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M.Tuberculosis:
nuovi farmaci per
nuovi scenari
Roberto Parrella
UOC Malattie infettive ad indirizzo respiratorio
Obiettivi del trattamento anti-TB
 Guarire il paziente, ripristinare una buona
qualità di vita, recuperare una adeguata
funzionalità produttiva e favorire il
reinserimento sociale in un periodo di
tempo accettabile
 Prevenire la morte per TB e ridurre le
sequele post-TB (anatomiche e funzionali)
 Prevenire ed evitare le recidive
 Ridurre/bloccare la trasmissione della TB
attiva ad altre persone all’interno della
comunità
 Prevenire lo sviluppo e la trasmissione di
ceppi chemioresistenti
mediante un
corretto regime terapeutico
High dose GFX, EMB, PZA, CFZ, supplemented 4 months intensive phase KM, PTH, INH
WHO – June 2013
WHO – Oct. 2014
New Drugs: 1. Bedaquiline
 First new TB drug class in more than 40 years
 Chemical class: diarylquinoline
 Novel target: ATP synthase inhibitor
 Phase IIb data: placebo-controlled trial of BDQ in
combination with background MDR-TB therapy
(BT)
o Showed greater efficacy of BT + BDQ than BT +
placebo at 6 months
 Approved by FDA (accelerated procedure) in
December 2012 "as part of combination therapy to
treat adults with multi-drug resistant tuberculosis
when other alternatives are not available"
GLOBAL TB
PROGRAMME
ATP: adenosine triphosphate
New Drugs: 2. Delamanid
• Phase IIb trial: placebocontrolled safety, efficacy, and
PK of delamanid combined
with optimized background
therapy (OBT)
• 2 test arms:
(i) delamanid (100mg BID) +
OBT ;
(ii) delamanid (200mg BID) +
OBT
45,4 %
41,9 %
29,6 %
• Primary endpoint: 2-month
sputum culture conversion
(SCC)
GLOBAL TB
PROGRAMME
Survival Analysis of Days to Sputum-Culture Conversion
(Source: Gler et al, N Engl J Med 2012;366;2 – n= 481
New Drugs: 3. Pretomanid (PA-824)
 Chemical class: nitroimidazole (nitroimidazo-oxazine sub-class)
 active against drug-sensitive and multidrug-resistant strains of M. tuberculosis
 Potent bactericidal activity against replicating and static bacilli
 Several Phase I studies completed - no significant food effect at anticipated
clinical dose; not a significant inhibitor/inducer of CYP3A4
 Phase II: Two 14-day EBA studies in patients with newly diagnosed, smear +,
drug sensitive pulmonary TB
 14 days EBA study of a new combination : PA-824 + Moxi + PZA showing
promising results
GLOBAL TB
PROGRAMME
Phase IIb study on bactericidal activity of moxifloxacin,
pretomanid (PA-824), and pyrazinamide during the first 8
weeks of TB treatment
MPa100Z=moxifloxacin, 100 mg pretomanid, and pyrazinamide.
MPa200Z=moxifloxacin, 200 mg pretomanid, and pyrazinamide.
HRZE=isoniazid, rifampicin, and pyrazinamide-ethambutol.
DRMPa200Z=patients with MDR-TB treated with moxifloxacin,
200 mg pretomanid, and pyrazinamide.
