Anthony J. Hickey

RTI International, Research Triangle Park, NC, USA

IPAC-RS/UF Orlando Inhalation Conference

March 18th, 2014

Overview Introduction

Why now? Why us?

Opportunities Generic Product

Metered Dose Inhaler Dry Powder Inhaler

Enhanced Therapy with Novel Systems Nebulizer example

Unexploited Products Tuberculosis Therapy

Conclusion

Overall Trend in Pharmaceutical R and D efficiency, inflation adjusted

*Adjusted for inflation, PDUFA,Prescription Drug User Fee Act

The number of new drugs approved by the FDA per billion US dollars (inflation-adjusted) spent on research and development (R&D) has halved roughly every 9 years since 1950. J.W. Scannel et al, Nature Rev. Drug Disc., 2012, 11:191-200

Headline Chemical and Engineering News. Dec 9th, 2013

Number of entries in Mendelian Inheritance in Man.

Amberger J et al. Nucl. Acids Res. 2009;37:D793-D796

© 2008 The Author(s)

Rare disorder with a molecular basis follow same trend now at approx. 4500 identified

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

550019

8719

8819

8919

90 1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

Disorders with Known Molecular Basis

Source: Online Mendelian Inheritance in Man, Morbid Anatomy of the Human Genome Slide courtesy of Chris Austin, Director,, NCATS

250 with therapy

Important Developments The convergence of related disciplines will have a

major impact on the future of pulmonary drug delivery. New developments in biomarkers, diagnosis and

concepts of disease may define novel treatment approaches.

Rapid, efficient and reproducible product development from target identification to commercialization can be facilitated by: Large existing databases lend themselves to informatics

exploration Quality by design strategies afford statistical process

control.

Chemical and Engineering News. Dec 9th, 2013

A.J. Hickey, ‘Back to the future: Inhaled drug delivery’, J.Pharm Sci.,2013

Why should pharmaceutical aerosol scientists and engineers take responsibility?

Opportunities in the field of therapeutic aerosols and pulmonary drug delivery

Areas can be identified in which advances would bring significant rewards including: generic products; enhanced therapy with novel systems; proven but as yet unexploited products;

Capitalizing on: globalization and emerging markets; regulatory harmonization.

Overview Introduction

Why now? Why us?

Opportunities Generic Products

Metered Dose Inhaler Dry Powder Inhaler

Enhanced Therapy with Novel Systems Nebulizer example

Unexploited Products Tuberculosis Therapy

Conclusion

Comparison of predicted initial drop sizes issued from a pMDI for various propellants

Dunbar and Hickey

Summary of CI particle size data for varying percentages of HFA-134a propellant (mean ± SD, n = 3).

Smyth and Hickey AAPSPST, 2003

FDA Draft Guidance on Albuterol Sulfate – April 2013

Advair/Seretide Diskus

Dispersion Using Powder Specific Energy Input

ga 2ω

=Γ

Proprietary algorithm

Powder characterization

Dispersion

“Vertically vibrated granular materials”

Pak and Behringer,

“Control of powder aerosolization and dispersion (separation) can be achieved by applying vibrational energy to the powder based on qualitative descriptors of the powder interactions”

Crowder and Hickey

Emitted Dose (albuterol blend) variation with lactose size/source

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

Meggle Inhalac 120 DMV Pharmatose 325

ED

(%)

Oriel Product Development

Multi-dose; Single entity or combination

Single-dose

Blister incorporating piezo material

Prototypes Commercializable Device

FDA Draft Guidance on Fluticasone/Salmeterol Powder

September 2013

Overview Introduction

Why now? Why us?

Opportunities Generic Product

Metered Dose Inhaler Dry Powder Inhaler

Enhanced Therapy with Novel Systems Nebulizer example

Unexploited Products Tuberculosis Therapy

Conclusion

Air Jet Nebulizer Acorn Pari

Aerosol

Baffle

Drug Solution

Compressed Air

Vibrating Mesh and Ultrasonic Nebulizers Aeroneb (Aerogen) MicroAir (Omron)

tPAD Nasal Aerosol Delivery System

Experimental Testing Overview: 8 hour runs Background to the experiments (standard 8 hour experiment):

8 hour nebulisation (n = 3)

Nebuliser characterisation pre/post-experiment (to detect drift)

1 minute direct capture (filter capture of emitted dose over 1

minute) 0, 0.5, 1, 2, 4, 6, 8 hours

Spraytec acquisition to determine Dv50 of aerosol emitted at

prongs 0, 0.5, 1, 2, 4, 6, 8 hours

Parion tPAD: Aerosol DV50 Measured Over Continuous 8 Hour Administration

Emitted droplet size at prongs: ~ 2 micron Dv50

Parion tPAD: Aerosol Output of Continuous 8 Hour Administration

NaCl delivery rate: ~ 4 mg NaCl/min

Overview Introduction

Why now? Why us?

