Photo courtesy of ASH
SAN DIEGO—The first-in-class humanized anti-P-selectin antibody SelG1, also known as crizanlizumab, significantly reduced sickle cell pain crises (SCPC) when compared to placebo in the phase 2 SUSTAIN trial.
The higher dose of SelG1 tested reduced the annual rate of SCPC by 45% (P=0.01) and the annual rate of uncomplicated SCPC by 63% (P=0.015).
Acute painful crises are the primary cause for patients with sickle cell disease (SCD) to seek medical attention.
Kenneth I. Ataga, MD, of the University of North Carolina at Chapel Hill, explained that upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interaction involved in the pathogenesis of SCPC. SelG1 binds to P-selectin and inhibits its interaction with P-selectin glycoprotein ligand 1.
Dr Ataga presented results from the SUSTAIN study during the plenary session of the 2016 ASH Annual Meeting (abstract 1).
The study was also published in NEJM. The research was sponsored by Selexys Pharmaceuticals Corporation, which was recently acquired by Novartis.
Patient population
A total of 198 patients were randomized, 67 to high-dose SelG1 (5.0 mg/kg), 66 to low-dose SelG1 (2.5 mg/kg), and 65 to placebo.
They received a loading dose in the first 2 weeks of treatment, followed by monthly dosing for a year.
Patients had to have a diagnosis of SCD, including genotypes HbSS, HbSC, HbSb0-thalassemia, or HbSB+-thalassemia.
They had to have at least 2 but not more than 10 acute sickle-related pain events within 12 months of study entry.
Patients ranged in age from 16 to 57 years, about 70% had HbSS, and 60% were on concomitant hydroxyurea therapy.
Patients not already receiving hydroxyurea were not permitted to start it during the study. And patients could not be on chronic transfusion therapy.
Study endpoints
The primary endpoint was the annual rate of adjudicated SCPC.
“Painful crisis was defined as an active episode of pain, and it was felt to be related to sickle cell disease-specific events and no other medically defined causes,” Dr Ataga explained.
The pain episodes also had to result in a visit to a medical facility and require treatment with parenteral or oral narcotics or parenteral nonsteroidal anti-inflammatory drugs.
The definition of SCPC included not only typical painful episodes but also acute chest syndrome (ACS), hepatic or splenic sequestration, and priapism.
Secondary endpoints included the annual rate of days hospitalized, time to first and second SCPC, the annual rate of uncomplicated pain crises, and the annual rate of ACS, among others.
Efficacy
The median annual rate of SCPC was 1.63 in the high-dose arm, 2.01 in the low-dose arm, and 2.98 in the placebo arm, amounting to a significant 45.3% reduction with the higher dose of SelG1 compared to placebo. The low dose resulted in a reduction of 32.6% compared to placebo, but this was not significant.
Twenty-four patients in the high-dose arm had an SCPC rate of 0, compared with 12 in the low-dose arm and 11 on placebo.
SCD genotype or concomitant hydroxyurea use did not impact these results.
Patients in the high-dose arm had a median annual rate of 4 hospitalization days, compared with 6.87 in both the low-dose and placebo groups. The difference was not significant, although the reduction in the high-dose arm was 41.8%.
The median annual rate of uncomplicated SCPC was 1.08 in the high-dose arm, 2.00 in the low-dose arm, and 2.91 in the placebo arm. Uncomplicated SCPC excluded ACS, splenic or hepatic sequestration, and priapism.
The reduction in the high-dose arm compared to placebo was significant, at 62.9% (P=0.015).
“The rate of ACS was pretty rare,” Dr Ataga said, “so the median rate across the various groups was 0.”
And time to the first SCPC was 4.1 months (P=0.001) in the high-dose group, 2.2 months (P=0.136) in the low-dose group, and 1.4 months in the placebo group.
“The curves separated pretty early,” Dr Ataga noted, “and were maintained throughout the course of the treatment phase, suggesting that the beneficial effect of SelG1 manifested pretty early following initiation of treatment.”
The time to second event was also significant in the high-dose arm compared to placebo, at 10.3 months and 5.1 months, respectively (P=0.022).
Safety
One or more adverse events occurred in over 85% of patients in each group.
Adverse events that occurred in at least 10% of SelG1-treated patients and amounted to at least double the number in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.
Five patients died while on study, but none of these deaths were related to the study drug.
Despite the adverse events, Dr Ataga said the drug was, overall, well-tolerated among the patients who received treatment.
