New Anti-TB Drugs: What and When?

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?