Transcript 1 - LATA Association

NEW TB DRUGS
Jacques Choucair MD
Infectious Diseases specialist, Hotel Dieu de France
Lecturer at the Saint Joseph University
School of Medicine
History of TB Treatment
• The development of treatment for TB can be
roughly classified into 3 stages:
• Classical approach
– beliefs such as letting out of blood, avoidance of
taking meat and alcohol.
• Sanatorium
– In the 1850's, sanatoria were built in Western
Europe and America in high attitude, fresh air and
nutritious food for the TB patients (artificial
pneumothorax, lobectomy, and pneumonectomy)
History of TB Treatment
• Chemotherapy
– Various agents were tried for the treatment of TB:
mercury, iodine, creosote, etc.
– In 1890, Dr. Robert Koch discovered tuberculin
and tried it for treatment of TB.
– In 1938, Rich & Follis reported that sulfanilamide
could inhibit the growth of TB germs in guinea
pigs.
History of TB Treatment
• In 1945, streptomycin was discovered but initial
response was soon followed by deterioration and
development of drug resistance.
• Other drugs were also discovered subsequently:
para-aminosalicylic acid, isoniazid, pyrazinamide,
cycloserine and kanamycine.
• The advent of rifampicin in the late 1970's
marked the beginning of the era of short course
therapy; from more than 2 years to a period of 6
months.
Epidemiology
• Tuberculosis, a scourge since prehistoric
times, affects more than 9 million people and
causes death in 1.5 million people each year.
• Effective treatment has been available for 60
years, but generally takes 6 months, and
resistance to the drugs, which is
increasing throughout the world, threatens
the effectiveness of treatment.
What is the standard regimen for
drug-susceptible tuberculosis?
• The standard treatment regimen for presumably
drug-susceptible tuberculosis
– rifampin, isoniazid, and pyrazinamide, to which
ethambutol is added as protection against resistance.
• Once susceptibility to isoniazid, rifampin, and
pyrazinamide has been confirmed, ethambutol
can be discontinued. The induction phase is
followed by a consolidation phase consisting of
rifampin and isoniazid for an additional 4 months
of treatment.
What challenges are associated with the relatively
lengthy course of treatment for tuberculosis?
• Managing drug toxicity and ensuring adherence
to the full course of treatment.
• Drug toxicity is substantial;
– 3 to 13% of patients have hepatotoxic effects.
– 15% incidence of interruption or discontinuation.
– Of these adverse reactions, 7.7% resulted in
hospitalization, disability, or death.
• Overall, 16 to 49% of patients do not complete
the regimen.
– adverse drug reactions, cost of treatment, stigma, and
the patient’s belief that cure has been achieved when
symptoms have resolved and bacteria can no longer
be recovered from the sputum.
What factors might explain the poor response of
some patients to antimycobacterial therapy?
• Mycobacterium tuberculosis bacteria are sequestered
in compartments that are inaccessible to antibiotic
action; the interior of granulomas, abscesses, and
cavities.
• Another potential explanation for the poor clinical
responses in some patients is inadequate serum
antimycobacterial drug levels, since low serum levels
further impede the ability of drugs to penetrate
infectious foci. inadequate absorption
• Genetically determined metabolic pathways can also
influence serum drug levels. this slow-acetylator
genotype is present in more than 50% of
white populations.
What new antimycobacterial drugs are
on the horizon?
• Several new classes of antimycobacterial drugs
have been developed in the past 15 years.
• Two of these agents, the diarylquinoline
bedaquiline and the nitroimidazooxazole
delamanid, have received accelerated regulatory
approval
• Other new drug classes (benzothiazinones and
imidazopyridines) show promise in preclinical
studies but have not yet progressed to
clinical trials.
beta-Lactamase activity in mycobacteria including
Mycobacterium avium and suppression of their
growth by a beta-lactamase-stable antibiotic.
• All the mycobacteria tested possess the
enzyme, which explains their resistance to
beta-lactam antibiotics.
• Growth of the mycobacteria was suppressed
by novel combinations of the betalactam/beta-lactamase-inhibitors, and by a
new beta-lactamase-stable cephalosporin,
Cefepime (aminothiazolyl methoxyimino
cephalosporin).
Microbios.1995;81(328):177-85.Prabhakaran K1, Harris EB, Randhawa B, Hastings RC.
