Janssen Pipeline
UK CAB
20th January 2012
Dr Michael Aboud
Medical Lead Virology
This presentation has been produced in response to a specific request and may
contain information about a non-approved indication and product
Key Drugs in Clinical Development at Janssen
Name
Drug Class
Phase
Under investigation for:
Darunavir (TMC114)
HIV protease
inhibitor
Approved
HIV/AIDS treatment
Etravirine (TMC125)
NNRTI
Approved
HIV/AIDS treatment
Rilpivirine (TMC278)
- Oral formulation
- Long-acting
NNRTI
Approved
Phase I
HIV/AIDS treatment
HIV/AIDS treatment, prevention
Telaprevir (VX-950)
HCV protease
inhibitor
Approved
HCV treatment
TMC120 (dapivirine)
NNRTI
Phase IIa
HIV/AIDS prevention (microbicide)
Antifungal
Approved
Oropharyngeal candidiasis
Diarylquinolone
Phase III
Tuberculosis (multi-drug
resistant)
HCV protease
inhibitor
Phase III
HCV treatment
Tibozole (miconazole)
TMC207
TMC435350
NNRTI, non-nucleoside reverse transcriptase inhibitor; RTI, reverse
transcriptase inhibitor
Data on file.
Tuberculosis infection and
disease
TMC207 core slide set
TB is a global problem
WHO estimated prevalence of TB cases 2008
Per 100,000 population
WHO http://gamapserver.who.int/mapLibrary/Files/Maps/MDG6_TBincidence_08.png)
TMC207: slide 3
Tuberculosis Is the Most Common
Infectious Disease
•
•
Worldwide, 2 billion people are infected with TB (LTBI)
16 million+ patients have active TB
• 9.27 million new cases in 2007
• = 139 cases per 100,000 population
• 2 million TB deaths per year
• 1.32 million people not infected with HIV
• 456,000 people who were infected with HIV
• 95% Of TB cases and 98% of TB deaths in low- and middle-income
countries
• 22 high burden countries account for 80% of cases (India,
China, Indonesia, Nigeria, South Africa)
 Globally, tuberculosis is the #1 cause of death in HIV+ patients
•
•
MDR-TB cases = 500,000 in 2007 (289,000 new cases, with highest
rates in India, China, Russia, South Africa, Bangladesh)
55 countries have reported cases of XDR-TB by the end of 2008
Mycobacterium tuberculosis
• Slowly replicating, rod-shaped
Gram-positive bacteria
• Obligate intracellular
pathogen: multiplies in
macrophages
• Inhibition of fusion with
lysosomes
• Waxy cell wall resists
lysosomal enzymes
• Macrophage lifespan is
several months
Phagocytosis of
Mycobacterium tuberculosis
http://microbiologybytes.wordpress.com/2008/06/25/theinfluence-of-host-and-bacterial-genotype-on-the-development-oftuberculosis/
Diagnosis of tuberculosis
TMC207 core slide set
Signs, Symptoms and Diagnosis of TB
• X-ray
• Sputum smear
microscopy
• Culture
Diagnosis of pulmonary TB
• Sputum smear
• Acid fast stain (>10,000 CFU/ml)
• Bronchoscopy
• Chest X-Ray
• Tuberculin skin testing (TST)
National Cancer Institute. 2006
http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/1607.jpg
TMC207: slide 8
Tuberculosis treatment
and multidrug resistance
TMC207 core slide set
Treatment of Pulmonary Tuberculosis
 Active TB
 Global standard of care:
Direct Observed Treatment
Short-course (DOTS)
Month 1
Month 2
H,R,Z(,E)
Month 3
H,R
Month 4
H,R
Month 5
 HIV co-infection challenging
because of DDI
H,R,Z(,E)
Month 6
H,R
Intensive Phase
Rapid reduction of
bacterial load to reduce
infectiousness
Continuation Phase
Eliminate remaining
bacteria to prevent
subsequent relapse
H,R
 MDR-TB
• No global standard of care (4 drugs, one injectable, for 18-24 months)
H = Isoniazid
R = Rifampin
Z = Pyrazinamide
E = Ethambutol
Failure of first-line TB treatment:
drug resistance
• Multidrug-resistant (MDR) TB
In-vitro resistance to at least isoniazid and rifampicin
– 3.6% of all incident TB cases globally are estimated to have MDR-TB
– 390 000–510 000 cases of MDR TB were estimated to emerge in 2008
– The highest proportions of MDR-TB are found in countries of Eastern
Europe and Central Asia
• Extensively drug-resistant (XDR) TB
MDR plus resistance to fluoroquinolones and at least 1 of the 3
second-line injectable drugs (amikacin, kanamycin, capreomycin)
– 963 cases of XDR-TB reported to WHO globally from 33 countries in 2008
