Evaluation of the AERx   System for the Pulmonary Delivery of Recombinant Human Interferon alfa-2b to Healthy Subjects Gu...
Introduction <ul><li>rH Interferon alfa-2b (MW of 19,265 Da) </li></ul><ul><li>Specific activity = 2.6 x 10  8  IU/mg </li...
Advantages of Using AERx for Delivery of Interferon Alfa <ul><ul><ul><li>Non-invasive convenient therapy which should impr...
CMC Goals <ul><li>Systemic Dose </li></ul><ul><li>Blister Contents  </li></ul><ul><li>Fill Volume  </li></ul><ul><li>Targe...
Formulation Composition
Clinical Release Test Results  <ul><li>Content uniformity: 99.9 % LC , 3.5 % RSD </li></ul><ul><li>pH: 7.4 </li></ul><ul><...
Calculated Dose Levels
Clinical Study <ul><li>A Single-Center, Open-Label, Dose Escalation Study to Compare the Safety, Pharmacokinetics, and Pha...
Study Design (1) Clinical Site: Hospital Beaumont, Lausanne, Switzerland Sponsor: Aradigm Corp. Washout period = 10 days
Study Design (2) <ul><li>Blood Samples </li></ul><ul><li>PK: 3 days (0, 30m, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 hrs). </li>...
Study Design (3) <ul><li>Safety </li></ul><ul><li>1.  Methacholine challenge </li></ul><ul><li>  (screening & end of study...
Results - Subjects <ul><li>15 received IFN   -2b SC (38.5 μg/10 MIU)  </li></ul><ul><li>13 received AERx IFN   -2b & com...
Results - Safety Summary <ul><li>1.  Adverse Events </li></ul><ul><li>  41(33 mild, 8 moderate) after SC </li></ul><ul><li...
PK Results  SC: 38   g (10 MIU) Inhaled: 46   g (12 MIU) Inhaled: 146   g (38 MIU) Inhaled: 291   g (76 MIU) Time (hr)
PK Results 35 (41%) 8.8 (21%) 514 (48%) 10 19   (20%) 10   (0%) 302   (38%) 12 3 10 34 ND 64   (37%) 6.8 (19%) 665 (40%) -...
PD Results – β2 microglobulin SC: 38   g (10 MIU) Inhaled: 291   g (76 MIU) Inhaled: 146   g (38 MIU) Inhaled: 46   g ...
PD Results – 2-5AS SC: 38   g (10 MIU) Inhaled: 291   g (76 MIU) Inhaled: 146   g (38 MIU) Inhaled: 46   g (12 MIU)
Relationship Between Inhaled Doses and Corresponding AUC
Conclusions  <ul><li>AERx IFN bioavailability is 10-12 % relative to IFN SC. </li></ul><ul><li>PD response  was found to b...
Acknowledgements <ul><li>Aradigm Corporation, Hayward, CA </li></ul><ul><ul><li>Dr. Stephen Farr, VP Research & Developmen...
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Presentation at the CRS Mtg 2002

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Pulmonary delivery of Recombinant Human Interferon alpha-2b

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Presentation at the CRS Mtg 2002

