Formulating Peptides/proteins
for Oral Delivery: a Clinical Case
Study
John S. Vrettos, Ph.D.
Sr. Principal Scientist
Formulation Development
2014 AAPS National Meeting and Exposition
Enteris BioPharma
•
Clinically validated solid oral dosage formulation technology
•
•
for peptides and challenging small molecules
Enteris has effectively addressed both permeability and
solubility challenges with a simple, elegant and scalable solution
•
Privately held, New Jersey based biotech company
•
Owned by Victory Park Capital, a Chicago-based investment firm
•
Extensive scientific know-how and R&D experience
•
Proven GMP tablet and API manufacturing capabilities
•
Demonstrated a track record of clinical success across a range of
compounds and therapeutic indications
•
Enteris offers robust IP protection
•
•
Patents extend to 2030
Feasibility study and licensing business model
2
Manufacturing
• Enteris cGMP Manufacturing
• 32,000 ft2 cGMP facility located in Boonton, NJ
• Separate tableting and nasal spray filling suites
• Multi-kilogram scale microbial fermentation and
purification suites
• Full QA/QC and regulatory support
• Commercial product in US distribution
• Fortical ® Calcitonin-Salmon (rDNA origin) Nasal
Spray, marketed by Upsher-Smith Laboratories
3
Clinically Validated Oral
Delivery Technology
• Clinically validated oral peptide delivery technology
•
•
•
•
Positive Phase 3 oral Calcitonin: Osteoporosis(1)
Positive Phase 2 oral PTH: Osteoporosis(2)
Positive Phase 2 oral Calcitonin: Osteopenia(3)
Positive Phase 1 oral CR845: Neuropathic Pain(4)
• Sponsored preclinical peptide programs
• Several ongoing or completed formulation programs
•
•
•
•
(1) Tarsa Therapeutics, Inc. (JBMR 27, No.8, 2012, 1821-1829)
(2) Unigene Laboratories, Inc. (Bone 53, 2013, 160-166) (Clin Pharm 52, No. 6, 2013)
(3) Tarsa Therapeutics, Inc. (ASBMR, 2012)
(4) Cara Therapeutics, Inc. (data on file)
4
Potential Commercial
Benefits of Peptelligence™
• Increases product uptake and utilization vs.
parenteral administration
• Increased physician starts; fewer patient refusals
• Enhanced patient compliance
• Better patient outcomes
• Protects and extends product exclusivity and
commercial life
• Provides compelling differentiation in competitive markets
• Adds extra layer of robust IP protection until 2030
• Refreshes and extends commercial life of products
5
Challenges to Solid Oral
Dosage Formulations
Oral peptide delivery
•
•
GI tract is designed to degrade and
digest peptides
Low permeability through the
intestinal cell layer
Peptelligence™ solution to these
challenges
•
•
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Reduces peptide degradation
Increases paracellular transport
No modification of the peptide
required
Oral small molecule delivery
•
•
Solubility or dissolution limited
absorption
Poor permeability due to interaction
with efflux transporters or other
mechanisms
Peptelligence™ solution to these
challenges
•
•
Permeation enhancer acts as a
surfactant
Paracellular transport bypasses
transcellular permeation hurdles
6
Bioavailability Data in Dogs:
Peptides and Small Molecules
Absolute Bioavailability (%)
25
20
SMALL MOLECULES
zanamivir
PEPTIDES
tigecycline
CR-845
15
PROPRIETARY PEPTIDES
kanamycin
tobramycin
10
leuprolide
octreotide
5
calcitonin
PTH 1-34
insulin
0
0
1000
2000
3000
4000
5000
6000
Molecular Weight (Da)
7
Mechanism of Drug Delivery
8
Enteric Coat Dissolves at
Neutral pH in the Small Intestine
• Acid-stable enteric coating prevents
tablet release in stomach
• Less susceptible to food effects or
dilution with liquids
• API protected from degradation by
acid and pepsin
• Peptides
• Acid-labile small molecules
• Water-soluble sub-coat acts as a
partition layer between the enteric
coat and the acidic tablet core
• Simultaneous release of API and
excipients
9
pH Modifier, Permeability
Enhancers and API Released
• Citric acid (CA), sugar-coated granules
• Increases stability of tablet formulation
• Compatible with peptides and small
molecules
• Acts as protease inhibitor for peptides
• Calcium chelator and membrane
permeation enhancer
• pH-lowering agent that increases
absorptive flux
• Membrane wetting/charge dispersal agent
10
API Absorbed Across Intestinal
Wall via Paracellular Transport
• Lauroyl-L-carnitine (LLC)
• Modulates tight junctions in the intestinal
enterocytes and enhances paracellular
transport
• Acts as a solubilizing agent due to
surfactant properties
• Inhibits P-gp efflux transporters
• Brittle powder, not a wax or liquid
• Type V DMF on file
11
Criteria for Selection of Peptides:
Developability Assessment
1.
