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  • Sieversbang

    1. 1. Inhalable Dry Powder Aerosol Attenuated Live Virus Measles Vaccine R. Sievers 1,3 , S. Winston 1 , D. Griffin, P. Rota, B. Quinn 1 , J. Searles 1 , D. Krank 1 , P. Bhagwat 1 , P. Pathak 1 , L. Rebits 1 , R. Dhere 2 , V. Vaidya 2 , R. Muley 2 , J. Burger 3 , D. McAdams 3 , S. Cape 1,3 K.Powell 4 , C. Shermer 4 , L. Chan 4 and K. Kisich 5 1 Aktiv-Dry LLC, 6060 Spine Rd., Boulder, CO USA, 2 Serum Institute of India Ltd., Pune, Maharashtra, India, 3 University of Colorado, Boulder, CO USA 4 BD Technologies, Research Triangle Park, NC, USA 5 National Jewish Medical and Research Center, Denver, CO USA
    2. 2. GRAND CHALLENGE 3: NEEDLE-FREE DELIVERY <ul><li>What is specifically needed: </li></ul><ul><li>Well-formulated free flowing stable microparticles with less than 1% residual moisture, with high virus titers, rapidly dissolved, to replicate and create an immune response. </li></ul><ul><li>Inexpensive unidose blister packs or capsules with overwraps to protect vaccine from contamination, decomposing, reaction with water, oxidants and UV, and to reduce vaccine wastage. (Presently 40% is destroyed.) </li></ul><ul><li>Simple active dry powder inhalers that can disperse powder agglomerates to generate high emitted doses with high fine particle fractions. </li></ul>
    3. 3. ADVANTAGES OF AEROSOL DRY POWDER OVER LIQUID VACCINES <ul><li>Powders inherently more stable than liquids </li></ul><ul><li>No line current or batteries required for aerosolization </li></ul><ul><li>Lower risk of disease transmission </li></ul><ul><li>Less vaccine wastage </li></ul><ul><li>More difficult to contaminate </li></ul><ul><li>No skin puncture or contact with blood </li></ul><ul><li>No re-use of needles </li></ul><ul><li>No need for water-for-injection (WFI) </li></ul>
    4. 4. NEEDLE-FREE DELIVERY VACCINE DEVELOPMENT <ul><li>Needle-free vaccination by inhalation of an aerosol of fine dry powder microparticles,~1-5 microns MMAD </li></ul><ul><li>In-vivo rapid dissolution in moist respiratory mucosa </li></ul><ul><li>Replication of live-attenuated measles vaccine virus </li></ul><ul><li>Robust immune response demonstrated by plaque neutralization in two animal models: Rhesus macaques and Cotton rats; macaques will be challenged with wild-strain of measles virus one year after immunization. </li></ul><ul><li>After demonstration of inhalation safety of the myo-inositol stabilizer in Sprague-Dawley rats and the E-Z live-virus vaccine in Rhesus macaques, an IND will be submitted for Phase I clinical trials in India. </li></ul>
    5. 5. PATH TO COMMERCIALIZATION <ul><li>CAN-BD is a closed, continuous process similar to spray-drying (but with a proprietary nebulizer), and is potentially faster and less expensive than freeze-drying. </li></ul><ul><li>Demonstrated ability to manufacture sufficient materials for pre-clinical and early phase human clinical trials. </li></ul><ul><li>Pilot scale GMP CAN-BD system has been designed, built, and installed at SIIL; scale-up to 400 million doses per year will be required for full-scale commercial production. </li></ul><ul><li>Unidose packaging in blisters or capsules will prevent cross-contamination, circumventing vaccine wastage. </li></ul>
    6. 6. <ul><li>Particles formed at 50 - 60 °C from an aqueous solution containing 11% total dissolved solids (50 g/L myo-inositol, 25 g/L gelatin, 16 g/L arginine-HCl, 1 g/L alanine, 2.1 g/L histidine, 3.5 g/L lactalbumin hydrolysate, 3 g/L tricine, pH 6.5 - 7.0). Microparticles averaged 1 µm in diameter and encased spherical virus particles averaged 120 nm. </li></ul><ul><li>Mean viral potency of measles vaccine powder samples was 4.6 log CCID50 / 10 mg. </li></ul>FREEZE-FRACTURE SEM OF E-Z SUB-MICRON MEASLES VIRUS ENCASED IN MYO-INOSITOL-STABILIZED EXCIPIENT MICROPARTICLES
    7. 7. SAFETY OF MYO-INOSITOL STABILIZER AND REFORMULATED E-Z LIVE-VIRUS MEASLES VACCINE <ul><li>Successfully completed in-life phase of GLP toxicology study in Sprague-Dawley rats. Final report not yet available, but no deaths or serious adverse events from myo-inositol inhalation reported to date. </li></ul><ul><li>Inhalation of dry powder measles vaccine by macaques in a pilot immunogenicity study was well tolerated with no deaths or adverse events reported. A robust measles-specific immune response was generated. </li></ul><ul><li>An inhalation toxicology study in additional Rhesus macaques is planned for next year. </li></ul><ul><li>A Phase I clinical trial is planned in 2010. </li></ul>
