Liver‐directed drugs for t<scp>ransthyretin‐mediated</scp> amyloidosis

Brannagan, Thomas H.; Berk, John L.; Gillmore, Julian D.; Maurer, Mathew S.; Waddington-Cruz, Márcia; Fontana, Marianna; Masri, Ahmad; Obici, Laura; Brambatti, Michela; Baker, Brenda F.; Hannan, Lisa A; Büchele, Gustavo Luiz; Viney, Nicholas J.; Coelho, Teresa; Nativi-Nicolau, José

doi:10.1111/jns.12519

Cited by 14 publications

(4 citation statements)

References 81 publications

(225 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This study adds to the growing body of evidence related to TTR gene silencing in general, and hepatic-targeted therapies in particular, for patients with ATTRv polyneuropathy, and these therapies are suggested as among first-line treatments in ATTRv amyloidosis expert consensus statements …”

Section: Discussionmentioning

confidence: 93%

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Coelho,

Marques,

Dasgupta

et al. 2023

JAMA

Self Cite

View full text Add to dashboard Cite

ImportanceTransthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.ObjectiveTo evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and ParticipantsNEURO-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.InterventionsSubcutaneous 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 MeasuresPrimary 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.ResultsAmong 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 &lt; .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 &lt; .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P &lt; .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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10

show abstract

Section: Discussionmentioning

confidence: 93%

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Coelho,

Marques,

Dasgupta

et al. 2023

JAMA

Self Cite

View full text Add to dashboard Cite

show abstract

“…[13] The two main gene silencing compounds that have undergone extensive clinical assessment in ATTR include inotersen (ASO) and patisiran (siRNA) and have been approved for treating stage 1 and 2 ATTRv. [14] Patisiran (siRNA) with a reduction [15] of 85% after the second dose to a maximum of 96% with adverse reactions related to infusion and inotersen which was shown through phase III clinical trials to improve the course of polyneuropathy in stages I and II as well as the quality of life of patients, estimated by results in the score on the Norfolk Quality questionnaire reported by the patient. [16] Life-Diabetic Neuropathy (QOL-DN) questionnaire.…”

Section: Discussionmentioning

confidence: 99%

Experience of Hereditary Amyloidosis with Rare Variant in Ecuador: A Series of Cases

Luzuriaga,

Abrigo Maldonado,

Villacorta

2024

Preprint

View full text Add to dashboard Cite

Approximately more than 120 transthyretin mutations are known whose variation in clinical presentation is heterogeneous, as the course of disease onset depends on genetic variation and level of penetrance. It is little known in Ecuador, and some of the reported cases; suggest to the family tree analysis that they come from a province that is possibly considered endemic. The main objective is to carry out a descriptive cross-sectional analysis on the presentation of transthyretin amyloidosis in families carrying the p.Ser43Asn gene from the index case identified.

show abstract

“…The SM-102, ALC-0315 and the alternative cholesterol are proprietary molecules and have not been revealed. However, looking at the previous LNP research, ionizable lipids likely resemble DLin-MC3-DMA which were approved by the Food and Drug Administration (FDA) for transthyretin-mediated amyloidosis [220,221]. Like phenothiazines, LNPs enter the cells, including neurons, through the endocytic pathway (EP).…”

Section: Vehicles: Lipid Nanoparticlesmentioning

confidence: 99%

The Future of Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

Sfera,

Imran,

Sfera

et al. 2024

Preprint

View full text Add to dashboard Cite

For the past 70 years, dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling, antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there was limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal, senescence, brain volume loss, attenuation of gamma oscillations on electroencephalogram and oxidation of lipids in plasma and mitochondrial membranes. We surmise that aberrant activation of aryl hydrocarbon receptor by toxins derived from the gut microbes or the environment drives premature cellular, including neuronal, senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: 1. To summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders. 2. To discuss novel strategies for improving long-term outcome in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor.

show abstract

Liver‐directed drugs for transthyretin‐mediated amyloidosis

Cited by 14 publications

References 81 publications

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Experience of Hereditary Amyloidosis with Rare Variant in Ecuador: A Series of Cases

The Future of Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

Contact Info

Product

Resources

About