New anti tb drugs and new targets

Pharmacotherapy of TB. Recommended regimen for TB under RNTCP(2016). New drugs under research and new targets.

1. Newly recommended regimens (under RNTCP 2016) for treatment of Pulmonary Tuberculosis and Recent advances in anti-tubercular drugs Dr KG Bandekar Dept of Pharmacology

2. Sub topics Introduction Current drugs and regimes New Regimens Need for newer drugs New targets, drugs/molecules under research

3. Introduction Tuberculosis is chronic granulomatous disease. Causative agent - Mycobacterium tuberculosis bacterium. M. tuberculosis is aerobic. In India – 2.3 million cases. TB – a notifiable disease in India. RNTCP(Revised National Tuberculosis Control Programme ) – launched to control and treat.

4. Mechanism of actions

5. Drugs currently used 1st line drugs . docx 2nd line drugs.docx 1 st line drugs – High efficacy and low toxicity 2 nd line drugs – Either low efficacy or higher toxicity or both – are reserved drugs.

6. ADRs 1 st line drugs Non hepatotoxic drugs – E and S Safe drug in Renal failure – R ( as it is secreted in bile) – No dose adjustment in RF Least toxic drug – R

7. ADRs 1 st line drugs H is metabolised by acetylation. Slow acetylators - peripheral neuritis; fast acetylators - hepatotoxicity Hepatotoxicity due to R is uncommon unless pre existing liver disease is present and presents as ‘ hyperbilirunemia without SGPT elevation ’. E – optic neuritis ( low visual acuity, red/ green colour blindness – green more than red)

8. Rifabutin and rifapentine Supplementary 1 st line drugs Rifabutin is less effective against M. tuberculosis than ‘R’. Rifabutin is used in HIV patients who are on protease inhibitors / NNRTIs – less enzyme induction compared to ‘R’. ( Rifapentine is not used) No dose adjustment in liver disease

9. 2 nd line drugs

10. Fluroquinolones (FQ) Ciprofloxacin( Cfx ), ofloxacin ( Ofx ), moxifloxacin ( Mfx ) and levofloxacin ( Lfx ) Mfx the most effective. Effective in HIV patients.

11. Thioacetazone Causes bone marrow suppression Not used in HIV – risk of severe hypersensitivity reactions e.g exfoliative dermatitis Not used in intermittent regimens.

12. Kanamycin (Km) and Amikacin (Am) Bacteriocidal . Less vestibular toxicity than hearing loss. Equally nephrotoxic. Am lesser toxic than Km.

13. Ethionamide ( Eto ) Mechanism similar to H Causes hepatitis, optic neuritis, hypothyroidism Used also in leprosy

14. Cycloserine (Cs) Inhibition of cell wall synthesis – inhibits recemizing enzyme. Causes neuropsychiatric disorders. Capreomycin (Cm) Injectable polypeptide. Causes ototoxicity, nephrotoxicity, low K + and low Mg 2+ .

15. PAS Related to sulfonamides. Affects folate synthesis. Least active drug. Only delays resistance. Causes kidney, liver, thyroid dysfunction.

16. Kanamycin and amikacin Injectable aminoglycosides. Can be used in Multi Drug R esistant -MDR cases

17. Macrolides

18. Linezolid Oxazolidinone gp synthetic antibiotic. Inhibition of protein synthesis –unique binding site 23 S of 50 S. Use in TB – off label use .

19. Bedaquiline Newer approved drug. Inhibits mycobacterial ATP synthase. Long half life. Used in MDR-TB. Pregnancy is a contraindication. Causes QT prolongation.

20. Clofazimine Co- amoxyclav

21. Chemotherapy Objective – Cure - elimination of both, fast and slowly multiplying bacilli (including persisters ) Effectiveness evaluation – elimination of bacilli from patient’s sputum. Correct drugs, correct dose, and for correct length of time.

22. Rational of combination anti tubercular drugs To prevent resistance. Resistant mycobacterial population (in normally susceptible) -1 bacillus in 10 6 Normally lesion contains > 10 8 bacilli. Hence – resistant strain readily selected if only single drug is used.

23. Rational of combination anti tubercular drugs contd… Two independently acting drugs in combination are more effective. Probability of bacillus resistant to both drugs initially – 1 in 10 6 X 10 6 = 10 12 .

