AZ, Ionis hail phase 3 data for ATTR drug eplontersen

AstraZeneca have broken out the data they teased last month for transthyretin amyloidosis (ATTR) therapy eplontersen, showing that the drug was effective at slowing down disease progression in patients with polyneuropathy caused by the disease.

The results of the NEURO-TTRansform trial were presented at the American Academy of Neurology (AAN) annual congress today, based on 66 weeks of follow-up, and showed that eplontersen reduced levels of the biomarker serum transthyretin (TTR) by 82%, while an external placebo group saw an 11% reduction.

That is in line with an 81% reduction seen at an earlier 35-week data analysis from the trial, suggesting the antisense drug does not start to lose its efficacy over time. Patients will continue to be followed on treatment until week 85.

When it came to clinical endpoints, eplontersen dramatically reduced disease progression as measured by modified Neuropathy Impairment Score +7 (mNIS+7), with a 0.28 point increase compared to a 25 point increase for the control group.

At 66 weeks, 47% of patients treated with the antisense drug had improvements in neuropathy symptoms, compared to 17% of the placebo group, while quality-of-life scores improved in 58% and 20%, respectively.

Patients with hereditary ATTR with polyneuropathy suffer debilitating nerve damage throughout their body, resulting in the progressive loss of motor function that typically leads to disability within five years of diagnosis and can be fatal within 10.

According to the principal investigator for NEURO-TTRansform – Sami Khella of the University of Pennsylvania – most patients with the disease see continued deterioration, as treatment options are limited.

“Today’s important results demonstrate that eplontersen has a consistent and sustained treatment effect and reinforces its potential as an important medicine for the thousands of patients living with this debilitating and fatal disease, “ he said.

The presentation of the data at AAN comes as AZ and Ionis are waiting for the outcome of the FDA’s review of eplontersen for ATTR-polyneuropathy, which has an action date of 22nd December.

AZ licensed rights to the new drug in 2021 for $200 million upfront in a deal valued at up to $3.6 billion, so there’s a lot riding on the new data, as well as the results of a second trial in ATTR-cardiomyopathy called CARDIO-TTRansform that is due to read out shortly.

If approved, it will be Ionis’ second drug for ATTR after Tegsedi (inotersen), which has lagged behind rivals in the market including Alnylam’s Onpattro (patisiran), as well as Pfizer’s $2.5 billion blockbuster Vyndaqel/Vyndamax (tafamidis), which is also approved to treat ATTR-cardiomyopathy.

Alnylam has also filed for approval of Onpattro for ATTR-cardiomyopathy, and brought a second polyneuropathy drug to market last year after it got FDA approval for Amvuttra (vutrisiran), which has hit the ground running with sales of $69 million in the last quarter of the year, helped by subcutaneous dosing every three months.

Eplontersen needs to be dosed once a month, so is at a disadvantage in terms of patient convenience to Amvuttra, but better than Onpattro, which needs to be given by IV infusion every three weeks. AZ and Ionis will hope eplontersen’s robust clinical efficacy results will help it to make inroads into the market, particularly in a large, as-yet untreated ATTR population.