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TIDES 2014 Nasal, Pulmonary, Oral, Transdermal,
and Microneedle Technologies for Peptide Delivery
Peptide Delivery Outline o Peptide Properties and Delivery o Non-invasive Technology o Marketed Peptides in Non-Invasive Systems o Technologies in Development for Peptides o Peptides / Delivery Systems in Development
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Goals for Non-Invasive Delivery Systems
o Improve uptake through improved convenience, compliance, ease of use o Must be a simple system to be adopted by physicians
and patients
o Small portion of market has needle phobia (10-25%) o But, most can get used to simple injections
o Must maintain safety / side effect profile o In some cases, can improve either or both
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Non-Invasive Market Preference
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Injection
Oral
Simple >> Complex Once per day > BID >>> TID
Patients ~ Doctors
Nasal Buccal
Sublingual Transdermal
Market Preference
Limited Non-Invasive Product Precedents
Pen Injection Auto-injector
Vial Syringe
Pulmonary Oral
Transdermal
Risk
Reward
= Commercialized Products = Products in Development
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Nasal
Sublingual / Buccal
Properties of Peptides o Typically water soluble > 1 mg/ml o Stability in solution is often limited
o Hydrolysis, deamidation in aqueous solution
o Stability as solid is good when water content is low o Synthesis < 5000 g/mol > recombinant o Immunogenicity and safety
o Naturally derived peptides are typically risk reduced because safety of the endogenous molecule is well understood
o Immunogenicity a concern for analogues and non-natural
o Half-life short for natural amino acid peptides o Minutes to hours
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Biomolecule Delivery Constraints
MW (kD)
Dose (mg)
Half-life (hour)
1 10 100
1
10
100
1
10
100
Peptides
Proteins
Antibodies
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Typical Product Life Cycle for Peptide Therapeutics
o First drug product is usually solution for injection o Store in lyophilized form, or store in solution at 2-8C
o Immediate product improvements to commercial product o Improve product presentation (Vial / syringe to pen/injector) o Predictable cost, time, high probability
o Next Generation: Sustained exposure injection technologies o Formulations (lipids, polymer, gels, implants)
o Moderate cost and moderate probability o Covalent (PEG, Fc, Albumin, Ab binding conjugates)
o Higher cost (NCE), risk-reduced if known target / pharmacology and follow on program
o Additional considerations: Non-invasive or minimally invasive o Nasal, Pulmonary, oral, microneedle, implant o Typically a device combination product, except most orals o High cost and lowest probability
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Life Cycle for Peptides
Risk
&
Cost
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Pen Injection Auto-injector
Vial Syringe
Sustained Exposure Injection
Non-Invasive
Time from First Launch + 5 Yrs + 10 Yrs
Non-Invasive Challenges
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o Compatibility of drug, formulation, device
o Predictability of in vitro and in vivo methods
o Variability in Exposure (Cmax, AUC, Tmax)
o Overall cost of the system
o Bioavailability, novel excipient, device, manufacturing
o Maturity of the technology
o Phase 1 PK, or late stage phase 2/3 development
o Scale up experience, manufacturing systems
o Regulatory experience and acceptance
Mucosal Transport of Biomolecules is Limited
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o Low passive diffusion across mucosal barrier o Some active transport systems
o Significant permeation across pulmonary epithelial lining o Alveoli in deep lung show good permeability to peptides o Efficiency of deposition in deep lung limits bioavailability o Overall bioavailability typically 5 to 10% versus SC
o Permeation enhancers typical for nasal, oral, buccal, sublingual o Bioavailability typically < 2 to 4% versus SC
o Transdermal typically involves an active penetration or permeation o Penetration - microneedles, microporation (ablation) o Membrane disruption - iontophoresis, sonophoresis o Bioavailability can be significant > 20 to 40% versus SC
Molecule • Efficacy / side effects • Continuous or pulsatile • Cost per gram • Physicochemical properties
Delivery System • Process complexity • Bioavailability • Cost per unit • Compatibility with molecule
Device • Device complexity • Ease of use / acceptance • Cost per unit • Formulation compatibility
Biology & Chemistry
PK & Formulation Device & Handling
Peptide Products: Combination Products with Trivalent Complexity
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Non-invasive Program Expectations
