Novel Drug Potentially 'Disease Modifying' in Sickle Cell Disease

Nancy A. Melville

June 17, 2019

AMSTERDAM — The novel drug voxelotor (GBT440, Global Blood Therapeutics) has shown efficacy in the treatment of sickle cell disease with an innovative strategy of targeting the core mechanisms behind the disease, according to phase 3 results from the HOPE trial.

"The results show that voxelotor has the potential to modify the morbidity of chronic organ damage associated with sickle cell disease by improving anemia and hemolysis," said senior investigator Jo Howard, MD, consultant hematologist at Guy's and St. Thomas' NHS Foundation Trust at King's College, London, United Kingdom.

"This represents a potential paradigm shift for sickle cell disease treatment toward addressing hemolytic anemia and organ damage, which is a major growing need," she added.

Howard was speaking at a press conference here at the 24th Congress of the European Hematology Association (EHA), where the study was presented. It was concurrently published online in the New England Journal of Medicine.

Voxelotor is a first-in-class, once-daily, oral hemoglobin-oxygen affinity modulator that has the novel capability of being disease-modifying by targeting the mechanisms that cause anemia and other damage from sickle cell disease, Howard told Medscape Medical News.

"This drug is the first to target red cell polymerization — this reduces and acts at the root cause of red cell damage, improving anemia and reducing hemolysis," she explained.

"Other drugs have targeted vaso-occlusion, but voxelotor targets the hemolytic anemia that can lead to chronic organ damage, stroke, and premature death," she said.

In preclinical and clinical studies, voxelotor was associated with improved red blood cell deformability and decreased blood viscosity, while showing rapid and sustained increases in hemoglobin with a reduction in hemolysis.

Study Details

For the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, 274 patients with sickle cell disease were randomized to receive treatment with voxelotor 1500 mg/day (n = 90), 900 mg/day (n = 92), or placebo (n = 92) for at least 24 weeks.

The patients, who had a median age of 25 (range 12 to 59 years) and were 42% male, had hemoglobin levels between 5.5 and 10.5 g/dL, and experienced between 1 and 10 vaso-occlusive crises in the prior 12 months. They were permitted to continue treatment with concurrent hydroxyurea if their dose had been stable for 90 days or more.

The patients' mean hemoglobin levels were 8.7 g/dL in the 1500 mg group, 8.3 g/dL in the 900 mg group and 8.6 g/dL in the placebo group.

Rates of hydroxyurea use at the study entry were 58% (1500 mg), 63% (900 mg), and 58% (placebo).

The full results from the trial show that at week 24, the primary endpoint of proportion of patients with a greater than 1.0 g/dL increase in hemoglobin from baseline was met, with significantly higher rates among voxelotor 1500 mg (59.5%; P < .001) and 900 mg (38%;  P < .001) compared with placebo (9.2%).

Significant improvements were also seen in measures of hemolysis. There was a 29.1% reduction in indirect bilirubin in the voxelotor 1500 mg group and a 20.3% reduction in the 900 mg group, vs a reduction of only 3.2% in the placebo group. In addition, the reduction in reticulocytes was most notable in the 1500 mg group (-19.9%), vs a reduction of 1.3% in the 900 mg group and an increase of 4.5% in the placebo group.

There were no significant differences in treatment-emergent adverse events (TEAEs) between the voxelotor and placebo groups. The most common TEAEs, occurring in 10% or more of patients, were headache and diarrhea. The rates of grade 3 or higher TEAEs and discontinuations were similar among the groups.

With a substantial increase in hemoglobin, fewer vaso-occlusive crises occurred in the treatment groups, and there were no treatment-related increases in erythropoietin, suggesting preserved tissue oxygenation with the treatment, Howard noted.

While the study was not powered to show an effect on pain, Howard said the results showed some encouraging improvement in the mechanisms that could cause pain.

Potential to Reduce Stroke Risk?

In another presentation at EHA, a preliminary report of three cases treated with voxelotor showed encouraging reductions in cerebral blood flow on MRI in 2 of the 3 patients.

"These preliminary findings of decreasing cerebral blood flow with rising hemoglobin levels in two patients suggest improved oxygen flow to the brain," the authors said. "Further study of the effects of voxelotor on cerebral hemodynamics and oxygen delivery is warranted."

Howard noted that those findings are encouraging, as they suggest a potential to help reduce stroke risk in sickle cell disease.

"This is promising data that suggests [the drug] may reduce stroke risk, and this will be investigated more in the upcoming Hope-Kids 2 trial," she said. This is a post-approval confirmatory trial that the manufacturer plans to initiate later this year, she added.

The FDA has granted voxelotor fast track, organ drug, rare pediatric disease and breakthrough drug designations, based on encouraging results from phase 1 and 2 of the HOPE study.

Most Frequent Red Blood Cell Disorder  

Asked to comment on the study, Anton Hagenbeek, MD, PhD, professor of hematology in the Academic Medical Center at the University of Amsterdam, the Netherlands, said the findings appear to represent an exciting development for sickle cell disease.

"I think It's a fantastic study," he told Medscape Medical News.

"Sickle cell is the most frequent red blood cell disorder in the world and youngsters have painful crises and organ damage," said Hagenbeek, who was not involved with the current research. "It's really a big problem in many parts of the world and this is a significant step forward, with the treatment showing a significant increase in hemoglobin and less destruction of red cells."

"We need to wait longer and see results on more patients, but I was impressed by the data," he said.

The study was supported by Global Blood Therapeutics . Howard is consultant for and on the advisory boards for Global Blood Therapeutics, Inc and Imara, Inc, and is on speakers bureaus for Addmedica, Novartis, and Terumo. Hagenbeek is a consultant for Takeda USA.

European Hematology Association (EHA) 2019 Annual Meeting: Abstract S147. Presented June 14, 2019.

NEJM. Published online June 14, 2019. Abstract

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