17 th Club Phase 1 Annual Meeting April 5, Pierre Maison-Blanche Hopital Bichat, Paris, France

Transcription

1 Practical Issues for the clinical evaluation of QT/QTc interval prolongation 17 th Club Phase 1 Annual Meeting April 5, 2018 Pierre Maison-Blanche Hopital Bichat, Paris, France

2 Disclosure Chiesi Pharmaceuticals Sanofi Genzyme Novartis Bioprojet AMPS LLC

3 Data accumulated from > 300 TQT Studies since 2005

4 TQT Primary End Point A negative thorough QT/QTc study is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect* of the drug on the QTc interval is < 10ms. This definition is chosen to provide reasonable assurance that the mean effect of the study drug on the QT/QTc interval is not greater than around 5ms, which is the threshold level of regulatory concern (Intersection Union Test, IUT, for multiple end points) Positive otherwise * time-matched mean effect at each time point after dosing is the difference in the QT/QTc interval between the drug and placebo (baseline adjusted) AT EACH MATCHED TIMEPOINT.

5 IUT drawbacks E14 Successful in terms of detecting drugs with a QT effect Based on a conservatively chosen threshold (10 ms) and requirement that the QT effect is evaluated separately at each post-dosing time point (with more hypothesis tests, the likelihood of finding a statistically significant result by chance increases) Without consideration of the pharmacology of the drug (measurements taken around the Cmax as well the ascending and declining phase of the exposure), the study is overly sensitive and has therefore resulted in a number of false positives, i.e., drugs are labeled as QT prolongers without a demonstrated underlying pro-arrhythmic risk

6 TQT is a late Study

7 C-QT analysis is a secondary end point in formal TQT Studies The Division of Pharmacometrics plays a leading role on the QT Interdisciplinary Review Team (IRT). The QT IRT was established in 2006 to provide expert review advice to sponsors and review divisions on QT studies and to contribute to the evolution of the science by developing alternative methods for evaluating repolarization effects.

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11 C Garnett, FDA/DIA in 2011

12 Need for a dedicated Phase 1 Study FDA analyzed > 300 TQT Studies in their database 55 interpreted by FDA as positive TQT studies FDA had Phase 1 ECG data for 17 drugs Of these 17, 6 drugs had a positive QT effect in Phase 1 None of the early studies at FDA had concentration effect modeling

13 CSRC Proposal Conduct a prospective Phase 1 study with marketed QT prolonging drugs to evaluate if robust ECG monitoring with C-ECG modeling could detect QT prolongation at the level of regulatory concern (10 msec) If the Study is successful, it is likely that FDA will agree that «early QT assessment» will serve as an alternative to the TQT Study

14 C-QTc Relationship Outcomes

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25 Pre Specified LME Model QTc ijk = µ i +β i C(t ijk )+Treatment j +Time k +ε ijk Where i=subject, j=treatment (1=active, 0=placebo), k=time µ i, β i are respectively the intercept and slope, both can be set as random effects in the model to account for inter-subject variability C(t ijk ) is concentration for subject i, treatment j and time k. For Treatment=0, C(t ijk ) is set to 0 for all k Treatment is a 2 level treatment effect and does not account for the dose when treatment=1 QTc computed at the treatment level using contrast Time is a the time factor representing the time elapsed since administration ε ijk is the residual error

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31 If no adequate exposure margin Include QTc data at higher exposures CHMP in 2015 recommended approval for the use for the treatment of narcolepsy Therapeutic doses anticipated to be 20 mg daily.. increased to 40 mg daily TQT conducted in 2010, with 40 and 120 mg single doses SAD conducted in 2014, with 160, 200 and 240 mg single doses to extend higher the dose range investigated in the TQT

32 SAD for higher exposures And Moxifloxacin 3 parallel groups of 8 subjects, all males, receiving supratherapeutic doses of the new drug (x4, x5 and x6 factors) All subjects received open label 400 moxifloxacin on Day1, and after 1 week of WO on Day 8 the assigned single dose of the new drug (6 active and 2 placebo) For moxifloxacin vs placebo, only the 6 subjects entered the analysis PK samples and triplicates ECG on Day1

33 Early QT Assay Sensitivity Moxifloxacin

34 ER Moxifloxacin

35 Early QT Assay Sensitivity Moxifloxacin A 400 mg single oral moxifloxacin dose has been used for years in ICH E14 thorough QT studies and is recognized by agencies No new validation needed Easy to manage to insert in SAD and/or MAD design Slightly prolongs trial duration Slightly Increase size and cost of the trial

