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Jolene L. Lau, Michael K. DunnFerring Research Institute, 4245 Sorrento Valley Blvd, San Diego, CA. 92121, USA

Of the 474 therapeutic peptides in the core data set, just under halfare approved or in clinical development.

Approved, 56, 12%

Withdrawn, 8, 2%

31%

52%

15%

2%Phase I

Phase II

Phase III

Preregistration

Phase breakdown of peptides in development

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1980s 1990s 2000s 2010-present*

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Discontinued/Withdrawn

Phase I Phase II Phase III Preregistration Approved

Final fate known:

98% 90% 63% 18%

Most of the peptides that entered the clinic in the 1980s and 1990shave either been discontinued or approved in one or morecountries. However, 37% and 82% of peptides that entered clinical

trials in the 2000s or 2010s are still in development.

Primary Therapeutic Area (TA) 1980s 1990s 2000s 2010-presentMetabolic 1 (2%) 12 (12%) 30 (15%) 40 (35%)Oncology 5 (11%) 8 (8%) 32 (16%) 15 (13%)Gastroenterology 3 (7%) 6 (6%) 9 (4%) 8 (7%)Cardiovascular 8 (19%) 9 (9%) 19 (9%) 8 (7%)Allergy and Immunology 2 (4%) 6 (6%) 9 (4%) 6 (5%)Antimicrobial & antiviral 2 (4%) 11 (11%) 18 (9%) 5 (4%)Respiratory 1 (2%) 4 (4%) 2 (1%) 6 (5%)Urology 3 (7%) 9 (9%) 11 (5%) 4 (3%)CNS 3 (7%) 12 (12%) 14 (7%) 3 (2%)Endocrinology 3 (7%) 3 (3%) 7 (3%) 3 (2%)Ophthalmology 0 (0%) 1 (1%) 7 (3%) 3 (2%)Hematology 1 (2%) 3 (3%) 7 (3%) 2 (1%)Pain 0 (0%) 6 (6%) 10 (5%) 2 (1%)Dermatology 1 (2%) 2 (2%) 10 (5%) 2 (1%)Hepatology & critical care 0 (0%) 0 (0%) 1 (0%) 2 (1%)Infertility and OB-GYN 8 (19%) 3 (3%) 4 (2%) 1 (0%)Orthopedics 0 (0%) 1 (1%) 2 (1%) 1 (0%)Dental 0 (0%) 0 (0%) 0 (0%) 1 (0%)Bones and connective tissues 1 (2%) 4 (4%) 6 (3%) 0 (0%)Total number of candidates entering clinical trials: 42 100 198 112

The cardiovascular and infertility TAs were the most popular forpeptide development in the 1980s, but over a third of peptides thatentered clinical trials since 2010 address metabolic diseases.

The peptide therapeutics space is one of active research and development. New methodologies have enabled the production of longer peptides and peptides conjugated to more complex chemical moieties, and companies are testing peptides in a wide range of disease indications.

We would like to thank Karina Mena and Denise Riedl foreditorial support, and Claudio Schteingart, Gebhard Neyer,Jennifer Liberal, Geoffrey Harris, and the FRI brainstormingteam for valuable feedback and suggestions.

Peptides are an important class of therapeutics, with over 60peptide drugs now approved in the US and other major markets.Peptides continue to enter clinical development at a steady pace.We have compiled and maintain a comprehensive dataset on >500peptides that have entered human clinical studies (~250 currentlyapproved or in active development by pharmaceutical companies).

Abstract

Key inclusion criteria for the peptide therapeutics database:• Each molecular entity was included only once in the database• Recombinant peptides <50aa in length; no length limit on

synthetic peptides; thus, insulin products are not included• Peptide vaccines are not included• Peptide made through synthetic or recombinant methods

rather than (non-ribosomal) bacterial fermentation• Potential regulatory/development path forward (i.e. not

purely academic-sponsored)

Only peptides with activity in major pharmaceutical markets (US,Europe, Japan) were included in the figures shown here.

Other definitions: “Development” refers to peptides being testedin clinical trials; “withdrawn” refers to previously approvedproducts no longer on the market; “discontinued” refers toprograms that were terminated prior to approval.

An analysis of peptide therapeutics development trends waspreviously published 2010 Janice Reichert, et al. with funding fromthe Peptide Therapeutics Foundation.

Definitions and Introduction

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Time Period *as of 10/5/2016

Although the average number of peptides entering clinical trialsincreased in the 1990’s and 2000’s, this pace has slowed in the2010–present timeframe. Note that these numbers are per-yearaverages.

Average Number of Peptides Entering Clinical Trials

Current Development Status of Peptides

Current Status/Fate of Therapeutic Peptides

0%

5%

10%

15%

20%

Allergy andImmunology

Antimicrobial; Antiviral

Bones and connectivetissues

Cardiovascular

CNS

Dermatology

Endocrinology

Gastroenterology

Hematology

Hepatology andCritical Care

Infertility and OB-GYN

Metabolic

Oncology

Ophthalmology

Orthopedics

Pain

Respiratory

Urology

Discontinued Approved In Development

Values are given as a percentage of all peptides within the group.Each peptide was assigned to a primary TA.

