FDA Approves Eplontersen for Polyneuropathy of Hereditary Transthyretin Amyloidosis

With the approval, eplontersen becomes the first approved treatment for patients with hereditary transthyretin-mediated amyloid polyneuropathy that can be self-administered via an autoinjector.

According to an announcement, the FDA has approved eplontersen (Ionis, AstraZeneca), a ligand-conjugated antisense oligonucleotide, for the treatment of adult patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). Approved under the market name Wainua, the therapy is the only approved treatment for ATTRv-PN that can be self-administered via an autoinjector.¹

Data from the interim analysis of the phase 3 NEURO-TTRansform trial (NCT04136184) was the basis for the approval, with results indicating that eplontersen reduced serum transthyretin (TTR) at 35 weeks. Presented the results at the 2022 American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting, the least square mean percent reduction of TTR was 81.2% after 35 weeks of treatment with eplontersen, compared with a 14.8% reduction for the placebo group (P <.0001). Also of note, the treatment resulted in reductions in neuropathy impairment and improvements in quality of life compared with placebo.

"This is wonderful news for patients. Another treatment option to combat this devastating disease and give patients an improved quality of life," principal investigator Sami Khella, MD, chief, department of neurology at Penn Presbyterian Medical Center and professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine, told NeurologyLive®.

NEURO-TTRansform was an open-label study where patients were randomly assigned 6:1 to eplontersen (n = 144) or inotersen (Tegsedi), AstraZeneca’s previously approved therapy for hATTR, for a 66-week double-blind period, followed by an open-label extension. The study also included a 60-patient external placebo control group. Quality of life, assessed through the Norfolk QoL-DN, was substantially improved in treated patients, with mean changes of –6.2 from baseline at week 85. In comparison, at week 66, there was a least square mean difference (LSMD) of –19.7 (95% CI, –25.6 to –13.8; P <.0001) when comparing with placebo. At week 66, 57.6% of treated patients showed improvements on Norfolk QoL-DN compared with only 20.0% of those on placebo.

"This is another positive step in treating ATTRv. With treatments such as this, the disease has been remarkably transformed from a relentless progressive and disabling process into one that is treatable. When diagnosed and treated early, patients can avoid the loss of independence and mobility that they witnessed in siblings, parents and grandparents," investigator Michael J. Polydefkis, MD, professor of neurology at Johns Hopkins University School of Medicine, told NeurologyLive."Eplontersen provides an additional treatment option that can only benefit patients."

On secondary end points, eplontersen treatment resulted in a statistically significant difference in change from baseline in the Neuropathy Impairment Score plus 7 (mNIS+7) and the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (QoL-DN) compared with external placebo (P <.0001 for both). The treatment effect and efficacy of eplontersen were consistent across disease stage and mutation type for the mNIS+7 and Norfolk QoL-DN end points, and with previous treatment by stabilizers for mNIS+7.

As for safety, treatment-emergent adverse events (AEs) related to study drug and drug discontinuation rates were lower or similar for the eplontersen compared with the external placebo. Overall, the authors deemed the treatment favorably safe and tolerated, with a low incidence of injection site reactions (1.4%), and no serious AEs related to treatment.

Eplontersen, formerly known as IONIS-TTR-LRX, is designed to reduce the production of TTR protein at its source. As announced in a statement, the treatment will be available in the U.S. starting in January 2024.¹

Top Clinical Takeaways

Eplontersen (Wainua) gains FDA approval as the sole self-administered treatment with an autoinjector for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) in adults.

Eplontersen showcases an 81.2% reduction in serum transthyretin (TTR) at 35 weeks, presenting significant improvements in neuropathy and quality of life, based on positive results from the NEURO-TTRansform trial.

Eplontersen demonstrated consistent efficacy across disease stages and mutations, maintaining a favorable safety profile with lower adverse event rates and drug discontinuation compared with the external placebo. Anticipated U.S. availability is set for January 2024.

In another analysis of the study, eplontersen resulted in halted neuropathy progression and improved quality of life at 85 weeks in patients with ATTRv-PN.²At week 85, investigators observed a mean reduction of 81.8% in serum TTR concentration relative to baseline for eplontersen-treated patients vs a 70.4% (95% CI, –75.2 to –65.7%; P <.0001) LSMD at week 65 for those on placebo. Patients on eplontersen showed improvement in neuropathy impairment through 19 months of treatment, indicated by mean reductions of –2.9 in modified Neuropathy Impairment Score +7 (mNIS+7) composite score.

