In the Phase III NEURO-TTRansform study, patients treated with eplontersen – a ligand-conjugated antisense oligonucleotide (LICA) – demonstrated a significant benefit of the three co-primary endpoints, plasma transthyretin (TTR) concentration, neuropathy and quality of life (QoL).
05 MAG – Results from the Phase III NEURO-TTRansform study in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) demonstrated that eplontersen – a ligand-conjugated antisense oligonucleotide (LICA) – met all co-primary endpoints and secondary endpoints at 66 weeks versus the external placebo group.
ATTRv-PN is a debilitating disease that causes damage to the peripheral nervous system resulting in motor disability five years after diagnosis and, without treatment, has life-threatening outcomes within ten years.
The positive results of the study – presented in the Emerging Science session at the 2023 Annual Meeting of the American Academy of Neurology (AAN) held in Boston (Massachusetts) – demonstrate that the efficacy, safety and administration profile of eplontersen represents a important new therapeutic option for this disease, which is associated with potentially fatal outcomes if left untreated and which is still characterized by a significant unmet clinical need.
At 66 weeks, patients treated with eplontersen demonstrated a significant benefit of the three co-primary endpoints, plasma transthyretin concentration (TTR), neuropathy-related functional impairment and quality of life (QoL), respectively.
Eplontersen achieved a mean least squares (LS) reduction of 82% in plasma TTR concentration from baseline, compared with an 11% reduction in the external placebo group (p
The drug halted disease progression by determining a 0.28-point change from baseline in the composite score assessing neuropathy (modified Neuropathy Impairment Score, mNIS+7, where higher values indicate greater severity of impairment), a compared with an increase of 25.06 points in the external placebo group (24.8 points LS mean improvement; p<0.0001).
Overall, 47% of eplontersen-treated patients achieved improvement from baseline in neuropathy after 66 weeks of treatment versus 17% in the external placebo group. Among those who completed the study, 53% of treated patients showed improvement in neuropathy at 66 weeks from baseline versus 19% in the external placebo group.
Eplontersen also improved quality of life (QoL) by demonstrating a decrease (improvement) of 5.5 LS mean points in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN), compared with an increase (worsening) of 14 .2 points in the external placebo group (LS mean improvement of 19.7 points; p<0.0001).
Overall, 58% of treated patients showed an improvement in QoL from baseline after 66 weeks of treatment compared with 20% in the external placebo group. Among those who completed the study, 65% of treated patients showed an improvement in QoL at 66 weeks from baseline, versus 23% in the external placebo group. Eplontersen demonstrated statistically significant benefits on both mNIS+7 and Norfolk QoL-DN at 35 weeks compared to the external placebo group, which further improved at 66 weeks.
Eplontersen also demonstrated statistically significant improvement in all secondary endpoints compared to the external placebo group and continued to demonstrate a favorable safety and tolerability profile. The rate of treatment-emergent adverse events in the eplontersen group was comparable or similar to the external placebo group in all major categories. There were no adverse events of particular interest that would cause discontinuation of the study drug.
“Transthyretin-mediated hereditary amyloid polyneuropathy is a rare genetic disease,” he says Laura Obici of the Systemic Amyloidosis Center, IRCCS Policlinico San Matteo di Pavia Foundation, and investigator of the NEURO-TTRansform trial – It is a complex and debilitating disease, with rapidly developing therapeutic options, but still characterized by a strong unmet clinical need. In the absence of effective treatment, transthyretin-mediated hereditary amyloid polyneuropathy is relentlessly progressive. The NEURO-TTRansform study showed that eplontersen, by reducing plasma levels of transthyretin, halts disease progression and improves patients’ quality of life compared to placebo. These important results demonstrate the consistent and sustained benefit of eplontersen and confirm its potential to further revolutionize current treatment. With this drug it will be possible to substantially modify the course of the disease with the benefit of patients living with this debilitating and fatal disease”.
Eplontersen is currently being evaluated in the Phase III CARDIO-TTRansform study for the treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), a progressive, life-threatening, systemic disease that typically causes progressive heart failure and often leads to death within three to five years of onset.
05 maggio 2023
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