SAN DIEGO — A first-in-class drug has demonstrated efficacy in reducing sickle-cell–related pain crises (SCPC), a substantial cause of morbidity in sickle cell disease (SCD).
The novel agent is a humanized antibody against P-selectin, crizanlizumab (SelG1, developed by Selexys Pharmaceuticals, which has been acquired by Novartis).
Results of the Phase 3 SUSTAIN trial show crizanlizumab reduced the frequency of pain crises by nearly half compared with placebo.
In addition, median times to first and second crises with high-dose crizanlizumab were 2 to 3 times as long compared with placebo, explained lead author Kenneth I. Ataga, MBBS, of the University of North Carolina at Chapel Hill.
The new findings suggest SCD patients may soon have another option to treat these episodes. Currently, only one treatment is available, hydroxyurea, which was approved about 15 years ago by the US Food and Drug Administration (FDA).
The results of the SUSTAIN study were presented during the plenary session here at the American Society of Hematology 58th Annual Meeting and simultaneously published in the New England Journal of Medicine.
Treatment with high-dose crizanlizumab resulted in a significant and clinically meaningful reduction in the frequency of SCPC in patients with SCD, the authors conclude.
“There was a substantial reduction in frequency of SCPC with high-dose crizanlizumab treatment vs placebo regardless of concomitant hydroxyurea use or SCD genotype,” commented Dr Ataga, who presented the findings.
He added that the incidence of adverse events with the drug was low.
Need for More Options
SCD is characterized by the presence of sickle hemoglobin, chronic hemolysis, recurrent pain episodes, multiorgan dysfunction, and often an early death.
Crises are thought to be caused by vascular occlusion in the microcirculation, increased inflammation, and alterations in nociception.
“The pathogenesis of vaso-occlusion is complex,” explained Dr Ataga, and is caused by adhesion of the sickle erythrocytes and leukocytes to the endothelium, which results in vascular obstruction and tissue ischemia.
Thus, the prevention of crises could minimize or prevent tissue and organ damage and decrease the subsequent risk of death among patients with SCD.
However, at the present time, hydroxyurea is the only FDA-approved treatment for complications of SCD, and while it is effective, many patients continue to experience acute painful episodes or are unable to tolerate them.
Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin and blocks its interaction with P-selectin glycoprotein ligand 1 (PSGL-1).
Preclinical studies have identified P-selectin as a key molecule in the initiation of leukocyte rolling on the vessel wall that leads to firm attachment and extravasation to underlying tissues during inflammation. These new data support the concept that P-selectin blockade could reduce the risk of vaso-occlusion, inflammation, and SCPC.
“We still have a way to go to see what the FDA response is to this, but I am very positive,” said Kim Smith-Whitley, MD, clinical director, division of hematology and director of the Comprehensive Sickle Cell Center at The Children's Hospital of Philadelphia, Pennsylvania, who was approached by Medscape Medical News for comment.
“One reason that I am so positive is it gives a whole subpopulation of individuals with sickle cell disease who have not been eligible for hydroxyurea a brand new option,” she said. “This is a drug that can reduce pain episodes.”
A second reason is that it is a new target in SCD. “That is very exciting, as it will allow patients who have had somewhat of a response to hydroxyurea — but who are still coming into the hospital with symptoms — another option to reduce pain and improve their quality of life,” she pointed out. “So this can be used as an adjunct to hydroxyurea as well.”
Another reason is the dosing schedule, as it is administered once a month as opposed to hydroxyurea, which is given daily. “Drug adherence and compliance can be a problem, particularly in teenagers,” Dr Smith-Whitley said.
But as with any new drug, there is always the concern of accessibility. “I live in a nice academic health environment, but I struggle with individuals who are more than 10 miles outside of my geographic radius and how I can get them the care they need in a timely fashion,” she emphasized.
“So it will be interesting to see if the company is interested in working with the sickle cell community to see if a subcutaneous preparation of this drug could be available, so that individuals who are far away can administer it at home,” said Dr Smith-Whitley.
The SUSTAIN study included 198 patients randomized to 2.5 or 5.0 mg/kg crizanlizumab or placebo. The primary endpoint was the annual rate of SCPC in the 5.0 mg/kg group compared with placebo.
The median rate of SCPC per year in the high-dose arm was 1.63 (P = .01), compared with 2.01 in the lower-dose arm (P = .18) and 2.98 in the placebo arm — reductions of 45.3% for the 5-mg group and 32.6% for the 2.5-mg group, compared with placebo.
Thus, the authors noted that the effect of crizanlizumab was dose-dependent.
The median time to first crisis was significantly longer for patients in the high-dose arm than with placebo (4.1 vs 1.4 months; P = .001) — a 2.93-fold increase, explained Dr Ataga.
The median time to second crisis was doubled with high-dose crizanlizumab vs placebo (10.3 vs 5.1 months; P = .02).
The annual rate of uncomplicated SCPC at the higher dose was reduced by 62% vs placebo (median 1.1 vs 2.9; P = .015), and the annual rate of days of hospitalization showed a nonsignificant 42% reduction with the higher dose vs placebo (median 4.0 vs 6.9; P = .450).
Adverse events that occurred in 10% or more of participants in either treatment group, and at a rate at least as high as in the placebo group, included arthralgia, diarrhea, pruritus, vomiting, and chest pain.
The SUSTAIN trial was not designed to determine if there was a survival benefit, Dr Ataga said, and longer-term follow-up studies are needed to establish that endpoint.
The study was funded by Selexys Pharmaceuticals and grants to Selexys Pharmaceuticals from the National Heart, Lung, and Blood Institute of the National Institutes of Health and FDA Orphan Products Grant Program. Dr Ataga had no disclosures. Disclosures for the coauthors are listed in the abstract. Dr Smith-Whitley is an advisory committee member for Pfizer.
American Society of Hematology 58th Annual Meeting. Abstract. Presented December 4, 2016.
N Engl J Med. Published online on December 3. Article
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Cite this: Novel Agent Reduces Pain Crises in Sickle Cell Anemia - Medscape - Dec 04, 2016.