F uture of TB Therapy Putting science to work for better faster TB cures Achieving maximum impact will require Short simple regimens that are adopted available and affordable Ideally a universal regimen consisting of all novel drugs that is effective in all people with active TB ID: 613468
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Slide1
Divining the Future of TB Therapy
Putting science to work for better, faster TB curesSlide2
Achieving maximum impact will require:Short, simple regimens that are adopted, available and affordable.Ideally, a universal regimen consisting of all novel drugs that is effective in all people with active TB.
All TB treatments are appropriately formulated for children.
Discover, develop and deliver better and faster TB regimens
TB Therapy Goals
2Slide3
3Slide4
Nix-TB Trial (BPaL) Slide5
5
Patients with XDR-TB or Who Have Failed MDR-TB Treatment
Nix-TB Trial in XDR-TB
Pretomanid
200 mg
Bedaquiline 200 mg tiw after 2 week load
Linezolid 1200 mg qd**
Sites:
Sizwe
and Brooklyn Chest, South Africa
6 months of treatment
Additional 3 months if sputum
culture positive at 4 months
XDR-TB
Follow up for relapse-free cure over 24 months
**Just amended from
600 mg bid strategySlide6
6
67 participants enrolled as of 23 January 2017
60% male, 40% female; 49% HIV infected
79% XDR-TB; 21% MDR failures or intolerant36 completed therapy
None required longer than 6 months of treatment20 followed through 6 months after completion of treatment with final results of sputum cultures; 30 completed 6 months f/u (sputum cultures pending on final months in approximately 10)
Total of 4 died (all in 2015, within first 7 weeks of start of treatment)Causes:Severe pulmonary tuberculosis and disseminated tuberculosisUpper gastrointestinal bleeding
Acute severe worsening of tuberculosis
Multi-organ failure
One microbiological relapse or reinfection to date
56 yo w/XDR-TB, HIV+ - Clinically well but cultures MTB+ at 3 mos f/u after end of 6 months of drug regimen therapy – genome sequencing not yet available
Update on Ongoing ParticipantsSlide7
Linezolid (L) Sterilizing Activity on Background of Bedaquiline Plus Pretomanid (BPa) in BALB/c Mice— Data From Eric Nuermberger
*p = 0.11 vs. BPa; †p≤ 0.001 vs. RHZ
Proportion relapsing after treatment for:
Regimen
2
months
3 months
2RHZ/RH
8/14
(57%)
BPa
3/14
(21%)
3BPaL
6/15
(40%)
0/15*
†
(0%)
2BPaL/1BPa
0/15*
†
(0%)
1BPaL/2BPa
9/15
(60%)
0/15*
†
(0%)
7Slide8
Evaluate Linezolid doseEvaluate Linezolid duration
Plans for Next
BPaL Trial
8Slide9
Patients with XDR-TB, Pre-XDR-TB or who have failed or are intolerant to MDR-TB Treatment
B-Pa-L Linezolid Optimization Trial:
TB Alliance Study NC-007
Pa dose = 200 mg daily; B Dose = 200 mg daily X 8
wks
, then 100 mg daily
6 months of treatment
Extension study for patients who relapse or who are sputum positive at end of 6 months of regimen dosing
1
o
follow up for relapse-free cure 6 months after end of treatment; Full f/u 24 mos after end of treatment
9
B-L-Pa
L=1200 mg/d x 6 mos
B-L-Pa
L=1200 mg/d x 2 mos
B-L-Pa
L=600 mg/d x 6 mos
B-L-Pa
L=600 mg/d x 2 mos
Randomize
N=45 per group; total 180
(30/group XDR)Slide10
NC-005: Testing Combinations of Bedaquiline, Pretomanid, Pyrazinamide and Moxifloxacin (
BPaZM
)Slide11
11
B, Pa, Z and M containing regimens
Participants with newly diagnosed smear positive DS- and MDR-TB
B
(200mg
daily)
- Pa - Z
Rifafour
B
(200mg
daily)
- Pa - Z - M
B(registered dosing) - Pa - Z
Z
=pyrazinamide (1500mg daily),
M = moxifloxacin 400mg daily, Pa
= PA-824 200mg daily , J(registered dosing) = bedaquiline 400mg for 14 days then 200mg three times a week, J(200mg daily) = bedaquiline 200mg daily
60 per DS group
Up to 60 MDR
DS
Randomize
8 Weeks
Serial 16 hour pooled sputum samples for TTP/CFU Count
MDR
Primary Analysis
2 Years
Survival Follow-up Visits at 6, 12, 18 and 24 Months
NC-005 – 8 week SSCC Study
of B-Pa-Z-MSlide12
M1.5
(+3)
M2 (+3)
M3 (+3)
M4 (+3)
M5 (+3)
RHZ
10/15
2/15
Pa
50
MZ
6/14
0/14
PaMZ
10/143/15BPaM2/15
0/14BPaZ13/14
0/150/15
BPaMZ3/150/150/15
Mouse Relapse DataRank order: BPaMZ > BPaZ > BPaM > PaMZ > RHZ
12Slide13
13
Liquid
Culture
Solid Culture
B(loading)
PaZ
1.7* (1.1 – 2.8)
1.3 (0.9 – 1.8)
B(200mg)
PaZ
2.0* (1.3 – 3.2)
1.1 (0.8 – 1.6)
BPaZM
(MDR) Z-sensitive
3.5* (2.1 – 5.6)
2.2* (1.5 – 3.2)BPaZM (MDR) Z-resistant2.0* (1.1 – 3.4)2.6* (1.5 – 4.6)HRZE Control---- Hazard Ratio vs HRZETime to Culture Negativity*
Statistically significant vs HRZESlide14
14
Overnight
Overnight
B(loading)
PaZ
66%
89%
B(200mg)
PaZ
75%*
84%
BPaMZ
(MDR
) Z-sensitive
96%*
100%*BPaMZ (MDR) Z-resistant78%*95%*HRZE control51%86%
Growth Medium Liquid SolidPercent of Patients Culture Negative at 2 Months
Kaplan-Meyer Analysis* statistically significant vs HRZESlide15
Proposed Treatment Algorithm
GenXpert
or Empiric Assessment
Rif sensitive
Rif resistant
BPaMZ
(3-4 months)
Rapid quinolone test
Quinolone resistant
Quinolone sensitive
BPaMZ
(3-6 months)
(duration dependent on
PZA sensitivity; if unknown 6
mo
)
BPaL
(6 months)
Common backbone of
BPa for allCommon therapy for virtually all DS and MDRAll treatments conducive to FDCsMarked simplification and rationalization of present state15Slide16
Success will require novel drug combinationsPotential high impact role of therapeutic vaccines
Chemotherapeutic Regimens
in Development
3
-6
Months
Addition of Therapeutic
Vaccines
1-2
Months
16
Shortening treatment from
3-6
months to
no more than
2
months
Faster cures will increase adherence, decrease toxicity, decrease costs
to patients and health care systems Slide17
Thank
You !