Panel says innovative sickle cell treatment is safe enough for patients

A panel of experts said Tuesday that a breakthrough treatment for sickle cell disease was safe enough for clinical use, paving the way for likely federal approval by Dec. 8 of a powerful potential cure for a disease that affects more than 100,000 Americans.

The Food and Drug Administration had previously found that the treatment, known as exa-cel and jointly developed by Vertex Pharmaceuticals of Boston and CRISPR Therapeutics of Switzerland, was effective. The panel’s conclusion on Tuesday on exa-cel’s safety sends it to the FDA for a decision on whether to greenlight it for widespread use by patients.

Exa-cel frees patients from the debilitating and painful effects of this chronic, fatal disease. If approved, the Vertex product would be the first drug to treat a genetic disease using the CRISPR gene editing technique.

It could also be the first of a series of new options to cure the excruciating disease. By December 20, the FDA will decide on a second potential cure for sickle cell disease, a gene therapy created by the Somerville, Massachusetts, company Bluebird Bio.

Sickle cell disease is caused by a gene mutation that causes blood cells to become misshapen so that they resemble sickles or crescents. It affects millions of people around the world, most of whom have African descent. The misshapen cells become stuck in blood vessels, causing strokes, organ damage and episodes of agonizing pain as the muscles are deprived of oxygen.

The toll of sickle cell disease begins early in life. Evelyn Islam of Milwaukee, now 8, has had 22 blood transfusions and had her spleen removed before she was 3. “Gene therapy is our last hope for a cure,” said her mother, Melissa Nicole Allen.

But the new gene therapies will come too late for many.

Ashley Valentine, co-founder of the national advocacy group Sick Cells, had to take three months off work in 2016 to help her brother Marqus cope with the symptoms of sickle cell disease. When he had a hip replacement in 2018, her father eventually accepted resigning from his job to care for him.

“And that’s just us,” she said.

Marqus died in 2020, at the age of 36, from a stroke caused by sickle cell disease.

New treatments like the ones approved Tuesday are expected to cost millions of dollars per patient, although Vertex has not yet said what it will charge. But lifelong care for patients with the disease is also enormously expensive, estimated to cost the healthcare system $3 billion per year.

It is not yet clear how many people will seek the new therapy. The new therapies are also not easy to tolerate and pose hardships for patients, who will have to undergo chemotherapy and spend more than a month in the hospital. Family members are also affected; they may need to take time off work during the most intensive phase of treatment.

Additionally, most Americans with sickle cell disease are black and may not trust them healthcare system that has often failed to provide the most basic preventive and therapeutic care to people with the disease. Some with sickle cell disease are afraid to undergo medical treatment that is at the cutting edge of biotechnology.

But for doctors who have watched patients suffer for years, and for many parents who have watched their children in pain for years, there is elation about what lies ahead.

“We are finally at a point where we can devise widely available treatments for sickle cell disease,” said Dr. John Tisdale, director of the National Heart, Lung and Blood Institute’s Division of Cellular and Molecular Therapeutics and a member of the advisory committee. .

Dana Jones of San Antonio wants her daughters Kyra, 18, and Kami, 20, to get a shot at one of the new therapies. Both had strokes that left them with learning disabilities — injuries that likely could have been prevented if they had received a screening test and long-established treatment to prevent nine out of ten strokes in children with the disease. Kyra is now in intensive care while doctors try to control her pain.

Mrs. Jones is overwhelmed by the possibility that her daughters can be healed.

“It is my prayer that Kami and Kyra can be healed from this terrible disease and finally live truly again,” she said.

A new treatment and a new technology

The cause of sickle cell disease has been known for nearly seventy years, but research has lagged, a situation that many believe occurred at least in part because so many patients were black and from poor and working-class families.

There are a number of treatments to reduce the impact of sickle cell disease. Some patients can receive bone marrow transplants that can cure the condition. But that requires finding a donor and, after the transplant, taking medication to prevent the body from rejecting the foreign cells.

