USA Jun – Jul 2005 Single dose of 70mg (50 µCi) on Dl after an overnight fast Cholestyramine for 7 d (D22 to D28) 31.2 ± 9.89 (21 —47)y Healthy TDR10892 * 1 centre France Assess tolerability, safety, and PK parameters repeated oral doses of teriflunomide 70mg Randomized, double-blind, placebo-controlled, repeated dose study Teriflunomide 14mg tablets 70mg (5 tablets) QD for 14 d (Dl through D14) Placebo (5 tablets) QD for 14 d (Dl through D14) Cholestyramine for 13d (D15 to 27) 13/4 6M/7F 48.8 ± 13.6 teriflunomide: 10 placebo: 3 Healthy Bioavailability Study Reports 1002 * 1 centre Germany July - Nov 2000 To assess the effect of food on bioavailability of teriflunomide 20mg Open-label, randomized, 4-period, 2-treatment crossover study with 7d washout between 2 treatment administrations Teriflunomide 20-mg tablets single dose Period1: loading dose of 20mg on Day l under, fasted conditions Periods 2 and 3:20mg under fasted conditions on either Day18 or 38 and 20mg under fed conditions (15 mm after high-fat meal) on either Day 18 or 38 Period 4 – Oral Cholestyramine for 9d 16/14 16M 48 ± 8.1 (40 — 65)y Healthy ALI6504 To assess effect of food on bioavailability of teriflunomide 7 and 14mg tablets Teriflunomide:7-and 14mg tablets in fed (high- fat breakfast) or fasted conditions 30/26 day
* 1 centre France Jan – May 2010 Open-label, randomized, single-dose study with 2 parallel groups and a 2-treatment by 2- sequence crossover Single dose for Group 1 or 14mg for Group 2 Cholestyramine for 5d 20M/10F 1: 39.6 ± 12.5 (23-60)y Group 2: 36.8 ± 14.3 (20 —58)y Grp 1:16 Grp 2: 14 Intrinsic Factor PK Reports POP6507 * 1 centre Russia Dec 2007 – Jun 2008 Assess PK of a single teriflunomide 14mg dose in patients with mild and moderate hepatic impairment (HI) and in matched subjects with normal liver function single-dose, parallel design study in 3 groups of subjects Teriflunomide 14mg tablets Single dose of 14mg under fasted conditions on Dl Activated charcoal for 2 d (054 through D55) to assist washout 25/24 19M/6F 47.0 ± 11.9 (25 - 62)y Mild HI: 9; Moderate HI: 8; Healthy: 8 POP11432 * 1 centre Germany Assess effect of severe renal impairment on PK of a single 14mg dose teriflunomide. Open-label, single-dose study Teriflunomide 14mg tablets Single dose of 14mg under fasted conditions on Dl Cholestyramine for 2 d 16/16 12M/4F 59.5 ± 5.6 (41 - 75)y 8 severe renal impairment;
Nov 2010 – Mar 2011 8 healthy Extrinsic Factor PK Study Reports INT6039 (D1003) * 1 centre USA Apr – Aug 2005 Effect of repeated doses of rifampin on PK profile of a single 70-mg dose of teriflunomide Single-dose, open-label, randomized, 2-way crossover study with 2 treatment periods (teriflunomide alone and coadministration) and a washout period of at least 21 d between treatments Teriflunomide 14mg tablets Single dose of 70mg (5 tablets) on D8 of each period Rifampin 300mg capsules 600mg QD for 22 d (Dl through D22) Cholestyramine for7d 21/19 21M Healthy 31.0± 12.2 Group A: 11 Group B: 10 INTl1720 * 2 centres France Jan – Apr 2011 Assess effect of repeated doses of teriflunomide on PK of caffeine, omeprazole, and metoprolol used as probe substrates for their respective CYP1A2, CYP2C19, and CYP2D6 activities. Open study using a single sequence 2 period crossover design Healthy subjects, excluding poor metabolizers of CYP2C1 9 and 2D6 and subjects with Gilbert’s syndrome Teriflunomide 14mg tablets 70mg QD for 4 d (Dl through D4) in P2, then 14mg QD for 9 d (D5 through D13) in P2 In fed conditions (except when co administered with cocktail (D12, P2) Cocktail Caffeine: 25-mg vials; omeprazole: 20mg capsules; metoprolol: 100-mg coated tablets given as a single dose on Dl, P1, and D12, P2 orally in fasted condition Cholestyramine for lld (Dl4 through D24) Teriflunomide: 13d 36/34 36/0 28.1 ± 7.1 (18—46) 32/3/1 Cocktail alone: 36 Teriflunomide alone: 35
