Microneedle Patch Delivery System

Microneedle Patch Delivery System
Development:
Where Are We Now?
Peter Daddona, PhD
CSO
May 19, 2010
1

Zosano Pharma’s
ZP-Microneedle Patch Technology
• Most advanced microneedle patch delivery technology
• Technology (formerly MACROFLUX) developed over 8 years
at ALZA Corp (the world’s leading developer of commercial
drug delivery products)
• Spun out as a private company from ALZA/J&J in 2006
• Lead program- ZP-PTH patch (parathyroid hormone 1-34,
teriparatide) for daily treatment of severe osteoporosis
• ZP-PTH product entering Phase 3 clinical development
2

Zosano’s Drug Coated Microneedle Patch-
A Simple and Effective Delivery System
Drug-coated patch
(size of a US quarter)
50X Magnified
drug-coated
microprojections
Tip-
Drug
Coated
Patch
Dead Skin
(10-15 µm)
Drug
Epidermis
(50-150 µm)
Dermis
Capillaries
Nerve
endings
3

ZP-Drug Coated Microneedles Deliver
Drug Into the Superficial Skin Layers
ZP-Drug Coated
Microneedle
Patch
(190 µm long)
Dead skin (10-15 µm)
Cellular epidermis (50-150 µm)
Dermis (750-1500 µm)
Hypodermic Needle:
28 gauge has outside
diameter = 362 µm.
and length =5000
µm.
General needle
ranges: 26-31 gauge;
length 5mm- 13mm
Subcutaneous fat
4

ZP-Patch and Applicator System: Developed for
Controlled & Convenient Patient Self-Administration
Drug-coated
Zosano Patch
Patch
Applicator
Class 1 Device,
Purpose built
Patch
Ring
Combination
Drug Product
Zosano
Patch in
Applicator:
Patch
Applied
Press to Apply
Patch wear time
30 minutes
5

ZP-Transdermal Drug-Coated Microneedle
Delivery System: Value Statement
• Ideal solution for delivery of peptides, proteins and hydrophilic drugs
• Traditional transdermal products best suited for hydrophobic drugs
• Single step therapeutic drug delivery
• High patient acceptance, user friendly, and travel friendly
• Cost effective, alternative to outpatient injection
Additional benefits:
• Ready-to-use drug-coated patch (unit dose) with reusable low cost
applicator
• No product refrigeration required
• Short patch wear time (

ZP-Microneedle Patch Ring Components
Are All Biocompatible
Adhesive Patch- Commercial Grade
Microneedle Array- Titanium, Grade 2
Inner Ring –USP Class VI polycarbonate
Outer Ring - USP Class VI polycarbonate and
moldable desiccant
7

ZP-Titanium Microneedle Arrays Easily
Manufactured With Different Sizes and Geometries
• Flexible Process :autocad design, photomask and chemical etching
•Advancing to reel to reel system
• Microprojection array design can be optimized for drug
loading by changing geometry of coating area
Designs with
Increased Tip Area
Microneedle Array Design
ZP-PTH
40 µg
Higher Dose Products
Up to 3mg
8

Automated Drug Coating Process:
Allows Adjustable and Uniform Dose Loading
• Multiple Dips Increases Coated Amount per microneedle –
• Automated process taken from the printing industry
Microprojection Patch
Microprojection Patch
Coated
Microprojection
Liquid Drug Formulation
Liquid Drug
Formulation
Rotating Drum
1 coat 3 coats 5 coats
Ref: Ameri,M. et al.,
Pharm Res. 27,303,2009
5 µg PTH
30 µg PTH
60 µg PTH
9

ZP-Patch Dose Can Also Be Controlled By
Size Of Drug-Coated Microneedle Array Area
• Increase Coated Array Area/Patch
• Method used in all transdermal products- Increase drug coated
area and increase dose.
• No formulation or coating process change
1cm 2 10
2cm 2
3cm 2

ZP- Patch Packaging Designed to Maintain
Product Stability at Ambient Temperature
• Heat-sealed foil pouch or
cup provides moisture and
oxygen barrier for product
stability
• Nitrogen purge
• Desiccant
Foil Pouch Package
Cup Package
11

Lead Phase 3 Program: ZP-PTH Microneedle Patch
for Treatment of Severe Osteoporosis
• Treatment of severe osteoporosis is growing market
• Parathyroid hormone, PTH (1-34), Forteo® is the only US
approved anabolic agent (bone building) for severe
osteoporosis
• Forteo® requires a once daily injection and requires product
refrigeration.
• Daily, short PTH plasma pulse is critical to the anabolic
mechanism of action
• ZP-PTH patch being developed to provide a:
• Rapid pulse PK profile to drive the PTH anabolic effect
• Patient-friend patch dosage (no injection, RT storage)
12

Lead Product ZP-PTH Microneedle Patch
Developed With Excellent Storage Stability
PTH patch shows better stability than Forteo at 25°C and even at 2-8°C;
>24 months RT shelf-life can be expected
Phase 2 Zosano PTH 40 µg vs. Forteo
100
PTH %Purity
95
90
85
Forteo RT
ZP-PTH
2yr RT
Stable
Forteo (2-8 o C)
80
0 5 10 15 20 25 30 35
Storage Time (Months)
Ref: Ameri, M., et al. Pharm Res, 26, 2454, 2009
13