  1. 1. Evaluation of the AERx  System for the Pulmonary Delivery of Recombinant Human Interferon alfa-2b to Healthy Subjects Gul Balwani, Brooks Boyd, John Whatley, John Thipphawong, Richard Morishige, Jerry Okikawa, Babatunde Otulana, Emmanuel Tamchès, Thierry Buclin, Jerome Biollaz, François Spertini, Igor Gonda CRS Meeting July 23, 2002
  2. 2. Introduction <ul><li>rH Interferon alfa-2b (MW of 19,265 Da) </li></ul><ul><li>Specific activity = 2.6 x 10 8 IU/mg </li></ul><ul><li>Indications </li></ul><ul><ul><li>Hepatitis B and C Infection </li></ul></ul><ul><ul><li>Various cancers (Hairy cell leukemia, Malignant Melanoma, Follicular Lymphoma) </li></ul></ul><ul><li>Therapy </li></ul><ul><ul><li>Chronic parenteral administration for at least six months </li></ul></ul><ul><li>Doses </li></ul><ul><ul><li>Hep. C: 3 MIU 3x/week </li></ul></ul><ul><ul><li>Hep. B: 10 MIU 3x/week or 5 MIU/day </li></ul></ul>
  3. 3. Advantages of Using AERx for Delivery of Interferon Alfa <ul><ul><ul><li>Non-invasive convenient therapy which should improve patient compliance. </li></ul></ul></ul><ul><ul><ul><li>Precise, reliable and efficient dosing similar to subcutaneous injections. </li></ul></ul></ul>
  4. 4. CMC Goals <ul><li>Systemic Dose </li></ul><ul><li>Blister Contents </li></ul><ul><li>Fill Volume </li></ul><ul><li>Target Concentration </li></ul><ul><li>Stability </li></ul><ul><li>3-4 million units/dosage form </li></ul><ul><li>250  g or 65 million units </li></ul><ul><li>45 microliters </li></ul><ul><li>5.56 mg/ml </li></ul><ul><li>> 6 months at 5 o C </li></ul>
  5. 5. Formulation Composition
  6. 6. Clinical Release Test Results <ul><li>Content uniformity: 99.9 % LC , 3.5 % RSD </li></ul><ul><li>pH: 7.4 </li></ul><ul><li>Dimers: Less than limit of detection (0.1%) </li></ul><ul><li>Emitted Dose & EDU: 65.9 %, 4.3 % RSD </li></ul><ul><li>PSD: 2 μm MMAD, 1.35 GSD, 97 % FPF </li></ul><ul><li>Endotoxin: < 0.6 EU/ml </li></ul><ul><li>MLT: < 1 CFU/ml and absence of indicator organisms </li></ul><ul><li>Bioassay: 1452 MIU/ml (65.34 MIU/DF) </li></ul>
  7. 7. Calculated Dose Levels
  8. 8. Clinical Study <ul><li>A Single-Center, Open-Label, Dose Escalation Study to Compare the Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous and Inhaled Interferon  ‑2b [IFN  -2b] in Healthy Volunteers </li></ul>
  9. 9. Study Design (1) Clinical Site: Hospital Beaumont, Lausanne, Switzerland Sponsor: Aradigm Corp. Washout period = 10 days
  10. 10. Study Design (2) <ul><li>Blood Samples </li></ul><ul><li>PK: 3 days (0, 30m, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 hrs). </li></ul><ul><li>PD: 2 weeks (0, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 168 hrs). </li></ul><ul><li>Endpoints </li></ul><ul><li>PK – IFN  2b </li></ul><ul><li>PD – 2’ 5’-AS,  2 microglobulin, neopterin </li></ul>
  11. 11. Study Design (3) <ul><li>Safety </li></ul><ul><li>1. Methacholine challenge </li></ul><ul><li> (screening & end of study) </li></ul><ul><li>2. Pulmonary Function Tests (PFT) </li></ul><ul><li> (0, 30m, 60m, 90m, 3, 6 hrs. & end of study) </li></ul><ul><li>3. Labs: Hematology, biochemistry, urinalysis </li></ul><ul><li> (screening & end of study) </li></ul><ul><li>4. Adverse experiences </li></ul>
  12. 12. Results - Subjects <ul><li>15 received IFN  -2b SC (38.5 μg/10 MIU) </li></ul><ul><li>13 received AERx IFN  -2b & completed Part B </li></ul><ul><li>(2 subjects dropped out after Part A) </li></ul><ul><li>AERx IFN  -2b </li></ul><ul><li> Dose n </li></ul><ul><li> 46 μg/12 MIU 2 </li></ul><ul><li> 146 μg/38 MIU 3 </li></ul><ul><li> 291 μg/76 MIU 8 </li></ul>
  13. 13. Results - Safety Summary <ul><li>1. Adverse Events </li></ul><ul><li> 41(33 mild, 8 moderate) after SC </li></ul><ul><li> 22 (all mild) after AERx </li></ul><ul><li>2. No SAEs </li></ul><ul><li>3. ECG – no clinically relevant changes </li></ul><ul><li>4. Vitals – low grade fever in all groups (< 10 hours) </li></ul><ul><li>5. Lab – small variation in monocyte/lymphocyte count and transaminases (expected after SC) </li></ul>
  14. 14. PK Results SC: 38  g (10 MIU) Inhaled: 46  g (12 MIU) Inhaled: 146  g (38 MIU) Inhaled: 291  g (76 MIU) Time (hr)
  15. 15. PK Results 35 (41%) 8.8 (21%) 514 (48%) 10 19 (20%) 10 (0%) 302 (38%) 12 3 10 34 ND 64 (37%) 6.8 (19%) 665 (40%) - C max (IU/ml) T max (h) AUC 0-inf (h.IU/ml) F rel to SC (%) AERx 76 MIU (%CV) n=8 AERx 38 MIU (%CV) n=3 AERx 12 MIU (%CV) n=1 SC 10 MIU (%CV) n=13 Mean PK Parameter
  16. 16. PD Results – β2 microglobulin SC: 38  g (10 MIU) Inhaled: 291  g (76 MIU) Inhaled: 146  g (38 MIU) Inhaled: 46  g (12 MIU)
  17. 17. PD Results – 2-5AS SC: 38  g (10 MIU) Inhaled: 291  g (76 MIU) Inhaled: 146  g (38 MIU) Inhaled: 46  g (12 MIU)
  18. 18. Relationship Between Inhaled Doses and Corresponding AUC
  19. 19. Conclusions <ul><li>AERx IFN bioavailability is 10-12 % relative to IFN SC. </li></ul><ul><li>PD response was found to be similar for all doses of AERx IFN and 10 MIU of IFN given SC thereby allowing lower dosing by pulmonary route. </li></ul><ul><li>Lower incidence and severity of adverse events by the pulmonary route compared to SC. </li></ul><ul><ul><li>Local skin reaction seen by SC can be eliminated by pulmonary route. </li></ul></ul><ul><li>AERx intersubject variability similar to SC. </li></ul>
  20. 20. Acknowledgements <ul><li>Aradigm Corporation, Hayward, CA </li></ul><ul><ul><li>Dr. Stephen Farr, VP Research & Development </li></ul></ul><ul><ul><li>Beth Mallory </li></ul></ul><ul><ul><li>Evelyn Gabatan </li></ul></ul><ul><ul><li>Christine Inose </li></ul></ul><ul><ul><li>Lawrence Linn </li></ul></ul><ul><li>Division of Clinical Pharmacology, CHUV, Lausanne, Switzerland </li></ul><ul><li>Division of Immunology and Allergy, CHUV, Lausanne, Switzerland </li></ul><ul><li>Triskel Integrated Services, Geneva, Switzerland </li></ul>

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