Yanan Zheng

Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies

Introduction In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. Methods LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies. Results The median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. Conclusions These data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment. Trial registration numbers The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids

BACKGROUND Asthma is a disease with marked heterogeneity in its clinical course and response to treatment. IL-13 is central to type 2 inflammation, which contributes to many key features of asthma. Lebrikizumab is an anti-IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy, especially in periostin-high patients. OBJECTIVE This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of lebrikizumab in asthmatic patients not receiving inhaled corticosteroids. METHODS Patients were randomized to receive 125, 250, or 500 mg of lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period. The primary efficacy end point was the relative change in prebronchodilator FEV1 from baseline to week 12. RESULTS A total of 212 patients were randomized. The mean relative change in FEV1 was numerically higher in all lebrikizumab dose groups versus the placebo group, although the difference was neither statistically nor clinically significant. There were no meaningful differences in changes in FEV1 between the dose groups and the placebo group by the periostin subgroup. Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo (P < .001), and results were similar by the periostin subgroup, with no apparent differences between doses of lebrikizumab. Lebrikizumab was generally well tolerated. CONCLUSION Blocking IL-13, a single cytokine, in this population of asthmatic patients is insufficient to improve lung function. There is evidence that IL-13 blockade may improve disease control, as measured by prevention of protocol-defined treatment failure in these patients.

The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge.

Interleukin 13 (IL13) is a T‐helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with lebrikizumab, an anti‐IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV1) in a subset of subjects with uncontrolled asthma.

A guide to rational dosing of monoclonal antibodies.

Background and ObjectiveDosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach.MethodsIn this analysis, the body weight-based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (θbw_cl) and on the central volume of distribution (θbw_vl). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [Cmin] and peak serum concentration [Cmax]) was compared between body weight-based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study.ResultsResults from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of θbw_cl and θbw_vl in the population pharmacokinetic model are <0.5, fixed dosing results in less variability and less deviation than body weight-based dosing; when both θbw_cl and θbw_vl are >0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either θbw_cl or θbw_vl is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (θbw_cl and θbw_vl <0.5 or ∼0.5). The difference of variability in exposure between body weight-based and fixed dosing is generally less than 20% and the percentages of deviation for light and heavy subpopulations are less than 40%.ConclusionsThe analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials.

Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration

Subcutaneous (SC) delivery is a common route of administration for therapeutic monoclonal antibodies (mAbs) with pharmacokinetic (PK)/pharmacodynamic (PD) properties requiring long-term or frequent drug administration. An ideal in vivo preclinical model for predicting human PK following SC administration may be one in which the skin and overall physiological characteristics are similar to that of humans. In this study, the PK properties of a series of therapeutic mAbs following intravenous (IV) and SC administration in Göttingen minipigs were compared with data obtained previously from humans. The present studies demonstrated: (1) minipig is predictive of human linear clearance; (2) the SC bioavailabilities in minipigs are weakly correlated with those in human; (3) minipig mAb SC absorption rates are generally higher than those in human and (4) the SC bioavailability appears to correlate with systemic clearance in minipigs. Given the important role of the neonatal Fc-receptor (FcRn) in the PK of mAbs, the in vitro binding affinities of these IgGs against porcine, human and cynomolgus monkey FcRn were tested. The result showed comparable FcRn binding affinities across species. Further, mAbs with higher isoelectric point tended to have faster systemic clearance and lower SC bioavailability in both minipig and human. Taken together, these data lend increased support for the use of the minipig as an alternative predictive model for human IV and SC PK of mAbs.

Translational pharmacokinetics and pharmacodynamics of an FcRn-variant anti-CD4 monoclonal antibody from preclinical model to phase I study.

MTRX1011A is a humanized anti‐CD4 antibody with an amino acid substitution (N434H) to improve its binding to the neonatal Fc receptor (FcRn). Pharmacokinetic/pharmacodynamic (PK/PD) data in baboons suggest that the increased binding to FcRn reduces the nonspecific elimination rate (Kel) of MTRX1011A by ~50% but does not affect its PK–PD relationship. The human PK/PD data of MTRX1011A from a phase I study in patients with rheumatoid arthritis (RA) were compared with those previously reported for TRX1, its predecessor antibody, using population PK–PD modeling. The results suggest a comparable PK–PD relationship and no significant difference between the Kel values of the two antibodies. However, the results may have been confounded by the differences in the clinical populations in which the two antibodies were studied and the presence of preexisting immunoglobulin M (IgM) antibodies in the RA sera that recognize N434H in MTRX1011A. This study highlights the challenges in translating from animal studies to human application the effects of FcRn‐directed mutations on the PK of monoclonal antibodies.

MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a Phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments

IntroductionThe purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA).MethodsIn the single ascending dose (SAD) portion of the study, patients received single doses of a placebo or MTRX1011A at 0.3, 1.0, 3.5 and 7.0 mg/kg intravenously (IV) or 1.0 and 3.5 mg/kg subcutaneously (SC), followed by five weeks of evaluation. In the multi-dose (MD) portion of the study, placebo or MTRX1011A was administered weekly for eight doses at 1.5 or 3.5 mg/kg SC, or 5 mg/kg IV, followed by eight weeks of evaluation.ResultsMTRX1011A was well tolerated in the SAD phase up to 7 mg/kg IV and in the MD phase up to 1.5 mg/kg SC. At weekly doses of 3.5 mg/kg SC and 5 mg/kg IV, a moderate pruritic papular rash was observed in some MTRX1011A-treated patients, which was considered a dose-limiting toxicity for this clinical indication. No serious adverse events occurred in any cohort. Reduction in disease activity was modest. PD assessments demonstrated that MTRX1011A induced a dose-dependent down-modulation of CD4 expression on peripheral blood CD4 T cells, CD4 receptor occupancy, increases in serum sCD4-MTRX1011A complexes and up-regulation of CD69 on T cells, but was non-depleting.ConclusionsThe maximum tolerated dose of MTRX1011A was 1.5 mg/kg SC administered weekly. At this dose MTRX1011A did not achieve maximum PD activity expected to be required for reduction in disease activity.