ADA - Knockdown result boosts Isis and antisense alike

Positive data from a tiny phase II study of Isis Pharmaceuticals’ ISIS-APOCIIIRx have not only resulted in a partnering opportunity, they have also given antisense another boost and validated ApoC-III as a target for lowering triglycerides.

The result lifted Isis’s stock by 29% yesterday, equating to a remarkable 172% rise year to date and valuing the antisense specialist at $2.9bn. Much remains to be proved; the project’s side-effect profile will be closely watched, and a bigger phase II trial reading out later this summer will indicate its true market potential.

Most exciting

Isis’s chief executive, Stan Crooke, said on a call that ISIS-APOCIIIRx was the “single drug about which I’m most excited” – a remarkable statement given a portfolio that comprises numerous more advanced projects and is capped by the marketed drug Kynamro.

After a long and tortured adolescence antisense finally came of age in January with Kynamro's approval for homozygous familial hypercholesterolaemia, and big pharma has also bought in, with GlaxoSmithKline, Biogen Idec, Pfizer and Roche featuring among Isis’s partners (Isis hooks another partner as big pharma looks for sense in antisense, April 10, 2013).

The first phase II data with ISIS-APOCIIIRx, presented at the American Diabetes Association meeting, lend further support. ISIS-APOCIIIRx involves the knockdown of the gene coding for ApoC-III, a glycoprotein that inhibits lipase and thus prevents clearance of triglycerides from the blood.

The results show its impressive profile, neatly fitting the mechanistic thesis that reducing ApoC-III restores lipase activity, resulting in increased levels of HDL (ie, “good”) cholesterol. It then takes only a short step to suggest that the resulting increased reverse cholesterol transport can reduce atherosclerosis.

The phase II study had sought to recruit 27 diabetic patients with moderately elevated triglycerides and type 2 diabetes, though in the event only 11 were recruited. The results showed an 88% reduction in ApoC-III versus placebo – the primary endpoint – 72% reduction in triglycerides and 40% increase in HDL cholesterol.

The company was enthusiastic that every lipid measure was “going in the right direction for reduced cardiovascular risk”. ApoC-III and triglycerides are validated risk factors for cardiovascular disease, and an earlier phase I study in 32 volunteers had shown a shorter course of ISIS-APOCIIIRx to cut triglycerides by 43-44%.

In comparison, current treatments – niacin, fibrates and fish oils like Lovaza – reduce triglycerides by up to 50% but tend to increase non-HDL cholesterol. ISIS-APOCIIIRx also showed consistent numerical improvements in insulin sensitivity, a secondary endpoint, and this could differentiate its profile.


However, subcutaneous delivery will work against it given that the competitors are dosed orally; injection site reactions are a major drawback with Kynamro, and while ISIS-APOCIIIRx showed good tolerability and very mild site reactions this was after all a very small study.

Which is why the second phase II trial is so important. This tests ISIS-APOCIIIRx in patients with severely high triglyceride levels – a large market with limited treatment options – and is due to yield results in two stages this summer, first relating to patients on stable-dose fibrates and then those not on any triglyceride-lowering therapy.

Meanwhile, Isis is wasting no time in planning for pivotal trials, hoping to move into phase III in early 2014. Clearly, an FDA requirement for a large cardiovascular outcomes study represents a huge risk, but Isis says this is unlikely given the severity of the indication sought.

The company insists that it wants to fund phase III on its own before seeking a licensee, although if the second phase II trial mirrors the results of the first partners could come knocking on its door early.

Having completed a $183m public stock offering in May Isis will be certain to drive a hard bargain.

Study Trial ID
Phase II study in 24 type 2 diabetic patients NCT01647308
Phase II study in 102 patients with severe or uncontrolled hypertriglyceridaemia NCT01529424

To contact the writer of this story email Jacob Plieth in London at or follow @JacobEPVantage on Twitter

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