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Abstract Introduction AT-02 is a humanized, recombinant IgG1 monoclonal antibody fusion protein containing a peptide that mediates binding to all forms of amyloid. AT-02 has been shown to bind synthetic amyloid fibrils and diverse forms of human amyloid extracts with EC90 <1 nM, stimulate phagocytosis of amyloid fibrils, bind tissue amyloid in murine amyloidosis models and reduce amyloid deposits in animal models. Because AT-02 binds to amyloid deposits and triggers amyloid reabsorption through opsonization, it may provide clinical benefit over therapies that reduce precursor proteins slowing amyloid deposition, which frequently do not result in restoration of organ function. Study Design The AT-02 Phase 1/2 clinical program in AL participants consists of a single arm, open label 8-week multiple dose, dose escalation Phase 1 study (AT02-001 Part 3) and a Phase 2 open label extension study (OLE; AT02-003). The first dose in the OLE was administered at the Week 8 visit in the Phase 1 study to provide uninterrupted AT-02 exposure throughout the Phase 1/2 clinical program. Eligible AL participants achieved a hematologic VGPR or CR for at least 12 months prior to screening and had a confirmed diagnosis of AL amyloidosis with evidence of cardiac amyloidosis based on screening serum NT-proBNP (>650 and < 8500 pg/mL for AL participants) and extracellular volume >40% measured by contrast-enhanced CMR. Serum and urine biomarkers were obtained at Baseline (prior to AT-02 exposure) and during treatment. Estimated glomerular filtration rate (eGFR) was determined using the CKD-EPI formula. Renal evaluable participants had urine albumin-creatine ration (uACR) >300 mg/g or eGFR < 90 ml/min/1.73m2 at Baseline. Results Fourteen AL participants were enrolled in Part 3 of the Phase 1 study and entered the Phase 2 / OLE in one of two dose cohorts: 2500 mg q4w (5 participants) and 2500 mg q2w (9 participants). Ninety-two percent of AL participants were male, mean age was 63.4 years, 36% had kappa iFLC, 64% had lambda iFLC, 36% were in heme VGPR, 64% were in heme CR, and mean disease duration was 2.8 years. Ten of the 14 AL participants were renal evaluable: 3 participants received AT-02 2500 mg q4w and 7 participants received AT-02 2500 mg q2w in the OLE. The mean (SD) duration of treatment was 84.3 (15.2) and 43.8 (7.3) weeks for the 2500 mg q4w and 2500 mg q2w cohorts, respectively. Mean Baseline eGFR was 73 and 57 mL/min/1.73m2 in the 2500 q4w and 2500 q2w dose cohorts, respectively. After 40 weeks of AT-02 treatment, mean eGFR in the AT-02 2500 mg q4w group decreased from Baseline by 5.1 mL/min/1.73m2 whereas mean eGFR in the AT-02 2500 mg q2w group increased from Baseline by 16.3 ml/min/1.73 m2. Using a mixed model of repeated measures, the LS mean difference between the treatment groups after 40 weeks of AT-02 treatment was 17.74 mL/min/1.73m2 (p=0.0027). The increase in the eGFR in the AT-02 2500 mg q2w cohort was gradual and consistent throughout the treatment period with mean eGFR increases from Baseline of 4.3, 5.8, 9.0, 16.3 mL/min/1.73 m2 following 12, 16, 24 and 40 weeks of treatment, respectively. Eighty-three percent (5/6) participants in the 2500 mg q2w cohort with data after 40 weeks of AT-02 treatment had an increase in eGFR from Baseline with 67% (4/6) experiencing a >10 mL/min/1.73 m2 increase. Improvements in eGFR were observed in participants with kappa or lambda iFLC, in participants with hematologic VGPR or CR and in participants with hematologic responses ranging from 1-6 years prior to initiating AT-02 treatment. One participant in the q2w dose cohort also met the proteinuria criteria with a baseline uACR 1349 mg/g. uACR decreased by 70% and 84% following 8 and 40 weeks of treatment with AT-02 2500 mg q2w, respectively. The early rapid decline in uACR was followed by a slower progressive decline over the treatment period. No renal evaluable AL participant developed new or worsening proteinuria. Conclusion These initial data support the potential for AT-02, a novel pan-amyloid depleting Ig fusion protein, to improve renal function in AL patients with renal disease who have achieved hematologic response.