The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.

Does partial muscle reinnervation preserve future re-innervation potential?

INTRODUCTION: Late revision nerve surgery for incomplete motor recovery due to partial reinnervation would improve muscle function if all muscle fibers were protected from developing denervation atrophy. METHODS: Sixty immature Sprague-Dawley rats underwent the following tibial nerve manipulations (n = 15/group): group A, partial denervation (two thirds of nerve resected and the remaining one third crushed), revision repair at 8 months; group B, partial denervation; group C, complete denervation, immediate reconstruction; group D, complete denervation, reconstruction at 8 months; and group E, control. Final testing at 11 months included muscle force, weight, and histology. RESULTS: Muscle weight was significantly (P < 0.05) different among all groups (highest to lowest: E > B > C > A > D), and force was significantly lower in groups A and D compared with E. Muscle fiber cross-sectional area was statistically smaller in group A than in groups B, C, or E. DISCUSSION: Partial reinnervation still allowed substantial muscle recovery, but it did not preserve the non-innervated muscle fibers. Muscle Nerve 56: 1143-1148, 2017.

Population pharmacokinetics of IND/GLY (indacaterol/glycopyrronium) in COPD patients.

OBJECTIVE: Indacaterol/glycopyrronium (IND/GLY) is a fixed-dose combination (FDC) of indacaterol, an inhaled long-acting ß2-agonist (LABA), and glycopyrronium, an inhaled long-acting muscarinic antagonist (LAMA), developed as a maintenance bronchodilator treatment for patients with chronic obstructive pulmonary disease (COPD). A population pharmacokinetic (PK) analysis was performed to describe the PK profiles of indacaterol and glycopyrronium following the twice daily (b.i.d.) and once daily (o.d.) inhalation regimens as FDC or as monotherapies and to determine the effect of covariates. METHODS: PK data in 556 COPD patients were pooled from three phase 3 studies. Two phase 3 studies investigated IND/GLY 27.5/12.5 µg b.i.d. and the third study investigated IND/GLY 110/50 µg o.d. Body weight was included in the model with fixed allometric coefficients for indacaterol and glycopyrronium. RESULTS: Statistically significant effects of smoking, age, and sex on apparent clearance of indacaterol; smoking, and estimated glomerular filtration rate at baseline on apparent clearance and Japanese ethnicity on apparent central volume of distribution of glycopyrronium were identified. CONCLUSION: Systemic exposure to indacaterol and glycopyrronium was shown to be dose-proportional and time-independent following inhalation either as monotherapies or FDC. None of the identified covariate effects was judged to be clinically relevant. There is no PK drug-drug interaction between indacaterol and glycopyrronium in its FDC.

A program for individual and population optimal design for univariate and multivariate response pharmacokinetic-pharmacodynamic models.

The design of pharmacokinetic and pharmacodynamic experiments concerns a number of issues, among which are the number of observations and the times when they are taken. Often a model is used to describe these data and the pharmacokinetic-pharmacodynamic behavior of a drug. Knowledge of the data analysis model at the design stage is beneficial for collecting patient data for parameter estimation. A number of criteria for model-oriented experiments, which maximize the information content of the data, are available. In this paper we present a program, Popdes, to investigate the D-optimal design of individual and population multivariate response models, such as pharmacokinetic-pharmacodynamic, physiologically based pharmacokinetic, and parent drug and metabolites models. A pre-clinical and clinical pharmacokinetic-pharmacodynamic model describing the concentration-time profile and effect of an oncology compound in development is used for illustration.