Use of dose–exposure–response relationships in Phase 2 and Phase 3 guselkumab studies to optimize dose selection in psoriasis

2019 ◽  
Vol 33 (11) ◽  
pp. 2082-2086 ◽  
Author(s):  
M. Lebwohl ◽  
R.G. Langley ◽  
Y. Zhu ◽  
H. Zhou ◽  
M. Song ◽  
...  
Keyword(s):  
Phase 2 ◽  
Dose Selection ◽  
Phase 3 ◽  
Exposure Response

SAT0149 EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY OF FILGOTINIB AND ITS METABOLITE GS-829845 IN SUBJECTS WITH RHEUMATOID ARTHRITIS BASED ON PHASE 2 AND PHASE 3 STUDIES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1013-1014
Author(s):  
A. Meng ◽  
K. Anderson ◽  
C. Nelson ◽  
B. Kirby ◽  
L. Ni ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Response Rates ◽  
High Response ◽  
Phase 2 ◽  
Phase 3 ◽  
Once Daily ◽  
Exposure Response ◽  
Serious Infections ◽  
Wide Range ◽  
Grade 3

Background:Filgotinib is an orally administered small molecule that provides selective inhibition of JAK1, a signaling molecule that helps drive inflammatory pathways underlying rheumatoid arthritis (RA).Objectives:Exposure-response (ER) analyses were performed for efficacy following completion of Phase 2 studies over a wide range of doses to support evaluation of 200mg and 100 mg once daily in Phase 3 studies. ER analyses were subsequently performed by using Phase 3 efficacy data to support selection of the proposed registrational dose. ER analyses for safety based on pooled Phase 2 and Phase 3 studies were conducted to examine the safety of evaluated doses.Methods:Population PK analyses were conducted to estimate plasma exposures of filgotinib and GS-829845 (major circulating active metabolite of filgotinib) in both Phase 2 (DARWIN 1 and DARWIN 2) and Phase 3 studies (FINCH 1, FINCH 2, and FINCH 3) encompassing a dose range of 25 to 100 mg twice daily and 50 to 200 mg once daily. As both filgotinib and GS-829845 contribute to efficacy via JAK1 inhibition, their exposures were combined into single parameters, AUCeff and Ctau-eff (effective area under the curve and effective concentration at trough, by accounting for relative inhibition potency and molecular weight) in the ER analyses for various efficacy endpoints (e.g ACR20/50/70 responses) at Week 12 and Week 24. The ER analyses for safety endpoints (the 5 most frequent treatment-emergent adverse events [TEAEs] and Grade 3 or 4 laboratory abnormalities, serious TEAEs, and serious infections) were performed separately for filgotinib and GS-829845 exposures to characterize the individual safety profile of each analyte. The 5 evaluated TEAEs were nausea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension; the 5 Grade 3/4 laboratory abnormalities included lymphocytes decrease, glucose increase, phosphate decrease, triacylglycerol lipase increase, and creatine kinase increase.Results:In the ER analyses for efficacy based on Phase 2 studies, high response rates were demonstrated in ACR20/50/70 across all octile groups in subjects with RA receiving filgotinib and the ER supported further evaluation of both 200 mg and 100 mg once daily doses in Phase 3 clinical studies. Similarly, ER relationships based on pooled Phase 3 studies across various endpoints (e.g ACR20/50/70) consistently revealed high response rates across the exposure range for both the filgotinib 200 mg and 100 mg doses. A trend of increasing response with increasing exposure was observed over the exposure range for multiple secondary efficacy endpoints including ACR50 and ACR70 with the effective exposures at filgotinib 200 mg primarily residing on the plateau of the ER curves.Filgotinib was generally well-tolerated with no individual TEAE or Grade 3 or 4 laboratory abnormality > 5% in the filgotinib 200 mg once daily group up to Week 12. No relationships were observed between filgotinib and GS-829845 exposures (AUC0-24 and Cmax) and the most frequent TEAEs, Grade 3/4 laboratory abnormalities, serious TEAEs, or serious infections up to Week 52.Conclusion:ER analyses demonstrate that both the 200 mg and 100 mg once daily filgotinib doses are efficacious in subjects with moderately to severely active RA without clear dose-dependent effects on safety. The trend towards greater efficacy with higher exposures for some secondary endpoints (ACR50 and ACR70) and a lack of exposure-safety relationship supports a dose of 200 mg once daily over 100 mg once daily since it presents the best benefit/risk ratio among the doses tested.Disclosure of Interests: :Amy Meng Shareholder of: Gilead Sciences, Employee of: Gilead, Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Sciences, Cara Nelson Shareholder of: Gilead, Employee of: Gilead, Brian Kirby Shareholder of: Gilead, Employee of: Gilead, Liyun Ni Shareholder of: Gilead, Employee of: Gilead, Shu-Min Chuang Shareholder of: Gilead, Employee of: Gilead, Brian Kearney Shareholder of: Gilead, Employee of: Gilead, Anita Mathias Shareholder of: Gilead, Employee of: Gilead

