New Drugs: What and When?
Dr Philipp du Cros Manson Unit, MSF
39 year old female with XDR TB • HIV + on AZT / 3TC / EFV • Renal impairment (estimated CrCl=32 ) • XDRTB diagnosed 2009 DST resistant to H-R-E-S-Am-Km-Ofx-Eto • 3 years: Cm-Mfx-PAS-Ter-Amx/clav-Clr-Z still culture positive
New Drugs Repurposed
New Clinical Entities
• Linezolid • Clofazimine • High dose isoniazid
• Bedaquiline (TMC 207) • Delamanid (OPC 67683)
• Carbapenems
• PA 824 • Sutezolid • SQ 109
Linezolid RCT in XDR TB Randomisation 2 41 XDR TB pts
No Treatment response 6 months treatment
Randomisation 1
After culture conversion or 4 months
Add Lzd 600mg
Lzd 600 mg
Wait 2 months then add linezolid 600mg
Lzd 300 mg
Lee et al. N Engl J Med 2012;367:1508-18.
Linezolid trial XDR TB • 4 months culture conversion – 79% immediate-start group – 35% delayed-start group (P = 0.001). • 87% negative sputum culture within 6 months • Four cases of acquired resistance to linezolid
Linezolid • Dose 600 mg daily (? Can reduce dose) • Significant side effects – – – –
Anaemia thrombocytopenia Peripheral neuropathy Optic neuropathy
• Pre-qualified generic version
Bedaquiline (TMC 207) • New class: diarylquinolines • Novel mechanism of action targeting the subunit c of the ATP synthase of M.TB • Mouse studies – potential to reduce duration of MDR TB treatment
Bedaquiline: phase 2b RCT
Median time to culture conversion: 83 days (95%CI: 56, 97) bedaquiline group vs 125 days (95%CI: 98, 168) in placebo group
Bedaquiline (TMC 207) • Dose 400mg daily 2 weeks then 200mg 3 times per week • Adverse events – Prolonged QTc interval – Nausea, diarrhoea, rash – Hepatotoxicity
• Bedaquiline is metabolized by CYP3A4 – interactions with antiretrovirals
WHO recommendation for bedaquiline inclusion in MDR treatment • Standard Regimen = Z + four second-line drugs considered to be effective: – fluoroquinolone + 2nd-line injectable + two bacteriostatic drugs (pto/eto + Cs or PAS)
• Bedaquiline added if: – Resistance to fluoroquinolone or 2nd line injectable – Unable to construct regimen with 4 likely effective drugs due to resistance, intolerance, previous TB drug use
WHO recommendation for bedaquiline inclusion in MDR treatment 1. Treatment closely monitored 2. Proper patient inclusion (no children / pregnant women) 3. Patient informed consent 4. Adherence to principles of designing a WHOrecommended MDR-TB regimen 5. Pharmacovigilance and proper management of adverse drug reactions and prevention of drug窶電rug interactions
Compassionate use (CU): • Physician requests a drug for a specific individual patient. • Applies directly to the manufacturer. • The manufacturer provides the drug to the physician for use for that specific patient, and the patient’s condition must meet criteria established by the manufacturer • In general, the country of residence is required to have regulations in place permitting such ‘compassionate use’ of an unapproved drug.
nitro-dihydro-imidazooxazole derivatives • Delamanid (OPC-67683) and PA 824 • Inhibit mycolic acid synthesis • Both have shown potent in vitro and in vivo activity against DR-TB • Delamanid: Dose 100mg twice daily • Adverse events: QT prolongation, nausea
Delamanid Phase 2 Trial 204
Delamanid: Trials 208 and 116 • 6 month extension of trial 204 • Follow up for 24 months • Successful outcomes: – 143/192 patients (74.5%) delamanid ≥6 months – 126/229 patients (55.0%) delamanid for ≤2 months.
• Mortality reduced from 8.3% to 1% among those receiving long-term delamanid, p<0.001. • Caution in interpretation: Study design issues
Clofazimine Pros
Cons
• Potent anaerobic and intracellular activity • Potent sterilising activity in mouse models • Synergy effect in combo studies in mouse • Low frequency of resistance development • Novel Mechanism of action
• Limited data of efficacy in humans…….yet • QT prolongation • Skin discolouration • Long half life (70 days)
Lungs of mice at month 2 and 5 of Treatment
Grosset et al. Webinar presentation Dec 2012 IUATLD
High Dose Isoniazid • Kat G mutations MICs > 2 • Mutations in promoter region InhA low-level INH resistance + ethionamide resistance • RCT: high-dose INH (16–18 mg/kg) vs INH (5 mg/kg) ↑ sputum culture conversion • Increased peripheral neuropathy
NC001 14 day early/extended bactericidal activity of new combinations Bi-linear20Regression: LogCFU changes from baseline LogCFU change from baseline
0.5 0.5 00 -0.5 -0.5 -1-1 -1.5 -1.5 -2-2 -2.5 -2.5 -3-3 00
22
44
66
88
1010
1212
1414
Day Rifafour e275 TMC207 TMC207 & PZA Rifafour Rifafour e275 e275 Rifafour TMC207 e275 Rifafour TMC207 TMC207 e275& PZA TMC207 TMC207 PA-824&&PZA TMC207 PA-824 & PZA PA-824 & TMC207
6
NC001 14 day early/extended bactericidal activity of new combinations Bi-linear21Regression: LogCFU changes from baseline LogCFU change from baseline
0.5 0.5 00 -0.5 -0.5 -1-1 -1.5 -1.5 -2-2 -2.5 -2.5 -3-3 00
22
44
66
88
1010
1212
1414
Day Rifafour e275 TMC207 TMC207 & PZA Rifafour Rifafour Rifafour e275 e275e275 Rifafour TMC207 PA-824 e275& TMC207 PZA TMC207PA-824 & PZA TMC207 &TMC207 PZA PA-824 & Moxifloxacin &&PZA TMC207 PA-824 & PZA PA-824 & TMC207
6
MDR TB Regimen Trials • • • • • •
Bedaquiline phase 3 Delamanid phase 3 STREAM-TB TB Alliance: NC002, NC003, etc ACTG MARVEL Nix Trial – XDR TB salvage regimens
Conclusions • Based on current evidence all XDR TB patients should receive: – Bedaquiline – Linezolid +/- Clofazimine
• Bedaquiline can be accessed through compassionate use mechanism • There is an urgent need for MDR TB regimen clinical trials
Questions?