Population PKPD modeling of RO7046015 (PRX002/RG7935), an Anti--Synuclein Monoclonal Antibody for the treatment of Parkinson’s Disease
Valérie Cosson (1), Vincent Buchheit (1), Jay Soto (2), Daniel Ness (2), Martin Koller (2), Meret Martin-Facklam (1) and Bénédicte Ricci (1)
(1) Clinical Pharmacology, Pharmaceutical Sciences, Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, Switzerland, (2) Prothena Biosciences Inc, South San Francisco, CA, USA
Objectives: RO7046015 (also known as PRX002 or RG7935), a monoclonal antibody (Ab) targeting alpha-synuclein (aSyn), is currently in development for the treatment of Parkinson’s disease (PD). The objectives of the analysis are to describe the PK of RO7046015 and the PKPD relationship between free RO7046015 serum concentrations and free and total aSyn serum concentrations in healthy subjects during the Single Ascending Dose (SAD) study and PD patients during the Multiple Ascending Dose (MAD) study using population approach.
Methods: RO7046015 and aSyn samples were collected in two phase 1 double-blind, placebo-controlled studies: a SAD in healthy subjects and a MAD (3 doses administered 4 weeks apart) study in PD patients. Healthy subjects were enrolled into 5 ascending-dose cohorts and randomly assigned to receive an intravenous RO7046015 dose of 0.3, 1.0, 3.0, 10, 30 mg/kg or placebo. PD patients were enrolled into 6 ascending-dose cohorts and randomly assigned to receive an intravenous RO7046015 dose of 0.3, 1.0, 3.0, 10, 30, 60 mg/kg or placebo. In total, data from 40 healthy subjects and from 80 PD patients were included in this analysis. A sequential approach [1, 2] was followed: RO7046015 serum concentrations were fitted first to a pharmacokinetic model and subsequently the relationship between free, total aSyn and RO7046015 serum concentrations were fitted to a full target-Ab binding model [3]. All models were developed using non-linear mixed-effects modelling implemented in NONMEM V7.2.0 [4]. Simulations using the PK model were performed to compare the distribution of exposure metrics between weight-based dosing and flat dosing.
Results: The PK of RO7046015 was adequately described by a 3-compartment mammillary disposition model with first-order elimination. Good precision of the fixed and BSV on CL and V1 were obtained with RSE below 25%. The PK of RO7046015 was similar in healthy subjects and PD patients. The estimated clearance was equal to 0.583 L/day, approximately 2.5-3 fold higher than predicted for a typical IgG1 [5]. The population effective half-life equals ~14 days. As for many therapeutic monoclonal antibodies, body weight was found to have a significant effect on the PK of RO7046015, with both clearances and volumes function increasing with weight with a power of 0.837 for clearances and of 0.625 for volumes. When compared with the value of CL in a patient weighing 76 kg, the CL decreased by 34% for patients with the lowest weight (i.e., 46 kg) and increased by 32% for those with the highest weight (i.e., 106 kg). Similarly, weight positively correlated with V1, leading to a deviation from typical of −29% for patients with the lowest weight and +26% for those with the highest weight. The simulations showed that the distributions of the exposure metrics largely overlap between the weight-based and flat dosing.
The PKPD relationship between free RO7046015 and both free and total aSyn serum levels was adequately described with a full target-antibody binding model. Reasonably good precision of the fixed and random effect parameters were obtained: the RSE were between 5 and 38% except for BSV on complex elimination for which the RSE was 61%. The estimated in vivo KD is found similar in healthy subjects (75 nM) and in patients (90nM). The comparison of the simulated PKPD profiles of free and total aSyn shows a quasi-complete overlap between the two populations. The steady state for decrease of free aSyn and increase of total aSyn is achieved after 5 monthly IV administrations of RO7046015. At steady-state, RO7046015 maintains the free aSyn serum concentrations below 22, 48 and 67 % of the baseline over the dosing interval of 10, 30 and 60 mg/kg dose, respectively.
Conclusions: As RO7046015 is always in excess compared to free aSyn in serum even at low doses, the target-mediated elimination pathway of RO7046015 is saturated and its PK is linear over the dose range. The PK of RO7046015 supports the use of flat dosing. A trend for higher exposure in patients with lower weight can be mitigated by selecting a lower dose for these patients. The PKPD model confirms a clear dose-dependent binding of free RO7046015 to free aSyn in serum.
References:
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