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Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.

ABSTRACT: Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.

SUBMITTER: Peffault de Latour R

PROVIDER: S-EPMC7687070 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.

Peffault de Latour Régis R Brodsky Robert A RA Ortiz Stephan S Risitano Antonio M AM Jang Jun H JH Hillmen Peter P Kulagin Alexander D AD Kulasekararaj Austin G AG Rottinghaus Scott T ST Aguzzi Rasha R Gao Xiang X Wells Richard A RA Szer Jeff J

British journal of haematology 20200524 3

Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications ...[more]

PMID: 32449174

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Project description:BackgroundCemdisiran, an N-acetylgalactosamine (GalNAc) conjugated RNA interference (RNAi) therapeutic, is currently under development for the treatment of complement-mediated diseases by suppressing liver production of complement 5 (C5) protein. This study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cemdisiran in healthy subjects and in patients with paroxysmal nocturnal hemoglobinuria (PNH) in order to support dose selection for late-stage clinical trials.MethodsHealthy volunteers (HVs; n = 32, including 12 Japanese subjects) were randomized (3:1) to receive single doses of subcutaneous cemdisiran (50-900 mg) or placebo, or repeat doses of subcutaneous cemdisiran (100-600 mg) or placebo weekly, biweekly, weekly/biweekly, or weekly/monthly for 5, 8, or 13 weeks (n = 24). Cemdisiran 200 or 400 mg was administered weekly in an open-label manner, for varying durations, as monotherapy in three eculizumab-naïve PNH patients or in combination with eculizumab in three PNH patients who were receiving stable label doses of eculizumab (900 or 1200 mg biweekly) before the start of the study. After the last dose of cemdisiran, patients were followed for safety and ongoing pharmacologic effects with the eculizumab regimen (600 or 900 mg every month).ResultsIn HVs, cemdisiran was rapidly converted to a major active metabolite, AS(N-2)3'-cemdisiran, both declining below the lower limit of quantification (LLOQ) in plasma within 48 h, and showing minimal renal excretion. AS(N-2)3'-cemdisiran exhibited more than dose-proportional PK. The C5 protein reductions were dose-dependent, with > 90% reduction of C5 protein beginning on days 21-28 and maintained for 10-13 months following single and biweekly doses of 600 mg. The dose-response relationship, described by an inhibitory sigmoid maximum effect (Emax) model, estimated half-maximal effective dose (ED50) of 14.0 mg and maximum C5 reduction of 99% at 600 mg. The PK and PD were similar between Japanese and non-Japanese subjects, and PNH patients and HVs. One of 48 subjects tested transiently positive for antidrug antibody with low titer, with no impact on PK or PD. In PNH patients, C5 suppression by cemdisiran enabled effective inhibition of residual C5 levels with lower dose and/or dosing frequency of eculizumab, which was maintained for 6-10 months after the last dose of cemdisiran.ConclusionsConsistent with the PK/PD properties of liver targeting GalNac conjugates, cemdisiran and AS(N-2)3'-cemdisiran plasma concentrations declined rapidly while showing rapid and robust C5 suppression maintained up to 13 months following single and multiple doses, which indicates long residence times of cemdisiran within hepatocytes. The long PD duration of action in liver, low immunogenicity and acceptable safety profiles enables low, infrequent SC dosing and support further evaluation of cemdisiran in complement-mediated diseases as monotherapy or in combination with a C5 inhibitor antibody.Clinical trial registration noNCT02352493.

Project description:AimsParoxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening intravascular hematologic disorder with significant morbidity and premature mortality. Clinical trials (NCT02946463 and NCT03056040) comparing ravulizumab with eculizumab for PNH have supported the non-inferiority of the former and similar safety and tolerability. This secondary analysis compared PNH trial participants after 26 weeks on either treatment (n = 438) to a general-population sample (GenPop) (n = 15,386) and investigated response-shift effects.MethodsMultivariate analysis of covariance (MANCOVA) investigated function and symptom scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 of people with PNH as compared to GenPop, after covariate adjustment. Risk-factor groups were created based on clinical indicators known to be associated with worse PNH outcomes, and separate MANCOVAs were computed for lower- and higher-risk-factor groups. Differential item functioning (DIF) analyses examined whether item response varied systematically (1) by treatment, (2) compared to GenPop, and (3) over time, the latter two suggesting and reflecting response-shift effects, respectively. DIF analyses examined 24 items from scales with at least two items. Recalibration response shift was operationalized as uniform DIF over time, reflecting the idea that, for a given group, the difficulty of endorsing an item changes over time, after adjusting for the total subscale score. Reprioritization response shift was operationalized as non-uniform DIF over time, i.e., the relative difficulty of endorsing an item over time changes across the total domain score.ResultsAcross PNH risk-factor levels, people who had been on either treatment for 26 weeks reported better-than-expected functioning and lower symptom burden compared to GenPop. Ravulizumab generally showed larger effect sizes. Results were similar for lower and higher PNH risk factors, with slightly stronger effects in the former. DIF analyses revealed no treatment DIF, but did uncover group DIF (9 items with uniform DIF, and 11 with non-uniform) and DIF over time (7 items with uniform DIF, and 3 with non-uniform).ConclusionsThis study revealed that people with PNH on ravulizumab or eculizumab for 26 weeks reported QOL levels better than those of the general population. Significant effects of DIF by group and DIF over time support recalibration and reprioritization response-shift effects. These findings suggest that the treatments enabled adaptive changes.

Dataset Information

Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.

Publications

Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.

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