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NCATS Calls for Regulatory Partners to Develop, Market Potential Rare Disease Treatment

The National Center for Advancing Translational Sciences (NCATS) is the newest addition to the National Institute of Health (NIH), and perhaps the one center most closely aligned with the goal of regulatory affairs.

Formed in 2011 as the brainchild of NIH Director Francis Collins, the center aims to bridge the so-called valley of death, making sure more discoveries are able to bridge the gap between bench and bedside.

But with the exception of some announcements regarding cooperative ventures with large pharmaceutical companies, NCATS has largely been in a silent growth mode during the first year of its existence.

That is, until now.

The center just announced that, in combination with NIH's National Human Genome Research Institute (NHGRI), it is seeking out a partner to, in its words, "collaborate in the final stages of lead optimization, evaluation and preclinical development" of two new therapies; one for Gaucher disease and the other for the treatment of heart failure and fibrosis.

Gaucher Disease

NCAT's first Federal Register notice concerns a novel selective series of non-inhibitory chaperones of glucocerebrosidase (GCase).

NCATS believes GCase will be useful in treating Gaucher disease and other related diseases. Gaucher is a rare disease affecting just a few thousand people in the US, and is most commonly found in those in Ashkenazi Jews, most of whom hail from Eastern and Central Europe.

The disease is marked by a lack of the GCase enzyme, which causes substances to build up in the body's organs. The severity of the disease depends on which of three types is inherited by the patient, but the disease is often fatal.

NIH said it hopes its GCase chaperones will be able to guide the enzymes to lysomes after synthesis in the ribosome instead of accumulating in the endoplasmic reticulum. This is more difficult than it seems, NIH wrote in its Federal Register announcement.

"The main challenge in the development of molecular chaperones for Gaucher disease is that chaperones are inhibitors of the enzyme. This complicates their clinical development, because it is difficult to generate an appropriate in vivo exposure at which a compound exhibits chaperone activity, but does not inhibit the enzyme's function."

The good news, it said, is that high throughput screening has identified several small-molecules that do not inhibit the enzyme. "These lead molecules were found to increase the specific activity of the enzyme, promote the translocation of GCase to the lysosome in Gaucher fibroblasts and macrophages, reduce the accumulated substrate, and restore efferocytosis of these cells."

NIH added that the compound could also come to be used as a treatment for Parkinson’s disease, which exhibits some genetic parallels with Gaucher disease, or more generally to "enhance the efficacy of enzyme replacement therapy."

Heart Failure and Fibrosis

Its second Federal Register notice references recombinant relaxin hormone, which NIH said is already in Phase III trials for the treatment of acute heart failure.

Researchers wrote that the compound is "difficult to study in chronic settings due to the short half-life and the need for intravenous administration of the recombinant hormone." A new, recombinant version of the hormone—the likes of which NCATS has been studying—would hypothetically "have numerous benefits and will allow investigating additional therapeutic applications where chronic administration is required."

As with the GCase Chaperones, NCATS said it has successfully identified a series of small-molecule agonists that it said are "potent, highly selective, easy to synthesize, and with reasonable metabolic and physical properties" that display "similar efficacy as the natural hormone in several functional assays."

If successfully marketed, the product could mean big money for its sponsor. Heart failure—the disease which NCATS thinks this product would be most successful at treating—affects millions of Americans and is understood by the American Heart Journal to be the leading cause of hospitalizations for those over the age of 65.

An Unusual Proposition

What's unusual about NCAT's Cooperative Research and Development Agreement (CRADA) is not that it's looking for partners—it does that quite often—but that it's looking for a partner that already has a sense of the regulatory challenges ahead of it. "The CRADA scope will also include studies beyond candidate selection including all aspects of pre-clinical studies such as toxicity studies and chemistry good manufacturing practice (GMP) scale up of select compound(s) and manufacture of controls leading to a successful investigational new drug (IND) application," it wrote.

NIH routinely licenses technology to outside groups, but usually without the preconditions that it be able to bring a drug to market using the technology or their history as a company.

Not so with its CRADA.

"Collaborators should have experience in the pre-clinical development of small molecules and a track record of successful submission of IND applications to the FDA for rare and neglected diseases," it added.

The agency said it hopes the compound can be "expeditiously commercialized and brought to practical use."

Though the compounds are still relatively early in the development cycle—NIH notes that it's only undergone early-stage in vivo and in vitro testing to determine absorption, distribution, metabolism and elimination (ADME) and activity studies on human macrophages—it still represents a potential new pipeline for patients suffering from rare or neglected diseases, as well as a potential source of profit for companies whose own pipelines have been notoriously stagnant in recent years.

But even as this new treatment may hold promise, it's far from a sure thing. The product will still need to obtain approval to begin clinical trials, and then undergo Phase I, II and (likely) III testing to show that it is both safe and effective for its given purpose. Approximately 90% of treatments starting Phase I testing never obtain approval, leaving the prospect of this therapy obtaining approval very much in jeopardy.