Inhaled Therapy for TB

Transcription

1 7 th International Workshop on Clinical Pharmacology of TB Drugs Inhaled Therapy for TB Edward A. Nardell, MD Brigham & Women s Hospital Harvard Medical School No conflicts of interest 1

2 1. Capreomycin Inhalation Powder (CMIP) First TB antibiotic formulated for dry powder inhalation Edward Nardell, MD, PI Ashwin Dharmadhikari, MD Brigham & Women s Hospital Harvard Medical School

3 Acknowledgements Harvard University David Edwards, Ph.D. Katharina Elbert, Ph.D. Matthew Thomas Jean Sung, Ph.D. University of North Carolina Anthony Hickey, Ph.D. Lucila Garcia-Contreras, Ph.D. Sponsors NIAID Bill & Melinda Gates Foundation through MEND (Medicine in Need) Bernard Fourie, PhD, U. Pretoria

4 History and Properties of Capreomycin Drug originally developed in early 1950 s by Eli Lilly as Capastat Used in combination as second-line therapy with 4-6 other antibiotics to treat MDRTB (can be for up to 2 years) Capreomycin sulfate is a polypeptide antibiotic very active against pulmonary TB In-vitro potency: MIC M. Tb (H37Rv): 2 ug/ml Very poor oral bio-availability However, high pulmonary bioavailability (~60%)* Rapid absorption via the lung

5 Rationale for development of CMIP Route of Administration: Noninvasive Inhalation represents opportunity for better compliance versus injectable* Eliminates needle-based risks of cross-infection (HIV, Hepatitis Eliminates pain at side of injection, esp. for underweight adults and children Handling: No reconstitution versus the injection No medical professionals required for dose administration

6 Development Goals Replace the CM injectable with CMIP in multiple drug regimen for MDR-TB treatment Develop spray dried capreomycin as a model powder formulation with MEND (i.e., David Edwards) technology to obtain advantages of lung administration Evaluate and benchmark the suitability of MEND s technology platform (cost, complexity, etc.) for preparation of other inhalable powders of drugs and vaccines

7 CMIP: pre-clinical PK 20 mg/kg of CMIP delivered by insufflation to guinea pig Lung concentrations of drug after single dose reached times the MIC of Mtb in BAL and times the MIC in lung tissue (100-fold higher than plasma levels) AUC/half-life/lung residence time longer/higher concentration after 2 and 3 doses Study data suggest that high doses daily of powder will treat TB systemically More drug is available in lungs to kill mycobacteria for a longer period (still present at 8 hours, last time point tested)

8 CMIP development program: Pre-clinical PK results Capreomycin Plasma Concentration (µg/ml) PLASMA CONCENTRATION versus time curves after administration of a SINGLE DOSE (20 mg/kg) of capreomycin powder for inhalation by insufflation Time (h) 7MC 8MC 28MC 31MC 32MC 9MC 10MC 11MC 14MC 15MC 16MC 17MC 74MC 75MC Bronchoalveolar lbavage (BAL) of animals receiving a SINGLE DOSE of capreomycin by intramuscular injection (IM) or insufflation at different time points (0.5, 2, 4 and 8 h) after dose administration Capreomycin concentration (µg/ml) h 2h 4h 8h IM * * Insufflation * * TBD

9 CMIP development program: Pre-clinical PK results AVERAGE concentrations in LUNG TISSUE of animals receiving a SINGLE DOSE of capreomycin by intramuscular injection (IM) or insufflation at different time points (0.5, 2, 4 and 8 h) after dose administration AVERAGE capreomycin concentrations in LUNG TISSUE of animals receiving the DIFFERENT DOSING REGIMENS of capreomycin (by intramuscular injection (IM) or insufflation) at the end of the dosing period (8, 16 and 24 h) Capreomycin concentration (µg/g of tissue) h 2h 4h 8h * * * * Capreomycin concentration (µg/g tissue) h 16h 24h * * * 0 IM Insufflation 0 IM single insufflation double insufflation triple insufflation TBD

10 CMIP: Formulation MEND spray-drying process API Hisun (via Lilly) Formulation: Capreomycin Sulfate/Leucine (80:20) Powder MMAD: microns Potency: 25 mg per Capsule (HPMC) in alum. blister pouch Product stable for at least 1 year at room temperature Delivery device commercially available hand held device Intellectual property Technology licensed to MEND from Harvard University

11 CMIP: Current Delivery device Hand-held Breath-activated Disposable Inexpensive The current device in use for CMIP is a dry-powder inhaler commercially-available from Plastiape, Italy. Future developing world device under development (cost equivalent to injectable product)

12 CMIP: Status (no longer current) Phase 1a clinical program (single, escalating dose and plasma PK) Successfully dosed 4 cohorts (n=5) each at doses of 25, 75, 150 & 300 mg. Well tolerated with no significant adverse events (SAE). Minor coughing (dose independent) Study conducted at Brigham & Women s Hospital in Boston, MA CMC GMP compliant global supply chain established for both CTM and commercial production Sensitive PK bioanalytical method (~20 ng/ml) in plasma, urine and lung fluid has been developed/validated at GLP compliant CRO.

