NIH Program Keeps Sickle Cell Disease Drug Alive

Last month, the health care giant Baxter agreed to buy AesRx, a virtual biotech firm developing a drug for sickle cell disease. If successful, the drug, Aes-103, could be the first dedicated treatment for the more than 85,000 people in the U.S. with sickle cell.

But despite a sizable market and significant need, the drug might just as easily have disappeared into obscurity. Developing drugs for sickle cell has proven daunting, and investors were not interested in Aes-103. The compound was kept alive in large part because of a National Institutes of Health program called Therapeutics for Rare & Neglected Diseases (TRND). It was started in 2009 to forge partnerships with companies or institutions in need of help with drug development projects that are high risk but potentially offer high therapeutic reward.

Sickle cell is the result of a mutation in hemoglobin, the component of red blood cells tasked with carrying oxygen from the lungs to the rest of the body. After releasing its oxygen, the errant hemoglobin polymerizes, causing the red blood cell to warp and stiffen. The sickle-shaped cell can clog blood vessels, depriving organs and tissues of oxygen-rich blood.

Currently, the only treatment for sickle cell disease is hydroxyurea, an anticancer compound that doesn’t work for everyone and is replete with side effects.

For years, researchers tried to develop molecules that prevent sickling by increasing the mutated hemoglobin’s affinity for oxygen. Most of the efforts centered on aromatic aldehydes, an avenue that proved effective—one compound got all the way to Phase II clinical studies—but was stymied by toxicity.

A team led by Virginia Commonwealth University medicinal chemist Donald J. Abraham decided to look at aromatic aldehydes found in food. He reasoned that anything we eat should be safe as a drug, explains VCU chemist Martin Safo, who was a postdoc in Abraham’s lab at the time.

The researchers landed on 5-hydroxymethylfurfural (5-HMF), which is found in coffee and dried fruit and is a by-product of browning sugar. VCU patented the compound and licensed it in 2005 to Xechem International, which secured a small-business grant from NIH to support toxicity studies.

But Xechem went bankrupt in late 2008 and sold 5-HMF to the newly formed AesRx. The new owner’s chief executive, Stephen R. Seiler, immediately began looking for capital to advance the drug, now called Aes-103. “I’ve been in the industry for 20 years, and when I acquired control of 103, I went around to the usual suspects,” Seiler recalls.

But the timing was terrible: It was just a few months after the collapse of Lehman Brothers, and venture capitalists (VCs) weren’t interested in risky projects. Moreover, drugs for orphan diseases, now a hot commodity, weren’t popular at the time.

The biggest hurdle, however, was the perception that the path to approval was too onerous. VCs were turned off by the prospect of running a clinical trial similar to the one that got hydroxyurea approved as a sickle cell treatment. A Phase III study of that drug began in 1992, and it took until 1998 for it to be approved because recruiting patients proved difficult.

The worry was that Aes-103 would run into the same patient recruitment challenge. “Over the next 12 months, we really got no positive feedback from VCs,” Seiler says.

Then, in the spring of 2010, Seiler met John C. McKew, acting director of TRND’s preclinical division. AesRx struck a deal with TRND later that year, and the partners quickly set out a series of objectives and “go/no-go” decision points, Seiler says. The idea was to get the project, which still needed preclinical tests, into a Phase II study, a stage at which investors’ interest might be piqued.

Indeed, the results from a Phase I/II trial of Aes-103 and the start of a Phase II study lured Baxter. The collaboration with TRND removed uncertainty around the program, Seiler says. Not only did data on the compound grow, but NIH also helped smooth its clinical path by organizing a meeting with the Food & Drug Administration related to clinical trial design, a key consideration for potential investors.

Moreover, the collaboration with TRND helped AesRx secure other financing to stay afloat. In 2011, the firm won a $750,000 loan—recently repaid with interest—from Massachusetts Life Sciences Center.

NIH learned a lot by working with AesRx, one of its first TRND collaborators, such as how to set up government contracts to advance a drug development project, according to TRND’s McKew. And the agency had to work out how it would handle any intellectual property generated through a TRND collaboration.

Aes-103 is one of four molecules in the TRND program to have moved into clinical studies and the first to be acquired. Some of the corporate partners have been successful in securing funding from VCs or patient groups based on the progress made through TRND.

TRND’s capacity is limited: The program can take on only about three new projects a year. But the projects that are ­adopted move swiftly through development, partners note. The TRND scientists were “transparent in decision making and collaborative, and their turnaround time was really quick,” Seiler says. “This is not your father’s NIH.”