In vitro activities of fourteen antimicrobial agents
against drug susceptible and resistant clinical
isolates of Mycobacterium tuberculosis and
comparative intracellular activities against the
virulent H37Rv strain in human macrophages.
• isoniazid (0. 02-0.04), rifampin (0.2-0.4), ethambutol and
streptomycin (0.5-2.0), ethionamide (0.25-0.5), D-cycloserine
(25-75), capreomycin (1-2), kanamycin (2-4), amikacin (0.51.0), clofazimine (0.1-0.4), ofloxacin (0.5-1.0), ciprofloxacin
(0.25-1.0), and sparfloxacin (0.1-0.4).
• among the first-line drugs, rifampin > ethionamide =
isoniazid > ethambutol > streptomycin > D-cycloserine;
• among second-line drugs, clofazimine = amikacin >
kanamycin = capreomycin;
• among fluoroquinolones, sparfloxacin > ofloxacin >
ciprofloxacin.
Curr Microbiol. 1996 Sep;33(3):167-75.Rastogi N, Labrousse V, Goh KS
•
•
•
•
Suppression of the growth of six potentiallypathogenic mycobacteria by beta-lactam/betalactamase-inhibitors.
More than 50-80% inhibition of the
mycobacterial growth was observed at drug
levels of 40-100 micrograms/ml in the medium
Amp-sulb, amox-clav and pip-tazo were active
even when the detergent was omitted.
Against four of the mycobacteria,
ampicillin/sulbactam proved to be the most
active.
The beta-lactam/beta-lactamase-inhibitor
combinations may be of use as rational
therapeutic agents against mycobacterial
infections
Microbios. 1997;91(366):7-14. Prabhakaran K1, Harris EB, Randhawa B
Imipenem for Treatment of
Tuberculosis in Mice and Humans
• Although it was less effective than isoniazid,
imipenem significantly reduced the numbers
of M. tuberculosis organisms in lungs and
spleens and improved survival of mice.
• Imipenem had antimycobacterial activity both
in a mouse model and in humans at high risk
for failure of treatment for MDR tuberculosis.
Antimicrob Agents Chemother. 2005 Jul; 49(7): 2816–2821. Henry F. Chambers,* Joan Turner, Gisela F. Schecter,
Masae Kawamura, and Philip C. Hopewell
TMC207 (bedaquiline): the first compound of a new
class of potent anti-tuberculosis drugs..
TMC207 is a first-in-class diarylquinoline compound
which inhibit bacterial ATP synthase, and potent activity
against drug-sensitive and drug-resistant TB.
It has bactericidal and sterilizing activity against M.
tuberculosis and other mycobacterial species. In patients
with MDR-TB taking TMC207 plus a standard background
regimen, the drug appeared to be safe and well
tolerated, and showed significant efficacy .
TMC207 use to shorter first-line regimens or using it in second-line regimens for
drug-resistant M. tuberculosis infections are both being pursued.
Finally, the remarkable sterilizing capacity of TMC207 also makes it an attractive
drug in the strategy of TB elimination
Future Microbiol. 2010 Jun;5(6):849-58. Matteelli A1, Carvalho AC, Dooley KE, Kritski A
Present and future in the use of antitubercular drugs.
• Time to approval as a antiTB drug is 10-15 years, consisting
of phases of preclinical and clinical research.
• TMC207, a diarylquinoline with a unique way to address
Mycobacterial ATP synthetase, shows high activity in vitro
against Mycobacterial strains sensitive or resistant to all
drugs in the first and second line including quinolones.
• TMC207 was added to a basic standard regimen in a study
of MDR-TB patients. After two months and satisfactory
tolerability, sputum conversion rate in culture was 48%
(versus 9% in the placebo group).
Pneumologia. 2011 Oct-Dec;60(4):198-201. Didilescu C1, Craiova UM.
Present and future in the use of antitubercular drugs.
• Two nitroimidazole (PA-824 and OPC-67683) are currently
in clinical development.
• PA-824 demonstrated good safety and tolerability in adult
patients with pulmonary TB in South Africa, when given
once daily for 7 days. Associating isoniazid, would prevent
the selection of mutants resistant to Isoniazid.
