Antibody Engineering & Therapeutics December 14, 2017 - Janice M. Reichert, Ph.D. Executive Director, The Antibody Society Editor-in-Chief, mAbs ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Antibody Engineering & Therapeutics
December 14, 2017
Janice M. Reichert, Ph.D.
Executive Director, The Antibody Society
Editor-in-Chief, mAbs
1
The Antibody Society
• The Antibody Society is a non-profit trade association
representing individuals and organizations involved in
antibody R&D
• We pursue initiatives intended to broadly benefit the
field of antibody R&D, e.g.,
• INN source infix issue
• Development metrics
• Standards for next-generation sequencing data (Adaptive
Immune Receptor Repertoire Community)
• We engage in activities that broadly benefit our
members, such as education and publishing, and help
to organize conferences
2
Topics for discussion
• Newly on the market (or soon to be)
• Recent first approvals for antibody therapeutics
• Antibodies in regulatory review
• Antibodies in late-stage clinical development
• Possible near-term marketing application submissions
(details in supp. slides)
• Near-term study primary completion dates (supp. slides)
• Antibody therapeutics development metrics
• Data collected
• Success rates
3
4
First US or EU approvals of mAbs
12
10
Number of first approvals for mAbs
9
8
6 6
6
4
2
0
02
17*
97
98
99
00
01
03
04
05
06
07
08
09
10
11
12
13
14
15
16
Year of first US or EU approval
*Projected number of first approvals. Table of approvals and antibodies in review at antibodysociety.org
5
10 first US or EU approvals in 2017
• Sarilumab (Kevzara)
• Targets IL-6R; US and EU approved for rheumatoid arthritis
• Brodalumab (Siliq, Lumicef)
• Targets IL-17RA; US and EU approved for plaque psoriasis
• Guselkumab (Tremfya)
• Targets IL-23p19; US and EU approval for plaque psoriasis
• Dupilumab (Dupixent)
• Targets IL-4Ra; US and EU approval for atopic dermatitis
• Ocrelizumab (Ocrevus)
• Targets CD20; US for multiple sclerosis; EC decision pending
6Ten first approvals in 2017… (cont.)
• Benralizumab (Fasenra)
• Targets IL-5a; US approval for asthma, EC decision pending
• Emicizumab (Hemlibra
• Targets Factor Ixa, X; US approval for hemophilia A, EU
review
• Avelumab (Bavencio)
• Targets PD-L1; US and EU approval for Merkel cell
carcinoma
• Durvalumab (Imfinzi)
• Targets PD-L1; US approval for urothelial carcinoma, EU
review
• Inotuzumab ozogamicin (Besponsa)
• Targets CD22; US and EU approval for acute lymphoblastic
leukemia
7Nine first EU or US approvals in 2018?
• Ibalizumab, targeting CD4 for drug resist. HIV infection
• Priority review; Breakthrough Therapy, US orphan designations
• PDUFA date Jan 3, 2018
• Burosumab, anti-FGF23 for X-linked hypophosphatemia
• Breakthrough Therapy designation in US;
• PDUFA date Apr 2018
• Tildrakizumab, targeting IL-23p19 for plaque psoriasis
• Caplacizumab, targeting von Willebrand factor for acquired
thrombotic thrombocytopenic purpura
• Positive Phase 3 results released in Oct 2017; FT, but no BLA
yet
Source: antibodysociety.org
81st EU or US approvals in 2018?
