Alnylam failure puts RNAi under the spotlight again

Alnylam is adamant that the discontinuation of its lead RNA interference candidate, revusiran, will not hit the rest of its pipeline. But after a safety signal in a phase III study the RNAi approach now looks set to come under the spotlight – for all the wrong reasons.

The company will need to show that its second-generation technology is not associated with the same issues, with phase III results on its follow-up patisiran due next year. Its decision will also have a knock-on effect on The Medicines Company, which is using Alnylam’s RNAi technology in its PCSK9si.

In the meantime, Alnylam’s shares are set for a rocky ride, and the stock was down 46% in early trading today. The Medicines Company was also hit hard, with its shares falling 11%.

Unfortunate timing

For the latter group it was a case of unfortunate timing, since it came out with a safety update on PCSK9si (ALN-PCSsc), its own RNAi project for elevated cholesterol, almost simultaneously to the Alnylam announcement.

The New Jersey-based group said its independent data-monitoring committee reported a 90-day safety review for all 501 patients in the Orion-1 trial and found no signs of drug-related neuropathy, elevation of liver enzymes or changes in renal function.

But the news on revusiran has cast a shadow over it because PCSK9si was licensed from Alnylam; the project shuts down PCSK9 synthesis in the liver, rather than binding to PCSK9 in the bloodstream as do Sanofi and Regeneron’s Praluent, and Amgen’s Repatha.

Alynylam discontinued development of revusiran in hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM) after a number of deaths in the phase III Endeavour trial.

It would not give more details on a conference call, except to say there had been 18 deaths out of 206 patients overall, with a higher number in those receiving revusiran versus placebo. Its chief medical officer, Akshay Vaishnaw, added that there was no explanation for the safety finding.

The increased mortality rate was uncovered in the first place when Endeavour was unblinded to investigate reports of peripheral neuropathy in a phase II open-label extension trial.

Meanwhile, The Medicines Company expects to present the interim analysis at the American Heart Association meeting in New Orleans in November, as well as full 180-day data on 200 patients. Given the Alnylam news and the number of patients that could be prescribed with a cholesterol-lowering medication, adverse events data will be closely examined for any signal.


While revusiran is now headed for the scrap heap, the potential of Alnylam’s other lead asset, patisiran, could also be thrown into doubt.

This is because revusiran and patisiran are closely related molecules and, though they are strictly speaking not identical, they do target some overlapping RNA sequences. Patisiran is in the phase III Apollo study in transthyretin (TTR)-mediated amyloidosis, with topline results due in mid-2017.

Alnylam also believes that patisiran and the rest of its pipeline might avoid the mortality issue that has hit revusiran because these next-generation products use different delivery technologies that allow a lower dose.

The amyloidosis pipeline has already been hit with the loss of Ionis Pharmaceutical’s IONIS-TTRRx – an antisense project – in May and Bellus Health’s Kiacta in June (Therapy focus – Amyloidosis pipeline still looks to Alnylam for answers, June 23, 2016).

Another failure here would spell one more setback to the amyloidosis pipeline and the RNAi approach alike.

Project Study Trial ID
Revusiran Endeavour NCT02319005
Patisiran Apollo NCT01960348

An EP Vantage staff report. To contact the writers of this story email or follow @EPVantage on Twitter

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