mAbs

ISSN: 1942-0862 (Print) 1942-0870 (Online) Journal homepage: http://www.tandfonline.com/loi/kmab20

Antibodies to watch in 2019

Hélène Kaplon & Janice M. Reichert

To cite this article: Hélène Kaplon & Janice M. Reichert (2018): Antibodies to watch in 2019,
mAbs, DOI: 10.1080/19420862.2018.1556465

To link to this article: https://doi.org/10.1080/19420862.2018.1556465

Accepted author version posted online: 05

Dec 2018.

Submit your article to this journal

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=kmab20
Publisher: Taylor & Francis

Journal: mAbs

DOI: 10.1080/19420862.2018.1556465

‘Perspective’ article for publication in KMAB issue 11.2

t
ip
Submitted to production team on December 3, 2018.
Please note that this article is non-peer reviewed content; no revisions were done so there is no ‘revised’

cr
date.
Page charges are waived, because a member of the mAbs editorial staff (JR) is an author; The Antibody
Society will pay for open access.

us
an
Antibodies to watch in 2019
Hélène Kaplon1 and Janice M. Reichert2*
M
1. Institut de Recherches Servier
125 chemin de ronde, 78920 Croissy-sur-Seine
[email protected]
ed

2. The Antibody Society

247 Prospect Street
Framingham, MA USA 01701
pt

508 808-8311
[email protected]
ce

*Corresponding author

Keywords: antibody therapeutics, Food and Drug Administration, European Medicines Agency,
Ac

cancer, immune-mediated disorders, success rates

1
Abbreviations:
ADC, antibody-drug conjugate
AE, adverse events
ARR, annualized relapse rate
ART, antiretroviral therapy
aTTP, acquired thrombotic thrombocytopenic purpura

t
BCG, bacillus Calmette-Guérin

ip
BLA, biologics license application
C5, complement component 5

cr
CCR4, CC chemokine receptor 4
CGRP, calcitonin gene-related peptide

us
CHMP, Committee for Medicinal Products for Human Use
CIS, carcinoma in situ
CLL, chronic lymphocytic leukemia
an
CR, complete response
CSCC, cutaneous squamous cell carcinoma
M
CTCL, cutaneous T-cell lymphoma
DLBCL, diffuse large B-cell lymphoma
ed

EC, European Commission

EMA, European Medicines Agency
EpCAM, epithelial cell adhesion molecule
pt

EU, European Union

FDA, US Food and Drug Administration
ce

FL, follicular lymphoma

HAE, hereditary angioedema
Ac

HCL, hairy cell leukemia

HIV, human immunodeficiency virus
HLH, hemophagocytic lymphohistiocytosis
IV, intravenous
mAb, monoclonal antibody
MF, mycosis fungoides
MM, multiple myeloma

2
MMD, monthly migraine days
MSI, microsatellite instability
nAMD, neovascular age-related macular degeneration
NDA, new drug application
NGF, nerve growth factor
NMIBC, non-muscle invasive bladder cancer

t
NMOSD, neuromyelitis optica spectrum disorder

ip
NMPA, National Medical Products Administration
PD-1, programmed cell death 1 protein

cr
PD-L1, programmed death ligand 1
PFS, progression-free survival

us
PNH, paroxysmal nocturnal hemoglobinuria
SC, subcutaneous
scFv, single-chain variable fragment
an
SCLC, small cell lung cancer
SS, Sézary syndrome
M
US, United States
XLH, X-linked hypophosphatemia
ed

Abstract
pt

For the past 10 years, the annual ‘Antibodies to watch’ articles have provided updates on key events in the
ce

late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in
the year before publication or were anticipated to occur during the year of publication. To commemorate the
10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or
Ac

Medicine, which were given for work that is highly relevant to antibody therapeutics research and
development, we expanded the scope of the data presented to include an overview of all commercial clinical
development of antibody therapeutics and approval success rates for this class of molecules. Our data
indicate that: 1) antibody therapeutics are entering clinical study, and being approved, in record numbers; 2)
the commercial pipeline is robust, with over 570 antibody therapeutics at various clinical phases, including 62
in late-stage clinical studies; and 3) Phase 1 to approval success rates are favorable, ranging from 17-25%,

3
depending on the therapeutic area (cancer vs. non-cancer). In 2018, a record number (12) of antibodies
(erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), burosumab (Crysvita), lanadelumab
(Takhzyro), caplacizumab (Cablivi), mogamulizumab (Poteligeo), moxetumomab pasudodox (Lumoxiti),
cemiplimab (Libtayo), ibalizumab (Trogarzo), tildrakizumab (Ilumetri, Ilumya), emapalumab (Gamifant)) that
treat a wide variety of diseases were granted a first approval in either the European Union (EU) or United
States (US). As of November 2018, 4 antibody therapeutics (sacituzumab govitecan, ravulizumab,

t
risankizumab, romosozumab) were being considered for their first marketing approval in the EU or US, and

ip
an additional 3 antibody therapeutics developed by Chinese companies (tislelizumab, sintilimab,
camrelizumab) were in regulatory review in China. In addition, our data show that 3 product candidates

cr
(leronlimab, brolucizumab, polatuzumab vedotin) may enter regulatory review by the end of 2018, and at
least 12 (eptinezumab, teprotumumab, crizanlizumab, satralizumab, tanezumab, isatuximab, spartalizumab,

us
MOR208, oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) may enter regulatory review in
2019. Finally, we found that approximately half (18 of 33) of the late-stage pipeline of antibody therapeutics
for cancer are immune checkpoint modulators or antibody-drug conjugates. Of these, 7 (tremelimumab,
an
spartalizumab, BCD-100, omburtamab, mirvetuximab soravtansine, trastuzumab duocarmazine, and
depatuxizumab mafodotin) are being evaluated in clinical studies with primary completion dates in late 2018
M
and in 2019, and are thus ‘antibodies to watch’. We look forward to documenting progress made with these
and other ‘antibodies to watch’ in the next installment of this article series.
ed
pt
ce
Ac

4
Introduction
The rise in the importance of monoclonal antibody (mAb) therapeutics to medical care over the past
30 years has been extraordinary. During this time, a plethora of scientific and technological advances both
large and small have facilitated the discovery and development of mAb therapeutics, over 80 of which have
been granted marketing approvals. In 2018, scientists responsible for two advances critical to antibody
discovery, phage display and immune checkpoint modulation, were awarded Nobel prizes. George P. Smith

t
and Sir Gregory P. Winter were jointly awarded Nobel Prizes in Chemistry for phage display of peptides and

ip
antibodies.1 George Smith first described the use of phage display in 1985, 2 and the proof of concept for
phage-displayed peptide libraries in 1990. 3 Also in 1990, Sir Gregory Winter and colleagues reported the

cr
display of a folded and fully functional antibody fragment on filamentous phage. Since then, this technology
has been used for research and development of antibodies by organizations located world-wide, 4, 5 yielding

us
over 80 antibodies that entered clinical study. Of these, more than 10 have been granted marketing
approvals. In 2002, adalimumab became the first mAb therapeutic derived from phage display to be granted
a marketing approval. It has since become the most successful mAb on the market, and is currently
an
prescribed for a wide variety of immune-mediated disorders (rheumatoid arthritis, juvenile rheumatoid
arthritis, Crohn's disease, psoriatic arthritis, psoriasis, axial spondyloarthritis, ulcerative colitis, uveitis,
M
hidradenitis suppurativa and Behçet syndrome).

