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Therapeutics for Rare and Neglected Diseases

Aes-103 for Sickle Cell Disease

Sickle cell disease (SCD) is a genetic blood disorder that alters red blood cells. The disease affects millions worldwide and about 80,000 patients in the United States, in particular, one in every 500 African American births. A defect in hemoglobin (a protein that helps the cells carry oxygen through the body) causes red blood cells to become rigid and take on a crescent (sickle) shape, blocking small blood vessels and causing decreased blood flow, inflammation, pain and strokes in children. To date, the only drug approved by the Food and Drug Administration (FDA) to treat SCD is hydroxyurea, an anticancer drug that is indicated for use only in adults. Hydroxyurea is only moderately effective and has undesirable side effects that limit its use. The purpose of this project is to develop Aes-103 as an effective treatment for adults and children with SCD.

Scientific Synopsis

Sickle cell disease (SCD) is a recessive, genetic (i.e., inherited) blood disorder affecting the hemoglobin of red blood cells. Deoxygenation of the abnormal hemoglobin leads to formation of polymers, which causes the red blood cells to become rigid and take on a crescent (sickle) shape. These rigid, sickle-shaped cells can block small blood vessels, decreasing blood flow, which can result in significant and permanent damage to tissues and can be fatal. Although SCD was first described in the medical literature more than 100 years ago (James Herrick, 1910) and was the first disease determined to be of genetic origin (Linus Pauling, 1949), no drugs have been developed specifically for the treatment of SCD. A number of agents have been studied, but the only drug approved for use in treating SCD patients is the anticancer agent hydroxyurea.

Sickle shaped red blood cell

Hydroxyurea is approved for use only in adults, but as an anticancer drug it is only moderately effective against SCD and has undesirable side effects — all of which have limited its use in SCD patients. The novel compound Aes-103 is the first drug candidate to directly target the underlying cause of SCD by maintaining the abnormal hemoglobin molecule in a conformation that does not undergo polymerization and sickling. 

Lead Collaborator

AesRx, LLC, Newton, Massachusetts
Stephen Seiler

Collaborator

National Heart, Lung and Blood Institute, Bethesda, Maryland

Gregory Kato, M.D.

Public Health Impact

SCD affects millions worldwide, including approximately 80,000 patients in the United States. It affects 1 in every 500 African American births. With no approved therapies for use in children, there is a high-priority medical need.

Outcomes

Less than a year after signing the collaborative agreement with AesRx, TRND completed the pre-clinical toxicology, chemistry, manufacturing, controls and regulatory studies necessary to support an Investigational New Drug (IND) application to the FDA were completed, and the IND was filed. Upon clearance from the FDA, Aes-103 was moved into Phase I clinical trials in both healthy volunteers and SCD patients. TRND has established a project team that includes TRND staff, AesRx and a leading SCD clinical researcher at NIH’s National Heart, Lung, and Blood Institute. After adoption into the TRND portfolio, AesRx obtained a Massachusetts Life Sciences Center Accelerator Loan to support additional studies needed to complete clinical development of Aes-103.

In July 2014, the biopharmaceutical company Baxter International acquired Aes-103 for further clinical development — the first time a company has acquired a drug candidate developed in part by TRND researchers.

Publications

5-hydroxymethyl-2-furfural Modifies Intracellular Sickle Haemoglobin and Inhibits Sickling of Red Blood Cells • British Journal of Haematology • February 2005

Structural Basis for the Potent Antisickling Effect of a Novel Class of Five-Membered Heterocyclic Aldehydic Compounds • Journal of Medicinal Chemistry • Sept. 9, 2004

Related Information

News Release: First Drug Candidate from Innovative NIH Program Acquired by Biopharmaceutical Company

News Release: Baxter Acquires AesRx, LLC, Including Its Investigational Sickle Cell Disease Treatment

News Release: AesRx Presents Phase 1/2a Trial Data of Anti-Sickling Agent Aes-103 at ASH

News Release: AesRx Announces Collaboration With National Institutes of Health (NIH) to Develop Aes-103 for Sickle Cell Disease

Last updated: 09-06-2017
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