Characteristics of the API
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What is the peptide sequence (or number of amino acids)?
• Are there any chemical modifications to the peptide (and if so, what are they)?
•
2.
3.
What is the total molecular weight (including any modifications)?
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Is the peptide soluble in pure water? Buffers or salt solutions (which ones)? Acidic pH?
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Does it aggregate?
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Is it susceptible to proteolysis (qualitatively)?
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Is it cyclic? How large is the macrocycle?
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What is the overall net charge? The pI?
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Any special phys-chem properties that should be known?
Project status
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Is this in clinical development?
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What is the indication?
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Assuming we’re successful, do you have a target date for getting a tablet formulation into the clinic?
Feasibility for oral delivery
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What is the injectable dose (IV/IM/SC)?
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What’s the mechanism of action (e.g., agonist or antagonist)?
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What’s the therapeutic window?
12
Pre-clinical and Clinical
Peptide Experience
13
Dog Model Predicts
Bioavailability in Humans
Human/Dog Correlation (sCT)
Dose Linearity in Dogs (39 aa peptide)
Plasma Cmax (pg/ml)
4500
1000
Human Cmax (pg/ml)
4000
3500
3000
2500
2000
1500
1000
500
0
0
1
2
3
Dose (mg)
4
5
100
10
10
100
1000
10000
Dog Cmax (pg/ml)
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Enteris' dog model for oral delivery shows high degree of linearity with respect to dose
offering a wide range of dosing strategies
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Comparability of PK results in dog and human shows that Enteris’ dog model is an
appropriate success predictor for human studies
14
Absorption of LHRH Analog in Dogs
as a Function of Enteric Coat
Capsule
(formulation)
Enteric coat
composition
(weight gain)
Tmax
(min)
Capsule Formulation in Dogs
Bioavailability
(% F)
12000
A
A
(+ CA/LLC)
L30D-55
(10%)
111
B
(+ CA/LLC)
L30D-55
(15%)
116
C
(+ CA/LLC)
L30D-55 / FS30D
(12%)
152
3.0
4.6
7.2
LHRH (pg/mL)
10000
Formulation B
8000
Unformulated C
6000
B
C
Formulation D
D
4000
2000
0
D
(– CA/LLC)
L30D-55
(10%)
0
130
0.1
100
200
300
400
500
Time Relative to Tmax (minutes)
15
Bioavailability of Cara’s CR845 in
Preclinical & Phase I
16%
20%
13%
13%
Rat
Dog
15%
10%
5%
0%
Man
16
Phase I Oral CR845 Study
CR845 Demonstrated 16% Oral Bioavailability
N = 8/group
100
CR845 (ng/mL)
0.5 mg
1 mg
3 mg
10 mg
10
1
0.1
0
4
8
12
16
Time (hours)
20
24
Mean + SEM
17
PTH Phase II Study
Mean PTH Cmax Values for Subjects
Receiving Oral PTH(1-31)NH2 and Forsteo®
18
Development of Oral Calcitonin for
Osteoporosis
19
