We finally have new drugs for sickle cell disease. Why are so few patients taking them?

Related: Companies and researchers are finally pouring resources into a search for better sickle-cell treatments.  

At first, Lena Harvey didn’t realize anything had changed. She just started doing strange, unexpected things: Cleaning her living room, for example, or playing with her puppy, a black schnauzer named Apollo.

It hit her as she walked in from the patio one day. She looked at her husband, Anthony, and asked, “Honey, I haven’t been complaining about pain, have I?”


“No,” he said, shaking his head. “No you haven’t.”

Harvey smiled. Born with sickle cell disease, her life had been marked by pain: Not just the disease’s hallmark crises — the sudden episodes that could send her to the hospital — but low-down kind of pain, a constant, grinding ache that, in recent years, often sapped the energy she needed to get out of bed.

That week, though, in February 2021, she filled her prescription of Oxbryta. Approved in November 2019, the thrice-daily pill is just the fourth ever medication for sickle cell, a blood disorder that primarily affects people of African ancestry and has long been overlooked by drugmakers.


Harvey said it has changed her life. Where she once spent the better part of every week resting, the 37-year-old mother has now turned herself into a full-time patient advocate; she spends her days assuring other patients get proper care in emergency departments, where people with sickle cell often face racism and stigma for requesting pain medication. (Harvey has no formal relationship with any drug company.)

Yet cases like Harvey’s remain rare. Oxbryta’s manufacturer says “over 12,000” people have ever filled a prescription, “the vast majority” of them in the U.S. That means only a fraction of the 100,000 Americans living with sickle cell are actively on it. Another treatment approved the same month to reduce pain crises, called Adakveo, has reached still fewer. Even older, more basic interventions are vastly underused.

Behind Oxbryta’s underwhelming first three years is debate over its expense and effectiveness, along with a long history of bias against sickle cell patients within the medical establishment, and red tape from insurers. Many doctors say Global Blood Therapeutics, Oxbryta’s inventor, has been charging around $125,000 per year for a drug that is, at best, modestly effective. But GBT and many advocates, including some physicians, say the U.S. has simply failed to invest in the kind of health infrastructure and equity that would allow a sickle cell drug — any sickle cell drug — to reach patients.

The question now is whether that will change. Pfizer this summer bought Global Blood Therapeutics for $5.4 billion, part of a wave of industry investments in sickle cell treatments.

“I’ve been taking care of kids with sickle cell for about 30 years now, and what we first had was this overall frustration that there were no treatments,” said Lewis Hsu, who runs a sickle cell center at University of Illinois Chicago.

Now there are new treatments and more in the pipeline. But if their promise is to be realized, society will have to answer a more basic question: How do you get cutting-edge medicines to patients who have often been denied access to even the most basic care?

We told the FDA: ‘You forgot about us’”

Elizabeth Rendon remembers, with the soft, blurry haze of a childhood scene, sitting in a doctor’s office in Chicago as a physician told her parents there were no other options.

She was 8 or 9 and, like thousands of other children with sickle cell, had been prescribed hydroxyurea, a colorful daily capsule containing a 50-year-old chemotherapy. The doctor hoped it would help alleviate the pain that often kept Rendon out of school and in the hospital.

It was one of several interventions academics introduced since the 1980s, alongside an ultrasound technique to detect patients at high risk of stroke and prophylactic penicillin to prevent infections in children under 5. But after more than a year, Rendon’s pain and fatigue were just as bad, if not worse. Her parents wanted an alternative.

They were out of luck. “I remember the doctor just telling them, like, ‘this is the only thing we have, it’s either this or nothing,’” Rendon said.

Although the molecular cause of sickle cell had been known since 1956, pharma had never shown much interest. Industry had yet to realize that rare diseases could be lucrative. And the few they invested in tended to be conditions, like hemophilia and cystic fibrosis, that primarily affected white people. CF also received far more philanthropic and government funding, greasing the wheels for therapies that have transformed the disease.

