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In June 2025, Eli Lilly announced it would acquire Verve Therapeutics in a deal valued at up to $1.3 billion, centered on a one-time gene-editing therapy, VERVE-102, aimed at permanently silencing the PCSK9 gene in liver cells, a dramatic change from lifelong cholesterol-management pills and injections to a potential single-dose cure.
That bold bet comes on the heels of a very different milestone: in 2023, the Supreme Court of the United States unanimously ruled against Amgen in Amgen Inc. v. Sanofi, invalidating its broad patents over PCSK9-targeting antibodies for lack of enablement, underscoring that while PCSK9 remains among the most coveted cardiovascular targets, the winning modalities are no longer just monoclonal antibodies.
Together, these two billion-dollar moments frame the next chapter in PCSK9 therapies: once the domain of injectable antibodies, the target is now being contested by RNA-silencers, oral inhibitors, vaccines, and even permanent gene-edits. Let’s take a look at what is coming along around the PCSK9 target.
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What does PCSK9 do?
PCSK9, short for proprotein convertase subtilisin/kexin type 9, plays a central role in regulating cholesterol levels. The protein binds to LDL receptors on liver cells and directs them for degradation instead of allowing them to recycle to the cell surface. With fewer receptors available to clear LDL cholesterol from the bloodstream, LDL-C levels rise.
The biology was compelling long before the first drugs existed. People with genetic variants that increase PCSK9 activity tend to have very high cholesterol and a greater risk of coronary heart disease, while those with loss-of-function mutations have strikingly low LDL-C levels and a remarkable degree of protection. That simple genetic story provided one of the clearest examples in modern medicine of a target whose inhibition should translate directly into fewer heart attacks.
The hypothesis was confirmed clinically in two landmark studies. In FOURIER, patients with cardiovascular disease who received evolocumab on top of statins saw LDL-C fall by roughly 60% compared to placebo and had a 20% reduction in major cardiovascular events over a median follow-up of just over two years. Around the same time, ODYSSEY OUTCOMES tested alirocumab in patients recovering from acute coronary syndromes and found similar LDL-C reductions alongside meaningful drops in cardiovascular risk, even hinting at lower all-cause mortality.
The first generation of monoclonal antibodies, evolocumab and alirocumab, proved that PCSK9 inhibition works and lowers LDL-C. But their success also came with limitations: high production costs, cold-chain logistics, and the need for regular injections. With biology and efficacy settled, the field’s focus began to shift toward the next question: how to make PCSK9 inhibition simpler, long-lasting, and more accessible.
The evolving toolkit for targeting PCSK9
The first genuine shift beyond antibodies came from RNA interference. Novartis’ inclisiran reduces hepatic PCSK9 production by cleaving its mRNA in hepatocytes and, after an initial loading dose, settles into a twice-yearly maintenance rhythm. In routine and trial settings, it reliably drives substantial LDL-C reductions, and recent randomized studies reinforced that, even as a monotherapy, it outperforms ezetimibe across six months with a clean safety profile.
The open question is outcomes: large event-driven trials like ORION-4 and VICTORION-2 PREVENT are designed to answer whether two injections a year translate into fewer heart attacks and strokes; until those readouts, most guidelines see inclisiran as an adherence-friendly LDL-lowering tool awaiting definitive hard-outcome confirmation.
Hot on RNA’s heels is the push to make PCSK9 inhibition as easy as taking a pill. Merck’s enlicitide (MK-0616), a macrocyclic oral PCSK9 binder, delivered a clean sweep of LDL-lowering in multiple phase 3 studies in 2025, with an outcomes trial program underway. If efficacy holds up alongside tolerability and payer-friendly pricing, an oral PCSK9 could expand use far beyond patients willing to inject or attend clinic visits.
AstraZeneca’s AZD0780 also posted phase 2b data showing robust, dose-dependent LDL-C reductions and has been highlighted for a potentially simpler use profile compared with some peptide-based orals. Together, these oral agents are poised to test whether convenience can finally unlock PCSK9 therapy at population scale.
A more speculative avenue is vaccination against PCSK9. The concept is straightforward: train the immune system to generate anti-PCSK9 antibodies that persist, ideally cutting LDL-C for months or years after a single course. Early programs like AT04A and VXX-401 provide the contours of what might be possible: sustained antibody responses and LDL-lowering signals in preclinical models and non-human primates, with modest human signals so far for AT04A and ongoing optimization of vaccine platforms and carriers. The promise is long-interval dosing at low cost, but translation to consistent, durable LDL-C lowering in large patient populations remains to be proven.
And then there’s the moonshot: in vivo base editing for a one-and-done effect. VERVE-102 is designed to install a precise edit in hepatocytes that permanently turns off PCSK9, aiming at lifelong LDL-C reduction after a single treatment. The program received U.S. Food and Drug Administration (FDA) Fast Track in 2025, moved through phase 1b testing in high-risk cohorts, and became the centerpiece of Eli Lilly’s up-to-$1.3 billion acquisition of Verve. The scientific and regulatory bar will be high: long-term follow-up, careful off-target characterization. But if it works, gene editing could compress decades of adherence into a single visit.
What comes next for PCSK9 therapies
After nearly two decades of progress, the science of PCSK9 inhibition is no longer in question. The focus has shifted to proving which of the emerging technologies can deliver lasting, real-world benefits.
Across the field, the next few years will bring pivotal tests: the first outcome readouts for RNA-based approaches, longer-term safety and durability data for oral inhibitors, and early clinical validation for gene-editing candidates. Each will help answer the same question from a different angle, whether LDL-C lowering through PCSK9 translates into sustained cardiovascular protection, and at what cost in complexity, safety oversight, or price.
These results will also define how new PCSK9 therapies fit into practice. Twice-yearly injections or one-off edits may solve adherence, but they must earn the confidence of regulators and payers wary of cost and permanence. Oral molecules, on the other hand, could scale rapidly if they maintain efficacy.
More than any other target, PCSK9 now reflects the diversity of modern biotechnology. What began as an antibody success story has evolved into an experiment in therapeutic innovation: testing how RNA, vaccines, and base editing each handle the same biological challenge.
If the first wave of PCSK9 drugs proved that the target works, the next wave will determine which approach can make it enduring, accessible, and economically viable. That, more than mechanism or novelty, will decide who truly wins the PCSK9 race.