Peptide Approvals and Discontinuations, by TA

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Percentage of Conjugated Peptides

Conjugated

Not conjugated

14%

6%

19%

21%

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632 4

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Length of Peptide Candidates

2 to 10

11 to 20

21 to 30

31 to 40

41 to 50

Unknown

Peptide Length

Data labels represent the percentage of conjugated peptides entering clinical studyover the given time period.

Peptides entering the clinic in recent decades are of increasingcomplexity with respect to length and conjugation.

Length and Physical Properties of Peptides Entering Clinical Study, by Time Period

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Time Period

Common Conjugate Moieties

Conjugated to other entity

Conjugated to Peptide

Conjugated to Other SmallMoleculeLipidated

PEGylated

Fused/conjugated/ complexedto protein

*as of 10/5/2016.

23%

41%

79%

92%

4%10%

58%

90%

23%28%

69%

97%

0%

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100%

Phase I Phase II Phase III Regulatory

Pro

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NBE, CMR

NCE, CMR

Peptide, PTX DB

Peptide regulatory success rates are intermediate between NBE andNCE rates. Most peptides are considered chemical entities byregulatory agencies. NBE=new biological entity; NCE=new chemicalentity. Sources: CMR 2015 Factbook; FRI Peptide TherapeuticsDatabase 2015

Probability of Regulatory Success by Molecule Type

native, 23, 19%

analog, 69, 58%

conjugate, 16, 14%

non-native chemistry,

10, 8%

Most late-stage peptide candidates are analogs of native peptidesthat have been modified to improve activity or pharmacokinetics.

Chemical Basis of Approved/Phase 3 Peptide Therapeutics

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% o

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IntracellulartargetsOther extracellulartargetsIon channels

Anti-microbialtargetsCatalytic receptors

GPCR

GPCRs are popular peptide targets, but other extracellular targets,such as receptor tyrosine kinases and ion channels have increased inpopularity in recent years. Few peptides with intracellular targetsenter the clinic.

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GPCR-AantagonistGPCR-B agonist

GPCR-Bantagonist

Most Therapeutic Peptides Are Directed at GPCRs and other Extracellular Targets

Molecular Targets of Peptides

Peptide Modes of Action at GPCR Targets

*as of 10/5/2016

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Afamelanotide

Dulaglutide

Oritavancin

Albiglutide

Lixisenatide

Teduglutide

Linaclotide

Carfilzomib

Pasireotide

Peginesatide

Lucinactant

Tesamorelin

The bars indicate the time period from start of clinical trials to firstregulatory approval. This graph includes all peptides approved inthe US and/or EU in 2010–2016.

Development Time for Peptides Approved 2010–2016

$- $1,000 $2,000 $3,000 $4,000 $5,000

Johnson & JohnsonAmylin

Zealand PharmaSanofi-AventisDaiichi Sankyo

GlaxoSmithKlineShire

The Medicines CompanyIronwood

FerringAbbott/AbbVie

IpsenAmgen

MallinckrodtTakedaEli Lilly

AstraZenecaNovartis

Novo NordiskTeva

Global Sales – Millions of USD

2015 Peptide Sales

2009 Peptide Sales

The Peptide Sales Landscape

$- $1,000 $2,000 $3,000 $4,000 $5,000

linaclotide

lanreotide

carfilzomib

romiplostim

exenatide CR

goserelin

leuprolin acetate

corticotropin

teriparatide

octreotide

liraglutide

glatiramer

Global Sales – Millions of USD

Peptide Top Sellers, 2015

Conclusions

Acknowledgments

*as of 10/5/2016

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First approval, any country

First approval, US

Over 60 peptides were approved in major markets worldwide, as of2016. This figure includes peptides that were initially approved butlater withdrawn from the market. No new peptides have beenapproved in 2015 and 2016 (as of 10/20/2016), aside from the USapproval of a peptide previously approved in Europe.

Cumulative Number of Peptide Regulatory Approvals

Development, 178, 37%

Discontinued, 232, 49%

Native: sequence directly taken from a natural ligand.

Analog: native sequence subjected to a limited number of modifications

Conjugate: native sequence linked to an additional motif

Non-native chemistry: novel peptide developed through phage display or medicinal chemistry

Median time from clinical start to approval: 10.9 years

FDA PDUFA Dates• Abaloparatide for osteoporosis (Radius Health): Q1 2017• Plecanatide for CIC and IBS-C (Synergy Pharma): January 2017• Etelcalcetide for secondary hyperparathyroidism (Amgen):

unknown pending re-submission

EMA submissions• Plitidepsin for multiple myeloma: 2H 2017

Upcoming Peptide Regulatory Decisions

Primary TA of Peptides Entering the Clinic, by Time Period