A novel drug may prevent red blood cells from assuming a mutant, sickled shape.

Gopal Murti/Science Source

Update: FDA issues speedy approval of innovative sickle cell drug

*Update, 26 November, 3:30 p.m.: The U.S. Food and Drug Administration (FDA) approved the sickle cell disease medication Voxelotor for market on 25 November, fully 3 months ahead of a statutory deadline for agency action. “Today’s approval provides additional hope to the 100,000 people in the U.S., and the more than 20 million globally, who live with this debilitating blood disorder,” acting FDA Commissioner Brett P. Giroir said in a statement.

The new drug, developed by Global Blood Therapeutics (GBT), will be sold under the trade name Oxbryta and will cost about $125,000 annually. It is the first sickle cell disease treatment to target the root cause of the disease: the “sickling” of red blood cells, in which they become rigid, sticky, and shaped like sickle blades or crescent moons. “Today is a major milestone not only for GBT but, most importantly, for people living with [sickle cell disease], their families and those who care for them,” the company’s chief executive, Ted Love, said in a statement.

“My family and I are overjoyed at the approval,” says Ashley Valentine, a co-founder of Sick Cells, a patient advocacy group based in Naperville, Illinois, whose brother has the disease. (Valentine is a paid participant on GBT’s community advisory board.)

But Robert Kruse, a pathologist who tends patients with sickle cell disease at Johns Hopkins Hospital in Baltimore, Maryland, said that although he has “some excitement” for patients the drug may help, “I remain very concerned with the high price tag per month [$10,417] for a drug that did not improve quality of life in trials and did not reduce hospital admissions from pain crises.” The original story from 17 September is below: 

A new drug for sickle cell disease, a grave genetic malady that afflicts an estimated 100,000 people in the United States alone and has no truly effective therapy, should be cause for rejoicing. Instead, what could be a rapid march to approval for voxelotor, which acts directly on the mutant protein that causes the disease, has sparked a dispute over the U.S. Food and Drug Administration’s (FDA’s) efforts to evaluate an urgently needed therapy.

This month, the drug’s developer, Global Blood Therapeutics (GBT) in South San Francisco, California, revealed that FDA has launched a “priority review” of voxelotor and does not plan to have a group of external experts provide advice on the matter before a 26 February 2020 deadline. Critics of the drug expect FDA will give a green light to the therapy, and they say approval would be premature. The drug improves “surrogate” endpoints that can be measured in lab tests but has not yet been proved to reduce the disease’s symptoms. “Why are we approving a drug that hasn’t shown that it has clinically meaningful benefit?” asks Robert Kruse, a pathologist at Johns Hopkins Hospital in Baltimore, Maryland, who treats sickle cell patients.

Sickle cell disease originated in Africa, where it’s estimated to prematurely kill 50% to 90% of the millions of people born with it. A mutation that alters the oxygen-carrying protein hemoglobin inside red blood cells is the culprit. Normal red blood cells are flexible enough to squeeze through small blood vessels. But the mutation causes hemoglobin to aggregate into rock-hard rods that give cells a sickle shape. Sickled cells clump, blocking blood vessels and triggering episodes of intense pain called vaso-occlusive crises. The cells are also brittle and prone to shattering, causing anemia that, in the long term, starves organs of oxygen. That leads to serious problems, such as kidney failure and strokes, and often to early death.

Voxelotor attaches to the mutant hemoglobin and, by increasing its affinity for oxygen, prevents it from aggregating. (Only deoxygenated hemoglobin causes sickling.) In June, The New England Journal of Medicine (NEJM) published a phase III clinical trial of 274 sickle cell patients in which the drug produced significant improvements in blood hemoglobin levels and in two measures of red blood cell destruction over a 24-week period. But it failed to significantly reduce vaso-occlusive crises. GBT’s CEO Ted Love says the published trial was too short and had too few patients to show a statistically significant drop in such crises.

To Ashley Valentine, co-founder of Sick Cells, a patient advocacy group based in Naperville, Illinois, “The FDA is absolutely doing the right thing” by speeding voxelotor’s review. The drug is a “game changer” because it attacks the root cause of the disease, she says. (Valentine, whose brother has sickle cell disease, this year joined GBT’s community advisory board and was paid $1000 to attend an August meeting.)

FDA’s regulations allow approval of a drug based only on surrogate endpoints, if it addresses an unmet medical need and the condition is serious. And the agency has increased such approvals in recent years. But in the past, sickle cell drugs had to reduce the number of painful crises in order to win approval, and voxelotor’s skeptics say its data are simply not compelling. “There’s a famous saying in medicine: Don’t treat numbers, treat the patient. This very much feels like we are treating a number and not the patient,” Kruse says.

Elliott Vichinsky, a pediatric hematologist at the University of California, San Francisco, Benioff Children’s Hospital in Oakland, and first author on the NEJM paper, counters that “rigid requirements that sickle cell [drug trial] outcomes should be based on pain events are very narrow minded.” (Vichinsky is a paid adviser to GBT.)

Alexis Thompson, a hematologist at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois, adds that “organ damage is the primary contributor to the shortened life span” in sickle cell disease. To the extent that the drug’s effects on hemoglobin prevent sickling, she says, it’s “likely to reduce organ injury in the long run.” Still, she adds: “My response at this point is somewhat measured. I am certainly looking forward to additional clinical trials for this drug.”

Other researchers worry about under-the-radar side effects. By making the mutant hemoglobin bind more tightly to oxygen, the drug could keep oxygen from being released in the brain and lead to “silent” strokes, for which those with sickle cell disease are already at risk, argues hematologist Robert Hebbel at the University of Minnesota Medical School in Minneapolis. The phase III trial did not include the extensive neurological exams required to detect them, he notes.

FDA could still ask outside experts to review voxelotor. And when it grants approvals based on surrogate endpoints, the agency requires companies to conduct additional trials to prove a drug clinically benefits patients. If these fail, approval can be withdrawn.

Such follow-up is crucial, stresses Arthur Caplan, a bioethicist at New York University’s School of Medicine in New York City. He understands FDA’s urgency to approve more therapies for a “big, terrible disease. … But you are gambling when you go fast. The more permissive you are about skipping regulatory steps, the deeper the obligation to monitor your subjects really, really closely.”