Monica Rosa Ph.D. Sigmoid Pharma

SmPill

Innovative Solution for Oral Delivery

STRICTLY PRIVATE & CONFIDENTIAL

© Sigmoid Pharma Limited 2012

Not to be circulated or copied without prior approval

“Innovative Delivery, Delivering Innovation”www.sigmoidpharma.com

Mónica Rosa, Ph.D.Bio Pharma Summit, October 31st 2012, Convention Centre Dublin

Agenda

� Introduction to Sigmoid Pharma

� SmPill™ Overview SmPill™ Overview

� SmPill™ Poorly Soluble Drugs Oral Delivery

� SmPill™ Peptide Oral Delivery

� SmPill™ Vaccines Oral Delivery� SmPill™ Vaccines Oral Delivery

� Conclusion

STRICTLY PRIVATE & CONFIDENTIAL 1

Sigmoid Pharma

Leveraging Drug Delivery for Product Development

IRL

� Private, development stage, speciality Pharma company

� Headquarters, development and clinical manufacturing operations in Dublin

� Founded in 2003 by Dr. Ivan Coulter with ~20 Employees. Over €13 million

funding to date

� Core expertise in SmPillTM has broad applicability� Core expertise in SmPillTM has broad applicability

� Lead product CyColTM has completed Phase IIa clinical trial

• Colon-targeted, solubilized cyclosporine

• Proof-of-principle achieved in ulcerative colitis

� Extensive network of clinical, academic and industry collaborations

� Robust and growing patent portfolio2


Promising Product and Platform Opportunities

Program Indication Preclinical Phase I Phase II Phase III Marketed

CyColTM Ulcerative

PK CyCol Ulcerative

Colitis

CyCronTM Crohn’s

Disease

AlloCol™ GI-GvHD

CyLow™ Immuno-

suppression

SmPill™ Broadly applicable across all BCS classes – most advanced product in late

Cy

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spo

rin

eo

pp

ort

un

ity

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sist

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ds

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ibil

ity

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lea

se&

PK

pla

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rm

ma

ny

3

SmPill™ Broadly applicable across all BCS classes – most advanced product in late

phase II

Oral

vaccine

Preclinical evidence of effect in gastrointestinal enteric pathogens

Oral

peptide

Compelling preclinical data with model peptide, which provides support for

applications to other novel peptides

* US FDA Orphan Designations granted in 2009

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� SmPill™ Overview

Agenda

� SmPill™ Overview



� SmPill™ Vaccines Oral Delivery



� Conclusion

Industry Challenges in Drug Delivery

Solubility

40% Drugs Poor Solubility

Permeability

50% Drugs Low Permeability

Drug not in free molecular form

Require high dose

Increase side effect risk

Limits clinical development

Drug not absorbed

Require high dose

Require i.v.



Stability

30% Drugs Low Stability

Release Profile

Effective targeting

5STRICTLY PRIVATE & CONFIDENTIAL

30% Drugs Low Stability

Drug not in active form

Degradation in GI tract

Precipitation in solution

Processing stability

Requires cold-chain


Target to drug receptor

Target for optimal absorption site

Target to treat GI disease

Require high dose

Systemic, not local



Industry Approaches Focus on Enhancing Dissolution

Traditional approaches use top-down (e.g. particle size reduction) or bottom-up (e.g.

controlled crystallization) techniques to increase surface area and enhance

dissolution rate. Dissolution/Solubilisation must occur in gastro-intestine from the

dosage form.dosage form.

