SmPill - Innovative Solution for Oral Delivery

1. SmPill™
Innovative Solution for Oral Delivery
Mónica Rosa, Ph.D.
Bio Pharma Summit, October 31st 2012, Convention Centre Dublin
“Innovative Delivery, Delivering Innovation” STRICTLY PRIVATE & CONFIDENTIAL
© Sigmoid Pharma Limited 2012
www.sigmoidpharma.com Not to be circulated or copied without prior approval

2. Agenda
Introduction to Sigmoid Pharma
SmPill™ Overview
SmPill™ Poorly Soluble Drugs Oral Delivery
SmPill™ Peptide Oral Delivery
SmPill™ Vaccines Oral Delivery
Conclusion
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3. 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
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 portfolio
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4. Promising Product and Platform Opportunities
Program Indication Preclinical Phase I Phase II Phase III Marketed
CyColTM Ulcerative
- Flexibility in release & PK
Cyclosporine opportunity
Colitis
- Consistent core beads
CyCronTM Crohn’s
Disease
AlloCol™ GI-GvHD
CyLow™ Immuno-
suppression
SmPill™ Broadly applicable across all BCS classes – most advanced product in late
applicability to many
Technology platform
phase II
Oral Preclinical evidence of effect in gastrointestinal enteric pathogens
with broad
vaccine
molecules
Oral Compelling preclinical data with model peptide, which provides support for
peptide applications to other novel peptides
* US FDA Orphan Designations granted in 2009
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5. Agenda
Introduction to Sigmoid Pharma
SmPill™ Overview
SmPill™ Poorly Soluble Drugs Oral Delivery
SmPill™ Peptide Oral Delivery
SmPill™ Vaccines Oral Delivery
Conclusion
STRICTLY PRIVATE & CONFIDENTIAL 4

