Why gene therapy for sickle cell disease is slow to catch on in patients By Reuters

By Deena Beasley

LOS ANGELES (Reuters) – College student Zoe Davis, 20, was just a few weeks into her first year when she landed back in the hospital with severe sickle cell pain earlier this month. She does everything she can to prevent the crippling attacks in her arms, legs and abdomen that are becoming more frequent.

She knows that new gene therapies can provide long-term relief to some of the 100,000 Americans like her who suffer from sickle cell disease. But she refrains from trying one.

“It’s so new … I wanted to see more success stories before I committed,” said Davis, who is studying veterinary science at North Carolina Agricultural and Technical University in Greensboro.

Her reluctance illustrates a common reason why adherence to the life-changing treatments, which cost between $2 million and $3 million in the U.S., is proving even slower than expected, according to interviews with half a dozen specialists in the U.S. and six sickle cell patients.

Younger patients — weighing school schedules and reluctant to add more medical burden to their lives — were less enthusiastic than expected, said Dr. Leo Wang, a hematologist-oncologist at City of Hope Children’s Cancer Center near Los Angeles.

“Some kids just aren’t interested,” he said, adding that patients in their 20s and 40s are, but some have such severe disease that they aren’t good candidates.

The unique new treatments, approved in the US last December, have so far been used on around 100 people globally, including in clinical trials. They need chemotherapy, which increases the risk of cancer and can cause infertility.

Some patients say the time involved – up to a year – is a daunting prospect for anyone whose condition is not critical.

Worldwide, an estimated 8 million people have sickle cell disease, an inherited disease, according to the National Institutes of Health. The majority of those in the US are black.

Patients’ red blood cells have an abnormal “sickle” shape that can block their flow through 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: a single copy of the gene has been shown to protect against malaria infection.

By September, at least 30 people worldwide had started a single gene therapy outside of trials, according to the two drugmakers whose therapies have been approved in America.

Both treatments involve a months-long process to remove stem cells from a patient’s bone marrow and genetically modify them in a laboratory. Patients are given chemotherapy and are admitted to the hospital to be monitored for weeks after the cells are reinfused.

Doctors say use of the therapies could increase as more data emerges about safety and effectiveness, but many patients are waiting on the sidelines — timing pregnancies, weighing the cost of fertility treatments or being put off by the lengthy process. Others seek insurance approval: Hospitals must confirm payments in advance.

Also, the disease of some younger patients is still under control with standard drugs. Older people are prone to complications, hematologists said. 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 Sickness Program for Children in Washington, DC.

“You DON’T like me hot”

Companies, doctors and analysts say more than 80 percent of U.S. patients are ineligible for the therapies, which are approved only for those over 12 with a history of severe pain attacks. Doctors and insurers have stricter criteria.

One of the drugmakers, Bluebird Bio (NASDAQ: patients have started his sickle cell regimen so far.

The other firm, Vertex Pharmaceuticals (NASDAQ: ), said in August that 20 patients worldwide had begun its treatment process, but still called the therapy “a potential multibillion-dollar opportunity” for about 58,000 U.S. patients , Europe and Saudi Arabia. and Bahrain.

Bluebird shares are down about 64% this year to about 50 cents. Vertex rose about 14% to about $463, matching gains in the Healthcare index.

Wall Street analysts on average expect Vertex’s Casgevy sales to reach $500 million by 2026, according to LSEG data. No consensus forecast is available in the data for the Bluebird treatment, Lyfgenia. This week, the company said it would cut 25 percent of its workforce, mostly from research, to put more resources into selling its existing products.

Thomas Klima, Bluebird’s chief operating officer, told Reuters that sickle cell patients are “excited” about Lyfgenia, but the payer approval process and clinical preparation steps are taking longer than for a typical drug treatment.

Vertex COO Stuart Arbuckle said in an email that the company was pleased with the response from payers, physicians and patients, but “this will always be a base year” for Casgevy.

Among other gene therapies approved in recent years, only one has achieved successful sales of more than $1 billion a year: Novartis (SIX:)’ Zolgensma for spinal muscular atrophy in infants. Uptake of others, including unique therapies for hemophilia, has been slow.