Compared to phage display, the discovery of immune system checkpoints in the 1990s appeared to
be less directly related to the field of antibody research and development, but it is arguably now equally
ed

important. In acknowledgement of the value of this work, the 2018 Nobel Prize in Physiology or Medicine
was awarded to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of
negative immune regulation. 6 Tasuku Honjo and colleagues first described the programmed cell death 1 (PD-
pt

1) protein in 1992, 7 and James Allison and colleagues reported in 1996 8 that blocking CTLA-4’s inhibitory
effects improved immune responses directed toward tumor cells. Since then, the number of proteins known
ce

to function as either stimulatory or inhibitory checkpoints of the immune system has dramatically expanded,
9
and numerous antibody therapeutics targeting PD-1 (cemiplimab, nivolumab, pembrolizumab), the ligand
Ac

for PD-1 (PD-L1; durvalumab, avelumab, atezolizumab ) or CTLA-4 (ipilimumab) have been granted marketing
approvals. Because these therapeutics act by enhancing the immune system response rather than targeting a
tumor antigen, they are used to treat many types of cancers, including melanoma, non-small-cell lung cancer,
renal cell cancer, urothelial carcinoma, hepatocellular cancer, gastric cancer, colorectal cancer, head and
neck cancer, Merkel cell carcinoma and Hodgkin's lymphoma. Remarkably, there are ~120 antibody immune
checkpoint modulators currently in clinical studies, together comprising ~20% of the total commercial clinical

5
pipeline of antibody therapeutics. MAbs in the clinical pipeline target CTLA-4, PD-1 and PD-L1, but also other
immune system checkpoints such as CD40, GITR, LAG-3, OX40, TIGIT and TIM-3.

Numerous scientific discoveries, including phage display and immune checkpoint modulation,
technological advances, and substantial efforts by a multitude of researchers and medical professionals
enabled the increase in the number of commercially sponsored first-in-human clinical studies of antibody
therapeutics from ~12 per year in the early 1990s to ~30 per year by the mid-2000s, 10 and then to ~70 per

t
year in 2014 (Figure 1). During 2015 to 2017, however, the number of antibody therapeutics entering a first

ip
Phase 1 study each year did not gradually increase, but rather soared upward, averaging just over 100 per
year over the 3-year period. Data from this 3-year period also shows a remarkable trend toward

cr
development of antibody therapeutics for cancer at the expense of the development of such therapeutics for
non-cancer indications. It remains to be seen whether these trends continue into the future.

us
The comparatively high approval success rates for mAbs may be one reason for the growing interest
in the development of these therapeutics. As reported by Hay et al., 11 biologics such as mAbs have a
an
likelihood of approval of near 1 in 4 compared to that of new molecular entities, which approach 1 in 8.
Simply put, mAbs are granted marketing approvals at twice the rate of small molecule drugs.

To verify results reported in Hay et al., and to provide additional detail about clinical phase transition
M

and approval success rates for mAbs, we collected data in the public domain for over 680 antibody
therapeutics that entered clinical studies sponsored by commercial firms between January 1, 2000 and
ed

December 31, 2014. The data was collected from various websites, and included sources such as company
pipelines and press releases, clinical trials registries, and an open-access database of therapeutic antibodies
(IMGT/mAb-DB, http://www.imgt.org/mAb-DB/). The available data was cross-checked against several
pt

commercial databases (Beacon Targeted Therapies, Therapeutic Antibody Database, BioMedTracker).

Antibody therapeutics developed solely by non-commercial organizations, e.g., National Institutes of Health,
ce

and all biosimilar antibodies were excluded. Molecules with at least one binding site derived from an
antibody gene were included, but Fc fusion proteins were excluded. We defined success as a first marketing
approval in either the US or EU. Each molecule was assigned one therapeutic category and one of 9 possible
Ac

phases of development (Phase 1, 2 or 3 clinical study; regulatory review in the US or EU; approved in the US
or EU; all development terminated at Phase 1, 2 or 3, or terminated in regulatory review in the US or EU). The
phase of development was determined from the data available for the most advanced phase of the
molecules. For example, a molecule in Phase 3 studies was assigned to Phase 3 regardless of whether Phase 1
or Phase 2 studies were also in progress. Molecules were considered terminated if they were not listed in the
relevant company pipeline or no development had recently been reported, regardless of whether the
molecule was described as a licensing opportunity. Our dataset appears to be substantially larger than the

6
mAb subset of Hay et al.; the method we used to calculate success rates was most closely aligned with their
‘lead indications’ approach.

We analyzed our data when stratified by time (entry into clinical study during 2000-2009 and 2005-
2014) and by therapeutic category (non-cancer and cancer) (Figures 2 and 3). For all mAbs that entered
clinical study during 2000-2009 (n=357), the Phase 1 to 2, Phase 2 to 3, Phase 3 to regulatory review and
regulatory review to approval transition rates were 75%, 44%, 71% and 91%, respectively, with an overall

t
(Phase 1 to approval) success rate of 21% (Figure 2). These results are nearly identical to those reported by

ip
Hay et al., for their biologics data analyzed by lead indications (75.1%, 44.0%, 71.7% and 88.0% for phase
transitions in the order listed above, with an overall success rate of 20.8%). Our data for mAbs entering

cr
clinical studies during 2000-2009 indicated that mAbs developed for cancer indications had lower phase
transition rates and a lower overall approval success rate compared to those developed for non-cancer

us
indications. This trend toward lower success rates for oncology drugs was also reported by Hay et al. It should
be noted that approximately one-quarter of the mAbs were in clinical studies or regulatory review at the time
an
we calculated the success rates shown in Figure 2, and thus the rates may vary somewhat when the final
fates (approval or termination) for all molecules in the cohort become known.

For all mAbs that entered clinical study during 2005-2014 (n=569), the Phase 1 to 2, Phase 2 to 3,
M
Phase 3 to regulatory review, and regulatory review to approval transition rates were 69%, 45%, 77% and
94%, respectively, with an overall success rate of 22% (Figure 3). The overall approval success rates for the
two periods is thus very similar, although there was some variability in phase transition rates. Our data for
ed

this cohort also showed that approval success rates were lower for mAbs developed for cancer vs non-cancer
indications, but the difference (21 vs 24%, respectively) was less pronounced compared to the rates for mAbs
pt

that entered clinical study during 2000-2009 (17% vs 25%, respectively). Nearly half of the mAbs that entered
clinical study during 2005-2014 were still in clinical study or regulatory review at the time of our analysis. We
ce

look forward to reporting updated success rates for this cohort when the final fates of more molecules
become known in the future.

