NOVEL APPROACHES TO ENHANCE THE PULMONARY DELIVERY OF BIOTHERAPEUTICS

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NOVEL APPROACHES TO ENHANCE THE PULMONARY
DELIVERY OF BIOTHERAPEUTICS

• William Zimlich

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Why Pulmonary Drug Delivery?
Alveolar Region Area 140 m² 500 Million
Alveoli Distance to blood 1 µm VAir 2 - 6
L VBlood 100 - 200 mL
Source Peter Gehr, Bern
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Why Pulmonary Drug Delivery?
Alveolar Region Area 140 m² 500 Million
Alveoli Distance to blood 1 µm VAir 2 - 6
L VBlood 100 - 200 mL
Source Peter Gehr, Bern
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The Respiratory System
Source Peter Gehr, Bern
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Agenda

• Parameters determining Regional Lung Deposition
• Formulation and Device Strategies
• Examples ?-1 Antitrypsin, LMW Heparin
• Activaeros Project Approach

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Parameters
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Total Deposition 3µm Aerosol Particles
Spontaneous- Breathing

• 18 Patients
• Inhalation with own commercial Device
• Measurement of Flow and Volume

1.0
0.8
Total-Deposition
0.6
Peripheral-Deposition
0.4
0.2
0.0
Total Deposition Lung Extrathoracic
Deposition
Brand, P. et. al. J Pharm Sci 6/2000
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Total Deposition and Inhaled Volume
1,0
0,9
0,8
0,7
0,6
Total Deposition
0,5
0,4
0,3
0,2
0,1
0
0
500
1000
1500
2000
Inhaled Volume ml
Brand, P. et. al. J Pharm Sci 6/2000
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Parameters
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Peripheral Lung Deposition

• Model Calculation
• Breathing pattern of the 18 patients from Study
  Brand
• Particle size of recently approved Insulin Powder
  (2 µm)
• Lung Deposition Modelling according ICRP lung
  deposition model

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Peripheral Lung Deposition

• Results
• DEal 26.8 9.6
• DEal 16.1 5.8Relative to filled dose
• Worst patientDEal 9.6
• Best patientDEal 45.3
• Under optimal breathing conditions (slow and
  deep) DEal 69.6

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Mouth / Oropharyngeal Deposition
Particle Size Inhalation Flow Rate Impaction
parameter d²Q
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Drug Targeting to the Lung Periphery

• Small particles (2 - 5 µm)
• Slow Flow rate (200 400 ml/sec)
• Deep inhalation (aerosol) volume(1000 ml 2000
  ml)

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Agenda

• Parameters determining regional lung deposition
• Formulation and Device Strategies
• Examples ?-1 Antitrypsin, LMW Heparin
• Activeros Project Approach

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Formulation and Device Strategies

• Dry Powder
• Liquid Aerosol

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Formulation and Device Strategies
?
?
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Dry Powder
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Dry Powder
Van der Wals ForceF 1 / d
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Dry Powder

• Issue
• Patient has to apply the dispersion energy
• The faster the inhalation, the higher the small
  particle fraction
• The faster the inhalation, the higher the throat
  deposition
• Result
• Limited and small deep lung deposition
• High variability

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Dry Powder for Protein delivery

• Nektars solution
• - Patients breathing and particle production is
  separated.

• Alkermes solution
• - Large porous particles to reduce van der Wals
  Force

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Liquids

• With standard delivery technology
• Low lung dose
• Low drug load per particle
• Long treatment time
• Liquids are used regularly for feasibility and
  first clinical tests
• Reason Easy to formulate a protein
  solution/suspension
• Inexpensive and fast development

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Device Efficiency of conventional Nebulizers
Drug Losses with Nebulizers
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AKITA Inhalation Technology

• Patient-Individual Breathing Pattern ?ensures
  highest deposited dose by controlling inspiration
• Breath-acutated ? no aerosol production during
  exhalation phase-less drug use
• Smart Card Technology ? best Breathing Pattern
  for each Drug?Compliance documentation with
  Read-Write ability

