Rivipansel Granted FDA’s Rare Pediatric Disease Designation for SCD

The U.S. Food and Drug Administration (FDA) has granted rare pediatric disease designation to GlycoMimetics’ investigational therapy rivipansel (GMI-1070) for the treatment of sickle cell disease (SCD).

This designation is given to experimental treatments that have the potential to provide clinically meaningful benefits to patients, primarily those younger than age 18, with serious rare diseases.

Should the FDA approve rivipansel, GlycoMimetics may quality for a voucher redeemable for the priority review of a subsequent application for a different product. This voucher program, which can lead to the expedited evaluation of another medicine in a company’s development pipeline, is an incentive designed to encourage pharmaceutical companies to develop treatments for rare pediatric diseases that might otherwise not be profitable.

“The FDA’s designation recognizes the morbidity and mortality burdens of sickle cell disease as well as its significant impact during childhood with life-long implications,” Helen Thackray, chief medical officer of GlycoMimetics, said in a press release.

“With this designation, the agency acknowledges the urgent need for improved treatment of children living with sickle cell disease,” Thackray said.

In April, GlycoMimetics completed a transfer back from Pfizer — its former collaborator in rivipansel’s development — of the commercial and development rights and licenses to the therapy.

The transfer followed Pfizer’s announcement in 2019 that the Phase 3 RESET trial (NCT02187003), which was assessing the safety and efficacy of rivipansel in treating pain associated with vaso-occlusive crisis (VOC) in SCD patients, failed to meet both its primary and secondary goals.

However, a post hoc analysis of the trial’s data — a statistical analysis specified after the data were seen — conducted by GlycoMimetics suggested that SCD patients treated soon after the onset of VOC pain may benefit from the therapy. The analysis showed that patients treated with rivipansel within approximately 26 hours of the onset of pain in their crisis experienced statistically significant improvements.

“With global rights for rivipansel in our hands, we are exploring options to move forward in sickle cell disease, including discussions with the FDA as to whether there is a regulatory path to approval,” said Rachel King, CEO of GlycoMimetics.

A serious and common complication of SCD, VOC is associated with severe pain. It occurs when sickled red blood cells clump together and adhere to the inner walls of the blood vessels, reducing blood flow and ultimately leading to blood vessel blockage.

VOC symptoms currently are managed with analgesics (painkillers), including opioids and non-steroidal anti-inflammatory treatments, known as NSAIDs. However, more effective therapies are needed.

Rivipansel works by blocking the activity of selectins, which are cell adhesion proteins found in high levels in the blood vessels of SCD patients. These selectins increase blood cells’ stickiness to surfaces and other cells, eventually obstructing blood flow.

By blocking selectins, the therapy is thought to reduce the adhesion of sickled red blood cells to blood vessel walls, ultimately preventing blood flow obstruction and VOCs.

Previous data from a Phase 1 trial (NCT00911495) showed rivipansel was well-tolerated and able to lower the levels of several cell adhesion biomarkers. A subsequent Phase 2 trial (NCT01119833) confirmed these benefits, and showed the therapy led to an 83% drop in opioid use for pain management, while also reducing the length of patient hospitalization.

These positive results supported the launch of RESET, which evaluated rivipansel’s safety and effectiveness in 345 SCD patients, ages 6 and older, experiencing a VOC requiring hospitalization and intravenous (into-the-vein) opioid treatment for pain management.

The participants, who had a mean age of 22 years, were randomly assigned to receive either rivipansel (173 patients) or a placebo (172 patients). Both were administered directly into the bloodstream every 12 hours until VOC could be managed only with oral analgesics, or to a maximum of 15 doses. The patients were followed for 35 days after their last dose.

The trial’s main goal was to assess changes in time to readiness-for-discharge, defined as the time difference between the first rivipansel dose and the patient’s readiness to be released from the hospital. The assessments reflected the achievement of multiple criteria measuring healthcare utilization and clinical improvement prior to leaving the hospital.

Secondary goals included assessing changes in time to discharge, opioid cumulative use, time to opioid discontinuation, and safety measures.

RESET’s top-line results and the findings from the post-hoc analysis were presented in a poster session at the 14th Annual Sickle Cell Disease Research & Educational Symposium and 43rd National Sickle Cell Disease Scientific Meeting, recently held virtually.

The poster was titled “Efficacy and Safety of Rivipansel (GMI-1070) in the Treatment of Vaso-Occlusive Crisis in Hospitalized Patients With Sickle Cell Disease: Results From the RESET Phase 3 Study.”

The presented data showed rivipansel shortened the time to readiness-for-discharge and discharge, lowered opioid cumulative use, and reduced time to opioid discontinuation, compared with a placebo. However, these differences did not reach statistical significance.

The lack of significant and clinically meaningful benefits with rivipansel were observed despite significant drops in the levels of a cellular adhesion biomarker, E-selectin, which indicated that the therapy had the intended biological effect.

Notably, the post-hoc analysis showed that patients starting rivipansel treatment up to 26.4 hours after the onset of VOC pain had a significantly shorter median time to readiness-for-discharge  (65.7 hours) than those given a placebo (122 hours).

In addition, rivipansel’s safety profile was comparable with that of the placebo. The most common adverse events, which occurred in 16–20.9% of the participants, included constipation, fever, anemia, and nausea.

As noted by Thackray in June,  when the analysis was first released, these findings “confirm the critical role of E-selectin in acute vaso-occlusion, as well as the importance of treating individuals early in the course of their acute painful crisis.”

“The favorable safety profile of rivipansel observed in this trial, as evaluated in a population with pediatric, adolescent, and adult patients, is highly encouraging to us,” she had added.

“We are actively considering options for rivipansel in this acute treatment setting, for which there are no approved [therapies] and, to our knowledge, no [treatments] currently in late-stage development,” she said.

GlycoMimetics plans to share RESET’s full data at upcoming medical meetings.