EASL 2019 – Novo buys into Gilead’s Nash combo plan

Today’s deal will see the companies take a triple combination into clinical trials.

The diabetes specialist Novo Nordisk has already worked in Nash, so today’s clinical trial alliance with Gilead marks another baby step towards developing a treatment.

The tie-up is noteworthy for other reasons, too, marking another buy-in to the theory that Nash needs to be treated with a combinatorial approach, and underlining its link with diabetes. But could this mean that existing diabetes drugs could be used for Nash? And what happens to the bull thesis that Gilead is on the lookout for acquisition targets in this liver disease?

The buyout thesis has helped keep Nash enthusiasm going despite two late-stage setbacks this year, one of which involved Gilead's own selonsertib. However, Gilead striking small, clinical trial tie-ups suggests a far more cautious attitude from a company that many think needs to do M&A, though of course this does not entirely rule out future acquisitions.

A little air escaped the Nash bubble yesterday, largely as a result of Intercept’s underwhelming data at the EASL conference, and even Viking, which presented a promising update for VK2809, ended the day down 2% (EASL 2019 – Viking to push the limits of its Nash contender, April 11, 2019).

Three-way tie

The Gilead/Novo tie-up will see the former’s cilofexor and firsocostat combined with the latter’s semaglutide, a GLP-1 analogue marketed for diabetes.

Nash followers will be familiar with all three approaches. The Gilead compounds are already being combined, and a 20-subject proof-of-concept trial presented at EASL showed that 74% had at least a 30% fall in liver fat, as measured by MRI-PDFF, from baseline after 12 weeks.

Novo has an ongoing phase II trial of semaglutide monotherapy in Nash. And liraglutide, another Novo GLP-1 analogue diabetes drug, has already yielded impressive monotherapy results, showing Nash resolution in 39% subjects, versus 9% for placebo, in a small study.

This is a threat to novel Nash projects. However, the fact that the Danish group has now seen the need to put semaglutide into a combo should give some comfort to those fearing the worst.

It is thought that Nash, diabetes and obesity are related, but a developing school of thought holds that a combined approach is needed to affect fat metabolism and reduce fibrosis. Intercept, for instance, licensed Aralez’s PPAR agonist bezafibrate to combine with Ocaliva, though this was also driven by a need to broaden the latter’s therapeutic window.

Selected Nash projects
Asset Mechanism Company Comment Trial ID
Cilofexor (GS-9674)  FXR agonist Gilead Same mechanism as Ocaliva NCT02854605 (monotherapy trial)
Firsocostat (GS-0976) ACC inhibitor Gilead Dual combo with cilofexor NCT03449446
Semaglutide GLP-1 analogue Novo Nordisk Triple combo with cilofexor & firsocostat NCT02970942 (monotherapy trial)
Selonsertib Ask-1 inhibitor Gilead Not part of Novo deal NCT03053063 (failed study)
Liraglutide GLP-1 analogue Novo Nordisk Nash monotherapy trial NCT01237119
Seladelpar PPAR delta agonist Cymabay Preclinical combo with selonsertib or liraglutide  
NN9499  FGF 21 analogue   Novo Nordisk Obesity project with Nash potential  

It will not go unnoticed that PPAR agonism is also used to treat diabetes. Yet another player, Cymabay, is developing the PPAR delta agonist seladelpar for Nash, and one of its EASL presentations today concerned preclinical results of a combo with either Gilead's selonsertib, an Ask-1 inhibitor, or with liraglutide.

Selonsertib appeared to show little additive effect on top of seladelpar, and notably the former was not part of today’s Novo deal with Gilead. But adding the GLP-1 to seladelpar caused a much greater reduction in liver fat than using either agent alone.

“GLP-1 receptor agonists are increasingly being recognised as having significant potential for the treatment of Nash,” Charles McWherter, Cymabay’s chief scientific officer, told Vantage today at EASL. “When used in combination, they may represent an opportunity to take novel agents into Nash patients with earlier stages of fibrosis.”

Pfizer, another GLP-1 player, agrees. “If we can induce significant weight loss we can have a positive impact on [Nash],” said Roberto Calle, a director in Pfizer’s internal medicine research unit. “And the GLP-1s have been proven to do that.”

One consideration is that a monotherapy approval might be needed before any combination of the novel agents can hit the market. This, along with Gilead’s caution, could act as a further brake on the bull case for Nash.

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