Discovery & Development: Bedaquiline For Drug Resistant Tuberculosis. Wim Parys, MD Head R&D J&J Global Public Health
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1 Discovery & Development: Bedaquiline For Drug Resistant Tuberculosis Wim Parys, MD Head R&D J&J Global Public Health
2 Y (Turkey): TB infection suggestive bone lesions Y (Alit-Yam, Israel) DNA confirmed TB bone lesions Tuberculosis an old public health enemy but still very much alive
3 Tuberculosis (TB) is an Ancient, Lethal Disease Airborne disease caused by Mycobacterium TB Mostly affecting the lungs, but can involve any organ Global control complicated by growing resistance to current therapies TB is the leading cause of death globally from a single infectious agent in million deaths among HIV-negative people 0.9 million deaths among HIV-positive people WHO report 2016
4 Timeline of most relevant TB therapeutics J.A. Villemin TB is contagious Streptomycin PAS INH (Isoniazid) Pyrazinamide Cycloserine 1965 Rifampicin 1961 Ethambutol 1962 Quinolone 2012 Bedaquiline 1882 R. Koch MTB discovery 1960 INH+PAS+Streptomycin Rifampicin+INH +Ethambutol+Pyrazinamide
5 TB Bacteria: Classification/Definitions DS MDR* Pre-XDR* XDR* Rifampin Rifampin Rifampin Rifampin Isoniazid Isoniazid Isoniazid Isoniazid Fluoroquinolone Fluoroquinolone OR Amikacin or Kanamycin or Capreomycin Amikacin or Kanamycin or Capreomycin * The proposed indication for BDQ is MDR-TB as being at least resistant to H & R. Pre-XDR & XDR-TB are subsets of MDR-TB
6 DS TB 95% Cure 3-4 drugs, 6-9 months XDR TB 33% Cure 40% Mortality 7+ drugs >24 months MDR TB 48% Cure 15% Mortality 4-5 drugs, months 25% of the patients develop depression or psychosis and a significant proportion becomes suicidal. 30% becomes deaf.
7 Multi Drug-Resistant-TB Represents a Field with Huge Unmet Medical Need Low diagnosis rates w < 23% of estimated MDR-TB cases detected Few treatment options Toxic Severe and difficult to tolerate side effects Lengthy 9-24 months w Costly $3B annually for just second-line drugs 22% of MDR-TB patients receive treatment = 126K patients Poor treatment outcomes w Average MDR-TB treatment success rate is 50%
8 Drug resistant Tuberculosis: is an increasing public health problem and there is a huge need for a more effective, safer and shorter treatment
9 Discovery and Development of a Drug Discover and optimize a lead compound Select a development candidate Discover mechanism of action Convince research community (in- externally) Generate preclinical development data Convince management to move into development Development of compound File Regulatory Documents Convince regulatory agencies Convince clinicians appropriate use Convince and support the payer/ha to implement the new drug
10 Bedaquiline discovery and early development 1997 Hit in the phenotypic screening of M. smegmatis Start of chemical synthesis (optimization) Selection of molecules for ADME and tox screening In vitro and in vivo experiments to determine TB activity 2002 Selection of development candidate (NME declaration) 2003 Compound s unique antibacterial spectrum determined
11 Non-mycobacteria: MIC 4 g/ml Mycobacteria: MIC g/ml H. pylori Str. pyogenes Br O H N M. tuberculosis MDR M. tuberculosis St. aureus N O S. typhimurium M. Leprae M. pneumoniae M. ulcerans E. coli M. avium E. faecalis M. bovis E. faecium M. fortuitum P. aeruginosa M. marinum H. influenzae M. kansasii M. smegmatis Andries et al., Science 2005, 307, 223
12 Bactericidal Activity in the Mouse Model Number of Bacteria in Lungs (Log CFU) Controls at Day 12 R = rifampicin 10 mg/kg 7 R = rifampicin 10 mg/kg H = isoniazid 25 mg/kg Z = pyrazinamide 150 mg/kg 6 B = bedaquiline 25 mg/kg wks 8 weeks 4 weeks 4 wks
13 Bedaquiline: Mechanism of Action In strains resistant to bedaquiline, mutations were identified in the gene coding for ATP synthase Provides energy (ATP) from a transmembrane proton gradient Adapted from Science 2005, 307, 214
14 Bedaquiline: Microbiology Summary In vitro: Active on DS-TB and MDR-TB Targets mycobacterial ATP synthase Kills both replicating and non-replicating bacilli In mice: Increases bactericidal and sterilizing activity of first and second line regimens Shortens treatment duration ATP Synthase (Science cover)
15 Data generation Active metabolite (M2) High Protein binding Long Half-life Phospholipidosis Activity on dormant bacilli Synergy with pyrazinamide Activity in guinea pig model Strong Bactericidal efficacy Strong Sterilizing efficacy
16 Log C p TM C 207 (ng/m L) Problem 1: A terminal terminal half-live Mean terminal t 1/2 bedaquiline= 5 months 3 NOAEL Dog (6 m) 2 6 months: mean 157 ng/ml Last drug intake D ay
17 Problem 2: Phospholipidosis Br O H N PE N O n Hydrophobic rings Hydrophile side chain with charged cationic amine group Bedaquiline = CAD = Cationic Amphiphilic Drug CADs interact with phospholipids and their metabolic enzymes Intracellular phospholipids become trapped into lysosomes within macrophages/lymphocytes CADs have extensive tissue distributions and long halflives Phospholipidosis is considered an adaptive change - but sometimes associated with myopathy, hepatotoxicity
18 2005 Problem 3: Weak Bactericidal Activity in EBA study in patients monotherapy RHZ 0.8 log bedaquiline Reference compounds Rustomjee et al., AAC 2008, 52, 2831
19 Change QTcF Plasma TMC207 concentration (ng/ml) Enough reasons for A Complete Stop of the program PE Terminal t 1/2?? Phospholipidosis?? n D ay QTc Effect? Limited Efficacy?? TMC207 25MG TMC MG TMC MG RIFAMPIN 600MG ISONIAZID 300MG D7-Pre dose D7-5H post dose Follow up