– As of Jan 2010, 58 countries had reported to WHO at least one case
of XDR-TB
WHO. Multidrug and extensively drug-resistant TB (M/XDR-TB). 2010 Global Report on Surveillance and
Response. Available at: http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf
TMC207: slide 11
A high proportion of previously treated
TB cases are multidrug-resistant (MDR)
Estimated global incidence and proportion
of MDR among TB cases, 2004
New Cases
Previously treated cases
Total cases
Zignol M, et al. JID 2006; 194: 479-85
TB cases
MDR cases
%
8,897,743
272,906
2.7
982,639
181,408
18.5
9,880,382
424,203
4.3
TMC207: slide 12
Distribution of MDR among new cases
(1994─2009)
WHO. Multidrug and extensively drug-resistant TB (M/XDR-TB). 2010 Global Report on Surveillance and
Response. Available at: http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf
TMC207: slide 13
Distribution of MDR among previously
treated cases (1994─2009)
WHO. Multidrug and extensively drug-resistant TB (M/XDR-TB). 2010 Global Report on Surveillance and
Response. Available at: http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf
TMC207: slide 14
Diagnosis of MDR-TB
• Risk factors
–
–
–
–
–
History of prior therapy
History of non-adherence
Residence in an MDR-endemic area
Exposure to known or suspected MDR-TB case
HIV infection (in some settings)
• Early recognition of treatment failure
– Lack of sputum conversion, persistent or recurrent cough, continued
fever, night sweats and failure to gain weight
• Drug susceptibility testing (DST)
– WHO recommends DST for previously treated patients and patients
living with HIV (and in all patients at start of therapy where
availability permits)
TMC207: slide 15
There are several classes of
second-line agents
Class
Agents
Comments
Aminoglycosides
Amikacin (Am)
Kanamycin (Km)
Injectable
Cyclic polypeptides
Capreomycin (Cm)
Injectable
D-alanine analogues
Cycloserine (Cs)
Terizidone (Trd)
Oral bacteriostatic agents
Carbothionamides
Ethionamide (Eto)
Protionamide (Pto)
Oral bacteriostatic agents
Fluoroquinolones
Ciprofloxacin
Gatifloxacin
Levofloxacin (Lfx)
Moxifloxacin (Mfx)
Oxofloxacin (Ofx)
Antifolates
p-aminosalicylic acid (PAS)
Phenazine derivatives
Clofazimine (Cfz)
WHO guidelines for the programmatic management of drug-resistant tuberculosis: emergency
update 2008. Available at:
http://www.who.int/tb/publications/2008/programmatic_guidelines_for_mdrtb/en/index.html
TMC207: slide 16
Treatment of MDR-TB: general
principles
• Use at least 4 drugs certain to be active
– Drugs to which resistance is known to be rare
– DST results show susceptibility (with good laboratory reliability e.g.
injectables, fluoroquinolones)
– Drugs not commonly used in the area
– Drugs with no prior history of failure in an individual patient
• Do not use drugs for which there is a possibility of crossresistance
• Eliminate drugs that are not safe
• Include first-line agents, injectables and fluoroquinolones before
other options
• If DST unavailable, a standard regimen is proposed by WHO
WHO Treatment of tuberculosis: guidelines (4th Edn.). Available at:
http://www.who.int/tb/publications/tb_treatmentguidelines/en/index.html
TMC207: slide 17
Common adverse effects of TB treatments
Adverse effect
Associated with:
G.I. complaints
Ethionamide, cycloserine, p-aminosalicylic acid,
fluoroquinolones, clofazimine
Hepatotoxicity
Ethionamide, pyrazinamide,
p-aminosalicylic acid, fluoroquinolones
Peripheral neuropathy
Ethionamide, cycloserine, linezolid
Rash
All
Headache
Fluoroquinolones, cycloserine, ethionamide,
ethambutol
Seizures
Cycloserine
Hypothyroidism
Ethionamide, p-aminosalicylic acid
Hearing loss, vestibular toxicity
Aminoglycosides, capreomycin
Behavioral changes
Cycloserine, ethionamide, fluoroquinolones
Visual changes
Ethambutol, rifabutin, linezolid
Renal failure, hypokalemia, hypomagnesemia
Aminoglycosides, capreomycin
Arthralgia
pyrazinamide
Elevated uric acid
pyrazinamide
TMC207: slide 18
Drug interactions
• Relatively few drug interactions substantially change
concentrations of anti-TB drugs
