A new drug and more on the way for sickle cell disease

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.


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.

Photo by Thinkstock
Photo by Thinkstock.

“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.

Another prospect is the monoclonal antibody crizanlizumab, which inhibits cell-cell adhesions by targeting P-selectin. In a double-blind phase 2b trial, crizanlizumab was associated with a 45% reduction in the annual rate of painful vaso-occlusive crises in patients with sickle cell disease.

The most common adverse effects included arthralgia, diarrhea, pruritus, vomiting, and chest pain, investigators reported in the Feb. 2 New England Journal of Medicine. A pharmacokinetic/pharmacodynamics study of healthy volunteers is underway. If the results are acceptable, manufacturer Novartis plans to submit a biologics license application to the FDA by the end of 2018.

Many other trials are testing agents intended to increase fetal hemoglobin expression, inhibit red cell sickling, decrease leukocyte or erythrocyte adhesiveness, promote vasodilation, or inhibit clotting in sickle cell disease, Dr. Kato said. His group is leading a phase 2 trial of riociguat, a soluble stimulator of guanylyl cyclase, in patients who have sickle cell with indicators of vasculopathy. The study will continue through 2018.

Researchers also continue to study hematopoietic stem cell transplantation, which remains the only current cure for sickle cell disease. Transplantation has cured some 2,000 patients worldwide, but only about 15% of all patients with sickle cell have a stem cell donor available, Dr. Kato said. Nearly 40 trials are now seeking to expand the donor pool, improve the cure rate, and minimize adverse outcomes, he said.

Finally, several gene therapy trials are recruiting patients with sickle cell, and early results look promising, Dr. Kato said. Studies of gene editing in sickle cell mice also look “very exciting,” he added. “They could potentially move to human clinical trials in the coming decade and have even stronger potential for cure.”

Hospitalists should convey this positivity to patients with sickle cell, he said: “Encourage hope and optimism that current research will lead to better treatments and to cures in our lifetime. Encourage participation in the clinical trials that will develop and test those new treatments.”

Practical tips for today

Experts also offered tips for managing sickle cell crisis. First, red blood cell transfusion is not recommended for adults who have chronic anemia or uncomplicated pain crises, said Sophie M. Lanzkron, MD, an associate professor of medicine and oncology at Johns Hopkins School of Medicine in Baltimore. The American Society of Hematology Choosing Wisely campaign and the National Heart, Lung, and Blood Institute recommend against routine transfusion in this setting.

However, monthly transfusions are appropriate for many pediatric patients, experts noted. Studies using Doppler ultrasound found that at least 10% of these patients are at high risk of stroke and that monthly transfusion therapy almost completely eliminates this risk, Dr. Kato said. Regular transfusions also help prevent other complications of sickle cell disease in children and adolescents. “This generation of children is just reaching adulthood now,” he said. “[Transfusion] is changing the natural history of sickle cell disease.”

Hospitalists also should get comfortable with hydroxyurea because its use in sickle cell is rising. This oral medication promotes fetal hemoglobin synthesis, which helps prevent acute vascular events. But it takes weeks to work, doesn't help all patients, and probably doesn't reverse chronic organ damage, Dr. Hassell said. “Hospitalists should not look for a stat consult to start it—that should be done in the outpatient setting,” she advised. “I don't worry about interrupting it in the hospital, although it's nice to sustain it.”

Finally, consider designating a core team of hospitalists to care for sickle cell patients and standardizing care among physicians, suggested Corey Karlin-Zysman, MD, FACP, chief of the division of hospital medicine at the Zucker School of Medicine at Hofstra-Northwell in New Hyde Park, N.Y.

This approach enabled her hospital to cut average length of stay by almost two days and reduce 30-day readmission rates, she said. “We've also received better patient satisfaction scores, and we've been able to maintain this for years now. I can't think of another project where we've had those kinds of results.”

To make these changes, a task force at Long Island Jewish Medical Center, Northwell Health developed standardized, evidence-based protocols for patients admitted with sickle cell crisis. Order sets covered fluid therapy, deep venous thrombosis prophylaxis, oral diphenhydramine, NSAIDs, and opioid therapy with a high-dose patient-controlled analgesia (PCA) pump, which patients preferred to clinician-administered opioids despite an initial learning curve, Dr. Karlin-Zysman said.

“We feel PCA pump is safer than IV bolusing,” she said. “Patients are in control, not waiting for a nurse to give their pain medication. It's a staggering dose compared to, say, a postsurgical patient—16 to 20 milligrams of [hydromorphone] every four hours. But the total daily amount of narcotics a day is a lot less when patients are on PCA pump instead of bolusing.”

Patients also receive IV ketorolac tromethamine and stay on outpatient analgesics such as gabapentin, Dr. Karlin-Zysman said. Some also receive adjunctive lidocaine patches and warm compresses.

The team continues to meet monthly to reinforce the practices and includes hospitalists, hematologists, nursing managers, and an outpatient physician who takes regular referrals to streamline care and prevent lengthy opioid prescriptions at discharge. “Patients only get about a five-day supply because the outpatient doctor has built-in availability. Collaboration with the outpatient doctor has been instrumental in reducing length of stay and total admissions,” said Dr. Karlin-Zysman.

Smaller hospitals can implement this approach by identifying one or two core hospitalists who take primary responsibility for sickle cell patients, she said. “Over time, they will become more comfortable with managing them and with the high doses of analgesics they need. One of the causes of prolonged length of stay is that you didn't get the pain controlled right from the start. If they're controlled within hours of emergency department admission, they're going to leave a lot sooner.”