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Peptides in Clinical Development
CACO San Francisco
11 May 2012
Christopher A. Rhodes, Ph.D.
Content
•Peptide Products Market Overview
•Properties of Peptides
•Late Stage Development Programs
•Product Development Strategies
•Early Stage Development Programs
•Research Programs
•Peptide Delivery Programs
•Case Study
2 11MAY2012 CACO-SF CRhodes
Peptide Market Opportunity Is Attractive
•Peptides are reaching blockbuster status (2008 Sales)
•Glatiramate (Copaxone) $3.18B
•Leuprolide acetate (Lupron) $2.12B
•Goserelin acetate (Zoladex) $1.14B
•Octreotide acetate (Sandostatin) $1.12B
•Exenatide (Byetta) $0.75B
•Teriparatide (Forteo) $0.78B
J. Reichert, Devel. Trends Peptide Therapeutics,
Peptide Therapeutics Foundation 2010
3 11MAY2012 CACO-SF CRhodes
Peptides in Clinical Development
•334 therapeutic peptides reviewed 2010 (J Reichert)
•131 in Development, 54 Approved, 149 Terminated
•18% studied for cancer
•17% for metabolic (diabetes, obesity, osteoporosis)
•Allergy, immunological, cardiovascular disease
•Most for extracellular receptors, most GPCR agonists
0 20 40 60 80
Phase 1
Phase 2
Phase 3
In Review
4 11MAY2012 CACO-SF CRhodes
Molecular Weight (kD)
Do
se (
mg
)
Ha
lf-l
ife
(hrs
)
1 10 100
1
10
100
1
10
100
Peptides
Proteins
Antibodies
Properties of Biologics
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Properties of Peptides
•Typically water soluble > 1 mg/ml
•Stability in solution is often limited
•hydrolysis, deamidation
•Store in lyophilized form, or store in solution at 2-8C
•Stability as solid is good when water content is low
•Peptides < 4000 g/mol – peptide synthesis
•Peptides > 4000 g/mol – usually recombinant manuf
•Immunogenicity and safety
•Naturally derived peptides are typically risk reduced because
safety of the class is well understood
•Immunogenicity is a concern
•Drug product is usually solution for injection
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PK profiles for insulin zinc products
Short-acting (solution) – Drug property controlled
absorption and elimination phase
Intermediate-acting
(suspension)
Long-acting (suspension) – Dissolution
controlled absorption results in longer exposure
Intermediate-acting
(suspension)
Peptide
Pharmacokinetics
8 8 11MAY2012 CACO-SF CRhodes
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)
Molecule
•Efficacy / side effects
•Continuous or pulsatile
•Cost per gram
•Physicochemical properties
Formulation
•Process complexity / scale-up
•Bioavailability / efficiency
•Cost for process / fill / finish
•Compatibility with molecule
Device
•Device complexity
•Ease of use / acceptance
•Cost per unit
•Formulation compatibility
Biology & Chemistry
PK & Formulation Device & Handling
Peptide Drug Products:
Combination Products with Trivalent Complexity
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Selected Peptides FDA Approved in 2000-2010
Product generic name Status Indication Company (Partner)
Victoza liraglutide 2010 Diabetes Novo
Egrifta tesamorelin 2010 HIV-associated
lypodistrophy
EMD Serono
Firmagon degarelix 2008 Prostate cancer Ferring
Somatuline
Depot
lanreotide 2007 Acromegaly Biomeasure
Byetta exenatide 2005 Diabetes Amylin (Lilly)
Symlin pramlintide 2005 Diabetes Amylin
Levemir insulin detimir 2005 Diabetes Novo
Fuzeon enfurvirtide 2003 HIV infection Roche
Plenaxis abarelix 2003 Prostate cancer Praecis
Forteo teriparatide 2002 Osteoporosis Eli Lilly
Natrecor nesiritide 2001 Heart failure Scios
Lantus insulin glargine 2000 Diabetes Sanofi - Aventis
Selected Peptide Properties
generic name Derived from / analogues / unique chemistry MW
liraglutide Long-acting analogue of GLP-1 (fatty acid modified
after recombinant production)
3751
degarelix Synthetic analogue of GnRH decapeptide 1692
lanreotide Synthetic analogue of somatostatin in self-forming
gel concentrate
1096
exenatide Synthetic hormone from saliva of the Gila monster