Among these findings, eplontersen continued to show a favorable safety and tolerability profile at 85 weeks. Specifically, treatment-emergent adverse event (TEAE) incidence remained consistent with previous observations at week 66, and no TEAEs of special interest led to study drug discontinuation. In total, 18.8% of treated patients experienced a serious TEAE, although none were considered related to the study drug. In comparison, 21.7% of those on placebo reported serious TEAEs as well. Investigators continued to report no imbalance of ocular events excluding vitamin A decrease or deficiency. Of note, 3 non-drug related deaths were reported in the eplontersen group, all related to the sequelae of ATTR amyloidosis.

"The FDA approval of eplontersen marks an important milestone for patients living withATTRv-PN, who will now have an effective, well-tolerated treatment that can be self-administered via auto-injector to combat this devastating disease," Brett P. Monia, PhD, chief executive officer at Ionis, said in a statement.¹ "It is also a pivotal moment for Ionis as eplontersen will be the first in a steady cadence of potential commercial launches for the company. We are proud to have discovered and, together with AstraZeneca, developed eplontersen, and are grateful to the patients, caregivers and investigators who participated in our clinical studies, as well as for the dedication of our scientists and researchers."

These data were consistent with positive 66-week findings presented at the 2023 American Academy of Neurology Annual Meeting, held earlier this year. In that data, 47.2% of patients treated with the agent showed improvements on mNIS+7 compared with 16.7% of those on placebo. Consistent improvement across all secondary end points compared with placebo was also observed in the eplontersen group. Neuropathy Symptom and Change (NSC) scores, used to assess symptom severity, showed least square mean differences of 0.3 for eplontersen and 8.2 for placebo (difference, –8.2; 95% CI, –10.7 to –5.8; P <.0001). Additionally, more patients on eptlontersen demonstrated improvement or no change in polyneuropathy disability.³

"Patients with ATTRv-PN, and other forms of amyloidosis, are often misdiagnosed since symptoms can mirror other conditions," Isabelle Lousada, president and chief executive officer at the Amyloidosis Research Consortium, said in a statement.¹ "The path to getting an accurate diagnosis can often be a long, arduous journey and it is critical that a timely and accurate diagnosis is made not only for the individual experiencing symptoms but for their families and loved ones. It is exciting to see new innovations coming through and increased efforts to raise awareness in an area that has often been overlooked or neglected."

In a previous phase 1 trial (NCT03728634) of healthy volunteers, injections of eplontersen at a dose of 90 mg per month showed a mean reduction in TTR levels of 94% after 13 weeks of treatment. Eligible participants were assigned to 1 of 3 multiple-dose cohorts (45, 60, and 90 mg) or a single-dose cohort (120 mg), and then randomly assigned 10:2 (active: placebo) to receive a total of 4 subcutaneous doses (Day 1, 29, 57, and 85) in the multiple-dose cohorts or 1 subcutaneous dose in the single-dose cohort.⁴

All randomized participants completed the treatment period with no serious AEs reported. In the multiple-dose cohorts, those on eplontersen 45, 60, and 90 mg demonstrated reduced TTR levels of –85.7% (SD, 8.0), –90.5% (SD, 7.4), and –93.8% (SD, 3.4), compared with –5.9% (SD, 14.0) for pooled placebo (P <.001). A maximum mean reduction in TTR levels of –86.3% (SD, 6.5) from baseline were achieved after the single-dose 120 mg of eplontersen.5

"There is an urgent medical need for new therapies for people living with ATTRv-PN," Ruud Dobber, executive vice president of the BioPharmaceuticals Business Unit at AstraZeneca, said in a statement.¹"The U.S. approval of eplontersen offers a new treatment option that provides consistent and sustained reduction in serum TTR concentration compared to baseline while halting disease progression and improving quality of life for people living with this debilitating condition."

Previously, the treatment was granted an orphan drug designation, and is also being evaluated in the phase 3 CARDIO-TTRansform study (NCT04136171) assessing it in the treatment of amyloid transthyretin cardiomyopathy (ATTR-CM), a systemic, progressive and fatal condition that leads to progressive heart failure and death within 4 years of diagnosis.⁵ The primary composite end point is cardiovascular (CV) mortality and recurrent CV clinical events comparing the two study arms up to week 140. Secondary end points include the change from baseline in the 6-minute walk test and the Kansas City Cardiomyopathy Questionnaire scores at week 121, as well as the rates of CV mortality, CV clinical events and all-cause mortality at week 140.In an announcement, the study completed enrollment with more than 1,400 patients included in the clinical trial.