Novel Agent Attacks the Cause of Vaso-Occlusive Crisis in Sickle Cell Disease

Vaso-occlusive crisis (VOC) is a severely painful disease manifestation in adolescent and adult patients with sickle cell disease (SCD). Currently, treatment is limited to controlling pain, most commonly with opioids, but a new investigational therapy may be able to disrupt the underlying causes of these blood vessel obstructions.

A multi-institutional research team evaluated the efficacy of a pan-selectin inhibitor, GMI-1070, in treating these occluded blood vessels and found encouraging results in terms of reducing the time to VOC resolution. “I think it’s the most promising study to date regarding a potential new therapy that would intervene in the process of vaso-occlusion,” lead investigator Marilyn Telen, MD, from Duke University Medical Center in Durham, North Carolina, told ASH Clinical News.

The intense pain associated with VOC is believed to be caused primarily by binding of both red blood cells and leukocytes to endothelial selectins, which restricts blood flow causing local tissue ischemia and pain. GMI-1070 functions by reducing the adhesion of leukocytes and the capture of sickle red cells by leukocytes, thus improving VOC and survival, explained Dr. Telen. The agent has been granted orphan drug and fast-track status from the Food and Drug Administration (FDA) for the treatment of VOC.

Dr. Telen and investigators enrolled 76 patients (56 adults, 20 adolescents) from 22 North American sites participating in the phase 2, double-blind study. Eligible patients were between ages 12 and 60 years, had not been transfused in the prior 14 days to receiving GMI-1070, and had five or fewer VOC episodes in the previous six months.

Time to resolution of VOC, the study’s primary efficacy endpoint, was defined as a sustained 1.5-cm decrease in visual analog scale (VAS) pain score from baseline and transition to oral analgesia, or documentation for discharge. Secondary endpoints were length of hospital stay, cumulative opioid use, safety, and pharmacokinetics.

Patients were randomly assigned to receive either placebo or GMI-1070 every 12 hours for a maximum of 15 doses. The study drug or placebo was administered intravenously at a loading dose of 20 mg/kg, followed by 10 mg/kg doses to reach a minimum plasma level of >20 µg/mL within 24 hours of initial evaluation. After a pre-planned population analysis in the first 11 subjects, the dosages were doubled in the remaining subjects (31 patients at original dose; 45 at higher dose).

All patients achieved the primary efficacy endpoint of VOC resolution. The time to resolution of VOC was substantially – although not statistically significantly – shorter for GMI-1070 than for placebo: a 41-hour (or 28%) reduction in mean time to resolution and a 63-hour (or 48%) reduction in median time to resolution (TABLE).

In terms of safety, the investigational agent was safe, with few treatment-emergent adverse events; again, there were not statistically significant differences between the two treatment arms.

The 83 percent reduction in IV opioid analgesic use with GMI-1070 was an “unexpected” finding (p=.010), Dr. Telen noted. “I think the emphasis is that we’re making people’s pain better so they are not using opioids as much,” she said. “If you ask patients what they want, they want the pain to stop.”

While the study was small in size, the positive findings suggest that GMI-1070 effectively interferes with the pathophysiology of progression of VOC and may promote its early reversal. Dr. Telen added that, although the current study evaluated GMI-1070 as a monotherapy, the agent could possibly be combined with other therapies to improve VOC resolution.

“My personal view is that, ultimately, we will use therapy that is aimed toward multiple therapeutic targets, such as the combination of antiplatelet, anticoagulant, and beta-blocker therapies used in heart attacks,” she said. “We need to do something similar in sickle cell vaso-occlusive crises – targeting basically every piece of the process that caused this occlusion of coronary vessels.”


Telen M, Wun T, McCavit T, et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood. 2015 March 2. [Epub ahead of print]

GMI-1070 (n=43)

Placebo (n=33)

Time to resolution of VOC, hours
Mean (SD)

110.13 (128.04)

147.72 (139.42)

Median (CI)

69.6 (44.3 – 115.5)

132.9 (67.0 – 164.2; p = 0.187)

Time to transition to oral analgesia, hours
Mean (SD)

110.35 (129.58)

157.69 (134.71)

Median (CI)

71.7 (48 – 116.1)

147.4 (60.9 – 181.0; p = 0.089)

Hospital length of stay, hours
Mean (SD)

132.36 (129.80)

183.20 (148.26)

Median (range)

84.8 (66.1 – 132.4)

165.1 (79.6 – 187.8; p = 0.093)

VAS at discharge, cm
Mean (SD)

3.02 (2.75)

4.03 (2.97)

Median (range)

2.8 (0 – 9.8)

3.6 (0 – 10)

Cumulative parenteral opioid use (MEU mg/kg)
Mean (SD)

12.92 (20.8)

57.91 (109.8)

Median (range)

3.42 (0.1 – 93.5)

11.17 (0 – 487.3)