New Antituberculous New Antituberculous DrugsDrugs

Hail M. Al-Abdely, MDHail M. Al-Abdely, MDConsultant, Infectious DiseasesConsultant, Infectious DiseasesKing Faisal Specialist Hospital and King Faisal Specialist Hospital and Research CenterResearch Center

Driving forces behind Driving forces behind Drug developmentDrug development Good marketGood market

– Common Common NOTNOT rare (pseudomonas versus rare (pseudomonas versus Burkhelderia)Burkhelderia)

– Common in the rich (HIV versus Tuberculosis)Common in the rich (HIV versus Tuberculosis)– Difficult to treat with current agentsDifficult to treat with current agents

Emerging new organisms (Fungi in immune Emerging new organisms (Fungi in immune suppressed patients)suppressed patients)

Resistance in old organisms (several bacteria)Resistance in old organisms (several bacteria) Better kinetics and safety (Ampho B versus Better kinetics and safety (Ampho B versus

Azoles)Azoles) Basic Human needBasic Human need

The FactThe Fact

Despite this enormous market in Despite this enormous market in terms of patients, only 5% of the terms of patients, only 5% of the 16 million people currently sick 16 million people currently sick with TB can pay for treatment - a with TB can pay for treatment - a lack of buying power that has lack of buying power that has dissuaded investors for decades.dissuaded investors for decades.

Alliance against TB.org

1940 1950 1960 1970 1980 1990 2000

Streptomycin-1944

INH-1952

Pyrazinamide-1954

Ethambutol-1962

Rifampin-1963

Timeline Development of Antituberculous DrugsTimeline Development of Antituberculous Drugs

2010

Why do we need new Why do we need new drugs?drugs?

Current therapyCurrent therapy– Too longToo long– Too toxic Too toxic – Too complexToo complex

ResistanceResistance

Epidemiology of MDR TBEpidemiology of MDR TB

85,008 (4.5)Western Pacific

75,062 (2.5)Southeast Asia

45,964 (7.9)45,964 (7.9)Eastern Mediterranean

25,199 (1.8)Africa, high HIV

15,014 (1.9)Africa, low HIV

17,269 (5.5)Eastern Europe

8508 (2.2)Latin America

882 (0.7)Established market economies

272,906 (3.2)All countries (n = 136)

No. of MDR TB cases (% of all new cases)Geographic region

Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

WHO Surveillance and WHO Surveillance and Incidence of MDR TBIncidence of MDR TB

Country % MDR TB of all new cases

Estonia 14.1

Latvia 9.0

China (non-DOTS) 7.7

China (DOTS) 2.8

Russia 6.0

India 3.4

Iran 5.8

Dominican 6.6

Ivory Cost 5.3

Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

WHO Estimates of MDR TB in Some Arabian WHO Estimates of MDR TB in Some Arabian CountriesCountries

Country % MDR TB of all new cases

Morocco* 2.2

Oman* 0.8

Algeria 0.7

Egypt 5.6

Jordan 2.8

Kuwait 3.3

Lebanon 3.4

Saudi Arabia 3.0

Sudan 10.1

Syria 6.7

Yemen 12.4

Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002* Surveyed* Surveyed

The target Drug For TBThe target Drug For TB

EffectiveEffective Quick-acting sterilizing agentQuick-acting sterilizing agent Kills persisting bacilliKills persisting bacilli Avoid cross-resistance with Avoid cross-resistance with

existing drugs existing drugs Low toxic side-effectsLow toxic side-effects

New New Chemotherapeutic Chemotherapeutic AgentsAgents

Not many. Low interest from industryNot many. Low interest from industry Derivatives of RifamycinDerivatives of Rifamycin

– Rifabutin: Sensitive subset of Rifampin resistant strainsRifabutin: Sensitive subset of Rifampin resistant strains– Rifapentine: Extended half-life but more mono-resistance Rifapentine: Extended half-life but more mono-resistance

to rifamycinsto rifamycins– Rifazil. benzoxazinorifamycin. In vitro and animal models. Rifazil. benzoxazinorifamycin. In vitro and animal models.