24. Dose

25. Wt -band dose recommendations

26. Regimens Long course – classical regimen - 18 months H + 1/2 bacteriostatic drug/s Sterilisation mainly dependent on H Short course chemotherapy - 6-8 months Rapid bacteriological conversion Low failure rates Lower incidences of drug resistance Intensive phase (2/3 months)+ Continuation phase (4 – 5 months)

27. DOTS - Directly Observed Treatment Shot course Chemotherapy By WHO Strategy to ensure cure by providing the most effective medicine and confirming that it is taken.

28. Current Regimen Cat Intensive phase Continuation phase Duration (months) Remark Cat I New patient (2) HRZE daily (4) HR daily 6 Optional (2) HRZE daily (4)HR 3/week 6 If DOTS ensured (2) HRZE 3/week (4) HR 3/week 6 DOTS ensured or No HIV inf Cat II Previously treated (2) HRZES daily + (1) HRZE daily (5) HRE daily 8 Low/medium risk of MDR-TB Empirical ( standardised ) MDR-TB regimen – country specific Empirical ( Standardised ) MDR-TB regimen – country specific 18-24 or Sensitivity test is avl High risk MDR-TB

29. Chemotherapy of TB in pregnancy Except S continue all 1 st line drugs Breast feeding mothers – full course ( breast feeding to be continued) Mothers receiving H and breastfed baby – Vit B6 supplementation daily

30. Drug regimen recommended in RNTCP(2016) Daily dose regimen MDR/RR-TB cases (without additional resistance) XDR-TB H resistant TB BDQ containing regimen Shorter MDR-TB regimen(as per WHO 2016)

31. 1. Daily dose regimen 2 categories New Previously treated Type of TB case Regimen in Intensive phase (IP) Regimen in Continuation phase (CP) New (2) HRZE (4) HR E Previously treated (2) HRZES + (1) HRZE (5) HRE

32. FDC daily dose regimen doses

33. Drug resistance Multi drug resistance (MDR) – Resistance to H and R and may be to any 1 st line drug/s. Extensively drug resistance ( XDR) – Resistance to H,R,FQ and either aminoglycoside or Cm or both.

34. 2. MDR/RR-TB cases (without additional resistance) Type of TB case Regimen during IP Regimen during CP R resistant + (H sensitive or unknown) (6-9) km Lfx Eto Cs ZEH (18) Lfx Eto cs E H MDR TB (6-9) km Lfx Eto Cs Z E (18) Lfx Eto Cs E

35. 3. XDR-TB Type of TB case Regimen in IP Regimen in CP XDR (6-12) Inj Cm, PAS , Mfx , high dose H, Cfz Lzd , Amx / Clv (18) PAS , Mfx , high dose H, Cfz Lzd , Amx / Clv

36. 4. H resistant TB Type of TB case Regimen in IP Regimen in CP R sensitive ad H resistant (3-6)km Lfx R E Z (6) Lfx R E Z

37. 5. BDQ containing regimen Eligibility for BDQ regimen – Either of - MDR/Rifampicin TB + res to all FQs MDR/Rifampicin TB + res to all 2 nd line drugs XDR TB Dose and duration 0-2 week – Tab BDQ 400 mg daily + optimised background regimen (OBR) 3-24 week – Tab BDQ 200 mg 3/week + OBR 25 week – to end of treatment – Continue OBR

38. BDQ containing regimen contd…

39. 6.Shorter MDR-TB regimen(as per WHO 2016)

40. New anti-tubercular drugs

41. Pretomanid Stage 3 clinical trial Bacteriocidal . Interferes - ATP synthesis and mycolic acid synthesis. 6 months regimen for pulmonary XDR-TB– Linezolid + bedaquiline + pretomanid . PaMZ ( Pretomanid + Z + Moxiflox ) regimen – RCT in new pul TB patients. PRACTICAL study

42. Delamanid Stage 3 clinical trial Interferes synthesis of methoxy and keto mycolic acid. (Unlike ‘H’ which inhibits alfa mycolic acid) Bacteriocidal .(Comparable to ‘R’) Only against mycobacteria. No cross resistance with H,R,E,S In MDR TB – [ Delamanid + levofloxacin + linezolid+ Z] – (‘A5343’ trial at Korea)

43. Sutezolid Stage 2 clinical trial Linezolid analogue. Bacteriocidal .

44. SQ109 Stage 2 clinical trial Bacteriocidal Acts by inhibiting mmpl3.(Mmpl3, an inner membrane protein, responsible for transport of lipids to outer membrane to synthesise mycolic acid)

