Even in an era when the pace of medical innovation is increasing rapidly, relatively few new treatments for disease can rightfully be called “breakthroughs.” But in the case of two new therapies approved by the Food and Drug Administration (FDA) late last year, the term is justified. The therapies treat sickle cell disease, an inherited condition that affects about 100,000 people in the United States, the majority of them Black.

The new treatments for sickle cell disease genetically modify a patient’s own red blood cells to prevent or lower the risk of sickling, the process that makes the cells assume a stiff and sticky crescent shape. The misshapen impede the body’s ability to transport the oxygen that organs need to function properly. The sickle cells also die more quickly, which decreases the number of red blood cells.

Patients can suffer from debilitating pain and damage to organs and require frequent hospitalizations. Until now, the only treatment options have been a handful of medications to manage symptoms or a donor stem cell transplant, which cures the disease but is also risky and relies on finding an exact match.

The process of genetically modifying cells and infusing them in patients with sickle cell disease is lengthy and expensive, but the therapies offer a new path to freedom from the tyranny of sickle cell disease, said Dr. Kathryn Hassell, a hematologist and sickle cell disease specialist at the UCHealth Blood Disorders and Cell Therapies Center on the Anschutz Medical Campus. Hassell is also a professor of Medicine-Hematology at the University of Colorado School of Medicine and director of the Colorado Sickle Cell Treatment and Research Center.

To help answer common questions about the new sickle cell gene therapies, we spoke with Hassell. She discussed how the new therapies work, what they will cost and what kind of long-term outcomes patients can expect.

What are the two recently approved gene-based therapies to treat sickle cell disease?

They are Lyfgenia and Casgevy, both of which received FDA approval in December 2023. Casgevy was developed by Vertex Pharmaceuticals Inc.; Lyfgenia was developed by Bluebird Bio Inc.

How do these gene-based therapies work?

Both use bone marrow cells harvested from the blood of patients with an apheresis machine, which separates blood parts, Hassell said.

The collected cells then go to the respective manufacturers, which alter them in different ways, she said.

Who can receive the therapies?

Individuals 12 years and older who have sickle cell disease are eligible to receive the new sickle cell gene therapies. However, there are exclusions. More on that below.

Let’s start with Lyfgenia. How does it work?

The Lyfgenia treatment uses what Hassell calls a “gene insertion” approach. People with sickle cell disease have two genes that code for the production of hemoglobin S — the culprit in causing red blood cells to stiffen and take a crescent shape. By contrast, the red blood cells in people with sickle cell trait — just one gene with the sickling code—produce more hemoglobin A than S. Hemoglobin A transports oxygen normally throughout the body, Hassell said.

“As long as there is more normal hemoglobin and less of the hemoglobin S inside a cell, it can’t sickle,” Hassell said.

The Lyfgenia therapy attempts to “recapitulate” that lesson from nature, Hassell said. The manufacturing process inserts a gene that instructs the red blood cells to produce what Hassell called a “super” hemoglobin A with exceptional anti-sickling power.

Patients receive an infusion of the cells with the revved-up hemoglobin A. These cells get the same kind of numerical upper hand over the S sickling gene that people with sickle cell trait have, Hassell said.

“Nature has shown us that if you just make more A than S in a cell, that for the most part, you can eradicate sickle cell disease,” she said.

How does Casgevy work?

While Lyfgenia relies on gene insertion in red blood cells, Casgevy works through gene editing technology, called CRISPR/Cas 9. The CRISPR mechanism allows scientists to cut DNA at key points that control particular traits — such as cell sickling — and modify and use in its place cellular material that “repairs” the problem area in different ways, Hassell said.

The editing target in Casgevy is a gene that “turns off” production of fetal hemoglobin, the kind of blood a fetus relies on to transport oxygen, after a baby is born. That genetic change creates havoc for people with sickle cell disease, she said.

