Written by Dina Beasley
LOS ANGELES (Reuters) – Student Zoe Davis, 20, was just weeks into her first year of school when she returned to the hospital with severe sickle cell pain earlier this month. She does what she can to prevent the bouts of paralysis in her arms, legs and stomach, which are becoming more frequent.
She knows that new gene therapies may provide long-term relief for some of the 100,000 Americans like her who have sickle cell disease. But she postpones one attempt.
“It’s very new,” said Davis, who studies veterinary science at North Carolina Agricultural and Technical State University in Greensboro. “I wanted to see more success stories before I committed to it.”
Her reluctance explains a common reason why take-up of potentially life-changing treatments, which cost $2 million to $3 million in the United States, has been slower than expected, interviews with six American specialists and six sickle cell patients show.
Younger patients — weighing their school schedules and hesitant to add more medical burden to their lives — were less enthusiastic than expected, said Dr. Liu Wang, a hematologist and oncologist at City of Hope Children’s Cancer Center near Los Angeles.
“Some kids aren’t interested,” he said, adding that patients ages 20 to 40 are interested, but some are so ill that they are not good candidates.
The new single-use treatments, which were approved in the United States last December, have so far been used in about 100 people globally, including in clinical trials. It requires chemotherapy, which increases the risk of cancer and can cause infertility.
Some patients say the time it takes for treatment – up to a year – is a scary prospect for anyone whose condition is not critical.
Worldwide, an estimated 8 million people have sickle cell disease, a genetic disorder, according to the National Institutes of Health. Most of those in the United States are black.
The red blood cells of those infected have an abnormal “sickle” shape that can prevent their flow through the blood vessels, causing excruciating pain and sometimes leading to strokes, organ damage, and premature death. The mutation that causes sickle cell is most prevalent in places where malaria is endemic: one copy of the gene has been shown to protect against malaria infection.
By September, at least 30 people worldwide had started a one-time gene therapy outside of trials, according to the two drugmakers whose treatments were approved in America.
Both treatments involve a months-long process to remove the patient’s bone marrow stem cells and genetically modify them in a laboratory. Patients are given chemotherapy and admitted to hospital to be monitored for weeks after the cells are re-injected.
Doctors say use of the treatments could increase as more data on safety and effectiveness emerges, but many patients are waiting on the sidelines — timing pregnancy, weighing the cost of fertility treatments, or putting off because of the long process. Others seek insurance approval: Hospitals need to confirm payments in advance.
Some younger patients’ disease remains under control with standard medications. Hematologists said that the elderly are vulnerable to complications. Those with significant organ damage, a history of stroke or infections such as HIV or hepatitis may not be eligible.
“You have to be sick, but not too sick,” said Dr. Andrew Campbell, director of the National Comprehensive Pediatric Sickle Cell Program in Washington, D.C.
“Not like hotcakes.”
Companies, doctors and analysts say more than 80% of patients in the United States are unsuitable for the treatments, which are approved only for those over 12 with a history of acute pain crises. Doctors and insurance companies have more stringent standards.
One drugmaker, Bluebird Bio (NASDAQ:), in August cut its forecast for use of all three gene therapy products this year to 85 at most, down from 105. And earlier this week, it said 10 patients so far have started the sickle cell regimen. .
The other company, Vertex Pharmaceuticals (NASDAQ:), said in August that 20 patients worldwide had begun the treatment process, but still described its treatment as a “potential multi-billion-dollar opportunity” for about 58,000 patients in the United States, Europe and Saudi Arabia. And Bahrain.
Bluebird shares are down about 64% this year at about 50 cents. Vertex stock rose about 14% to about $463, on par with gains in the health care index.
On average, Wall Street analysts expect Vertex’s Casgevy sales to reach $500 million by 2026, according to LSEG data. There are no consensus data available for treatment of Bluebird, Levgenia. The company said this week that it would cut 25% of its workforce, mostly from research, to devote more resources to selling its existing products.
Thomas Klima, Bluebird’s chief operating officer, told Reuters that sickle cell patients are “excited” about Levgenia, but that the payer approval process and clinical readiness steps take longer than a typical drug treatment.
Stuart Arbuckle, Vertex’s chief operating officer, said in an email that the company was pleased with the response from payers, doctors and patients, but “this was always going to be a foundational year” for Casgevy.
Among other gene therapies approved in recent years, only one has generated sales exceeding $1 billion annually: Novartis (VI:)’ Zolgensma for spinal muscular atrophy in children. Uptake of the rest, including one-time hemophilia treatments, has been slow.
