好色先生

好色先生

Explore the latest content from across our publications

Log In

Forgot Password?
Create New Account

Loading... please wait

Abstract Details

Pharmacokinetics, Pharmacodynamics, and Exposure-response Analyses of Ocrelizumab in Patients With Multiple Sclerosis
Multiple Sclerosis
N4 - Neuroscience in the Clinic: Immunotherapies in Neurological Disease (2:00 PM-2:15 PM)
001

Ocrelizumab is a CD20+ B cell-selective monoclonal antibody approved for treatment of relapsing MS (RMS) and primary progressive MS (PPMS).

To describe the population pharmacokinetics, pharmacodynamics, and exposure-efficacy/safety relationships of ocrelizumab in patients with multiple sclerosis (MS).

Ocrelizumab Phase II/III data were analyzed using a non-linear mixed-effects model to describe ocrelizumab pharmacokinetics and assess covariate effects. Exposure-response relationships for clinical efficacy (annualised relapse rate [ARR], 12-/24-week confirmed disability progression [CDP]) and safety parameters (serious adverse events, serious infections, infusion related reactions) were assessed.

A two-compartment model with time-dependent clearance and body weight as main covariate described accurately ocrelizumab pharmacokinetics in patients with RMS (N=941) and PPMS (N=482). Exposure (area under the serum concentration–time curve) was 26% higher in patients with RMS <60kg and 21% lower in those >90kg versus a 75kg reference patient. Blood B-cell depletion correlated with ocrelizumab exposure. Patients with RMS obtained similar benefit with regards to ARR independent of exposure, however, risk reductions in 12-/24-week CDP was exposure-dependent in patients with RMS (12-week CDP hazard ratios by exposure quartile 1–4: 0.77, 0.80, 0.45 and 0.33 versus interferon-beta 1a, respectively) and PPMS (12-week CDP hazard ratios by exposure quartile 1–4: 0.87, 0.83, 0.78 and 0.59 versus placebo, respectively). All safety parameters assessed were similar across the exposure quartiles.

Higher ocrelizumab exposure led to greater B-cell depletion. Clinical benefit on ARR was independent of exposure, but greater risk reduction in CDP was observed with higher ocrelizumab exposure in patients with RMS and PPMS, suggesting that higher ocrelizumab exposure (and greater B-cell depletion) is important for control of disability progression. The fact that effects are more pronounced in patients in higher exposure groups indicates that the current approved dose is closer to the lower part of the dose-response curve. The safety profile was similar across all exposure quartiles.

Authors/Disclosures
Stephen L. Hauser, MD (UCSF Weill Institute for Neurosciences)
PRESENTER
Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NGM Bio. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nurix Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gilead. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Accure. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Annexon. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hinge Therapeutics. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Neurona. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Roche that is relevant to AAN interests or activities. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Novartis that is relevant to AAN interests or activities.
Heidemarie Kletzl Heidemarie Kletzl has received personal compensation for serving as an employee of Hoffmann-La Roche.
No disclosure on file
No disclosure on file
Francois Mercier No disclosure on file
No disclosure on file
Qing Wang Qing Wang has nothing to disclose.
Fabian Model No disclosure on file
Ludwig Kappos, MD, FAAN (RC2NB, University Hospital Basel) The institution of Dr. Kappos has received research support from Bayer. The institution of Dr. Kappos has received research support from Biogen. The institution of Dr. Kappos has received research support from Genentech. The institution of Dr. Kappos has received research support from Genzyme. The institution of Dr. Kappos has received research support from Janssen. The institution of Dr. Kappos has received research support from Merck Serono. The institution of Dr. Kappos has received research support from Minoryx. The institution of Dr. Kappos has received research support from Novartis. The institution of Dr. Kappos has received research support from Roche. The institution of Dr. Kappos has received research support from Sanofi. The institution of Dr. Kappos has received research support from Santhera. The institution of Dr. Kappos has received research support from Swiss MS Society, Swiss National Research Foundation, European Union, Roche Research Foundation, Innosuisse. The institution of Dr. Kappos has received research support from Shionogi. The institution of Dr. Kappos has received research support from Japan Tobacco. The institution of Dr. Kappos has received research support from Auriga Vision AG. The institution of Dr. Kappos has received research support from EMD Serono. The institution of Dr. Kappos has received research support from Glaxo Smith Kline. The institution of Dr. Kappos has received research support from Wellmera AG. The institution of Dr. Kappos has received research support from Eli Lilly (Suisse) SA. The institution of Dr. Kappos has received research support from Bristol Myers Squibb. The institution of Dr. Kappos has received research support from Celltrion Inc. Dr. Kappos has received intellectual property interests from a discovery or technology relating to health care.