help other people with sickle cell as well, Gladwin said, such as those who don’t want chemotherapy or prefer to wait for more data on the new therapies before pursuing one themselves.
The price of about $10,000 per year for red blood cell exchange also seems like a bargain compared to curative therapies and even the newer medications, which don’t control the disease as well as the transfusions but can cost between $40,000 and $60,000 per year, Gladwin said.
In the meantime, Law said some preliminary studies are looking at whether the gene therapies will work with less intense conditioning regimens, perhaps a lower-dose chemotherapy.
For half-match bone marrow transplants, Brodsky said the next step will be to show how effective they can be in children before many severe problems develop.
But already, Brodsky said each new advance “means options for people with sickle cell, who really didn’t have options before.”
Correction: This article has been updated to correct the amount of time Simone Day was out of work following her transplant. Day went back to work after five months.
