Dive Brief:

• A nucleic acid-based medicine from AstraZeneca and Ionis Pharmaceuticals missed its main objective in a big study of people with a deadly heart condition in a major setback with notable ramifications for multiple other drugmakers. 
• In a pair of statements, the companies said that when compared to a placebo in people with transthyretin-mediated amyloid cardiomyopathy, or ATTR-CM, their drug, eplontersen, didn’t significantly reduce the risk of death or recurrent cardiovascular events after 140 weeks. Eplontersen had no treatment effect among participants already receiving a commonly used “stabilizer” medication. A 29% risk reduction was observed in people who weren’t getting those drugs, AstraZeneca and Ionis said.
• The companies didn’t provide additional study details, only noting that the drug was “well tolerated” and showed positive signs on multiple other secondary study measures. Those specifics will be presented at a medical meeting in August. But the news caught Wall Street analysts and investors by surprise and sent shares of AstraZeneca and Ionis tumbling 8% and 21%, respectively, early Thursday. 

Dive Insight:

Eplontersen’s study was among the most eagerly anticipated readouts in the biopharmaceutical sector this year. Success would yield a substantial market opportunity and was largely expected by industry watchers. The only “question going in” was how eplontersen might compare to an already-marketed medicine from Alnylam Pharmaceuticals, wrote Stifel analyst Paul Matteis, in a Tuesday client note.

The condition at the center of the trial, ATTR-CM, has become one of the more competitive battlegrounds in the industry. Three medicines from Alnylam, BridgeBio Pharma and Pfizer are now available, and all are either blockbuster medicines or soon expected to be. Pfizer’s market-leading Vyndamax eclipsed $6 billion in sales last year. 

AstraZeneca and Ionis’ drug stood to be the fourth, and has already succeeded in a different form of transthyretin amyloidosis that affects the nerves. Further boosting confidence was the fact that eplontersen, like Alnylam’s medicine, Amvuttra, is similarly designed to stop production of the protein that’s misfolded and causes damage in people with the disease. 

But eplontersen is a different type of nucleic acid-based therapy than Amvuttra, and the study it’s involved in is larger and designed differently than Amvuttra’s key trial. One crucial distinction, for instance, was that a higher percentage of patients were already on other medicines, among them protein “stabilizers” like Vyndamax. AstraZeneca noted, in its statement, that 57% of patients in each study arm received a stabilizer at the study’s start, and another 24% got one during the trial. By comparison, 53% of patients were on a stabilizer at some point in Alnylam’s study.

That kind of trial design gave AstraZeneca and Ionis the chance to better see whether their treatment might benefit people already on a stabilizer, and separate eplontersen from Amvuttra. Instead, eplontersen missed its mark, leaving the drug’s future in ATTR-CM in doubt. 

AstraZeneca and Ionis didn’t mention plans to seek approval or run an additional study, and “trying to approach regulators here on these data would seem like a stretch,” Matteis wrote.

Both companies saw sharp stock declines as analysts sorted through the ramifications. For Ionis, the setback erases the chance for profit-sharing opportunities, sales royalties, and future milestone payments. And while AstraZeneca’s $80 billion-in-annual-sales target may not be threatened, the “bigger issue” is a “credibility loss” given the company’s confidence level heading into the readout, Jefferies analyst Michael Leuchten wrote. 

AstraZeneca is “meant to be able to have exceptionally good trial design ability,” he added. 

Shares of Alnylam and BridgeBio, meanwhile, surged by double digits with the apparent removal of a key competitor. The findings could establish Amvuttra as the only drug of its kind for ATTR-CM, “which is a huge positive,” Stifel’s Matteis wrote.