Ionis and AstraZeneca Report Positive Results for ATTRv-PN Therapy

Rare Daily Staff

Ionis Pharmaceuticals and AstraZeneca reported that the phase 3 NEURO-TTRansform study for eplontersen in patients with hereditary transthyretin-mediated amyloid polyneuropathy met all co-primary endpoints and secondary endpoints at 66 weeks versus an external placebo group.

The positive results are being presented in an Emerging Science Session at the American Academy of Neurology 2023 Annual Meeting in Boston.

Hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with ATTRv-PN experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively compromises their function. The damage from misfolded TTR protein accumulation leads to disability within five years of diagnosis and is generally fatal within a decade.

Eplontersen, an investigational LIgand-Conjugated Antisense (LICA) medicine designed to inhibit the production of TTR protein, is being developed as a monthly self-administered subcutaneous injection to treat all types of ATTR.

NEURO-TTRansform is a global, open-label, randomized trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN. The trial enrolled 168 adult patients with ATTRv-PN Stage 1 or Stage 2 and up to week 66 eplontersen is being compared to the external placebo group from the NEURO-TTR registrational trial for inotersen that Ionis completed in 2017. The final analysis comparing eplontersen to external placebo was completed at week 66 and all patients will be followed on treatment until week 85, when they will have the option to transition into an open-label extension study.

At 66 weeks, patients treated with eplontersen demonstrated consistent and sustained benefit on the three co-primary endpoints measuring serum transthyretin (TTR) concentration, neuropathy impairment and quality of life.

Eplontersen achieved least squares (LS) mean reduction of 82 percent in serum TTR concentration from baseline, compared to an 11 percent reduction from baseline in the external placebo group.

Eplontersen halted disease progression as measured by modified Neuropathy Impairment Score +7 (mNIS+7), resulting in a 0.28 point LS mean increase compared to a 25.06 point increase for the external placebo group from baseline (24.8 point LS mean improvement). Overall, 47 percent of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 17 percent in the external placebo group. Among study completers, 53 percent of treated patients showed improvements in neuropathy at 66 weeks compared to baseline versus 19 percent in the external placebo group.

Eplontersen improved quality of life demonstrating a 5.5 point LS mean decrease (improvement) on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN), compared to a 14.2 point increase (worsening) in the external placebo group (19.7 point LS mean improvement). Overall, 58 percent of treated patients showed improvements in QoL at 66 weeks compared to baseline versus 20 percent in the external placebo group. Among study completers, 65 percent of treated patients showed improvements in QoL at 66 weeks compared to baseline versus 23 percent in the external placebo group.

Eplontersen demonstrated statistically significant benefits on both mNIS+7 and Norfolk QoL-DN at 35 weeks versus the external placebo, which were further improved at 66 weeks. It also achieved statistically significant improvements in all secondary endpoints versus the external placebo group.

Eplontersen continued to demonstrate a favorable safety and tolerability profile. The rate of treatment emergent adverse events in the eplontersen group was comparable to the external placebo group across all major categories. There were no adverse events of special interest that led to study drug discontinuation.

“In the past, patients with hereditary transthyretin amyloid polyneuropathy usually deteriorated given the limited available treatments. This new study shows eplontersen can halt progression of neuropathy and improve quality of life at 66 weeks when compared to placebo,” said Sami Khella, chief, department of neurology at Penn Presbyterian Medical Center, professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine and a principal investigator on the NEURO-TTRansform study. “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.”

As part of a global development and commercialization agreement, Ionis and AstraZeneca are seeking regulatory approval for eplontersen for the treatment of ATTRv-PN in the U.S. and plan to seek regulatory approval in Europe and other parts of the world. The U.S. Food and Drug Administration accepted the New Drug Application for eplontersen for the treatment of ATTRv-PN with a PDUFA action date of December 22, 2023. Eplontersen was granted Orphan Drug designation in the United States.

Eplontersen is also currently being evaluated in the phase 3 CARDIO-TTRansform study for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), a systemic, progressive and fatal condition that typically leads to progressive heart failure and often death within three to five years from disease onset.

Photo: Sami Khella, chief, department of neurology at Penn Presbyterian Medical Center, professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine