Amy Meng

Aims: Filgotinib is a potent, oral, JAK1‐preferential inhibitor for the treatment of rheumatoid arthritis (RA). This report describes exposure‐response (ER) analyses of filgotinib for dose confirmation based on three phase 3 and two phase 2 studies in moderate to severe RA patients.Methods: The pharmacokinetic exposures used in ER analyses were derived from population pharmacokinetic analysis. The exposure‐efficacy relationships were assessed for efficacy endpoints (ACR20/50/70 and DAS28) over effective area under curve (AUC_eff), the combined exposures of filgotinib and GS‐829845 (major, active metabolite), with nonlinear logistic regression models developed. Also, a t‐test was performed to compare the exposure between subjects who achieved response and those who did not. For the ER analyses of safety, exposures were examined between subjects who experienced and who did not experience the evaluated safety events, which was conducted separately for filgotinib and GS‐829845.Results: The nonlinear logistic regression showed increasing response with increasing exposure, with exposures at 200 mg dose primarily residing on the curve plateau. Also, AUC_eff was significantly higher in the subjects who achieved responses compared to those who did not (10 900 vs 9900 h*ng/mL for ACR20, P value < .0001). For exposure‐safety analyses, filgotinib and GS‐829845 exposures were similar irrespective of the presence/absence of the evaluated safety endpoints, indicating no exposure‐safety relationship for common treatment‐emergent adverse events (TEAEs)/laboratory abnormalities and serious TEAEs/infections.Conclusions: ER analyses confirmed that filgotinib produced more robust therapeutic effects across the exposure range observed at 200 mg once daily compared to lower doses, and collectively with the lack of exposure‐safety relationship, the 200 mg once daily dose was supported for commercialization.

Tirabrutinib is an irreversible, small-molecule Bruton’s tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU^®) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two Phase 1 studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis (RA). The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either QD or BID, with adequate BTK occupancy (>90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.

Aims:Filgotinib is a potent, oral, JAK1-preferential inhibitor for the treatment of rheumatoid arthritis (RA). This report describes exposure-response (ER) analyses of filgotinib for dose confirmation based on three Phase 3 and two Phase 2 studies in moderate to severe RA patients. Methods:The PK exposures used in ER analyses were derived from population pharmacokinetic analysis. The relationship between filgotinib exposures and various efficacy endpoints (ACR20/50/70 and DAS28) was assessed over octile groups of exposures by using combined exposures of filgotinib and GS-829845 (major, active metabolite). For the ER analyses of safety, exposures were examined between subjects who experienced and who did not experience the evaluated safety events, which was conducted separately for filgotinib and GS-829845. Results:Exposure efficacy relationships consistently revealed high response rates across the exposure range for filgotinib 200 mg once daily dose. A trend of increasing response with increasing exposure was observed over the exposure range for the primary and multiple secondary efficacy endpoints, with exposures associated with the 200 mg dose primarily residing on the curve plateau. For exposure-safety analyses, filgotinib and GS-829845 exposures were similar irrespective of presence/absence of the evaluated safety endpoints, indicating no exposure-safety relationship for common TEAEs, common laboratory abnormalities, serious TEAEs, or serious infections. Conclusions:ER analyses confirmed that filgotinib produced more robust therapeutic effects across the exposure range observed at 200 mg once daily compared to lower doses. The positive exposure-efficacy relationship and a lack of exposure-safety relationship on the evaluated safety endpoints supported the 200 mg once daily dose for commercialization.

Inhibitors of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway have demonstrated efficacy in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Differences in selectivity of JAK inhibitors for JAK1, JAK2, JAK3 and TYK2 may influence their respective safety profiles, and the mechanisms responsible are not currently known. Filgotinib (FIL), a JAK1 inhibitor, did not negatively impact haemoglobin, LDL:HDL ratios or natural killer (NK) cell counts in clinical trials. Here, we compare the in vitro mechanistic profiles of four JAK inhibitors at clinically relevant doses. JAK inhibitors (FIL, FIL metabolite [GS-829845], baricitinib [BARI], tofacitinib [TOFA], and upadacitinib [UPA]) were evaluated in vitro in human-cell-based assays. Growth of erythroid progenitors from human cord blood CD34⁺ cells was assessed using a HemaTox™ liquid expansion assay, NK cell proliferation was induced by IL-15 and LXR agonist-induced cholesteryl ester transfer protein (CETP) expression was assessed in the hepatic cell line, HepG2. Using assay-generated IC50 values and the reported human plasma concentrations from clinical studies, we calculated the target coverage for each JAK inhibitor at clinically relevant doses. The activity of FIL in humans was based on PK/PD modelling of FIL + GS-829845. Inhibition of cellular activity was calculated for each JAK inhibitor based on in vitro dose-response data, human exposure data and modelled PK/PD relationships. At clinically relevant doses, FIL resulted in lower calculated inhibition of NK cell proliferation compared with other JAK inhibitors. FIL 100 mg and 200 mg also reduced CETP expression, whereas other JAK inhibitors had no effect. There was no difference in the effect of FIL vs. other JAK inhibitors on erythroid progenitor cell differentiation or maturation. FIL, a JAK1 inhibitor, resulted in less inhibition of NK cell proliferation compared with BARI, TOFA, and UPA. FIL also reduced LXR agonist-induced CETP expression, while the other inhibitors did not alter these levels. These results provide a potential mechanistic link between the observed reduction of CETP concentration following FIL treatment and the previously observed reduction in the LDL:HDL ratio in RA patients.

Background SOF 400 mg and LDV/SOF 90/400 mg are approved HCV treatment in adults and adolescents. Pharmacokinetic (PK) data indicates that SOF 200 mg and LDV/SOF 45/200 mg are appropriate doses in children 6 to Methods HCV-infected children (3 to Results All but 1subject completed IPK assessments. At baseline, median age and weight for subjects was 5 y and 17 kg in SOF+RBV PK lead-in (N=11) and 5 y and 20 kg in LDV/SOF subjects (N=14). The predefined PK criteria were met as GS-331007 and LDV AUCtau were within the 50–200% boundaries as compared with the adult Phase 2/3 population (table 1). The GS-331007 Cmax (SOF+RBV) was modestly higher; these increases are not considered clinically relevant based on established exposure-safety analyses. SOF concentrations were within the range of those observed in the SOF and LDV/SOF adult Phase 2/3 population (data not shown). Comparison of GS-331007 and LDV exposures in children versus adult Ph2–3 population Conclusions SOF 200 or 150 mg or LDV/SOF 45/200 or 33.75/150 mg, for subjects ≥17 kg or <17 kg, respectively, were well tolerated and provided similar exposures to those observed in adults. These data support the ongoing evaluation of these doses in children 3 to <6 y.