increased bioavailability via multiple routes

2013 Aegis Therapeutics LLC 2013 Aegis Therapeutics, LLC

16870 W. Bernardo Drive, Suite 390 San Diego, CA 92127 Phone: 858-618-1400 Facsimile: 858-618-1441 www.aegisthera.com

Novel Formulations for Non-Invasive Delivery of Peptides

and Small molecule Drugs

2013 Aegis Therapeutics LLC

Intravail/ProTek Technologies - Based on

Alkylsaccharides (sugar + alkyl chain - various linkages)

2

Typical linkages:

glycosidic

thioglycosidic

amide linkage

ureide

ester

Typical oligosaccharides: maltose maltotriose maltotetraose sucrose trehalose sucrose trehalulose turanose maltulose leucrose palatinose isomaltose maltitol

Typical alkyl chain lengths:

10-18 carbons

O

O

O

CH2OH

OH

OH

OH

OH

OH

O

CH2OH

(CH2)n

CH3

n

O

O

O

OH

OH

OH OH

OH

CH2OH

COCH2

O

(CH2)nH3C

HOCH2n


General Intravail /ProTek Characteristics

Safe, odorless, tasteless, non-toxic, non-mutagenic, and non-irritating

Synthetic pure chemical entities prepared under GMP

Provides unmatched bioavailability - comparable to subcutaneous injection, via the intranasal and other mucosal membrane administration routes (up to ~30KDa MW)

Allows controlled transient mucosal permeation by both paracellular (tight-junction) and transcellular routes

Soluble in water or oils compatible with routine liquid formulation and dispensing processes for ease of scale-up and production

Shown to be highly effective (orally) for BCS Class III/IV small peptides and small molecules

Shown to greatly increase oral bioavailability in tablets, oils (i.e., soft-gel compatible), and flash-dissolve oral (Zydis-like) formats

3


Multiple Modes of Transmucosal Delivery

for Macromolecular Drugs

4

Nasal

Oral (gastrointestinal)

Oral cavity (buccal, sublingual)

Flash dissolve Edible films

Metered spray pumps

Gelcaps Tablets


Diazepam 0.28kDa B/A=96%

OB-3 ~1kDa B/A=363%

Intravail Provides Intranasal

Bioavailability Comparable to Injection

5


Paracellular Absorption: Reduction in TEER* (Normal Human Tracheal/Bronchial Epithelial Cell Derived Mucociliary Tissue)

6

0

20

40

60

80

100

120

Typ

e A

, 0.1

%

Typ

e A

, 0.2

%

Typ

e B

, 0.1

%

Typ

e B

, 0.2

%

Typ

e C

, 0.1

%

Typ

e C

, 0.2

%

Non

-Int

r.X ,

0.1

%

Non

-Int

r.X, 0

.2%

Non

-Int

r.Y, 0

.1%

Non

-Int

r.Y, 0

.2%

PBS

% T

EE

R D

ec

re

as

e

Non-Intravail

Alkylsaccharides

Intravail Excipients

*1h. exposure

C14M C12M C12S C8G C7G

PBS 0.1% 0.2% 0.1% 0.2% 0.1% 0.2% 0.1% 0.2% 0.1% 0.2%

*Adapted from: Chen,S.-C., Eiting,K.T.,Li, A.A.W., Lamharzi, N. and Quay, S.C. (2005), 45th American Society for Cell Biology Meeting, December 10-14, 2005, San Francisco (late abstract) Peptide Drug Permeation Enhancement By Select Classes of Lipids

Key: MMaltoside, S Sucrose ester, G Glucoside


Intravail Interacts With Nasal Mucosa Not Drug

7

Calcitonin

0 20 40 60 80 100120

0

10

20

30

40

50

Se

rum

So

ma

tro

pin

(n

g/m

L)

Time (minutes)

Somatropin

0 40 80 1200

50

100

150

200

250

300

350

0 minutes

60 minutes

120 minutes

Pla

sm

a C

alc

ito

nin

(p

g/m

L)

Time (minutes)

Rat Model Data

Time between Intravail & API

Arnold, Fyrberg, Meezan, Pillion (2010) J Pharm Sci. 99(4):1912-20.