Crystalline

solid

Particle size reduction = increased surface area = increased dissolution rate in liquid

Top-down


Crystalline or

amorphous

solid

Particle size control= increased surface area = increased dissolution rate in liquid

Bottom-up

SmPill™ - A Solution Not Dissolution

SmPill™ pre-solubilises the drug into a solution, encapsulates the liquid solution in a solid

oral dosage form and may target delivery of the drug solution within the gastro-intestine

Crystalline or

amorphous

API

Aqueous –based process;

functional excipients added

Drug in solution Drug solubilised in

targeted mini-spheres

Drug solubilised in

mini-spheres in dosage

form


SmPill™ Integrated TechnologyAddresses Solubility, Permeability, Stability and Release Collectively

SmPill™ Mini-Spheres Produced Via a Gentle, Modified,

Melt-Extrusion-like Process

NozzleHeated Pumping System

• API Solution uses

GRAS excipients

• Tailored to unique

attributes of drug

&target formulation

• Screening may use • Cooling solution is

API Solution Cooling

• Screening may use

< 0.5 g API• Cooling solution is

gentle and non-toxic

• Manufacturing and

processing technology

compatible with

and/or uses

conventional systems

X-ray Tomography

• Uniform spherical shape

• Smooth surface


API Solution Cooling

Solution

SmPill™ Process is Highly Scalable and Cost-Comparable to Other

Multiparticulate Dosage Forms

• Smooth surface

• Homogenous interior dispersion

SmPill™:

Encapsulated Drug Solution in Solid Oral Dosage Form

Coating protects inner SmPill™

mini-sphere from gastro -intestinal

contents including stomach acid

and digestive enzymes and permits

targeting to specific regions of GI

Different populations of

coated or un-coated

SmPill™ mini-spheres can

be combined in one hard

gelatine capsule. Suitable

for drug combinations Drug maintained in its fully Solubilised / active


SmPill™ Delivers Liquid Drug in an Oral Solid Dosage form which Permits

GI Targeting of the Drug in a Stable and Molecularly Active Form

for drug combinations

and/or modular release

profiles

Drug maintained in its fully Solubilised / active

form for optimal pharmacological activity at target site.

Solubilised state maintained throughout gastrointestinal

transit and release through outer coating

Agenda


� SmPill™ Overview � SmPill™ Overview






� Conclusion

Cyclosporine Formulated SmPill

Drug Properties:• Low Solubility (< 5µM in water)

•High Permeability (small Intestine)

•Cyclic Peptide (11 aa)

•Hepatic Metabolism•Hepatic Metabolism

•Intestine Epithelial Metabolism

•Indicated for treatment of transplant

rejection, rheumatoid arthritis, severe

psoriasis

•Used off-label to treat severe UC (i.v.) and

mild/moderate UC (suppositories/enemas)

Objectives:


Objectives:• Cyclosporine formulated with SmPill

for oral delivery

•Improve solubility

•Reduce toxicity

•Achieve appropriate pharmacokinetics

Model Drug:

Cyclosporine

Cyclosporine Formulated SmPill versus Neoral

600

800M

ea

n W

ho

le B

loo

d C

on

cen

tra

tio

n

(ng

/ml) Neoral®

SmPill™ CyA Fast Release

“Fit-For-Purpose” Bioavailability

Human PK

0

200

400

600

Me

an

Wh

ole

Blo

od

Co

nce

ntr

ati

on

(n

g/m

l)

SmPill™ CyA Fast Release

Therapeutic Window1 125-250 µg/L in the first few months post-

transplant and can be reduced to 80-150 µg/L thereafter

17 volunteersToxic


1 Bowers, LD. Therapeutic Monitoring for Cyclosporine: Difficulties in Establishing a Therapeutic Window. Clin Biochem. Vol. 24, 1991, 81-87

Similar BA while reducing toxicity side effects

-200

0 2 4 6 8 10 12 14 16 18 20 22 24Time/Hour

Agenda








� Conclusion

SmPill™ Is Suitable for Oral Delivery of Peptides

Drug Properties:• High Solubility

•Low Permeability

•Low oral bioavailability

•32 amino acid peptide•32 amino acid peptide

•Hepatic metabolism

•Heat sensitivity

•sCT available as nasal spray & injection

•Indicated for treating postmenopausal

osteoporosis, Paget's disease of bone, and

hypercalcemia

Objectives:


