Giulia Lestini, Luyuan Qi, Marina Savelieva, Jing Yu, Irina Baltcheva.
Pharmacometrics, Analytics GDD, Novartis
Introduction: The complement system (CS) is an important component of innate immunity and can be stimulated by three pathways. Iptacopan is the first oral complement inhibitor targeting factor B to selectively inhibit the alternative complement pathway (AP) that is approved by the FDA for paroxysmal nocturnal hemoglobinuria (PNH). Several other indications are driven by AP dysregulation, including C3 glomerulopathy (C3G), a rare, aggressive kidney disease with genetic and acquired links to AP dysregulation [1,2]. In the Phase II trial NCT03832114, the effects of various doses of iptacopan were explored in patients with C3G (n=16) as well as transplanted C3G patients (n=11), as the risk of C3G recurrence in post-kidney transplantation remains notably high.
Objectives:
- To characterize the exposure-response (ER) relationship between iptacopan and serum C3 levels (a biomarker of particular interest for C3G) and clinical surrogate parameter outcomes such as the urinary protein to creatinine ratio “UPCR” in C3G patients.
- To explore potential differences in the treatment effect of iptacopan between C3G patients with and without a history of kidney transplantation.
- To further explore iptacopan dose supporting its registration in C3G.
Methods:
Modeling of serum C3 levels used data from the Phase II study NCT03832114 in C3G (n=27). UPCR data from 24h urine collection from NCT03832114 were pooled with the iptacopan Phase II study NCT03373461 in immunoglobulin A nephropathy (IgAN) (n=112) with potential difference between diseases (C3G vs IgAN) explored in the covariate analysis.
A longitudinal mixed effects modeling approach was applied to serum C3. C3 increased monotonically, with saturation of effect and without apparent time lag, which was expected based on iptacopan’s mode of action. Therefore, a direct response sigmoid Emax model was considered as most appropriate and biologically plausible structural model. The sigmoid Emax model was characterized by the following parameters: baseline biomarker level, a maximal effect (Emax), the concentration at which the effect is half-maximal (EC50), and possibly a shape parameter (gamma). Another important parameter was calculated based on EC50 and gamma: EC90, the concentration at which the effect is 90% of the maximum. It was assumed that exposures beyond EC90 are linked with near-maximal biomarker response (maximal efficacy). The exposure metric driving the response was the observed time-matching PK data. Covariates were explored.
An Emax indirect response model characterizing the observed longitudinal UPCR and the impact of iptacopan on UPCR over time was built. This kinetic-pharmacodynamic (KPD) model linked the amount of drug given to the longitudinal UPCR data, and relevant covariates (e.g., transplantation status and disease) were tested. The parameters of the KPD model were the elimination rate from the biophase (kpd); the drug effect on the production rate (Kin) of UPCR, baseline UPCR and the drug’s in vivo apparent potency at steady state (EDK50).
Results: The final ER model was able to adequately describe serum C3 response at different iptacopan concentrations in C3G patients. The individual baseline C3 level had a significant impact on Emax, whereas there was no effect of age, weight, gender, ethnicity, nor kidney transplantation on the response to treatment with iptacopan. Population EC90 of C3 was of 2100 ng/ml. Concentration levels of 200 mg bid were near the plateau of the ER relationship for C3. The maximum % increase from baseline of C3 (Emax) was estimated as 180%.
The final KPD model adequately described the longitudinal UPCR response under iptacopan treatment with different doses. Transplant status and disease (C3G vs IgAN) were statistically significant covariates on baseline UPCR, which was estimated as 390 mg/mmol for C3G patients with native kidney. No difference in treatment effect (EDK50) according to either transplantation status or disease (C3G vs IgAN) was detected. The EDK50 parameter, was estimated as 285 mg/day and its inter-individual variability was high (250%). UPCR 24h showed maximum reduction in the 200 mg bid treatment group.
Conclusions: The drug effect on C3G-specific outcomes, including serum C3 and UPCR showed no differences between C3G patients with or without kidney transplantation, similarly to previous observations regarding various AP biomarkers [5]. Iptacopan 200 mg bid led to maximal inhibition of AP biomarkers [5], C3 levels increase and proteinuria reduction in C3G patients.
References:
[1] Barbour TD, Ruseva MM, Pickering MC (2016). Update on C3 glomerulopathy. Nephrol Dial Transplant; 31(5):717-25.
[2] Thomas S, Ranganathan D, Francis L, et al (2014). Current concepts in C3 glomerulopathy. Indian J Nephrol; 24(6):339-48.
[3] Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, et al (2014). C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol; 9(1):46-53.
[4] Bomback AS, Santoriello D, Avasare RS, et al (2018). C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int; 93(4):977-85.
[5] Baltcheva I, Bartels C, Valentin MA, et al; Exposure-Response Relationships between the Factor B Inhibitor Iptacopan and Complement Biomarkers in Healthy Volunteers and Patients (Pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH), C3 Glomerulopathy (C3G) or IgA Nephropathy (IgAN). Blood 2023; 142 (Supplement 1): 5640. doi: https://doi.org/10.1182/blood-2023-180004
Reference: PAGE 32 (2024) Abstr 11098 [www.page-meeting.org/?abstract=11098]
Poster: Drug/Disease Modelling - Other Topics