“In utero, we don’t make hemoglobin S or A, we make only fetal hemoglobin,” Hassell said. But after birth, most newborns cease producing fetal hemoglobin and begin producing hemoglobin A and in some, hemoglobin S and the risk of sickle cell disease.

Nature provides another lesson useful in fighting the disease, Hassell said.

In some people, the gene that signals the body to produce fetal hemoglobin within each red blood cell doesn’t turn off. Even if the other gene within the cell continues to make hemoglobin S, the fetal hemoglobin counteracts the sickling, and thus prevents sickle cell disease, she said.

Casgevy works by gene editing that “breaks apart” the genetic block that “turns off” the production of fetal hemoglobin, Hassell explained. With that obstacle removed, production of fetal hemoglobin returns to the body “as it was in utero,” she said. She emphasized that, as with Lyfgenia, Casgevy does not stop the production of hemoglobin S.

“You are modifying other hemoglobins that are in the blood so you can counteract what the sickle [cells] would do,” she said.

What’s it like to receive one of the gene-based therapies, and how long does it take?

Individuals must first be assessed to ensure they are good candidates for the therapies, Hassell said. More on the assessment factors below.

For several months before the procedure, patients receive chronic blood transfusion treatments to decrease the number of sickle cells in their blood. Cells from bone marrow — which are responsible for generating armies of blood cells day in and day out — are then harvested from blood circulating in the body and sent to the cell manufacturers to be genetically modified. That process can take two to three months. Around the time the cells are ready, patients undergo chemotherapy for several days. When they have finished that treatment, they are infused with the modified cells, Hassell said.

It may take two to five weeks for the modified cells to “engraft” or take hold in patients’ bone marrow and begin to restore them to health, Hassell said. She added that clinicians may save some of the new cells for a second infusion in case the initial treatment doesn’t take hold in the bone marrow.

There is also a long follow-up period, Hassell noted. The FDA has requested that providers approved to administer the therapy follow patients for 15 years, although the process by which that will happen has not been settled, she said.

Are these therapies available to patients in Colorado?

Partially.

Dr. Christopher McKinney, assistant professor in the Department of Pediatrics at the University of Colorado School of Medicine, said Children’s Hospital Colorado is an approved, qualified treatment center for Lyfgenia. Children’s Colorado has not yet been approved as a qualified treatment center for Casgevy, McKinney added.

Can patients be excluded from receiving the therapies?

Yes. Patients with irreparable damage to the liver, heart and other organs may not be viable candidates, Hassell said. It’s not that the gene therapy itself is harmful, but rather that these patients may not be able to withstand the rigors of the regimen to prepare them for it, she said.

In addition, a person who has built up a lot of iron in the blood from transfusions to treat their sickle cell disease may require treatments with compounds called chelators that draw the metal from the blood. Those treatments may take six to eight months or longer, Hassell said. Without them, these patients are at risk of damage from the chemotherapy treatments that prepare them for the cell infusions.

Hassell also noted that patients with alpha thalassemia, a condition that decreases the amount of hemoglobin A that the body produces, cannot receive the Lyfegenia treatment, but could receive Casgevy. That’s because of adverse events reported in patients with alpha thalassemia in the clinical trials of Lyfgenia.

What are the risks of receiving either of the gene-based therapies?

Aside from the physical toll on patients, Hassell said one potential risk, still to be determined, lies in how the body reacts to the introduction of a modified gene. She noted that the body responds to and cleans up cancer and other rogue cells constantly. That process keeps us healthy, but what if the body encounters genes delivered by the infusions of Lyfgenia or Casgevy and sees them as intruders?

“There may be regulatory mechanisms that say, ‘Hey, wait. That’s not right. That’s something that has busted into the middle of my DNA that I may need to pull out or fix or turn off,’” Hassell said.

The FDA also lists a number of possible side effects of Casgevy, including low platelet counts, which impair the body’s ability to clot blood. Hassell said the trials of Lyfgenia reported two cases of acute myeloid leukemia, a cancer that originates in the bone marrow and can spread to the blood and other parts of the body. Hassell noted, however, that “rigorous testing” did not show that the inserted gene was associated with the leukemia cell and therefore to blame for the disease.