• Erenumab, targeting CGRP receptor for prev. of migraine
• Fremanezumab, targeting CGRP for migraine prevention
• Galcanezumab (LY2951742), IgG4 targeting CGRP for
migraine prevention
• Fast track designation for treatment of cluster headache, with
Phase 3 trial results expected in 2018
• Romosozumab, targeting sclerostin for osteoporosis
• Heart-related side effects observed in Phase 3 study
• Complete response letter requesting additional clinical data from
Phase 3 studies (ARCH and BRIDGE) in July 2017
• Mogamulizumab, targeting CCR4 for cutaneous T cell lymphoma
Source: antibodysociety.org
910
mAb pipeline
275
250
225
200
175
150
125 260 250
100
75
50
25 54
0
Phase 1 Phase 2 Late-stage study
Total pipeline = ~560 mAbs. Commercial development; Phase 1/2 included with Phase 2, Phase 2/3 included with
Phase 3. Tables of mAbs in Phase 3 available at www.antibodysociety.org and in ‘Antibodies to watch in 2018’ paper
11Antibodies in late-stage studies*
60
53 54
52
Number of mAbs in Phase 3 50
40 39
33
30 29
26 25 25
20
10
0
2010 2011 2012 2013 2014 2015 2016 2017 2018#
Year of article publication
* Data from ‘Antibodies to watch’ articles published in mAbs; #: projection
12First applications submitted in late
2017 or during 2018?
• 8 for non-cancer indications: lanadelumab, crizanlizumab,
ravulizumab, eptinezumab, risankizumab, satralizumab,
brolucizumab, PRO140
• 4 for cancer indications: sacituzumab govitecan,
moxetumomab pasudotox, cemiplimab, ublituximab
• See supplemental slides posted in presentations section
at www.antibodysociety.org and ‘Antibodies to watch in
2018’, soon to be posted in the Latest articles section of
the mAbs website, for details
1314
Drug development metrics
• Assess performance of the pharmaceutical industry, and
serve as benchmarks for individual companies
• Success rates are useful for setting expectations for
clinical development of drugs, e.g.,
• Phase transition and approval success rates
• Phase 1 to 2, Phase 2 to 3, Phase 3 to reg. review;
overall rate from Phase 1 to approval
• Global, US or EU approvals
15Data collected
• Top-level data on all commercially sponsored antibodies
currently in clinical study and those that entered clinical
study during 2000-2016, but were terminated
• Name(s) and company
• Molecular characteristics (sequence source, isotype,
any modifications, target)
• Clinical development data (dates of transitions,
indications of studies)
• First regulatory review (focus on EU and US)
• First marketing approval (focus on EU and US)
• As of Oct 1, 2017, dataset includes over 950 molecules
16Rates comparison
100 94
90 88
80 75 75
72 71
70
60
50 44 44
40
30
21 22
20
10
0
Phase 1 to 2 Phase 2 to 3 Phase 3 to RR RR to approval Phase 1 to approval
Biologics (1) All mAbs, '00-09 (3)
Sources: 1. Hay et al Nat Biotechnol 2014; 2. Society est. 9/05/17
17Study start 2000-09, US/EU approvals
100 94 96
90
90
82
80 78
75 74
69 71 71 71
70
60
50 44 46 44
41
40
30
22 20 24 24
20
10
0
Phase 1 to 2 Phase 2 to 3 Phase 3 to RR RR to approval Phase 1 to approval
00-09, all Cancer only Non-cancer only Unmod., full-length, non-murine
# of molecules: 00-09, all, n=358; Cancer only, n=176; Non-cancer only, n=182; Unmod., full-length, non-murine, n=265.
Final fates (approval or termination) are known for 71%. Three approvals outside the US/EU regions (mogamulizumab approval in
Japan, italizumab and Rmab approvals in India) classified as Phase 3
18Study start 2005-14, US/EU approvals
100
90
79 80 80 80 82
80 74
72
70 64
60
51
50 46
43 44
40
30 26 26 27 27
20
10
0
Phase 1 to 2 Phase 2 to 3 Phase 3 to RR RR to approval Phase 1 to approval
00-09, all Cancer only Non-cancer only Unmod., full-length, non-murine
# of molecules: 05-14, all, n=566; Cancer only, n=270; Non-cancer only, n=296; Unmod., full-length, non-murine, n=426. Final fates
(approval or termination) are known for 47%. Three approvals outside the US/EU regions (mogamulizumab approval in Japan,
italizumab and Rmab approvals in India) classified as Phase 3
19To conclude…
• Number of mAbs in late-stage clinical studies expected
to drive trend toward first approvals for ~6-9 new mAbs
per year (or more) into the future
• 2018 will be an active year! Currently watching:
• 11 applications in US or EU regulatory review
• 12 possible marketing application submissions (8 non-cancer,
4 cancer)
• 19 antibodies with top-level Phase 3 results expected (10
non-cancer, 9 cancer)
• Success rates for antibody therapeutics development
holding at relatively high levels (20-24%, P1-approval)
20Support provided by… 21
Support also provided by… 22
Please join us!