• Anti-TB drugs sometimes change concentrations of other drugs
– Rifamycins can decrease serum concentrations of many drugs,
(e.g., most of the HIV-1 protease inhibitors), to sub-therapeutic
levels
– Isoniazid increases concentrations of some drugs (e.g., phenytoin)
to toxic levels
TMC207: slide 19
TMC207 (bedaquiline) update
20
TMC207 (bedaquiline)
In vitro:
•
•
•
•
Active on DS-TB, MDR-TB and XDR-TB
Targets mycobacterial ATP synthase
First drug to interfere with energy production
Kills replicating and non-replicating bacilli
In mice:
• Shortens treatment duration of DS TB
from 6 to 4 months when added to SOC
• Shortens treatment duration of MDR TB
from 24 to 6 months when added to SOC
In patients:
• Proof-of-Principle in one week
early bactericidal activity (EBA) trial
•Increases culture conversion by ~ 40%
in MDR TB patients (8 week trial)
Andries et al., Science 2005, 307, 223
Lounis et al., AAC 2006, 50, 3543
Koul et al., NCB 2007, 3, 323
Koul et al., JBC 2008, 283, 25273
Rustomjee et al., AAC 2008, 52, 2832
Diacon et al., NEJM 2009, 360, 2397
21
Ibrahim et al. AJRCM 2009, in press
Key Phase I PK findings
Linear PK
Positive food effect (2-fold increase in exposure)
Metabolized by CYP3A4
•
No inhibition or induction of CYP3A4 in vitro
Administration of Rif lowers TMC207 levels 50% (thru CYP3A4)
Administration of ketoconazole & LPV/r modestly increased TMC207 exposure
(22%).
Administration of NVP does not affect TMC207 exposure
Long terminal elimination half-life (steady state levels not achieved by day 14)
McNeeley D, et al. IUATLD 2006. oral
Van Heeswijk et al., ICAAC 2007, A-780
Van Heeswijk, et al., IUATLD 2007, PS-71358-11
Van Heeswijk et al, IAS 2010, WEPE0097
Van Heeswijk et al, IAS 2011, MOPE172
22
TMC207-C208 Stage 2
Efficacy and Safety Results
23
C208 – Trial Design – randomized
controlled multi-center
Rif washout
period
Patients with
newly
diagnosed
sputum
smear
positive
pulmonary
MDR-TB
infection
Stratification by
• Site
• Lung cavitation
double-blind phase
BR alone
BR + TMC207
BR + placebo
1w
24 weeks
Stage II (n=161)
•
•
•
•
•
•
•
•
Brazil
India
Latvia
Peru
Philippines
Russia
South Africa
Thailand
• 2 y follow-up
• 18-24 month total
MDR-TB treatment
TMC207 regimen:
• 400 mg QD for 14 days, then
• 200 mg TIW
2
McNeeley, et al. 41st IUATLD
24
2010. Oral presentation
C208 Stage 2 Objectives
• Demonstrate superiority of TMC207 compared to placebo
at 24 W of treatment
• Primary analysis = time to sputum culture conversion
• Sputum culture conversion is defined as 2 consecutive negative MGIT
cultures collected at least 25 days apart
and not followed by a confirmed positive culture.
• Subjects who drop out during the 24W are considered failed,
irrespective of their culture status at time of dropout.
• Secondary analysis = culture conversion rates at 24 W
McNeeley, et al. 41st IUATLD
2010. Oral presentation
25
Inclusion Criteria
• Male and female 18-65 years
• Positive sputum smear > 1+
• Confirmed resistance to INH and RIF
• HIV negative or HIV+ with CD4+ > 300 and no ART
• No previous 2nd line anti-tuberculosis agents
• No significant extrapulmonary TB or concomitant illness
McNeeley, et al. 41st IUATLD
2010. Oral presentation
26
C208 Baseline Characteristics
Placebo
N=81
TMC207
N=79
Gender - male (%)
61
66
Age - median (yrs)
35
31
HIV negative (%)
82
91
Body weight - median (kg)
53
54
McNeeley, et al. 41st IUATLD
2010. Oral presentation
27
C208 - Populations for Analysis
Screened (282)
Placebo
TMC207
Randomized (161)
81
80
ITT (160)
81
79
Modified ITT (132)
66
66
ITT population: Randomized subjects who had at least one dose of TMC207 or placebo
Modified ITT population (mITT):
- Non-MDR subjects
- XDR subjects
- MGIT results not evaluable
ITT subjects excluding:
(8 placebo + 4 TMC207)
(4 placebo + 3 TMC207)
(4 placebo + 7 TMC207)
McNeeley, et al. 41st IUATLD
2010. Oral presentation
28
Background Regimen
The preferred 5-drug background regimen consisted of:
• Ethionamide, Pyrazinamide, Ofloxacin, Kanamycin, and
Cycloserine/(Terizidone in South Africa).