• Linezolid 600 mg is currently being tested in a Phase II for
treatment of XDR-TB in the Republic of Korea.
• PNU-100480, analogous to the previous one, has the
potential to significantly shorten the treatment in cases
where there is sensitivity and in those with resistance to
drugs. 300 mg dose is under investigation in a phase II pilot
study in MDR-TB in South Africa.
Pneumologia. 2011 Oct-Dec;60(4):198-201. Didilescu C1, Craiova UM.
New drugs for the treatment of
tuberculosis: hope and reality.
• Rifapentine, a rifamycin with low MIC, long half-life did not confirm its
potential in a recent short-term clinical trial and is being extensively
re-evaluated.
• Moxifloxacin, a fluoroquinolone, improved the activity of the standard
drug regimen when substituted for ethambutol (EMB). It is being
studied to shorten the duration of treatment for fully drug-susceptible
TB (Remox study).
• Clofazimine requires further study because it has been included in a
successful short 9-month combined drug regimen for the treatment of
multidrug-resistant TB.
• The diarylquinoline TMC207 is the most promising among the new TB
drugs because of its clinical rate of culture conversion.
Int J Tuberc Lung Dis. 2012 Aug;16(8):1005-14. Grosset JH1, Singer TG, Bishai WR.
New drugs for the treatment of
tuberculosis: hope and reality.
• 200 mg daily doses of the nitroimidazo-oxazine
PA-824 and the nitro-dihydro-imidazooxazole
OPC-67683 were safe and induced a bactericidal
effect
• The new oxazolidinones PNU-100480 and AZD5847 might be at least as active as linezolid and
much less toxic.
• SQ109 is an EMB analogue that does not have
cross-resistance with EMB and might have
synergistic activity in combined regimens.
• Benzothiazinones and dinitrobenzamides show
exciting in vitro anti-microbial activity.
Int J Tuberc Lung Dis.2012 Aug;16(8):1005-14. Grosset JH1, Singer TG, Bishai WR.
Novel compounds and drugs and recent patents in
treating multidrug-resistant and extensively drugresistant tuberculosis.
• A number of recent studies revealed that
successful treatment of the patients with
MDR/XDR- TB was not achieved due to high
resistant rates to many second-line drugs such as
kanamycin and prothionamide including poor
adherence of the lengthy treatment.
• Many new drugs and compounds such as
benzothiazinones, meropenem, PA-824,
isoflavonoids, rhein, PNU-100480, TMC207,
SQ109, OPC-67683, AZD5847, and linezolid are
currently in development pipeline.
Recent Pat Antiinfect Drug Discov. 2012 Aug;7(2):141-56.Cheepsattayakorn A1,
Cheepsattayakorn R.
Tuberculosis: the drug development
pipeline at a glance.
• Compounds as gatifloxacin, moxifloxacin,
metronidazole or linezolid are currently
evaluated in clinical phases 2 or 3 for treating
tuberculosis.
• In addition, analogues of known TB drugs (PA824, OPC-67683, PNU-100480, AZD5847,
SQ609, SQ109, DC-159a) and new chemical
entities (TMC207, BTZ043, DNB1, BDM31343)
are under development.
Eur J Med Chem. 2012 May;51:1-16. Villemagne B1, Crauste C, Flipo M, Baulard AR, Déprez B,
Willand N.
Improving the health of the
tuberculosis drug pipeline.
• Moxifloxacin and levofloxacin have equally good efficacy
and safety in the early phase of treatment of multidrugresistant TB (MDR-TB),
• linezolid has the potential to cure refractory cases of MDRTB.
• Bedaquiline and delamanid may be the best drug
candidates for enhancing treatment options for MDR-TB.
• New chemicals, such as sutezolid, AZD5847, PA-824, SQ109,
and BTZ043, show potent activity against Mycobacterium
tuberculosis.
• Late-generation fluoroquinolones in combination with the
first-line and second-line anti-TB drugs have been used to
shorten the treatment duration in drug-susceptible and
MDR-TB.
Lancet Infect Dis. 2014 Feb;14(2):102-3.
Curr Opin Pulm Med. 2014 May;20(3):280-6.
Pentacyclic nitrofurans with in vivo efficacy and
activity against nonreplicating Mycobacterium
tuberculosis.
