AstraZeneca and Ionis Miss Primary Endpoint in Phase III ATTR-CM Trial for Eplontersen

The setback clouds expansion plans for the RNA-targeted therapy after a pivotal cardiovascular outcomes study failed to demonstrate a significant benefit in patients with transthyretin amyloid cardiomyopathy.

AstraZeneca and Ionis Pharmaceuticals have reported disappointing results from the Phase III CARDIO-TTRansform trial, with their investigational therapy eplontersen failing to meet its primary endpoint in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).

The announcement dealt a significant blow to the programme, with AstraZeneca's share price falling sharply following the news. The outcome also raises questions over the therapy's commercial expansion beyond its current approved indication.

A Key Growth Opportunity Falls Short

Eplontersen is already approved in the US and Europe for adults with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), where it is marketed as Wainua in the US and Wainzua in Europe.

Success in ATTR-CM was widely viewed as the next major commercial opportunity for the RNA-targeted medicine, placing it in direct competition with therapies including Alnylam's Amvuttra (vutrisiran) and Pfizer's Vyndaqel/Vyndamax (tafamidis).

The programme also formed part of AstraZeneca's longer-term growth strategy as it works towards its ambition of generating $80 billion in annual revenue by 2030.

Phase III Trial Misses Primary Endpoint

The global CARDIO-TTRansform study enrolled 1,432 patients with either hereditary or wild-type ATTR-CM.

Participants received either eplontersen or placebo alongside standard-of-care treatment, with the primary endpoint measuring a composite of cardiovascular death and recurrent cardiovascular events over 140 weeks.

The study failed to demonstrate a statistically significant improvement in the overall patient population.

However, a pre-specified subgroup analysis suggested patients receiving eplontersen as monotherapy experienced a nominally significant reduction in cardiovascular events compared with placebo.

No meaningful treatment benefit was observed among patients already receiving transthyretin stabiliser therapy.

Changing Treatment Landscape May Have Influenced Results

According to the companies, the widespread use of stabiliser therapies during the study may have affected the trial outcome.

More than 57% of participants were receiving stabiliser treatment when they entered the study, while an additional 24% began stabiliser therapy during the trial.

Ionis CEO Brett Monia said the findings reflected the rapidly evolving treatment landscape, where stabiliser therapies have become increasingly common in routine clinical practice.

Encouraging Secondary Findings

Although the primary endpoint was missed, the companies highlighted several positive secondary outcomes.

Multiple imaging and biomarker analyses favoured eplontersen over placebo, while the therapy produced large and sustained reductions in transthyretin protein levels.

The safety profile also remained consistent with previous studies, with no new safety concerns identified.

AstraZeneca and Ionis plan to conduct further analyses of the full dataset before presenting detailed results at the upcoming European Society of Cardiology (ESC) Congress.

Competitive Pressure Continues

The setback arrives as competition within ATTR-CM continues to intensify.

RNA-targeted medicines and transthyretin stabilisers are increasingly competing to improve outcomes for patients with this progressive and often fatal cardiac disease.

The trial outcome may strengthen the positions of existing therapies while prompting AstraZeneca and Ionis to reassess eplontersen's future role within the evolving treatment landscape.

Why the Results Matter

The study highlights several important trends across cardiovascular drug development:

• Demonstrating additional benefit on top of existing standard-of-care therapies is becoming increasingly challenging.

• ATTR-CM is rapidly evolving as new treatments become integrated into routine clinical practice.

• RNA-targeted medicines continue to show strong biological activity, but translating biomarker improvements into clinical outcomes remains critical.

• Large cardiovascular outcome trials remain one of the highest hurdles in late-stage drug development.
  

Summary

AstraZeneca and Ionis have reported that the Phase III CARDIO-TTRansform trial of eplontersen failed to meet its primary endpoint in transthyretin-mediated amyloid cardiomyopathy.

While secondary analyses and biomarker data remained encouraging, the results represent a setback for the therapy's expansion into ATTR-CM and underline the increasing complexity of developing new treatments in an evolving standard-of-care environment.

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