Cocktail: 2d Cocktail + teriflunomide: 34 INT11932 * 1 centre USA Feb – May 2011 Assess effect of repeated oral doses of teriflunomide on PKs of bupropion (CYP2B6 probe). Assess teriflunomide trough plasma concentrations (Ctrough). Assess clinical and laboratory safety of teriflunomide co-administered with bupropion. A single-centre, open-label, nonrandomized, single-sequence, 2-treatment, 2- period study with a minimum 3-day washout following single oral administration in Period 1 Initially given buprion150mg tablet single dose on P1, D 1 Then(P2 only) teriflunomide (14mg tablets) 70mg single dose QD for 4d followed by 14mg QD for 10d, 12th dose of teriflunomide given 30 min before bupropion 150-mg tablet 17/17 17M 32.4 ± 7.1 (23 - 44)y Bupropion 17 Teriflunomide alone: 17 Bupropion + teriflunomide: 17 Healthy INTl1697 * 1 centre USA Jan – Apr 2011 Assess effect of repeated doses of teriflunomide on PK of a single dose of repaglinide. Open-label, nonrandomized, 2-period, 2-treatment, single sequence study Teriflunomide 14mg tablet Loading dose of 70mg (5 tablets) QD for 4d followed by 14mg (1 tablet) QD for 8d (P2 only); 12th dose given 30 mm before repaglinide In fed conditions except when co administered with repaglinide 20/18 20M 31.8 ± 5.8 (21 - 44)y Teriflunomide: 20
N0v 2005 – Apr 2006 Open, randomized, single- dose, 3-period crossover, 3- sequence study with a 21d washout between doses of teriflunomide. Cholestyramine for 5d (D6 through D10) of each period B: 25 C: 26 Healthy BEQ10169 * 1 centre UK Feb – Jun 2007 Determine bioequivalence of teriflunomide 7 and 14mg test tablets and teriflunomide 7 and 14mg reference tablets, respectively randomized, single-dose, 2-treatment by crossover study performed in 2 parallel groups, with a 32d washout Between doses of teriflunomide Teriflunomide test tablets 7 and 14mg tablets without colloidal silica Single doses of 7mg (Group 1) or 14mg (Group 2) on Dl fasting Cholestyramine for 3d(D27 through D29) 94/84 60M/34F Grp 1: 27.8 ± 6.0 (19-44)y; Grp 2: 27.2 ± 6.4 (18-45)y Grp 1: 47; Grp 2: 47 Healthy *[Information redacted] In vitro studies The in human biomaterials studies for teriflunomide evaluated its potential interaction with p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) (Study AIV0202), its transport in hepatocytes (Study TRE0034), its protein binding (Studies HMR008477, HMR010274, HMR015182, HMR014543), its hepatic metabolism (Studies DMPK/USA/2005-0050, HMR14997, HMR017949, MIH0794), its effect on uric acid renal transport (DIV1516) and its potential for non-metabolic-based drug-drug interactions (Study TRE0029) or metabolic-based drug-drug interactions (Studies DMPK/USA/2005-0097, MIH0376, MIH0542, MIH0793, MIH0882, MIH0318). 2 In vitro studies 14C-teriflunomide metabolism
Table14. Submitted pharmacodynamic studies. Study * Objective(s) Study design Treatment Subjects M/F * single centre Mar 2010 - Feb 2011 Assess effect of repeated of teriflunomide on QTcF interval, compared to placebo and using moxifloxacin (400mg, single dose) as a positive control Randomized, double-blind, repeated dose, study, stratified by gender, conducted in 3 parallel groups Teriflunomide tablets: 70mg QD for first 4 days, then14mg QD for 8 days, Placebo: matched to teriflunomide tablets QD for 14days Moxifloxacin capsules: 400mg on D12 All treatments preceded by a placebo run-in day Placebo: matched to moxifloxacin capsules QD for 11days (moxifloxacin group ) or 12days (teriflunomide and placebo groups) 192/179 (87M/95F) healthy subjects Teriflunomide: 64 Placebo: 56 Moxifloxacin: 62 41.6 ± 16.1 (18 – 65) yr * 1 centre UK Feb – Jul 2007 Assess effect of repeated daily oral doses of teriflunomide on PD and PK profile of warfarin after a single oral dose of 25mg warfarin; assess safety of teriflunomide co administered with warfarin compared to warfarin alone Open, nonrandomized, single sequence, 2- treatment, 2-period study Teriflunomide 14mg tablets Loading dose of 70mg QD for first3d of P2, followed by 14mg QD for 8 consecutive days Warfarin 5mg tablets Single dose of 25mg (5 tablets) on P1, Dl and on P2, D5 Cholestyramine for 11d (D12 to D22) Teriflunomide: 11d Warfarin: 2d 14/12 14M 31.0 ± 9.0 (19 - 45) P1: 14 (warfarin); P2: 12 (warfarin+ teriflunomide) Healthy controlled 40