delamanid: a new treatment for mdr -tb · overview of mdr-tb treatment trials for delamanid trial...
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TB innovation for tomorrow.
Delamanid: A New Treatment for MDRDelamanid: A New Treatment for MDR--TBTBXVIII International TB Workshop. UITBXVIII International TB Workshop. UITB--2014 2014
4545thth Union World Conference on Lung HealthUnion World Conference on Lung Health
29 October, Barcelona, Spain
PROPRIETARY AND
CONFIDENTIAL
Proprietary and Confidential
2
Overview
• Background
• Review of Delamanid Phase 2B Program
• Ongoing Delamanid Phase 3 Trial
• Delamanid Paediatric Program
Proprietary and Confidential
Background
• Otsuka searching for new treatment options for TB for > 30 years
• Delamanid (Deltyba†) discovered in house in 2002 with first-in-man testing in 2004
• Delamanid 14-day EBA trial conducted in 2006
‒ Treatment effect approximately that of rifampicin
‒ Determined exposure range/dose required for efficacy
• MDR-TB program designed in 2007; first trial launched in 2008
• Phase 3 confirmatory trial launched September 2011
• Registration
‒ European Medicines Agency, April 2014
‒ PMDA (Japan), July 2014
†Currently authorized for marketing in U.K, Germany, Japan
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Delamanid has Novel Mechanism of Action and
No Cross Resistance to Existing Anti-TB Drugs
Nitro-dihydro-imidazooxazole derivative
Mechanism of Action: Inhibition of key mycolic acid synthesis
MIC (µg/mL)
Standard strains
H37Rv RFP1-resistant
H37Rv INH2-resistant
H37Rv EB3-resistant
H37Rv SM4-resistant
Delamanid
0.006
0.012
0.012
0.012
RFP:>100
INH: >100
EB: 50
SM: >100
1RFP: Rifampicin, 2INH, Isoniazid, 3EB: Ethambutol, 4SM: Streptomycin
N
N O
O2N
ON
O
OC F3
Structure:
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Experience Experience from Delamanid Phase from Delamanid Phase 2B Program2B Program
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Summary Schematic for Trials 204/208/116
September 2013 0113M-9480
2 mo 6 mo.
Trial 204 Trial 208Trial 116 (observational)
Long-Term
Outcome at 24 mo.Delamanid
OBR
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Overview of MDR-TB Treatment Trialsfor Delamanid
�Trial 204 ‒ RCT of safety, efficacy, and PK of delamanid or placebo in combination with OBR in 481 patients
‒ 1°endpoint - sputum culture conversion (SCC) at 2 months; defined as 5 negative weekly cultures
‒ Hospitalization during treatment period
�Trial 208 ‒ 6-month treatment extension for patients completing Trial 204; 45% participated
‒ Largely outpatient with DOT plans for all patients
�Trial 116
�Vital status
‒ Observational study of Trial 204 patients up to 2 years after Rx initiation to assess sustainability of SCC and final treatment outcomes; 87.5% assessed
‒ on 464/481 (96.5%) at ≥ 24 months
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Trial 204 Primary Efficacy Endpoint†
SCC using liquid media (MGIT) at 2 months
0
20
30
40
50
OBR + PlaceboOBR + Delamanid
100mg BID
29.6 %
45.4 %
p=0.008
p=0.039
200mg BID
41.9 %
(57/136)
(64/141)
(37/125)
Treatment with Delamanid →→→→ ~50% increase in SCC at 2 months
†Gler, et al. NEJM, June 2012
% P
atie
nts w
ith S
CC
Proprietary and Confidential9
Consistency in Primary & Secondary Analyses Demonstrates Robustness of Efficacy Results
SCC = sputum culture conversion
TTD = time to detection in MGIT system (bacterial load)
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Trial 204: 2-month SCC among XDR-TB Patients
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Summary of Safety Findings for Trial 204†‡
� Hospital-based treatment period
� Daily assessment of AEs
� Weekly assessment of clinical laboratory parameters
� Frequent ECG monitoring
� > 400 AEs reported by at least 1 patient†
‒ Balanced across three treatment groups
‒ Type/frequency of AEs consistent with reports for OBR
� Increased AEs of QT interval prolongation based on ECG assessments by investigators; none coupled with clinical manifestations
