FIRST APPLICATION OF EXPOSURE-RESPONSE MODELING TO OPTIMIZE CLINICAL OUTCOMES OF TASOCITINIB (CP-690,550) IN KIDNEY TRANSPLANT PATIENTS: PRELIMINARY RESULTS

CLINICAL IMMUNOSUPPRESSION - NEW AGENTS

S. Krishnaswami¹, M. Lamba¹, M. Hutmacher², J. French¹, L. Harnisch³, U. Meier-kriesche⁴, K. Budde⁵, D.M. Cibrik⁶, W. Weimar⁷, S. Cohney⁸, G. Chan^9
1, Pfizer, New London/UNITED STATES OF AMERICA, ², Ann Arbors Pharmacometrics Group, Ann Arbor/UNITED STATES OF AMERICA, ³, Pfizer, Sandwich/UNITED KINGDOM, ⁴, University of Florida, Gainesville/UNITED STATES OF AMERICA, ⁵Medizinische Klinik, Universitätsklinik Charité, Berlin/GERMANY, ⁶Internal Medicine, University of Michigan, Ann Arbor/MI/UNITED STATES OF AMERICA, ⁷Kidney Transplantation, Room D-408, Erasmus Medical Center, Rotterdam/NETHERLANDS, ⁸, Royal Melbourne Hospital, Parkville/AUSTRALIA, ⁹, Pfizer, New London/CT/UNITED STATES OF AMERICA

Body: Introduction: Tasocitinib (CP-690,550) is an orally active JAK inhibitor being developed for CNI-free immunosuppression in kidney transplant patients (KT pts). Exposure-response (E-R) modeling was applied to the 6-month interim data of a dose/exposure-finding Phase 2B study in de novo KT pts to optimize clinical outcomes. Methods: Patients were randomized in this 12-month, multicenter trial 1:1:1 to either CsA, tasocitinib15 mg BID decreasing to 10 mg BID after month 6, or tasocitinib 15 mg BID decreasing to 10 mg BID after month 3. All pts received concomitant MPA, basiliximab induction and corticosteroids. Semi-parametric (Cox proportional hazards) and parametric time-to-event (TTE) analyses were performed to characterize the relationship between 2-hour postdose steady-state concentration (C2) of tasocitinib and clinical outcomes such as acute rejection (AR) and serious infections within 6 months. Data from 176 patients in the two tasocitinib groups were pooled for E-R analysis. Results: 6-month incidence rates for various clinical outcomes by tasocitinib C2 quartiles compared to CsA are shown below (observed data).

Exposure	Locally diagnosed AR	Biopsy-proven AR	CMV disease	CMV-related events (disease or viremia)	Serious infections
Tasocitinib
1st (lowest) quartile (n=44)	11%	14%	2%	7%	17%
2nd quartile (n=44)	14%	7%	5%	16%	19%
3rd quartile (n=44)	21%	23%	29%	49%	43%
4th (highest) quartile (n=44)	5%	5%	22%	46%	49%
CsA (n~107)	19%	19%	3%	13%	20%

Consistent with the observed data, Cox regression indicated that tasocitinib C2 correlated strongly with increasing risk of serious infections (p<0.01 for the slope of the E-R relationship), CMV related events (p<0.002) and CMV disease (p=0.07). In contrast, tasocitinib C2 only correlated weakly with decreasing AR rate within the range of C2 evaluated (~50 to 250 ng/mL) (p=0.13 for locally diagnosed AR and p=0.24 for biopsy-proven AR). Parametric models generally yielded similar results but supported a nonlinear effect of C2 on the hazard for CMV-related events. At a C2 of ~100 ng/mL (expected median C2 for 10 mg BID) the model-estimated 3- and 6-month incidence rates for CMV-related events were 10% and 20%, respectively. The corresponding incidence of CMV-related events for a C2 of ~150 ng/mL (expected median C2 for 15 mg BID) were 23% and 42%, respectively. At these concentrations, the 3-to-6 month, model-predicted rates for locally diagnosed AR were 9-11% for 150 ng/mL and 13-15% for 100 ng/mL. Clinical trial simulations of alternative regimens including more rapid tapering of fixed doses and concentration-controlled regimens suggested that the risk of serious infections could be reduced while maintaining efficacy. Tasocitinib exposure did not significantly correlate with the incidence of anemia, neutropenia or leukopenia. Conclusions: Within the range evaluated, tasocitinib exposure had a strong correlation with the risk of infections but only a weak correlation with the risk of AR. This preliminary analysis identified a target range of tasocitinib exposure that was associated with reduced risk of infections while maintaining a low risk of AR.

Disclosure: All authors have declared no conflicts of interest.