AZ, Ionis’ Wainua misses phase 3 endpoint: ‘No added benefit with stabilizer combination’

The key reason AstraZeneca (AZ) and Ionis’ gene-silencing therapy Wainua fell short of expectations in a phase 3 trial was the lack of additional benefit from combining it with standard therapy.

According to U.S. pharmaceutical industry publication Fierce Pharma on the 30th (local time), AZ released detailed results from the phase 3 Cardio-TTRansform trial of Wainua in transthyretin amyloid cardiomyopathy (ATTR-CM) at the European Society of Cardiology (ESC) annual congress in Munich, Germany, that day.

AZ and Ionis said in July that Wainua had failed to meet the primary endpoint of reducing cardiovascular death or recurrent cardiac events.

In an interview with Fierce Pharma, Mina Makar, AZ’s executive vice president of global cardiovascular, renal and metabolic diseases, said, “As a monotherapy, the efficacy is very strong,” adding, “It works as expected across quality of life, 6-minute walk and cardiovascular events.”

She continued, “The question this study was designed to answer was whether adding a silencing mechanism would provide additional benefit in patients whose disease is progressing despite treatment with a stabilizer,” explaining, “Unfortunately, there was no such additional benefit.”

According to the detailed data, 381 primary endpoint events occurred among 210 patients in the Wainua group, compared with 392 events among 231 patients in the placebo group. There were 74 cardiovascular deaths in the Wainua group and 70 in the control group.

The study included 1,432 patients with wild-type or hereditary ATTR-CM, divided into 715 patients in the Wainua group and 717 in the placebo group.

Notably, 57% of patients were using transthyretin stabilizers, such as Pfizer’s Vyndamax, at baseline. That proportion rose to slightly more than 80% by the end of the trial.

In a subgroup analysis limited to patients who were not using a stabilizer at baseline, the Wainua group had fewer cardiovascular events on the primary composite endpoint than the placebo group, and the ESC assessed the result as having reached “nominal statistical significance.”

Makar said that the lack of increased benefit from adding a silencing mechanism on top of a stabilizer was “very useful information for treatment guidelines and clinical practice.”

Meanwhile, Jefferies analysts assessed Wainua’s secondary endpoint results as “strong but not statistically significant enough to claim.” They noted that Cardio-TTRansform enrolled a more severely ill and intensively treated patient population than the HELIOS-B study, which supported Alnylam’s approval of Amvuttra.

William Blair analysts said the results could have broader implications for the current ATTR-CM treatment class, including Vyndamax, BridgeBio’s Attruby and Alnylam’s Amvuttra.

The Jefferies team also added that the AZ-Ionis results “could suggest a higher bar for next-generation silencing therapies in clinical development,” potentially making it more difficult to demonstrate additional cardiovascular benefit using hard endpoints.

Wainua is currently approved to treat the related condition ATTR polyneuropathy. AZ is scheduled to present additional, more detailed data on baseline stabilizer use later that day at the congress.