ACC 2023 – Merck’s oral cholesterol lowerer shows mid-stage promise

The oral PCSK9 project MK-0616 meets its targets in phase 2, which could be bad news for Novartis.

Merck & Co’s cardiovascular franchise is coming into focus as the group looks for new growth drivers to replace its aging megablockbuster Keytruda. And two pillars of its heart push scored today at the American College of Cardiology meeting.

One of these projects, the oral PCSK9 inhibitor MK-0616, puts this drug class back on the agenda after previous commercial disappointments. Today, a phase 2 study met expectations and the group is quickly pushing into phase 3 with both a lipid-lowering and cardiovascular outcomes trial slated to start this year.

This could be bad news for Novartis, which paid $10bn for the Medicines Company and its long-acting therapy Leqvio, but has seen sales underwhelm so far. The Swiss group recently played down the threat from Merck’s oral rival, but the risk of impending competition could give investors jitters, particularly with the readout of Leqvio’s cardiovascular outcomes study delayed from 2024 to 2026.

Analysts are currently pencilling in a 2026 launch for MK-0616, although outcome data are likely to emerge later. 

PCSK9 promise

Three injectable PCSK9 inhibitors are approved: Amgen’s Repatha, Sanofi and Regeneron’s Praluent, and the aforementioned Leqvio. The first two products are given once monthly or every two weeks, while Leqvio is administered twice yearly.

Hopes were once high for this class of drugs, but they have not lived up to expectations, with the route of administration thought to be a factor – although high price tags also did not help.

Merck hopes to revive the space with MK-0616. As Joerg Koglin, vice-president of global clinical development, puts it: “Can we come up with a risk/benefit profile that compares very well to injectables and then have the advantage of an oral that is much more accessible and might reach a broader patient population?”

In the phase 2 dose-ranging trial, presented at ACC today and simultaneously published in the Journal of the American College of Cardiology, Merck achieved this goal. MK-0616 was dosed at 6, 12, 18 or 30mg per day, and the primary efficacy endpoint was LDL cholesterol lowering at week eight. Before the readout, Mizuho analysts had set a target of a 40-60% reduction from baseline.

Handily, MK-0616-treated patients showed placebo-adjusted LDL-C lowering of 41.2-60.9%, with a dose response. This is in line with the other PCSK9s, and not far off the roughly 65% LDL-C lowering in phase 1 that first triggered excitement around this project.

LDL lowering with PCSK9-targeting therapies
Product/project Company Description Study LDL lowering
MK-0616 Merck & Co Oral PCSK9 Ph2 6mg: 41%
12mg: 56%
18mg: 59%
30mg: 61%
Praluent Sanofi/Regeneron SC PCSK9 MAb Odyssey Long Term  58%
Repatha Amgen SC PCSK9 MAb Descartes 55%
Leqvio (inclisiran) Novartis SC PCSK9 RNAi therapy Orion-10 & 11 51-52%
All data placebo adjusted; Repatha, Praluent & Leqvio + background statins, MK-0616 + range of statin therapy (~60% of pts on statins); SC=subcutaneous; Source: product labels & ACC.

Just as important will be MK-0616’s tolerability profile. Here, Mizuho was looking for a treatment-related discontinuation rate of under 3%. Again, the study achieved this, with 2% of MK-0616-treated patients discontinuing due to adverse events, versus 1% in the placebo group.

While there were more serious adverse events with MK-0616 – eight across the dose groups, compared with none in the placebo group – none of those were deemed drug-related, according to Merck's Koglin.

The most common adverse event was Covid-19; the next most common were diarrhoea and dyspepsia, but Koglin says these gastrointestinal events were all mild and did not lead to discontinuations. He concedes that GI side effects will be closely watched in phase 3.

Merck plans to take MK-0616 into pivotal development in the second half of this year, with a cholesterol-lowering trial – which will support a filing if all goes well – starting around the same time as a cardiovascular outcomes trial.

Koglin says the outcomes trial could include primary as well as secondary prevention patients, but that this is something that will have to be ironed out with regulators. It is notable that Repatha and Praluent’s outcomes studies only enrolled a secondary prevention population.

If the project succeeds, Berenberg analysts reckon it could sell $5bn at peak – bullish considering the entire PCSK9 class brought in around $2bn last year. Price will be an important factor, but Merck is yet to disclose any plans here.

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