scholarly journals Exposure-Response Relationships for Efficacy and Safety of Filgotinib and its metabolite GS-829845 in Subjects with Rheumatoid Arthritis Based on Phase 2 and Phase 3 Studies

2021 ◽  
Author(s):  
Amy Meng ◽  
Kacey Anderson ◽  
Cara Nelson ◽  
Liyun Ni ◽  
Shu-Min Chuang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Therapeutic Effects ◽  
Phase 2 ◽  
Phase 3 ◽  
Two Phase ◽  
Once Daily ◽  
Exposure Response ◽  
Daily Dose

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.

scholarly journals Dose Selection Process for Younger Children Participating in a Phase 3 Study to Evaluate the Efficacy and Safety of Rivipansel (GMI-1070) in the Treatment of Vaso-Occlusive Crisis in Hospitalized Patients with Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3643-3643
Author(s):  
Brinda Tammara ◽  
Frank E. Shafer ◽  
Lutz Harnisch
Keyword(s):  
Phase 2 ◽  
Efficacy And Safety ◽  
Cell Disease ◽  
Dose Selection ◽  
Phase 3 ◽  
Time Profiles ◽  
Concentration Time ◽  
Phase 2 Study ◽  
Population Pk ◽  
Adults And Children

Abstract Background: Rivipansel is a pan-selectin inhibitor in development for the treatment of sickle cell disease (SCD) vaso-occlusive crisis (VOC). A single phase 3 study was planned to evaluate the efficacy and safety of rivipansel (GMI-1070) in the treatment of VOC in hospitalized patients with SCD. Selection of the dose to be used in this phase 3 study was based on the efficacy, safety, and pharmacokinetic (PK) results from the rivipansel phase 2 study. Modeling and Simulation (M&S) was used to determine the dosing for adults and children aged >6 years with SCD. To ensure that the predicted drug exposure is actually achieved in patients aged 6-11 years (cohort 2), we conducted a blinded review of the PK data obtained from several subjects enrolled in cohort 2. The methodology for this evaluation is presented here. Methods: Pharmacokinetic data for 109 subjects receiving doses of 2 to 40 mg/kg in 4 previous studies (3 Phase 1 and 1 Phase 2) were integrated to build a 3-compartment model, which was used to perform simulations to aid dose selection. As rivipansel is almost entirely renally excreted, the simulations of clearance considered renal function as well as hyperfiltration, as this type of altered renal filtration is common in SCD patients. This model allowed for scaling of the PK exposure from the model developed in adults and older children (aged 12-17 years) (Tammara BK, Harnisch LO. CPT Pharmacometrics Syst Pharmacol 2017;6:845-54) into the model for younger children (aged 6-11 years). Simulations from the model in the adult and pediatric population are presented in Figure 1. To confirm the predicted exposure in cohort 2, in particular their average concentration at steady-state (Cavg,ss), age- and weight-dependent cumulative distribution functions (CDFs) of parameters in the population PK model (eg, CL Vss) were derived for the first 6 actively treated