o Pulsatile exposure compared to SC injection o Limited absorption phase due to permeation and penetration aid
o Much lower bioavailability than SC o Can be a challenge to COGs and manufacturing scale
o Increased variability in exposure o Can be challenging for peptides with limited tolerability window
o Handling of a device 1X to 3X per day o Nasal, pulmonary, transdermal, microneedle
o Increased regulatory scrutiny o Change in route of delivery and formulation o Concern for change in safety profile / immogenicity
o Significant development time and cost o Increased drug consumption in pharmaceutical development o Potential for plant and equipment capital investment prior to phase 3
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PK of GLP-1s
Vilsbøll T et al. JCEM 2003;88:220-224
Native GLP-1: t½ 2 min (IV)
Liraglutide (Victoza): t½ 13 hrs (SC)
Kothare P A et al. J Clin Pharmacol 2008;48:1389-1399
Exenatide (Byetta): t½ 1-2 hrs (SC)
Peptide Delivery TIDES 2014 05/15/14 14
J. Eng license to Amylin 1996 FDA approved 2005 Twice daily injection
Novo FDA approved 2010 Once daily injection
DDAVP Nasal Spray and Oral Commercial Products
o DDAVP (desmopressin acetate) o MW 1183, anti-diuretic o Synthetic analogue of natural hormone arginine vasopressin o Multiple generic versions available
o DDAVP Nasal Spray (Sanofi, 1984) o 10 mcg / spray o Bioavailability ~10%, half-life 55 minutes
o DDAVP Tablets (Sanofi, 1995) o 100 to 200 mcg / tablet o Bioavailability 5% vs nasal, 0.2% vs Intravenous injection
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Oxytocin Nasal Spray Commercial Product
o Nasal Oxytocin o MW 1007, Initial milk letdown o FDA approval 1960 (Novartis) o Removed from US market in 1997 for commercial reasons o Still marketed in EU / ROW as Syntocinon (Novartis, Sigma-Tau)
o Development programs o Significant interest from several companies in CNS indications o Autism, Schizophrenia, anorexia, etc…
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Salmon Calcitonin Nasal Spray Commercial Product
o Nasal calcitonin o MW 3432, 32 amino acids o Post-menopausal osteoporosis o FDA approval 1995 (Sandoz) o CHMP and FDA recommend removal from market in 2012/2013, Health Canada Mandates removal in 2013
o Mean bioavailability of 2 to 3% vs IM injection o Range of 0.03 to 30 % in small human PK study
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Insulin Oral Inhalation Commercial Product
o Exubera (Pfizer / Nektar) o MW 5807, 51 amino acids, two polypeptide chains o FDA approved 2006 o Type I and II diabetes o Bioavailability vs SC injection ~10% o First inhalable insulin approved, proved that good engineering
could produce similar PK profiles to SC injection o Pfizer pulled from market in 2007 due to poor acceptance
o Afrezza (Mannkind) o Technosphere Insulin Inhalation System o Under final FDA review 2014
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Non-invasive Programs in Clinical Development
o Inhaled Insulin o Dance Pharmaceuticals, founded by John Patton (Nektar) o Based on the Aerogen device
o Oral Insulin o Biocon technology originally licensed from Nobex based on
PEGylated insulin conjugates – IN-105 o Failed to reach primary endpoint in phase 3 study
o Oramed – phase 2 study o Diabetology o Ora-Lyn (Generex buccal spray)
o All technologies have bioavailability << 10% vs SC injection o Ref: L Heineman and Y Jacques, Journal of Diabetes Science and
Technology Volume 3, Issue 3, May 2009
o Nasal Insulin o Nasulin (CPEX) failed in a phase 2 trial in 2011 and was halted
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Non-invasive Programs in Clinical Development
o Nasal Oxytocin o Retrophin, other companies o Clinical exploration in multiple CNS indications
o Oral Calcitonin o Tarsa Therapeutics licensed Unigene Labs product o Completed phase 2, in phase 3 readying for submission? o Oral bioavailability 1 to 2% versus SC injection
o PTH1-34 Microneedles o Zosano stainless steel microneedle system (Alza Macroflux
technology) o Radius (3M plastic microneedle system) o Bioavailability 20 to 40% versus SC injection
o Exenatide Implant (minimally invasive) o Intarcia titanium implant with 6 and 12 month of exenatide (Alza
Duros technology)
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Molecule • Efficacy / side effects • Continuous or pulsatile • Cost per gram • Physicochemical properties
Delivery System • Process complexity • Bioavailability • Cost per unit • Compatibility with molecule
Device • Device complexity • Ease of use / acceptance • Cost per unit • Formulation compatibility
Biology & Chemistry
PK & Formulation Device & Handling
Prospective Non-Invasive Peptide?: Consider Indication / Patients Needs First, Then Technical Feasibility in The Space
05/15/14 Peptide Delivery TIDES 2014
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