Welcome to your weekly digest of approaching clinical readouts. Two mid-stage Nash projects, one from NGM Biopharmaceuticals and one from Enanta Pharmaceuticals, are due to yield data in the third quarter. This should help investors judge whether these companies are serious contenders in the closely-watched Nash space.
First to NGM, which is developing an FGF19 analogue called NGM282. FGF19 is a cell signalling protein involved in lipid metabolism and bile and glucose regulation; the company believes that NGM282 could reverse fibrosis and reduce liver fat, inflammation and hepatocellular ballooning, which is a form of liver cell death typically seen in patients with steatohepatitis.
The company has conducted a broad phase II study to test this hypothesis, and it is the fourth and final cohort of the trial that is due to report soon. Earlier data pointed to dramatic reductions in liver fat and NGM282 seemed to have an impact on fibrosis, although patients also recorded gastrointestinal problems and hikes in LDL cholesterol levels.
As a result, the final cohort tests the lower 1mg dose in conjunction with statins, where necessary; liver fat reduction and fibrosis improvement are the key endpoints, which will be measured over 24 weeks.
In previous cohorts the 1mg dose produced an improvement in fibrosis by at least one stage in 25% of patients over 12 weeks; F1 is the first stage of fibrosis, while a patient with cirrhosis is scored F4. Liver fat content was reduced by 57%, as measured by MRI-PDFF.
Analysts at Stifel wrote recently that to be considered a win, this final cohort needs to show at least a 30% reduction in liver fat, while more than 10% of patients must show at least a one-stage improvement in fibrosis, both on a placebo-adjusted basis.
A strong showing would raise hopes for NGM’s recently initiated phase IIb Alpine study, of NGM282 in patients with confirmed Nash and F2 or F3 fibrosis, though this is not due to report until next year. And as the only clinical-stage FGF19 in development for Nash, a win could prompt others to jump in on this approach.
Backers of NGM’s April IPO will also be hoping for a positive readout. After floating at $16 a share, the stock is currently trading at $14.39.
|Clinical trial IDs|
|Phase II Nash||NCT02443116|
|Phase II Nash||NCT03421431|
Enanta meanwhile will be hoping that EDP-305 can deliver a second pipeline hit for its R&D efforts. A separate candidate, the RSV project EDP-938, successfully completed a phase IIa trial in June, although a subsequent slump in the company’s share price suggests that investors were either underwhelmed by the data or alarmed by the prospect of further studies.
RSV is a high-risk space, although of course the same can be said of Nash, which has delivered more blow ups than success stories so far. As such, Enanta will have to deliver unequivocal evidence of EDP-305’s utility to convince seemingly sceptical shareholders.
The project is a FXR agonist, the same class as Intercept’s Ocaliva; however, the two agents are structurally different, according to Enanta. A key aspect is that Ocaliva is a bile acid derivative while EDP-305 is not. The company claims that its agent can bind more tightly to FXR, producing greater potency and avoiding the itching side effect that has blighted the Intercept product.
A phase II trial called Argon-1 has recruited around 125 patients and is testing two doses of EDP-305 against placebo. Change in ALT at week 12 is the primary efficacy endpoint; this is a measure of liver inflammation and a signal of Nash activity.
Clinical trials of Ocaliva showed 25-30% declines in ALT at 12 weeks, so beating this would suggest improved potency for EDP-305, analysts believe. Patients’ LDL cholesterol levels are also something to watch; this could well be a sticking point for Ocaliva as it goes in front of regulators for Nash later this year.
With several rival FXR agonists in development – Novartis, Metacrine and Allergan also have clinical stage assets – Enanta theoretically does not have just Intercept to beat here. In fact, the company has already professed a plan to work on “follow-on” FXR agents, which could well be an admission that EDP-305 is unlikely to emerge as best in class.