Lim-Watson, Michelle

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive disease caused by the deposition of transthyretin (TTR) as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis. METHODS: This phase 2, double-blind, placebo-controlled trial randomized participants with transthyretin amyloidosis with cardiomyopathy to receive infusions every 4 weeks of either coramitug at 2 dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary end points were the change from baseline to week 52 in the 6-minute walk test and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular events (comprising hospitalization caused by cardiovascular events or urgent heart failure visits). RESULTS: In total, 104 participants (median age, 77 years; 93% men; 84% New York Heart Association class II; 13% with variant transthyretin amyloidosis with cardiomyopathy) were randomized and dosed: 34 to 10 mg/kg of coramitug, 35 to 60 mg/kg of coramitug, and 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range, 1224, 3406). In total, 90% of participants were receiving disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with transthyretin silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, 60 mg/kg of coramitug significantly reduced NT-proBNP levels compared with placebo (–48% [95% CI, –65% to –22%]; P =0.0017). The change in 6-minute walk test from baseline to week 52 was not statistically different from placebo with either dose. Coramitug (60 mg/kg) was associated with improved functional echocardiographic parameters and was well tolerated. CONCLUSIONS: This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in transthyretin amyloidosis with cardiomyopathy, was well tolerated and, at a dose of 60 mg/kg, resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6-minute walk test within 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05442047.

Background Recurrent pericarditis is characterized by painful flares and inflammation, which negatively impact health‐related quality of life. RHAPSODY (rilonacept inhibition of interleukin‐1 alpha and beta for recurrent pericarditis: a pivotal symptomatology and outcomes study) evaluated the efficacy and safety of rilonacept (IL‐1α and ‐β cytokine trap) in recurrent pericarditis. A secondary analysis of these data evaluated the patient‐reported outcome questionnaire score change during the trial. Methods and Results Participants completed 5 patient‐reported outcome (PRO) questionnaires assessing pericarditis pain, health‐related quality of life, general health status, sleep impact, and overall symptom severity. PRO score changes during the treatment run‐in period (12 weeks) and the blinded randomized withdrawal period (up to 24 weeks) were evaluated using descriptive statistics and mixed model repeated measures analyses. Participants with PRO data from the run‐in period (n=84) and the randomized withdrawal period (n=61; 30 rilonacept, 31 placebo) were included in analyses. Run‐in baseline PRO scores indicated that pericarditis symptoms during pericarditis recurrence impacted health‐related quality of life. All PRO scores significantly improved ( P <0.001) on rilonacept treatment during the run‐in period. For the randomized withdrawal period, PRO scores were maintained for participants receiving rilonacept. For those receiving placebo and who experienced a recurrence, PRO scores deteriorated at the time of recurrence and then improved following rilonacept bailout. At randomized withdrawal Week 24/End of Study, scores of participants who received bailout rilonacept were similar to those of participants who had continued rilonacept. Conclusions These results demonstrate the burden of pericarditis recurrences and the improved physical and emotional health of patients with recurrent pericarditis while on rilonacept treatment. These findings extend prior rilonacept efficacy results, demonstrating improvements in patient‐reported health‐related quality of life, sleep, pain, and global symptom severity while on treatment. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03737110.

Abstract Background Recurrent pericarditis (RP) patients report that painful, debilitating flares negatively impact their health-related quality of life (HRQoL). RHAPSODY, the Phase 3 trial of rilonacept (IL-1α/IL-1β cytokine trap), included a daily pain diary and patient-reported outcome SF-36v2 to measure HRQoL throughout the trial. Purpose The purpose of this research is to evaluate the effect of rilonacept on HRQoL in relation to changes in pain for RP patients who have a recurrence. Methods RHAPSODY enrolled 86 patients with acute symptomatic RP to receive weekly rilonacept for a 12-week run-in (RI) period and randomized 61 patients (1:1) to receive placebo (n=31) or continue rilonacept (n=30) for the event-driven randomized-withdrawal (RW) period. Patients on placebo who experienced a qualifying recurrence during RW (return of pericarditis pain and increase in C-reactive protein) were rescued with bailout rilonacept. Patients reported daily pericarditis pain electronically, using a 0–10 numeric rating scale (NRS), and completed the SF-36v2 at study visits prior to clinician interaction. Scores from RI Baseline (BL), RI Week 12 (RW BL), Recurrence visit, and RW up to Week 24 (or end of study; EOS) were evaluated for patients who experienced recurrence in RW. Analyses exclude one patient randomized to placebo who had a recurrence after Week 24 of the RW period. Results Analyses focused on the 22 of 30 patients (73%) in the placebo group who experienced a recurrence before Week 24 of RW (median time from RW BL to recurrence: 8.6 weeks). During RI, daily pain scores decreased while on rilonacept (Cohen's effect size [ES] d=−2.0), and SF-36v2 scores improved, with scores at RI BL (Fig. 1 red line) below the general population average of 50 and near or above average at RI Week 12 (Fig. 1 blue line); ES were all large (d&gt;0.8), ranging from 0.917 (Mental Component Summary) to 2.021 (Bodily Pain). At recurrence, pain scores increased (d=6.5; Fig. 2) and SF-36v2 scores were below the population average (Fig. 1 orange line), with largest reductions between RI Week 12 (RW BL) and recurrence for Bodily Pain (−13.4) and Physical Component Summary (−10.6). Following rilonacept bailout, average pain decreased (d=−2.1; Fig. 2), and by RW Week 24/EOS, SF-36v2 scores returned to similar levels as at the end of the RI period (Fig. 1 green line). Conclusion Impaired RI BL SF-36v2 scores indicate negative impact of RP on HRQOL in RP patients. While receiving rilonacept, HRQoL scores improved to near or above population averages, in conjunction with patient-reported pain. After discontinuing rilonacept during RW, HRQoL scores worsened at recurrence and improved upon receipt of bail-out rilonacept, similar to pain. These results provide support for the broader benefit of rilonacept treatment beyond pain, when administered on top of conventional therapies and as mono-therapy, providing evidence of its potential to improve HRQoL in this patient population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Kiniksa Pharmaceuticals, Ltd.