A string of disappointing readouts from the Nash pipeline means that the pressure is building on remaining projects to deliver more conclusive evidence of potential in this disease. The next pivotal data are some months away, but mid-stage projects from NGM Biopharma and Enanta Therapeutics should provide some more immediate interest.
The collapse of Conatus this week serves to underline the risks of Nash, however. True, the failure of the third mid-stage trial of that company’s experimental agent was hardly a surprise in the wake of two previous blow-ups. But emricasan was effectively all Conatus had, and similarly exposed Nash players should be looking on with trepidation at the company’s fate.
This includes Genfit which, besides its phase III asset elafibranor, has little else to speak about. The French developer sold China rights to the project this week in a deal its supporters tried to spin as a good omen before pivotal data, but a quick look at the history of elafibranor, and the track record of Nash product development more widely, suggests that such a bold claim should be quickly dismissed as hyperbole.
Genfit received $35m up front for rights to elafibranor in China and a handful of other adjacent territories, in a deal that could also yield $193m in milestones and mid-teen royalties on any sales. The rights were bought by Tern Pharmaceuticals, a liver disease-focused biotech based in China and San Francisco that has been generously funded by venture backers since being founded in early 2017.
Elafibrinor becomes Tern’s most advanced asset, joining three Nash projects licensed from Lilly, the most advanced of which is Tern-101, an FXR agonist. The deal will see the two companies explore combinations of elafibrinor, a PPAR agonist, with Tern’s pipeline agents. This could yield useful insights, though if anything shows promise Genfit will still have to pay for formal access to its partner’s assets.
This is all moot ahead of pivotal data on elafibrinor, of course: topline readout from the pivotal Resolve-It study is due in the fourth quarter. This has resolution of Nash with no worsening of fibrosis as its primary endpoint, a measure on which elafibrinor failed an earlier trial (Behind the management smokescreen, Genfit study is still a fail, 27 March 2015).
That Genfit pushed into phase III based on a multiple post-hoc analysis of a failed trial is probably the biggest red flag here, though there are also mechanistic concerns when it comes to PPAR agonism. Data from the class to date have been far from conclusive: as well as elafibrinor’s opaque track record, Cymabay’s seladelpar failed to show any impact on liver fat in a phase II trial earlier this month (Cymabay can’t buck the Nash disappointment trend, June 11, 2019).
The two projects are different, Genfit bulls point out: while seladelpar hits only the alpha form of the receptor, elafibrinor hits both alpha and delta receptors. Another agent, Inventiva’s lanifibranor, also hits the third receptor, gamma. Phase IIb data from Inventiva’s Native trial are due early next year, and should help determine the relative importance of these receptors, and indeed any role that PPAR agonism might play in Nash.
Of course no mechanism has actually displayed unequivocal efficacy in Nash to date. Conatus’s emricasan was a pan-caspase inhibitor, a class that now looks like a dead end in Nash, while Gilead’s disappointment with selonsertib, which has failed in two phase III trials, has lowered hopes for Ask1 inhibition.
Gilead has another shot with selonsertib, at least, which is being tested in a phase II combination trial called Atlas. Data, due before the end of the year, represent one of the most keenly awaited Nash readouts of the coming months; it is widely suspected that more than one mechanistic approach will be needed to have an impact on the disease.
The Atlas trial has recruited advanced patients, many with compensated cirrhosis, and tests seven different combinations of selonsertib, the ACC inhibitor firsocostat and cilofexor, an FXR agonist.
|State of play: recent progress for key Nash projects and selected upcoming trial readouts|
|Ocaliva||Intercept||FXR agonist||NCT02548351||Due to be filed in Q3'19|
|Selonsertib||Gilead||Ask1 inhibitor||NCT03053050||Stellar phase III programme failed|
|Cenicriviroc||Allergan||CCR type 2/5 dual antagonist||NCT03028740||Top-line results expected 2020|
|Elafibranor||Genfit||PPAR alpha & delta agonist||NCT02704403||Top-line Resolve-IT results due by YE'19|
|Emricasan||Conatus||Caspase inhibitor||NCT02960204||Programme looks likely to be abandoned|
|Seladelpar||Cymabay||PPAR delta agonist||NCT03551522||Fails to reduce liver fat in phase II trial; 52 week data due Q2'20|
|Gemcabene||Gemphire||PPAR alpha agonist||NCT03508687||Phase IIa top-line results due Q3'19|
|NGM282||NGM||FGF19 analogue||NCT02443116||Phase IIa data due H2'19; phase IIb started in April 2019|
|Selonsertib, firsocostat, cilofexor||Gilead||Ask1 inhibitor, ACC inhibitor, FXR agonist||NCT03449446||Phase II Atlas trial to report H2'19|
|MSDC-0602K||Cirius||mTOT modulator (2nd gen TZD)||NCT02784444||Phase IIb Emminence trial due to report H2'19|
|EDP-305||Enanta||FXR agonist||NCT03421431||Phase IIa Argon-1 trial due to report Q3'19|
|Lanifibranor||Inventiva||Pan-PPAR agonist||NCT03008070||Phase IIb Native trial due to report H1'20|
|LJN452 (tropifexor)||Novartis||FXR agonist||NCT02855164||Phase IIb Flight trial to report in 2020|
|Source: EvaluatePharma, analyst notes & company statements.|
The FXR agonist class is of course led by Nash's most advanced project, Intercept’s Ocaliva, which is due to be filed with regulators in the coming months. It remains to be seen whether similar agents like Enanta’s EDP-305 and Novartis’s tropifexor can improve on Ocaliva’s dubious efficacy and tolerability profile – as well as being associated with a worrying hike in LDL cholesterol levels, the drug caused more than half of patients to experience serious itching (EASL 2019 – Intercept and medics clash in Nash, April 12, 2019).
Enanta is slated to unveil data from a 125-patient phase II study any day now, though results from Novartis’s much more expansive programme are unlikely to emerge until next year.
Other approaches due to receive scrutiny this year include NGM’s FGF19 analogue NGM 282. This company has already pushed into a larger phase IIb trial, so investors will be keen to see the latest cut of the data.
Meanwhile an update is also due from Cirius Therapeutics on its mTOT modulator MSDC-0602K; encouraging data from the large Emminence trial should see the company heading to the public markets (EASL 2019 – Having filed to float, all Cirius needs now is the data, April 12, 2019).
Cirius has everything riding on MSDC-0602K, though this can be said of several of the Nash players. Conatus is unlikely to be the only casualty of this race.