LOS ANGELES, Sept 28 (Reuters) - Student Zoe Davis, 20,

was just weeks into her junior year when she landed back in the

hospital with severe sickle cell pain earlier this month. She is

doing what she can to prevent the crippling attacks in her arms,

legs and abdomen that are becoming more frequent.

She knows new gene therapies may provide long-term relief to

some of the 100,000 Americans like her who suffer from sickle

cell disease. But she's holding off trying one.

"It is so new ... I wanted to see more success stories

before I committed to it," said Davis, who is studying

veterinary science at North Carolina Agricultural and Technical

State University in Greensboro.

Her hesitation illustrates a common reason why take-up for

the potentially life-changing treatments, which cost $2 million

to $3 million in the U.S., is proving even slower than expected,

interviews with half a dozen U.S. specialists and six sickle

cell patients show.

Younger patients - weighing school schedules and reluctant

to add more medical burden to their lives - have been less

enthusiastic than predicted, said Dr. Leo Wang,

hematologist-oncologist at City of Hope Children's Cancer Center

near Los Angeles.

"Some kids are just not interested," he said, adding that

patients between ages 20 and 40 are, but some have such severe

disease that they are not good candidates.

The new one-time treatments, approved in the U.S. last

December, have so far been used on around 100 people globally,

including in clinical trials. They require chemotherapy, which

raises 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, 8 million people are estimated to have sickle

cell disease, an inherited disorder, according to the National

Institutes of Health. Most of those in the U.S. are Black.

Sufferers' 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 begun a

one-time gene therapy outside trials, according to the two

drugmakers whose therapies were approved in America.

Both treatments involve a months-long process to remove a

patient's bone marrow stem cells and genetically modify them in

a lab. Patients are given chemotherapy and admitted to hospital

to be monitored for weeks after the cells are reinfused.

Doctors say use of the therapies could increase as more data

emerges on safety and efficacy, but many patients are waiting on

the sidelines - timing pregnancies, weighing the cost of

fertility treatments or put off by the lengthy process. Others

are seeking insurance approval: Hospitals need to confirm

payments in advance.

Also, some younger patients' disease is still under control

with standard medicines. Older ones are liable 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 Children's National Comprehensive

Sickle Cell Disease Program in Washington D.C.

'NOT LIKE HOTCAKES'

The companies, doctors and analysts say that more than 80%

of U.S. patients are not suitable for the therapies, which are

approved only for those over 12 with a history of severe pain

crises. Doctors and insurers have stricter criteria.

One of the drugmakers, Bluebird Bio ( BLUE ), in August cut

its forecast for use of all three of its gene therapy products

this year to 85 at most, down from 105. Earlier this week, it

said 10 patients had so far started its sickle cell regimen.

The other firm, Vertex Pharmaceuticals ( VRTX ), said in

August that 20 patients worldwide had begun its treatment

process, but still called its therapy "a potential multi-billion

dollar opportunity" for about 58,000 patients in the U.S.,

Europe, Saudi Arabia and Bahrain.

Bluebird's shares are down about 64% this year at around 50

cents. Vertex has risen about 14% to around $463, on par with

with gains in the S&P 500 Healthcare index.

Wall Street analysts, on average, expect sales of Vertex's

Casgevy to reach $500 million by 2026, according to LSEG data.

No consensus forecast is available in the data for Bluebird's

treatment, Lyfgenia. This week the company said it would cut 25%

of its workforce, mostly from research, to put more resources

into selling its existing products.

Thomas Klima, Bluebird's chief operating officer, told

Reuters sickle cell patients are "excited" about Lyfgenia, but

the payer approval process and steps to clinical readiness take

longer than for a typical drug treatment.

Vertex COO Stuart Arbuckle said in an email that the company

has been pleased with the response from payers, physicians and

patients, but "this was always going to be a foundational year"

for Casgevy.

