Orca Pharmaceuticals Ltd. and Astrazeneca plc are joining a growing list of alliances seeking to leverage retinoic acid-related orphan nuclear receptor gamma (RORγ) inhibitors to address a wide range of autoimmune diseases. The exclusive collaboration, adopting Orca's full RORγ pipeline, carries up-front and milestone payments of up to $122.5 million for the Oxford, UK-based company and will likely yield a candidate by year-end ahead of possible 2016 first-in-human studies.

The three-year partnership will focus on autoimmune diseases for which there are currently no safe, orally available and effective treatments and it gives Astrazeneca worldwide rights and an option to acquire the Orca compounds at the end of the collaboration. Orca remains free to start programs in other areas; it has yet to do so.

"A lot of companies are investing a lot of time and money in their RORγ programs," Roy Pettipher, Orca's co-founder and chief scientific officer, told BioWorld Today. "The challenge has been to identify compounds that have good metabolic stability, are well absorbed after oral administration and are not too rapidly cleared."

The "reasonably low" molecular weight, good absorption and promising pharmacokinetic properties of Orca's compounds proved a key driver of the deal, he said. Orca's work on biomarkers, or genetic signatures, capable of identifying patients with active RORγ-dependent disease to guide the indication were also important, Pettipher said, noting that biomarkers may also be able to be used as as surrogates for drug response in clinical trials.

London-based Astrazeneca did not return a request for comment on the deal.

While the new partners are still homing in on the right indications to pursue, Pettipher said the strongest data at the moment would suggest that a RORγ inhibitor is likely to be effective in psoriasis, an indication in which Orca focused earlier efforts.

RORγ plays a key role in the immune system, helping convert CD4-positive T cells into T-helper 17 (TH17) cells which, in turn, produce cytokines that drive the immune response. But excessive activity of TH17 cells and other RORγ-positive immune cells has been implicated in a wide range of conditions such as inflammatory bowel disease, psoriasis, arthritis and multiple sclerosis.

"I think the potential is enormous. That's why there's so many people working on it," said Pettipher. "The new anti-IL 17 antibodies, such as such as ixekizumab, brodalumab and others have shown quite remarkable efficacy in psoriasis. We should be able to mimic that with a small-molecule RORγ inhibitor."

Ixekizumab is in development by Eli Lilly and Co., while brodalumab is being developed by Amgen Inc.

Founded in 2013, Orca has been backed by investments of about $2.8 million to date, financing led by Cleveland-based Biomotiv LLC, a for-profit accelerator aligned with the Harrington Project for Discovery & Development, with participation from the NYU Innovation Ventures Fund. The company's technology is based on intellectual property developed in the laboratory of TH17 cell immunology expert Dan Littman, of New York University, and has close ties with Oxford University.

Long on potential, the hot RORγ space has sparked a growing list of partnerships, including Sanofi SA's link-up with Dutch biotech company Lead Pharma Holding BV, announced Feb. 18. Other alliances include tie-ups between San Diego-based Orphagen Pharmaceuticals Inc. and partner Japan Tobacco Co. Ltd.; Lycera Corp. and Merck & Co. Inc.; Exelixis Inc. and Bristol-Myers Squibb Co.; Karo Bio AB and Pfizer Inc.; Phenex Pharmaceuticals GmbH and Johnson & Johnson; Teijin Pharma Ltd. and Amgen; and Tempero Pharmaceuticals Inc. and Glaxosmithkline plc. (See BioWorld Today, Feb. 19, 2015.)

"It's going to be interesting to see who comes out on top," said Pettipher. "It's still quite early."