The prevalence of sickle cell disease (SCD) is a challenge for the healthcare systems around the world. There are very limited treatment options and, as yet, no effective therapies that address the underlying cause of the disease. The Centers for Disease Control and Prevention (CDC) currently estimates that there are 90,000 to 100,000 Americans living with the condition, which occurs in approximately one out of every 500 African-American births and one out of every 36,000 Hispanic-American births. Chronic and recurring pain are among the most common symptoms of the disease.

Fortunately, a number of biotechnology companies are reporting that they are advancing innovative potential treatments for the disease and its associated complications into clinical trials. Some of the research progress that has been made to date was presented during the recent American Society of Hematology (ASH) meeting.

Gene editing

Sangamo Biosciences Inc., of Richmond, Calif., presented preclinical data that demonstrate that its zinc finger nuclease (ZFN) gene-editing technology enables permanent increase in the expression of fetal gamma-globin in adult red blood cells (RBCs). This increase restores the normal balance of globin proteins that together form the oxygen-carrying hemoglobin of RBCs. In addition, the preclinical studies demonstrate that this can be accomplished at clinical-scale reproducibly achieving high levels (up to 80 percent) of gene editing in hematopoietic stem cells (HSCs).

During development, a fetal form of hemoglobin is made using a beta-like globin called gamma- or fetal-globin, the company explained. In infancy, this fetal form of hemoglobin fully protects beta-thalassemia and SCD patients from developing disease symptoms. Later in childhood however, production of fetal hemoglobin ceases and is replaced by synthesis of adult-type beta-globin chains that are defective in beta-thalassemia and SCD patients and symptoms of disease appear.

The ZFN genome-editing technology is used to precisely knock out key regulators of the transcriptional switch from fetal to adult beta-globin expression, such as BCL11A, enabling the permanent production of therapeutic fetal hemoglobin. Importantly, by performing this genome editing in HSCs that are isolated and returned to the same patient, an approach that eliminates both the need for a matched donor, and the risk of acute and chronic graft-versus-host disease (GvHD).

Also at ASH, Global Blood Therapeutics reported new data demonstrating that GTx011, its lead drug candidate for the treatment of sickle cell disease, prevents the sickling of red blood cells in preclinical models of SCD.

Increasing affinity

The data showed that GTx011 increases the affinity of hemoglobin S (HbS), an altered form of hemoglobin, for oxygen, and is the most potent compound currently reported to be in development for SCD. In the disease, polymerization of deoxygenated HbS causes the sickling of red blood cells, which in turn causes impaired blood flow, organ damage and reduced life expectancy. GTx011 delays HbS polymerization in a dose-dependent manner and reduces the viscosity of blood from SCD patients. The profile of GTx011 is similar to that of natural hemoglobins that also delay polymerization and are known to ameliorate disease in individuals with one or two copies of the gene for HbS.

“With these properties, GTx011 addresses the underlying cause of this devastating blood disease, which may lead to benefits in both the acute symptoms and chronic consequences of SCD,” said company CEO Mark Goldsmith. “These data, including preclinical pharmacokinetics, help to validate our best-in-class hemoglobin modifier strategy, and enable us to continue advancing toward clinical development.”

Glycomimetics Inc., of Gaithersburg, Md., said recent studies of a new selectin inhibitor compound GM 1070 in animals have demonstrated efficacy in reducing vaso-occlusive crisis (VOC) in that model system. To test the safety and efficacy of GMI 1070 in sickle cell disease (SCD) patients, investigators conducted a Phase II trial of the drug, randomizing 76 patients (ages 12-51) experiencing VOC to receive up to 14 doses of either GMI 1070 or placebo. All treated patients reached the primary endpoint of resolving their VOC. While VOC typically lasts five to seven days, VOC episodes in patients who received GMI 1070 in the study were two to three days shorter than in those who received placebo. Furthermore, patients who received GMI 1070 required significantly less narcotics during their VOC compared to the patients randomized to placebo. (See BioWorld Today, Dec. 10, 2013.)

In collaboration with the National Institutes of Health, Aesrx LLC, of Newton, Mass., presented results of a Phase I/IIa clinical trial of its anti-sickling agent Aes-103, with data showing a significant reduction of pain in SCD patients following single dosing. Additional signals of potential anti-sickling activity were observed, including higher hemoglobin levels in patients receiving Aes-103 compared to placebo, as well as a reduction in LDH (a biomarker of red blood cell hemolysis).

Based on its positive clinical results, a Phase II study has been initiated in the UK. It is a randomized, double-blind controlled study of Aes-103 or placebo with daily dosing for 28 days in patients with sickle cell anemia.