High intra-cellular concentrations.High intra-cellular concentrations. NitroimidazolesNitroimidazoles

– related to metronidazole. May work better against latent related to metronidazole. May work better against latent bacillibacilli

Amoxicillin/Clavulenic acidAmoxicillin/Clavulenic acid– Anectodes of few casesAnectodes of few cases

1940 1950 1960 1970 1980 1990 2000

Streptomycin-1944

INH-1952

Pyrazinamide-1954

Ethambutol-1962

Rifampin-1963

Fluroquinolones

Timeline Development of Antituberculous DrugsTimeline Development of Antituberculous Drugs

2010

FluoroquinolonesFluoroquinolones

Ciprofloxacin Ciprofloxacin Levofloxacin Levofloxacin SparfloxacinSparfloxacin Moxifloxacin Moxifloxacin GatifloxacinGatifloxacin

Antimicrobial agentMICs (µg/ml)

50% 90% Range

GAT 0.031 0.031 0.007-0.12

MXF 0.062 0.125 0.031-0.12

LVX 0.5 1 0.12-1

MICs (µg/ml) of GAT, MXF, and LVX against 23 M. tuberculosis isolates

Alvirez-Freites EJ. Antimicrob Agents Chemother. 2002 Apr;46(4):1022-5

Randomized controlled trial of a drug regimen that Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of includes ciprofloxacin for the treatment of pulmonary tuberculosis pulmonary tuberculosis ( ( Kenneday et al. CID 22:827, 1996)Kenneday et al. CID 22:827, 1996)

INH-6, RIF-6, CIP-4 INH-6, RIF-6, CIP-4 versusversus INH-6, RIF-6, INH-6, RIF-6, PZA-4, ETH-2 (drug-duration in months)PZA-4, ETH-2 (drug-duration in months)

Excluded previous exposure to any Excluded previous exposure to any study drugstudy drug

Smear/culture positiveSmear/culture positive 168 evaluable patients (HARZE 86, HRC 168 evaluable patients (HARZE 86, HRC

82)82) The two groups matched well including The two groups matched well including

number of HIV+ patientsnumber of HIV+ patients

Kennedy N, et al. Clin Infect Dis. 1996 May;22(5):827-33.

Relapse rateRelapse rate

At 6-12 monthsAt 6-12 months

HRZEHRZE 0/81 (0.0%) 0/81 (0.0%)

HRCHRC 7/75 (9.3%)7/75 (9.3%)

Randomized controlled trial of a drug Randomized controlled trial of a drug regimen that includes ciprofloxacin for regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis the treatment of pulmonary tuberculosis ……

Kennedy N, et al. Clin Infect Dis. 1996 May;22(5):827-33.

HIV negative

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HIV positive

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Kennedy N, et al. Clin Infect Dis. 1996 May;22(5):827-33.

Fuoroquinolones: Where do they stand in current recommendation?

CDC, ATS, IDSA recommendation . MMWR, June 2003

Quinolones for Other Quinolones for Other infections and TBinfections and TB

A 36-year-old man with AIDS presented with weight loss, flank pain, A 36-year-old man with AIDS presented with weight loss, flank pain, fever, and dysuria. Examination revealed prostatic nodules, and CT fever, and dysuria. Examination revealed prostatic nodules, and CT scan revealed abscesses. He received scan revealed abscesses. He received six dayssix days of of levofloxacinlevofloxacin therapy for prostatitis. There was no clinical improvement. He then therapy for prostatitis. There was no clinical improvement. He then received received ciprofloxacinciprofloxacin alone for alone for seven daysseven days and afterward and afterward underwent transurethral prostatic resection; acid-fast smears were underwent transurethral prostatic resection; acid-fast smears were positive. A urine culture obtained four days before the initiation of positive. A urine culture obtained four days before the initiation of levofloxacin therapy grew levofloxacin therapy grew M. tuberculosisM. tuberculosis (isolate 1). A culture of a (isolate 1). A culture of a prostatic abscess subsequently also grew prostatic abscess subsequently also grew M. tuberculosisM. tuberculosis (isolate 2). (isolate 2).

Ginsburg AS, et al. N Engl J Med. 2003 Nov 13;349(20):1977-8

Isolate 1 was sensitive to all fluoroquinolonesIsolate 2 was resistant to all fluoroquinolones

1940 1950 1960 1970 1980 1990 2000

Streptomycin-1944

INH-1952

Pyrazinamide-1954

Ethambutol-1962

Rifampin-1963

Fluroquinolones

Timeline Development of Antituberculous DrugsTimeline Development of Antituberculous Drugs

2010

? Oxazolidinone

LinezolidLinezolid

First agent of the First agent of the Oxazolidinones Mainly a gram positive Mainly a gram positive

antibacteria agentantibacteria agent Developed mainly for VRE and Developed mainly for VRE and

