In light of Fourier data, what future for Alnylam and TMC's PCSK9 inclisiran?

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Inclisiran can dramatically lower blood cholesterol with dosing as little as twice a year.

Alnylam and The Medicine Company's PCSK9 inhibitor inclisiran can dramatically lower blood cholesterol with dosing as little as twice a year, according to new phase 2 data. That profile could make it a staunch competitor to Amgen and Sanofi/Regeneron's already marketed drugs—but could it be chasing a share of a small market?

Not necessarily, say analysts, who reckon TMC and Alnylam can learn from experiences with the established drugs for their phase 3 program, which is due to start mid-year, and set themselves up for success.

One of the problems facing Amgen's Repatha and Sanofi/Regeneron's Praluent is that their high price relative to widely used statin drugs has resulted in significant barriers to access, with new data from Amgen suggesting 80% of prescription claims for PCSK9 inhibitors are initially rejected.

Added to that, another study has found that more than a third of patients don't stick to treatment with the current drugs, which are given at least once a month. The result? Sales of Repatha came in at $141 million last year and Praluent made around $112 million, well shy of initial expectations.

Amgen and Sanofi/Regeneron have been hoping that new data showing that reductions in LDL cholesterol (LDL-c) are mirrored by significant reductions in the cardiovascular complications of high cholesterol will drive uptake, and Amgen reported the results of its outcomes trial—Fourier—at the American College of Cardiology (ACC) meeting over the weekend.

That showed a significant benefit, but was not sufficient to be called a home run and, according to Leerink analysts, puts a question mark over the PCSK9 inhibitor category. The results dragged down Amgen's shares and also those of other PCSK9 inhibitor developers, including TMC and Alnylam although the latter two have now bounced back.

"Investors have grown more cautious on the PCSK9 space following the less-than-stellar Fourier data from Amgen," said the analysts in a research note. "However, we believe the negative sentiment encompassing … inclisiran appears excessive and ignores important signals that lie beneath Fourier's headline results which [TMC and Alnylam] can leverage."

The ORION-1 trial presented at ACC looked at the effects on LDL-c of one or two injections of inclisiran at three doses (200 mg, 300 mg and 500 mg) compared to placebo over more than six months, and updated previous results reported last year.

The best dose turned out to be 300 mg given three months apart, which cut LDL-c by around 45% at nine months, and there have been no additional concerns about safety after the fatal heart attack in one patient reported last year. The results have also been published in the New England Journal of Medicine.

Leerink says Fourier showed a clear link between LDL-c reduction and cardiovascular outcomes such as heart attack and ischemic stroke, and a correlation between the length of treatment and clinical benefit. That could help TMC design its upcoming outcomes trial (ORION-4) with the best chance of success and also cut costs, it says.

Fourier—as well as the SPIRE-2 trial of Pfizer's now-defunct PCSK9 inhibitor candidate bococizumab—have "laid the groundwork like a typical phase 2 trial would; issues raised/identified (e.g. dose(s), endpoint(s), and trial duration) are expected to increase the probability of delivering a more robust outcomes data in support of inclisiran," write the analysts.

Analysts at Jefferies also think TMC's management can draw on those datasets for the design of ORION-4, which they suggest would likely involve 10-14,000 patients, have a two-year-plus follow-up and could—potentially—show a 30% reduction in cardiovascular events.

The trial could take up to four years to complete, so Repatha and Praluent, which has an outcomes study due to report data later this year, will have plenty of time to try to consolidate their lead. However, if ORION-4 generates solid outcomes data and inclisiran's more favorable dosing can help tackle the compliance issue, TMC and Alnylam could be well placed to capture a slice of the market.