April 24, 2023 07:00 AM EDTUpdated 09:16 AM R&DPharma
AstraZeneca, Ionis unveil full PhIII data for ‘mega brand’ ATTR drug
Max Gelman
Senior Editor
AstraZeneca and Ionis fleshed out a Phase III win for eplontersen Monday morning at this year’s American Academy of Neurology meeting, illustrating why the pair is so confident in its potential success.

Eplontersen all but halted patients’ disease progression after 66 weeks in a fatal neurodegenerative disease known as hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). In a composite score of polyneuropathy clinical measurements like muscle strength and blood pressure, patients taking eplontersen recorded a 0.28-point average increase from baseline compared to a 25.06-point average increase in the placebo group.

The difference of 24.8 points between the groups was good for a p-value of p<0.0001. Sami Khella, a principal investigator of the Phase III NEURO-TTRansform study, told Endpoints News the patients who took eplontersen saw results fairly quickly and the data were “robust and persistent.”

“This is sort of spine-tingling stuff,” Khella said. “It’s amazing that you can really stabilize patients like this, and it [also] looks like there’s a trend to improvement and quality of life, which is really something that is unique in therapies of people with a neuropathy.”

Two other co-primary endpoints showed eplontersen resulted in an 82% reduction of serum TTR concentration in active arm patients compared to 11% in the placebo group, and a 19.7-point average increase in a quality of life questionnaire. TTR is the affected gene in this disease, causing a buildup of misfolded proteins.

AstraZeneca and Ionis are pitching eplontersen as an alternative to Onpattro, Alnylam’s siRNA drug approved to treat ATTRv-PN in 2018. The pair touts eplontersen’s convenience relative to Onpattro — eplontersen is a once-a-month injectable shot that can be self-administered while Onpattro patients receive an IV infusion every three weeks — as a big selling point.

And there is a lot of money on the line: AstraZeneca forked over $200 million in upfront cash to Ionis to partner on eplontersen in December 2021, promising another $485 million in regulatory milestones and up to $2.9 billion in sales-related biobucks.

Mina Makar
Senior AstraZeneca VP Mina Makar, who runs the company’s commercial cardiovascular, renal and metabolic efforts, wouldn’t say how much the company is forecasting in peak sales. But he said eplontersen, which is also being studied in a related condition caused by the same genetic mutation that instead results in cardiomyopathy, will be a “significant” product.

“We expect it to be a mega brand,” Makar said. “We expect it to deliver significant performance, we expect it to help a lot of patients and to change a lot of lives, and hopefully save a lot of lives.”

Eplontersen has some work left to do to close the gap with Onpattro. In Alnylam’s pivotal trial for Onpattro’s FDA approval, the drug induced a 34-point average difference in the same composite measurement used in eplontersen’s study, with patients in the active arm seeing an average change of minus-6 points. Usual caveats for cross-trial comparisons apply: For example, Alnylam studied Onpattro over 85 weeks and NEURO-TTRansform hasn’t yet hit that threshold.

Regardless, AstraZeneca and Ionis are banking on convenience as their way into the market. The FDA has already accepted the companies’ new drug application, using data from the interim analysis at the 35-week mark, and a decision is expected by the end of this year. Monday’s presentation also comes after the pair boasted the topline win last month without divulging the data.

Eugene Schneider
Ionis will, however, have one advantage over Alnylam should eplontersen be approved — a Big Pharma partner. When the FDA greenlighted Onpattro five years ago, Alnylam took the commercialization route on its own. But Ionis, in teaming with AstraZeneca, hopes it can convert patients to eplontersen while also introducing others to treatments for the first time.

“This is a completely underdeveloped market where less than one in five is currently on treatment,” Eugene Schneider, Ionis’ chief clinical development officer, told Endpoints. “What we see is likely to happen is really just the proportion of patients with ATTR-PN who are receiving effective treatment, and newer therapies, is just going to grow.”

Editor’s note: This story has been updated to clarify the nature of Mina Makar’s job at AstraZeneca. He works on commercial efforts, not drug development.