Changes in the background regimen occurred over time due to:
• DST results and side effects
• Switches within the same drug class (due to shortage on site)
McNeeley, et al. 41st IUATLD
2010. Oral presentation
29
C208 - Baseline Drug Resistance
Second Line Drug
Resistance n (%)
Asia
Europe
South America
South Africa
Ethionamide
N = 11
1 (9 %)
N = 15
1 (7 %)
N = 32
0 (0 %)
N=71
9 (13%)
Kanamycin
0 (0 %)
10 (67 %)
10 (31 %)
2 (3 %)
Ofloxacin
4 (36 %)
3 (20 %)
6 (19 %)
5 (7 %)
Pyrazinamide
4 (36 %)
11 (73 %)
16 (50 %)
46 (65%)
Similar distribution of resistance in TMC and Placebo groups
No resistance to TMC207
30
C208-Most frequent AEs ITT (≥10% in at least 1arm)
Placebo
N=81
TMC207
N=79
Nausea
29 (36%)
27 (34%)
Arthralgia
20 (25%)
27 (34%)
Hyperuricaemia
25 (31%)
20 (25%)
Vomiting
22 (27%)
20 (25%)
Headache
15 (19%)
21 (27%)
Haemoptysis
12 (14%)
15 (19%)
Dizziness
10 (12%)
9 (11%)
Pruritis
12 (15%)
10 (13%)
Abdominal pain upper
7 (9%)
9 (11%)
Back pain
5 (6%)
8 (10%)
Insomnia
9 (11%)
10 (13%)
Pyrexia
7 (9%)
8 (10%)
Deafness unilateral
7 (9%)
8 (10%)
McNeeley, et al. 41st IUATLD 2010.
Oral presentation
31
C208 Safety
• Adverse events evenly distributed across treatment groups
• Discontinuations due to adverse events were unrelated to the study drug
• Placebo: 4 discontinuations during the treatment phase
(drug exposure during pregnancy, amylase/lipase increase, urticaria and pregnancy)
• TMC207: 3 discontinuations during the treatment phase
(transaminase increases: 2 cases of acute Hep B infections and 1 alcoholic binge)
• No serious adverse events related to study drug
• No clinically significant differences in laboratory tests
• QTcF prolongation seen
- no adverse events associated with QTcF changes
- no pathologically prolonged QT intervals (> 500 msec)
McNeeley, et al. 41st IUATLD 2010.
Oral presentation
32
1.0
C208 - Time to Conversion(TtC)- mITT
0.6
0.4
58%
79%
0.2
Proportion of Culture Positive Patients
0.8
Secondary analysis:
p=0.008 for the
difference in proportion
0.0
Placebo
TMC207
BAS
W 4
W 8
W 12
W 16
W 20
W 24
Time to Culture Conversion (in Days)
Time to 50% culture conversion: 12 weeks in the TMC207 group
Subjects
out are
censored at 24W
and 18
weeks dropping
in the placebo
group
McNeeley, et al. 41st IUATLD
2010. Oral presentation
3
33
Conclusions from study C208
TMC207 was safe and well-tolerated over 24 weeks
Addition of TMC207 to a 5-drug MDR-TB regimen
resulted
• In faster culture conversion within 24 weeks (p=0.003)
• In median time to culture conversion of 12 versus 18 weeks.
• In a higher sputum conversion rate at 24 weeks 79% vs 58%
(p=0.008)
McNeeley, et al. 41st IUATLD
2010. Oral presentation
34
TMC207-C209 Open label study:
Trial Design
Open label
Patients
with newly
and nonnewly
diagnosed
sputum
smear
positive
pulmonary
MDR-TB;
25% PreXDR and
21% XDR
OBR + TMC207
2w
screening
24 weeks
(n=233 ITT)
(n=205 mITT)
(mITT excluded DS TB and
MGIT non-evaluable)
TMC207 regimen:
• 400 mg QD for 14 days,
then
• 200 mg TIW
OBR alone
• China
• Estonia
• Latvia
• Peru
• Philippines
• Russia
• South Africa
• South Korea
• Thailand
• Turkey
• Ukraine
• 2 y follow-up
• 18-24 month total
MDR-TB treatment
24 w data available
OBR= optimized background regimen
35
C209 Inclusion Criteria
• Male or female, 18 years or older
• Positive sputum smear > 1+
• Confirmed resistance to INH and RIF, including Pre-XDR and XDR
(if 3 TB drugs in BR to which the isolate = susceptible)
• HIV negative or HIV+ with CD4+ > 250 & ART (triple nuke)
• No significant extrapulmonary TB or concomitant illness
36
C209: Background Regimen
The majority of patients had a baseline background regimen consisting of:
–
–
–
–
–
–
Fluoroquinolones (89%)
Ethionamide/Protionamide (79%)
Pyrazinamide (76%)
Aminoglycosides (72%)
Cycloserine/Terizidone (58%)
Ethambutol (52%)
A large number of other miscellaneous anti-TB drugs were used
Changes in the background regimen occurred over time due to:
• DST results
• Side effects
• Switches within the same drug class (due to shortage on site)
* Approx. 86% of the MDR TB patients were on previous TB treatment with a median duration of 36 days prior to baseline.
