ORLANDO — For decades, a repurposed cancer drug was the only treatment option for the tens of thousands of Americans who suffer from sickle cell disease, an inherited disorder that warps red blood cells to potentially devastating effects.

That's since changed, following a Food and Drug Administration approval for Endari in 2017 and then, just last month, for two new drugs from Novartis and Global Blood Therapeutics.

"We had nothing. Then, all of a sudden, we have three new drugs in the past couple of years," said Ifeyinwa Osunkwo, a sickle cell disease specialist at Atrium Health in North Carolina, in an interview. "It's exciting. It's phenomenal. But it's not enough."

The flurry of approvals, along with advancing development for nearly 20 other experimental therapies, is a dramatic change for a sickle cell disease community that hasn't always been a focus for drug developers. The disease more commonly affects black and Hispanic people. Many of those affected are less well off and are covered by government insurance.

"It's an invisible population," said Osunkwo.

A study last year, for example, found research into cystic fibrosis, another genetic disease that's rarer than sickle cell, received 3.4 times as much funding from the National Institutes of Health between 2008 and 2016. The gap in private foundation founding was even more stark — nearly 1,000-fold greater for cystic fibrosis than sickle cell from 2013 to 2016.

"It's been a question of finance. It's been a question of science," said Charles Abrams, director of a hematology center run by the University of Pennsylvania and the Children's Hospital of Philadelphia, in an interview. "Now we're at a point when suddenly it's turned into a very hot field."

Such interest is evident at the American Society of Hematology's annual meeting, which this year featured 271 study abstracts, up 12% from 2018. And it's not just drugmakers: In October, the NIH and the Gates Foundation committed to investing $100 million over the next four years into gene-based therapies for sickle cell and HIV.

While hope is running high, the new treatments are only partially answers to a disease that causes a cascade of complications.

Sickle cell stems from a mutation in the hemoglobin gene, resulting in an abnormal version of the oxygen-carrying protein and triggering the disease's characteristic red blood cell sickling. Chronic anemia ensues, leading over time to organ damage and reducing life expectancy by decades. The sticky, sickled cells, meanwhile, cause acute pain episodes that are a persistent part of patients' lives.

Novartis' Adakveo, which is infused intravenously, helps prevent those vaso-occulsive crises. Global Blood's pill Oxbryta, by contrast, is designed to reduce red blood cell sickling, helping the oxygen-carrying cells survive and reducing anemia.

Their high expense brings real concerns for patient access. Both drugs cost more than $100,000 per year, a price point that's become common for rare disease drugs but one that's sharply more than hydroxyurea, a mainstay generic treatment.

And neither drug is yet proven to improve the other longer-term effects of sickle cell, such as acute chest syndrome, bone damage, leg ulcers or stroke.

"Although we have some efficacy data in one area or another, we don't have a global picture of what those drugs are doing in our sickle cell patients," said Marilyn Telen, a professor of medicine at Duke University, in a presentation to a packed conference hall at ASH on Sunday.

Global Blood believes Oxbryta could protect patients' organs, too, and will run a confirmatory study in about 200 children to test whether treatment decreases stroke risk.

"Many people instinctively have reacted [and said] that hemoglobin is just a blood measurement," said Ted Love, Global Blood's CEO, in an interview. "But so is your glucose level in diabetes. We don't develop drugs for diabetes by looking at survival. We develop drugs for diabetes by looking at your mean hemoglobin levels over time, your hemoglobin A1C."

"The problem in sickle cell is that, quite frankly, no one had innovated," he added. "No one had connected the dots."

In theory, Adakveo and Oxbryta could be used together, although combination treatment with the two has not been studied. Both drugs can be given with hydroxyurea.

Behind Adakveo and Oxbryta in development are several gene therapies that promise the potential for a one-time, or at least long-lasting, treatment of the disease's underlying cause.

At ASH, biotech Bluebird bio presented updated data from a Phase 1/2 study of its gene therapy LentiGlobin, which is derived from a patient's own stem cells. Among 12 patients with at least six months of follow-up after infusion of LentiGlobin, total hemoglobin levels reached close to what's considered normal. Eleven experienced no vaso-occlusive crises or cases of acute chest syndrome post treatment.

It's taken time for Bluebird bio to refine its manufacturing of LentiGlobin for sickle cell, and the data unveiled Saturday are from the third patient cohort of the trial. A Phase 3 study is expected to begin enrolling patients next year.

Others, including Sangamo Therapeutics and CRISPR Therapeutics, are exploring whether the course of disease can be changed by stimulating production of fetal hemoglobin, a variant of the protein that the body stops making a few months after birth.

CRISPR, which is partnered with Vertex, recently shared data from the first sickle cell patient treated with its drug.

Abrams, the UPenn-CHOP center director, is confident that gene therapy will eventually become part of sickle cell treatment. But, with recently introduced gene therapies for other diseases costing millions of dollars, he is skeptical that many of the roughly 100,000 patients in the U.S., or the 20 million patients globally, will be able to access the one-time treatments.

Telen, from Duke, shared a similar view with ASH attendees Sunday.

"The health of millions of patients living with sickle cell today depends on the success of developing and delivering — not the bone marrow transplant or the gene therapies, which may well be the therapies of the future — but targeted and multi-agent therapeutic approaches," said Telen.

Broader changes in patient care will be needed, too, especially for those who might not have insurance or don't have regular access to specialists. 

"What you can't treat with a drug is discrimination and stigma," said Osunkwo. 



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