Of other gene therapies approved in recent years, only one

has reached blockbuster sales of over $1 billion a year:

Novartis' Zolgensma for spinal muscular atrophy in babies.

Uptake of the rest, including one-time hemophilia therapies, has

been slow.

The sickle cell therapies are "pretty awesome 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 they are not expected "to sell like hotcakes,"

with early use seen mainly in patients with severe disease.

WEEKS OF PAIN

Debilitating sickle cell pains can strike any part of the

body, but they most commonly occur in the hands, feet, chest,

and back. They can last for a few hours to several weeks.

Existing treatments include blood transfusions, antibiotics

for infections, opiates for severe pain and the generic drug

hydroxyurea, an anti-cancer pill that helps red blood cells

return to normal shape. Pfizer ( PFE ) said this week it was

withdrawing its sickle cell disease treatment, Oxbryta, citing

risks of a painful complication and deaths.

Until now, the only potential cure for sickle cell disease

was a bone marrow transplant, but it is hard to find matched

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

temperature changes, alcohol or smoking, high altitudes or

strenuous exertion, and to steer clear of infection risks. Also,

stress can bring on an acute attack that lands them in the

emergency room.

Student Davis said moving to college from her home in

Virginia heightened the disease progression that many experience

as they age. She takes hydroxyurea and folic acid daily, but

still her pain crises frequently need hospital treatment.

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 her donor fell through at the

last minute.

She is interested in receiving gene therapy, which her

doctors have recommended given that she is young with little to

no organ damage. But her insurance coverage is uncertain.

"I turn 26 in November and will be dropped off of my mom's

insurance," Smith Owens said. To avoid being cut off at that

time, she and her medical team hope the insurer will grant an

extension.

Health insurers that have outlined terms are adhering

closely to them, said Jennifer Cameron, executive director for

patient access at Children's National Hospital, whose job

entails communicating with insurers.

"If they say there are 10 points that the patient must meet,

they are holding us to those 10 points," she said, noting that

insurers have turned down gene therapy coverage for some sickle

cell patients whom doctors had recommended.

Vertex partnered with CRISPR Therapeutics to

develop its $2.2 million therapy Casgevy, the first

U.S.-approved treatment using gene editing technology to trim

faulty parts of a gene and allow patients to produce normal red

blood cells.

Bluebird's Lyfgenia uses a viral envelope to deliver a

healthy hemoglobin-producing gene. The company sells the $3.1

million therapy only in the U.S.

After infusion with Casgevy, trial data showed that 36 out

of 39 patients did not have a severe pain crisis for at least 12

consecutive months. Bluebird's study showed that 32 out of 34

patients had not experienced a severe pain crisis after around

three years.

FERTILITY BARRIER

Doctors say they are cautiously weighing the risks of the

two gene therapies against the potential benefits.

If patients are doing well on current treatment, Dr.

Michael DeBaun, director at Nashville's Vanderbilt-Meharry

Center of Excellence in Sickle Cell Disease, questioned the

logic of recommending a new gene therapy used so far on so few

people.

"You wouldn't do that for cancer," he said. "You would only

offer that to people who had the most severe disease who were

likely going to die."

Dr. Mark Walters at UCSF Benioff Children's Hospital in

Oakland, California expects the therapies to initially be used

for about 10% of sickle cell patients, noting the field is

moving quickly as researchers aim for therapies that may not

require chemo.

"The chemotherapy drug we use causes infertility in most,"

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

another $400 a year for storage, the group estimates.

Sickle cell patient Dominique Goodson, 38 and pregnant with

her first child, said she would like to get a gene therapy a

year or so after she gives birth in December, but she needs to

make sure she can preserve fertility options for a second child.

Both Vertex and Bluebird have programs to help with payment

for fertility services, but these are not available to patients

in the federal government's Medicaid plan for low-income

individuals, which covers more than half of U.S. sickle cell

patients.

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 normalish life ... just being

able to enjoy the simple things," she said.