Peptides in Clinical Development, CACO 2012

Peptides in Clinical Development

CACO San Francisco 11 May 2012

Christopher A. Rhodes, Ph.D. [email protected] 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

11MAY2012 CACO-SF CRhodes 2 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

11MAY2012 CACO-SF CRhodes 3 Peptides in Clinical Development •334 therapeutic peptides reviewed 2010 (J Reichert) •131 in Development, 54 Approved, 149 Terminated

In Review Phase 3

Phase 2

Phase 1

0 20 40 60 80 •18% studied for cancer •17% for metabolic (diabetes, obesity, osteoporosis) •Allergy, immunological, cardiovascular disease •Most for extracellular receptors, most GPCR agonists

11MAY2012 CACO-SF CRhodes 4 Properties of Biologics

100 Antibodies 100

10 10 (hrs) life -

Dose (mg) Dose Proteins Half

1 Peptides 1

1 10 100 Molecular Weight (kD)

11MAY2012 CACO-SF CRhodes 5 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

11MAY2012 CACO-SF CRhodes 6 PK profiles for insulin zinc products

Short-acting (solution) – Drug property controlled Intermediate-acting absorption and elimination phase (suspension)

Long-acting (suspension) – Dissolution Intermediate-acting controlled absorption results in longer exposure (suspension) Peptide Exenatide (Byetta): t½ 1-2 hrs (SC) Pharmacokinetics

Native GLP-1: t½ 2 min (IV)

Kothare P A et al. J Clin Pharmacol 2008;48:1389-1399

Liraglutide (Victoza): t½ 13 hrs (SC)

Vilsbøll T et al. JCEM 2003;88:220-224

11MAY2012 CACO-SF CRhodes 8 Peptide Drug Products: Combination Products with Trivalent Complexity

Molecule Formulation Device •Efficacy / side effects •Process complexity / scale-up •Device complexity •Continuous or pulsatile •Bioavailability / efficiency •Ease of use / acceptance •Cost per gram •Cost for process / fill / finish •Cost per unit •Physicochemical properties •Compatibility with molecule •Formulation compatibility

Biology & Chemistry PK & Formulation Device & Handling

11MAY2012 CACO-SF CRhodes 9 Selected Peptides FDA Approved in 2000-2010 Product generic name Status Indication Company (Partner) Victoza liraglutide 2010 Diabetes Novo Egrifta tesamorelin 2010 HIV-associated EMD Serono lypodistrophy Firmagon degarelix 2008 Prostate cancer Ferring Somatuline lanreotide 2007 Acromegaly Biomeasure Depot 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 3751 after recombinant production) degarelix Synthetic analogue of GnRH decapeptide 1692 lanreotide Synthetic analogue of somatostatin in self-forming 1096 gel concentrate exenatide Synthetic hormone from saliva of the Gila monster 4187 (GLP-1 agonist) 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

11MAY2012 CACO-SF CRhodes 12 Selected Peptides in Late Stage Development Product Product Status Indication Company Strategy (Partner) Firazyr Acute use SC Appro Acute Hereditary Shire (Jerini self-injection ved Angioedema buy-out) Bydureon Weekly, Appro Type II Diabetes Amylin (Lilly) microsphere ved Omontys Monthly, PEG Appro Anemia in Chronic Affymax (peginesatide) peptide dimer ved Renal Failure pts (Takeda) Linaclotide Daily oral Ph 3 Irritable Bowel / CC Ironwood Davunetide Daily injection Ph 2/3 Progressive Allon Tau-related Supranuclear Palsy KAI – 4169 IV Ph 2 Secondary KAI hyperparathyroidism 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 11MAY2012 CACO-SF CRhodes 13 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

11MAY2012 CACO-SF CRhodes 14 Content

11MAY2012 CACO-SF CRhodes 15 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)

11MAY2012 CACO-SF CRhodes 16 Selected Peptides in Early Development

Product Product Strategy Status Indication Company (Partner)

Cilengitide Cyclic RGD Ph 2 Glioblastoma Merck Serono pentapeptide Cenderitide Infusion pump Ph 1 Heart failure Nile (Medtronic) Mutliple Weekly PEG, dual Ph 1 Diabetes Roche compounds agonists ($Marcardia) VRS-859 Monthly, XTEN Ph 1 Diabetes Diartis VRS-317 Monthly, XTEN Ph 1 GH deficiency Versartis ATX-MS- 4 peptides mimicing Ph 1 Multiple Apitope 1467 Myelin basic protein sclerosis (Merck Serono) Danegaptide Dipeptide, IV, Oral Ph 1 Cardiovascular Zealand Pepducins Lipidated peptide, Preclin Oncology and Anchor (Ortho allosteric modulator metabolics McNeil Jannsen) RM131 Ghrelin agonist Preclin GI disorders Rhythm RM493 MC4R agonist Obes & Diab Therapeutics Content