    8. 8. SAFETY… (Continued) <ul><li>Lam et al.* have completed a Phase I clinical trial of orally ingested myo-inositol powder with no SAEs reported following intake of up to 18 g per day for one month; Phase II clinical trials are beginning in Canada. </li></ul><ul><li>Normal concentration of myo-inositol in human plasma is about 4-5 mg/liter. </li></ul><ul><li>Intracellular concentration is 5-500x higher than in plasma. </li></ul><ul><li>Average dietary intake is 1 gram in the form of inositol hexaphosphate or myo-inositol in phospholipids. </li></ul><ul><li>Human milk contains about 450 mg/liter of myo-inositol. </li></ul><ul><li>*S. Lam, A. McWilliams, J. leRiche, C. MacAulay, L. Wattenberg, E. Szabo, &quot;A Phase I Study of myo-Inositol for Lung Cancer Chemoprevention&quot;, Cancer Epidemiol Biomarkers Prev, 15 (8): 1526-1531, 2006. </li></ul>
    9. 9. Structure of myo-inositol <ul><li>SEM of Tsuno (rice-derived) myo-inositol (modified with amino acid) microparticles produced by CAN-BD for inhalation safety study in rats </li></ul>
    10. 10. Modifications to CAN-BD for Processing Larger Volumes of Vaccine Fluids <ul><li>Used to produce batches of powder (6 to 8 grams): </li></ul><ul><ul><li>Solovent and PuffHaler stability studies </li></ul></ul><ul><ul><li>2nd round of Cotton rat study </li></ul></ul><ul><ul><li>Monkey immunogenicity study </li></ul></ul>
    11. 11. <ul><li>GMP CAN-BD system installed and manufacturing microparticulate live-virus measles vaccine at the Serum Institute of India in Pune </li></ul>
    12. 12. MYO-INOSITOL BASED FORMULATION STABILITY IN AKTIV-DRY PUFFHALER™ BLISTERS <ul><li>Viral potency stability of the reformulated E-Z live-attenuated measles vaccine microparticles at 5 °C sealed in Aktiv-Dry PuffHaler blisters. </li></ul>
    13. 13. <ul><ul><ul><li>Requirements </li></ul></ul></ul><ul><ul><ul><ul><li>Deliver microparticles to subjects from 9 months to 40 years of age with active dry powder inhaler devices using air pressurization, then depressurization </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>B-D’s Solovent® and Aktiv-Dry’s PuffHaler® DPIs are both designed specifically to disperse the powder- with only muscle power- into the necessary size range to coat the entire respiratory tract </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Micoparticles with Mass Median Aerodynamic Diameter ~3  m, with a high fine particle fraction to encase and preserve virus nanoparticles </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>ACI testing of both the Solovent and PuffHaler has shown dispersive performance similar to an FDA-approved DPI </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Readily deliverable and acceptable in developing countries with minimal caregiver training </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Both systems can be used without line-power or batteries, and no water for reconstitution is required </li></ul></ul></ul></ul></ul>Active Dry Powder Inhaler Specifications
    14. 14. The Devices The PuffHaler (L) and Solovent (R) inhalers configured for delivery through a mask .
    15. 17. SOME ADVANCES TO CELEBRATE <ul><li>Live-attenuated E-Z measles vaccine was reformulated as microparticles that rapidly dissolve in moist respiratory mucosa and become the functional equivalent of the wet-mist measles vaccine successfully administered to more than 3 million children. </li></ul><ul><li>Dried and micronized stabilized live virus measles vaccine without greater loss of viral activity than in the present commercial lyophilization process. </li></ul><ul><li>Pressure release valves or rupturable membranes facilitate dispersion and create stable aerosol clouds comparable to an FDA-approved active DPI. </li></ul><ul><li>Greatly reduced cost and complexity of DPI‘s. </li></ul>
    16. 18. SOME ADVANCES TO CELEBRATE (Continued) <ul><li>Reduced water content of powders to < 1% and increased fine particle fractions (FPF) to ~20% (w/w) FPF < 3.3 µm and ~46% (w/w) FPF < 5.8 µm. </li></ul><ul><li>Myo-inositol stabilized powders pass the WHO test for stability at 37 °C for one week with less than one log loss in viral activity. </li></ul><ul><li>Generation of immune responses in Cotton rats and Rhesus macaques. </li></ul><ul><li>Development of myo-inositol as a stabilizing excipient; no general safety issues observed in two animal models and awaiting data analysis from formal GLP toxicology study of inhaled myo-inositol. </li></ul>