3-Way Human Crossover Study Intravail Increases Calcitonin Bioavailability >5-fold

0

10

20

30

40

50

60

0

0.2

5

0.5

0.7

5 1

1.2

5

1.5

1.7

5 2

2.2

5

2.5

2.7

5 3

3.2

5

3.5

3.7

5 4

Time (hrs)

Calc

ito

nin

ng

/mL

Injection Nasal-No Intravail Nasal + Intravail

Average Intravail bioavailability ~37%

No Intravail control ~ 6.6%

Pla

sm

a C

on

cen

tra

tio

n

8

Mean Plasma Drug Concentration vs. S.C. Injection in 10 Healthy Females

Maggio, Meezan, Ghambeer, and Pillion (2010) Drug Del Tech. 2010;10:5863.


Multiple Modes of Transmucosal Delivery

for Macromolecular Drugs

9

Nasal

Oral (gastrointestinal)

Oral cavity (buccal, sublingual)

Flash dissolve Edible films

Metered spray pumps

Gelcaps Tablets


[D-Leu-4]OB3 First Orally Active Weight Loss & Anti-Diabetic Peptide

Patented (7-mer peptide) leptin derived fragment

Reduces weight gain & food intake in mouse obesity models

Normalizes blood glucose in mouse diabetes/obesity models

Increases osteocalcin may prevent/reverse bone loss associated with weight loss & osteoporosis

High oral bioavailability (56% w. Intravail)

High nasal bioavailability (100% w. Intravail) for rapid onset

Multiple issued patents*

* Dr. Patricia Grasso et al., Albany Medical College

10


Time

0 20 40 60 80 100 120

Se

ru

m P

ep

tid

e C

on

c.

(ng

/mL

)

0

2000

4000

6000

8000

10000

Oral Delivery of [D-leu-4]OB3 Anti-Obesity Peptide

in Rodents (~1kD MW)

552,710 ng*min/mL

137,585 ng/mL/min

With Intravail

No Intravail

Lee et al. Regulatory Peptides 160 (2010) 129132

11


Oral OB-3 Administration - Body Weight

Gain and Serum Glucose in ob/ob Mice

12

Novakovic, Grasso, et al. Diabetes Obes Metab. (2010) 12(6):532-9.


0

1

2

3

4

5

6

7

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190

Ti me ( mi nut e s)

Octr

eo

tid

e a

ceta

te (

ng

/ml)

A

Uptake of 30ug Octreotide

in PBS s.c.

0

10

20

30

40

50

60

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190

Time (minutes)

Octr

eo

tid

e a

ceta

te (

ng

/ml)

1

21

B

AUC (ng/ml/min)

AUC1 353.03

AUC2 901.04

AUC (ng/ml/min) 311.63

1254.08

Oral Bioavailability with Intravail

Exceeds That of S.C. Injected Octreotide

Oral Uptake of 30ug Octreotide

in Intravail

Maggio & Grasso Regulatory Peptides 167 (2011) 233238

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Human Clinical Data

Nasal sumatriptan Six human trials to date Tmax reduced to 8 min. from 60-120 min. for Imitrex Therapeutic drug levels equivalent to Imitrex achieved in 2-3 min.. (i.e., 20X 30X

faster) Licensee a Top-10 multinational generics company

Nasal diazepam Nasal spray designed as an alternative to the Diastat rectal gel Bioequivalent to Diastat 96% absolute bioavailability Licensee Neurelis Inc. (San Diego)

Nasal PTH 1-34 (~4000 Da) Nasal spray Three phase 1 trials completed: single dose/7 day b.i.d, and 6 weeks b.i.d. Approximately 30% nasal bioavailability compared to Forteo injection

Oral endocrine peptide (~1000 Da)

Formatted as a 3 sec. flash dissolve (Zydis) wafer 14 patient feasibility study completed


Intravail Summary

Unmatched intranasal bioavailability (up to ~30kD)

Unmatched oral bioavailability for certain peptides

Rapid onset of action

Greater patient convenience and compliance

Elimination of needle stick injuries/infections

Avoidance of gastric hydrolysis & first pass effect

Compatible with off-the-shelf metered nasal spray

devices & oral tablet/capsule/flash-dissolve formats

15


16870 West Bernardo Drive, Suite 390 San Diego, CA 92127 Phone: 858-618-1400

Facsimile: 858-618-1441 www.aegisthera.com

Edward T. Maggio, Ph.D., Chief Executive Officer

[email protected]

Ralph R. Barry, Chief Business Officer & CFO

[email protected]

Contact Information:

increased bioavailability via multiple routes

Documents

oral bioavailability

type c

type b

calcitonin bioavailability

intravail api arnold

typical linkages

oral zydis

kda ba