A potentially groundbreaking investigational drug designed to treat the painful vaso-occlusive crises that are the hallmark of sickle cell disease has been found to be safe following a clinical trial at UC Davis.
Vaso-occlusive crises, during which red blood cells slump together and impede blood flow, cause agonizing pain for people with sickle cell disease. The Phase I clinical trial found the drug, called GMI 1070, safe, maintaining adequate blood concentrations, a key milestone for therapeutic benefit.
Published online in the journal Public Library of Science ONE (PLoS ONE), the study did not focus on the drug's efficacy. However, there was evidence that it did improve blood flow and reduced the markers of cell activation, said Ted Wun, associate dean for research at the UC Davis School of Medicine.
"These are encouraging results," said Wun. "Vaso-occlusive crises cause around 70,000-80,000 hospitalizations each year, and there are currently no specific treatments."
Sickle cell disease is a chronic condition that affects approximately 100,000 people in the United State, mostly African Americans, and many more around the world. The disease can affect any organ, particularly kidneys, lungs and spleen. Patients experience many severe complications, including stroke, infections, pulmonary arterial hypertension and heart failure.
The disease is caused by abnormal hemoglobin, which change the shape of red blood cells into the tell-tale sickle shape. These misshapen red blood cells are both stiffer and stickier. Cell-adhesion proteins called selectins, which normally mediate interactions between cells, contribute to this abnormal stickiness. As a result, cells clump together and reduce blood flow, precipitating a vaso-occlusive crisis. The resultant severe pain is generally centered in the hips, back, and proximal long bones. However, abdominal and chest pain is also common.
"White blood cells bind to inflamed blood vessel walls and sickle red cells stick to white cells, but interestingly the initiating event is the white cells," said Wun. "If we could interrupt that white cell interaction, we could stop the cycle that leads to vaso-occlusions."
GMI 1070 is designed to do just that. By mimicking sugars attached to selectin proteins, which mediate the proteins' stickiness, the drug inhibits three different selectins (L-, E- and P-selectin), increasing blood flow in animal models. However, the first round of human clinical trials was primarily focused on the drug's safety and pharmacokinetics. In other words, the researchers wanted to know if there were any severe side effects and whether the drug maintained adequate concentrations in the blood.
The trial included 15 sickle cell patients, five of whom were enrolled at UC Davis's National Institutes of Health-supported Clinical and Translational Science Center. Overall, the drug was well tolerated, with only 16 complications, primarily headaches. With one exception, all complications were grade 1 or 2, the least severe. No participants discontinued the drug.
In the pharmacokinetic tests, patients were given a loading dose followed by smaller maintenance doses, which successfully maintained GMI 1070 blood concentrations.
Though secondary to safety and pharmacokinetics, the trial also showed marked decreases in P- and E-selectins, as well as other markers associated with coagulation and inflammation. The study also found small increases in blood flow.
In addition to these findings, a randomized double-blind phase II trial for GMI 1070 has also been completed. Preliminary results have been positive, and the study has been submitted for publication. A phase III trial currently is being planned.
"Vaso-occlusive crises generate intense pain and suffering," said Wun. "If the phase III study confirms that GMI 1070 is effective, it would be a huge advance for the sickle cell community."
GMI 1070 (trade name Rivipansel) is produced by GlycoMimetics, Inc., a biotechnology company based in Gaithersburg, Maryland.The company sponsored the trial.