The success of antibody therapeutics has motivated hundreds of companies to engage in the
Ac

development of these molecules. Collectively, companies are currently sponsoring clinical studies of more
than 570 mAbs. Of these, ~90% are undergoing early-stage studies designed to assess the safety (Phase 1) or
safety and preliminary efficacy (Phase 1/2 or Phase 2) of the molecules in various patient populations (Figure
4). Reflecting the recent substantial increase in the number of anti-cancer antibodies entering clinical study,
most (~70%) of the mAbs at Phase 1 are for cancer. The numbers of mAbs intended to treat cancer vs non-
cancer indications are similar for mAbs currently at Phase 2 and late-stage clinical studies (pivotal Phase 2,
Phase 2/3 or Phase 3). The ‘Antibodies to watch’ article series has documented the substantial increase in the

7
number of mAbs in late-stage studies that has occurred over the past 10 years (Figure 5). 12-20 The 62 mAbs
currently undergoing evaluation in late-stage studies represent the largest number at this stage to date, with
the increase, at least in part, due to the advancement of mAbs developed by companies based in China.

Following in the tradition of the ‘Antibodies to watch’ article series, we provide here updates on
recent and anticipated events relevant to antibody therapeutics clinical development. We describe the
antibody therapeutics that were approved in either the US or EU during 2018, and those undergoing

t
regulatory review in these two regions as of November 2018. In acknowledgment of the rapid progress in the

ip
development of novel antibody therapeutics in China, we also discuss several antibody immune checkpoint
inhibitors undergoing regulatory review by China’s National Medical Products Administration (NMPA). Finally,

cr
we provide an overview of antibody therapeutics in late-stage clinical study that may progress to regulatory
review in late 2018 or 2019, based on public disclosures by the sponsoring companies.

Antibody therapeutics approved in the US or EU in 2018

us
an
A total of 12 new antibodies were granted approvals in either the US or EU during 2018 (Table 1).
Perhaps reflecting the higher approval success rate for antibodies that are treatments for non-cancer
M
indications, the majority (75%) of the products are for such diseases, including 3 for migraine prevention and
1 for human immunodeficiency virus (HIV) infection.

Erenumab (Novartis). On May 17, 2018, the US Food and Drug Administration (FDA) approved erenumab-
ed

aooe (Aimovig) for the preventive treatment of migraine in adults. Erenumab is a human IgG2 mAb that
targets calcitonin gene-related peptide (CGRP) receptor, thereby blocking the activity of CGRP, which is
pt

involved in migraine attacks. The treatment is given by once-monthly subcutaneous (SC) injections. The
approval was based on data from three clinical trials that compared erenumab-aooe to placebo. Over 2000
participants were included in the studies. In the first study (STRIVE, NCT02456740), which included 955
ce

participants with a history of episodic migraine, patients administered erenumab-aooe experienced, on

average, one to two fewer monthly migraine days than those on placebo over a 6-month period. In the
Ac

second study (ARISE, NCT02483585), which included 577 patients with a history of episodic migraine,
patients administered erenumab-aooe experienced, on average, one fewer migraine day per month than
those on placebo over a 3-month period. In the third study (NCT02066415), which evaluated 667 patients
with a history of chronic migraine, patients treated with erenumab-aooe experienced, on average, 2.5 fewer
monthly migraine days than those receiving placebo over a 3-month period.21 On July 26, 2018, erenumab
was issued a marketing authorization in the EU for prophylaxis of migraine in adults who have at least 4
migraine days per month.

8
Fremanezumab (Teva Pharmaceuticals). On September 14, 2018, the FDA approved fremanezumab-vfrm
(AjovyTM) for the preventive treatment of migraine in adults. The drug may be administered as either 225 mg
monthly, or 675 mg quarterly, SC doses. 21 Fremanezumab-vfrm is a humanized mAb that binds to CGRP,
thereby blocking the binding of this ligand to its receptor. In a Phase 3 study (NCT02629861) of patients with
migraines administered fremanezumab, mean migraine days per month decreased from 8.9 days to 4.9 days
in the fremanezumab 225 mg dosing group, from 9.2 days to 5.3 days in the fremanezumab 675 mg dosing
group, and from 9.1 days to 6.5 days in the placebo group, as assessed from baseline to 12 weeks. 22 A

t
ip
marketing authorization application for fremanezumab is undergoing review by the European Medicines
Agency (EMA).

cr
Galcanezumab (Eli Lilly & Company). On September 27, 2018, the FDA approved galcanezumab-gnlm
(Emgality®) for the preventive treatment of migraine in adults, making Emgality the third antibody

us
therapeutic approved by FDA in 2018 for this indication. Like fremanezumab, galcanezumab is a humanized
mAb that binds to CGRP. The recommended dosage of Emgality is 240 mg loading dose (administered as two
an
consecutive injections of 120 mg each), followed by monthly doses of 120 mg. The efficacy and safety of
Emgality was demonstrated in two Phase 3 clinical trials in patients with episodic migraine (EVOLVE-1
(NCT02614183), EVOLVE-2 (NCT02614196)) and one Phase 3 clinical trial in patients with chronic migraine
M
(REGAIN (NCT02614261)). In all three studies, patients were randomized to receive once-monthly placebo,
Emgality 120 mg after an initial loading dose of 240 mg, or Emgality 240 mg. In EVOLVE-1, the mean change
from baseline (days) was -4.7 days (n =210) for Emgality 120 mg compared to -2.8 days (n=425) for placebo
ed

(p<0.001), while in EVOLVE-2, the mean change from baseline (days) was -4.3 days (n =226) for Emgality 120
mg compared to -2.3 days (n=450) for placebo (p<0.001). In the REGAIN study, the mean change from
baseline (days) was -4.8 days (n =273) for Emgality 120 mg compared to -2.7 days (n =538) for placebo
pt

(p<0.001). 24 In November 2018, the European Commission (EC) granted marketing authorization for
Emgality® for the prophylaxis of migraine in adults who have at least four migraine days per month.
ce

Burosumab (KRN23; Kyowa Hakko Kirin Co. Ltd, Ultragenyx Pharmaceutical Inc.). On February 19, 2018, the
EC issued a conditional marketing authorization in the EU for burosumab (Crysvita) as a treatment for X-
Ac

linked hypophosphatemia (XLH) in children 1 year of age and older, and adolescents with growing skeletons.
Burosumab is a human IgG1 mAb that binds to and inhibits the activity of fibroblast growth factor 23, thereby
reducing loss of phosphate from the kidney and other metabolic abnormalities, and ameliorating bone
changes that are a hallmark of the disease. 25 In a double-blind, placebo-controlled, Phase 3 study of
symptomatic adults with XLH administered SC burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks,
across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum
phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p

9
< 0.001). 26 Burosumab was granted Orphan Drug designations in the EU and US, and FDA granted the drug
Breakthrough Therapy designation for pediatric XLH. Burosumab-twza was approved by the FDA on April 17,
2018. 27

