- Four months after teaming up on an alliance worth as much as $3.5 billion, Ionis Pharmaceuticals and partner AstraZeneca have altered a clinical trial at the center of their deal, announcing Friday plans to extend the size and length of an ongoing Phase 3 study in an inherited heart disease known as transthyretin amyloidosis cardiomyopathy.
- The study was designed to include 750 patients and evaluate a drug called eplontersen over the course of about 28 months, with results expected in 2024. Ionis and AstraZeneca now plan to recruit 1,000 patients and extend treatment for an additional five months, meaning study results should come in 2025.
- The trial was amended to "ensure a highly positive study outcome and generate an even more robust data set," Ionis said in a statement. Still, the decision raises questions for Ionis as well as rival Alnylam Pharmaceuticals, whose Phase 3 study in TTR cardiomyopathy should produce results by July, according to Stifel analyst Paul Matteis.
Over the past few years, TTR cardiomyopathy, a progressive heart condition that often leads to heart failure, has become a target for several drugmakers.
In 2019, the Food and Drug Administration approved a treatment, Pfizer’s Vyndaqel, that can help slow the disease’s progression. Better diagnostic tools have helped increase awareness. And drugmakers have a better sense of how to combat the disease, which affects many more people than companies originally thought.
Drugs from Alnylam and Ionis are now in advanced stages of clinical testing, and other companies, including Intellia Therapeutics and Novo Nordisk, are following with programs either developed in-house or acquired through deals.
Yet the field faces questions, too. In December, a medicine from BridgeBio Pharma failed the main goal of a Phase 3 trial when study participants in its placebo group performed better on a walking test after one year than history suggested they would. The finding spurred speculation among experts and industry analysts that clinical development plans in the disease may need to be adjusted. As TTR cardiomyopathy patients are being identified earlier, when they’re less sick, studies may need to be larger and longer to detect a prospective drug’s benefit, some said, for instance.
An ongoing Phase 3 study from Alnylam will put that theory to the test. Like Bridge Bio, Alnylam is testing its drug’s impact on a walking test after a year, and despite BridgeBio’s surprising result, executives have expressed confidence that Onpattro will succeed. Yet the trial has become a polarizing subject among biotech investors, and Ionis’ decision to make its own study larger and longer raises important questions about both companies’ trials, wrote Stifel's Matteis in a research note.
For example, Matteis questioned whether Ionis and AstraZeneca changed their trial as a “reaction” to BridgeBio’s findings, or because study participants may have “considerably milder” disease than those who were involved in Pfizer’s study.
The changes also delay the drug’s path to market and suggest the rate of cardiovascular hospitalizations and deaths in the study are tracking “below expectations,” wrote Luca Issi, an analyst at RBC Capital Markets.
There are implications for Alnylam, too. Neither the study of Onpattro nor a Phase 3 trial of its next-generation TTR amyloidosis drug, vutrisiran, run as long as Ionis’ trial. In the vutrisiran trial, Alnylam is testing whether its drug can reduce the risk of hospitalizations and deaths after 2.5 years. The fact that Ionis made its study longer than that raises questions as to whether “Alnylam is comfortable that 30 months is long enough,” Matteis wrote. Even Vyndaqel's benefits weren't clear immediately in clinical testing.
“Trial design questions in the TTR space are becoming far more nuanced now,” he added.
AstraZeneca paid Ionis $200 million in December for rights to eplontersen and could add another roughly $3.3 billion in future payouts if the drug hits various milestones and sales targets. Eplontersen is also being tested in the form of the disease characterized by nerve damage, with results expected in the middle of the year.