(GLP-1 agonist)
4187
enfurvirtide Synthetic peptide sequence from HIV gp41 4492
nesiritide Recombinant Beta-natriuretic peptide 3464
Content
•Peptide Products Market Overview
•Late Stage Development Programs
•Product Development Strategies
•Early Stage Development Programs
•Research Programs
•Peptide Delivery Programs
•Case Study
12 11MAY2012 CACO-SF CRhodes
Selected Peptides in Late Stage Development Product Product
Strategy
Status Indication Company
(Partner)
Firazyr Acute use SC
self-injection
Appro
ved
Acute Hereditary
Angioedema
Shire (Jerini
buy-out)
Bydureon Weekly,
microsphere
Appro
ved
Type II Diabetes Amylin (Lilly)
Omontys
(peginesatide)
Monthly, PEG
peptide dimer
Appro
ved
Anemia in Chronic
Renal Failure pts
Affymax
(Takeda)
Linaclotide Daily oral Ph 3 Irritable Bowel / CC Ironwood
Davunetide Daily injection
Tau-related
Ph 2/3 Progressive
Supranuclear Palsy
Allon
KAI – 4169 IV Ph 2 Secondary
hyperparathyroidism
KAI
CR845 IV infusion Ph 2 Post-operative pain Cara
Bremelanotide Daily injection Ph 2 Sexual Dysfunction Palatin
AZX100 Cell permeant Ph 2 Dermal scarring Capstone
13 11MAY2012 CACO-SF CRhodes
Selected Product Development Strategies
generic name Derived from / analogues / unique chemistry MW
Firazyr Peptidomimetic decapeptide, daily administration 1304
Omontys Synthetic dimeric peptide based ESA, PEG 45kD
Linaclotide Synthetic 14 mer with 3 disulfides, orally available 1527
Davunetide Synthetic octapeptide, daily injection 824
KAI – 4169 IV in clinical studies, alternates include transdermal <2000
Bremelanotide Synthetic cyclic heptapeptide, daily administration 1025
14 11MAY2012 CACO-SF CRhodes
Content
•Peptide Products Market Overview
•Late Stage Development Programs
•Product Development Strategies
•Early Stage Development Programs
•Research Programs
•Peptide Delivery Programs
•Case Study
15 11MAY2012 CACO-SF CRhodes
Product Development Strategies
•Chemical modification of peptide structure •Glycopeptides
•Amphipathic peptides
•Cell-penetrating peptides
•Conformational stabilization •Aileron staples, bicycle therapeutics cysteine loops, Pepscan
•Covalent strategies for extending exposure •PEG, Fc fusion and other antibody fragments
•Albumin binding domain, Albumin conjugate, Antibody conjugate
•Self-forming gels, fatty acid conjugates / multimers
•Formulation and device strategies •Non-invasive (oral, nasal, buccal, sublingual, transdermal)
•Depot systems for sustained release injection (daily,weekly, monthly polymer
microparticles, gel-forming systems)
16 11MAY2012 CACO-SF CRhodes
Selected Peptides in Early Development
Product Product Strategy Status Indication Company
(Partner)
Cilengitide Cyclic RGD
pentapeptide
Ph 2 Glioblastoma Merck Serono
Cenderitide Infusion pump Ph 1 Heart failure Nile (Medtronic)
Mutliple
compounds
Weekly PEG, dual
agonists
Ph 1 Diabetes Roche
($Marcardia)
VRS-859 Monthly, XTEN Ph 1 Diabetes Diartis
VRS-317 Monthly, XTEN Ph 1 GH deficiency Versartis
ATX-MS-
1467
4 peptides mimicing
Myelin basic protein
Ph 1 Multiple
sclerosis
Apitope
(Merck Serono)
Danegaptide Dipeptide, IV, Oral Ph 1 Cardiovascular Zealand
Pepducins Lipidated peptide,
allosteric modulator
Preclin Oncology and
metabolics
Anchor (Ortho
McNeil Jannsen)
RM131
RM493
Ghrelin agonist
MC4R agonist
Preclin GI disorders
Obes & Diab
Rhythm
Therapeutics
Content
•Peptide Products Market Overview
•Late Stage Development Programs
•Product Development Strategies
•Early Stage Development Programs
•Research Programs
•Peptide Delivery Programs
•Case Study
18 11MAY2012 CACO-SF CRhodes
Research Programs – Peptide classes 1
•Melanocortin system (MC4R) – for metabolic
disease
•Leptin system for obesity and lypodystrophy
•Urotensin related peptides
•JAM-A adhesion protein for cardiovascular
disease
•Human insulin / relaxin family
•GLP-1 constrained analogues
•GnRH analogues and self depoting gel (Ferring) Ref: Proceedings of the Twenty-First American Peptide Symposium
