Ionis's third shot at the Nash target goes astray

After two other liver disease projects fade into the background Ionis delays the antisense asset AKCEA-ANGPTL3-LRx by a year.

As 2019 has been billed as the year of Nash the antisense specialist Ionis will have been keeping a close eye on recent competitor developments. It has three pipeline projects targeting this apparently common but often asymptomatic and largely undiagnosed liver disease.

However, the company has gone quiet about all but one of these, AKCEA-ANGPTL3-LRx, which is designed to reduce angiopoietin-like 3 protein. And that project, being developed by Ionis’s wholly owned subsidiary Akcea, has just been delayed by a year, it emerged yesterday.

AKCEA-ANGPTL3-LRx is in a phase II study that had been due to yield results imminently. But on Akcea’s fourth-quarter analyst call yesterday management said the trial would now not deliver data until the first half of 2020. Ionis reported its 2018 financials today.


If the unequivocal failure of Gilead’s selonsertib, and highly equivocal success of Intercept’s Ocaliva, have made Ionis nervous this is understandable.

It might even be that doubts about the promise of Nash lie behind recent reticence over its two other Nash assets. IONIS-AZ6-2.5-LRx (AZD2693) was licensed to Astrazeneca in April, but does not appear in Astra’s R&D pipeline, though this might just be because it is still in preclinical trials; in November IONIS-DGAT2Rx completed a phase II trial in type 2 diabetics, but no data have been released.

Thus the focus rested on AKCEA-ANGPTL3-LRx, whose phase II trial recruited 144 subjects and tested three doses versus placebo. The study has already been delayed once, having initially been expected to read out last year.

At its third-quarter financials call Ionis explained the rationale for AKCEA-ANGPTL3-LRx and IONIS-DGAT2Rx, whose development was at the time ongoing in parallel, saying in general the company was targeting Nash’s lipid and/or fibrotic components.

Ionis says elevated levels of angiopoietin-like 3 protein (ANGPTL3) are associated with an increased risk of premature heart attacks, increased arterial wall thickness and multiple metabolic disorders. As such the group describes AKCEA-ANGPTL3-LRx as a “general dyslipidaemia agent” that might be used to treat Nash among several possible diseases.

Meanwhile, IONIS-DGAT2Rx is “a very selective and specific liver triglyceride drug” being developed to treat Nash. The basis for this is that DGAT2 (diacylglycerol acyltransferase 2) catalyses the final step in triglyceride synthesis in the liver, and its inhibition improved liver steatosis in animal models of obesity and fatty liver disease.

Ionis assets with a possible role in treating Nash
Project Target Status Trial ID
AKCEA-ANGPTL3-LRx ANGPTL3 Phase II readout delayed from Feb 2019 to H1 2020 NCT03371355
IONIS-DGAT2Rx  DGAT2 No data since phase II completed Nov 2018 NCT03334214
IONIS-AZ6-2.5-LRx Undisclosed No mention since licensed to Astrazeneca Apr 2018 None
Source: company presentations &

It will not go unnoticed that the AKCEA-ANGPTL3-LRx phase II trial does not test the project specifically in Nash. It enrolled subjects with elevated triglycerides, type 2 diabetes or non-alcoholic fatty liver disease – a loose description for conditions like Nash that involve excessive fat storage in the liver.

Its primary endpoint measures change in fasting triglyceride levels from baseline for three doses versus placebo at six months; it is not clear what the statistical analysis plan is, but the three doses will be compared individually as well as being pooled.

Those investors fixated on the project’s potential in Nash will pay particular attention to one secondary endpoint: the effect of AKCEA-ANGPTL3-LRx on changes in liver fat at six months. It is not clear at this point, however, whether these data will be split out when the trial’s results are toplined.

For any asset to be viable commercially in Nash it should improve liver fibrosis with no Nash worsening and an acceptable safety profile, but 2019’s first two big Nash readouts, for Gilead’s selonsertib and Intercept’s Ocaliva, have shown how unattainable this goal still is (Intercept's Nash hopes rest on Ocaliva's borderline hit, February 19, 2019).

It probably makes sense for Ionis to keep its options open. With pivotal data still expected this year from Allergan’s cenicriviroc and Genfit’s elafibranor a lot more about Nash will be known by the time the AKCEA-ANGPTL3-LRx trial reads out at last.

This is an updated version of an earlier story

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