For decades, life with sickle cell disease (SCD) was marked by a lack of treatment options. When people with the disease had a stroke or a debilitating pain episode — symptoms that combined to cut decades off their lives — doctors had little to offer besides pain medications.
The last five years brought a wave of new drugs that address the underlying causes of the inherited blood disorder. But bone marrow transplants, the only treatment capable of curing SCD, are still risky and available to only a small minority of patients who have an eligible stem cell donor.
That might start to change in December, when federal officials could approve two cutting-edge gene therapies for SCD. The new procedures are basically improved bone marrow transplants. Regina Hartfield, CEO of the Sickle Cell Disease Association of America, called the development of gene therapies “historic” in part because they have the potential to expand access to long-term relief from excruciating symptoms.
Like traditional bone marrow transplants, the new treatments will be harsh and time-intensive. Eligible patients will have to weigh the costs against the chance at a functional cure. Doctors won’t recommend that every sickle cell patient undergo these procedures, even if the therapies are approved by federal regulators.
Some people with SCD may opt for less invasive treatments than gene therapy.
“I like my life, and I don’t feel like I’m at the point where I’d need something that drastic,” said D’Juan Johnson, 34, a Detroiter who has severe SCD.
People who are open to trying the new gene therapies will have to answer an intimidating list of questions to reach an informed decision. Those questions are best navigated with a doctor. To help get the conversation started, we talked to doctors, reviewed research publications and attended two conferences on sickle cell disease.
What are gene therapies for sickle cell disease?
Most people with SCD are Black. The Detroit area is home to the largest sickle cell community in Michigan and one of the largest in the country.
The two new gene therapies, exa-cel and lovo-cel, work differently, but both alter patients’ DNA to increase healthy blood cells. This can eliminate the symptoms of the disease.
In a traditional bone marrow transplant, patients receive healthy stem cells from a donor, ideally a sibling. But fewer than one in five people with sickle cell disease have an eligible donor.
The gene therapy process is effectively a bone marrow transplant, but the patient acts as their own stem cell donor. Doctors harvest patients’ stem cells, alter their genetic material in a laboratory and then infuse the altered version back into the patient.
This method eliminates the need for a donor and reduces the risk that the patient’s body will reject the new stem cells.
What is it like to get gene therapy?
Doctors begin treatment by harvesting the stem cells that make blood. To prepare for this process, patients may stop taking any medications and then receive blood transfusions starting three months in advance. Over several days at the hospital, patients take a medication that causes bone marrow to release the stem cells that make blood cells. Doctors collect those cells intravenously.
The stem cells are genetically modified in a lab, a process that can take weeks. If the modifications work and the cells meet safety standards, patients return to the hospital. Over a week, they receive chemotherapy drugs that kill existing stem cells to make space for the newly modified cells. Patients then receive the modified cells through an IV.
Patients need to spend the next month or two after the infusion on a protective ward in the hospital. Chemotherapy weakens the immune system, so an infection at this point would be dangerous.
Once the immune system has recovered, patients can go home. The treatment is one time, but doctors will want to follow up for years afterward.
What’s the difference between the two medicines up for approval in December?
Both therapies increase the production of healthy blood cells by altering the sickle cell patient’s DNA, but they do so in different ways.
Lovo-cel uses the shell of a virus to add a new gene to patients’ blood stem cells. (All the viral genes are removed and modified to deliver only therapeutic genes.) The new genes tell the body to create new, healthy blood cells.
Exa-cel deletes a gene that suppresses fetal hemoglobin, a type of red blood cell that remains healthy, even in people with sickle cell disease. Fetal hemoglobin mostly disappears from the blood following infancy. That’s why most people with sickle cell disease don’t develop symptoms until they are at least six months old.
When exa-cel tells the body to stop suppressing it, fetal hemoglobin rebounds to high levels, all but eliminating sickle cell symptoms. Exa-cel would be the first Food and Drug Administration-approved drug to use CRISPR-Cas9, a gene editing tool that won a Nobel Prize for its inventors in 2020.
Lovo-cel is manufactured by a company called bluebird bio. Exa-cel is manufactured by CRISPR Therapeutics and Vertex Pharmaceuticals.
Both therapies offer similar benefits when compared to current therapies, and are expected to be priced similarly, according to an August publication from the Institute for Clinical and Economic Review (ICER), a nonprofit that evaluates medical treatments. ICER physicians said they did not have enough evidence to say that either therapy was better than the other.
How is this different from a bone marrow transplant?
Bone marrow transplants have been used to treat sickle cell disease since the mid-1980s. In 1984, a patient received a bone marrow transplant for leukemia, then found that the transplant had eliminated her sickle cell disease symptoms.
Since then, the treatment, which is technically known as hematopoietic stem cell transplantation (HSCT), has effectively cured more than 1,000 people with SCD.