6. Industry Challenges in Drug Delivery
Permeability Solubility
50% Drugs Low Permeability 40% Drugs Poor Solubility
Drug not absorbed Drug not in free molecular form
Require high dose Require high dose
Require i.v. Increase side effect risk
Increase side effect risk Limits clinical development
Limits clinical development
Stability Release Profile
Effective targeting
30% Drugs Low Stability
Target to drug receptor
Drug not in active form
Target for optimal absorption site
Degradation in GI tract
Target to treat GI disease
Precipitation in solution
Require high dose
Processing stability
Systemic, not local
Requires cold-chain
Increase side effect risk
Limits clinical development
Limits clinical development
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7. 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.
Top-down
Crystalline
solid
Particle size reduction = increased surface area = increased dissolution rate in liquid
Bottom-up
Crystalline or
amorphous
solid
Particle size control= increased surface area = increased dissolution rate in liquid
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8. 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
Drug solubilised in
Aqueous –based process; Drug in solution Drug solubilised in mini-spheres in dosage
functional excipients added targeted mini-spheres form
SmPill™ Integrated Technology
Addresses Solubility, Permeability, Stability and Release Collectively
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9. SmPill™ Mini-Spheres Produced Via a Gentle, Modified,
Melt-Extrusion-like Process
• API Solution uses
GRAS excipients
• Tailored to unique
attributes of drug Heated Pumping System Nozzle
&target formulation
• Screening may use • Cooling solution is
< 0.5 g API gentle and non-toxic
• Manufacturing and
processing technology
compatible with
and/or uses
conventional systems
X-ray Tomography
• Uniform spherical shape
API Solution Cooling • Smooth surface
Solution • Homogenous interior dispersion
SmPill™ Process is Highly Scalable and Cost-Comparable to Other
Multiparticulate Dosage Forms
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10. 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
and/or modular release form for optimal pharmacological activity at target site.
profiles Solubilised state maintained throughout gastrointestinal
transit and release through outer coating
SmPill™ Delivers Liquid Drug in an Oral Solid Dosage form which Permits
GI Targeting of the Drug in a Stable and Molecularly Active Form
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11. Agenda
Introduction to Sigmoid Pharma
SmPill™ Overview
SmPill™ Poorly Soluble Drugs Oral Delivery
SmPill™ Peptide Oral Delivery
SmPill™ Vaccines Oral Delivery
Conclusion
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12. Cyclosporine Formulated SmPill™
™
Drug Properties:
• Low Solubility (< 5µM in water)
•High Permeability (small Intestine)
•Cyclic Peptide (11 aa)
•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:
• Cyclosporine formulated with SmPill™
Model Drug: for oral delivery
Cyclosporine •Improve solubility
•Reduce toxicity
•Achieve appropriate pharmacokinetics
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13. Cyclosporine Formulated SmPill™ versus Neoral®
™
“Fit-For-Purpose” Bioavailability
Human PK
800
Neoral®
Mean Whole Blood Concentration (ng/ml)
SmPill™ CyA Fast Release
600
Toxic
17 volunteers
400
200 Therapeutic Window1 125-250 µg/L in the first few months post-
transplant and can be reduced to 80-150 µg/L thereafter
0
-200
0 2 4 6 8 10 12 14 16 18 20 22 24
Time/Hour
Similar BA while reducing toxicity side effects
1 Bowers, LD. Therapeutic Monitoring for Cyclosporine: Difficulties in Establishing a Therapeutic Window. Clin Biochem. Vol. 24, 1991, 81-87
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14. Agenda
Introduction to Sigmoid Pharma
SmPill™ Overview
SmPill™ Poorly Soluble Drugs Oral Delivery
SmPill™ Peptide Oral Delivery
SmPill™ Vaccines Oral Delivery
Conclusion
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15. SmPill™ Is Suitable for Oral Delivery of Peptides
Drug Properties:
• High Solubility
•Low Permeability
•Low oral bioavailability
•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:
•sCT formulated with SmPill™ for oral delivery
Model Peptide: •Improve permeability while ensuring safety
•Ensure manufacturing stability
Salmon Calcitonin
•Avoid peptide gut degradation
•Select release targeting site
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16. Jejunum Release of sCT Delivers Good Oral Bioavailability
Oral Gavage Targeting Jejunum Dissolution in Enteric Media
20 150
A+ SmPill™
E+ SmPill™
% sCT Released
15
[sCT] (ng/ml)
F1+ SmPill™
100
10
50
5
A+ SmPill™
E+ SmPill™
0 F1+ SmPill™
0 2 4 6 8 10 0
0 2 4 6 8 10
Time (Hour)
Time (Hour)
Formulation Permeation F (0- ∞ min) • Published comparative BA benchmarks with
enhancer (%) other formulations :
A √ 4.8 • 0.5-1.4% demonstrated in Phase I1
• < 2.5% in Phase III2
E √ 10.8
• <1.8% in pre-clinical (rat model) 3
F1 - 4.6
Bioavailability Higher than Benchmarks
Formulation E Performs Better but F1 (no PE) still Good
1 Buclin et al., J. Bone Mineral Res., vol. 17 (8), 2002, page 1478-1485 STRICTLY PRIVATE & CONFIDENTIAL 15
2 Karsdal et al., Osteoarthritis & Cartilage, vol. 18 (2), page 150-159
3Chen et al., Drug Development and Industrial Pharmacy, 2010; 36(3): 362–370

17. Agenda
Introduction to Sigmoid Pharma
SmPill™ Overview
SmPill™ Poorly Soluble Drugs Oral Delivery
SmPill™ Peptide Oral Delivery
SmPill™ Vaccines Oral Delivery
Conclusion
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18. Oral Vaccination Study Design
Female BALB/c mice
Oral Gavage Immunisation
Blood & Fecal Samples
Day 0 Day 13 Day 27 Day 35 Animal Sacrifice
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
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
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19. SmPill™ Formulated Antigen X Oral Vaccine Protection
100% protection
100
Bacteria Subunit
% of mice protected
75
50
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100% oral protection in mouse-model using Formulation 2
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> 70% oral protection in mouse model using Formulation 1 and 3
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Similar Studies Performed with whole killed cell; strong serum and mucosa immune responses
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20. Agenda
Introduction to Sigmoid Pharma
SmPill™ Overview
SmPill™ Poorly Soluble Drugs Oral Delivery
SmPill™ Peptide Oral Delivery
SmPill™ Vaccines Oral Delivery
Conclusion
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21. Conclusion
SmPill™ 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
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