Acoramidis
In a phase 3 trial of patients with transthyretin amyloid cardiomyopathy (ATTR-CM), acoramidis (an oral investigational transthyretin stabilizer) was superior to placebo with respect to a hierarchical composite primary endpoint (all-cause mortality, cumulative frequency of cardiovascular [CV]-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6-minute walk distance).[191]American College of Cardiology. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy - ATTRibute-CM. Nov 2023 [internet publication].
https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2023/08/24/02/29/attribute-cm
[192]ClinicalTrials.gov. Efficacy and safety of AG10 in subjects with transthyretin amyloid cardiomyopathy (ATTRibute-CM). ClinicalTrials.gov Identifier: NCT03860935. Jul 2023 [internet publication].
https://clinicaltrials.gov/study/NCT03860935
In an earlier phase 2 study, acoramidis was well-tolerated and demonstrated a near-complete stabilization of TTR tetramers (at the highest dose tested).[193]Judge DP, Heitner SB, Falk RH, et al. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2019 Jul 23;74(3):285-95.
https://www.sciencedirect.com/science/article/pii/S0735109719339208?via%3Dihub
http://www.ncbi.nlm.nih.gov/pubmed/30885685?tool=bestpractice.com
CAEL-101
A fibril-reactive monoclonal antibody, CAEL-101 targets an epitope on human light-chain amyloid fibrils, resulting in the reduction and/or elimination of amyloid deposits.[194]Solomon A, Weiss DT, Wall JS. Therapeutic potential of chimeric amyloid-reactive monoclonal antibody 11-1F4. Clin Cancer Res. 2003 Sep 1;9(10 Pt 2):s3831-8.
http://clincancerres.aacrjournals.org/content/9/10/3831s.full
http://www.ncbi.nlm.nih.gov/pubmed/14506180?tool=bestpractice.com
[195]Solomon A, Weiss DT, Wall JS. Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies. Cancer Biother Radiopharm. 2003 Dec;18(6):853-60.
http://www.ncbi.nlm.nih.gov/pubmed/14969598?tool=bestpractice.com
Results from phase I and II clinical trials of CAEL-101 in patients with AL amyloidosis are promising.[196]Edwards CV, Gould J, Langer AL, et al. Analysis of the phase 1a/b study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with relapsed or refractory AL amyloidosis. Amyloid. 2017 Mar;24(sup1):58-9.
http://www.ncbi.nlm.nih.gov/pubmed/28434347?tool=bestpractice.com
[197]Valent J, Silowsky J, Kurman MR, et al. CAEL-101 is well-tolerated in AL amyloidosis patients receiving concomitant cyclophosphamide-bortezomib-dexamethasone (CyborD): a phase 2 dose-finding study (NCT04304144). Blood. 2020;136 (suppl 1):26-7.
https://doi.org/10.1182/blood-2020-139323
Isatuximab
An anti-CD38 monoclonal antibody approved for multiple myeloma, isatuximab may be effective in patients with previously treated AL amyloidosis.[198]Parker TL, Rosenthal A, Sanchorawala V, et al. A phase II study of isatuximab (SAR650984) (NSC-795145) for patients with previously treated AL amyloidosis (SWOG S1702; NCT#03499808). Blood. 2020;136(supp 1):20–21.
https://doi.org/10.1182/blood-2020-143180
Eplontersen
Eplontersen, an investigational ligand-conjugated antisense drug, has been granted orphan drug designation in the US for the treatment of transthyretin-mediated amyloidosis. It is currently in phase 3 clinical trials for amyloid transthyretin cardiomyopathy and polyneuropathy.[199]ClinicalTrials.org. CARDIO-TTRansform: a study to evaluate the efficacy and safety of eplontersen (formerly known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in participants with transthyretin-mediated amyloid cardiomyopathy (ATTR CM). Mar 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04136171
[200]ClinicalTrials.org. NEURO-TTRansform: a study to evaluate the efficacy and safety of eplontersen (formerly known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in participants with hereditary transthyretin-mediated amyloid polyneuropathy. Mar 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04136184
NTLA-2001
NTLA-2001 is the first investigational CRISPR therapy candidate to be administered systemically, and could potentially be curative for ATTR amyloidosis. NTLA-2001 is an in vivo gene-editing therapeutic that is designed to reduce serum transthyretin levels. The treatment uses lipid nanoparticles to deliver a two-part genome editing system to the liver consisting of single-guide RNAs targeting transthyretin, and mRNAs for the Cas9 protein. Preclinical studies have shown durable knockout of the transthyretin protein after a single intravenous dose.[201]Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. 2021 Aug 5;385(6):493-502.
https://www.nejm.org/doi/10.1056/NEJMoa2107454
http://www.ncbi.nlm.nih.gov/pubmed/34215024?tool=bestpractice.com
A phase 1 trial is ongoing.[202]ClinicalTrials.org. Study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001 in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and patients with transthyretin amyloidosis-related cardiomyopathy (ATTR-CM). Dec 2022 [internet publication].
https://www.nejm.org/doi/10.1056/NEJMoa2107454
NTLA-2001 has been granted orphan drug designation in the US for the treatment of transthyretin amyloidosis.