Why two promising heart drugs flopped and what's next
Two major cardiovascular drug trials—Novartis's lipoprotein(a) therapy and Novo Nordisk's IL-6 inflammation drug—recently failed, disappointing investors and the industry despite being genetically validated targets. The failures signal a broader reckoning about over-reliance on genetic data in drug development and may significantly dampen investment in expensive, long-term cardiovascular outcome trials.
Summary
The Read Out Loud podcast discusses several major developments in biotech following a summer hiatus. The FDA approved eight novel drugs, two cell and gene therapies, and one vaccine in August and September despite ongoing leadership transitions. Notable approvals included RepliMune's melanoma therapy (after two prior rejections) and Revolution Medicine's pancreatic cancer drug. Heidi Overton was nominated as the next FDA commissioner, handpicked by HHS Secretary Robert F. Kennedy Jr.
A significant safety theme emerged regarding patient deaths in clinical trials. Novartis paused CAR-T therapy trials for autoimmune conditions but initially failed to disclose three patient deaths—information only revealed after reporter inquiry. Similar non-transparent deaths occurred in investigator-initiated trials of gene and cell therapies in China. Additionally, Vicat XR (Neurocrine's drug for Prader-Willi syndrome) is showing unexpected toxicity and deaths in real-world use after market approval, illustrating how rare disease drug development with small patient populations can miss safety signals.
The primary focus centers on two high-profile cardiovascular drug failures. Novartis invested billions in a years-long outcome trial testing a drug targeting lipoprotein(a)—a hereditary cholesterol particle affecting one in five people—but the trial failed to show benefit. Simultaneously, Novo Nordisk discontinued trials of an IL-6 inflammation-targeting drug after disappointing results. Both drugs were considered "genetically validated" targets with strong epidemiological support. Guest expert Dr. Ethan Weiss, a UCSF cardiologist and Mireya Therapeutics CSO, explains that the field sought to address "residual risk"—the continuing heart attacks in patients already on optimal therapy including statins and PCSK9 inhibitors. Weiss suggests that powerful background medications may mask the effects of single-target interventions and that genetic predictions, while seemingly robust, may not account for short-term trial dynamics or the heavily medicated patient populations studied.
About this episode
On this week’s episode of “The Readout LOUD”: The pharma industry invested billions of dollars to develop drugs heralded as the next era in the treatment of heart disease — but why did they fail? And what does this mean for the development of new heart medicines moving forward? Cardiologist and biotech entrepreneur Ethan Weiss joins us to discuss the surprising failures and long-term implications of two large clinical trials involving drugs developed from Novo Nordisk and Novartis, respectively. Plus, we have a recap of biotech news we missed while on hiatus, including a spurt of FDA drug approvals and the next big thing in cancer treatment from Merck and Moderna.
Key Insights
- Dr. Ethan Weiss argues that powerful background medicines (statins, PCSK9 inhibitors, blood pressure drugs) may suppress the observable benefit of single-target therapies in outcome trials, making genetic predictions that account for lifelong loss-of-function inadequate for predicting short-term trial results.
- The hosts and expert emphasize that genetic validation, previously considered 'undefeated' as a predictor of drug efficacy in outcome studies, can no longer be relied upon as the sole basis for billion-dollar cardiovascular programs after these two genetically-validated drugs failed.
- Dr. Weiss predicts these failures will create a prolonged investment drought in cardiovascular outcome trials, as investors will redirect capital to lower-risk opportunities, making it 'almost impossible' for small biotech companies to secure funding for multi-year cardiovascular studies.
- The podcast documents a pattern of delayed transparency regarding patient deaths across multiple contexts—Novartis only disclosed CAR-T deaths after reporter inquiry, and Chinese investigator-initiated trials' deaths became public only through investigative reporting—suggesting systemic issues with trial safety disclosure beyond geographic borders.
- Dr. Weiss suggests the field may have overstated LP(a) as a therapeutic target because the genetics showed only modest risk reduction predictions, and questions whether patients simply need better adherence to existing therapies rather than new drug targets to address residual cardiovascular risk.
Topics
Transcript
Welcome to this week's episode of The Read Out Loud, a weekly biotech podcast from STAT. I'm Allison DeAngelis. I'm Adam Forrestein. And I'm Elaine Chen. We are back from break and we have a lot to talk about. The industry has invested billions of dollars to develop drugs heralded as the next era in the treatment of heart disease. But why did they fail? And what does this mean for the development of medicines moving forward? This is going to pop a hole in the balloon, and it's going to be a long time before somebody wants to do something like this again. I think investors are going to run away from this. That story and the most recent…
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