Phase 1: ZP-PTH Patch Delivers A Shorter
PTH Plasma Pulse Than Forteo ® SC Injection
PTH 1-34 (pg/mL) +/- SE
125
100
75
50
25
ZP PTH 30 µg Thigh
ZP PTH 30 µg Upper Arm
ZP PTH 30 µg Abdomen
FORTEO Inj 20µg Thigh
30 min patch wear time
T max =3 X faster
t ½ =2 X shorter
0
0 0.08 0.17 0.25 0.5 1 2 3 4 8
Time (h)
Ref: Daddona, P., et al., Pharm Res, (in press), 2010
14

PTH 1-34 (pg/mL)( +/- SE)
Phase 1: ZP-PTH Delivery Is
Rapid and Complete In 30 minutes
300
200
100
0
Patch delivery is complete within 30min
Patch applied to abdomen
ZP PTH 40 µg 0.5 h
ZP PTH 40 µg 2 h
0 0.08 0.17 0.25 0.50 0.75 1 2 3 4
Time (h)

Study Design
Phase 2: ZP–PTH
Dose Response Study
• 6 month multi-national study in165 post menopausal women with
established osteoporosis
• Daily dose, patient self administered
• ZP-PTH patch at 3 doses (20 µg, 30 µg and 40 µg)
• ZP-Placebo patch as control
• Forteo ® injection product (20 µg) as active comparator
• Measured PTH anabolic effect -increase in bone mineral density
• Lumbar Spine and Total Hip
• Safety Assessments- systemic and topical
Ref: Cosman, F., et al. J.Clin. Endocrin Metab, 95,151,2010
16

Phase 2: ZP-PTH Provides Rapid Pulse
and Dose Proportional Delivery
PK Over Time
Mean AUC by Dose
PTH Concentration (pg/ml)
0 20 40 60 80 100 120
0 1 2 3 4
Hours
• Patch delivers faster Tmax, higher Cmax, shorter half life than Forteo injection
• Excellent dose proportional delivery
• High drug bioavailability at 40%
AUC (pg hr/ml)
50 100 150 200 250
Forteo ZP-20 ZP-30 ZP-40
17

Phase 2: ZP-PTH Patch Is Similar To Forteo ® in
Increasing Lumbar Spine Bone Density
% Change from Baseline (Mean+/-SEM)
6
5
4
3
2
1
0
-1
Placebo
-0.33
ZP-30
ZP-20
ZP-40
4.97
Forteo
3.55
3.47
2.96
All active treatments vs Placebo p=

Phase 2: ZP-PTH Produced An Early and
Significant Increase in Total HIP Bone
1.5
Density Over Forteo ®
1.331
*
ZP-40
Total Hip BMD (%)
1
0.5
0
-0.5
Placebo
ZP-20
0.138
ZP-30
0.553
Forteo
0.094
*vs ZP-Placebo 95% CI = 0.595 – 2.755
* vs Forteo 95% CI = 0.077 – 2.386
-0.634
-1
ZP-Placebo ZP-PTH 20 ZP-PTH 30 ZP-PTH 40 Forteo
19

ZP-PTH Phase 2 Outcomes
• ZP-PTH system performance validated with consistent
dose delivery response; variability similar or better
than SC injection
• Efficacy (increased bone mineral density) is similar to
Forteo at Lumbar Spine but improved at Hip
• Systemic safety profile no different than commercial
product
• Topical effects minimal;
• No skin infections
• No anti PTH antibody formation
• Study Validates Technology Platform
20

Regulatory Implications For ZP-PTH
Drug Device Combo Product
• Single NDA can cover both the ZP-PTH transdermal patch
and the purpose designed applicator
• Based on Primary Mode of Action (PTH absorbed
systemically to provide anabolic bone building), jurisdiction
for NDA review by CDER with consult by CDRH (Device)
reviewers
• Compliance with Drug GMPS’s for the manufacture of the
ZP-PTH Patch
• Compliance with Device Quality System Regulations (21
CFR Part 820) for the applicator and Critical Device
Elements of the ZP-PTH System (i.e. microneedle array)
21

Regulatory Implications For ZP-PTH
Drug Device Combo Product
• NDA filing to follow 505 (b) (2) regulatory pathway
• Relies on previous finding of safety and efficacy of
marketed reference product
• Required to show non-inferiority to Forteo for bone
mineral density response
• Do not need to match PK profile
• Do not need a bone fracture reduction study
• A single 12-month Phase 3 trial with 6-month safety
extension is sufficient for registration for
postmenopausal women with severe osteoporosis
22

Summary
• ZP- Transdermal microneedle patch technology is a
novel combination product
• Drug-coated microneedle patch and applicator system
• First transdermal microneedle patch product to
reach Phase 3
• Clinically validated in Phase 2
• FDA confirmed Phase 3 product specifications and
505(b)(2) regulatory pathway
• Advancing ZP- PTH to Phase 3 clinical testing
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