| 1. |
- Coelho, Teresa, et al.
(author)
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Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy
- 2023
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In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 330:15, s. 1448-1458
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Journal article (peer-reviewed)abstract
- Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group.Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P <.001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P <.001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P <.001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.
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| 2. |
- Elger, Christian, et al.
(author)
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Pooled efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: Data from four double-blind placebo-controlled pivotal phase III clinical studies
- 2017
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In: CNS Neuroscience and Therapeutics. - : Wiley. - 1755-5930 .- 1755-5949. ; 23, s. 961-972
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Journal article (peer-reviewed)abstract
- © 2017 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd. Purpose: Pooled evaluation of the key efficacy and safety profile of eslicarbazepine acetate (ESL) added-on to stable antiepileptic therapy in adults with focal-onset seizures. Methods: Data from 1703 patients enrolled in four phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2week titration period, ESL was administered at 400mg, 800mg, and 1200mg once-daily doses for 12weeks (maintenance period). Pooled efficacy variable was standardized (/4weeks) seizure frequency (SSF) analyzed over the maintenance period as reduction in absolute and relative SSF and proportion of responders (≥50% reduction in SSF). Pooled safety was analyzed by means of adverse events and clinical laboratory assessments. Results: SSF was significantly reduced with ESL 800mg (P<0.0001) and 1200mg (P<0.0001) compared to placebo. Median relative reduction in SSF was 33.4% for ESL 800mg and 37.8% for 1200mg (placebo: 17.6%), and responder rate was 33.8% and 43.1% (placebo: 22.2%). ESL was more efficacious than placebo regardless of gender, geographical region, epilepsy duration, age at time of diagnosis, seizure type, and type of concomitant antiepileptic drugs (AED). Incidence of adverse events (AEs) and AEs leading to discontinuation was dose dependent. Most common AEs (>10% patients) were dizziness, somnolence, and nausea. The incidence of treatment-emergent AEs (dizziness, somnolence, ataxia, vomiting, and nausea) was lower in patients who began taking ESL 400mg (followed by 400mg increments to 800 or 1200mg) than in those who began taking ESL 600mg or 800mg. Conclusions: Once-daily ESL 800mg and 1200mg showed consistent results across all efficacy and safety endpoints, independent of study population characteristics and type of concomitant AEDs. Treatment initiated with ESL 400mg followed by 400mg increments to 800 or 1200mg provides optimal balance of efficacy and tolerability.
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| 3. |
- Trinka, Eugen, et al.
(author)
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Efficacy and safety of eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: A phase III double-blind, randomized, parallel-group, multicenter study.
- 2018
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In: Epilepsia. - : Wiley. - 1528-1167 .- 0013-9580. ; 59:2, s. 479-491
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Journal article (peer-reviewed)abstract
- We assessed the efficacy and safety of once-daily eslicarbazepine acetate in comparison with twice-daily (BID) controlled-release carbamazepine (carbamazepine-CR) monotherapy in newly diagnosed focal epilepsy patients.This randomized, double-blind, noninferiority trial (NCT01162460) utilized a stepwise design with 3 dose levels. Patients who remained seizure-free for the 26-week evaluation period (level A: eslicarbazepine acetate 800mg/carbamazepine-CR 200mg BID) entered a 6-month maintenance period. If a seizure occurred during the evaluation period, patients were titrated to the next target level (level B: eslicarbazepine acetate 1200mg/carbamazepine-CR 400mg BID, level C: eslicarbazepine acetate 1600mg/carbamazepine-CR 600mg BID) and the evaluation period began again. The primary endpoint was the proportion of seizure-free patients for 6months after stabilization in the per protocol set. The predefined noninferiority criteria were -12% absolute and -20% relative difference between treatment groups.Eight hundred fifteen patients were randomly assigned; 785 (388 in the eslicarbazepine acetate group and 397 in the carbamazepine-CR group) were included in the per protocol set, and 813 (401 in the eslicarbazepine acetate group and 412 in the carbamazepine-CR group) were included in the full analysis set for the primary analysis. Overall, 71.1% of eslicarbazepine acetate-treated patients and 75.6% of carbamazepine-CR-treated patients were seizure-free for ≥6months at the last evaluated dose (average risk difference = -4.28%, 95% confidence interval [CI] = -10.30 to 1.74; relative risk difference = -5.87%, 95% CI = -13.50 to 2.44) in the per protocol set. Rates of treatment-emergent adverse events were similar between groups for patients in the safety set. Noninferiority was also demonstrated in the full analysis set, as 70.8% of patients with eslicarbazepine acetate and 74.0% with carbamazepine-CR were seizure-free at the last evaluated dose (average risk difference = -3.07, 95% CI = -9.04 to 2.89).Treatment with eslicarbazepine acetate was noninferior to BID carbamazepine-CR. With its once-daily formulation, eslicarbazepine acetate provides a useful option for first-line monotherapy for adults with newly diagnosed epilepsy and focal onset seizures.
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