Novartis AG’s (NYSE:NVS) Phase 3 Lp(a)HORIZON setback carries implications beyond the Swiss drugmaker. Pelacarsen significantly lowered lipoprotein(a), or Lp(a), but failed to produce a statistically significant reduction in major cardiovascular events, according to the information provided.
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That disconnect matters for companies developing other Lp(a)-lowering treatments. Citi believes it could influence CRISPR Therapeutics’ (NASDAQ:CRSP) choice between two gene-editing candidates, while the bank sees limited immediate damage to Ionis Pharmaceuticals (NASDAQ:IONS), which originally developed pelacarsen.
Bull Case
For CRISPR Therapeutics, the result may encourage greater emphasis on CTX321, its next-generation Lp(a) program. Citi believes the unsuccessful HORIZON outcome increases the likelihood that CRISPR prioritizes CTX321 over its earlier candidate, CTX320. The company has already described CTX321 as using an updated guide RNA that demonstrated approximately twice the potency of CTX320 in preclinical testing. It uses the same lipid-nanoparticle delivery system and is undergoing studies needed to support regulatory applications for clinical testing. CRISPR expects to provide an update on the program in 2026.
CTX320 has generated Lp(a) reductions of as much as 73% during dose escalation, according to CRISPR. However, the pelacarsen outcome underscores why the ability to lower a biomarker may not be enough. Advancing the more potent candidate could give CRISPR a better opportunity to demonstrate a clinically meaningful effect, although that remains unproven. Citi retains a Buy rating and an $88 price target on CRISPR shares. That position suggests the firm continues to see value in the company’s broader pipeline and gene-editing platform despite the additional uncertainty surrounding Lp(a).
Citi is also relatively constructive on Ionis. Analyst Eric Joseph expects less than 5% of immediate downside from the HORIZON result because investor expectations for pelacarsen were already modest. Following a check-in with management, the firm said it does not expect the result to affect Ionis’ fiscal 2026 guidance. Citi characterized the readout primarily as a clearing event that could support more constructive positioning once uncertainty surrounding the trial is removed. It maintained a Buy rating and a $100 price target on Ionis.
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Bear Case
The principal concern is broader than the failure of one drug. Pelacarsen was designed to inhibit the liver’s production of apolipoprotein(a), thereby reducing circulating Lp(a). The large cardiovascular-outcomes study was intended to determine whether that reduction translated into fewer cardiovascular events. Its failure to meet that endpoint raises questions about how much Lp(a) must be lowered, how long patients must be treated, and whether different therapeutic approaches can deliver better clinical outcomes. CTX321’s greater preclinical potency does not establish that it will prevent heart attacks or other cardiovascular events in humans.
CRISPR also has not formally announced that it will abandon CTX320 or make CTX321 its sole priority. Citi’s conclusion concerns an increased probability, not a disclosed development decision. Moreover, CTX321 remains earlier in development, leaving substantial clinical, regulatory, and execution risk.
For Ionis, limited near-term share-price downside would not make the trial failure inconsequential. Pelacarsen was discovered by Ionis and licensed to Novartis in 2019 for worldwide development and commercialization. The disappointing outcome therefore removes momentum from an important partnered program and weakens a potential validation of Ionis’ antisense technology in Lp(a)-driven cardiovascular disease.
Conclusion
HORIZON’s failure is a warning that lowering Lp(a) and improving cardiovascular outcomes are not interchangeable achievements. Citi nevertheless sees different paths forward, which include a possible shift toward the more potent CTX321 at CRISPR and limited immediate financial fallout for Ionis.
That makes the readout less of a definitive judgment on either company than a reset of expectations. The next decisive evidence must show not merely that experimental therapies lower Lp(a), but that doing so produces meaningful benefits for patients.
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This article is originally published at Insider Monkey.
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