Ferring Research Institute, 4245 Sorrento Valley Blvd, San...
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Jolene L. Lau , Michael K. Dunn Ferring Research Institute, 4245 Sorrento Valley Blvd, San Diego, CA. 92121, USA Of the 474 therapeutic peptides in the core data set, just under half are 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 Approved, 56, 12% Withdrawn, 8, 2% 31% 52% 15% 2% Phase I Phase II Phase III Preregistration Phase breakdown of peptides in development 0 20 40 60 80 100 120 1980s 1990s 2000s 2010-present* Number of Peptides Discontinued/ Withdrawn Phase I Phase II Phase III Preregistration Approved Final fate known: 98% 90% 63% 18% Most of the peptides that entered the clinic in the 1980s and 1990s have either been discontinued or approved in one or more countries. 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-present Metabolic 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 for peptide development in the 1980s, but over a third of peptides that entered 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 for editorial support, and Claudio Schteingart, Gebhard Neyer, Jennifer Liberal, Geoffrey Harris, and the FRI brainstorming team for valuable feedback and suggestions. Peptides are an important class of therapeutics, with over 60 peptide 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 >500 peptides that have entered human clinical studies (~250 currently approved 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 tested in clinical trials; “withdrawn” refers to previously approved products no longer on the market; “discontinued” refers to programs that were terminated prior to approval. An analysis of peptide therapeutics development trends was previously published 2010 Janice Reichert, et al. with funding from the Peptide Therapeutics Foundation. Definitions and Introduction 4.2 10 19.8 16.6 0 5 10 15 20 25 1980s 1990s 2000s 2010-present* Average Number of Peptides/Year Time Period *as of 10/5/2016 Although the average number of peptides entering clinical trials increased in the 1990’s and 2000’s, this pace has slowed in the 2010–present timeframe. Note that these numbers are per-year averages. Average Number of Peptides Entering Clinical Trials Current Development Status of Peptides Current Status/Fate of Therapeutic Peptides 0% 5% 10% 15% 20% Allergy and Immunology Antimicrobial; Antiviral Bones and connective tissues Cardiovascular CNS Dermatology Endocrinology Gastroenterology Hematology Hepatology and Critical 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 0 50 100 150 200 250 1980s 1990s 2000s 2010-present* Peptides entering the clinic Percentage of Conjugated Peptides Conjugated Not conjugated 14% 6% 19% 21% 34 53 70 26 0 16 42 23 4 10 24 12 2 14 32 21 0 3 6 3 2 4 24 27 0 10 20 30 40 50 60 70 80 1980s 1990s 2000s 2010-present* Number of Peptides 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 study over the given time period. Peptides entering the clinic in recent decades are of increasing complexity with respect to length and conjugation. Length and Physical Properties of Peptides Entering Clinical Study, by Time Period 0 5 10 15 20 25 30 35 40 1980's 1990's 2000's 2010-present* Conjugates entering the clinic Time Period Common Conjugate Moieties Conjugated to other entity Conjugated to Peptide Conjugated to Other Small Molecule Lipidated PEGylated Fused/conjugated/ complexed to protein *as of 10/5/2016. 23% 41% 79% 92% 4% 10% 58% 90% 23% 28% 69% 97% 0% 20% 40% 60% 80% 100% Phase I Phase II Phase III Regulatory Probability of Regulatory Approval NBE, CMR NCE, CMR Peptide, PTX DB Peptide regulatory success rates are intermediate between NBE and NCE rates. Most peptides are considered chemical entities by regulatory agencies. NBE=new biological entity; NCE=new chemical entity. Sources: CMR 2015 Factbook; FRI Peptide Therapeutics Database 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 peptides that have been modified to improve activity or pharmacokinetics. Chemical Basis of Approved/Phase 3 Peptide Therapeutics 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1980's 1990's 2000's 2010-present* % of Peptides Entering Trials Intracellular targets Other extracellular targets Ion channels Anti-microbial targets Catalytic receptors GPCR GPCRs are popular peptide targets, but other extracellular targets, such as receptor tyrosine kinases and ion channels have increased in popularity in recent years. Few peptides with intracellular targets enter the clinic. 0 5 10 15 20 25 30 35 40 1980's 1990's 2000's 2010-present* Number of Peptides Entering Trials GPCR-A agonist GPCR-A antagonist GPCR-B agonist GPCR-B antagonist 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 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Afamelanotide Dulaglutide Oritavancin Albiglutide Lixisenatide Teduglutide Linaclotide Carfilzomib Pasireotide Peginesatide Lucinactant Tesamorelin The bars indicate the time period from start of clinical trials to first regulatory approval. This graph includes all peptides approved in the 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 & Johnson Amylin Zealand Pharma Sanofi-Aventis Daiichi Sankyo GlaxoSmithKline Shire The Medicines Company Ironwood Ferring Abbott/AbbVie Ipsen Amgen Mallinckrodt Takeda Eli Lilly AstraZeneca Novartis Novo Nordisk Teva 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 0 10 20 30 40 50 60 70 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Cumulative Number of Approved Peptides First approval, any country First approval, US Over 60 peptides were approved in major markets worldwide, as of 2016. This figure includes peptides that were initially approved but later withdrawn from the market. No new peptides have been approved in 2015 and 2016 (as of 10/20/2016), aside from the US approval 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
Transcript of Ferring Research Institute, 4245 Sorrento Valley Blvd, San...
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
0
20
40
60
80
100
120
140
1980s 1990s 2000s 2010-present*
Nu
mb
er
of
Pe
pti
de
s
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
4.2
10
19.8
16.6
0
5
10
15
20
25
1980s 1990s 2000s 2010-present*
Ave
rage
Nu
mb
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of
Pe
pti
de
s/Ye
ar
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
0
50
100
150
200
250
1980s 1990s 2000s 2010-present*
Pe
pti
de
s e
nte
rin
g th
e c
linic
Percentage of Conjugated Peptides
Conjugated
Not conjugated
14%
6%
19%
21%
34
53
70
26
0
16
42
23
4
10
24
12
2
14
32
21
03
632 4
2427
0
10
20
30
40
50
60
70
80
1980s 1990s 2000s 2010-present*
Nu
mb
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of
Pe
pti
de
s
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
0
5
10
15
20
25
30
35
40
1980's 1990's 2000's 2010-present*
Co
nju
gate
s e
nte
rin
g th
e c
linic
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%
20%
40%
60%
80%
100%
Phase I Phase II Phase III Regulatory
Pro
bab
ility
of
Re
gula
tory
Ap
pro
val
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
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1980's 1990's 2000's 2010-present*
% o
f P
ep
tid
es
Ente
rin
g Tr
ials
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.
0
5
10
15
20
25
30
35
40
1980's 1990's 2000's 2010-present*
Nu
mb
er
of
Pe
pti
de
s En
teri
ng
Tria
ls GPCR-A agonist
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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95
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20
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07
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20
09
20
10
20
11
20
12
20
13
20
14
20
15
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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90
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Cu
mu
lati
ve N
um
be
r o
f A
pp
rove
d
Pe
pti
de
s
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