20 Time for a chat with senior leadership..
21 The Great Escape from a Complete Stop DMC: Dev. Management Comm: 11 Jan 2006 CDT: Compound Development Team: 16 Feb 2006 PEM: Preclinical Tox Expert Meeting: 28 Feb 2006 Next trial FDA CAM DMC FIHC PEM CDT: Compound Development Team : 1 March 2006 DMC: Dev. Management Comm: 8 March 2006 CDT: Compound Development Team: 14 March 2006 TMC 207 DMC FIHC: First in Human Committee: 13 April 2006 CAM: Clinical Advisory Meeting: 15 May 2006 FDA: Food and Drug Administration: 15 July 2006 DMC: Dev. Management Comm: 9 August 2006 DMC: Dev. Management Comm: 18 October 2006
22 Rescue Action 1: Intermittent Dosing prevents Accumulation Toxic UD trough level in dog NOAEL UD trough level in dog Active UD level in mouse Daily dosing = accumulation Intermittent dosing = OK
23 Rescue Action 2: Intermittent Dosing prevents Toxicity Toxic effects of 2x140 mpk/week <<< 7x40 mpk/week =280 =280 Liver and muscle enzymes COMPLETELY RECOVERED.after just lowering the dose by 50%
24 Rescue Action 3: A second look at the efficacy data monotherapy 0.8 log Low sputum concentrations? Sputum protein binding? Time to steady state? ATP pool depletion? Under dosing? We should not have been surprised!!
25 Rescue Action 3: Bactericidal Activity in vitro Log CFU M. tuberculosis controls 1.0 log B 10x MIC B 100x MIC Days of incubation Andries et al., Science 2005, 307,223
26 2006 Decision: One more study in MDR TB pts Study C208/1-50 patients Safety and PK (not efficacy!) Standard of care plus 2 months bedaquiline or placebo Study C208/2-150 patients Safety and efficacy Standard of care plus 6 months bedaquiline or placebo!! Pivotal study for Accelerated/Conditional Approval
27 Effect of 2 months treatment (n=44) 8.7% culture negative 47.5% culture negative Bedaquiline + background regimen + background regimen p = Diacon et al. NEJM 2009, 360:2397 p-value from Cox proportional model adjusting for strata
28 Proportion of culture positive patients PhII C208 Stage 2: Significant Reduction in Time to Conversion Primary analysis: p<0.001 for the difference in TtC Secondary analysis: p=0.008 for the difference in proportion % Placebo + BR (n=81) 58%t 0.2 Bedaquiline + BR (n=79) 79% 0 BAS p-value from Cox proportional model adjusting for strata The intersection of horizontal dotted line and each treatment arm represents the median time to sputum conversion Diacon AH, et al. N Engl J Med 2014;371: Median time to culture conversion (mitt) = 83 days for bedaquiline versus 125 days for placebo
29 2012.phase 2b trial sustained response and lower relapse rates Study Definition WHO Definitions Diacon et al. NEJM (2014)
30 But.Problem 4: Mortality Imbalance Related to bedaquiline? Average time after stopping BDQ = >300 days Preclinical experience: side effects disappear after stopping BDQ Clinical evidence: Qtc effect disappears after stopping BDQ No increased plasma levels (AUC) observed No increased Qtc signals observed No pattern of specific pathology observed
31 Nov 29, 2012: FDA Advisory Committee The FDA uses advisory committees to obtain independent expert advice on scientific, technical and policy matters. Company and FDA present data (60 min each), followed by all day Q&A Preparation is huge: several mock rehearsal meetings to prepare the presentation, identify all possible questions, answers to those questions and responders. Prepare a 250 pp briefing book, 2000 slides, a system to get immediately to the right slide.