MRSAMRSA Showed good activity against Showed good activity against

mycobacteria including mycobacteria including M. M. tuberculosistuberculosis

In vitro activities (MIC (µg/ml)In vitro activities (MIC (µg/ml) of linezolid against 117 clinical isolates of of linezolid against 117 clinical isolates of M. tuberculosisM. tuberculosis

M. tuberculosis isolates (no. of isolates)

Range 50% 90%Geometric

mean

Susceptible to first-line drugs (73) 0.25-1 0.5 0.5 0.524

Resistant to first-line drugs (44)   0.125-1 0.5 1 0.477

Resistant to one first-line drug (25)   0.125-1 0.5 1 0.529

Resistant to multiple first-line drugs (19) 0.25-1 0.5 0.5 0.417

All (117)   0.125-1 0.5 1 0.506

Alcala L, at al. Antimicrob Agents Chemother. 2003 Jan;47(1):416-7

Cynamon MH, et al. Antimicrob Agents Chemother. 1999 May;43(5):1189-91

Oxazolidinones in Animal Model

Linezolid in Human Linezolid in Human TuberculosisTuberculosis A small series of 5 patients with MDR TB (isoniazid, rifampin, A small series of 5 patients with MDR TB (isoniazid, rifampin,

pyrazinamide, ethambutol, streptomycin and ciprofloxacin)pyrazinamide, ethambutol, streptomycin and ciprofloxacin) Three patients had prior pneumonectomiesThree patients had prior pneumonectomies All received linezolid, 600 mg orally twice a day for 4 to 33 months All received linezolid, 600 mg orally twice a day for 4 to 33 months

and aerosol interferon-gamma therapy (4 of 5 patients) three times a and aerosol interferon-gamma therapy (4 of 5 patients) three times a week in addition to their failing drug regimen week in addition to their failing drug regimen

Five of fiveFive of five patients treated with linezolid achieved culture conversion patients treated with linezolid achieved culture conversion in an average of 40 daysin an average of 40 days

One patient converted in 7 daysOne patient converted in 7 days one patient had the drug stopped because of toxicity (neutropenia) one patient had the drug stopped because of toxicity (neutropenia) Two of the five patients have completed 24 months of linezolid Two of the five patients have completed 24 months of linezolid

treatment and remained in remission. treatment and remained in remission. Two more are still taking and remain in remission on linezolidTwo more are still taking and remain in remission on linezolid One patient died from an unrelated condition One patient died from an unrelated condition Twice-daily treatment with linezolid costs $100 a day Twice-daily treatment with linezolid costs $100 a day

W Rom, T Harkin. 99th American Thoracic Society, Seattle, Abstract P621. 2003

Four patients MDR TBFour patients MDR TB Two M. bovis resistant to 12 anti-TB and 2 M. Two M. bovis resistant to 12 anti-TB and 2 M.

tuberculosis resistant to tuberculosis resistant to INH, rifampin, INH, rifampin, streptomycin, ethambutol,streptomycin, ethambutol, cycloserine, ethionamide cycloserine, ethionamide ofloxacinofloxacin

All the patients received All the patients received linezolidlinezolid with with thiacetazone, clofamizine and amoxicilin-thiacetazone, clofamizine and amoxicilin-clavulanateclavulanate– Patient #1: Lost at 5 monthsPatient #1: Lost at 5 months– Patient #2: Cured after 14 monthsPatient #2: Cured after 14 months– Patient #3: cured after 15 monthsPatient #3: cured after 15 months– Patient #4: Cured after 24 monthsPatient #4: Cured after 24 months

Fortún et Abstract L-921.- J. 44th ICAAC, Washington DC, 2004

Linezolid in Human Linezolid in Human TuberculosisTuberculosis

1940 1950 1960 1970 1980 1990 2000

Streptomycin-1944

INH-1952

Pyrazinamide-1954

Ethambutol-1962

Rifampin-1963

Fluoroquinolones

Timeline Development of Antituberculous DrugsTimeline Development of Antituberculous Drugs

2010

? Oxazolidinone

Novel Compounds

Diarylquinoline Diarylquinoline (R207910)(R207910)

Novel target, ATP synthase Novel target, ATP synthase inhibiterinhibiter

Rapidly bacteriocidalRapidly bacteriocidal No cross resistance with other No cross resistance with other

agentsagents Not toxic to miceNot toxic to mice No human experimentsNo human experiments

Andries K, Verhasselt P, Guillemont J, et al. Science 2005;307:223-7.

