Nimbus Thinks It Has “Non-First-Mover” Advantage In NASH

Working on an allosteric ACC inhibitor in NASH, Nimbus is not worried about being first to market but is willing to let others develop and prove out a pivotal development pathway in the indication, while it focuses on a unique mechanism of action.

Taking its first drug candidate into clinical development in non-alcoholic steatohepatitis (NASH), Nimbus Therapeuticsisn’t concerned about the increasing number of companies looking at this unmet medical need because it is content to let other players sort out the pivotal trial pathway.

You could call it a “non-first-mover” advantage, but Nimbus doesn’t think it needs to be first to market in NASH because its candidate, currently in IND-enabling studies, is a first-in-class inhibitor of acetyl-CoA carboxylase (ACC), a different approach to treating the burgeoning liver disease than competitors with more advanced programs like Intercept Pharmaceuticals Inc. and Tobira Therapeutics Inc. are pursuing (Also see "Deal Watch: NASH Space Heats Up With Tobira/Regado Reverse-Merger" - Pink Sheet, 26 Jan, 2015.).

Recently changing its name from Nimbus Discovery LLC to reflect its advancement into drug development, the Cambridge, Mass., biotech announced a $43 million Series B financing on March 18 and says it expects Phase I data for its unnamed lead candidate later in 2015. [See Deal] Pfizer Venture Investments and Lightstone Ventures led the round, joined by returning investors Atlas Venture, SR One, Lilly Ventures and Bill Gates from a $24 million Series A in 2011 [See Deal].

Biopharmas with further-advanced candidates for NASH, a widespread but also significantly undiagnosed hepatic condition that can lead to fibrosis, cirrhosis and the need for a liver transplant, are in somewhat of a holding pattern while a pivotal Phase III trial protocol is developed for the indication (Also see "Intercept Thinks Fibrosis Effect Could Carry Its NASH Candidate" - Pink Sheet, 17 Nov, 2014.). More established companies such as Gilead Sciences Inc. and Boehringer Ingelheim GMBH have made deals in recent months to move into a space some refer to as “the next big thing” in liver disease (Also see "Deal Watch: Gilead’s Move Into NASH Highlights Post-Holiday Deal-Making" - Pink Sheet, 12 Jan, 2015.).

In an interview, Nimbus CEO Don Nicholson said his firm’s computational drug design approach, which stems from a partnership with software maker Schrodinger Inc., enables it to come up with candidates addressing well-established but difficult-to-drug targets, such as ACC. Several companies have taken ACC inhibitors into the clinic, typically in type 2 diabetes, but have not yet succeeded in producing a drug, he said.

“ACC has applicability to a number of metabolic diseases,” Nicholson explained. “The genesis of our program was the potential that we could make chemical inroads against ACC as a target, and do that in a way that nobody else has been able to do. Our inhibitor is an extremely potent allosteric inhibitor of ACC, which is markedly different from what everyone else has put through clinical development or tried to unsuccessfully to this point.”

Lipo-Toxicity Hypothesis

In addition to approaching ACC with an indirect binding strategy, Nimbus also is working with one of several prevailing hypotheses about NASH, that it is driven by lipo-toxicity. This view holds that the toxicology of lipids when they accumulate in the liver drives apoptotic and necrotic death of hepatocytes and other liver cells, provoking the onset of fibrosis, the exec explained.

The increasing interest in NASH combined with joint efforts by FDA and the American Association for the Study of Liver Disease to develop a pivotal pathway for the indication created ideal timing for Nimbus to take its first candidate into clinical development in NASH, Nicholson said. The company is also doing preclinical work in oncology and immunology targeted at IRAK4, Tyk2 and Kras, while also working on a discovery collaboration with Shire PLC in lysosomal storage disorders [See Deal].

Nimbus anticipates that a paper published jointly by FDA and AASLD last December contains the beginnings of a framework for a pivotal trial pathway in NASH and expects an FDA guidance document this year.

“So we’re anticipating that those guidance documents will be available and we’re also working with a who’s who of people who have worked on other compounds in NASH to make sure that we’re participating in the medical, scientific and regulatory community as we move our molecule forward,” Nicholson said. “I think Intercept’s molecule, OCA [obeticholic acid], is a good barometer for how the field is going to evolve and we’re cheering them on in the hopes that they’ll show the path forward to registration in NASH.”

“It’s not finalized yet but I think it’s coming, it’s inevitable,” he added. “And it has to be when you think about the health care burden that the absence of treatment places on this country.”

While waiting for the Phase III pathway, Nimbus is tracking other companies’ work in ACC inhibition, particularly Pfizer Inc. The pharma’s pipeline lists PF-05175157 as an ACC inhibitor in Phase II for type 2 diabetes. Nicholson said publication in peer-reviewed journals about the Phase I data and other findings have been very helpful to Nimbus’ work on the target. (According to Nicholson, Pfizer has withdrawn the compound from active development for undisclosed reasons; Pfizer has not responded to inquiries, but the asset was listed on a pipeline updated Feb. 27).

Allosteric Modulation’s Benefits

Allosteric modulation of the target could position Nimbus to succeed where Pfizer and others have not so far, the exec said. Nimbus’ work is attempting to replicate the effects of a naturally occurring ACC inhibitor called soraphen A.

“We think that to tackle this enzyme properly, to get the potency and the selectivity that you need, you have to do something markedly different than trying to inhibit the active site of the enzyme,” Nicholson explained. “That’s why we went after this allosteric site that is well defined and well known in the literature.”

“Essentially, what we did was take a molecule that has no drug-like properties and build an entirely new scaffold, [creating] a molecule that does the exact same thing that soraphen A does modulating the allosteric site,” he continued. “By doing so, we can get a molecule that has much better drug-like properties than anything that we’ve seen from our intelligence on the companies that have worked in this space before.”

Nimbus’ partnership with Schrodinger is key to its potential success in addressing historically intractable targets, Nicholson said, because the company gets to work with Schrodinger’s latest software and provide real-time feedback on how it works and how it can be improved. The two companies have mutual exclusivity in NASH, making them deeply committed to each other’s success, he added.

Nicholson sees the investor interest by Pfizer, Lilly and GlaxoSmithKline PLC, the corporate parent of SR One, as validating its business strategy. And he is not shy about expressing the hope that those investments could augur future relationships with the big pharma companies.

“My understanding is that each of them is trying to build up companies that their R&D organizations might eventually be interested in,” he said. “I think that in all three cases, there are programs and capabilities and assets with Nimbus that their R&D organizations should be interested in.”