32 December 2012.FDA approval
33 Pending: Approvals: Regulatory Filing Status U.S. Russia* EU South Africa India China Taiwan Moldova* Uganda** South Korea Philippines Armenia* Macau Hong Kong Turkey Japan Peru Turkmenistan* New Zealand Thailand Ethiopia** Uzbekistan* Rwanda** Bangladesh Jan 2015 Brazil Feb 2017 Burundi** April 2016 Cameroon** Jan 2017 Ghana** May 2016 Indonesia Mar 2015 Kenya** April 2016 Mexico Oct 2015 Nigeria** Dec 2016 Tanzania** Mar 2016 Vietnam Aug 2013 Rejected: Azerbaijan, Kazakhstan, Kyrgystan (8% of treated patients in high MDR-TB burden countries); Withdrawn: Belarus (2%), Switzerland *MAH (Marketing Authorization Holder) is Pharmstandard ** WHO Collaborative Procedure for Accelerated Registration ***medicamentos vitales no disponibles: Colombia
34 > 60,000 Cumulative Treatments Delivered to 90+ Countries Numbers source: J&J Internal Finance Report August 2017 Map source: * Bedaquiline received FDA approval in December 2012
35 Effect Size of Bedaquiline on Mortality Bedaquiline N=1,556 No Bedaquiline N= 23,539 Total N=25, % 18.2% ART = antiretroviral therapy BCAP = bedaquiline clinical access program FLQ = fluoroquinolone * With propensity score adjustment; ** Adjusted for age, gender and type of resistance confirmation Source: WHO Meta-analysis Report, Figure 8 Favors BDQ Favors control Consistent reduction in mortality across all risk groups
36 South Africa: Tackling DR-TB through Access Framework, Sustained Investments & Diverse Partners Access and treatment Advocacy and Leadership Education and prevention e-health platforms ECG & Portable audiometers Patient brochures Data management MDR-TB Registry Advisory Boards HCW Training on MDR TB, treatment, ECG and audiometers Antibacterial surveillance Disease awareness Website (whatistb.com) Treatment outcomes in Pre/XDR TB are now overtaking our outcomes in MDR- TB: New Drugs are a top priority.
37 India: Comprehensive Approach to Tackling TB Research & Development CSIR-IMTECH collaboration Access and treatment Advocacy and Leadership Compassionate use Donation program ECG Data management MDR-TB Registry Advisory Boards Education and prevention HCW Training on MDR TB, treatment and ECGs Disease awareness BDQ uptake TOTAL '15 TOTAL '16 Q Q Q Q TOTAL 2017 India
38 Lessons learned.
39 High medical need High level of innovation PRV New MoA: no established PoC Limited effect in EBA No prior TB drug development experience Budget constraints/ Limited financial ROI Characteristics of the molecule QT prolongation Long t½ Phospholipidosis Liver target tox organ
40 New MoA: no established PoC / Limited effect in EBA No prior TB drug development experience Budget constraints/limited financial ROI Characteristics of the molecule QT prolongation Long t½ Phospholipidosis Liver target tox organ Collect necessary data Establish proof of efficacy Gain expert advice & support Develop strategy of defense Explain non-financial ROI Mitigation of the compound s intrinsic risks Convincing Risk / Benefit assessment
41 It isn t over till..
42 The World Aspires to Achieve A World Free of TB Without accelerated discovery, development, and deployment of new tools and technologies, this aspiration is not achievable
43 Targeting Energy synthesis pathway The respiratory chain in mycobacteria Cytochrome bc ATP synthase NDH-2 H + H + H + Proton motive force Cytochrome bd MK e - H + SDH NDH1 Carbon source NADH e - NAD + + H + O 2 e - H 2 O H + ADP+Pi ATP O 2 e - H 2 O e - MK ATP synthase + Cytochrome bc+ Cytochrome bd ( +/- ndh2)
44 Can we Develop a New Universal Drug Regimen for TB? Our aspirational aim - Single Pill Combo Universal treatment: MDR-TB DS-TB NTM Better bactericidal activity to reduce treatment duration Oral, safe & compatible with HIV treatment Better compliance & access Conventional MDR-TB treatment two years of treatment complex, expensive, and toxic - third of all MDR-TB patients die May WHO issued a conditional recommendation on the use of the shorter MDR-TB regimen (7 drugs, 9-12 months) Eight months of painful daily injections
45 Encouraging First In Vitro Drug Synergy results The combined inhibition of ATP synthase (BDQ) and 2 new targets is highly synergistic The triple combination achieves complete in vitro killing within 5 days faster than the standard of care RIF+INH (20 days) Triple regimen All compounds at 30xMIC Nature communication, 2016 Fast bactericidal activity Potential reduction of treatment duration
46
47 THANK YOU
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