Finally, the drugs used to clear out old bone marrow in any cell-based therapy cause infertility, obviously a major consideration, particularly for a young child, Hassell said.

Do these therapies cure sickle cell disease?

That depends on how one defines “cure,” Hassell said.

“For me, a ‘cure’ means that if I had breast cancer, there are no breast cancer cells in me anymore,” she said. “You ‘cured’ me because you eradicated the breast cancer. In sickle cell disease, with the gene therapies, we do not stop production of sickle hemoglobin within a red blood cell.”

Hassell added that however effective these new therapies are in eliminating the debilitating consequences of sickle cell disease, the individuals who are treated still have a sickle gene that they can pass on to their offspring.

So, is there a cure for sickle cell disease?

Yes. It is bone marrow transplant with blood from a closely matched donor, like a sibling, Hassell said. “In terms of what your bone marrow makes, if the transplant is successful, it makes only your [sibling’s] blood,” she said. That’s technically a cure and a permanent change because the transplanted blood does not have sickle hemoglobin, she added.

If bone marrow transplant cures sickle cell disease, why not use it for all patients?

The biggest barrier is that only about 20% of patients find a close family donor match, Hassell said. Secondly, as patients get into their teenage years and beyond, the toxic effects of the drugs necessary to prepare for a transplant are significant. Last, unless the patient has a perfect match — a brother or sister — the risks increase for complications like graft-versus-host disease (which triggers an immune response from the transplanted cells against the body of the recipient).

How much do the new sickle cell gene therapies cost?

The cost has yet to be finalized, but the new sickle cell gene therapies will be extremely expensive. The list prices range from $2.2 million for Casgevy to $3.1 for Lyfgenia for a one-time infusion. There are efforts underway to reduce those costs and improve access to the therapies, Hassell said. Broadly, the Centers for Medicare and Medicaid Services (CMS) has developed the voluntary Cell and Gene Therapy Access Model to help states pay for the costs of these therapies for people covered by Medicaid, as well as gather data on the health outcomes of the therapies. The model, which is to launch in January 2025, could greatly benefit patients with sickle cell disease, about half of whom have Medicaid coverage.

“What CMS is trying to do is work with those who produce these gene products to negotiate a better price,” Hassell said. But she predicted that even if those efforts prove successful, the cost of a single infusion will still fall between $1 million and $1.5 million.

Aren’t even those “lower” prices unaffordable?

Hassell said the approval of the two drugs is part of a large debate about their long-term costs and benefits. She noted that four FDA-approved medications to treat and manage sickle cell disease are themselves expensive and of course must be taken repeatedly. Many patients with sickle cell disease require periodic hospitalizations for severe pain episodes. Some patients, such as those who suffer a stroke in childhood, will need blood transfusions for the rest of their lives as well as drugs to remove iron from their blood, Hassell said. These and other costs continue to accrue during a patient’s lifetime.

Hassell contrasted that approach with gene-based therapies. “The younger you apply them, the less you incur downstream costs and the more health the person enjoys and life expectancy. It is fair to say that I anticipate a lot of health economic analyses to come about.”

What do you see as future developments in the treatment of sickle cell disease?

“I foresee an opportunity to make more available the curative therapy we have, which is stem cell transplant,” Hassell said.

That means expanding the number of donors and finding less toxic ways to do the transplants, with fewer long-term consequences, she added.

“I also envision the opportunity to modify how we deliver genetically modified cells,” Hassell said. “We will get more sophisticated in how we impact the genes in the red blood cells.”

That could mean using gene-editing technology like CRISPR to actually delete the sickle gene or pull out the “bad base pair” of genes and inserting the “good” pair — in both cases thwarting the threat of sickle cell disease.

“We’re nowhere near that now, but who knows? We will figure out how to better maneuver the genetics,” Hassell said.