drug delivery partnerships...

Drug Delivery Partnerships 2014

Development of an Active Transdermal System:

Complexity of Parallel Development of Formulation, Device, Patch, and

Manufacturing Systems

Outline o  Type II Diabetes Market 2000 to 2020 o  Exenatide for Type II Diabetes o  Exenatide Line Extension Options (Amylin-Lilly) o  Altea Passport Patch

o  Formulation Development o  Device Development o  Patch Development o  Manufacturing Systems Development

2 DDP 01/27/14 Transdermal System Development

1982-5 1995 2001

Diabetes Market 2005-6 Injectable Insulin / Orals

1922 1950 s 1996 2003

Sulfonylurea Sulfonylurea Sulfonylurea Sulfonylurea Human insulin

Lispro

Glinides Glinides

Glargine

Sulfonylurea Animal insulin

Lispro

Glitazones

Glargine

Aspart

Inhaled insulins GLP-1 analogs DPP – 4

2005

Aspart

Exenatide

Pramlintide Pramlintide

Detemir

Human insulin

Lispro

Human insulin Human insulin Metformin

2006

DDP 01/27/14 Transdermal System Development 3

� �e � � � � � � � � � � � � � n �•  � � � � ? � � � � � �•  � � � ?� � N � � N��

NH

O

NH

O

NH

O

NH

O

NH

O

CH3

NH

O

NH

O

NH

O

NH

O

NH

O

NH

O

SCH3 OHO

OHO OHO

CH3CH3

NH2N

NH2

CH3

CH3CH3

CH3

OHO

NH

O

NH

NH

O

NH

NH2

NH

O

NHO

NH

N

OO

NH

O

OH

NH

O

OH

NH

O

NHO

CH3

N

O

N

O

N

O

NH

O

OH

NH2

CH3

OH

O

O

CH3

O

OHOH

CH3

NH2

O

NH

O

NH

OO

NH

O

NHNH

O

NH

O

NH

O

NH

O

NH

O

NH

O

CH3OH

CH3

CH3

OH

NH2

O NH2OHO

O

NH

O

NHNH2

NHN

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ut � � � � � � � � ��

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oid � � � ��

� w�� ridc� � s� � � � � ��

H His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met

Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn

Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser NH2

10

20

30 39


CH

O

OH OH

OOHO

NHN

Byetta Launched 2005 by Amylin-Lilly Partnership


Diabetes Market 2006 to 2020

2006 2008 2010 2012 2014 2016 2018 2020

QD Oral QD Oral

BID SC Inj QD SC Inj

QW SC Inj

QW SC Inj

Monthly SC Inj

Oral GLP1 INS-GLP1 combos

HbA1C Change

-0.9% -0.7% -1.2% -0.7% -1.5%

Q6Mos or Yrly Implant GLP1

GLP-1s Move to Maximize Continuous Exposure

Liraglutide (Victoza)

Kothare P A et al. J Clin Pharmacol 2008;48:1389-1399

Exenatide (Byetta)

Kim D et al. Dia Care 2007;30:1487-1493

0 4 8 12 16 20 24 280

50100150200250300350400450500550

Last Injection

Active Treatment Period Follow-Up Period

Time (wk)P

lasm

a E

xena

tide

(pg/

mL)

Exenatide MS (Byrureon)


Liraglutide (Victoza)

-0.9%

-1.5%

HbA1C reduction

Competitive Product Profiles (Insulins, GLP-1s)


o  Patient self-administered o  Simple injection device for impaired patients

o  Minimal handling o  No or easy reconstitution o  30 day RT storage for daily pen (warehoused at 5C) o  24 hour storage at RT for weekly or monthly injection (warehoused at 5C)

o  Subcutaneous injection o  Daily injection

o  30 day pen containing cartridge and preserved solution (depends on PK) o  31 guage needle

o  Weekly or monthly o  Disposable auto-injector with pre-filled syringe (no preservative) o  No larger than a 27 guage needle (prefer 30 guage)

Is There A Role for Non-Invasive Exenatide?