Lanadelumab (Shire). On August 23, 2018, the FDA approved lanadelumab-flyo (TakhzyroTM) injection for
prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years of age and older. This
rare, genetic, and potentially life-threatening disorder can result in recurrent attacks of severe swelling in

t
various parts of the body, including the throat. HAE affects people with low levels of, or poorly functioning,

ip
C1 esterase inhibitor proteins, which function by inhibiting plasma kallikrein and preventing spontaneous
activation of the complement system. Takhzyro is a human mAb that targets plasma kallikrein, and thereby

cr
helps prevent attacks of edema. FDA’s approval of Takhzyro was based in part on data from the multicenter,
randomized, double-blind, placebo-controlled, parallel-group, Phase 3 HELP study (NCT02586805), which

us
included 125 patients with HAE. In this study, Takhzyro reduced the number of monthly HAE attacks an
average of 87% (n=27) or 73% (n=29) vs. placebo (n=41) when administered SC at 300 mg every two weeks or
at 300 mg every four weeks, respectively (adjusted P<0.001).28 The FDA had previously granted Takhzyro
an
Breakthrough Therapy and Orphan Drug designations. The biologics license application (BLA) for the drug was
granted a priority review. Takhzyro, which was designated as an orphan medicinal product in the EU in 2015,
M
was reviewed under EMA’s accelerated assessment program. In November 2018, the EC granted marketing
authorization for Takhzyro SC injection for the routine prevention of recurrent attacks of HAE in patients
aged 12 years and older.
ed

Caplacizumab (Sanofi). On August 31, 2018, the EC issued a marketing authorization for caplacizumab
(Cablivi™), a bivalent single-domain nanobody targeting von Willebrand factor, as a treatment of adults
pt

experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP). During episodes of this
rare, life-threatening blood clotting disorder, microclots can form, leading to low platelet counts, ischemia
ce

and organ dysfunction in aTTP patients. Caplacizumab was granted Fast Track designation in the US and
Orphan Drug designations in the US and EU for the treatment of aTTP. The BLA for caplacizumab is
undergoing a priority review at the FDA. A first action on the application is expected by February 6, 2019. 29
Ac

Caplacizumab was developed by Ablynx, a Sanofi company. The approval of caplacizumab in the EU was
based in part on the Phase 3 HERCULES study (NCT02553317), a placebo-controlled, randomized study to
evaluate the efficacy and safety of caplacizumab in more rapidly restoring normal platelet counts as a
measure of the prevention of further microvascular thrombosis. Positive results from this study were
presented at the 59th Annual Meeting of the American Society of Hematology in December 2017. 30 The
HERCULES study recruited 145 patients with an acute episode of aTTP who were randomized 1:1 to receive
either caplacizumab or placebo in addition to standard-of-care treatment, which was daily plasma exchange

10
(PEX) and immunosuppression. Patients were administered a single intravenous (IV) bolus of 10 mg
caplacizumab or placebo followed by daily SC dose of 10 mg caplacizumab or placebo until 30 days after the
last daily PEX. Depending on the response, the treatment could be extended for additional 7-day periods up
to a maximum of 28 days. The primary endpoint (time to platelet count response) and several secondary
endpoints of HERCULES study were met. In particular, caplacizumab provided faster resolution of an aTTP
episode with significantly shorter time to platelet count response, clinically relevant reduction in aTTP-

t
related death, exacerbation of aTTP, or a major thromboembolic event, and prevention of aTTP relapses

ip
when treatment is extended until resolution of underlying disease. 30 A 3-year Phase 3 follow-up study
(NCT02878603) of patients who completed the HERCULES study is in progress.

cr
Mogamulizumab (Kyowa Hakko Kirin). On August 8, 2018, the FDA approved Poteligeo® (mogamulizumab-
kpkc) for IV use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or

us
Sézary syndrome (SS) after at least one prior systemic therapy. The diseases are subtypes of cutaneous T-cell
lymphoma (CTCL), which is a rare and difficult-to-treat type of non-Hodgkin’s lymphoma. The FDA had
an
previously granted mogamulizumab Breakthrough Therapy and Orphan Drug designations, and the BLA for
mogamulizumab received a priority review. FDA’s approval was based on an open-label, multi-center,
randomized Phase 3 clinical trial (NCT01728805) of 372 patients with relapsed MF or SS who received either
M
mogamulizumab or vorinostat. Study sites were located in the US, Europe, Japan and Australia. Median
progression-free survival (PFS) was 7.6 months for patients administered mogamulizumab compared to 3.1
months for patients taking vorinostat in this clinical trial. 31 Poteligeo was designated as an orphan medicinal
ed

product in the EU in 2016. The EC granted a marketing authorization to Poteligeo® for the treatment of adult
patients with MF or SS who have received at least one prior systemic therapy in November 2018.
pt

Developed by Kyowa Kirin, mogamulizumab is a humanized glyco-engineered mAb that binds to CC

chemokine receptor type 4 on cancer cells. 32 Mogamulizumab was produced using Kyowa Hakko Kirin’s
ce

proprietary POTELLIGENT® platform, which produces antibodies with low / no fucose content. Such
antibodies have increased affinity to FcγRIIIa (CD16), and enhanced antibody-dependent cell-mediated
cytotoxicity activity. Mogamulizumab’s first approval, in 2012, was granted by the Japanese Ministry of
Ac

Health, Labour and Welfare for treatment of patients with relapsed or refractory CCR4-positive adult T-cell
leukemia-lymphoma.

Moxetumomab pasudotox (AstraZeneca). On September 13, 2018, the FDA approved moxetumomab
pasudotox-tdfk (Lumoxiti) for the treatment of adult patients with relapsed or refractory hairy cell leukemia
who have received at least two prior systemic therapies, including treatment with a purine nucleoside
analog. The drug is a recombinant immunotoxin targeting CD22 composed of a single-chain variable fragment
(scFv) fused to a truncated form of Pseudomonas exotoxin PE38. 33 In a pivotal, multi-center, open-label study

11
(NCT01829711) of moxetumomab pasudotox involving 80 patients (79% males; median age, 60.0 years), the
durable complete response rate was 30%, the complete response rate was 41%, and the objective response
rate (complete and partial response) was 75%.34 Due to the severity and rarity of the disease, the FDA
granted the application Fast Track and Priority Review designations, and moxetumomab pasudotox received
US Orphan Drug designation.

Cemiplimab (Sanofi). On September 28, 2018, the FDA approved cemiplimab-rwlc (Libtayo) for the treatment

t
of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not

ip
candidates for curative surgery or curative radiation. Cemiplimab-rwlc is the third antibody therapeutic
targeting PD-1 to be granted an FDA approval, but it is the first drug to be approved in the US specifically for

cr
advanced CSCC. FDA’s approval of Libtayo was based on a combined analysis of data from an open-label,
multi-center, non-randomized Phase 2 trial known as EMPOWER-CSCC-1 (Study 1540) and two advanced

us
CSCC expansion cohorts from a multi-center, open-label, non-randomized Phase 1 trial (Study 1423). A total
of 108 patients (75 with metastatic disease and 33 with locally-advanced disease) were included in the
efficacy evaluation. The confirmed objective response rate for all patients treated with Libtayo was 47%.35
an
FDA granted cemiplimab Breakthrough Therapy Designation status for advanced CSCC in 2017, and the drug’s
BLA was granted a priority review. A marketing authorization application for cemiplimab is undergoing EMA
M
review.

