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Celimmune revives Amgen anti-inflammatory drug for celiac disease

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By Jennifer Boggs
Managing Editor

In the biopharma space, finding potential new uses for shelved drugs has become a business model unto itself, with proponents touting successes such as AZT – a drug that bombed in cancer trials only to return two decades later as the first approved therapy for HIV – and the National Institutes of Health even endorsing the strategy, setting up the National Center for Advancing Translational Sciences as a matchmaker to hook up researchers with failed compounds in 2012. (See BioWorld Today, May 4, 2012.)

One of the latest attempts to revive an old drug sees recent start-up Celimmune LLC dusting off AMG 714, an anti-interleukin-15 (IL-15) monoclonal antibody it licensed from Amgen Inc., with plans to move into phase II trials this year in celiac disease.

AMG 714, which was originally developed in the 1990s, came to Amgen by way of its 2002 buyout of Immunex Corp., which had partnered with Copenhagen-based Genmab A/S on an anti-inflammatory program. Amgen later exercised its option to the drug – then designated Humax-IL15 – and pursued development in rheumatoid arthritis (RA) and psoriasis. However, data generated from studies in those indications fell short, at least when taking into account the crowded marketplace of existing RA and psoriasis drugs – the drug demonstrated rapid onset of action and was well tolerated – and Amgen set the program aside. (See BioWorld Today, July 2, 2003.)

But data emerging in recent years prompted another look at AMG 714. A paper published in Nature in 2009 showed that blocking IL-15 signaling decreased inflammation and tissue damage associated with celiac disease in mice. Another paper, published in Nature in February 2011, showed that transgenic mice overexpressing IL-15 had early signs of celiac disease and that blocking IL-15 could prevent the inflammatory response to gluten in mice. (See BioWorld Today, Feb. 15, 2011.)

"It was one of those cytokines that we learned more and more about in recent years," said Francisco Leon, Celimmune's CEO and chief medical officer, a clinical immunologist by training whose two decades of studying celiac disease goes back to long before much was known about the disease.

A relatively new disorder, celiac disease is described as a chronic, hereditary, systemic autoimmune and inflammatory disease triggered by gluten consumption and characterized by damage to the lining of the small intestine that can lead to debilitating symptoms and nutritional malabsorption. Roughly 1 percent of Western populations and 0.5 percent of Asian populations are believed to suffer from celiac disease, though those figures could increase as diagnoses improves and treatments become available.

Patients diagnosed with celiac must maintain gluten-free diets, which is not always easy given that gluten is found in unexpected places – the excipients used in oral drug tablets and even in cosmetics, for instance. But for about half of celiac patients, a gluten-free diet isn't enough, and a handful of companies are in development with drugs for diet non-responsive disease, including Alba Therapeutics Corp., where Leon previously served as chief medical officer, which is developing gastrointestinal permeability inhibitor AT-1001, and Alvine Pharmaceuticals Inc., which is working on a two-enzyme drug combination aimed at degrading gluten. (See BioWorld Today, Dec. 17, 2007, and May 15, 2013.)

Celimmune will join them, planning a phase II study in diet non-responders. But it also has its sights on an even smaller – and sicker – population of celiac patients.

The worst complication linked to celiac is refractory disease, which can lead to lymphoma, Leon explained. "It's what happens when patients are exposed to gluten for many, many years – decades."

And IL-15 appears to be the growth factor needed for the intraepithelial lymphocytes that cause intestinal mucosal atrophy and pathological progression to lymphoma in refractory celiac patients, he added. When biopsies were taken from the gut of refractory patients who had progressed to lymphoma, "they found that IL-15 was the key cytokine driving the survival of those lymphocytes;" an early test of AMG 714 found that it could trigger apoptosis of those lymphocytes.

Although believed to be extremely rare, refractory celiac disease has a 50 percent mortality rate.

So while the first phase II study will involve a gluten-challenge study in patients with diet non-responsive disease, the second proof-of-concept trial will evaluate the ability of AMG 714 to reduce lymphoma T cells.

RAPID GO/NO GO STRATEGY

Under terms of the licensing deal, Celimmune gets worldwide rights, excluding Japan, to develop, manufacture and commercialize AMG 714. No terms were disclosed, but Thousand Oaks, Calif.-based Amgen has the right to reacquire the asset upon completion of additional studies.

"The intent is for us to complete proof of concept, and it would be on the basis of these two studies that Amgen would review" and decide whether to exercise the option, said Ashleigh Palmer, Celimmune's executive chairman who also serves as president of advisory firm Creative Bioventures Corp.

The timeline for completing the studies has not been disclosed, but the small firm – with Leon and Palmer as the sole employees – will operate a virtual model, relying on a network of experts in the immunology space and trial designs designed to get to an answer quickly. It's a model Leon knows well, having just come from a stint as vice president in the translational medicine unit of Johnson & Johnson.

"He has expertise in conducting rapid go/no-go decisions at an early stage," Palmer told BioWorld Today. "That was his expertise at J&J."

Palmer, too, has experience leveraging networks vs. building infrastructure. He was previously part of spinning out inhaled nitric oxide assets into Ino Therapeutics Inc., which later became Ikaria Therapeutics Inc. "Our preference is to [conduct development] through a cooperative and be able to work with the best of the best in the world," he said.

The idea is to "kill assets very quickly, based on solid data, allowing companies to focus their resources," he added. "We believe we have a distinct capability."

Celimmune's plans could go beyond AMG 714, so don't expect it to go the way of other newcos that in-licensed a drug, developed it and then were swallowed up by its licensor. Stromedix Inc., which licensed from Biogen Idec Inc. an idiopathic pulmonary fibrosis candidate that Biogen regained with a buyout a few years later, is a good example. (See BioWorld Today, Feb. 15, 2012.)

"We could consider a number of different ways to partner or acquire assets," Palmer said. "In some instances, it might be to take on a deprioritized asset and allow that company [that licensed it] the option to take it back at advanced stages. In other instances, we might do more of a traditional in-licensing."

There is also the possibility of eventually testing AMG 714 in other indications. IL-15 plays a role in several other autoimmune diseases, including ulcerative colitis, lupus and type 1 diabetes, "so there's definitely interest in potentially expanding the indication," Leon said.

The company, which lists its headquarters in Lebanon, N.J., and Bethesda, Md., has not disclosed its funding and its initial objectives are to get through the two proof-of-concept studies as quickly as possible.

The drug already has shown safety and efficacy in RA and psoriasis patients. "We know the drug is bioactive and is well tolerated," Leon said. "The question is whether it will work in celiac."