NEW ORLEANS – An experimental cellular adhesion inhibitor was successful at reducing the severity and duration of vaso-occlusive crises in patients with sickle cell disease.
In a phase II trial of 76 patients with sickle cell disease, patients randomized to receive the pan-selectin inhibitor GMI 1070 early in their hospitalization for a vaso-occlusive crisis (VOC) had shorter lengths of stay and needed significantly lower cumulative doses of narcotics for pain control than did patients randomized to placebo, reported Dr. Marilyn J. Telen, chief of the hematology division at Duke University, Durham, N.C.
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"We see somewhere between 75,000 and 90,000 admissions [annually] for acute painful vaso-occlusive crisis among this patient population. Indeed, these crises are the most common and essentially the archetypal presentation of sickle cell disease. Nevertheless, up till this time, treatment for these crises or VOC in sickle cell disease, remain only supportive, focusing largely on using narcotics for symptom relief, and then other measures, some of which are used to counteract the ill effects of narcotics," said Dr. Telen at the annual meeting of the American Society of Hematology.
GMI 1070 (being developed by GlycoMimetics, in partnership with Pfizer) is a synthetic molecule designed to inhibit the glycoprotein cellular-adhesion molecules involved in inflammation. In previous studies, the drug has been shown to be safe, and in a mouse model of VOC, was successful at restoring blood flow, Dr. Telen said. The drug has received both orphan drug and fast-track status from the Food and Drug Administration, according to GlycoMimetics.
Dr. Telen and her colleagues enrolled 76 patients aged 12-51 years with sickle cell disease and randomized them to receive a loading dose of GMI 1070 delivered intravenously (43 patients), followed by up to 14 subsequent doses delivered every 12 hours, or placebo (33 patients), with other treatment left to the discretion of the participating institutions. After an interim pharmacokinetic analysis showed that the drug did not reach target nadir levels, the dose was doubled.
All 76 patients reached the primary endpoint of VOC resolution, defined as a composite of decreased pain, termination of the need for intravenous opioids, patient and physician agreement on the ability to discharge the patient, and actual hospital discharge.
A total of 58 patients continued on the assigned drug until they either reached the primary endpoint criteria or received the maximum number of doses allowed. The remaining 18 patients discontinued the drug either for adverse events, no improvement by day 5 on the assigned drug, or other reasons.
In an analysis pooling all patients assigned to GMI 1070, including those who started out on the lower dose, there was a consistent reduction over placebo in the mean time to resolution of VOC: 103 hours vs. 144 hours for patients treated with placebo. This difference was not statistically significant, however.
A Kaplan-Meier analysis showed a median time to resolution of 69.6 hours for GMI 1070, compared with 139 hours with placebo, a difference that was not significant.
There was an 83% reduction in the secondary endpoint of cumulative opioid analgesics administered during hospitalization, a difference that was statistically significant (P =.010). There was also a reduction by 84 hours in the median time to discharge, and by 55 hours in the mean time to discharge, among patients treated with the active drug, compared with those on placebo. These differences, while large, were not significant, Dr. Telen said.
She noted that although most of the endpoints in this study failed to reach statistical significance, the separation of the curves between the placebo- and GMI 1070–treated patients began early, usually within 2 days of the start of treatment.
Total adverse event rates, including serious events and those deemed to be treatment related, were comparable between the two study arms for all subgroups.
Dr. Telen noted that because the population of patients enrolled was more clinically diverse than the available literature would suggest, the study was underpowered to detect differences, given the size of the sample. She predicted that given the size of the effects seen, statistical significance would emerge in a larger study.
GlycoMimetics is currently working with Pfizer to develop a phase III trial of GM 1070 for this indication.
The study was supported by GlycoMimetics. Dr. Telen is a consultant to the company, and several coauthors are employees of the company.