Ibalizumab (Theratechnologies, Inc). On March 6, 2018, the FDA approved ibalizumab-uiyk (Trogarzo) for
adult patients infected with HIV who were previously treated with multiple HIV medications and whose HIV
ed

infections are resistant to currently available therapies. 36 Ibalizumab-uiyk, a humanized IgG4 mAb, is a CD4
domain 2-directed post-attachment HIV-1 inhibitor. The BLA was granted Breakthrough Therapy, Fast Track
pt

and Priority Review designations, and ibalizumab was granted an Orphan Drug designation by FDA.
Theratechnologies Inc. and TaiMed Biologics, Inc. have an agreement to market and distribute Trogarzo in
ce

the US and Canada. The product is IV administered as a single loading dose of 2,000 mg followed by a
maintenance dose of 800 mg every 2 weeks after dilution in 250 mL of 0.9% sodium chloride. The safety and
efficacy of ibalizumab-uiyk were evaluated in the Phase 3 TMB-301 study (NCT02475629), which was a single
Ac

arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected patients with
multidrug resistant HIV-1. 37 At Week 25, viral load <50 was achieved in 43% of patients, while 55% and 48%
of patients had a ≥ 1 log10 reduction in viral load and a ≥ 2 log10 reduction in viral load, respectively. The
most common adverse reactions reported in at least 5% of subjects were diarrhea, dizziness, nausea, and
rash. In total, 292 patients with HIV-1 infection were exposed to ibalizumab-uiyk IV infusion during clinical
studies. 38 A marketing authorization application for ibalizumab is undergoing EMA review.

12
Tildrakizumab (Sun Pharma). On March 20, 2018, the FDA approved tildrakizumab-asmn (Ilumya) for
treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or
phototherapy. Tildrakizumab, a humanized IgG1 kappa mAb, targets IL-23p19 and blocks the interaction of IL-
23 with its receptor, thereby inhibiting release of pro-inflammatory cytokines and chemokines. FDA approval
was supported by results from two Phase 3 trials (reSURFACE 1 and 2) in which patients were randomized to
tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo (2:2:1; reSURFACE 1), or to tildrakizumab 200 mg,

t
tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2; reSURFACE 2). In these trials, the tildrakizumab

ip
200 mg and 100 mg doses were well tolerated and found to be efficacious compared with placebo and
etanercept in the treatment of patients with moderate-to-severe chronic plaque psoriasis. The results of both

cr
studies were published in The Lancet in July 2017. 39 In a pooled analysis of three randomized controlled trials
that included over 2000 patients, tildrakizumab therapy for up to 64 weeks was well tolerated, with low rates

us
of serious treatment-emergent adverse events (AEs), discontinuations due to AEs, and AEs of clinical interest.
40
An EU-wide marketing authorization for tildrakizumab (Ilumetri) was issued to Almirall S.A. on September
17, 2018. In the EU, Ilumetri is indicated for the treatment of adults with moderate to severe plaque psoriasis
an
who are candidates for systemic therapy.

Emapalumab (Novimmune/ Swedish Orphan Biovitrum AB). On November 20, 2018, the FDA approved
M
emapalumab-lzsg (Gamifant) for the treatment of pediatric (newborn and above) and adult patients with
primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or
intolerance with conventional HLH therapy. 41 Developed by Novimmune SA, emapalumab is a human IgG1
ed

antibody that targets interferon γ. Emapalumab received a variety of designations intended to facilitate the
development of drugs for rare, serious or life-threatening diseases, including Breakthrough Therapy, Rare
Pediatric Disease, and Orphan Drug designations in the US, and Priority Medicines and Orphan Drug
pt

designations in the EU. The FDA’s approval was based in part on a clinical study of 27 pediatric patients with
suspected or confirmed primary HLH with either refractory, recurrent or progressive disease during
ce

conventional HLH therapy or who were intolerant of conventional HLH therapy. Results from this study
showed that 63% of patients experienced a response and 70% were able to proceed to stem cell transplant. A
Ac

marketing application for emapalumab is undergoing evaluation by EMA.

Antibody therapeutics undergoing regulatory review in the US or EU

As of November 2018, a total of 4 antibody therapeutics (sacituzumab govitecan, ravulizumab,

risankizumab, romosozumab) are being considered for their first marketing approvals in the US or EU (Table
2). Reflecting the diversity of mAbs in clinical development, the product candidates are for diseases in a

13
variety of therapeutic areas, such as cancer, cardiovascular/hemostasis, immune-mediated disorders, and
bone/skeletal diseases.

Sacituzumab govitecan (Immunomedics). This antibody-drug conjugate (ADC) is composed of a humanized

anti-Trop-2 antibody conjugated to SN38 (active metabolite of the topoisomerase I inhibitor irinotecan). A
BLA for approval of sacituzumab govitecan as third-line therapy for metastatic triple-negative breast cancer
was granted Priority Review by the FDA, and the action date is January 18, 2019. 42 Immunomedics is planning

t
clinical studies of the ADC in other cancers. Patients are being recruited for a pivotal Phase 2 study of

ip
sacituzumab govitecan as a treatment for metastatic urothelial cancer after failure of platinum-based
regimen or anti-PD-1 / PD-L1 based immunotherapy (NCT03547973) and a Phase 2 study of the ADC in

cr
patients with metastatic castration-resistant prostate cancer who have progressed on second generation
androgen receptor-directed therapy (NCT03725761).

us
Ravulizumab (Alexion Pharmaceuticals). Also known by the drug code ALXN1210, ravulizumab is a humanized
mAb targeting complement component 5 (C5). A BLA for approval of ravulizumab for treatment of patients
an
with paroxysmal nocturnal hemoglobinuria (PNH) is undergoing review at FDA. The BLA’s action date is
February 18, 2019, following an expedited eight-month review, instead of the standard 12-month review,
which was allowed by Alexion’s use of a rare disease priority review voucher. 43 Ravulizumab is also
M
undergoing regulatory review in the EU. The mAb was granted Orphan Drug designation in both the US and
EU for the treatment of patients with PNH. In a Phase 3 study, ravulizumab, demonstrated non-inferiority to
Soliris® (anti-C5 eculizumab) in complement inhibitor treatment-naïve patients with PNH. 44 Also developed
ed

by Alexion Pharmaceuticals, Soliris® was first approved for PNH in 2007.

Risankizumab (AbbVie). Like the recently approved products Tremfya (guselkumab) and Ilumya
pt

(tildrakizumab), risankizumab targets IL-23p19 and it was evaluated as a treatment for plaque psoriasis. The
BLA for risankizumab is supported by data from four Phase 3 studies, ultIMMA-1, ultIMMa-2, IMMhance and
ce

IMMvent, that evaluated the safety and efficacy of risankizumab in more than 2,000 patients with moderate-
to-severe chronic plaque psoriasis. In these four studies, all co-primary and ranked secondary outcome
measures were met and no new safety signals were observed. 45 Results of the UltIMMa-1 (NCT02684370)
Ac

and UltIMMa-2 (NCT02684357) studies were reported in The Lancet. 46 Assuming the BLA receives a standard
review, FDA may make a decision in April 2019. Risankizumab is also undergoing regulatory review in the EU.