Hydroxyurea, by contrast, was developed by academics, who proved its efficacy in the absence of almost any industry support. It doesn’t work for everyone. Rendon took the capsules for a couple more years before doctors finally let her go off it. She resolved to join clinical trials so that future patients would have more options than she did.

It was fortuitous timing. Efforts to get industry involved were emerging. Spurred by a new law, the Food and Drug Administration held a therapeutic development hearing in 2014. Patients and caretakers packed the room, some traveling from hundreds of miles away.

“Essentially, we told the FDA: ‘You forgot about us,’” said Ashley Valentine, who co-founded the advocacy group Sick Cells alongside her late brother Marqus, who lived to 36 years and died in 2020 from sickle cell complications.

GBT had launched in 2012 and, in 2014, hired as CEO Ted Love, a Black physician and entrepreneur who spoke often about watching sickle cell patients receive poor care while he was training at Harvard and Yale. He hired other Black executives and talked about how sickle cell “epitomizes healthcare inequality.”

The company had a molecule it said could treat the root cause of the disease. Sickle cell arises from mutations in hemoglobin, oxygen-carrying molecules that are crammed into red blood cells, like stuffing in a mattress. The misshapen hemoglobin misshape the cells. They become weaker, break down faster. They glom together and lodge in blood vessels. The result can be pain, fatigue, infections, organ damage and, often, early death.

By locking onto hemoglobin in just the right way, its molecule would prevent sickling, GBT said. Sure enough, results from a 274-patient trial in 2019 showed that half of all patients who received the drug saw their hemoglobin levels rise by at least 1 gram/deciliter, an indicator that cells were breaking down less often and delivering more oxygen. Rendon, who signed up for the trial, said she could feel the difference.

“I can’t imagine going through college with the fatigue I had before I started,” said Rendon, who is now a freshman at University of Illinois Chicago.

In petitioning the FDA for approval, GBT was unable to prove Oxbryta improved symptoms or clinical outcomes. But it claimed Oxbryta would slow patients’ daily organ damage and potentially extend their lives, pointing to circumstantial evidence — natural history studies linking higher hemoglobin to better lifetime outcomes, as well as clinical trials that showed hemoglobin-boosting transfusions prevented strokes. The FDA gave the drug accelerated approval, a provisional OK while the company collected more data.

Advocates saw its approval as a watershed moment. Alongside Adakveo and a supplement approved in 2017, the number of sickle cell drugs had quadrupled.

“I tweeted like crazy, ‘Oh we got a new drug! We got a new therapy!’” said Dominique Goodson, a patient advocate in New Jersey. “’They’re finally doing something for sickle cell!’”

ASH19 Gene Therapy Sickle Cell
A sickle cell, top, and normal red blood cells of a patient with sickle cell anemia. Janice Haney Carr/CDC/Sickle Cell Foundation of Georgia via AP

Red tape that ‘makes no sense’

On a recent weekday, Lewis Hsu received a fax and quickly texted his patient: Finally.

For four weeks, he had been dueling with insurers to refill the teenager’s Oxbryta prescription. It had dragged on long enough that he would’ve missed doses, had GBT not agreed to supply the drug early, on faith that reimbursement would come.

Three years after Oxbryta’s approval, Hsu was used to the hurdles. Insurers readily covered hydroxyurea, a generic drug that costs as little as 20 cents a pill. But Oxbryta retails for around $125,000 a year, and Hsu and other doctors say their lives have become a Kafkaesque dance of prescriptions, appeals and re-appeals, played to the tune of voicemail messages and fax tones. They rattle off stories of patients who gave up amid the bureaucracy or who finally got coverage, but switched jobs and lost it. Hsu said he’s been forced to curtail prescriptions. Some clinicians may not have the time or wherewithal to fight at all.

“For me it’s a bit of self-preservation, if I was going to prescribe it for everyone, my entire workweek would be dominated by insurance appeals,” said Hsu, who has previously received research funds from GBT. “I can’t tell you how frustrating it is.”

