New TB Drug for

Drug Resistant Tb
– A New hope
PIK Semarang, 23 Oktober 2018
Diah Handayani/
Yani Jane Sugiri
 WHO reported 3.5% of naive infections already expressed
MDR-TB
 20.5% of patients with relapsed disease have MDR-TB
 Complexity and toxicity of the current TB drug regimes
 Drugs to treat drug-resistant TB are expensive and extremely
toxic
 Interactions of the current TB drugs with the ARVs taken by
HIV positive people

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 1940 History - The development of PAS
 1943 History - Waksman & the development of Streptomycin
 1944 PAS and streptomycin was first given to patient
 1951 Isoniazid and combination therapy
 1952 Professor Waksman awarded Nobel Prize for Physiology or
Medicine
 1959 History – rifamycin
 1966 Rifampin first used clinically
 -----------------------------------------------------
 2012 History – Delamanid & Bedaquiline
“your ingenious, systematic and successful studies of the soil microbes that have led to
the discovery of streptomycin, the first antibiotic remedy against tuberculosis”

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 A novel mechanism of action to attenuate cross-resistance
 Rapid bactericidal activity  reduce duration of therapy
 Optimized pharmacokinetic/ pharmacodynamic (PK/PD)  1x-daily oral
administration
 Low potential for drug–drug interactions to allow combination therapy,
(especially with other TB drugs and current HIV therapeutics.
 Excellent safety profile to allow for use in children and pregnant

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 Inexpensive manufacturing,
 High compound stability,
 Narrow spectrum of activity,
 High tolerability
 Low rate of spontaneous resistance emergence.

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 New TB drugs need to provide:1

 Shorter and simpler, but still affordable,

multi drug regimes for drug sensitive TB
NEW HOPE  Shorter, more effective , less toxic, and

OF NEW less expensive regimes for drug resistant

TB
DRUG  Short, simple, easily tolerable and safe
regimes for latent TB
 Drugs with few drug drug interactions, so
they can be safely provided for people
with HIV.

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14 candidate drugs for drug-
susceptible, MDR, and latent
tuberculosis are in the clinical
stages of drug development;
nine are novel, and three have
been approved

(Lancet Infect Dis, 23 march 2018)

 Bactericidal, Inhibits ATP synthesis by targeting C subunit from
ATP synthase
 Reach Tmax in 5 hour, T1/2 up to 5,5 month
 Bedaquiline is mainly eliminated in faeces.
 The renal clearance of unchanged drug is insignificant
 Drug Interaction:
 Bedaquiline is metabolized by CYP3A4. Rifampicin (a CYP3A4
inducer) reduces bedaquiline in blood by half. Efavirenz based on a
single dose study appears to reduce the amount of bedaquiline
though inducing CYP3A4. CYP3A4 inhibitors (e.g. azole anti-fungal
drugs, some macrolides, protease inhibitors) can raise the level of
bedaquiline but can be considered for use if the benefits outweigh
the risk.
 Avoid use with other drugs that prolong the QT interval as additive
QT prolongation may occur (e.g. clofazimine, fluoroquinolones,
delamanid, azole anti-fungal drugs, and many others);
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 WHO’s targeted support to Belarus
 Belarus has the highest proportion of MDR-TB among new patients in the world, and has a
substantial share of XDR-TB among these. Treatment for XDR- and MDR-TB patients is expensive,
long and prone to adverse side effects.
 WHO/Europe has been providing continuous technical support to Belarus for the introduction of
new TB drugs and the development of national guidelines on management of TB and MDR-TB, on
drug safety monitoring and on the use of new TB drugs.
 With support from the Global Fund to Fight AIDS, Tuberculosis and Malaria, the WHO Country
Office in Belarus contracted 14 national specialists to ensure adequate active TB drug safety
monitoring and management (aDSM) while treating MDR-TB patients with new drugs.

