WHO Drug Information Vol. 20, No. 4, 2006 - World Health ...

Medicines for Tuberculosis
InhA Inhibitors (GlaxoSmithKline–
TB Alliance)
InhA, the enoyl reductase enzyme from
M. tuberculosis catalyses the last step in
the fatty acid biosynthesis pathway (FAS
II). Frontline anti-tuberculosis drugs such
as isoniazid (INH) target this enzyme.
Drug resistance to INH results primarily
from mutations in KatG, the enzyme that
activates INH. Consequently, InhA inhibitors
that do not require activation by KatG
are attractive candidates for drug discovery.
The main purpose for this screen is
therefore to bypass the activation step
and directly inhibit InhA. A possible
limitation is that cross-resistance with
isoniazid may occur.
Isocitrate Lyase Inhibitors
(GlaxoSmithKline–TB Alliance)
The isocitrate lyase (ICL) enzyme has
been shown to be essential for long-term
persistence of M. tuberculosis in mice,
but not required for bacilli viability in
normal culture or hypoxic conditions.
Inhibition of the two isoforms of isocytrate
lyase present in M. tuberculosis blocks
growth and survival of M. tuberculosis
bacteria.
The absence of ICL orthologs in mammals
should facilitate the development of
glyoxylate cycle inhibitors as new drugs
for the treatment for tuberculosis. Such a
new drug is expected to be able to kill
persistent bacteria and therefore have
sterilizing activity and shorten treatment
time. However, the structure of ICL active
site is making the screening for inhibitors
particularly lengthy and laborious.
Compounds originating from
existing families of drugs
Other promising candidate anti-TB drugs
include: Gatifloxacin, Moxifloxacin,
Diamine SQ-109, Non-Fluorinated
Quinolones, Nitrofuranylamides, Picolinamide
Imidazoles, Thiolactomycin
Analogs, Dihydrolipoamide Acyltrans-
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WHO Drug Information Vol 20, No. 4, 2006
ferase Inhibitors, Methyltransferas inhibitors,
and Quinolones.
Timeline for development
of candidate drugs
Clinical trials to register a TB drug represent
a lengthy and expensive process
that can take a minimum of six years,
generally longer than for other infectious
diseases. The greatest challenge in the
design of TB clinical trials is in Phase III
Trials. These trials are usually large
scale, randomized clinical trials designed
to show improvement or equivalent
efficacy compared to the standard
regimen among diseased patients.
Efficacy evaluation requires measurements
of relapse rate during a 1–2 year
follow-up after completion of the already
lengthy 6-month treatment regimen.
Relapse rate after chemotherapy is
commonly accepted as the endpoint to
determine the efficacy of a new therapy
and to assess whether a new drug
can improve sterilizing activity. Since
relapse rates under random clinical trial
conditions are often 3% or less, large
numbers of patients are needed to
demonstrate an improvement in relapse
rate. This results in high drug development
costs and long delays in introducing
new medicines.
Regulatory agencies require that efficacy
is demonstrated during phase III trials
involving a combination of traditional and
surrogate markers for activity. Since the
identification of biomarkers could significantly
streamline and accelerate clinical
development, the TB Alliance has recently
established a collaboration with BG
Medicine Inc. to identify biomarkers for
drug efficacy in TB treatment. Validated
surrogate markers of relapse could
provide evidence on the efficacy and the
sterilising activity of a drug/regimen
without requiring large numbers of patients.