Novartis pelacarsen trial misses primary endpoint in Lp(a) study

Novartis' Phase 3 HORIZON outcomes trial of pelacarsen, an antisense oligonucleotide targeting elevated lipoprotein(a), has failed to meet its primary endpoint in patients with atherosclerotic cardiovascular disease. The trial assessed whether pelacarsen could reduce a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularisation requiring hospitalisation, compared with placebo. Novartis has said it will present the full dataset at an upcoming medical congress.

The result lands a significant blow to the Lp(a)-lowering field. Lipoprotein(a) has attracted sustained drug development interest over the past decade, with a number of companies pursuing antisense, small-molecule, and gene-silencing approaches on the premise that elevated Lp(a) is a causal risk factor for atherosclerotic events. A large outcomes failure from a well-funded, late-stage programme will prompt reassessment of the evidence base, at least for the antisense modality, and may affect investor appetite for rival programmes earlier in development.

Financial read-across for Royalty Pharma

Royalty Pharma, which holds a royalty interest in pelacarsen through a January 2023 funding agreement with Ionis Pharmaceuticals, said the trial failure was anticipated in its deal structure. Of the $500 million it committed to Ionis under that agreement, $150 million was attributed to the pelacarsen royalty and $350 million to royalties on Spinraza, Biogen's approved spinal muscular atrophy therapy. The company said it does not expect to make any further milestone payments to Ionis following the HORIZON result.

Under the deal terms, Royalty Pharma acquired 25% of Ionis' Spinraza royalty payments through 2027, stepping up to 45% from 2028, on up to $1.5 billion in annual net sales. Those royalty payments will revert to Ionis once they reach $550 million in aggregate, representing a 1.1x return on the total capital deployed. Royalty Pharma characterised this as a modest positive return on the overall $500 million package.

The company also reiterated its 2030 Portfolio Receipts target of at least $4.7 billion, signalling that management does not consider the HORIZON failure material to its longer-term financial outlook.

Market and competitive context

The Lp(a) space remains active despite the setback. Rival programmes using different mechanisms, including RNA-interference and gene-editing approaches, are in various stages of clinical development, and some developers argue their candidate profiles may differ meaningfully from antisense approaches. Regulatory agencies have not yet approved any Lp(a)-lowering therapy for cardiovascular risk reduction, meaning the field lacks a validated surrogate-to-outcome link that could support future approval pathways without full outcomes data.

For Royalty Pharma, the result underlines the risk-mitigation logic at the centre of its business model: pairing speculative royalty bets with income from established commercial products. Spinraza generated substantial royalty flows for Biogen in prior years, though the therapy now faces competition in SMA from gene therapy and small-molecule alternatives. The degree to which Spinraza revenues hold through 2027 will determine whether Royalty Pharma's hedged position ultimately delivers on the 1.1x return it is projecting.