Pharmacokinetic/Pharmacodynamic framework to support the subcutaneous dosing regimen of nemolizumab in subjects with Prurigo Nodularis
Floris Fauchet (1), Wannee Kantasiripitak (1), Petra Jauslin (1), Vincent Duval (1), Antonio Goncalves (1), Anna Largajolli (1), Zarif Jabbar Lopez (2), Michael Graeber (3), Christophe Piketty (4), Patricia Fleuranceau Morel (3), Luca Loprete (4), Nathalie Wagner (3).
(1) Certara Strategic Consulting , (2)Galderma R&D, Basel, Switzerland, (3) Galderma R&D, Dallas, USA , (4) Galderma R&D, Zug, Switzerland
Introduction: Nemolizumab (NEMO) is a humanized anti-interleukin-31 (IL-31) receptor A monoclonal antibody. This novel mechanism of action is expected to have a therapeutic benefit in patients with prurigo nodularis (PN). Previous pharmacokinetic/ pharmacodynamic (PK/PD) models built from pooled data from subjects enrolled in phase 2 studies has been applied to select the optimal subcutaneous (SC) dose for the Phase 3 pivotal studies: 60 mg loading dose (LD) with 30 mg every four weeks (Q4W) for subjects <90 kg and 60 mg Q4W for subjects ≥90 kg. These PK/PD models have been updated with Phase 3 data and exposure-response (ER)-Safety assessment was performed to support the proposed SC dosing regimen in adult subjects with PN.
Objectives:
- To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationships between NEMO serum concentrations and the assessments of clinical efficacy: weekly average peak pruritus numerical rating score (PP NRS) and investigator global assessment (IGA)
- To assess the ER relationship for adverse events (AEs)
- To support the proposed dosing regimen in adult and adolescent patients with PN
Methods: Efficacy data were collected from 619 subjects with PN from 3 randomized placebo-controlled clinical studies (one Phase 2 study and two Phase 3 studies).
NEMO concentrations were described by a one-compartment population pharmacokinetic (popPK) model with linear elimination, first order absorption with lag time and a dose effect on bioavailability. Bodyweight (BW) was identified as a relevant predictor of NEMO exposure.
The PK/PD relationship between NEMO and PP NRS was described by an indirect response model (IRM) with a combined inhibiting effect of nemolizumab and placebo on the rate of production of the PD signal. For IGA assessment, a continuous time Markov model (CTMM) was applied based on a previously developed CTMM [1].
Linear logistic regression models were applied for the safety ER analysis considering the following AEs: eczematous reactions, headache, newly diagnosed asthma or worsening of asthma, facial and peripheral edema.
PP NRS and IGA models were implemented in NONMEM Software 7.4 [2] ER analysis was conducted in R.
As the exposure of NEMO decreases with increasing body weight, PK/PD simulations were conducted to assess the impact of BW on clinical efficacy endpoints of the Phase 3 studies. The proportion of IGA and PP NRS responders were evaluated in 3 different arms. 1000 virtual patients per arm were simulated by resampling of the phase 3 study subjects characteristics. The virtual patients received the dosing regimen of the Phase 3 studies:
- Arm 1: Low BW subject population (range: 39 to 89 kg); 30 mg Q4W with 60 mg LD
- Arm 2: High BW subject population (range: 90 to 181 kg); 30 mg Q4W with 60 mg LD
- Arm 3: High BW subject population (range: 90 to 181 kg): 60 mg, Q4W
Results:
An IRM with a maximum inhibitory effect of NEMO and a constant placebo effect on the production of the PP NRS response was found to adequately describe PP NRS time course. The NEMO amount in the turnover compartment was constrained by defining a logit-transformed PP NRS score. A similar proportion of PP NRS responders were observed in the 3 arms, suggesting that the variability in systemic exposure due to BW had no clinically meaningful impact on PP NRS responders.
A 4-compartment CTMM was used to describe IGA observations with a common linear stimulating drug effect on all descending transitions ([λdesc]) and a linear inhibiting drug effect on all ascending transitions ([λasc]). An effect of baseline IGA score on all λasc was characterized, higher IGA baseline values being associated with higher λasc, suggesting a lower response rate for subjects with severe IGA. A lower IGA response was predicted for subjects with BW ≥ 90 kg receiving the 30 mg Q4W regimen with a 60-mg LD compared to the 2 other arms.
Exposure-safety analysis did not evidence significant ascending relationship between nemolizumab exposure and the incidence of AEs.
Overall, PK/PD simulations showed a similar efficacy response for the 2 clinical primary endpoints, PP NRS and IGA responder rate, in both BW groups (<90 kg and ≥90 kg) when
the dose was adjusted according to BW with a cutoff of 90 kg.
Conclusion: Current framework was used to support the proposed subcutaneous dosing regimen in adult patients with PN, i.e. 30 mg Q4W (60 mg LD) with a dose adjustment (60 mg) based on BW considering a cutoff of 90 kg.
References:
[1] Shindler et al. PAGE 28 (2019) Abstr 9178 [www.page-meeting.org/?abstract=9178
[2] Beal SL et al. NONMEM 7.3.0 users guides. (1989–2013). Hanover: ICON Development Solutions.