children. During this blinded review, concentration time profiles for these children were generated and empirical Bayesian estimates (EBEs) for their corresponding Cavg,ss were derived. The percentiles in which the EBEs fell within the simulated CDFs from the model were used to guide decisions for a potential dose adjustment. This process is outlined in the flow chart in Figure 2 and in the percentile plot diagram shown in Figure 3. Results: The PK data from the Phase 2 study supported fixed flat dosing for patient aged 12 years and older. Pharmacokinetic M&S predicted that a loading dose of 1680 mg followed by a maintenance dose of 840 mg every 12 hours would result in exposures similar to those observed with the lower dose used in the Phase 2 study, such that a minimum plasma concentration >10 μg/mL would be maintained throughout the dosing interval. For patients in cohort 2, weight-based dosing was considered, as it is the most conservative approach, given that children in this age range have not been studied previously. For each dosing regimen tested, the simulated demographic target distribution in pediatric SCD patients was used to derive concentration-time profiles. A summary of the Cavg,ss distribution across different ages is shown in Figure 1. The simulations showed that for children aged 6-11 years, a 40-mg/kg loading dose (maximum 1680 mg) followed by 20 mg/kg every 12 hours (maximum 840 mg) would likely result in concentrations similar to those observed with the 20/10 mg/kg dosing used in adults in the Phase 2 study. To confirm the validity of the exposure predictions, PK assessments were performed in the Phase 3 study and a blinded interim analysis of pediatric exposures was conducted. Conclusions: A population PK model for rivipansel has been developed, applicable to the whole target SCD population of adults and children older than 12 years. Its applicability in children aged 6-11 years is under investigation as part of the ongoing Phase 3 study, and interim assessments of the PK exposure have been done in small cohorts of 6 patients. The corresponding decision framework has been implemented, exercised successfully, with the results of potential dose adaptations to be published once the Phase 3 study has been concluded. Disclosures Tammara: Pfizer Inc.: Employment. Shafer:Pfizer Inc.: Employment. Harnisch:Pfizer Inc.: Employment.

scholarly journals Pharmacokinetics and Exposure-Response of Luspatercept in Patients with Anemia Due to Low- or Intermediate-1-Risk Myelodysplastic Syndromes (MDS): Preliminary Results from Phase 2 Studies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1990-1990 ◽  
Author(s):  
Nianhang Chen ◽  
Abderrahmane Laadem ◽  
Dawn M. Wilson ◽  
Xiaosha Zhang ◽  
Matthew L. Sherman ◽  
...  
Keyword(s):  
Dose Titration ◽  
Phase 2 ◽  
Individual Dose ◽  
Employment Equity ◽  
Phase 3 ◽  
Exposure Response ◽  
Base Study ◽  
Starting Dose ◽  
Equity Ownership ◽  
Hematopoietic Response

Abstract Background: Luspatercept is a modified ActRIIB-IgG Fc fusion protein that corrects ineffective erythropoiesis. In phase 2 studies, luspatercept treatment led to long-term increases in hemoglobin (Hb) levels and reduction in transfusion burden in patients (pts) with IPSS Low- or Intermediate-1-risk MDS. Aims: To characterize the pharmacokinetics (PK) of luspatercept and explore the exposure-response relationship for efficacy and safety in pts with MDS, thereby informing selection of the starting dose for phase 3 studies of luspatercept in MDS. Methods : PK, safety, and efficacy data were collected from two phase 2 studies (base and extension). In the base study, luspatercept was administered once every 3 weeks by subcutaneous injection to sequential cohorts for up to 5 doses. The base study included a dose-finding phase (at fixed doses from 0.125 to 1.75 mg/kg), and an expansion cohort (at a starting dose of 1.0 mg/kg followed by individual dose titration up to 1.75 mg/kg). Pts completing the base study were eligible to enroll in an extension study, where they continued to receive luspatercept every 3 weeks for up to 24 months. Pts who had treatment interruption for ≥ 3 months before enrolling in the extension study received a starting dose of 1.0 mg/kg (followed by dose titration) and were treated as "new" pts in the exposure-response analysis. The main exposure endpoint was area under the luspatercept serum concentration−time curve (AUC). Clinical endpoints included Hb increase, transfusion reduction, and drug-related adverse events (AEs) in weeks 1-15. Responders were defined as pts achieving erythroid hematologic improvement (HI-E) per IWG criteria, i.e. Hb increase ≥ 1.5 g/dL for 8 weeks in low transfusion burden (LTB) pts, and transfusion reduction ≥ 4 RBC units/8 weeks in high transfusion burden (HTB) pts. Results : As of July 20, 2016, preliminary data were available for 66 pts: 22 LTB pts (baseline Hb 6.4-10.1 g/dL) and 44 HTB pts (baseline transfusion burden 4-18 units/8 weeks). Median age was 72 years (range 27-90); 41% were female. A total of 39 pts were eligible for individual dose titration; of these, ~49% had ≥ 1 dose escalation (to 1.33 mg/kg) and ~15% had 2 dose escalations (to 1.75 mg/kg) in the first 3 months. Luspatercept PK was adequately described by a 1-compartment PK model with linear absorption and elimination. Half-life of luspatercept in serum was ~10-14 days across doses. Body weight positively correlated with luspatercept clearance and its volume of distribution. Baseline transfusion burden (LTB vs HTB) and erythropoietin (EPO) level (10-4,752 U/L) had no significant effect on luspatercept PK. In LTB pts who were transfusion-free on treatment, higher luspatercept AUC correlated with greater Hb increase (P < 0.01). In HTB pts, AUC correlated with reduced transfusion units in pts with baseline EPO ≤ 500 U/L (P< 0.01) but not in pts with baseline EPO > 500 U/L. Median AUC was 148 d·µg/mL in LTB responders and 185 d·µg/mL in HTB responders. Luspatercept AUC also correlated with frequency of IWG HI-E responders for LTB pts, HTB pts (baseline EPO ≤ 500 U/L), and the 2 groups combined. In pts requiring transfusion (≥ 2 units/8 weeks) with baseline EPO ≤ 500 U/L, baseline transfusion burden was a significant predictor of achieving transfusion independence (TI) ≥ 8 weeks, and higher luspatercept AUC was associated with greater TI rate after accounting for baseline transfusion burden. Thus, individualized dosing based on baseline transfusion burden may increase the likelihood of achieving TI in HTB pts. Population PK simulation predicted that the starting dose resulting in 90% of LTB pts and 50% of HTB pts achieving efficacious AUC for HI-E would be 1 mg/kg and 1.1 mg/kg, respectively; higher doses would result in a higher proportion of pts achieving efficacious AUC. There was no significant relationship between severity and frequency of drug-related AEs and luspatercept serum exposure. Conclusions: Higher luspatercept serum exposure correlated with greater erythroid hematopoietic response for both LTB and HTB pts. Exposure-response modeling and PK simulation support a phase 3 starting dose of 1.0 mg/kg and intra-patient dose escalation up to 1.75 mg/kg according to erythroid hematopoietic response. A phase 3 study of luspatercept in regularly transfused ring sideroblast positive patients with lower-risk MDS according to IPSS-R criteria is ongoing (MEDALIST study; ClinicalTrials.gov NCT02631070). Disclosures Chen: Celgene Corporation: Employment, Equity Ownership. Laadem:Celgene Corporation: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Ritland:Celgene Corporation: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

Exposure-response analysis of tezepelumab in patients with severe asthma to guide phase 3 dose selection

2018 ◽  
Author(s):  
Neang Ly ◽  
Yanan Zheng ◽  
Janet M. Griffiths ◽  
René Van Der Merwe ◽  
Balaji Agoram ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Response Analysis ◽  
Dose Selection ◽  
Phase 3 ◽  
Exposure Response

scholarly journals Exposure-Response of Quizartinib Efficacy in Patients with Relapsed/Refractory AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1263-1263
Author(s):  
Dongwoo Kang ◽  
Julie Passarell ◽  
Malaz A Abutarif ◽  
Jeanne Mendell ◽  
Ophelia Yin
Keyword(s):  
Complete Remission ◽  
Phase 2 ◽  
Dosing Regimen ◽  
Phase 3 ◽  
Once Daily ◽  
Exposure Response ◽  
Phase 2 Study ◽  
Quartile Group ◽  
Cyp3a Inhibitor ◽  
To Receive