45. Sudoterb Stage 2 clinical trial Inhibits protein synthesis.

46. INH derivative LL-3835 Incorporation of lipophilic moieties (INH hybrids)into framework of INH can increase permeation into bacterial cell therby increasing anti –TB action. LL-3835 – INH pyrrole hybrid-in stage 2 clinical trial . (Few pyrrole compounds have been shown to have in vitro anti tubercular activity)

47. Aptamers Bind targets with great affinity. No immunogenicity. Mtb-Apt1 and Mtb-Apt-6 – shoed in vitro activity. Binds to ?polyphosphate kinase2(PPK2) as target. {PPK2- role in synthesis of mycolic acid}

48. New targets

49. New targets

50. A. Targeting actively growing Mtb 1. Maltosyltransferase ( GIgE ) – Utilises ‘maltose 1 phosphate’ to elongate 1,4- glutan chains. Accumulation of maltose 1 phophate – toxic to Mtb Affects respiratory electron transport in Mtb . Humans lack proteins homologous to GlgE – suitable target.

51. 2. Mycolic acid cyclopropanation Affects mycolic acid metabolism. Dioctylamine – inhibitor of cyclopropanation .

52. 3.DprE1/DprE2 Decaprenylphosphoryl-beta-D-ribose2’-epimerase. Biosynthesis of decaprenylphosphoryl -D-arabinose(DPA) – cell wall synthesis. Also required for growth and survival. Inhibitors – nitrobenzothiazinones (BTZs).

53. 4. Mycothiol ligase ( MshC ) Mycothiol – LMW thiol that protects Mtb from toxicity of drugs. Genes encoded – MshA,B,C,D . MshC important amongst them. Inhibitor – Dequalinium chloride - prevents growth of Mtb .

54. 5. HisG ATP phosphoribosyl transferase ( HisG ). Histidine biosynthesis. Inhibitors of HisG – cidal

55. 6. ATP synthase 3 subunits for enzyme a,b,c . Inhibitors of C subunit have shown growth inhibition. Inhibitor – R207910 – 20000 times more affinity than human ATP synthase.

56. 7. Deformylase ( def and fmt ) and methionine aminopeptidase ) mRNA translocation begins with incorporation of formylated methionine at N terminus. This residue is removed in 2 steps – deformylation by deformylase followed by hydrolysis of methionine by methionine aminopeptidase . Protein synthesis.

57. B. Targeting dormant Mtb Dormancy – Physiological state characterised by cessation in proliferation in in vitro and in vivo Persistence – Tolerance by subpopulation of bacteria to cidal effects of drugs.

58. 8. Isocitrate lyase ( Icl ) Icl - 1 and Icl-2 Inhibitors – growth inhibition, loss of virulence. Inhibitors also act against persistent bacteria in population.

59. 9. Proteasome complex Inhibition of proteasome activity increases susceptibility of Mtb to nitrogen intermediates which are antimicrobial molecules secreted by macrophages.

60. 10. L,D- traspeptidase Interferes peptidoglycan metabolism 11 . DosR ( DevR ) Hypoxia is sensed and transduced via DosR which activates ‘dormancy regulon ’ leading to physiological adaptation. Inhibitors of DosR affects dorancy .

61. 12. CarD Interacts with beta subunit of RNA polymerase and regulates stringent response. Inhibting CarD – limits ability of Mtb to initiate stringent response and to enter into dormancy.

62. 13. UDP- GlcNAc pathway

63. UDP- GlcNAc pathway Uridine diphospho -N-acetyl-glucosamine (UDP- GlcNAc ) – key component of bacterial cell peptidoglycan. Glmu (N acetylglucosamine-1-phosphate uridyltransferase ) involved in last step in synthesis of UDP- GlcNAc .

64. 14. Mmpl3 Mmpl3, an inner membrane protein, responsible for transport of lipids to outer membrane to synthesise mycolic acid.

65. Host directed therapies (HDT) Adjuvant treatment. Potentiate immune defenses against M.tuberculosis . Reduce inflammation H elps preserving lung fn E nhance ATT Target host proteins – less likely to develop resistance.

66. HDT contd… Examples – Bone marrow derived mesenchymal stromal cells Repurposing commonly used drugs for-epilepsy, diabetes, hypercholestrolemia , immune modulators