Trough Concentration (Cmin) – Virologic Success (RNA <400 copies/mL) Analysis

1. Trough Concentration (Cmin) – Virologic Success (RNA <400 copies/mL) Analysis Review team Pravin Jadhav Jenny Zheng Shashi Amur Kellie Reynolds Joga Gobburu John Lazor OFFICE OF CLINICAL PHARMACOLOGY (OCP) Maraviroc AC meeting--Pharmacometrics

2. Major aims • Is the proposed dosing regimen (150mg BID with PI or 300mg BID w/o PI) acceptable? • What is the utility of Cmin-Virologic success relationship? Maraviroc AC meeting--Pharmacometrics

3. Summary of Cmin-Virologic Success Analysis • Patients with Cmin ≥ 50-75 ng/mL have a better chance of virologic success. • In addition to Cmin, the probability of success is also influenced by other factors such as baseline CD4+ count, baseline viral load and OSS. • With the proposed doses (150mg BID and 300mg BID) 60% patients will be ≥ 75 ng/mL compared to the QD dosing (18%). • The maraviroc concentrations could be important to • Help explain lack of response. • Help assess compliance. • Help assess a need to dose adjust to increase virologic success. • For example, in patient population with Cmin <75 ng/mL, by doubling dose the probability of success is increased to 62% (vs 56% at the proposed dosing). In overall population this probability is 69% vs. 67%. Maraviroc AC meeting--Pharmacometrics

4. Data from studies A4001027, A4001028 were used • 973 patients were included in the analyses • 76 patients were ignored due to unavailability of covariate information • Plasma trough concentrations (Cmin) were used as an exposure variable • Virologic success was defined as RNA <400 copies/mL • Important predictors : Baseline viral load, Baseline CD4+ count, Baseline tropism, OSS etc. Maraviroc AC meeting--Pharmacometrics

5. Is virologic success dependent on maraviroc Cmin? Maraviroc AC meeting--Pharmacometrics

6. The probability of virologic success increases with maraviroc concentration • Other endpoints • <50 RNA copies/mL at week 24 • protocol defined failure • at least 1 log drop at week 4 • also exhibit consistent relationship Week 24 analysis Virologic success was determined in each Cmin quartile from 777 maraviroc patients and 196 placebo patients Maraviroc AC meeting--Pharmacometrics

7. Baseline CD4+ count, OSS, Cmin and baseline viral load are important predictors of virologic success Overall susceptibility score (OSS) Baseline Tropism Time since diagnosis, years Time since first treatment, years Number of NRTIs in the OBT Presence of tipranavir Presence and sensitivity to T20 Previous exposure to T20 Maraviroc AC meeting--Pharmacometrics

8. Maximum benefit is achieved at ≥ 50-75 ng/mL Cmin; Higher Cmin offers minimal additional benefit Maraviroc AC meeting--Pharmacometrics

9. The proposed BID dosing is consistent with the Cmin-Virologic success relationship With the proposed doses (150mg BID and 300mg BID) 60% patients will be ≥ 75 ng/mL compared to the QD dosing (18%). (w/o PI ) (with PI ) Maraviroc AC meeting--Pharmacometrics

10. What are the important predictors for lower Cmin? Maraviroc AC meeting--Pharmacometrics

11. 28% (150mg BID), 77% (300mg BID) of patients have Cmin < 75 ng/mL (with PI ) (w/o PI) Median 75 ng/mL Maraviroc AC meeting--Pharmacometrics

12. No baseline extrinsic/intrinsic factor explains Cmin variability well n = 5 n = 7 n =48 n = 339 BID regimen Maraviroc AC meeting--Pharmacometrics

13. What is the utility of Cmin-Virologic success relationship? Maraviroc AC meeting--Pharmacometrics

14. Utility of Cmin-Virologic Success Relationship • In clinical practice, in addition to intrinsic pharmacokinetic variability, there are several factors (such as compliance, concomitant medications etc.) that could lead to lower concentration • Controlling these factors becomes important to achieve the benefit shown in the controlled trials. • Maraviroc concentrations could be important to • Help explain lack of response • Help assess compliance • Help assess a need to dose adjust to increase the probability of success while not increasing the exposure related risk Maraviroc AC meeting--Pharmacometrics

15. Evaluation of the added benefit of, for instance, doubling dose in patients with lower Cmin • Based on the final model, simulations were conducted to assess the effect of doubling the dose in patients with Cmin below the defined threshold. • A total of 399 patients from studies A4001027 and A4001028 who received maraviroc 300mg or 150mg BID. • Doubling of dose in patients with efavirenz or nevirapine in OBT. • Doubling of dose if Cmin was below the defined threshold- 10, 25, 50, 75 or 100 ng/mL. • Only one doubling of the dose was permitted. Maraviroc AC meeting--Pharmacometrics

16. Doubling of dose could lead to 62% (vs 56%) success in patient population with Cmin <75 ng/mL. In overall population this probability is 69% vs. 67% 399 Patients were evaluated 146 Patients with <75 ng/mL In 146 patients the current probability of virologic success is 56%. Doubling of dose could increase the probability to 62%. At overall population level the benefit translates to ~2% Maraviroc AC meeting--Pharmacometrics

17. Practical aspects of individualized dosing • Cmin in 8% (150mg BID) and 33% (300mg BID) patients is < 25 ng/mL. • Doubling dose will not ensure Cmin ≥ 75 ng/mL • Safety experience at higher doses is limited • Individualization of treatment will need to consider tropism, OSS, viral load change, in addition to Cmin. Maraviroc AC meeting--Pharmacometrics

18. Summary of Cmin-Virologic Success Analysis • Patients with Cmin ≥ 50-75 ng/mL have a better chance of virologic success. • In addition to Cmin, the probability of success is also influenced by other factors such as baseline CD4+ count, baseline viral load and OSS. • With the proposed doses (150mg BID and 300mg BID) 60% patients will be ≥ 75 ng/mL compared to the QD dosing (18%). • The maraviroc concentrations could be important to • Help explain lack of response. • Help assess compliance. • Help assess a need to dose adjust to increase virologic success. • For example, in patient population with Cmin <75 ng/mL, by doubling dose the probability of success is increased to 62% (vs 56% at the proposed dosing). In overall population this probability is 69% vs. 67%. Maraviroc AC meeting--Pharmacometrics