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†Gler, et al, NEJM 2012
‡Summary of Medical Product Characteristics, 2014:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002552/WC500166232.pdf
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Final Outcomes for M(X)DR-TB Patients
from Trials 204/208/116 (N=421)†
Treatment
Outcome
Long-Term Treatment
(≥ 6 months delamanid)
N = 192
Short-Term Treatment
(≤ 2 months delamanid)
N = 229
no. (%) 95% CI no. (%) 95% CI
Favorable ‡ 143 (74.5)* 67.7 – 80.5 126 (55.0)* 48.3 – 61.6
Unfavorable 49 (25.5)* 19.5 – 32.3 103 (45.0)* 38.4 – 51.7
Died 2 (1.0)* 0.1 – 3.7 19 (8.3)* 5.1 – 12.7
Failed 32 (16.7) 11.7 – 22.7 26 (11.4) 7.6 – 16.2
Defaulted 15 (7.8)* 4.4 – 12.6 58 (25.3)* 19.8 – 31.5
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‡Favorable outcomes – cure + treatment completed (per WHO)
* Differences between long & short-term significant (p < 0.001)
†Skripconoka, et al, Eur Respir J 2013
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Outcomes for XDR-TB patients and those with Bilateral Cavitation
Experience from the Delamanid Phase 2 Programme
> 6 Months Delamanid
< 2 Months Delamanid
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Delamanid Phase 3 Trial 213
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Delamanid Phase 3 Study (Trial 213†) Design Considerations
Trial 213
(On-going)12-18 months OBR
6 mo. OBR* +
delamanid or placebo6-12 mo. follow-up
30-month Randomised, Blinded, Confirmatory Trial
* OBR: Optimised Background Treatment Regimen; †ClinicalTrials.gov Identifier: NCT01424670
• Trial 213 will be the confirmatory trial for the Conditional Approval by the EMA
o Confirms SCC and long-term outcomes in one randomized trial
• Regimen: Delamanid 100 mg BID x 2 months followed by 200 mg QD x 4 months
o 100 mg BID: exposure greater than required for maximum bactericidal effect
o 200 mg QD
• Significant bactericidal effect
• Several fold > highest observed clinical MIC
• Patients with HIV infection and concurrent treatment with ARV’s enrolled to explore
potential DDI’s (initial hospitalization required)
• Concurrent treatment with moxifloxacin allowed in this trial (initial hospitalization
required)
• Long-term outcomes include wide range of clinical parameters: Changes in CXR, signs
and symptoms, inflammatory markers
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Trial 213 Current Status
12-18 months OBR6 mo. OBR* +
delamanid or placebo6-12 mo. follow-up
30-month Randomised, Blinded, Confirmatory Study
Enrolment
completed 11/2013
6-month treatment
completed 5/2014
Last patient, last visit, May 2016
Completed report, 2016
OVERVIEW OF ENROLMENT N Ntotal = 511
Region -
Countries
Philippines 127 25%
Baltics/Moldova 126 25%
Peru 157 31%
S. Africa 101 20%
HIV-infected 48 9%
Treated with moxifloxacin 121 24%
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Paediatric Investigational Program
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Paediatric Investigation Plan (PIP), 2013-2017
• 10-week repeat-dose study in juvenile rats of toxicity
& toxicokinetics
• Development of paediatric formulation (rapid
dissolving tablet)
• Bioequivalence study: compare paediatric formulation
with tablet formulation in healthy adults
• Open-label PK trial in children with MDR-TB (birth to <
18 years); 4 age-group cohorts in descending order
• Open-label extension trial of PK study: evaluate long
term safety & tolerability over 6 months
September 2013 0113M-9480
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Future Studies
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Future Trials of Delamanid Based on
Collaborative Partnerships
• U.S. National Institutes of Health-sponsored trial
assessing DDI of co-administration of delamanid and
Sirturo® in the treatment of MDR-TB (ACTG 5343)
• Otsuka is actively seeking collaborations to evaluate
the optimization of delamanid in MDR-TB treatment
- fully oral, shorter course regimens, etc.