Transplants require intensive chemotherapy to kill the patient’s blood stem cells and make space for a donor’s healthy cells.
Gene therapy eliminates the need for a donor and reduces the risk of a patient’s body rejecting the new stem cells. But it doesn’t yet eliminate the need for chemotherapy, which can be painful and risky.
Will everyone with severe sickle cell have access to these therapies?
Both are expected to have a high initial price tag — as much as $2 million per patient.
The high cost means there is virtually no chance they will be affordable in Africa and India, where most people with sickle cell disease live.
Cost is expected to pose a major hurdle in the U.S., too. It’s not clear how the cost might be reduced, and the answers may not be clear for months after the drug is approved.
“I’m concerned that a few thousand people will get it, followed by tens of thousands who won’t,” said Vence Bonham, acting deputy director of the National Human Genome Research Institute. He added: “Everyone who desires should have access to gene therapies.”
In the worst-case scenario, disagreements over the price could keep the drug from becoming available at all. Bluebird bio, the manufacturer of lovo-cel, got approval for another gene therapy in Europe in 2019, but took the drug off the market because it couldn’t settle on a price with European healthcare agencies.
Which patients can consider gene therapy?
Lewis Hsu, a pediatric hematologist and the chief medical officer for the Sickle Cell Disease Association of America, said the question of which patients should consider gene therapy remains “very fuzzy.”
Broadly, these patients should be “willing to take risks,” he said in a presentation this year, and have such severe symptoms that the risks of treatment are worthwhile.
To get a sense of who doctors will recommend for gene therapy, take a look at who participated in the clinical trials.
Both new drugs were tested on people with severe sickle cell disease, meaning they’d been hospitalized with pain crises three or four times per year. Some participants in the trial had a history of strokes related to sickle cell.
Their symptoms shouldn’t be so bad tha “their kidneys (or other organs) are failing already and they would have difficulty handling the gene therapy process,” Hsu said.
Prospective patients will generally be younger. Gene therapy trials enrolled people between ages 12 and 38.
How were the gene therapies tested?
Dozens of people — mostly Black — received lovo-cel and exa-cel in clinical trials.
In the first years of evidence, severe pain crises — a common, disruptive symptom of SCD — were eliminated for everyone who got these therapies.
Lovo-cel’s application for approval by the FDA is primarily supported by a study in which 35 people were treated.
All the patients had a recent history of severe pain episodes resulting in hospitalization. Such episodes stopped entirely after patients received lovo-cel, though some continued to have some sickle cell-related pain.
In the main exa-cel study, 31 patients with severe sickle cell disease did not have any severe pain crises in the months after receiving treatment. Researchers report patients did not have any severe pain crises in the months — and up to two-and-a-half years — after treatment.. Prior to treatment, these patients had four crises per year on average.
What are the risks?
Chemotherapy drugs, such as Busulfan, can lead to numerous complications and side effects, including infections, hair loss, infertility and elevated risk of cancer.
There are other risks related to gene therapy. Botched gene insertion or editing could theoretically cause cancer or other problems.
All the possible risks might not yet be understood because lovo-cel and exa-cel were tested in short-term studies. Researchers plan to follow patients for 15 years to monitor the therapies’ effectiveness and safety.
In clinical trials, many patients also went through withdrawal from opioid painkillers — a common treatment for SCD pain — with symptoms that included nausea and pain.
Can patients still pass on the sickle cell gene after gene therapy?
Yes. These treatments change the DNA of patients’ blood cells. It does not impact sperm and egg cells. Even if gene therapy is successful, there’s a 50% chance that a patient’s biological child will inherit sickle cell disease if the other parent has sickle cell trait.
People with sickle cell trait often have no symptoms. Doctors can provide genetic testing to help would-be parents make informed decisions. Tests for sickle cell disease in a fetus can be conducted during a pregnancy.
Do gene therapies cure sickle cell disease?
We don’t know yet. Both therapies are intended to permanently eliminate symptoms of sickle cell disease, but it’s far too early to know if their effects will hold in the long run.
Researchers believe that a single treatment with either drug will last a lifetime, but it will take many years for that to be confirmed. Most patients who have received lovo-cel, for instance, only received the treatment within the last four years. Patients in trials of both gene therapies continue to have consistently high levels of genetically modified, healthy blood cells.
The treatments may have long-term effects, and they don’t reverse organ damage or other complications of sickle cell disease that occurred prior to treatment.
Both therapies all but eliminated severe pain crises in clinical trials, but researchers reported that a handful of patients who took lovo-cel continued to experience some sickle cell-related pain. (This information wasn’t reported for exa-cel).
Even if gene therapies are effectively cures, they won’t make sense for many patients who have less severe sickle cell disease or can get relief from other medications that are less time-consuming, expensive and risky.
Editors note: This story has been updated to clarify that sickle cell disease currently affects about 100,000 Americans.