Objectives:•sCT formulated with SmPill for oral delivery

•Improve permeability while ensuring safety

•Ensure manufacturing stability

•Avoid peptide gut degradation

•Select release targeting site

Model Peptide:

Salmon Calcitonin

Jejunum Release of sCT Delivers Good Oral Bioavailability

10

15

20A+ SmPill

E+ SmPill

F1+ SmPill

[sC

T]

(ng

/ml)

100

150

% s

CT

Rele

ased

Oral Gavage Targeting Jejunum Dissolution in Enteric Media

Formulation Permeation

enhancer

F (0- ∞∞∞∞ min)

(%)

A √ 4.8

• Published comparative BA benchmarks with

other formulations :

• 0.5-1.4% demonstrated in Phase I1

0 2 4 6 8 100

5

Time (Hour)

[sC

T]

(ng

/ml)

0 2 4 6 8 100

50

F1+ SmPill

E+ SmPill

A+ SmPill

Time (Hour)

% s

CT

Rele

ased

A √ 4.8

E √ 10.8

F1 - 4.6

STRICTLY PRIVATE & CONFIDENTIAL 151 Buclin et al., J. Bone Mineral Res., vol. 17 (8), 2002, page 1478-14852 Karsdal et al., Osteoarthritis & Cartilage, vol. 18 (2), page 150-1593Chen et al., Drug Development and Industrial Pharmacy, 2010; 36(3): 362–370

• 0.5-1.4% demonstrated in Phase I1

• < 2.5% in Phase III2

• <1.8% in pre-clinical (rat model) 3

Bioavailability Higher than Benchmarks

Formulation E Performs Better but F1 (no PE) still Good

Agenda








� Conclusion

Oral Vaccination Study Design

Oral Gavage Immunisation

Blood & Fecal Samples

Animal SacrificeDay 0 Day 13 Day 27 Day 35

Female BALB/c mice

� Blood samples to determine IgG and IgA antibody titres

� Fecal pellets to determine mucosal antibody responses

� Post the final immunization:

• saliva was obtained from all mice and subsequently the mice were sacrificed • saliva was obtained from all mice and subsequently the mice were sacrificed

and intestinal washes collected from the small and large intestines

• Tissue extracts from the small and large intestines were also obtained for

determination of antibody responses locally in the intestine using a modified

version of the “PERFEXT” 1


1 Villavedra et al. Res Immunol 1997 148: 257-266

SmPill™ Formulated Antigen X Oral Vaccine Protection

75

100

% o

f m

ice p

rote

cte

d

Bacteria Subunit

100% protection

PB

SC

TB s

olutio

nC

TB +

CT s

olutio

n

CTB

+ a

Gal

Cer

+ O

il3LED

DS

CTB

+ a

Gal

Cer

+ s

oluto

l LED

DS

CTB

+ a

Gal

Cer

+ s

oluto

l LED

DS (D

OTA

P/C

hit)

0

25

50

% o

f m

ice p

rote

cte

d

PBS

Thermostable!


CTB

sol

ution

CTB

+ C

T solu

tion

CTB

+ a

Gal

Cer

+ O

il3LED

DS

CTB

+ a

Gal

Cer

+ s

oluto

l LED

DS

CTB

+ a

Gal

Cer

+ s

oluto

l LED

DS (D

OTA

P/C

hit)

� 100% oral protection in mouse-model using Formulation 2

� > 70% oral protection in mouse model using Formulation 1 and 3

Broadly Applicable

Similar Studies Performed with whole killed cell; strong serum and mucosa immune responses

Agenda








� Conclusion

Conclusion

SmPill™ Successful DD TechnologySmPill™ Successful DD Technology

Novel, versatile, scalable drug delivery technology

Addresses common drug delivery challenges

Addresses unmet oral peptide and vaccine delivery challenges

Efficiency of Delivery Supported by Animal/Human Data

Applicable across all BCS classifications


Modulate Release Capability

Monica Rosa Ph.D. Sigmoid Pharma

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