For Hsu, this red tape is the No. 1 reason Oxbryta hasn’t been more widely used. The country’s three largest major pharmacy benefit managers don’t include Oxbryta on their list of preferred drugs. That means providers have to jump through extra hoops to obtain coverage.

The same holds true for Medicaid, which covers more than half of all sickle cell patients. Although Medicaid programs are required by law to cover every FDA-approved drug, they can manage its use. And at least 80% of states have put restrictions on Oxbryta, according to a report this year from Sick Cells.

These restrictions can mean doctors have to formally authorize every refill, or prove that a patient is improving to get the next dose. But, for some, the most frustrating has been STEP therapy, where patients have to fail cheaper medicines before they can move to pricier ones. Used to rein in spending on expensive pharmaceuticals, these policies have generated controversy for limiting access.

In sickle cell, that means many patients have to fail on hydroxyurea before getting Oxbryta. But, as doctors have pointed out in hearings, most patients have been on hydroxyurea at some point in their lives. In Oxbryta’s clinical trials, two thirds of patients took it in combination with hydroxyurea.

“We have some insurance companies that have developed these complicated algorithms for what you have to do in sequential order in order to get to the point where they’ll approve [Oxbryta],” said Alan Anderson, who runs a sickle cell center in South Carolina and has consulted for GBT. “And it makes no sense.”

The restrictions add to other hurdles, specific to Oxbryta and specific to sickle cell. For one, GBT R&D chief Kim Smith-Whitley notes, the company had barely started marketing the drug when the pandemic struck. At the time, Smith-Whitley was still head of the sickle cell center at Children’s Hospital of Philadelphia. She remembered sending everyone home.

“We’ve just had to worry about making sure we could get reasonable care to individuals,” said Smith-Whitley.

Marketing mattered more to GBT than to many biotechs. Vertex, the company whose medicines transformed CF, boasts about how it only needs a skeleton sales staff, because a national network of 100-plus centers assures that virtually every CF patient gets the highest standard of care — including Vertex’s medicines.

The comparable network for sickle cell, a more common disease, is ten centers established by the federal government in the 1970s but defunded in 2008. Most adult patients see general practitioners, said Alexandra Power-Hays, a hematology fellow at Duke University. In surveys, a substantial subset of these providers confess ignorance about basic guidelines or repeat myths, such as that hydroxyurea raises the risk of patients developing cancer.

Many patients, especially adolescents and young adults, don’t even have a primary care provider.

“If you’re seeking care at an emergency department, who is going to start you on a new treatment and then help you get the treatment?” said Valentine.

Longstanding interventions were, accordingly, already not being used. Ultrasounds and hydroxyurea — a drug, unlike Oxbryta, proven to prevent strokes and extend lives — have been available since the ’90s and recommended for every child with sickle cell since 2014, but a recent CDC report showed that each intervention reached half or fewer of patients under 18. Adult numbers are even lower.

“If a perfect, or a good, very effective, affordable oral medication existed, would patients with sickle cell get it? I think the answer is no.” said Power-Hays.

Harvey holds the medication, Oxbryta, that drastically changed her life. Lee Klafczynski for STAT

Waiting for a silver bullet

Many doctors give another reason Oxbryta isn’t more commonly used: It’s far from a perfect drug.

Julie Kanter, co-director of the sickle cell center at University of Alabama at Birmingham, worked on Oxbryta clinical trials but only gives it to a small subset of patients: mostly those with very low hemoglobin despite other interventions. Then about half of those patients discontinue, she said, because they don’t feel better, or side effects like diarrhea make them feel worse.

“There’s a huge lack of evidence for clinical efficacy,” said Kanter. “If it did everything it was supposed to, and patients felt better, more people would take it.”

The drug, for example, hasn’t been shown to lower pain crises. GBT has countered that its studies weren’t designed to show pain reductions, and that improving fatigue and halting the long-term damage from sickle cell is just as, if not more, important. But GBT has yet to prove Oxbryta actually slows long-term damage. Early efforts to collect patient reported outcomes came back muddied, while studies on stroke risk have yet to yield results.

