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Janssen Pipeline

Janssen Pipeline. UK CAB. Dr Michael Aboud Medical Lead Virology. 20 th January 2012. 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.

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Janssen Pipeline

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  1. Janssen Pipeline UK CAB Dr Michael Aboud Medical Lead Virology 20th January 2012 This presentation has been produced in response to a specific request and may contain information about a non-approved indication and product

  2. Key Drugs in Clinical Development at Janssen NNRTI, non-nucleoside reverse transcriptase inhibitor; RTI, reverse transcriptase inhibitor Data on file.

  3. Tuberculosis infection and disease TMC207 core slide set

  4. TB is a global problemWHO estimated prevalence of TB cases 2008 Per 100,000 population WHO http://gamapserver.who.int/mapLibrary/Files/Maps/MDG6_TBincidence_08.png)

  5. 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

  6. 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/the-influence-of-host-and-bacterial-genotype-on-the-development-of-tuberculosis/

  7. Diagnosis of tuberculosis TMC207 core slide set

  8. Signs, Symptoms and Diagnosis of TB • X-ray • Sputum smear microscopy • Culture

  9. 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

  10. Tuberculosis treatment and multidrug resistance TMC207 core slide set

  11. Treatment of Pulmonary Tuberculosis Month 1 H,R,Z(,E) • Active TB • Global standard of care: Direct Observed Treatment Short-course (DOTS) • HIV co-infection challenging because of DDI Intensive Phase Rapid reduction of bacterial load to reduce infectiousness Month 2 H,R,Z(,E) Month 3 H,R Continuation Phase Eliminate remaining bacteria to prevent subsequent relapse Month 4 H,R Month 5 H,R H = Isoniazid R = Rifampin Z = Pyrazinamide E = Ethambutol Month 6 H,R • MDR-TB • No global standard of care (4 drugs, one injectable, for 18-24 months)

  12. Failure of first-line TB treatment:drug resistance • Multidrug-resistant (MDR) TBIn-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) TBMDR 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

  13. A high proportion of previously treated TB cases are multidrug-resistant (MDR) Estimated global incidence and proportion of MDR among TB cases, 2004 Zignol M, et al. JID 2006; 194: 479-85

  14. 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

  15. 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

  16. 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)

  17. There are several classes of second-line agents 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

  18. 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 cross-resistance • 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

  19. Common adverse effects of TB treatments

  20. 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

  21. TMC207 (bedaquiline) update

  22. 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, 223Lounis et al., AAC 2006, 50, 3543 Koul et al., NCB 2007, 3, 323Koul et al., JBC 2008, 283, 25273 Rustomjee et al., AAC 2008, 52, 2832Diacon et al., NEJM 2009, 360, 2397 Ibrahim et al. AJRCM 2009, in press

  23. Key Phase I PK findings McNeeley D, et al. IUATLD 2006. oralVan Heeswijk et al., ICAAC 2007, A-780Van Heeswijk, et al., IUATLD 2007, PS-71358-11 Van Heeswijk et al, IAS 2010, WEPE0097 Van Heeswijk et al, IAS 2011, MOPE172 • 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)

  24. TMC207-C208 Stage 2 Efficacy and Safety Results

  25. C208 – Trial Design – randomized controlled multi-center double-blind phase Rif washout period BR alone BR + TMC207 Patients with newly diagnosed sputum smear positive pulmonary MDR-TB infection BR + placebo 1w 24 weeks • 2 y follow-up • 18-24 month total MDR-TB treatment • Stage II (n=161) • Brazil • India • Latvia • Peru • Philippines • Russia • South Africa • Thailand • Stratification by • Site • Lung cavitation • TMC207 regimen: • 400 mg QD for 14 days, then • 200 mg TIW McNeeley, et al. 41st IUATLD 2010. Oral presentation

  26. 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

  27. 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

  28. C208 Baseline Characteristics

  29. C208 - Populations for Analysis • ITT population:Randomized subjects who had at least one dose of TMC207 or placebo • Modified ITT population (mITT): ITT subjects excluding: • - Non-MDR subjects (8 placebo + 4 TMC207) • - XDR subjects (4 placebo+ 3 TMC207) • - MGIT results not evaluable (4 placebo + 7 TMC207)

  30. 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)

  31. C208 - Baseline Drug Resistance • Similar distribution of resistance in TMC and Placebo groups • No resistance to TMC207

  32. C208-Most frequent AEs ITT (≥10% in at least 1arm) McNeeley, et al. 41st IUATLD 2010. Oral presentation

  33. 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

  34. C208 - Time to Conversion(TtC)- mITT Primary analysis: p=0.003 for the difference in TtC Secondaryanalysis: p=0.008 for the difference in proportion 58% 79% McNeeley, et al. 41st IUATLD 2010. Oral presentation • Time to 50% culture conversion: 12 weeks in the TMC207 group • and 18 weeks in the placebo group

  35. Conclusions from study C208 McNeeley, et al. 41st IUATLD 2010. Oral presentation 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)

  36. TMC207-C209 Open label study: Trial Design OBR alone Open label Patients with newly and non-newly diagnosed sputum smear positive pulmonary MDR-TB; 25% Pre-XDR and 21% XDR • China • Estonia • Latvia • Peru • Philippines • Russia • South Africa • South Korea • Thailand • Turkey • Ukraine OBR + TMC207 24 weeks 2w (n=233 ITT) (n=205 mITT) screening • 2 y follow-up • 18-24 month total MDR-TB treatment (mITT excluded DS TB and MGIT non-evaluable) • TMC207 regimen: • 400 mg QD for 14 days, then • 200 mg TIW 24 w data available OBR= optimized background regimen

  37. 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

  38. C209: Background Regimen * Approx. 86% of the MDR TB patients were on previous TB treatment with a median duration of 36 days prior to baseline. • 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)

  39. C209: Demographics & baseline characteristics

  40. C209 - Baseline Drug Resistance

  41. C209 - Baseline Drug Resistance-Europe N: Rus-3; Est-5; Lat-10: Tuk-6; Ukr-10

  42. C209: Conversion rates (MGIT)-Wk 24 Analysis-mITT 79.5% response rate

  43. 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.

  44. 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

  45. 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

  46. Phase III Design

  47. TMC207-C210 Trial Design BR = (K4m)PrHLECZ (6m) + LECZ (3m)

  48. ARV Pipeline To edit footers: "insert tab>header and footer" and apply to all

  49. 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 To edit footers: "insert tab>header and footer" and apply to all

  50. ETRAVIRINE • Switch studies • UK Switch • Switch EE • Txt Naïve studies • SENSE • KALYINTE: Kaletra + ETR • Txt Experienced studies • INROADS: ETR + DRV/r QD To edit footers: "insert tab>header and footer" and apply to all

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