Opportunities Generic Product Strategy

Metered Dose Inhaler Dry Powder Inhaler

Enhanced Therapy with Novel Systems Nebulizer example

Unexploited Products Tuberculosis Therapy

Conclusion

Tuberculosis (TB) Global Tuberculosis

• 2 billion people latent tuberculosis infection

• 7-8 million developed active TB every year

• 2 million die of TB annually One of leading causes of death

from an infectious disease • Multi-drug resistant TB • Worsening of TB - HIV

epidemic

Denrell, Organ. Sci., 2003. 14: 228 Reyn et al. Vaccine, 2002. 35: 465

Drug distribution when administered by different routes

Muttil, Wang and Hickey, Pharmaceutical Research , 2009

Shading depicts difference in drug concentration in lungs and systemic circulation

Streptomycin Aerosol Study twelve children with advanced tuberculosis were

treated with aerosols of streptomycin all except three children with atelectatic lesions

responded to therapy by healing the most rapid response occurring in the children with

the greatest amount of infiltration, consolidation and cavitation

This is a remarkably positive outcome for an early study.

Miller JB, Abramson HA, Ratner B 1950. Aerosol streptomycin treatment of advanced pulmonary tuberculosis in

children. Am J Dis Child 80(2):207-237

Capreomycin formulation

Scanning electron micrograph of spray-dried capreomycin dry powder

80% CM-sulfate + 20% L-leucine in 50% ethanol

Niro Mobile Minor spray drier, feed flow rate 80 ml/min, inlet temp 189-192°C

Demonstrated efficacy in guinea pig model of Tuberculosis with 2 mg delivered dose.

bar = 5μm

Fiegel et al, Pharm Res, 2008 Preparation and in vivo evaluation of a dry powder for inhalation of capreomycin

Muttil, Wang and Hickey Pharmaceutical Research, 2009

Reports on Drug Formulation and Assessment

Capreomycin Inhalation Powder: Preclinical PK

20 mg/kg of CMIP delivered by insufflation to guinea pig Lung concentrations of drug after single dose reached 4-100

times the MIC of m.tb in BAL and 40-100 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 also to kill mycobacteria for a longer period (still present at 8 hours, last time point tested)

CMIP Status

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 cGMP compliant global supply chain established for both

CTM and commercial production

Dharmadhkari, et al. , AAC, 2013. Phase I Single dose, dose escalating study of inhaled dry powder capreomycin, anew approach to therapy of drug resistant tuberculosis

When could aerosols be used? As a supplement to standard of care to prevent

transmission As supplement to standard of care (SOC) to enhance

therapy As replacement for one element of the regimen in SOC

for convenience and minimally the same efficacy As replacement for one element of the regimen with

the intention of improving efficacy As combination therapy to supplement or replace

more than one element of the regimen with the intention of improving efficacy

For delivery of new drugs that cannot be delivered by other routes

Conclusions Industry is at a historical turning point. Lung delivery of drugs for the treatment of a variety of

diseases remains an important therapeutic strategy Interest in generic products gives new opportunities

for pharmaceutical product development activity. Nebulizer therapy is a mature strategy but still

presents new opportunities for improved treatment, Infectious diseases remain an important area for new

product development activity that require unique strategies. e.g. High dose delivery

Acknowledgements Former graduate students and post doctoral fellows:

Professor Hugh Smyth, University of Texas at Austin, TX Dr. Timothy Crowder, GSK, RTP, NC Professor Lucila Garcia Contreras, Oklahoma University

Health Sciences Center, OK Professor Pavan Muttil, University of New Mexico, NM

Collaborators Dr. Michiel VanOort, formerly GSK, RTP, NC Professor David Edwards, Harvard University, MA Professor Ed Nardell, Harvard University, MA Professor Bernard Fourie, Pretoria University, SA Dr. Mohan Kabadi, Dash Pharma, NJ. Dr. Robert Gerety, formerly MEND, MA

Acknowledgements Financial Support

Schering Plough (pMDI) GlaxoSmithKline (Powder Behavior) Oriel Therapeutics (DPI) Parion (Nebulizer) National Institute of Allergy and Infectious Disease

(Tuberculosis) Bill and Melinda Gates Foundation (PI: Dr. David

Edwards) (Tuberculosis)