36 Early Assay Sensitivity Food effect Stability of the food effect, related to C peptide?

37 MAD design Moxifloxacin and Food Double-blind, placebo controlled, 21-day multiple ascending dose study Moxifloxacin open conditions on Day -8 and then each volunteer will receive on Day -1 under single blind conditions placebo and then from study day 1 to 21 included either one drug X dose or placebo. Subjects hospitalized in the clinical unit at approximately 08:00 p.m. on Day -9 up to approximately the 6th hour post-dose (Day -8 in the afternoon) 4 groups of 12 subjects (9 active and 3 placebo) total 48 subjects and 12 placebo Day -8 ECG Moxifloxacin schedule, Day 21 ECG Drug X schedule, Day -1ECG, both Moxifloxacin and Drug X schedules

38 MAD design Moxifloxacin and Food effect Days -8, -1, 1 and 21, first meal well-balanced in carbohydrates, lipids and proteins served at 4 h post-dose (after the blood sampling planned at 4.0 h post-dose). Dinner served after blood sampling planned at 12.0 h post-dose Lunches identical for all subjects on Day-8. On Days -1 and 21, lunches have to be identical as well as dinners. Lunches have to contain at least 100 g carbohydrates in order to potentially enable the QT assay sensitivity Day-1 4th hour ECG extractions (baseline pre-lunch) will be compared to 6th and 8th ECG hour extractions to evaluate food effect

39 MAD design and ECG schedule Continuous 12-lead ECG recording performed on 3 occasions Moxi, from Day -9 evening (i.e. around 12 h before moxifloxacin administration) to Day -8 afternoon (i.e. up to 6 h after moxifloxacin administration) Baseline, from Day -1 morning (i.e. around 1.5 h before placebo) to Day 1 morning (i.e. up to 24 h after placebo administration) MAD, From Day 21 morning (i.e. around 1.5 h before Drug X or placebo administration) to Day 22 morning (i.e. up to 24 h after Drug X or placebo administration).

40 MAD design ER Moxifloxacin Estimate (SE) Confidence Interval (1) Parameters Intercept (Placebo, Male) (msec) (0.929) (-10.9; -7.22) Baseline Covariate (msec) (0.029) (-0.194; ) Moxifloxacin Slope (msec per ng/ml) (0.001) (0; 0.003) Shift Intercept (Moxifloxacin, Female) (msec) 12.8 (2.65) (7.60; 18.0) Shift Intercept (Moxifloxacin, Male) (msec) 6.04 (1.68) (2.74; 9.34) Shift Intercept (Placebo, Female) (msec) 2.23 (1.57) (-0.898; 5.36) Time point 1 h 6.12 (0.863) (4.43; 7.82) Time point 2 h 6.66 (0.875) (4.94; 8.38) Time point 3 h 5.61 (0.865) (3.91; 7.31) Time point 4 h 6.61 (0.852) (4.93; 8.28) Time point 5 h 4.39 (1.07) (2.29; 6.49) Variance Components BS Variance (Intercept) Residual Estimated ΔΔ (msec) 400 mg, Female (Cmax GM: 3815) 17.4 (1.09) (15.6; 19.2) 400 mg, Male (Cmax GM: ) 10.9 (0.707) (9.78; 12.1) Courtesy of Mathieu Felices (1) 95% CI for parameters estimates and 90% CI for ΔΔQTcF

41 MAD design Food effect

42 Early QT Assay sensitivity Food effect Food effect seems validated and presenting a good reliability from Dr Taubel published reports Up to now, not yet fully recognized in guidelines Not easier to handle than Moxi in a Phase 1 trial design Not significantly cheaper than inserting a Moxifloxacin day

43 Conclusions E14 (R3): 10 years later, regulatory challenges are still on high exposure and assay sensitivity Reasonable to insert a positive control in intensive ECG Phase 1 Studies, given uncertainty for the therapeutic dose As of today preference for moxifloxacin, food effect of interest Preferably either in both SAD and MAD studies or only in MAD since with a large dose range studied in a SAD a positive control should not be requested

44 Thank you Q&A

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47 IQ/CSRC Slopes and Predicted QTc 10 msec excluded

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51 Challenging Drugs (1)

52 Challenging Drugs (2)