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 A group of 192 MDR-TB patients who started treatment in Belarus with bedaquiline-containing
regimens between June 2015 and March 2016, 178 patients (92.7%) were treated successfully; 9
(4.7%) did not complete the treatment; 3 (1.6%) died, and for 2 (1%) treatment failed.
 These results, presented at the First Congress of Pulmonologists and TB Doctors of Belarus,
represent a major step forward compared to the 58% success rate among other MDR-TB patients
who started treatment in 2015 without the new drugs. They compare equally favourably with the
WHO European Region average treatment success rate for MDR-TB patients (55%) and extensively
drug-resistant TB (XDR-TB) patients (23%).
 Results from Belarus are very encouraging for countries engaged in achieving the regional target
of 75% treatment success rate for MDR-TB, set in the Tuberculosis Action Plan for the European
Region 2016–2020. Replicating this success in other countries and settings would constitute a
huge leap forward on the path to reaching TB elimination, and ending the suffering of millions of
people worldwide.

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 Inhibition of the synthesis of the mycobacterial cell wall
components, methoxy-mycolic and keto-mycolic acid
 Delamanid is a pro-drug that must be reduced by the deazaflavin-
dependent nitroreductase to its des-nitro metabolite to be active.
 The complete metabolic profile of delamanid in man has not yet
been fully elucidated
 Delamanid disappears from plasma with a t1/2 of 30-38 hours, not
excreted in urine.
 Drug Interaction:
 Avoid concomitant administration of strong CYP3A inducers (e.g.
rifampicin, carbamazepine)
 If co-administration of delamanid with any strong inhibitor of CYP3A
(e.g. ritonavir, ketokonazole) is necessary, consider more very frequent
monitoring of ECGs
 Avoid using with other drugs that prolong the QT interval as additive
QT prolongation may occur 20
  There is currently more experience with the use of
bedaquiline in the treatment of XDR-TB than there
is for delamanid.
FACTORS TO BE
 Delamanid's excellent safety profile was confirmed
TAKEN IN in the phase III clinical trial. There was also quicker
CONSIDERATION culture conversion in some of the analyses, but no
WHEN DECIDING significant effect on final

BETWEEN  Treatment outcome Bedaquiline has not

completed its phase III clinical trial.
BEDAQUILINE  Delamanid has less drug-drug interaction with ART
AND DELAMANID and other drugs metabolized by the cytochrome
P450 enzymes like CYP3A4.
 There is theoretical cross-resistance between
clofazimine and bedaquiline

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 The Nitroimidazoles are an existing class of drugs known to have antimicrobial activity. Two “next
generation” or derivatives of this class of drugs, OPC-67683 (now also known as delamanid) and
PA-824 are under development as potential TB drugs.

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 TB drug Pretomanid (PA-824)
PA-824 is another nitroimidazo-oxazole currently being developed by the TB Alliance.
Potentially be used for the treatment of both drug sensitive and drug resistant TB.
Also shown activity against both latent and active TB.
 TB drug TBA-354
In March 2016 it was announced that the TB Alliance had voluntarily halted the clinical
development program for TBA-354.7
 AZD5847
Potential new TB drug being developed by AstraZeneca.
In December 2012, the first patient had been enrolled in a Phase 2a trial in South Africa, for
patients with TB, including patients with HIV and TB coinfection.
The study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID),
part of the U.S. National Institutes of Health.
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 New drugs (Group D2):
Repurposed drugs:
 Linezolid (Lzd) (Group C).

 Bedaquiline (Bdq)  Clofazimine (Cfz) (Group C).

 Delamanid (Dlm)  Carbapenems (Group D3). Imipenem/cilastatin (Ipm/Cln) or

meropenem (Mpm) are the two most commonly used.
It is recommended to combine the carbapenem with clavulanic
acid (Amx/Clv). Meropenem is usually dosed three times daily.
Ertapenem (Epm) is also a carbapenem with an anti-TB activity
and can be dosed once daily.
 There is little experience with ertapenem to date and should
only be considered when the use of Ipm/Cln or Mpm is not
possible.