www.antibodysociety.org
Tables of approved antibody therapeutics, antibodies
in regulatory review and Phase 3 can be found in the
Members Only section
Janice M. Reichert, Ph.D.
Executive Director, The Antibody Society
Editor-in-Chief, mAbs
janice.reichert@antibodysociety.org
2324
8 first applications submitted in
late 2017 or during 2018?
• 3 for cardiovascular/hemostasis disorders
• 1 for pain indications
• 2 for immune-mediated disorder
• 1 for ophthalmic indication
• 1 for infectious disease
25CV / hemostasis
1. Lanadelumab (DX-2930), targeting plasma kallikrein for
hereditary angioedema attacks
• Positive results in Phase 3 HELP study
• Breakthrough therapy and Fast Track designations, EU and US
orphan designations
• Shire plans to submit a BLA by late 2017 or early 2018, MAA in H1
2018
2. Crizanlizumab (SEG101), targeting CD62 (aka P-selectin) for
sickle cell pain crises caused by vaso-occlusion
• Positive Phase 2 results reported in Dec 2016
• US and EU orphan designations
• Crizanlizumab was discussed with health authorities, and based
on their feedback Novartis expects to submit for regulatory
approval in the US in 2018. This assumes successful PK/PD
comparability study to final manufacturing process
26CV / hemostasis (cont.)
3. ALXN1210, targeting C5 for paroxysmal nocturnal
hemoglobinuria and atypical hemolytic uremic syndrome
• 2 Phase 3 studies in PNH with primary completion dates of
Dec 2017 and Mar 2018; 2 Phase 3 studies in aHUS with
primary completion dates in Dec 2017 and Dec 2018
• Orphan designations in EU and EU for PNH
• 2018 BLA submission planned
27Pain
Anti-calcitonin gene-related peptide mAb for migraine
prevention
4. Eptinezumab (ALD403), IgG1
• Positive results from Phase 3 PROMISE 1 study
• BLA may be submitted by end of 2018
28Immune-mediated disorders
5. Risankizumab (ABBV066, BI655066), targeting IL-23 p19
subunit for psoriasis
• 4 Phase 3 studies in psoriasis with primary completion dates
Nov 2016 – Mar 2017; data may be released in 2017
• BLA submission for psoriasis planned in 2018, with launch
expected in 2019
• 3 Phase 3 studies in Crohn’s disease not yet recruiting; US
orphan designation for CD in pediatric patients
6. Satralizumab (SA237), IgG2 targeting IL-6R for neuromyelitis
optica (NMO) and NMO spectrum disorder
• 2 Phase 3 studies, primary completions in July and Oct 2018
• Application submission anticipated in 2018 (as per Roche
pipeline)
29Ophthalmic
7. Brolucizumab, scFv targeting VEGF-A for
neovascular age-related macular degeneration
• Positive results from Phase 3 HAWK and HARRIER studies
• Brolucizumab enables much higher concentrations of
antibody in the eye than approved therapies. Given the
complexity of the formulation, Novartis has invested to
ensure a competitive, low cost of goods formulation over the
past 18 months to maximize long term value. Novartis
expects to complete the pharmacokinetic study with the final
manufacturing process to enable filing in 2018.