• incorporation of the outer ring elements of the
antitubercular nitroimidazole OPC-67683 successfully
increased stability of the resulting pentacyclic
nitrofuran lead compound Lee1106 (referred to as 9a).
• In vivo, 9a showed long half-lives and high volumes of
distribution and a lengthy post antibiotic effect and
was highly active against nonreplicating M.
tuberculosis grown under hypoxia.
• 9a showed a low potential for cross resistance to
current antitubercular agents.
• 9a is a nanomolar inhibitor of actively growing as well
as nonreplicating M. tuberculosis.
PLoS One.2014 Feb 5;9(2):e87909. doi: 10.1371/journal.pone.0087909. eCollection 2014. Rakesh1, Bruhn DF1, Lee RB1, Hurdle JG1, McNeil
MR2, Lenaerts AJ2, Meibohm B3, Lee RE4.
In vitro and in vivo activities of the nitroimidazole
TBA-354 against Mycobacterium tuberculosis.
• TBA-354 (SN31354[(S)-2-nitro-6-((6-(4trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl
compound with exceptional efficacy against chronic murine
tuberculosis.
• TBA-354 is narrow spectrum and bactericidal in vitro
against replicating and nonreplicating
Mycobacterium tuberculosis. The addition of serum
protein or albumin does not significantly alter this
activity.
Antimicrob Agents Chemother. 2015 Jan;59(1):136-44. Upton AM1, Cho S2, Yang TJ3, Kim Y2, Wang Y2, Lu Y4, Wang B4, Xu J4, Mdluli K3, Ma Z3,
Franzblau SG2.
In vitro and in vivo activities of the nitroimidazole
TBA-354 against Mycobacterium tuberculosis.
• Spontaneous resistant mutants appear at a
frequency of 3 × 10 -7.
• TBA-354 has high bioavailability and a long
elimination half-life and a low risk of drug-drug
interactions.
• It has time- and dose-dependent in vivo
bactericidal activity that is at least as potent as
that of delamanid and more potent than that of
PA-824.
• TBA-354 is suitable for once-daily oral dosing
Antimicrob Agents Chemother. 2015 Jan;59(1):136-44. Upton AM1, Cho S2, Yang TJ3, Kim Y2, Wang Y2, Lu Y4, Wang B4, Xu J4, Mdluli K3, Ma Z3,
Franzblau SG2.
The anti-tuberculosis agents under
development and the challenges ahead.
• Tuberculosis (TB) is a serious health problem causing
1.5 million deaths worldwide.
• Compounds such as gatifloxacin, moxifloxacin and
linezolid, the already known antibiotics are currently
being evaluated for their anti-TB activity.
• OPC-67683 and TMC207 have been approved for
the treatment of MDR-TB patients recently, while
– PA-824, SQ109, PNU-100480, AZD5847,
LL3858, SQ609, SQ641, BTZ043, DC-159a,
CPZEN-45, Q-203, DNB1, TBA-354 are in
various phases of clinical and preclinical
developments.
Future Med Chem. 2015;7(15):1981-2003. Kumar D1, Negi B1, Rawat DS1.
Metabolic Mechanism of Delamanid, a New
Anti-Tuberculosis Drug, in Human Plasma.
• Delamanid (OPC-67683, Deltyba) was rapidly
degraded by incubation in the plasma of all
species tested at 37°C, with half-life values
(hours) of 0.64 (human).
• A major metabolite, (R)-2-amino-4,5dihydrooxazole derivative (M1), was formed in
the plasma by cleavage of the 6-nitro-2,3dihydroimidazo(2,1-b)oxazole moiety of
delamanid by albumin.
Drug Metab Dispos. 2015 Aug;43(8):1277-83. Shimokawa Y1, Sasahara K2, Koyama N2, Kitano K2, Shibata M2, Yoda N2, Umehara K2.
Delamanid (OPC-67683) for treatment
of multi-drug-resistant tuberculosis.
• The research and development of delamanid was
carried out by Otsuka Pharmaceutical Development
and Commercialization (Osaka, Tokyo, Japan). It
belongs to the group of nitroimidazoles. It inhibits the
synthesis of mycolic acids.
• Its market approval was obtained in April 2014 in
Europe. Its bactericidal activity was demonstrated in
individuals with drug-susceptible, MDR- and XDR-TB.
