Ionis, AstraZeneca's polyneuropathy med improved patients' quality of life in phase 3, teeing up battle with Alnylam

Ionis and AstraZeneca are finally cracking open the hood to phase 3 data of eplontersen, a burgeoning competitor to Alnylam’s ATTR polyneuropathy franchise. 

Eplontersen stymied disease progression as measured by the Neuropathy Impairment Score +7, with a 0.28 point LS mean increase compared to a 25.06 point increase for patients on placebo. Treated patients also reported an improvement in a quality of life questionnaire while patients on placebo reported a worsening. Last but not least, eplontersen reduced serum transthyretin concentration by 82% from baseline, compared to 11% for placebo. The additional analysis was unveiled Monday at the American Academy of Neurology annual meeting. 

The data add fervor to what was already a closely watched December regulatory deadline for the FDA as the two companies chase Alnylam’s Amvuttra. Sami Khella, M.D., the primary investigator for the trial and head of the neurology department at Penn Presbyterian Medical Center said that the quality of life improvements stood out. 

“That’s dramatic,” he said in an interview with Fierce Biotech. “And it's the goal really of any therapy. So that’s most striking.” 

Khella says that eplontersen is a very safe drug, though detailed safety data were not available ahead of the companies’ presentation. There were a couple of cases of thrombocytopenia reported among treated patients, but they were mild and were able to continue treatment, according to Khella. No cases of glomerulonephritis, inflammation of filters in the kidney, were reported in either the treatment or placebo arms. 

Two patient deaths were reported but neither was attributed to eplontersen. Ionis Chief Clinical Development Officer Eugene Schneider, M.D., said the cases were reviewed by an independent data safety monitor board as well as by the sponsor and medical monitors to vet the attribution of the deaths. 

The performance in disease progression and quality of life set the stage for a competitive marketplace if—and more likely, when—eplontersen is approved by the FDA. The agency has a deadline near Christmas to decide on whether to approve the drug, and Schneider does not expect regulators to convene an advisory meeting as an early stocking surprise. 

Alnylam’s Amvuttra, which was approved in June 2022, had a 17-point difference in disease progression compared to placebo and a 16.2-point difference in reported quality of life. Amvuttra brought in $69 million in total revenue in the fourth quarter last year, making up for declines in the company’s first-generation treatment, Onpattro. 

For AstraZeneca, the data are validation of the up to $3.5 billion deal the company signed with Ionis to co-develop and commercialize the med. Mina Makar, AstraZeneca’s senior vice president of global cardiovascular, renal and metabolism work, says the Big Pharma’s existing commercial infrastructure and patient support system should bolster eplontersen’s prospects, which he described as having best-in-class potential.

“We have very aggressive plans to launch eplontersen not only in Europe, but in many, many other parts of the world,” he said. 

But ATTR polyneuropathy is just the start. A second phase 3 trial, slated to be the largest ATTR cardiomyopathy trial ever, continues to enroll. Ionis’ Shneider says given it's a 140-week trial, a readout is likely in 2025. Alnylam expects a top-line readout for Amvuttra in the same indication sometime in early 2024 after scrapping plans for an interim analysis.

Eplontersen is the main attraction by Ionis and AstraZeneca, but the two are also collaborating on three other clinical-stage meds, two of which are aimed at nonalcoholic steatohepatitis and a third for patients with chronic kidney disease. Makar says that while the two companies’ existing partnerships have proven fruitful, no collaboration expansion is on the horizon. 

“If there's opportunities for other areas, we certainly are always talking and looking. But it needs to be something that fits strategically into where we need to go,” he said.