Sickle cell therapies are “scientifically pretty awesome,” said Chris Bardon, co-managing partner of biotech investment firm MPM BioImpact, which has a portfolio that includes gene therapy companies.

But she said she doesn’t expect them 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 it most commonly occurs in the arms, legs, chest, and back. These can last from a few hours to a few weeks.

Existing treatments include blood transfusions, antibiotics for infections, opiates for severe pain and the generic drug hydroxyurea, a cancer pill that helps red blood cells return to their normal form. Pfizer (NYSE: ) announced this week that it is withdrawing its sickle cell disease treatment, Oxbryta, citing the risks of a painful complication and deaths.

Until now, the only potential cure for sickle cell disease has been a bone marrow transplant, but it’s hard to find suitable donors for that procedure, which also requires chemotherapy. There is a risk of transplant rejection.

People living with the disease are advised to avoid sudden changes in temperature, alcohol or smoking, high altitudes or strenuous exercise, and to avoid the risks of infection. Stress can also cause an acute attack that lands them in the emergency room.

The Davis student said moving to college from her home in Virginia accelerated the progression of the disease that many experience as they age. She takes hydroxyurea and folic acid daily, but still the pain attacks frequently require hospital treatment.

Kayla Smith Owens, a 25-year-old lawyer who describes her pain as “constant,” was accepted into a bone marrow transplant trial in 2020, but her donor failed at the last minute.

She is interested in receiving gene therapy, which her doctors recommended, given that she is young with little or no organ damage. But her insurance coverage is uncertain.

“I’m turning 26 in November and I’ll be off my mom’s insurance,” Smith Owens said. To avoid being cut off at that point, she and her medical team are hoping the insurer will grant an extension.

The health insurers that drafted the terms adhere closely to them, said Jennifer Cameron, executive director of patient access at Nationwide Children’s Hospital, whose job includes communicating with insurers.

“If they say there are 10 points that the patient has to meet, they hold us to those 10 points,” she said, noting that insurers have denied coverage for gene therapy for some sickle cell patients that doctors have recommended.

Vertex partnered with CRISPR Therapeutics to develop its $2.2 million therapy Casgevy, the first US-approved treatment that uses gene-editing technology to cut out faulty parts of a gene and allow patients to produce red blood cells normal.

Bluebird’s Lyfgenia uses a viral envelope to deliver a healthy hemoglobin-producing gene. The company sells $3.1 million worth of the therapy in the US alone

After the Casgevy infusion, trial data showed that 36 of 39 patients did not have a severe pain attack for at least 12 consecutive months. The Bluebird study showed that 32 of 34 patients did not experience a severe pain attack after about three years.

FERTILITY BARRIERS

Doctors say they are carefully weighing the risks of the two gene therapies against the potential benefits.

If patients do well with current treatment, Dr. Michael DeBaun, director of the Vanderbilt-Meharry Center of Excellence in Nashville, questioned the logic of recommending a new gene therapy used so far in so few people.

“You wouldn’t do that for cancer,” he said. “You would only give this to people who have the most severe disease, who are likely to die.”

Dr. Mark Walters of UCSF Benioff Children’s Hospital in Oakland, Calif., expects the therapies to be used initially in about 10 percent of sickle cell patients, noting that the field is moving quickly as researchers target therapies that might not require chemotherapy.

“The chemotherapy drug we use causes infertility in most of them,” Walters said.

A cycle of egg freezing can cost up to $15,000 and storage up to $500 a year, according to the non-profit Alliance for Fertility Preservation. Sperm banking can cost up to $1,000 with an additional $400 a year for storage, the group estimates.

Sickle cell patient Dominique Goodson, 38, who is pregnant with her first child, said she would like to have gene therapy about a year after giving birth in December, but needs to make sure she can keep fertility options for a second child.

Both Vertex and Bluebird have programs to help pay for fertility services, but they are not available to patients in the federal government’s low-income Medicaid plan, which covers more than half of sickle cell patients in the US.

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 led by Vertex and Bluebird.

“I want to be able to live a normal life … just be able to enjoy the simple things,” she said.