Date: Monday, October 22, 2018
Session Title: Osteoarthritis and Joint Biology – Basic Science Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: The anti-ADAMTS-5 Nanobody®, M6495, is a first-in-class, highly selective, bifunctional Nanobody® and a potent inhibitor of ADAMTS-5, with the potential to be the first self-administered disease modifying osteoarthritis drug (DMOAD). A model-based approach was used to explore the relationship between plasma concentrations of M6495 and the reduction of serum concentrations of the target engagement biomarker, the ADAMTS-5 generated neo-epitope of aggrecan (ARGS), in cynomolgus monkeys.
Methods: A dedicated single dose pharmacokinetics and pharmacodynamics (PK/PD) study was conducted in cynomolgus monkeys receiving subcutaneous (SC) M6495 at doses ranging from 0.01 to 6 mg/kg or vehicle. An additional group received intravenous M6495 which allowed the estimation of bioavailability. Both M6495 and ARGS concentrations were measured over time. The data were then pooled with PK/PD data collected in a separate multiple-dose study in cynomolgus monkeys that received weekly M6495 at doses up to 150 mg/kg. Plasma concentrations of M6495 and decrease in ARGS serum concentrations upon drug administration were modelled with a non-linear mixed effects PK/PD model.
Results: A 2-compartment model including linear and non-linear elimination from the central compartment and first order absorption upon SC administration, adequately described the drug concentration-time profiles of M6495. The non-linear PK indicated a mechanism of target-mediated drug disposition which can be saturated at higher serum concentrations of M6495. ARGS levels decreased upon drug administration, with higher decrease demonstrable at higher doses (see Figure), reaching levels below the lower limit of quantification (LLOQ) for M6495 doses of 6 mg/kg and higher, indicating a strong inhibition of ADAMTS-5 (higher than 70%). Furthermore, the bioavailability after SC injection was estimated to be close to 100%. A marked decrease in serum ARGS levels, lasting several weeks, could already be observed after a single dose of M6495. The decrease in ARGS serum concentrations was delayed in relation to the exposure, and could be described with an indirect response model.
Conclusion: A single injection of the anti-ADAMTS-5 Nanobody®, M6495, in cynomolgus monkeys lead to a long-lasting decrease in ARGS at the highest dose tested, indicating a long-term inhibition of ADAMTS-5. This PK/PD model can be used to explore the exposure/pharmacodynamic response relationship between M6495 serum concentrations and the ARGS serum biomarker.
To cite this abstract in AMA style:Pereira J, Ottevaere I, Serruys B, Dejonckheere E, Bay-Jensen AC, Siebuhr AS, El Bawab S, Ladel C, Lindemann S. Pharmacokinetic and pharmacodynamic modelling of the novel anti-ADAMTS-5 nanobody M6495 using the neo-epitope ARGS as a biomarker [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/pharmacokinetic-and-pharmacodynamic-modelling-of-the-novel-anti-adamts-5-nanobody-m6495-using-the-neo-epitope-args-as-a-biomarker/. Accessed September 26, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacokinetic-and-pharmacodynamic-modelling-of-the-novel-anti-adamts-5-nanobody-m6495-using-the-neo-epitope-args-as-a-biomarker/