June 7-12, 2009, Bloomington, IN, U.S.A., Edited by M. Lebl 2009
19 11MAY2012 CACO-SF CRhodes
Research Programs – Peptide classes 2
•GCSF receptor agonist peptides and B-cell
activating factor / TNF (Affymax)
•PTH fragments
•Amyloid polypeptide in cell membrane disruption
•Trifunctional peptides for pain, V Hruby, U of Ariz
•ApoE mimetic peptide
•Integrin ligands – fibronectin
Ref: Proceedings of the Twenty-First American Peptide Symposium
June 7-12, 2009, Bloomington, IN, U.S.A., Edited by M. Lebl 2009
20 11MAY2012 CACO-SF CRhodes
Content
•Peptide Products Market Overview
•Late Stage Development Programs
•Product Development Strategies
•Early Stage Development Programs
•Research Programs
•Peptide Delivery Programs
•Case Study
21 11MAY2012 CACO-SF CRhodes
Selected Peptides in Delivery Systems
Product Product
Strategy
Status Indication Company
(Partner)
Oracal Oral calcitonin Ph 3 osteoporosis Tarsa (Unigene)
Afrezza Inhalation
insulin
Ph 3 Diabetes Mannkind
PassPort
Patch
Transdermal
insulin
Ph 2 Diabetes Altea
Nasulin Nasal insulin Ph 2 Diabetes FSB (CPEX)
Viaderm
hPTH
Transdermal
PTH
Ph 2 Osteoporosis Transphama (Lilly)
ZP PTH Microneedle
PTH
Ph 2 Osteoporosis Zosano
ITCA-650 Implantable
exenatide
Ph 2 Diabetes Intarcia
Oral HDV-1 Oral insulin Ph 1 Diabetes Diasome
Smart
Insulin
Glucose
responsive INS
Ph 1 Diabetes Biodel
Case Study: GLP-1 Analogues
Product Product
Strategy
Status Technology Company
(Partner)
Bydureon Weekly
microsphere
Approv
ed
Medisorb
(Alkermes)
Amylin (Lilly)
Lyxumia
(lixisinetide)
Daily GLP-1
plus Lantus
Ph 2 Fatty acid
conjugate
Sanofi (Zealand)
LY2189265 Weekly GLP-1,
Fc fusion
Ph 2/3 Recombinant Fc Lilly
LAPS Exendin4
(HM11260C)
Monthly exen,
Fc conjugate
Ph 2 Chemically bound
Fc through PEG
Hanmi
ITCA 650 6 mo exendin
implant
Ph 2 Duros implant
(Alza)
Intarcia
Exendin XTEN Monthly exen
conjugate
Ph 1 Peptide oligomer
(Amunix)
Versartis
MAR701 GLP-1, GIP
dual agonist
Ph 1 Peptide dual
agonist, plus PEG
Roche (Marcadia)
Oral GLP-1
analogues
Ph 1 Permeation
enhancers
Novo (Emisphere,
Merrion)
24
NH
O
NH
O
NH
O
NH
O
NH
O
CH3
NH
O
NH
O
NH
O
NH
O
NH
O
NH
O
SCH
3OHO
OHO OHO
CH3
CH3
NH2
N
NH2
CH3
CH3
CH3
CH3
OHO
NH
O
NH
NH
O
NH
NH2
NH
O
NH
O
NH
N
OO
NH
O
OH
NH
O
OH
NH
O
NH
O
CH3
N
O
N
O
N
O
NH
O
OH
NH2
CH3
OH
O
O
CH3
O
OHOH
CH3
NH2
O
NH
O
NH
OO
NH
O
NH
NH
O
NH
O
NH
O
NH
O
NH
O
NH
O
CH3
OH
CH3
CH3
OH
NH2
O NH2
OHO
O
NH
O
NHNH2
NH
N
Exenatide Drug substance
39 amino acid peptide
Exenatide Disposable Pen-injector ‘Infinity’ platform
5 mcg or 10 mcg per injection 1.2 mL Demonstration pen
Exenatide Injection 1.2 & 2.4mL cartridge for injection
0.25mg/mL strength
H His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met
Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn
Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser NH2
10
20
30 39
Exenatide Introduction
Formulations to Shorten Exposure Time and Tmax
0 60 120 180 240 300 360 420 4800
100
200
300
400 5 mcg SC
600 mcg IN
10 mcg SC(previous study)
Time (min)
Pla
sm
a E
xen
ati
de (
pg
/mL
) Intranasal or
transmucosal
formulation
with permeation
enhancer
Kim D et al. Dia Care 2007;30:1487-1493
Poly-(d,l-lactide-co-glycolide)
Formulation to Lengthen Exposure Time
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
Know Your Technology Options
27 11MAY2012 CACO-SF CRhodes
Achieving the Optimum Peptide Product
•Know your drug properties
•dose, solubility, pharmacokinetics and clinical profile
•Know your business
•Generic, fast-follower, innovator
•Know your market
•competitive product profiles, pricing constraints
•Know your customers
•patients, physicians, nurse practitioners, regulators
•Know your technology options
•delivery profile, formulation constraints, device requirement, ease
of scale-up, manufacturing systems / supply chain, cost
Thank you
Dog Beach and Hotel Del Coronado, San Diego, CA
29 11MAY2012 CACO-SF CRhodes