Pharmacokinetic and pH Profile of Enteric Coated sCT
and Heidelberg Capsules in Dogs
pH
sCT
10
8
8
6
4
4
2
Intestinal pH
sCT (ng/ml)
6
2
0
0
0
30
60
90
120
150
180
Time (min)
20
Phase I sCT Exploratory Study
• Design: Single Dose, Open, Crossover Design Study
• Subjects: 18 Postmenopausal Women
• Study Medication Doses
• 500 μg Tablet (CA/LLC)
• 1500 μg Tablet (CA)
• 200 IU Fortical® Nasal Spray
• Assessments:
• PD Measurements (CTX-1) up to 24 hours Post Dosing
• PK Measurements up to 24 hours Post Dosing
21
sCT PK and PD Profiles Following Administration of
sCT to Postmenopausal Women
250
20
Mean change from baseline
plasma CTX (%)
Nasal
200
sCT (pg/mL)
500 µg PO
150
1500 µg PO
100
50
0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Time Relative Tmax (hours)
7.0
8.0
0
-20
-40
-60
-80
-100
0.0
3.0
6.0
9.0
12.0 15.0 18.0 21.0 24.0
Time (hours)
22
Dose Dependent Oral Absorption of sCT
Enteric-coated Tablets in Humans
Cmax Plasma sCT (pg/ml)
180
Mean Cmax
Individual Cmax
160
140
120
100
80
60
40
20
0
-20
0
50
100
150
200
Dose sCT (µg)
23
Phase II Oral sCT Dose Selection Study
• Design: Single Dose, Open, Crossover Design Study
• Subjects: 24 Post Menopausal Women
• Study Medication Doses:
• 50 μg Tablet (CA)
• 200 μg Tablet (CA)
• 200 IU Fortical® Nasal Spray
• Assessments:
• PD Measurements (CTX-1) Up To 24 hours Post Dosing
• PK Measurements Up To 24 hours Post Dosing
24
sCT PK and PD Profiles Following Administration
of sCT to Postmenopausal Women
30
20
Nasal
25
50 µg PO
200 µg PO
15
10
-20
sCT (pg/mL)
20
sCT (pg/mL)
0
-40
-60
5
-80
0
-100
0
5
10
0
Time Relative Tmax (hours)
•
5
10
Time Relative Tmax (hours)
Subsequent phase 2 study for osteopenia showed no effect from food on
PD markers (lumbar spine bone mineral density)
Osteoporos Int, Volume 25, Issue 11, pages 2649-2656
25
Phase 3 Trial of the Efficacy and Safety of Oral
Calcitonin in Postmenopausal Osteoporosis
(ORACAL)
• Design: Double-blind, Double-dummy, Multiple Dose,
Placebo-controlled, Parallel Group, 48-week
• Subjects: 565 Post Menopausal Women
• Study Medication Doses:
•
•
•
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200 μg Tablet (CA)
Placebo Tablet (CA)
200 IU Fortical® Nasal Spray
Placebo Nasal Spray
• Assessments:
• Primary Endpoint: Percent Change From Baseline in Bone
Mineral Density (BMD) of Axial Lumbar Spine
26
Cumulative Percent of Subjects
Phase III Oral Calcitonin Study
Percent Change in Lumbar Spine Bone Mineral Density
Journal of Bone and Mineral Research, Volume 27, Issue 8, pages 1821-1829
27
Phase III Oral Calcitonin Study
Primary Endpoint (Change in LS BMD) Achieved
Mean % Change LS-BMD
2.5
2.0
1.5
1.0
0.5
0.0
rsCT Tablet
p<0.001
Nasal Spray
p=0.014
Placebo
p=ns
28
Concluding Remarks
• Enteris BioPharma has:
• A clinically validated solid oral dosage formulation technology for
oral delivery of peptides
• Addressed both permeability and solubility challenges with a
simple, elegant and scalable solution
• Several successful pre-clinical and clinical programs
• Cara Therapeutics CR845 (neuropathic pain)
• Tarsa Therapeutics Ostora® (osteoporosis, osteopenia)
• Proprietary and internal programs
29
Thank You!
Questions?