A string of trials are underway to prove benefits across different organs, including reducing the risk of developing kidney failure or leg ulcers, alongside strokes. But results could be years away.

“It does have the potential to decrease other complications,” said Kenneth Ataga, Director of the Center for Sickle Cell Disease at University of Tennessee Health Science Center. “But until we have those data, we just can’t use [Oxbryta] for those other indications.”

Anderson, the University of South Carolina doctor, said too many sickle cell doctors are waiting for a silver bullet. Oxbryta, he argued, fits into a standard model for chronic disease, where incremental therapies build on each other. Hydroxyurea, he noted, was initially sparsely used until later studies showed how powerful it could be at reducing strokes and extending lives.

Some patient advocates think the attitude amounts to medical paternalism.

“It’s a bit like telling someone they are going to reserve seat belts for those that get in car accidents,” said Lakiea Bailey, executive director of the Sickle Cell Consortium. “It’s heartbreaking and also a bit enraging.”

But Kanter and others say they are simply using the best evidence they have available. If you’re going to try to get a patient one drug, as many doctors are, you’ll start — like the insurers insist — with hydroxyurea.

Many sickle cell doctors say there are more important inequities patients face. The list is long and includes issues that get far less media attention, such as heightened rates of depression and anxiety that are often overlooked. It’s a downside of accelerated approval, said Power-Hays — giving easier access to commercialization incentivizes companies to stay in sickle cell, but also brings drugs that might not have enough evidence to win over clinicians.

“It’s not that I don’t think the patients are worth every red cent,” said Jane Little, Director of the Adult Sickle Cell Program at UNC-Chapel Hill. “I just want to make sure that the money is being used on the best thing. We don’t have dental care, we don’t have red blood cell genotyping. There are lots of things that improve health care in a more boring way that Medicaid does not cover.”

Harvey with her son, Jaxon, at their home. Lee Klafczynski for STAT

‘Coming back to life’

Not long after Lena Harvey started taking Oxbryta, she went to her doctor for some bloodwork. It showed that her hemoglobin had shot up from 8 g/dl to 12, narrowly in the range of a person without sickle cell.

The increase has been everything. She spoke to STAT via Zoom from her home studio, filled with flowery decorations and uplifting slogans like “mind of a warrior” and “heart of a queen.”

“Last year, this room was completely empty,” she said. “There were no hopes and dreams in here, there was no camera, no lights, no sound panels, no pretty roses, and certainly no new education. This room was a manifestation of me coming back to life.”

The increase is also an extreme outlier. In clinical trials, patients’ average hemoglobin increased by just 1.1 g/dl. Drugmakers are hoping that future treatments will change that: For Pfizer, the real prize in the buyout may not have been Oxbryta but GBT601, a pill that in early studies increased hemoglobin by as much as 3 g/dl.

Ultimately, the goal is a pill that can match the efficacy of gene therapy, an intensive treatment that drugmakers and clinicians agree requires too much medical infrastructure and takes too harsh a toll on the body to be given to more than perhaps a third of U.S. patients, to say nothing of the millions of patients in Africa and South Asia.

Yet the first three years of Oxbryta shows that it will take more than a convenient formulation to make medicines for sickle cell widely available. Pfizer may be aware of that. Although the big pharma declined to comment on post-merger plans, GBT CEO Love has said he agreed to the deal because Pfizer had the capacity to make his medicines available worldwide. Prior to the buyout, GBT was among almost a dozen drugmakers supporting a bill that would create a national sickle cell network, as there is for other rare diseases.

Some advocates are confident Pfizer and their rivals are up to the task. For once, the Sickle Cell Consortium’s Bailey noted, the economics are on sickle cell patients’ side.

“I would hope that you don’t spend $4.2 or $4.5 or whatever billion it was and not push for access,” said Bailey. “I would guess that wouldn’t be a smart business move.”

Related: Companies and researchers are finally pouring resources into a search for better sickle-cell treatments.  

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Source: STAT