<p>In a first-in-human trial (NI006-101), the monoclonal antibody cliramitug, targeting misfolded transthyretin, demonstrated a favorable safety profile and time- and dose-dependent reductions in surrogate markers of cardiac amyloid burden over the course of 12 months in patients with amyloid transthyretin cardiomyopathy (ATTR-CM). Here we evaluate the long-term safety and efficacy of cliramitug in a subgroup of participants of the NI006-101 trial who continued treatment in a second open-label extension (OLE2) and further explore dose- and time-dependent effects on amyloid depletion, cardiac biomarkers and cardiac structure and function. Twenty-three participants (20 receiving background treatment with tafamidis, all male) entered OLE2 and received a median of 10 additional infusions, increasing the maximum total exposure to 24 infusions and extending the median follow-up to 29.3 months. Thirteen participants initially treated with ≤10 mg kg⁻¹ were up-titrated to 30 mg kg⁻¹ during OLE2. Treatment adherence was high (98%), with no treatment-related serious adverse events or discontinuations. Continued treatment and up-titration in participants with lower prior exposure led to further reductions in cardiac extracellular volume on MRI and tracer uptake on bisphosphonate scintigraphy. Improvements were also observed in NT-proBNP and troponin T levels, left ventricular relaxation, filling pressures and wall thickness. Increases in Kansas City Cardiomyopathy Questionnaire scores suggested potential quality-of-life benefits. Consistent with results from the original trial, cliramitug showed favorable long-term safety and further reductions in cardiac amyloid burden following up-titration to 30 mg kg⁻¹. These time- and dose-dependent improvements across structural, functional and biomarker endpoints support the therapeutic potential of amyloid-depleting therapy with cliramitug in ATTR-CM. ClinicalTrials.gov: <a href="https://clinicaltrials.gov/study/NCT04360434">NCT04360434</a>.</p>