Romosozumab (Amgen / UCB Pharma). This humanized IgG2 mAb, which targets sclerostin, has been
evaluated as a treatment for osteoporosis in women and men. A BLA for romosozumab as a treatment of
osteoporosis in postmenopausal women at high risk for fracture was submitted to the FDA in July 2016, but
additional safety and efficacy data was requested in the FDA’s complete response letter, as announced by

14
collaborators Amgen and UCB in July 2017. 47 In July 2018, Amgen and UCB announced that the BLA had been
resubmitted, 48 thus starting a second review cycle. In addition to data from early-stage clinical studies, the
original BLA included data from the Phase 3 placebo-controlled FRAME study, including 7,180
postmenopausal women with osteoporosis. The resubmitted BLA includes results from the more recent
Phase 3 ARCH study, an alendronate-active comparator trial including 4,093 postmenopausal women with
osteoporosis who experienced a fracture, and the Phase 3 BRIDGE study, which included 245 men with

t
osteoporosis. Romosozumab is also undergoing regulatory review in the EU.

ip
Antibody therapeutics undergoing regulatory review in China

cr
A decade ago, when the ‘Antibodies to watch’ article series was started, the innovative antibodies in
late-stage clinical studies were developed primarily by companies based in the US or EU. Since then, the

us
Chinese biopharmaceutical industry has made substantial strides in the clinical development of antibody
therapeutics, with the aim of gaining marketing approvals not only in China, but also globally. Chinese
an
companies are engaging with FDA, and developing their product candidates according to the standards of the
FDA and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use (www.ich.org). 49 In particular, Chinese companies have progressed multiple antibodies targeting
M
PD-1 into late-stage studies and regulatory review in China, including tislelizumab, sintilimab and
camrelizumab.
ed

Tislelizumab (BGB-A317; BeiGene Ltd.). This humanized IgG4 mAb binds to PD-1, but does not bind human
FcγRI or mediate crosslinking between PD-1 and FcγRI. Interactions with FcγRI were reported to have a
negative effect on anti-cancer activity of antibodies targeting PD-1. 50 In August 2018, BeiGene announced
pt

that China’s NMPA accepted a new drug application (NDA) for tislelizumab for the treatment of relapsed or
refractory Hodgkin’s lymphoma. 51 The NDA, which was granted a priority review, included results from a
ce

pivotal Phase 2 study (NCT03209973) of 70 Chinese patients showing an overall response rate of 85.7%,
including 61.4% complete response, with a minimum of 24 weeks of follow-up and a median follow-up time
of 7.85 months at the data cutoff. Tislelizumab is also being evaluated in Phase 3 studies of patients with
Ac

non-small cell lung cancer, hepatocellular carcinoma and esophageal squamous cell carcinoma.

Sintilimab (IBI308; Innovent Biologics). Innovent Biologics and Eli Lilly and Company are jointly developing
sintilimab, a human IgG4 antibody targeting PD-1, in China. In April 2018, the NDA for sintilimab for relapsed
and refractory classical Hodgkin’s lymphoma was submitted in China and granted priority review status. In
the Phase 2 registrational study ORIENT-1 (NCT03114683) that assessed the efficacy and safety profile of
sintilimab, the overall response rate was 79.2%, with disease control rate of 97.9%, among the 96 patients

15
with a minimum 24-week follow-up. 52 Sintilimab is also being evaluated as first-line treatment for patients
with non-squamous non-small cell lung cancer (NCT03607539 Phase 3 ORIENT-11 study) and as first-line
treatment for patients with previously untreated squamous non-small cell lung cancer (NCT03629925 Phase
3 ORIENT-12 study).

Camrelizumab (SHR-1210; Jiangsu Hengrui Medicine Co., Ltd.). An NDA for camrelizumab, a humanized IgG4
antibody targeting PD-1, for relapsed/refractory classic Hodgkin’s lymphoma submitted by Hengrui to China’s

t
NMPA was accepted in April 2018, and is currently under review. 53 Hengrui has partnered with Incyte

ip
Corporation to further develop camrelizumab. In two Phase 1/2 studies (NCT02961101, NCT03250962) of
camrelizumab with or without decitabine, the addition of decitabine increased the complete response rate of

cr
patients with relapsed/refractory classic Hodgkin’s lymphoma, and significantly reversed the resistance of
anti-PD-1 therapy. 54 The safety profile of the combination therapy was deemed acceptable. Camrelizumab is

us
undergoing evaluation as a treatment for other types of cancer, and results have been reports for early-
phase clinical studies of camrelizumab in patients with advanced non-squamous non-small cell lung cancer, 55
advanced hepatocellular carcinoma, gastric or esophagogastric junction cancer, 56 nasopharyngeal carcinoma,
an
57
advanced esophageal carcinoma, 58 and advanced solid tumors. 59

Antibodies to watch in 2019: Non-cancer indications

M
As of November 2018, 29 novel antibody therapeutics were in late-stage clinical studies for non-
cancer indications (Table 3). No single therapeutic area predominated, although, at ~40% of the total,
antibodies for immune-mediated disorders were the largest group. Of the 29 product candidates, two
ed

(leronlimab, brolucizumab) may enter regulatory review by the end of 2018, and at least five (eptinezumab,
teprotumumab, crizanlizumab, satralizumab, tanezumab) may enter regulatory review in 2019.
pt

Leronlimab (PRO140; CytoDyn). The chemokine receptor CCR5 is the principal HIV co-receptor, but it has
potential as a drug target for other diseases, such as cancer and immune-mediated disorders. 60 Leronlimab, a
ce

humanized IgG4 mAb that blocks CCR5, was granted FDA’s Fast Track drug designation for the treatment of
HIV infection. This designation allows a ‘rolling’ BLA submission, i.e., the BLA can be submitted in sections,
which may be in progress, as CytoDyn has indicated that they made progress toward filing a BLA for
Ac

leronlimab as a combination therapy for HIV and are confident that two-thirds of the BLA submission (i.e.,
clinical and non-clinical sections) will be completed by the end of 2018 and the last section, Chemistry,
Manufacturing and Controls, by the first quarter of 2019. 61 Leronlimab is undergoing evaluation in late-stage
clinical studies that include treatment-experienced HIV-infected patients with CCR5-tropic virus who
demonstrate evidence of HIV-1 replication despite ongoing antiretroviral therapy (ART) with documented
genotypic or phenotypic resistance to ART drugs within three drug classes (or within two or more drug
classes with limited treatment options). The primary efficacy endpoint of a pivotal 25-week study

16
(NCT02483078), 0.5log reduction in viral load after one week of therapy with leronlimab in combination with
the patient’s failing drug regimen, was met. An open-label extension of this study is continuing to enroll
patients. The successful results of this trial may serve as the basis for the BLA submission. CytoDyn is also
developing leronlimab as a treatment for graft-vs.-host disease and triple-negative breast cancer.