13 Phase 1: Mean Capreomycin Plasma Concentration-Time Profiles at the Four Doses Mean Plasma Concentration (ng/ml) Time (hr) 25 mg 75 mg 150 mg 300 mg MIC

14 Mean Capreomycin Plasma Concentration-Time Profiles at the Four Doses Route Inhalation Dose (mg) Statistic C max (ng/ml) AUC 0 (hr*ng/ml) Half-life (hr) t max (hr) Mean 169 2, SD 56 1, Mean 569 4, SD 344 1, Mean 972 9, SD 662 4, Mean 2,315 22, SD 1,390 12, MIC: 2,000 ng/ml; BAL = 10x of plasma conc. Estimated from GP data

15 Maximum Capreomycin Plasma Concentrations (C max ) at the Four Doses Cmax (ng/ml) Dose (mg)

16 Area Under the Plasma Concentration-Time Curve (AUC 0- ) at the Four Doses AUC0-inf (hr*ng/ml) Dose (mg)

17 CMIP Development plan on hold Co-Development: Current and future potential indications (mycobacterium & non-mycobacterium) Regulatory: MBD (and its partner(s)) will continue its dialogue with the FDA to pursue subpart-h and/or fast-track approval status Manufacturing: expertise to assist in the technology transfer of CMIP production via LPPs (established Letter of intent? with commercial manufacturer in Kenya

18 CMIP was well tolerated List of adverse events: Subject # Dose Group Adverse Event (severity) Relationship to Study Drug mg Cough (mild) Related mg Cough (mild) Related mg Headache (mild) Chest tightness (mild) mg Cough (moderate) IV infiltration (mild) Unrelated Unrelated Related Unrelated mg Cough (moderate) Related mg Cough (moderate) Migraine headache (moderate) Vomiting (moderate) Related Unrelated Unrelated

19 CMIP Conclusions: Inhaled CMIP is a promising technology Well tolerated May achieve systemic levels without injection and much higher lung levels than IM route Major concern powder load is high 300 mg is well above the usual amount of inhaled drug, but a fraction of the usual injected dose May work well for children and underweight adults Long-term tolerance is unknown Further development on hold 19

20 2. Inhaled Dry Powder Colistin: A novel approach for reducing M/XDR-TB transmission in congregate settings and in the community (First dry powder TB antibiotic used in TB patients) Edward A. Nardell, MD, (PI) Anton Stoltz, MD, PhD, (on-site PI) and the AIR Consortium: Brigham & Women s Hospital, MRC, U. Pretoria, CSIR, and U. Groningen 20

21 Rationale: Global MDR-TB Treatment Scale Up Estimated 500,000 new MDR- TB cases per year More than half result from transmission ,423 cases reported 7% of estimated cases 1% treated with quality assured drugs XDR is a by-product of MDR treatment and transmission Most are treated in hospitals for first 6 months injectables - until culture conversion No effective infection control strategies for XDR TB in hospital or in the community No new TB IC interventions in decades Possible routine treatment with inhaled colistin until proven not to have drug resistance XDR outbreak - KZN

22 Effective Treatment Stops Transmission Before Smear and Culture Conversion

23 Inhaled antibiotic: Nebulized kanamycin, or Dry powder capreomycin* Trachea and large airways Antibiotic concentration ,000 X MIC Microbes in epithelial fluid lining layer Rx Airborne infectious droplet nuclei Measures of infection control potential: Mtb cultured in daily 12 hr sputum Mtb cultured in cough aerosol samples Infection rate of exposed guinea pigs* Cough generating airborne infectious respiratory droplets Figure 1: Theoretical model and experimental approach to testing the inhaled antibiotics infection control hypothesis. (* indicates future planned studies) Hypothesis: A cohort of MDR-TB patients receiving systemic treatment for pulmonary TB plus inhaled dry powder colistin will be 75% less infectious for guinea pigs compared to the same cohort of MDR-TB patients receiving systemic treatment alone.

24 Inhaled Antimicrobials for TB: Among TB antimicrobials, only kanamycin is approved for inhalation by nebulization But resistance to KM is common Only capreomycin has been developed specifically for dry powder inhalation (Phase I clinical trial in Boston) Not yet available, and also growing drug resistance Colistin is active against a wide range of mycobacteria, but not at an MIC or MBC achievable (5 µg/ml and 50 µg/ml) systemically without renal toxicity Widely used systemically for resistant gram negative sepsis. Inhaled colistin has been safely used by nebulization in cystic fibrosis patients for 20 years A dry powder formulation of colistin sulfomethate and delivery system has been developed by the U. Groningen, Netherlands, and well tolerated by both human volunteers and CF patients No clinical trials of any inhaled antibiotic specifically to reduce TB transmission Potential therapeutic benefit not this study (& synergy) 24

