African american patient in pain with female nurse
NHLBI NEWS
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NHLBI funding leads to promising drug candidate to prevent sickle cell pain

Pain is one of the unfortunate hallmarks of sickle cell disease, often growing in intensity as patients age. It is a leading cause of emergency room visits and hospitalizations among people with the disease, and the frequency of those pain-related hospital admissions is a strong predictor of premature death. Researchers have tried for years to find effective pain-relieving alternatives to improve the management of the condition, but they have found limited success. 

That could soon change, thanks to technology developed by Selexys Pharmaceutical Corporation in Oklahoma City. The company developed a synthetic antibody that prevents red blood cells and other blood cell types from sticking to the walls of blood vessels, causing a cell pileup that restricts blood flow. That blockage is what leads to painful sickle cell crises and organ damage. The antibody, called crizanlizumab, could be administered once a month by injection to prevent painful sickle cell crises. It was developed and tested with support from the National Heart, Lung, and Blood Institute (NHLBI).

Selexys was founded in 2002 by Rodger (Rod) McEver, M.D., Richard Cummings, Ph.D., and Rick Alvarez, M.B.A., while the trio worked at the University of Oklahoma. The development of the antibody was based on McEver’s and Cummings’ basic research, which was funded largely by NHLBI. From 2004 to 2014, NHLBI awarded Selexys a series of grants under its Small Business Innovation Research (SBIR) program to support initial safety testing in animals and human clinical trials of crizanlizumab (also known as SelG1).

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This digitally colorized scanning electron microscope image shows a sickle red blood cell (left) next to normal red blood cells found in a blood sample of a person with sickle cell disease. Credit: Centers for Disease Control and Prevention (CDC) and Sickle Cell Foundation of Georgia.

“SBIR funding was instrumental in moving the antibody through preclinical studies and clinical trials,” said Alvarez, who is currently Vice President of Operations and Research of Tetherex Pharmaceuticals in Oklahoma City. “After many years of research, we’ve seen amazing progress for this promising drug candidate as it moves into advanced testing for the treatment of sickle cell disease.”

In a series of clinical trials, researchers demonstrated that crizanlizumab appears safe and significantly reduces the incidence of painful crises in patients with sickle cell disease. The drug candidate is now in an advanced stage of development and testing by the pharmaceutical company Novartis, which acquired Selexys in 2016. According to a press release issued by Novartis, the company anticipates that it will file for Food and Drug Administration (FDA) approval of the drug by the end of 2018. If approved, crizanlizumab would become only the third drug, along with hydroxyurea and Endari (L-glutamine oral powder), that is FDA-approved for the treatment of sickle cell crises and the only one that targets the cellular aggregation that blocks blood flow.  

The first breakthrough in the development of this potential therapy came when McEver co-discovered a cell surface protein called P-selectin, which allows white blood cells to stick to platelets and the lining of the blood vessels at sites where there has been tissue injury or infection. Researchers now believe that in sickle cell disease, P-selectin promotes excessive sticking together of blood cells that blocks blood flow and ultimately causes the intense pain suffered by patients.

McEver and Cummings later discovered a receptor for P-selectin on white blood cells. In 2008, they developed an antibody to block the binding of P-selectin to this receptor, preventing the attachment of white blood cells. After further refinement of this synthetic antibody, Selexys advanced the antibody through safety studies in animals and into clinical trials as a treatment for painful crises in patients with sickle cell disease. The disease affects about 100,000 people in the United States and millions worldwide.

From 2013 to 2016, Selexys conducted a Phase II clinical trial, called SUSTAIN, to determine whether crizanlizumab was effective in preventing or reducing sickle cell pain crises. In the study, investigators assigned about 200 sickle cell patients to one of three treatments: high-dose antibody, low-dose antibody, or placebo (no antibody).  The high-dose treatment reduced the rate of painful episodes by as much as 45 percent. Crizanlizumab also increased the length of time between painful episodes, as well as reduced the time patients spent in the hospital.

“This drug candidate is a giant step forward in providing relief for a debilitating disease that has few available treatments,” McEver said. “It’s a great success story for the NHLBI SBIR program that will hopefully prove beneficial to many patients with sickle cell disease in the near future.”

More about the NHLBI SBIR and STTR programs

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.

Disclaimer

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.

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