AKITA Inhalation System with innovative APIX
nebulizer
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Device Efficiency for AKITA² with APIX vibrating
membrane nebulizer
95
100
85
80
95
95
81
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Emitted
Inhaled
Lung
Filled Dose
Periphery
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AKITA² Protein Delivery Efficiency
Aerosol Output 0.9 -1.0 ml/min 10 Protein in
Solution/Suspension 80 Lung Deposition ? 300
mg (3ml) filled in device ? 240 mg lung dose
? 180 mg in the lung periphery ? ? 5 - 7 min
total treatment time
AKITA Inhalation System with innovative APIX
nebulizer
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Optimized Lung Delivery with AKITATM
SPECT gamma camera image
Intrathoracic Deposition (rel. emitted)
97 Extrathoracic Deposition (rel emitted)
2 Exhaled lt1
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Agenda

• Parameters determining regional lung deposition
• Formulation and Device Strategies
• Examples ?-1 Antitrypsin, LMW Heparin
• Activeros Project Approach

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Inhalation Therapy with A1-PI 1999

• Kropp et al. 2002 Prestudy from 1999 with
  commercial inhalation systems 4 - 10
  peripheral deposition. To get 50 mg in the lung
  periphery up to 1 g A1-PI was the required
  nebulizer fill volume.
• Result Treatment time was very high (60 - 100
  minutes)

Partnership with
formerly
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Alpha 1 Antitrypsin Deposition in COPD Patients

• 7 Patients (FEV1 40, between 25.9 70 years
  old)
• Goal 50 mg in Lung Periphery
• DEIntrathoracic 83.3 /- 1.6 (emitted)
• DEPeriphery 58.7 /- 1.6 (emitted)
• Time to deliver 50 mg to Lung Periphery 7.1 min
  /- 2.4 min

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LMW Heparin InhalationPharmacokinetic inhaled
vs. sc

• Feasibility Study (Dosefinding and
  Pharmacokinetic)
• Low Molecular Heparin sc formulation.
• Application in healthy individuals
• Goal was an Anti Xa activity in the blood gt0.2
  U/ml.
• LMW Heparin Certoparin Mono-EmbolexNM (Novartis)

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LMW Heparin Inhalation
Mean 5.7 CV 28 Range 1.9 9.3
Mean 9.4 CV 13 Range 6.8 12.7
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Conclusion

• Particle size and Breathing Pattern has to be
  considered
• Regional Drug targeting is now possible

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Future

• New innovative drugs will be delivered with new
  innovative and efficient devices. We dont want
  to waste an expensive or rare drug.
• Dose and target region should be predetermined by
  the device.
• PK and BA will be much better controlled and less
  variable.
• High amounts of drug can be deposited (up to 500
  mg).

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ACTIVAEROS EXPERTISE

• Pneumococcal Vaccine 400,000
• Alpha 1 Antitrypsin
  52,000
• Heparin
  3,000 57,000
• IL-2 15,600
• Antisense Oligonucleotides (ODN)
  13,200
• Non-disclosed Protein 12,000
• Insulin 6,000
• LMW Heparin 5,000
• Antibiotics 1,250
• Glutathione 300

Substance
Molecular Weight (Da)
It is possible to deliver proteins, peptides and
vaccines efficiently with the AKITA technology.
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COMPARISON OF DRUG COST IN CLINICAL PROJECTS

• Drug Cost 150 / g
• Target Lung Dose 100 mg per Day, per Patient
• Clinical Program 500 Patients, 1 Year

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Activaeros Project ApproachProve your
Compounds efficacy
Pre-Clinical
Phase I Phase II
Phase III
Drug Characterization Output Particle
Size Formulation
Studies with AKITA and selected Nebulizer
Drug Profiling Device Decision
Nebulizer Selection for Clincal Phase
Studies with the final Device
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ACTIVAERO BUSINESS PROFILE

• Technology/IP Out-Licensing
• Contract Development
• Logistics Services for Clinical Trials
• Aerosol Consulting
• Various Technologies and Patents in the field of
  Inhalation Technology
• Privately held

Gemünden/Wohra Headquarters Logistics
Munich-Gauting Device Development
Activaero America, Inc. Dublin, Ohio
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STRATEGIC PARTNERSHIPS

• Octoplus, NetherlandsContract Pharmaceutical
  Development, Clinical Trial Material
  Manufacturing
• Asklepios Clinics, Munich80 clinics and 15.000
  beds. Leading German center for the treatment of
  respiratory tract, lung and chest diseases,
  including oncology.
• Inamed Research, MunichLeading aerosol CRO,
  specializing in deposition clearance studies,
  device and aerosol characterizations.

ASKLEPIOS CLINICS MUNICH-GAUTING
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Activaero

• End of Presentation Thank You!

www.activaero.com