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
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Owned by Victory Park Capital, a Chicago-based investment firm
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Extensive scientific know-how and R&D experience
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Proven GMP tablet and API manufacturing capabilities
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Demonstrated a track record of clinical success across a range of compounds and therapeutic indications
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Enteris offers robust IP protection •
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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
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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)
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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
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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 • • •
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
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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
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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
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Criteria for Selection of Peptides: Developability Assessment 1.
Characteristics of the API •
What is the peptide sequence (or number of amino acids)? • Are there any chemical modifications to the peptide (and if so, what are they)?
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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 •
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 •
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?
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Pre-clinical and Clinical Peptide Experience
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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
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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
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PTH Phase II Study Mean PTH Cmax Values for Subjects Receiving Oral PTH(1-31)NH2 and Forsteo®
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Development of Oral Calcitonin for Osteoporosis
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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
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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)
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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
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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
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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: • • • •
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
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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
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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
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Thank You! Questions?