30Infectious disease
8. PRO140, IgG4 targeting CCR5 for HIV infection
• Two Phase 2/3 studies with primary completion dates in Oct and
Dec 2017
• Fast Track designation
• Cytodyn expects to submit rolling BLA; company has meeting
with FDA on Oct 12, 2017 purpose of the meeting will be to
address open issues set forth in an FDA memorandum
regarding the adequate number and type of evaluable patients
required for efficacy and safety necessary to support the filing of
a Biologics License Application
312017/8 Phase 3 results for 10 mAbs
• 1 for ophthalmic indication
• 3 for cardiovascular/hemostasis disorders
• 3 for neurological disorders (pain, Alzheimer’s disease)
• 3 for immune-mediated diseases
32Ophthalmic: Antibody to watch
1. Lampalizumab (RG7417, FCFD4514S), Fab
targeting Factor D
• NCT02247531 Spectri and NCT02247479 Chroma
studies are evaluating lampalizumab administered
intravitreally to patients with geographic atrophy
secondary to age-related macular degeneration
• Primary endpoint was not met in Spectri study
• Primary completion date of Chroma study is Nov 2017
33CV / hemostasis: Abs to watch
2. Roledumab (LFB-R593), targeting Rhesus D for Rh
disease
• Phase 2/3 NCT02287896 active, not recruiting patients;
primary completion date in November 2017
3. NEOD001, targeting amyloid for AL amyloidosis
• VITAL amyloidosis study has primary completion date in
January 2018
• Fast track designation for the potential treatment of AL
amyloidosis
• Topline results in the Phase 2b PRONTO study (129
patients) expected in the second quarter of 2018
34CV / hemostasis (cont.)
4. Emapalumab (NI-0501), targeting IFN gamma for primary
hemophagocytic lymphohistiocytosis
• Condition characterized by the overwhelming activation of
normal T lymphocytes and macrophages, invariably leading
to clinical and hematologic alterations and death in the
absence of treatment
• PRIority MEdicines (PRIME), orphan designations in EU
• Breakthrough therapy, rare pediatric disease, orphan
designations in US
• Phase 2/3 study has primary completion date in December
2017
35Pain: Antibodies to watch
Anti-nerve growth factor mAbs for pain due to osteoarthritis of
knee or hip, low back pain
5. Fasinumab (REGN475/SAR164877), IgG4
• Phase 2/3 primary completions: Jun 2017, Sep 2019
• Phase 3 primary completions: Feb 2018, Mar 2019, Aug 2020
• Phase 3 NCT03285646 study not yet recruiting
6. Tanezumab (PF-04383119), IgG2
• 7 Phase 3 studies recruiting, 1 Phase 3 study not yet
recruiting; NCT02528253 primary completion date in Nov
2017, other Phase 3 studies with primary completion dates in
May 2018 and Sep 2018
36Alzheimer’s disease: Ab to watch
7. Gantenerumab (RO4909832), targeting amyloid-b
• Phase 3 NCT02051608 study in patients with mild
Alzheimer’s disease initiated in March 2014 has primary
completion date in July 2018
• Phase 3 NCT01224106 study in patients with prodromal
Alzheimer’s disease initiated in November 2010 has primary
completion date in July 2020; 105 mg and 225 mg SC
doses are being evaluated
37Immune-mediated disorders:
Antibodies to watch
8. Etrolizumab targeting β7 subunit of α4β7 and αEβ7
integrin heterodimers for ulcerative colitis
• 2 Phase 3 studies, primary completions in March 2018
9. Anifrolumab, targeting type-I IFN receptor subunit 1 for
systemic lupus erythematosus
• 2 Phase 3 studies, primary completions in Jul, Sep 2018
3839
4 application sub in 2017/8?
1. Sacituzumab govitecan, humanized anti-Trop-2 antibody
conjugated to SN38
• Immunomedics announced that they were on track to submit a BLA for
accelerated approval of sacituzumab govitecan as third-line treatment for
mTNBC by the end of March 2018
• Fast track designation
2. Moxetumomab pasudotox, dsFv immunotoxin targeting
CD22 for hairy cell leukemia
• Phase 3 primary completion date May 24, 2017
• US orphan designation for hairy cell leukemia
• AstraZeneca estimates BLA filing date in 2018
404 application sub in 2017/8? (cont.)