In recent years, a number of biotechnology companies have tried new approaches. As Bluebird Bio continues to develop its gene therapy technique, Vertex and CRISPR Therapeutics focused on the CRISPR-Cas9 gene editing system, which can target specific parts of DNA and turn genes on or off. CRISPR has allowed researchers to knock out genes to assess their importance in biomedical research. But so far it has not been used as a treatment for patients with a genetic disease.

To treat sickle cell disease, CRISPR cuts a piece of DNA from bone marrow stem cells. That releases a blocked gene to make a form of hemoglobin normally only produced by a fetus. The fetal gene controls the production of hemoglobin that does not form into the sickle shape. In clinical trials, patients no longer had the complications of sickle cell disease and no longer required blood transfusions.

But there are concerns that CRISPR could inadvertently cut a piece of DNA in the wrong part of a patient’s genome. This can disrupt a gene and cause blood cancer.

No such problems emerged in the clinical trials, but the Vertex study involved only 44 patients, and only 30 were followed for at least 16 months. The company has done extensive comparisons of patients’ DNA with that of people in large databases and wondered how likely such CRISPR failures might be.

Vertex said it plans to follow patients from clinical trials for 15 years. The company’s data was sufficiently reassuring that the expert committee said on Tuesday it saw no reason to delay treatment.

Additional studies can always take place, noted committee member Alexis Komor, a professor of chemistry and biochemistry at the University of California, San Diego. But, she said, that would amount to “expecting perfection at the expense of progress.”

Dr. Joseph Wu of Stanford added: “We all agree that the benefits outweigh the risks. These patients are quite sick and this is a good therapy.”

Scot Wolfe of the University of Massachusetts Chan Medical School said, “We must be careful not to let the perfect become the enemy of the good.”

“There is a huge unmet need,” he added.

If it’s safe, who gets it?

Vertex estimates that 20,000 people could qualify for the treatment, and says Medicaid and private insurers are willing to pay for it.

“They can hardly do that not pay,” said Dr. David Williams, chief of hematology and oncology at Boston Children’s Hospital.

Dr. Williams, who has consulted for Vertex and Bluebird Bio, added that insurers are paying “$3 million each” for other gene therapies produced by Bluebird Bio for the diseases thalassemia and adrenoleukodystrophy. With sickle cell disease and the large number of black patients, he said, there is an issue of “equality of access and the enormous medical need.”

Some people with the disease may not qualify, depending on the FDA’s decisions. This may include young children with sickle cell disease and older patients whose bodies are so damaged that treatment may entail increased risks.

Kevin Wake of Kansas City, Missouri, hopes he’s not too old, at 55, or too damaged. He has had three strokes caused by the disease.

Although the treatments are curative, they are difficult.

Patients first receive blood transfusions for eight weeks, followed by treatment to release bone marrow stem cells into their bloodstream. The stem cells are then removed and sent to the companies to be treated. Patients then receive intensive chemotherapy to free their bone marrow for the treated cells. The treated cells are put back into the patients, but they must stay in the hospital for at least a month while the new cells grow and repopulate their bone marrow.

That treatment “can’t be provided in most hospitals,” said Dr. Alexis Thompson, chief of hematology at Children’s Hospital of Philadelphia, who consults for Vertex.

Another issue is how quickly Vertex can ramp up production. Each patient’s cells must be handled individually in a sterile environment, a difficult prospect.

Stuart Arbuckle, executive vice president and chief operating officer at Vertex, is confident. “We are ready for launch,” he said. But he added that he did not expect a huge wave of patients immediately.

“This is a pretty big decision for a patient to make,” Mr Arbuckle said.

One of the Vertex clinical trial patients, Marie-Chantal Tornyenu, 22, a senior at Cornell University, said patients also needed to be prepared for “mental adjustment” after treatment.

Ms. Tornyenu said she no longer had the pain crises that plagued her, especially in high school, when she was hospitalized almost every month.

But she has spent much of her life taking precautions and worrying about pain and complications from sickle cell disease. Those habits are difficult to break.

“It’s a major learning curve from having had sickle cell my entire life,” she said. “I still struggle with that mentality: ‘Sickle cell is you.’”