Formulating Peptides/proteins for Oral Delivery: a ... · Bioavailability Data in Dogs: Peptides...

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

• 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

0

5

10

15

20

25

0 1000 2000 3000 4000 5000 6000

Bioavailability Data in Dogs: Peptides and Small Molecules

Abso

lute

Bio

avai

labi

lity

(%)

Molecular Weight (Da)

SMALL MOLECULES PEPTIDES PROPRIETARY PEPTIDES

zanamivir

tobramycin

tigecycline

kanamycin

CR-845

calcitonin PTH 1-34 insulin

leuprolide

octreotide

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

• What is the peptide sequence (or number of amino acids)?

• Are there any chemical modifications to the peptide (and if so, what are they)?

• What is the total molecular weight (including any modifications)?

• Is the peptide soluble in pure water? Buffers or salt solutions (which ones)? Acidic pH?

• Does it aggregate?

• Is it susceptible to proteolysis (qualitatively)?

• Is it cyclic? How large is the macrocycle?

• What is the overall net charge? The pI?

• Any special phys-chem properties that should be known?

2. Project status

• Is this in clinical development?

• What is the indication?

• Assuming we’re successful, do you have a target date for getting a tablet formulation into the clinic?

3. Feasibility for oral delivery

• What is the injectable dose (IV/IM/SC)?

• What’s the mechanism of action (e.g., agonist or antagonist)?

• What’s the therapeutic window? 12

Pre-clinical and Clinical Peptide Experience

13

Dog Model Predicts Bioavailability in Humans

• Enteris' dog model for oral delivery shows high degree of linearity with respect to dose offering a wide range of dosing strategies

• Comparability of PK results in dog and human shows that Enteris’ dog model is an appropriate success predictor for human studies

0 1 2 3 4 5 0

500

1000

1500

2000

2500

3000

3500

4000

4500

Plas

ma

Cm

ax (p

g/m

l)

Dose (mg)

Dose Linearity in Dogs (39 aa peptide)

10 100 1000 10000 10

100

1000

Hum

an C

max

(pg/

ml)

Dog Cmax (pg/ml)

Human/Dog Correlation (sCT)

14

Absorption of LHRH Analog in Dogs as a Function of Enteric Coat

Formulation B

Unformulated C

Formulation D

Capsule (formulation)

Enteric coat composition (weight gain)

Tmax (min)

Bioavailability (% F)

A (+ CA/LLC)

L30D-55 (10%)

111 3.0

B (+ CA/LLC)

L30D-55 (15%)

116 4.6

C (+ CA/LLC)

L30D-55 / FS30D (12%)

152 7.2

D (– CA/LLC)

L30D-55 (10%)

130 0.1

0

2000

4000

6000

8000

10000

12000

0 100 200 300 400 500LH

RH

(pg

/mL)

Time Relative to Tmax (minutes)

Capsule Formulation in Dogs

A

B

C

D

15

Bioavailability of Cara’s CR845 in Preclinical & Phase I

0%

5%

10%

15%

20%13% 13%

16%

Rat Dog Man

16

Phase I Oral CR845 Study

Time (hours)

CR84

5 (ng

/mL)

0 4 8 12 16 20 240.1

1

10

100

3 mg

0.5 mg1 mg

10 mg

N = 8/group

Mean + SEM

CR845 Demonstrated 16% Oral Bioavailability

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

0 30 60 90 120 150 180

0

2

4

6

8

10

Time (min)

sCT

(ng/

ml)

sCT

0

2

4

6

8Intestinal pH

pH

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

0

50

100

150

200

250

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

sCT

(pg/

mL)

Time Relative Tmax (hours)

Nasal

500 µg PO

1500 µg PO

-100

-80

-60

-40

-20

0

20

0.0 3.0 6.0 9.0 12.0 15.0 18.0 21.0 24.0M

ean

chan

ge fr

om b

asel

ine

pl

asm

a C

TX (%

) Time (hours)

22

Dose Dependent Oral Absorption of sCT Enteric-coated Tablets in Humans

0 50 100 150 200 -20

0

20

40

60

80

100

120

140

160

180

Cm

ax P

lasm

a sC

T (p

g/m

l)

Dose sCT (µg)

Mean Cmax Individual Cmax

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

0

5

10

15

20

25

30

0 5 10

sCT

(pg/

mL)

Time Relative Tmax (hours)

Nasal

50 µg PO

200 µg PO

-100

-80

-60

-40

-20

0

20

0 5 10

sCT

(pg/

mL)

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:

• 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

Phase III Oral Calcitonin Study

Journal of Bone and Mineral Research, Volume 27, Issue 8, pages 1821-1829

Cum

ulat

ive

Per

cent

of S

ubje

cts

Percent Change in Lumbar Spine Bone Mineral Density

27

0.0

0.5

1.0

1.5

2.0

2.5

rsCT Tablet Nasal Spray Placebop=ns p=0.014 p<0.001

Phase III Oral Calcitonin Study

Mea

n %

Cha

nge

LS-B

MD

Primary Endpoint (Change in LS BMD) Achieved

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?