3. Cemiplimab (REGN2810), targeting PD-1
• NCT02760498, a potentially pivotal Phase 2 study, is enrolling patients
with metastatic cutaneous squamous cell carcinoma (CSCC) and
locally advanced and unresectable CSCC; initiation was Mar 2016 and
primary completion date is May 2019
• Breakthrough therapy designation for CSCC
• Phase 3 studies in cervical cancer and NSCLC, with primary
completion dates of May 2020 and Nov 2021, respectively
• Pending data results, the companies (Regeneron and Sanofi)
anticipate submitting a BLA for cemiplimab in Q1 2018
414 application sub in 2017/8? (cont.)
4. Ublituximab (LFB-R603, TGT-1101), mAb targeting
CD20 produced in low fucose (YB2/0 cell line) for chronic
lymphocytic leukemia
• Positive results from Phase 3 GENUINE study
(NCT02301156) in CLL; Phase 3 UNITY-CLL study
(NCT02612311) has primary completion date in Sep 2018
• TG Therapeutics 2017 milestones include meeting with FDA
to review the GENUINE Phase 3 data and discuss suitability
for filing for accelerated approval.
• Two Phase 3 studies in multiple sclerosis also recruiting
422018 Phase 3 results expected for
9 mAbs
1. Tremelimumab, targeting CTLA4, evaluated in combo with
durvalumab
• Phase 3 MYSTIC study in NSCLC did not meet primary
endpoint; Phase 3 ARCTIC and NEPTUNE studies in NSCLC
have primary completion dates in Nov 2017 and Oct 2018
• Phase 3 Kestrel (1st-line HNSCC), Phase 3 Eagle (2nd-line
HNSCC) studies with data expected in Feb and Mar 2018,
respectively
• Phase 3 NCT02516241 study in urothelial cancer has a
primary completion date in April 2018
• Phase 3 HIMALAYA study in unresectable hepatocellular
carcinoma not yet recruiting as of Oct 10
43Phase 3 results (continued)
2. Isatuximab (SAR650984), targeting CD38 for plasma cell
myeloma
• Phase 3 NCT02990338 study has primary completion
date in May 2018
3. Carotuximab, targeting CD105 (aka endoglin) for
angiosarcoma
• Phase 3 NCT02979899 study (TAPPAS) has primary
completion date in Sep 2018
• US orphan drug for the treatment of soft tissue sarcoma;
fast track designation, but in renal cell cancer
44Phase 3 results (cont….)
4. BCD-100, targeting PD-1 for melanoma
• Phase 2/3 NCT03269565 (MIRACULUM) study has
primary completion date in Aug 2018
5. Camrelizumab (SHR-1210), targeting PD-1
• Phase 3 NCT03099382 study in esophageal carcinoma
and Phase 2/3 NCT02989922 study in hepatocellular
carcinoma have primary completion dates in June and
Dec 2018, respectively
45Late-stage ADCs
6. Glembatumumab vedotin, ADC targeting gp NMB for
metastatic gpNMB over-expressing triple-negative BC
• Pivotal Phase 2 METRIC study has primary completion date
in December 2017
• Fast track designation for gpNMB+ breast cancer
7. Mirvetuximab soravtansine (IMGN853), ADC targeting
folate receptor alpha for FRa+ adv. ep. ovarian cancer,
primary peritoneal or fallopian tube cancer
• Phase 3 FORWARD I study has primary completion date in
November 2018
46Late-stage immunoconjugates
8. Oportuzumab monatox, PE-scFv targeting EpCAM for
bladder cancer
• Phase 3 has primary completion date in Dec 2018
9. L19IL2/L19TNF, scFvs targeting fibronectin extra-domain
B conjugated to either IL2 or TNF, evaluated as a
mixture, for melanoma
• Phase 3 study has primary completion date in Dec 2018
• Patients will receive multiple intratumoral
administrations into all injectable cutaneous,
subcutaneous, and nodal tumors of a mixture of L19IL2
and L19TNF once weekly for up to 4 weeks
47You can also read
