Eight Week Randomized Trial of Treatment with Pa-824, Moxifloxacin, and Pyrazinamide in Drug Sensitive and Multi-Drug Resistant Tuberculosis

July 21, 201420th International AIDS Conference

Daniel Everitt, MDFor the NC-002 Collaborators

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Participants with newly diagnosed smear positive DS and MDR Pulmonary TB

NC-002 Pa-M-Z Trial: First Novel Combination StudyIn patients with TB sensitive to Pa, M, and Z

Pa(200mg)-M-ZN=60

Pa(100mg)-M-ZN=60

H-R-Z-EN=60

Pa(200mg)-M-Z

N= up to 50

Pa = PA-824 M = moxifloxacin 400 mg Z = pyrazinamide at 1500mg

2 months of treatment

Randomize

Serial 16 hour pooled sputum samples for CFU Count

DS

DR

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South Africa• TASK Applied Science, Cape Town Lab• University of Cape Town Lung Institute• Helen Joseph Hospital• Tembisa Hospital, Tembisa• Klerksdorp Tshepong Hospital• KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH),

Durban Lab

Tanzania• Ifakara Health Institute, Bagamoyo Lab• NIMR- Mbeya Medical Research Programme Lab

Investigational Sites and Laboratories

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 Treatment group

 Total (N=207)

   Age (years) 31Males (%) 65Weight (kg) 56HIV-infected (%) 20Ethnicity   Black (%) 71 Mixed ethnicity (%) 29

Enrolment Demographic Characteristics

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Estimates of Mean Serial Log(CFU) Count Over Time Joint Bayesian NLME Regression

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Study Arm Log CFU Reduction per Day Over 56 Days

PA200-M-Z* (N=56) 0.155 CI [0.133; 0.178]PA100-M-Z (N=54) 0.133 CI [0.109; 0.155]PA200-M-Z-MDR (N=9) 0.117 CI [0.070; 0.174]H-R-Z-E (N=54) 0.112 CI [0.093; 0.131]

Daily Log CFU Reduction – 1o Endpoint

*p < 0.05 vs H-R-Z-E

No differences from above when adjusted for site, HIV status or baseline CFU as baseline covariates

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Estimates of Mean Serial log(TTP) Over TimeJoint Bayesian NLME Regression

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Study Arm Median Time to Culture Conversion (Days)

Solid LiquidPA200-M-Z 28* 49*PA100-M-Z 28 42PA200-M-Z MDR

35 56

H-R-Z-E 35 56

Time to Culture Conversion – 2o Endpoint

*Statistically significant differences compared to HRZE for both solid and liquid culture

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Culture Conversion is the Time when Culture is First Negative

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Study Arm Conversion to Negative Day 56 (%) Solid Liquid

PA200-M-Z 94.3 71.4*PA100-M-Z 82.9 65.7*PA200-M-Z-MDR

62.5 50.0

Rifafour 87.5 37.8

Eight Week Culture Conversion – 2o Endpoint

*Statistically significant difference from HRZE for liquid culture only

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Log CFU Daily Decreases and Pearson Correlation Coefficients

Study / Arm Log CFU Daily (Days 7-14)

Log CFU Daily (Days 7-56)

Correlation Coefficient

H-R-Z-E (N=15) Pa100-M-Z (N=16) Pa200-M-Z (N= 13)

0.13

0.16

0.14

0.12

0.13

0.14

0.98

0.90

0.96

Data from Participants Enrolled in the EBA Substudy

Summary of Safety Findings

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Grade 1 to 4 Treatment-Emergent Adverse Events

Severity Statistic* PA100-M-Z

(N=60)

PA200-M-Z

(N=62)

H-R-Z-E(N=59)

PA200-M-Z MDR

(N=26)

Total(N=207)

Grade I % 72 77 78 69 75Grade II % 42 50 46 50 46Grade III % 30 32 25 23 29Grade IV % 5 15 10 8 10

* % = Percentage of patients with at least one AE in each category

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• Pa-M-Z Regimen was statistically significantly better than the H-R-Z-E control for the primary and 3/5 key secondary endpoints– Greater reduction in colony counts over 56 days– More rapid time to culture conversion– Higher conversion to negative at 8 weeks – Nearly twice the number converted in liquid

culture

• No significant difference in response for HIV infected patients

• Similar effects for patients with MDR-TB, albeit with small numbers

• Safety comparable to control

• Next Step: The STAND Phase 3 Trial

NC-002 Summary of Key Results and Next Steps

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Participants with newly diagnosed smear positive DS- and MDR-TB

The STAND Trial - Phase 3 Trial of Pa-M-Z“Shortening Treatment by Advancing Novel Drugs”

Pa(100mg)-M-ZN=300

Pa(200mg)-M-ZN=300

H-R-Z-EN=300

Pa(200mg)-M-Z

N= up to 300

Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin 400 mg

4 months of treatment

Randomize

DS

DR

Pa(200mg)-M-ZN= 300

6 months of treatment

12 & 24 mosf/u afterrandomization

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• Robert Schall– University of the Free State, and

Quintiles Biostatistics, Bloemfontein, SA

• Christo Van Niekerk– TB Alliance, Pretoria, SA

• Almari Conradie– TB Alliance, Pretoria, SA

• Carl Mendel– TB Alliance, New York, USA

• Rodney Dawson– University of Cape Town Lung

Institute, Cape Town, SA

• Andreas Diacon– Stellenbosch University, Tygerberg,

and TASK Applied Science, Bellville SA

• Divan Burger– University of the Free State, and

Quintiles Biostatistics, Bloemfontein, SA

To the Patients with Tuberculosis who Participated, volunteer Community Advisory Boards, and Lead Investigators and Colleagues:

Sincere Acknowledgments:

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2014 International AIDS Conference

TB Alliance Supporters

Bill & Melinda Gates Foundation

EuropeanCommission

United States Food and Drug Administration

Irish Aid

National Institute of Allergy and Infectious Diseases

UK aid

United States Agency for International Development

AIDS Clinical Trial Group

Global Health Innovative Technology Fund

UNITAIDAustralian AID

Thanks to all those who support our mission for better, fast TB drugs