1

10

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Su

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INH, RIF, PZA R207910, RIF, PZA

Before treatment

After treatment

Andries K, Verhasselt P, Guillemont J, et al. Science 2005;307:223-7.

Activity of the novel compound R20910 against

Mycobacterium tuberculosis.

Family of diamines Family of diamines (Dipiperidines) SQ109, (Dipiperidines) SQ109, SQ609, SQ619SQ609, SQ619 Analogues of Ethambutol. Analogues of Ethambutol. They emerged from the synthesis and They emerged from the synthesis and

screening of a 100,000 compound screening of a 100,000 compound library of Ethambutol analogues library of Ethambutol analogues

Interfere with cell-wall synthesisInterfere with cell-wall synthesis As effective in vivo as Ethambutol at As effective in vivo as Ethambutol at

100-fold lower doses100-fold lower doses

NIKONENKO, et al. Abstract B-693, 44th ICAAC, Washington DC, 2004

ImmunotherapyImmunotherapy

Cytokine therapyCytokine therapy interferoninterferon– Interleukin-2Interleukin-2

VaccineVaccine– Killed organism (M. vaccae)-did not workKilled organism (M. vaccae)-did not work– DNA vaccineDNA vaccine

NutritionNutrition– Zinc, Vit A, Vit D Zinc, Vit A, Vit D ((Dolmans WM, et al. A double-blind,

placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response andvnutritional status. Am J Clin Nutr 2002;75:720–727

Cytokine therapyCytokine therapy

interferoninterferon– As aerosol 3xwk given to 5 patients with smear-As aerosol 3xwk given to 5 patients with smear-

positive MDR TBpositive MDR TB– Failing regimen continuedFailing regimen continued– Duration= 4wksDuration= 4wks– 4 of 5 became smear-negative4 of 5 became smear-negative– 1 of 5 smear from 4+ to 1+1 of 5 smear from 4+ to 1+– Wt stabilized or increasedWt stabilized or increased– After stoppage of interferon 4 of 5 became smear-After stoppage of interferon 4 of 5 became smear-

positive.positive.– Culture remained positive but the mean time to Culture remained positive but the mean time to

positive was extended from 17 to 24 dayspositive was extended from 17 to 24 days– Patients had radiological improvementPatients had radiological improvement

Condos R, Rom WN, Schluger NW. Lancet 1997;349:1513–1515

DNA vaccine A plasmid DNA encoding the Mycobacterium leprae 65 kDa A plasmid DNA encoding the Mycobacterium leprae 65 kDa

heat-shock protein (hsp65)heat-shock protein (hsp65) in order to boost the efficiency of the immune system, is a in order to boost the efficiency of the immune system, is a

valuable adjunct to antibacterial chemotherapy to shorten the valuable adjunct to antibacterial chemotherapy to shorten the duration of treatment, improve the treatment of latent TB duration of treatment, improve the treatment of latent TB infection and be effective against multidrug-resistant bacilli infection and be effective against multidrug-resistant bacilli (MDR-TB). We also showed that the use of DNA-hsp65 alone (MDR-TB). We also showed that the use of DNA-hsp65 alone or in combination with other drugs influence the pathway of or in combination with other drugs influence the pathway of the immune response or other types of inflammatory the immune response or other types of inflammatory responses and should augment our ability to alter the course responses and should augment our ability to alter the course of immune response/inflammation as needed, evidencing an of immune response/inflammation as needed, evidencing an important target for immunization or drug intervention.important target for immunization or drug intervention.

C L Silva et al. Gene Therapy (2005) 12, 281-287

ConclusionConclusion New drug development against M. tuberculosis has been New drug development against M. tuberculosis has been

unjustifiably slowunjustifiably slow

Fluroquinolones and oxazolidinones are promising and may Fluroquinolones and oxazolidinones are promising and may become a cornerstone in salvage therapy for MDR-TBbecome a cornerstone in salvage therapy for MDR-TB

The wide use of FQ and OZ for bacterial infection can alter the The wide use of FQ and OZ for bacterial infection can alter the epidemiology of TB resistance to these agentsepidemiology of TB resistance to these agents

Few Investigational drugs are under development with Few Investigational drugs are under development with promising potentialpromising potential

Immunotherapy can be synergistic to antituberculous therapy Immunotherapy can be synergistic to antituberculous therapy for MDR-TBfor MDR-TB

Cost and delivery will remain the main obstacle in future Cost and delivery will remain the main obstacle in future therapy of tuberculosis in endemic areastherapy of tuberculosis in endemic areas