• The safety and tolerability profile was good; the
notified increased QT interval was not clinically
relevant. It was approved for adults but ongoing clinical
trials in the pediatric population.
N Engl J Med 2015; 373:291-292July 16, 2015 DOI: 10.1056/NEJMc1415332 Article Citing Articles (3) Metrics
Ther Clin Risk Manag. 2015 May 13;11:779-91. doi: 10.2147/TCRM.S71076. eCollection 2015.Lewis JM1, Sloan DJ2.
Expert Rev Anti Infect Ther. 2015 Mar;13(3):305-15. Sotgiu G1, Pontali E, Centis R, D'Ambrosio L, Migliori GB.
Drug Des Devel Ther. 2015 Jan 29;9:677-82.Szumowski JD1, Lynch JB2.
Delamanid does not inhibit or induce
cytochrome p450 enzymes in vitro.
delamanid is unlikely to cause clinically relevant
drug-drug interactions when co-administered
with products that are metabolized by the CYP
enzyme system.
Biol Pharm Bull. 2014;37(11):1727-35. Shimokawa Y1, Sasahara K, Yoda N, Mizuno K,
Umehara K.
Novel drugs against tuberculosis: a
clinician's perspective.
• After decades of quiescence in the development of
antituberculosis medications, bedaquiline and
delamanid have been conditionally approved for the
treatment of drug-resistant tuberculosis, while several
other novel compounds (AZD5847, PA-824, SQ109 and
sutezolid) have been evaluated in phase II clinical trials.
• Before novel drugs can find their place in the battle
against drug-resistant tuberculosis, linezolid has been
compassionately used with success in the treatment of
fluoroquinolone-resistant multidrug-resistant
tuberculosis.
Eur Respir J. 2015 Apr;45(4):1119-31. Olaru ID1, von Groote-Bidlingmaier F2, Heyckendorf J1, Yew WW3, Lange C4,
Chang KC5.
Tuberculosis treatment and drug
regimens.
• The therapeutic approach for drug-resistant
tuberculosis is cumbersome, because of the poor,
expensive, less-effective, and toxic alternatives to the
first-line drugs.
• New antituberculosis drugs (bedaquiline and
delamanid) cannot represent the definitive solution to
the clinical management of drug-resistant tuberculosis
forms, particularly in intermediate economy settings
where the prevalence of drug resistance is high (China,
India, and former Soviet Union countries).
Cold Spring Harb Perspect Med. 2015 Jan 8;5(5):a017822. Sotgiu G1, Centis R2, D'ambrosio L2, Migliori GB2.
Contribution of the nitroimidazoles PA-824 and TBA354 to the activity of novel regimens in murine
models of tuberculosis.
• New regimens based on two or more novel agents are sought
in order to shorten or simplify the treatment of both drugsusceptible and drug-resistant forms of tuberculosis.
• PA-824 (nitroimidazo-oxazine) now in phase II trials and has
shown significant early bactericidal activity alone and in
combination with the newly approved agent bedaquiline or
with pyrazinamide with or without moxifloxacin.
• TBA-354, has been discovered to have in vitro potency
superior to that of PA-824 and greater metabolic stability than
that of the other nitroimidazole derivative in clinical
development, delamanid.
Antimicrob Agents Chemother. 2015 Jan;59(1):129-35.Tasneen R1, Williams K1, Amoabeng O1, Minkowski A1,
Mdluli KE2, Upton AM2, Nuermberger EL3.
Contribution of the nitroimidazoles PA-824 and TBA354 to the activity of novel regimens in murine
models of tuberculosis.
• TBA-354 monotherapy is 5 to 10 times more potent than PA824.
• (TBA-354 + bedaquiline) is 2 to 4 times more potent than (PA824 + bedaquiline),
• And at a dose equivalent to that of PA-824, TBA-354
demonstrated superior sterilizing efficacy.
• the addition of either nitroimidazole significantly improved the
sterilizing activities of bedaquiline and sutezolid, with or
without pyrazinamide, confirming the value of each agent in
this potentially universally active short-course regimen.
Antimicrob Agents Chemother. 2015 Jan;59(1):129-35.Tasneen R1, Williams K1, Amoabeng O1, Minkowski A1,
Mdluli KE2, Upton AM2, Nuermberger EL3.
delamanide
bedaquiline