25 Colistin Structures of CS and CMS (Falagas and Kasiakou 2005). Poly cationic cyclic peptide Formaldehyde reacted followed by sodium bisulphate CMS is a prodrug of CS (higher MIC s observed) Displaces divalent cations from phosphate groups, interacts with LPS, insertion into lipids, disruption of outer membrane membrane MIC = 5 ug/ml ; MBC = 50 ug/ml (David and Rastogi 1985; Rastogi et al. 1986). 27/11/2012 Shane Vontelin van Breda 25

26 Scanning EM images* of XDR culture, control and with 12.5 ug/ml colistin. Evidence of cell wall damage, deformation and bulging. Potential synergy with other drugs (rifampin) helps drug enter bacilli (*Courtesy of Shane Vontelin van Breda and Anton Stoltz. U. Pretoria) Colistin - non-specific detergent-like mechanism, poking holes in the cell wall. Damaging the organism and increasing access to other drugs. 26

27 Twincer Dry Powder Inhaler University of Groningen No nebulizer or electricity No sterile saline or mixing No toxic by-products Inexpensive Pre-loaded, foil sealed Good storage without refrigeration Regulatory approval for use in SA pending (1 issue in dispute) Many thanks to: Marcel Hoppentocht A. H. de Boer Erik Frijlink Dept of Pharmaceutical Technology 27

28 The Airborne Infections Research (AIR) Facility Witbank, Mpumalanga Province, SA U. Pretoria MRC CSIR CDC Harvard/ BWH Harvard CFAR/NIH Funding 28

29 (Usual intervention studies) 29

30 1 Colistin Experimental Plan Guinea Pig Cohort Receiving Aerosols from TB Ward Inhaled Administration to TB Patients Infectious Source A B A B B A B A A B A B B A B A ST only ST + IA ST only ST + IA ST + IA ST only ST + IA ST only TST-1 TST-2 TST-3 TST-4 TST-5 TST-6 Table 1: A schematic of key events during the course of the proposed study. Six MDR-TB patients, forming a patient group, will provide the infectious aerosols to expose susceptible guinea pigs in the study. Each Patient Group is required to remain in the TB Ward of the AIR facility for four weeks, after which a new set of 6 patients will be admitted. There are at most 4 patient groups recruited over the course of four months. After the Patient Group 4 is discharged from the study, only activities regarding the guinea pigs are maintained. Tuberculin Skin Tests are adminsitered to guinea pigs at six time points: before the start of the study, at 4, 8, 12, 16, and finally 20 weeks. Air from the ward is directed to Guinea Pig Cohort A when patients are on systemic therapy (ST) alone, while air is directed to Guinea Pig Cohort B when patients are receiving an inhaled antimicrobial (IA) on top of systemic therapy. ST only ST + IA ST only Patient Group 1 Patient Group 2 Patient Group 3 ST + IA ST + IA ST only ST + IA Patient Group 4 ST only TB exposure stopped to Animal Rooms Notes: 1. Alternate week modification was introduced to prevent a carry-over antibiotic effect 2. Numbers of subjects (6 per group X 4 groups, plus replacement subjects) based on experience of the number needed to include enough infectious patients to generate enough transmission during control weeks to be able to measure a significant reduction with the intervention. 3. End point is guinea pig infections, not subject-related, per se. 90 guinea pigs in control and intervention chambers has proven effective in measuring 50-80% efficacy in previous trials. 4. Efficacy is for the intervention against transmission of the entire cohort of subjects, not for individual subjects. We cannot determine which patients caused infections. 30

31 Safety Concerns Clinical studies of 9 normal volunteers and total of 19 CF patients (FEV %) showed minimal cough, and no significant change in FEV1. Cmax in normals 90 µgm/l, and in CF patients 66.3 µgm/l with 25 mg dry powder dose; compared to 144 µgm/l nebulized. T1/2 = 3 hrs in CF patients Note: iv dose 6-12 mg/kg colistimethate ( mg for 50 kg patient) for systemic infection Exclusion criteria: room air oxygen saturation <90% asthma (PEF < 50% predicted), or severe chronic obstructive lung disease (PEF < 50% predicted) egfr < 60 cc/min. Safety procedures: PEF before and after first colistin dose both weeks, Discharge from study > 20% fall in FEV1 without immediate response to bronchodilator Oximetry at intake and once post dosing, and with any complaint Weekly serum creatinine Adverse events logged and reported according to protocol Acute management by hospital nurses and physicians Investigation of all adverse events by Dr. Anton Stoltz, on-site PI 31

32 ICARUS study: results added per month Start Month 1 Month2 Month 3 Month 4 Month 5 Control Room Intervention room Start Month 1 Month2 Month 3 Month 4 Month 5 Intervention room Control Room

33 Conclusions: 1. Inhaled dry powder colistin used in advanced TB patients for the first time well tolerated 2. Suggestion of early effect of topical antibiotics on transmission confounded by study design that assumed no prolonged effect 3. Additional studies needed: a. Repeat transmission study with different protocol and higher dose b. Therapeutic trial but requires dose ranging study in animals c. GP studies also needed to assess synergy with other TB drugs. d. Role of EBA studies for inhaled drugs i.e., drug in sputum do results represent a real therapeutic effect? 33

34 1.4 mile Swim for Life across Provincetown Harbor 34