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Novel Agent Offers Hope for Hereditary ATTR Polyneuropathy

The investigational agent eplontersen (Ionis Pharmaceuticals/AstraZeneca) halted neuropathy disease progression and improved neuropathy impairment and quality of life for patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) in a pivotal phase 3 trial.

Eplontersen led to “clinically and statistically significant benefits at week 66 with an early and rapid sustained reduction in serum TTR [transthyretin] concentration, a halting of the progression of the neuropathy impairment, and a trend to improvement in quality of life,” said principal investigator Sami Khella, MD, professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine.

“These findings are further supported by the secondary endpoints, which all met statistical significance,” said Khella, chief of the Department of Neurology at Penn Presbyterian Medical Center.

Khella reported final data from the NEURO-TTRansform trial April 24 at the American Academy of Neurology (AAN) 2023 Annual Meeting.

Debilitating, Underrecognized

ATTRv-PN is a debilitating disease that leads to peripheral nerve damage with motor disability within 5 years of diagnosis. Without treatment, it is generally fatal within a decade.

Eplontersen is an investigational antisense oligonucleotide designed to reduce the production of the TTR protein to treat hereditary and nonhereditary forms of ATTR amyloidosis.

The NEURO-TTRansform trial evaluated the efficacy and safety of subcutaneously administered eplontersen in comparison with placebo for 168 adults with stage I or II ATTRv-PN.

At 66 weeks, patients who were treated with eplontersen demonstrated consistent and sustained benefit on the three coprimary endpoints of change from baseline in serum TTR concentration, neuropathy impairment, and quality of life.

Eplontersen led to a significant mean reduction of 82% in TTR serum concentration compared to an 11% reduction with placebo (P < .0001).

Eplontersen also led to “stabilization” of disease progression, as measured by modified Neuropathy Impairment Score +7 (mNIS+7). There was a 0.28-point increase with eplontersen, compared with a 25-point increase for placebo (P < .0001), Khella reported.

Overall, 47% of patients in the eplontersen group showed improvements in neuropathy at 66 weeks compared to baseline; in the placebo group, 17% of patients showed improvements.

Treatment with eplontersen also significantly (P < .0001) improved patient-reported quality of life, as assessed by the validated Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN).

Overall, 58% of patients who were treated with eplontersen showed improvements in quality of life at 66 weeks, compared with 20% of patients treated with placebo.

The results observed at 66 weeks confirm and extend the results achieved at 35 weeks.

“We were excited with the 35-week data, and with the week 66 data showing that quality of life continues to improve, it means potentially we may be able to give these patients some of their quality of life back,” Mina Makar, RPh, AstraZeneca senior vice president, US Respiratory and Immunology, told Medscape Medical News.

Early Diagnosis Key

Eplontersen was well tolerated and demonstrated an acceptable safety profile, Khella said.

The rate of treatment-emergent adverse events in the eplontersen group was comparable or similar to that in the placebo group across all major categories. There were no adverse events of special interest that led to study drug discontinuation, Khella noted.

Two deaths occurred in the eplontersen group prior to the interim analysis. Both were related to known sequelae of ATTR amyloidosis, and neither were regarded as drug related.

“Long-term safety and tolerability data are currently being assessed in the open-label extension,” Khella said.

Makar noted that ATTRv-PN is a rare disease. Roughly 40,000 patients worldwide have the disease, yet the majority of cases are not identified or treated.

“The earlier the diagnosis is made, the better patients do,” he said. He encouraged neurologists to “appreciate that this disease exists and look for it early. Word needs to get out that patients with a progressive neuropathy need to be further evaluated,” Khella told Medscape Medical News.

The US Food and Drug Administration has accepted a new drug application for eplontersen for the treatment of ATTRv-PN. The drug has a PDUFA date of December 22, 2023. Eplontersen has orphan drug designation in the US.

The study was sponsored by Ionis Pharmaceuticals. Khella has relationships with Ionis, Pfizer, Alnylam and Eidos. Makar is an employee of AstraZeneca, which has entered into a strategic collaboration with Ionis to develop and commercialize eplontersen.

American Academy of Neurology (AAN) 2023 Annual Meeting: Abstract 1150. Presented April 24, 2023.

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