11MAY2012 CACO-SF CRhodes 18 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

11MAY2012 CACO-SF CRhodes 19 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

11MAY2012 CACO-SF CRhodes 20 Content

11MAY2012 CACO-SF CRhodes 21 Selected Peptides in Delivery Systems

Product Product Status Indication Company Strategy (Partner) Oracal Oral calcitonin Ph 3 osteoporosis Tarsa (Unigene) Afrezza Inhalation Ph 3 Diabetes Mannkind insulin PassPort Transdermal Ph 2 Diabetes Altea Patch insulin Nasulin Nasal insulin Ph 2 Diabetes FSB (CPEX) Viaderm Transdermal Ph 2 Osteoporosis Transphama (Lilly) hPTH PTH ZP PTH Microneedle Ph 2 Osteoporosis Zosano PTH ITCA-650 Implantable Ph 2 Diabetes Intarcia exenatide Oral HDV-1 Oral insulin Ph 1 Diabetes Diasome Smart Glucose Ph 1 Diabetes Biodel Insulin responsive INS Case Study: GLP-1 Analogues

Product Product Status Technology Company Strategy (Partner) Bydureon Weekly Approv Medisorb Amylin (Lilly) microsphere ed (Alkermes) Lyxumia Daily GLP-1 Ph 2 Fatty acid Sanofi (Zealand) (lixisinetide) plus Lantus conjugate LY2189265 Weekly GLP-1, Ph 2/3 Recombinant Fc Lilly Fc fusion LAPS Exendin4 Monthly exen, Ph 2 Chemically bound Hanmi (HM11260C) Fc conjugate Fc through PEG ITCA 650 6 mo exendin Ph 2 Duros implant Intarcia implant (Alza) Exendin XTEN Monthly exen Ph 1 Peptide oligomer Versartis conjugate (Amunix) MAR701 GLP-1, GIP Ph 1 Peptide dual Roche (Marcadia) dual agonist agonist, plus PEG Oral GLP-1 Ph 1 Permeation Novo (Emisphere, analogues enhancers Merrion) Exenatide Introduction

O NH O OH 2 N O NH OH HO CH HO CH3 3 O OH O O O O O NH NH NH NH NH NH NH NH NH NH H2N NH NH O CH O O O O O O 3 Exenatide OH H N CH 2 Drug substance 3 O OH O OH NH CH H C 39 amino acid peptide 3 3 H C CH CH 3 3 3 O O O O O CH3 O O NH NH NH NH NH NH NH NH NH NH NH NH NH O CH O O CH3 O O O 3

NH2 S CH3 N NH O OH CH3 O OH 2 O

O NH2 O NH NH O OH NH NH O O O O O OH O N NH NH O NH NH N N N NH2 H2N O O CH NH OH 3 O

Exenatide Injection H His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met 10 Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn 1.2 & 2.4mL cartridge for injection 20

Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser NH2 0.25mg/mL strength 30 39

Exenatide Disposable Pen-injector ‘Infinity’ platform 5 mcg or 10 mcg per injection 1.2 mL Demonstration pen

24 Formulations to Shorten Exposure Time and Tmax

600 mcg IN Intranasal or 400 5 mcg SC transmucosal 10 mcg SC formulation (previous study) 300 with permeation enhancer

200

100

Plasma Exenatide (pg/mL) Exenatide Plasma 0 0 60 120 180 240 300 360 420 480 Time (min) Formulation to Lengthen Exposure Time

Poly-(d,l-lactide-co-glycolide)

Kim D et al. Dia Care 2007;30:1487-1493 Know Your Technology Options

Molecule Delivery System Device •Efficacy / side effects •Process complexity •Device complexity •Continuous or pulsatile •Bioavailability •Ease of use / acceptance •Cost per gram •Cost per unit •Cost per unit •Physicochemical properties •Compatibility with molecule •Formulation compatibility

Biology & Chemistry PK & Formulation Device & Handling

11MAY2012 CACO-SF CRhodes 27 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

11MAY2012 CACO-SF CRhodes 29