37
C209: Demographics & baseline
characteristics
ITT
N=233
mITT
N=205
Gender - male (%)
64
64
Age - median (yrs)
32
32
HIV negative (%)
95
95
Body weight - median (kg)
57
57
Non-newly diagnosed (%)
87
86
Extent of resistance (%)
MDR TB
Pre-XDR TB
XDR-TB
53
25
21
54
25
21
38
C209 - Baseline Drug Resistance
China
Eastern
Europe
South
America
South
Africa
N = 24
17%
N=40
28%
N = 34
24 %
N = 10
0%
N=59
10%
Kanamycin
29 %
30%
44 %
30 %
14 %
Ofloxacin
58 %
73%
38 %
10 %
12 %
Pyrazinamide
72 %
75%
88 %
90%
76%
Second Line Drug
Resistance n (%)
Ethionamide
Asia
(other)
39
C209 - Baseline Drug Resistance-Europe
Second Line Drug
Lativia
20%
Estonia
40%
Russian
Fed
0
Kanamycin
50%
60%
67%
50%
0
44 %
Ofloxacin
30%
80%
33%
50%
0
38 %
Pyrazinamide
80%
100%
100%
100%
67%
88 %
Ethionamide
Ukraine
0
Turkey
67%
Total
24 %
N: Rus-3; Est-5; Lat-10: Tuk-6; Ukr-10
40
C209: Conversion rates (MGIT)-Wk 24 Analysis-mITT
79.5% response rate
4
41
Time to conversion by subgroup
55.6% response rate
77.3% response rate
87.1% response rate
The intersection of horizontal dotted line and each treatment arm represents the median time to sputum
conversion.
42
Tabulation of most frequent AE’s
•Most frequently reported adverse
events (>10%) during the
investigational phase:
•nausea (11%),
•arthralgia (12%) and
•hyperuricaemia (14%)
•22% of the subjects stopped a
background TB drug due to an AE
•2% (n=4)of the subjects stopped
TMC207 prematurely due to an AE
43
Conclusions from study TMC207- C209
•Addition of TMC207 to an individualized MDR-TB regimen:
• Was safe and well-tolerated
• Resulted in an 80% culture conversion rate at week 24,
with median times to culture conversion of:
• 8 weeks for patients with MDR TB
• 12 weeks for patients with Pre-XDR TB
• 24 weeks for patients with XDR TB
•Responder rates were higher for:
• Patients with no cavitations (p* = 0.0157)
• Patients with lower extent of resistance (p* = 0.0006)
• Patients on 3 or more potentially active drugs in their BR
(p* = 0.0376)
* Cox proportional hazards model
44
Phase III Design
45
TMC207-C210 Trial Design
BR = (K4m)PrHLECZ (6m) + LECZ 46
(3m)
46
ARV Pipeline
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06.03.2010
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DARUNAVIR
 Paedatrics
 DRV liquid
 Nucleoside sparing regimens
 NEAT 001: DRV + RAL: 800 pts; Results 2013
 MODERN: DRV/r + MVC QD: 804 pts; Results 2014
 Monotherapy
 PROTEA
 Formulations:
 800mg tablet: Jan 2013
 GLIDE 1: DRV + GS9350
 GLIDE 2: DRV + GS9350 + FTC + GS7340
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ETRAVIRINE
• Switch studies
• UK Switch
• Switch EE
• Txt Naïve studies
• SENSE
• KALYINTE: Kaletra + ETR
• Txt Experienced studies
–INROADS: ETR + DRV/r QD
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RILPIVIRINE
• Approved Dec 2011
• Single tablet - Edurant
• FDC - Eviplera
• Further Trials:
–STAR: Atripla vs. Eviplera
–PI switch study
–Paedatric program
–PK in Pregnancy (DRV + ETR as well)
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THANK YOU
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