A New Drug and More on the Way for Sickle Cell Disease

From the December 2017 ACP Hospitalist

In July 2017, the FDA ended a nearly 20-year drought in new therapies for sickle cell when it approved a supplement, and additional treatments are in the pipeline.

By Amy Karon

For decades, hydroxyurea was the only approved treatment for sickle cell disease. But now there's a second option, and more therapies are just around the corner, experts say.

“Very few specific interventions are available for sickle cell disease beyond palliative treatment. But there's an explosion of company- and NIH-sponsored research trying to intervene in this disease,” said Kathryn L. Hassell, MD, a professor of medicine in the division of hematology and director of the Colorado Sickle Cell Treatment and Research Center at the University of Colorado Anschutz Medical Campus in Aurora.

In July 2017, the FDA ended a nearly 20-year drought in new therapies for sickle cell when it approved a supplement, L-glutamine oral powder (Endari), to help prevent acute complications of the disease. In a phase 3 trial, patients who received L-glutamine had 25% fewer hospital visits for sickle cell crisis, were hospitalized 33% less often, were discharged an average of 4.5 days sooner, and were 65% less likely to experience acute chest syndrome compared with the placebo group.

The findings have sparked some debate. “If you look carefully at the data, it's not really high-quality. It's hard to see how [L-glutamine] is going to be a major adjunct in the treatment of sickle cell disease,” said Martin H. Steinberg, MD, a professor of medicine in the division of hematology-oncology at Boston University School of Medicine.

L-glutamine therapy also is onerous, making long-term adherence questionable, Dr. Steinberg said. “You've got to take a lot of it and mix it up and drink it down two to three times a day. The dropout rate in the trial was pretty high—about a third of participants quit.”

Given L-glutamine's potential and shortcomings, some experts are taking a wait-and-see approach.

“There's often skepticism that an agent as simple as an amino acid could produce a significant effect in a complicated, clinically severe disease. But we should overcome that bias and give this therapy a chance,” said Gregory J. Kato, MD, ACP Member, professor of medicine in the division of hematology-oncology and director of the Adult Sickle Cell Center of Excellence at the Vascular Medicine Institute at the University of Pittsburgh.

Dr. Hassell agreed. “For some patients, [L-glutamine] might just make a difference. The data are hard to generalize because every person's experience with sickle cell disease and course of disease is unique,” she said. L-glutamine does appear to be safe, and while it's not a substitute for hydroxyurea, it can be added to it, experts said. It also doesn't require close medical monitoring like hydroxyurea does, so hospitalists and outpatient clinicians “probably should feel less reluctant” prescribing it, said Dr. Kato.

The FDA-approved form of L-glutamine consists of a different isomer than what's available over the counter at nutrition stores, but it's still unclear whether insurers will cover it, Dr. Hassell said. She noted that Medicaid has balked at covering supplements in the past even when they're medically indicated.

That could raise issues of access to the drug, particularly when a patient is hospitalized. However, it takes weeks to months for L-glutamine to produce an effect, so interrupting treatment is unlikely to prolong a hospitalization for sickle cell crisis, according to Dr. Hassell. “From a hospitalist's perspective, don't worry about getting an emergency formulary approval, but continue giving it if it is available,” she said.

The therapeutic pipeline

Many more sickle cell therapies are on the horizon, and some already are in late-stage trials.

One promising candidate is rivipansel, a small molecule that stops sickle erythrocytes from adhering to the vascular endothelium by inhibiting the adhesion molecules P-selectin and E-selectin.

In a double-blind phase 2 trial, treatment with the pan-selectin inhibitor shortened the duration of vaso-occlusive crisis by 63 hours compared with placebo. The most common treatment-emergent adverse effects were gastrointestinal symptoms and rash, but rates of serious adverse events were similar between study arms, researchers reported in April 2015 in Blood. Results from a phase 3 trial of the drug candidate are expected in July 2018.

Read the full article in ACP Hospitalist.

ACP Hospitalist provides news and information about hospital medicine, covering the latest trends and issues in the field.

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