(http://erj.ersjournals.com/content 2015)
 Evidence suggests Amoxicillin/Clavulanate (Amx/Clv) is at best
weakly effective, and should not be used alone without the
carbapenem 24
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 Medicines have been regrouped into three categories and
ranked based on the latest evidence about the balance of
effectiveness to safety
 Group A: Medicines to be prioritised: levofloxacin/moxifloxacin,
bedaquiline and linezolid
 Group B: Medicines to be added next: clofazimine,
cycloserine/terizidone
 Group C: Medicines to be included to complete the regimens and
when agents from Groups A and B cannot be used: ethambutol,
delamanid, pyrazinamide, imipenem-cilastatin,

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 Medicines no longer recommended are kanamycin and capreomycin,
given increased risk of treatment failure and relapse associated with
their use in longer MDR-TB regimens
 Amoxicillin-clavulanic acid is only to be used to accompany the
carbapenems
 Consultation on how best to optimise these aspects of MDR-TB
treatment is ongoing. This includes the minimum number of medicines
required in designing MDR-TB regimens based on the revised grouping,
while maximising regimen efficacy in the presence of resistance to or
tolerability of individual agents

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 Apart from the ranking by balance of
effectiveness and harms, choice is also
determined by:
REVISED  A preference for oral over injectable agents;
GROUPING OF TB  The results of drug-susceptibility testing (DST);
MEDICINES  The reliability of existing DST methods;
RECOMMENDED  Population drug resistance levels;
FOR USE IN  History of previous use of the medicine in a
LONGER MDR-TB patient;
REGIMENS  Drug tolerability;
 Potential drug-drug interactions.

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 Reduced no. of pills and three new TB drugs in Nix-TB trial
 Current drug regimen for the treatment of XDR-TB
 The Nix-TB trial is the first TB clinical trial to test a new drug
combination which has the possibility of being a shorter, all
oral, and affordable treatment for XDR-TB. This combination
does not require injections and has far fewer pills. The Nix-TB
drug combination is pretomanid, bedaquiline and linezolid.
This drug combination is predicted to be able to cure XDR-TB
in six to nine months.
 In February 2017 the results became available for the first 72
people to be treated in the study. Thirty one people have
completed treatment and 6 months of post treatment follow
up. Of these 31 people, 29 people cleared XDR-TB. This means
that TB bacteria could no longer be cultured from their sputum.
Twenty people stopped taking the drug after six months of
follow up and only one relapsed.
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(Lancet Infect Dis, 23 march 2018)
(Lancet Infect Dis, 23 march 2018)
(Lancet Infect Dis, 23 march 2018)
Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for
drug-sensitive Tuberculosis (TB): The “TRUNCATE-TB” Trial

THAILAND
Pilihan Regimen Central Chest Institute
Chulalongkorn Hospital

PHILIPPINES
Grup A: 24 minggu regimen standar: 8 minggu rifampicin, isoniazid, Lung Center of Philippines
pyrazinamide, ethambutol dilanjutkan 16 minggu rifampicin dan isoniazid Quezon Institute
De La Salle Hospital
Tropical Disease Foundation
Grop B: 8 minggu rifampicin (35mg/kg), isoniazid, pyrazinamide, Perpetual Succour Hospital
ethambutol, linezolid
SINGAPORE
Grop C: 8 minggu rifampicin (35mg/kg), isoniazid, pyrazinamide, National University Hospital
ethambutol, clofazimine
INDONESIA
Hasanuddin University
Grop D: 8 minggu rifapentine, isoniazid, pyrazinamide, linezolid, Universitas Indonesia
levofloxacin University of Padjadjaran
Dr Soetomo Hospital/ Airlangga
Univ
Grop E: 8 minggu isoniazid, pyrazinamide, ethambutol, linezolid,
Dr Saiful Anwar Hospital
bedaquiline /Brawijaya Univ
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 WHO TB Working Group New Drug, jan 2018.
 Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the
reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109
www.thelancet.com/journals/lancet
 Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December
2010, 2201-2214
 Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the
reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109.
 Tuberculosis: progress and advances in development of new drugs, treatment
regimens, and host-directed therapies, Lancet Infect Dis, 23 march 2018

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Thank you

(Labuan Bajo, maret 2018)

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