Culture conversion at week 8 was 71%
for PaMZ compared to 38% for HRZE
Decrease in serial weekly log 10 CFU counts of
MTB: estimates by joint Bayesian non-linear
mixed-effects regression
Dawson R, Lancet 2015: Published online March 18
CAPURAMYCIN
• Is a natural occurring antibiotic secreted by Streptomyces griseus
• Inhibits peptidoglycan biosynthesis
• Many capuramycin derivates have been synthetically generated
• Subclasses identified show impressive antimycobacterial potency and selectivity
• They exhibit rapid bactericidal activity
• Commonly suffer from poor aqueous solubility
• The lead from this series is SQ641
• Capuramycin have limited oral bioavailability and pharmaceutical properties
• CPZEN 45 – aerosol delivery of Capuramycin
• Is efficiently absorbed by lung tissue trough inhalation and can reach
terapeutically relevant concentrations at the primary site of Mtb infection
SPECTINAMIDES
• Semisynthetic derivatives of thae antibiotic spectinomycin produced by
Streptomyces spectabilis
• Works by inhibiting ribosomal translocation and consequent protein synthesis by
binding site on the 16S ribosomal subunit
• Excellent safety profile with no associated nephrotoxicity or ototoxicity but with
modest antitubercular activity
• Lee 1599 – spectinamide analog
• Greatly increased antitubercular activity
• Highly selectivity for Mtb – Marked postantibiotic effect
• Lack cross-resistance with any other protein-synthesis inhibitors
• Retained activity against MDR-TB and XDR-TB
• Lee 1599 is active in mouse models of acute and chronic TB infection
• Synergy in vivo when combined with RIF and PZA and additivity when
combined with second-line agents used for treating MDR-TB
• Lee 1599 is a good potential partner for novel treatment regimens
BENZOTHIAZONES
• Are potent amtymicobacterial agents
• The target is DprE1 (Decaprenylphosphoryl-b-D-ribose 2’-epimerase 1) that in
combination with DprE2 is involved providing a crucial precursor to the cell wall
arabinogalactan polysaccharide
•
As an essential aspect of Mtb survival and novel mechanisms of antitubercular
activity, optimized DprE1 inhibitors are thought of as powerful new classes for
the treatment of MDR-TB with limited cross-resistance to current therapeutic options
•
•
PBTZ 169 is the lead molecule in this series
BTZ 043 are being studied preclinically
ALTERNATIVE CLASSES OF DprE1 INHIBITORS
•
1,4-azaindoles
•
TCA 1
MmpL3 INHIBITORS
•
The Mycobacterial membrane protein Large (MmpL3) family of export proteins are
involved in transportation of metabolites from the cytosol of Mtb
• The Mtb genome contains 12 genes that express the MmpL proteins that are considered
resistance-nodulation-division proteins which play an important role in Mtb survival and
pathogenesis.
• MmpL3 is required for the export of mycolic acids to the periplasmic space or outer membrane
• MmpL3 is the only protein in this family that is essential for mycobacterial survival
• MmpL3 is an attractive drug target
• The most advanced MmpL3 inhibitor is SQ109
MACROLIDE
•
Macrolide antibiotics reinvestigation from the archive for MDR application because
of the efficacy of protein synthesis inhibitors
•
From the natural product sequanamycin A (SEQ-503) chemical optimization has
obtained SEQ-9
•
SEQ-9 has better mycobacterial potency and much better PK properties
(plasma stability, a better metabolic profile : high stability and
no CYP inhibition)
•
It is efficacious in acute in vivo murine models
•
It has notable activity against replicating Mtb, latent Mtb and intramacrophage
Mtb with submicromolar MIC80 activity in all three models
•
An exciting aspect is that there is no MIC shift in multiple lines of human
clinical Mtb isolates and does not appear to be hampered by inducible
mediated resistance (that restricts the use of other macrolides)
•
When researchers added SEQ-9 to combination study, they noted a dramatic
increase in the total bactericidal activity of those combinations.
DRUG-RESISTANT TUBERCULOSIS
CLINICAL TRIALS PROGRESS REPORT
Last updated July 11, 2016
DRUG-RESISTANT TUBERCULOSIS
CLINICAL TRIALS PROGRESS REPORT
Last updated July 11, 2016
DRUG-RESISTANT TUBERCULOSIS
CLINICAL TRIALS PROGRESS REPORT
Last updated July 11, 2016
Notable recent advance in drug discovery tecnologies for Mtb
1. Whole-genome sequenze and genetic tecnologies
2. Screening under defined growth conditions (Mtb life cycle)
3. MALDI-MS imaging of drug distribution within the infected lung