
PCSK9 pipeline shows signs of saturation
Astrazeneca and Ionis’s discontinuation could herald a nervous time for others in this space.

Astrazeneca’s decision last week to can its Ionis-partnered once-monthly PCSK9 inhibitor, ION449, was probably a sensible business move. The project, despite looking competitive on cholesterol lowering, might have had a hard time fitting into a market that already has an even longer-acting option, Novartis’s Leqvio.
A look at the remaining anti-PCSK9 pipeline shows a fair amount of activity, raising the question of whether Astra’s move should ring alarm bells for other players with next-gen contenders.
Still, many of the projects in development represent a different proposition entirely. The pipeline is generally split between daily oral options and gene-editing approaches that promise a “once-and-done” treatment.
Selected PCSK9-targeting projects in development | |||
---|---|---|---|
Project | Company | Description | Trial details |
Phase 2 | |||
ION449 (AZD8233) | Astrazeneca/Ionis | SC once-monthly antisense | Will not progress to ph3 for hypercholesterolaemia following ph2 Solano data |
MK-0616 | Merck & Co | Once-daily oral | NCT05261126 completes Nov 2022 |
NN6435 | Novo Nordisk | Oral | Ph2 completes H2 2022 |
Phase 1 | |||
AZD0780 | Astrazeneca | Oral | NCT05384262 completes Jun 2023 |
VERVE-101 | Verve Therapeutics | One-off in vivo gene editing | NCT05398029 enrolling in New Zealand & imminently UK, first data due 2023 |
Preclinical | |||
VXX-401 | Vaxxinity | "Long-acting" synthetic peptide vaccine | Ph1 slated for early 2023 |
PBGENE-PCSK9 | Precision Biosciences/Iecure | One-off in vivo gene editing | Iecure responsible for IND-enabling studies, not yet completed |
CTX330 | Crispr Therapeutics | One-off in vivo gene editing | |
STP135G | Sirnaomics | SC RNAi | |
Source: Evaluate Pharma & clinicaltrials.gov. |
ION449 might have found itself caught in the worst of both worlds, being neither convenient nor long-acting enough to compete.
If oral PCSK9 inhibitors and, further down the line, gene-editing therapies make it to market, it will be interesting to see if they have greater commercial success than the currently approved monoclonal antibodies, Repatha and Praluent. These agents are injected subcutaneously monthly or every two weeks. The jury is still out on Leqvio, which was only approved in the US late last year and is given via twice-yearly subcutaneous injection.
Oral vs gene editing
Among the oral players, Merck & Co looks to be most advanced with MK-0616, which yielded promising phase 1 data last year and is in a phase 2 trial set to complete next month.
Novo Nordisk also has an oral asset in mid-stage development, according to its most recent earnings presentation. And, interestingly, Astra still has a shot in PCSK9 inhibition with an oral candidate that it took into the clinic earlier this year.
Still, oral therapies in general, although more convenient than injections, are plagued by issues with compliance – something the likes of Verve Therapeutics and Precision Biosciences are banking on with their one-off in vivo gene editing approaches.
It is unclear how regulators will see these projects given outstanding questions about gene editing, including theoretical cancer risks. This is particularly pertinent in the field of PCSK9 inhibition – the FDA has shown it can be lenient with genetic medicines when there are no other options, but the risk/benefit equation might be different when therapies with the same mechanism are already available.
It is notable that Verve’s ongoing phase 1 trial has so far only recruited patients in New Zealand, although the group last week got the nod to begin enrolling UK subjects. US IND clearance has so far been conspicuous by its absence, with other in vivo gene editing players like Intellia also yet to treat US trial patients.
This has raised concerns among investors that the US regulator might need more reassurance before allowing clinical trials to begin, potentially causing delays. This was played down by Verve’s chief executive, Sekar Kathiresan, in a recent interview with Evaluate Vantage; he expects US trial clearance for VERVE-101 in the second half of this year.
Meanwhile, Precision appears to have had a delay with PBGENE-PCSK9: that group’s partner, Iecure, is responsible for preclinical and phase 1 development, but Precision recently said IND-enabling studies had not been completed, with no update on when they might be. The company had previously guided that an EU clinical trial application could happen as early as the year end.
The table in this story has been updated to include more information on Novo's NN6435.