The surprising failure of AstraZeneca and Ionis in a key phase 3 trial of Wainua in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) has sent the companies' shares tumbling, while those of their competitors are soaring.
Shortly after the market opened on Thursday—and several hours after the companies reported the stumble—the share price of AZ was down 7%, while its Wainua partner Ionis took a 20% hit. Meanwhile, shares for indication rivals Alnylam and BridgeBio were up 10% and 15%, respectively.
The U.S. biotechs were already on an upswing with the promising launches of their soon-to-be-blockbuster ATTR-CM drugs—Amvuttra in Alnylam's case and Attruby from BridgeBio. Now, AZ and Ionis' prospective challenger may be knocked out of the competition, although the partners did not address their Wainua plans in ATTR-CM directly moving forward.
While there was a strong investor response, analysts from Jefferies characterized the movement as an “over-reaction,” given that 2030 sales estimates are “only mildly impacted" by the trial miss, referencing AZ’s goal to generate $80 billion in annual sales by 2030.
“This was meant to be a slam dunk, making the outright failure surprising,” the Jefferies team wrote. “Pulling Wainua in ATTR-CM from our model though has limited impacts, a reflection of the breadth of AZ’s therapeutic positioning and the robustness of the growth trajectory. AZ remains a premium growth company.”
The CARDIO-TTRansform study included 1,432 patients from 20 countries who received a 45-mg subcutaneous injection of Wainua or placebo every four weeks. The study did not meet its primary endpoint, which centered on reducing cardiovascular deaths or recurrent cardiovascular events through 140 weeks.
Patients in the study also received standard of care, in most cases in the form of a stabilizer drug.
There was a positive footnote, however, as a prespecified subgroup of patients who were treated with Wainua as a monotherapy showed a “nominally significant” improvement over placebo on the composite endpoint. But AZ’s hope of demonstrating Wainua’s benefit as an add-on therapy did not materialize. At baseline, 57% of patients in each arm were receiving stabilizers and 24% added them during the trial.
“We believe these findings reflect the rapidly evolving treatment landscape, in which contemporary ATTR-CM patients are widely treated with stabilizers,” Ionis CEO Brett Monia, Ph.D., said in a release. “Although we are disappointed that the study did not meet the primary endpoint, these results have the potential to guide the treatment landscape for ATTR-CM and contribute to advancing future care for patients.”
The trial miss was a surprise to William Blair analyst Myles Minter, Ph.D., given the “well-documented combination use benefit of stabilizers and silencers” in Alnylam’s HELIOS-B trial of Amvuttra, a silencer which has the same mechanism of action as Wainua.
“Clearly, the data continue to support effectiveness of silencers in preventing cardiovascular events in a monotherapy setting,” Minter added.
Meanwhile, Jefferies suggested that the failure could impact investors’ long-held confidence in AZ’s management. The company is known for its “exceptionally good trial design ability," with the Wainua flop potentially causing a “credibility loss,” the analysts wrote.
Wainua was approved by the FDA in December of 2023 to treat polyneuropathy in adults with hereditary transthyretin-mediated amyloidosis (ATTR-PN), which affects approximately 40,000 people globally, compared to between 300,000 and 500,000 people who are living with ATTR-CM worldwide. Sales of Wainua reached $212 million last year, with Ionis collecting $49 million in royalties.