Brolucizumab (RTH258; Novartis). This ~26 kDa humanized scFv targets all isoforms of vascular endothelial
growth factor-A, and it is undergoing evaluation as a treatment for neovascular age-related macular

t
degeneration (nAMD). Novartis has indicated that regulatory submissions for brolucizumab may occur in

ip
December 2018. 62 In October 2018, Novartis released 96-week results from the Phase 3 HAWK
(NCT02307682) and HARRIER (NCT02434328) studies that reaffirmed positive 48-week findings. 63 The two

cr
studies included more than 1,800 patients in comparing the efficacy and safety of intravitreal injections of 6
mg brolucizumab or 3 mg brolucizumab (HAWK study only) versus 2 mg aflibercept in patients with nAMD.

us
The primary efficacy endpoint of the studies, non-inferiority to aflibercept (EYLEA®) in mean change in best-
corrected visual acuity (BCVA) at week 48, was met. The 96-week results indicate patients administered
an
brolucizumab maintained robust visual gains, with mean change in BCVA of 5.9 letters for brolucizumab 6 mg
versus 5.3 letters for aflibercept in the HAWK study, and 6.1 letters versus 6.6 letters, respectively, in the
HARRIER study. Superior reductions in retinal fluid and central subfield thickness (CST) demonstrated at 48
M
weeks were reaffirmed at 96 weeks. The percentage of patients with nAMD that had intra-retinal fluid and/or
sub-retinal fluid was 24% for brolucizumab 6 mg vs. 37% for aflibercept in HAWK (p=0.0001) and 24% vs.
39%, respectively, in the HARRIER study (P<0.0001). Absolute reductions in CST from baseline were -175 µm
ed

for brolucizumab 6 mg versus -149 µm for aflibercept in HAWK (p=0.0057) and -198 µm versus -155 µm,
respectively, in the HARRIER study (P<0.0001).
pt

Eptinezumab (Alder Biopharmaceuticals, Inc.). Like the marketed products Emgality and Ajovy, eptinezumab
targets CGRP and it is for migraine prevention. In November 2018, Alder announced that they are on track to
ce

complete a BLA submission in the first quarter of 2019 that will include chemistry, manufacturing, and
controls processes; positive results from a pharmacokinetic study intended to support the comparability
evaluation of the clinical supply for eptinezumab and its planned commercial supply; data from
Ac

eptinezumab’s PROMISE 1 (NCT02559895) and PROMISE 2 (NCT02974153) Phase 3 clinical studies; and long-
term safety data. 64, 65 The PROMISE 1 and PROMISE 2 studies evaluated the effects of eptinezumab in
episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively. In PROMISE 1, the
primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while
in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was
consistent with earlier eptinezumab studies. Alder announced one-year results from the PROMISE 1 study in
June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with

17
300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs,
compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth
quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a
reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients. 66 In addition,
~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from
baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released
in June 2018. 67 These results indicated that, after the first quarterly infusion, chronic migraine patients dosed

t
ip
with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6
fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second

cr
infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with
placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from

us
baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.

Teprotumumab (Horizon Pharma). This human IgG1 mAb targets insulin-like growth factor-1 receptor.
an
Teprotumumab is in development for moderate-to-severe thyroid eye disease, which is commonly associated
with Grave’s disease (hyperthyroidism). Data from the Phase 3 OPTIC study (NCT03298867) is expected in the
second quarter of 2019, and a BLA submission is expected mid-2019. 68 In the OPTIC study, participants
M
receive 8 infusions of teprotumumab or placebo every 3 weeks for a total of 21 weeks. Teprotumumab (10
mg/kg) is administered on Day 1, with 20 mg/kg administered for the remaining 7 infusions. The primary
endpoint at week 24 is the proptosis responder rate, defined as the percentage of participants with >2 mm
ed

reduction in study eye without deterioration (≥2 mm increase) of proptosis in the fellow eye. An open-label
extension study (NCT03461211; OPTIC-X) is enrolling by invitation. Teprotumumab was granted Fast Track,
Breakthrough Therapy and Orphan Drug designations by FDA.
pt

Crizanlizumab (SEG101; Novartis). Sickle cell disease, caused by mutations in the gene encoding hemoglobin
ce

subunit β, is characterized by production of red blood cells that are misshapen, prone to hemolysis and can
occlude the vasculature, causing pain. 69 P-selectin found on endothelial cells and platelets participates in cell-
cell interactions that contribute to the pathogenesis of vaso-occlusion and sickle cell-related pain crises.
Ac

Crizanlizumab, a humanized mAb, binds P-selectin and blocks these interactions. Post-hoc analysis of data
from the Phase 2 SUSTAIN study (NCT01895361) showed that more patients treated with crizanlizumab did
not experience a vaso-occlusive crisis (VOC) compared to those treated with placebo (35.8% vs 16.9%),
specifically patients with a history of 2-10 VOCs in the previous year. 70 Crizanlizumab was granted Orphan
Drug designation in the US and EU for the treatment of sickle cell-related pain crises. Novartis anticipates
submitting a BLA in 2019. 71

18
Satralizumab (SA237; Chugai Pharmaceutical Co., Ltd.). This humanized anti-interleukin-6 (IL-6) receptor mAb
is undergoing development as a treatment for neuromyelitis optica spectrum disorder (NMOSD), which is a
rare autoimmune disease that affects the central nervous system. The constant and variable regions of
satralizumab were engineered to give the molecule longer plasma half-life. In October 2018, Chugai
announced that positive results from the Phase 3 SAkuraSky Study (NCT02028884) of were presented at the
2018 Congress of European Committee for Treatment and Research in Multiple Sclerosis held October 10-12,

t
2018, in Berlin, Germany. In this study, satralizumab (120 mg) or placebo was added to baseline therapy

ip
(azathioprine, mycophenolate mofetil and/or corticosteroids). Both treatments were administered SC to
patients at week 0, 2, and 4, then subsequent treatment was continued at 4-week intervals. Satralizumab

cr
with immunosuppressive therapy significantly reduced the risk of relapse by 62% (hazard ratio = 0.38 [95%
confidence interval: 0.16-0.88], p=0.0184 [stratified log-rank test]) in patients with NMOSD including anti-

us
aquaporin-4 (AQP4) antibody positive (AQP4 Ab positive) and negative (AQP4 Ab negative) patients,
achieving the primary endpoint of time to first protocol-defined relapse in the double-blind period. The
proportion of patients relapse free at weeks 48 and 96 was 88.9% and 77.6% with satralizumab and 66.0%
an
and 58.7% with placebo, respectively. 72 Satralizumab has been granted US and EU orphan designations for
the treatment of NMOSD. According to the Roche pipeline listing, an application submission for satralizumab
M
is anticipated in 2019.