•  Non-invasive systems o  Multiple Daily Oral, Nasal, Pulmonary o  Potentially very large market by pushing product into earlier diabetes

continuum (larger patient population, general practitioner)

•  Transdermal System o  Potential for extended exposure from a bandaid-like patch o  ‘Non-invasive’ with continuous exposure efficacy

Transdermal System Development 8 DDP 01/27/14

Pulmonary inhalation product

•  Dry powder formulation •  Spray dry manufacturing process •  Alkermes or Nektar device •  Insulin products near market •  BID or TID administration

Non-Invasive Drug Delivery Systems

Nasal spray product

•  Aqueous solution formulation •  Simple manufacturing process •  Commercially available device •  Nasal peptide products in market •  BID or TID administration


Nasal Exenatide Exposure in Humans

Plasma exenatide peaked at 15-30 min vs. 2 hours with SC

0 60 120 180 240 300 360 420 4800

100

200

300

400 5 ug SC600 ug IN

10 ug SC(previous study)

Time (min)

Plas

ma

Exen

atid

e (p

g/m

L)

Transdermal System Development DDP 01/27/14 10

Exenatide Nasal Conclusions


o  Formulations identified and tested in rodents and primates

o  Two formulations tested in humans o  Human bioavailability low but not primary issue o  Variability in exposure too high at peak o  Byetta like efficacy was achievable with two to three

nasal sprays per day o  Program was halted

Choice of Active Transdermal Program

o  Altea had an attractive transdermal system o  Electroporation system

o  Phase 1 completed with insulin o  Opportunity to develop a 24 hour continuous patch o  Amylin and Lilly signed agreement with Altea o  Altea Passport Patch Development

o  Patch formulation needed for exenatide o  Device design and development needed o  Patch configuration development needed o  Commercial manufacturing systems needed

o  Lilly also had an active collaboration on PTH with Transpharma o  No continuous exposure formulation


Development Risks Identified

o  Exenatide 24 hour patch for once daily administration o  Uncertain until formulation work complete

o  Device and patch under development o  configuration sub-optimal and needed work to make it usable

o  Manufacturing systems and suppliers under-developed o  Patch and device supplier would need to be developed o  Some new materials for pharmaceutical device-drug product

o  Approvability uncertain o  No product precedent approved, but, some in development o  Safety related to immunogenicity (resolvable with phase 2b)

o  Decision was made to proceed despite concerns o  Potential commercial value significant

o  Patch form of GLP-1 delivering Bydureon-like efficacy


Application Process for Altea Passport Patch


Place patch on charged device, expose filament

Apply against skin, Activate current for msec pulse, Remove device leaving patch

Passport Patch

Fold formulation over pores leaving ‘bandaid’

Altea Prototype System


Electronic device: Delivers inductive current to filament

Patch system: Adhesives / layers house disposable filament and formulation / ‘bandaid’

Challenges •  Size of device / components

•  Patch application confusing •  Pealing off multiple layers •  Folding over formulation

onto pores •  Multiple MFG partners and

unique suppliers •  Regulatory risk of approval

Transdermal Program •  Develop exenatide polymer formulation

o  Optimize for continuous 24 hour exposure (designed for maximum efficacy) o  Consider minimally acceptable 2X per day application

•  Test in hairless rats for PK o  Identify formulations and poration conditions o  O ptimize bioavailability and onset and duration of exposure

•  Develop device o  Reduce size and improve handling by patients o  Develop manufacturing process and suppliers

•  Develop patch o  Improve handling and application process o  Develop manufacturing process and suppliers

•  Proof of feasibility o  Test formulation in human PK study


Exenatide Transdermal Development Program


Initial PK Feasibility

Optimize PK to Extend Exposure at Good BA

Monitor process integrity Stability prototypes

Identify Poration Intensity Pore Density, Patch Size

Formulation

Device

Patch

Device

Minimize device size and improve patient handling

Altea

Altea

Ideo

Human PK Study

Monitor process integrity Monitor process integrity Monitor process integrity Monitor process integrity

