Delamanid: A New Treatment for MDR -TB · PDF fileTB innovation for tomorrow. Delamanid: A New Treatment for MDR -TB XVIII International TB Workshop. UITB -2014 45 th Union World Conference

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

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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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Proprietary and Confidential8

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.