Introduction: Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor that has shown clinical activity in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3 internal tandem duplications in the phase 3 QuANTUM-R trial (Cortes et al, Lancet Oncol 2019; NCT02039726). In this analysis, exposure-response relationships of select efficacy endpoints of quizartinib were evaluated. Methods: Analysis was conducted for the following 2 studies separately: phase 2 study APS2689-CL-2004 and phase 3 QuANTUM-R study. Phase 2 study APS2689-CL-2004 enrolled 76 patients who were randomized to receive quizartinib 30 or 60 mg once daily (26.5 and 53.0 mg free base, respectively). Dose escalation was allowed and no dose reduction for strong cytochrome P450 3A (CYP3A) inhibitors was made in this study. In QuANTUM-R, 245 patients were randomized to receive quizartinib. The quizartinib dosing regimen was 30 mg/day and then escalated to 60 mg/day after 2 weeks if QTcF was ≤ 450 ms. Patients receiving a concurrent strong CYP3A inhibitor initiated quizartinib at 20 mg/day, with an increase to 30 mg/day, because concomitant use of a strong CYP3A inhibitor approximately doubles quizartinib exposure. Efficacy endpoints included in the analysis were rate of composite complete remission (CRc; complete remission (CR) + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery), duration of CRc, and overall survival (OS). Exposure measures in individual patients, such as average daily area under the curve (AUC), maximum concentration, and trough concentration, were obtained from a population pharmacokinetic analysis of quizartinib plasma concentration data (Kang et al, EHA 2019) and then used for correlating with the efficacy endpoints. Logistic regression analysis was used for CRc rate, and time-to-event analysis was performed for the duration of CRc and OS. The effect of quizartinib exposure on the percentage of subjects achieving bone marrow (aspirate) blasts of < 5% in QuANTUM-R was also assessed. Results: Patients were divided into 4 quartile groups according to average daily quizartinib AUC for the investigation of exposure-response relationships for OS and the duration of CRc. The lowest exposure quartile group showed shorter OS than the higher 3 quartile groups. The overall median OS from the intent-to-treat (ITT) population was 6.2 months in the phase 3 study; the median OS in the lowest exposure quartile group (Q1) was 4.5 months, whereas the median OS in the highest exposure quartile group (Q4) was 9.6 months (Fig. 1). Analysis of OS for the phase 2b study APS2689-CL-2004 demonstrated a similar trend, in which the lower AUC quartile demonstrated decreased OS. The overall OS from the ITT population was 5.2 months in the phase 2 study, and the median OS in Q1 and Q4 was 4.6 and 6.9 months, respectively (Fig. 2). Consistent with analyses for OS, the duration of CRc showed a trend of shorter duration of response in the lower AUC quartiles in both studies. Additionally, the lower AUC quartile appeared to result in a smaller proportion of subjects who achieved blast reduction of < 5% (ie, 33.3% in Q1 vs 45.6% to 52.6% in Q2 to Q4). However, no apparent trend of exposure-response relationship was shown for CRc (P > .05 from logistic regression analysis). Conclusions: Exposure-response analysis suggests a consistent trend for reduced clinical benefit at lower quizartinib AUC quartiles across various efficacy endpoints (but not CRc) in both the phase 2 and phase 3 studies. Current analysis supports the recommended dosing regimen of 30-mg starting dose with escalation to 60 mg as the target clinical dose. Figure Disclosures Kang: Daiichi Sankyo: Employment. Passarell:Cognigen Corporation: Employment. Abutarif:Daiichi Sankyo: Employment, Equity Ownership. Mendell:Daiichi Sankyo, Inc.: Employment. Yin:Daiichi Sankyo: Employment.

Sign in / Sign up

Export Citation Format

Share Document