Optimize Patch Handling

Identify Supply Partners

Cambridge Consulting

3M, others

Identify Supply Partners

Device manufacturer

Parallel Development Inter-related Uncertainties •  Formulation identity – Go No Go for proceeding •  Device and patch configuration – commercial

implications for patient acceptance •  Manufacturing systems and suppliers – implications for

COGs •  Integration challenge – moving parts have an impact on

one another •  Importance of market timing – causes parallel

development of formulation, device, patch


Exenatide Release and PK

0

20

40

60

80

100

0 4 8 12 16 20 24 Time (h)

Exen

atid

e R

elea

sed

(% ±

S.D

.)

0

20

40

60

80

100

0 4 8 12 16 20 24 Time (h)

Exen

atid

e R

elea

sed

(% ±

S.D

.)

0 5000

10000 15000 20000 25000

0 4 8 12 16 20 24 28 Time (h)

Exe

natid

e C

onc.

± S

.E. (

pg/m

l)

Figure 1. (Top) Exenatide released into PBS from extended-release transdermal film over 24 hours. (Bottom) Exenatide pharmacokinetics in the hairless rat after microporation and 24 h application of extended-release transdermal film.

0

10000

20000

30000

40000

50000

60000

70000

0 4 8 12 16 20 24 28 Time (h)

Exe

natid

e C

onc.

± S

.E. (

pg/m

l)

Figure 2. (Top) Exenatide released into PBS from rapid-release transdermal film over 24 hours. (Bottom) Exenatide plasma in the hairless rat after microporation and 24 h application of rapid-release transdermal film.


Rapid Release Slow Release

New and Improved Altea Device and Patch System


Preclinical proof of concept Device and patch optimized with IDEO for ease of handling by 55+ year old diabetic Patch redesigned with Cambridge Consultants for simplified application Manufacturing partners for supply chain identified (device, formulation / patch)

Exenatide Transdermal Conclusions


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References for Transdermal Technologies •  Transdermal drug delivery looks for new frontiers

o  Microneedles and 'active' patches extend the reach of transdermal applications o  Peggy Wright, Pharmaceutical Commerce, February 26, 2013

•  Transdermal, Topical & Subcutaneous Drug Delivery: o  Extending Pipelines & Improving Self-Administration o  Drug Development and Delivery, July/August 2013

•  Transdermal and Intradermal Delivery of Therapeutics: o  Application of Physical Technologies o  Ajay Banga, CRC Press 2011

•  Transdermal drug delivery o  Prausnitz MR, Langer R, Nat Biotechnol. 2008 Nov;26(11):1261-8

•  Painless drug delivery through microneedle-based transdermal patches featuring active infusion o  Roxhed N, Samel B, Nordquist L, Griss P, Stemme G. o  IEEE Trans Biomed Eng. 2008 Mar;55(3):1063-71


Thank You o  Altea Therapeutics

o  Frank Tagliaferi, PhD, VP, R&D, Altea o  Alan Smith, PhD, VP Clinical and Project Management, Altea o  Steve Damon, SVP, Business Development and Marketing o  Michael Hatch, PhD, VP Device Development, Altea

o  Amylin and Lilly o  Viren Sarin, PhD, Fellow, Eli Lilly o  Jim Dishong, Senior Director, Program Management, Eli Lilly o  Andy Eibling and Mark Glick, Project Management, Eli Lilly o  Robert Jennings, PhD, Senior Director, Drug Delivery Technology, Amylin o  Steve Prestrelski, PhD, MBA, VP, Pharm R&D, Amylin

o  Collaborators o  Ideo, 3M team, Cambridge Consultants

o  Mentors and Colleagues o  Solomon Steiner, William Vincek, Alain Baron o  Soumitra Ghosh, Christine Smith, Will Clodfelter, Maria Voerhoef, Jonathon Mow


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