More than 100,000 people in the United States and an estimated 20 million worldwide suffer from sickle cell disease, a group of inherited, often life-threatening blood disorders that wreak havoc on the body. Mainly affecting African-Americans, Hispanics and Asians, the disease is caused by a mutation in the gene that makes oxygen-carrying hemoglobin. Yet while researchers have understood these genetic underpinnings for decades, a widely available treatment has eluded them.
The Ohio-based biotech company EpiDestiny, founded in 2016, has been trying to change that by focusing on increasing the production of fetal hemoglobin in patients’ red blood cells. Found in the blood cells of the human fetus as the main carrier of oxygen during the last seven months of pregnancy, this hemoglobin is typically replaced by the adult form at around six months of age. In children with sickle cell disease, however, a defective, mutated form of the hemoglobin takes over, causing the red blood cells to form an abnormal, sickle shape. These sickled cells clog the blood vessels and deprive cells of oxygen, which in turn damages organs, causes severe pain and in many cases, leads to premature death.
The idea behind the new treatment is straightforward: increase the unmutated fetal hemoglobin so that it eventually replaces the sickle cell hemoglobin. Researchers have gleaned the benefits in sickle cell patients with naturally high levels of fetal hemoglobin beyond infancy – they simply have fewer complications of the disease.
EpiDestiny’s therapy, known as EPI01, is an oral, fixed-dose combination of two drugs, decitabine, which inhibits the enzyme that turns off the production of fetal hemoglobin after infancy, and tetrahydrouridine, which turns off an enzyme in the body that destroys decitabine. In 2012, with support from the National Heart, Lung, and Blood Institute (NHLBI), researchers at the Cleveland Clinic and the University of Illinois began testing this oral combination in humans.
The “proof of principle” phase 1 trial was small—it had 25 participants—but the results were encouraging. EPI01 safely increased the levels of fetal hemoglobin to replace the defective hemoglobin in sickle cell disease patients, and researchers are hoping the EPI01 technology will improve outcomes.
Yogen Saunthararajah, M.D., a Cleveland Clinic researcher and principal investigator for the trial, has received various NHLBI grants for research on sickle cell disease over the past ten years. This research was essential for the development of EPI01, a medication that could be taken orally and would simplify and increase the availability of treatment for sickle cell disease patients.
“The NIH funding was absolutely instrumental in enabling and driving this work,” said Saunthararajah.
“First, sickle cell is an orphan disease, and the pharmaceutical industry was not particularly interested in it until recently,” he said. In addition, he went on, one of the molecules in the new treatment – decitabine – was considered “old” because it was first synthesized in the 1960s. “It did not appear to have a novelty factor,” said Saunthararajah, “and many researchers had already made up their minds about how this molecule worked and what it could do.”
An important break came in 2013 when Saunthararajah received a Rapid Access to Interventional Drug Development (RAID) grant from the NHLBI and the National Cancer Institute (NCI), which supported the manufacture and preliminary evaluation of the components of EPI01. Only then, the researchers were able to submit an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to move from the laboratory to the clinic and begin exploring this drug combination for sickle cell disease.
In 2014, Saunthararajah received a grant from the NIH Centers for Accelerated Innovations (NCAI). Together, the RAID and NCAI work enabled the EpiDestiny team to receive a Direct to Phase II Small Business Innovation Research (SBIR) award from the NHLBI, which supported further clinical development.
“The NCAI and SBIR program provided substantial credibility for the science and its commercial potential, and, by connecting EpiDestiny to the SBIR team and resources at NHLBI, guided our SBIR grant application,” said Saunthararajah. “The SBIR funds enabled us to perform further clinical development.”
“It takes millions of dollars and immense cross-disciplinary expertise to be able to take a molecule from the lab to the patients,” said Saunthararajah. “The industry is profoundly risk averse. Without the NHLBI support, we would not have been able to do all the de-risking necessary to secure an industry partner.”
EpiDestiny licensed the technology from the University of Illinois for development for multiple clinical uses, and has been granted Rare Pediatric Disease, Fast Track and Orphan Designations by the FDA for EPI01.
In April, the Danish pharmaceutical company Novo Nordisk and EpiDestiny announced a $400 million deal to secure an exclusive worldwide license for EpiDestiny’s sickle cell disease program, EPI01.
“The collaborative efforts of EpiDestiny, NHLBI, and Novo Nordisk represent important steps in the discovery of EPI01 and its continued development for patients with this underserved, life-threatening disease,” said Santhosh Vadivelu, Ph.D., president and chief executive officer of EpiDestiny.
The NHLBI Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs support the development of the next generation of commercially promising technologies and products to prevent, diagnose, and treat heart, lung, blood, and sleep-related diseases and disorders. For more information on NHLBI’s small business programs, visit the NHLBI Small Business Program Funding Area page.
Reference to any specific commercial products, process, service, manufacturer, and/or company does not constitute an endorsement or recommendation by the National Heart, Lung, and Blood Institute (NHLBI), the NHLBI's Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs, or any other portion of the U.S. Government.