Final Results from Stage 1 of a Double-Blind, Placebo- Controlled Trial with TMC207 in Patients with Multi- Drug Resistant (MDR)

Transcription

1 Final Results from Stage 1 of a Double-Blind, Placebo- Controlled Trial with TMC207 in Patients with Multi- Drug Resistant (MDR) Tuberculosis (TB). AH Diacon*, A Pym**, MP Grobusch, G. Churchyard, T De Marez, N Lounis, R van Heeswijk, P Meyvisch, M Haxaire, K Andries, DF Mc Neeley *Stellenbosch University, **Medical Research y, Council Durban, University of the Witwatersrand and NHLS, Aurum Health, South Africa, and Tibotec

2 TMC207-C208 C 08 Trial Design esg Confirmed MDR Start of TMC207+BR or placebo+br End of TMC207 or placebo BR alone 1wk R washout 8 weeks Stage 1 n=47 24 weeks Stage 2 n=161 2 y follow-up, month MDR-TB treatment total

3 Stage 1 Objectives Primary Evaluate PK, safety and tolerability of TMC207 compared to placebo over 8 weeks Secondary Assess anti-bacterial activity of TMC207 compared to placebo In patients with newly diagnosed sputum smear positive pulmonary MDR-TB

4 Inclusion/Exclusion Criteria Male and female years Positive sputum smear > 1+ Confirmed resistance to H and R HIV negative or HIV+ with CD4+ > 300 and no ART No previous 2nd line anti-tuberculosis agents No significant extrapulmonary TB or concomitant illness

5 Demographics Placebo TMC207 N=24 N=23 Gender - male (%) Age - median (yrs) HIV negative (%) Body weight - median (kg)

6 Study Completion/Withdrawals Disposition Reason n (%) Placebo TMC207 Completed 11 (45.8) 13 (56.5) Discontinued 13 (54.2) 10 (43.5) Death* 0 1 (4.3) Pre-existing XDR 1 (4.2) 1 (4.3) XDR resistance developed 2 (8.3) 0 Patient Moved 1 (4.2) 0 Subject Lost to Follow-up 1 (4.2) 1 (4.3) Subject Non-compliant 4 (16.7) 4 (17.4) Subject Withdrew Consent 4 (16.7) 3 (13.0) * Myocardial infarction

7 Background Regimen The preferred BR regimen initiated at the beginning of Stage 1 was composed of the following drugs: Ethionamide, Pyrazinamide, Ofloxacin, Kanamycin and Terizidone/Cycloserine. Changes in the BR regimen occurred over time due to: DST results and culture positivity Switches within the same drug class (due to shortage on site)

8 Background drugs used during study Medication Name Placebo N=24 TMC207 N=23 Ethionamide 24 (100) 23 (100) Kanamycin/amikacin 24 (100) 23 (100) Pyrazinamide 24 (100) 23 (100) Fluoroquinolones 23 (95.8) 23 (100) Ethambutol t 17 (70.8) 18 (78.3) Terizidone/cycloserine 18 (75.0) 12 (52.2) Dapsone 4 (16.7) 0 Capreomycin 1(42) (4.2) 1(43) (4.3) Para - aminosalicylic acid (PAS) 2 (8.3) 0 Clarithromycin 2 (8.3) 0 Amoxi-clavulanic acid 1 (4.2) 0 Isoniazid (high dose) 1 (4.2) Abstract L1-521a 8

9 Adverse events in >15% of subjects

10 Safety Adverse events evenly distributed across treatment groups except nausea (> in TMC207) No discontinuations due to adverse events Grade 3/4 AEs similar for TMC207 (26%) and placebo (21%) No serious adverse events related to study drug No clinically significant differences in laboratory tests QTcF prolongation seen - relevance unclear No adverse events associated with QTcF changes

11 Microbiology parameters Sputum culture conversion in liquid media Analysis set = 44 patients Patients were considered cured following 2 consecutive negative cultures at least 28 days apart and no recurrence of TB.

12 MGIT Placebo (N=23 at start, N=11 completed) PLA MGIT Results over Time MGIT negative MGIT positive 0 50d 150d 250d 350d 450d 550d 650d 750d POSITIVE NEGATIVE CONTAMINATED BR DOSING INTERVAL TIME OF DROPOUT 57% of patients were culture negative at trial end or last observation

13 MGIT TMC207 (N=21 at start, N=13 completed) MGIT Results over Time TMC MGIT negative MGIT positive 0 50d 150d 250d 350d 450d 550d 650d 750d POSITIVE NEGATIVE CONTAMINATED BR DOSING INTERVAL TIME OF DROPOUT 81% of patients were culture negative at trial end or last observation

14 Time to conversion : 24-week analysis Patients received TMC207/ placebo for 8 wks only Culture Positiv ve Patients Proportion of Placebo TMC207 Significant reduction in median time to culture conversion compared to placebo 11 weeks for TMC207 vs 18 weeks placebo 74d 127.5d p=0.03 BAS W 4 W 8 W 12 W 16 W 20 W 24 Time to Culture Conversion (in Days) Subjects dropping out during the 24W period are carried forward as not converting p-value from Cox proportional model adjusting for strata Abstract L1-521a 14

15 Conclusions TMC207 was safe and well-tolerated over 8 weeks Addition of TMC207 to a 5-drug MDR-TB regimen resulted in: Significantly shorter time to culture conversion Median time - 11 weeks versus 18 weeks (p=0.03) 81% culture negative at trial end or last observation compared to 57% in the control arm. First results from Stage 2 (24 weeks of TMC207) are expected soon.

16 Acknowledgements The patients who participated p in our study Dr. Andreas Diacon and team, Stellenbosch University, Cape Town Dr. Alexander Pym and team Medical Research Council, Durban Dr. Martin Grobusch and team, University of the Witwatersrand Dr. Gavin Churchyard and team, Aurum Health, South Africa Members of the TMC207 compound development and clinical teams, Tibotec, Titusville, NJ (USA) and Beerse, Belgium.