Sickle cell treatments are “absolutely fascinating from a scientific standpoint,” said Chris Bardon, co-managing partner of biotech investment firm MPM BioImpact, which has a portfolio that includes gene therapy companies.
But she said it was not expected to “sell like hotcakes,” with early use seen mainly in patients with severe disease.
Weeks of pain
Debilitating sickle cell pain can affect any part of the body, but most commonly occurs in the hands, feet, chest, and back. It can last for a few hours to several weeks.
Current treatments include blood transfusions, antibiotics for infections, opioids for severe pain, and the generic drug hydroxyurea, an anti-cancer pill that helps red blood cells return to their normal shape. Pfizer (NYSE:) said this week it would withdraw its sickle cell disease treatment, Oxbryta, citing risks of painful complications and deaths.
Until now, the only potential treatment for sickle cell disease has been a bone marrow transplant, but it is difficult to find matching donors for this procedure, which also requires chemotherapy. There is a risk of transplant rejection.
People infected with the disease are advised to avoid sudden changes in temperature, drinking alcohol or smoking, high altitudes or strenuous exercise, and stay away from the risk of infection. Stress can also lead to a severe attack that lands them in the emergency room.
Student Davis said that moving to college from her home in Virginia led to an increase in the progression of the disease that many suffer from as they age. She takes hydroxyurea and folic acid daily, but her pain crises still often require hospitalization.
Kayla Smith Owens, a 25-year-old sickle cell advocate who describes her pain as “constant,” was accepted in 2020 into a bone marrow transplant trial, but the donor failed at the last minute.
She is interested in receiving gene therapy, which her doctors recommended since she is young and has no damage to her organs. But its insurance coverage is uncertain.
“I will turn 26 in November and will be excluded from my mother’s insurance,” Smith-Owens said. To avoid interruption of service at that time, she and her medical team hope the insurance company will grant an extension.
Health insurers that set the terms adhere closely to them, said Jennifer Cameron, executive director of patient access at Children’s National Hospital, whose job involves communicating with insurance companies.
“If they say there are 10 points that a patient must meet, they hold us to those 10 points,” she added, noting that insurance companies have refused to cover gene therapy for some sickle cell patients recommended by doctors.
Vertex has partnered with CRISPR Therapeutics to develop the $2.2 million Casgevy therapy, the first U.S.-approved treatment that uses gene editing technology to shrink defective parts of a gene and allow patients to produce normal red blood cells.
Bluebird Levigenia uses a viral envelope to deliver a healthy gene to produce hemoglobin. The company sells the $3.1 million treatment in the United States only
After KasGevi infusion, trial data showed that 36 out of 39 patients did not experience a severe pain crisis for at least 12 consecutive months. The Bluebird study showed that 32 out of 34 patients did not experience a severe pain crisis after about three years.
Fertility barrier
Doctors say they are carefully weighing the risks of the two gene therapies against the potential benefits.
If patients do well on current treatment, Dr. Michael DeBon, director of the Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease in Nashville, questioned the logic of recommending a new gene therapy that so far has been used in very few people.
“You wouldn’t do it for cancer,” he said. “You will only offer this to people with the most severe illnesses who are likely to die.”
Dr. Mark Walters of UCSF Benioff Children’s Hospital in Oakland, California, expects the treatments will initially be used for about 10 percent of sickle cell patients, noting that the field is moving quickly as researchers aim for treatments that may not require chemotherapy.
“The chemotherapy drug we use causes infertility in most people,” Walters said.
An egg freezing cycle can cost up to $15,000, and storage up to $500 per year, according to the nonprofit Alliance for Fertility Preservation. The group estimates that the cost of storing sperm can reach $1,000 plus another $400 per year for storage.
Sickle cell patient Dominique Goodson, 38 and pregnant with her first child, said she would like to have gene therapy a year or so after giving birth in December, but needs to be sure she can maintain fertility options for a second child.
Both Vertex and Bluebird have programs to help pay for fertility services, but those programs are not available to patients on the federal government’s Medicaid plan for low-income individuals, which covers more than half of sickle cell patients in the United States.
Medicaid has proposed a pilot program starting next year that would include some fertility services, but Vertex is challenging the government’s policy in court.
Goodson works with the non-profit Sickle Cell Consortium, focusing on the needs of the sickle cell community, and has participated in focus groups conducted by Vertex and Bluebird.
“I want to be able to live a normal life… just be able to enjoy the simple things,” she said.