Tanezumab (Pfizer Inc., Eli Lilly and Company). Therapeutics that block nerve growth factor (NGF) have the
potential to ameliorate pain associated with various disorders. 73 The humanized anti-NGF IgG2 antibody
ed

tanezumab has been studied extensively in late-stage clinical studies of patients with osteoarthritis pain,
cancer pain, and chronic low back pain. In July 2018, Pfizer and Lilly announced positive results from a 16-
week Phase 3 study (NCT02697773) evaluating the efficacy and safety of SC administration of tanezumab
pt

compared to placebo in patients with osteoarthritis of the knee or hip. 74 In this study, 698 patients were
randomized into one of 3 study arms, and they then received injections once every eight weeks. Patients in
ce

arm 1, 2 or 3 received two doses of placebo, two doses of tanezumab 2.5 mg, or one dose of tanezumab 2.5
mg followed by one dose of tanezumab 5 mg eight weeks later, respectively. Patients who received two
Ac

doses of tanezumab experienced a statistically significant improvement in pain, physical function and the
patients’ overall assessment of their osteoarthritis compared to those receiving placebo. Tanezumab was
granted FDA’s Fast Track designation for tanezumab for the treatment of osteoarthritis pain and chronic low
back pain. Lilly has indicated that a BLA for tanezumab for osteoarthritis pain may potentially be submitted in
2019. 75

Antibodies to watch in 2019: Cancer indications

19
As of November 2018, 33 novel antibody therapeutics were in late-stage clinical studies for cancer indications
(Table 4). Antibody therapeutics for solid tumors clearly predominated, with less than 20% of the total
developed solely for hematological malignancies. Of the 33 product candidates, polatuzumab vedotin may
enter regulatory review by the end of 2018, and at least 7 (isatuximab, spartalizumab, MOR208,
oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) may enter regulatory review in 2019.

Polatuzumab vedotin (DCDS4501A, RG7596; Roche). In collaboration with Seattle Genetics, Roche is

t
developing polatuzumab vedotin, which is composed of a humanized anti-CD79b IgG1 antibody conjugated

ip
to the antimitotic agent monomethyl auristatin E (MMAE). The antibody’s target is highly expressed on B cells
of patients with lymphoma. Polatuzumab vedotin was granted FDA’s Breakthrough Therapy designation,

cr
EMA’s PRIME designation, and US and EU Orphan Drug designations for diffuse large B-cell lymphoma
(DLBCL). Roche has indicated that, based on positive clinical data from a randomized Phase 2 study

us
(NCT02257567/ GO29365), 76 the company anticipates an accelerated submission for polatuzumab vedotin in
DLBCL in 2018. 77 The Phase 2 NCT02257567 study evaluated polatuzumab vedotin administered by IV
an
infusion in combination with standard doses of bendamustine (B) and rituximab (R) or obinutuzumab in
patients with relapsed or refractory follicular lymphoma (FL) or diffuse DLBCL. Study results indicating that, at
a median follow-up of 15 months, rates of PFS and complete response were similar among FL patients. In
M
contrast, the combination of polatuzumab vedotin and BR significantly increased all efficacy outcomes,
compete response (p=0.012), median PFS (p<0.0001), and median overall survival (p=0.0008), in the DLBCL
group. The combination of polatuzumab vedotin with R-CHP protocol (rituximab, cyclophosphamide,
ed

doxorubicin and prednisone) versus R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine and

prednisone) in DLBCL patients is currently being investigated in the Phase 3 POLARIX (NCT03274492) study.
The primary endpoint is PFS. Secondary outcome measures include PFS, compete response and overall
pt

survival. The estimated primary completion date of the study is December 2019.
ce

Isatuximab (SAR650984; Sanofi). This anti-CD38 IgG1 chimeric mAb is being evaluated as a treatment for
patients with multiple myeloma (MM). Isatuximab in combination with chemotherapy is being evaluated in
three Phase 3 studies (ICARIA, IKEMA, and IMROZ) of MM patients. Sanofi expects results from ICARIA by Q1
Ac

2019; positive clinical data may allow marketing application submissions for isatuximab in 2019. 78 In the
ICARIA study (NCT02990338), the effects of isatuximab in combination with pomalidomide and low-dose
dexamethasone are being compared to those of only the chemotherapy drugs in patients with refractory or
relapsed and refractory MM. 79 The primary endpoint is PFS. Key secondary endpoints include overall
response rate and overall survival. The IKEMA (NCT03275285) and IMROZ (NCT03319667) studies are
evaluating isatuximab with other chemotherapy combinations (carfilzomib/dexamethasone and

20
bortezomib/lenalidomide/dexamethasone, respectively) in MM patients. Isatuximab was granted US and EU
Orphan Drug designations for the treatment of MM.

Spartalizumab (PDR001, Novartis). This humanized IgG4 mAb binds PD-1 with sub-nanomolar affinity and
blocks interaction with PD-L1/PD-L2, thus preventing PD-1-mediated inhibitory signaling and leading to T-cell
activation. Spartalizumab is being evaluated in the randomized, double-blind, placebo-controlled Phase 3
COMBI-i study (NCT02967692) evaluating the safety and efficacy of spartalizumab combined with dabrafenib

t
(a BRAF inhibitor) and trametinib (a MEK inhibitor) versus matching placebo in combination with dabrafenib

ip
and trametinib in previously untreated patients with BRAF V600–mutant unresectable or metastatic
melanoma. Determination of dose-limiting toxicities, changes in PD-L1 levels and CD8+ cells in the tumor

cr
microenvironment, and PFS are the primary endpoints of the study. Key secondary endpoints are overall
survival, overall response rate and duration of response. The estimated primary completion date of the study

us
is July 2019. Novartis plans to submit marketing applications for PDR001 in combination with trametinib +
dabrafenib for the treatment of metastatic BRAF V600+ melanoma in 2019. 80 Spartalizumab is undergoing
an
evaluation in Phase 2 studies as a treatment for other cancers, including neuroendocrine tumors,
nasopharyngeal carcinoma, non-small cell lung cancer, triple-negative breast cancer, hepatocellular
carcinoma and colorectal cancer. Spartalizumab was granted US Orphan Drug designation for the treatment
M
of neuroendocrine tumors. 81

MOR208 (MorphoSys). Formerly known as Xmab®5574, MOR208 is a humanized Fc-engineered mAb directed
against CD19. The Fc domain contains 2 amino acid substitutions, S239D and I332E, that enhance cytotoxicity
ed

by increasing the affinity for activatory FcγRIIIa on effector cells. MOR208 has been shown to induce lysis of
leukemia cells that is mediated by natural killer cells. 82 The mAb was granted EU and US Orphan Drug
pt

designations for the treatment of chronic lymphocytic leukemia (CLL), as well as FDA’s Breakthrough Therapy
and Fast Track designations for DLBCL. MOR208 is under clinical investigation as a treatment option in
ce

combination with other anti-cancer agents for both of these hematological malignancies. In March 2018,
MorphoSys reported results from the Phase 2 L-MIND study (NCT02399085), which evaluated MOR208
combined with lenalidomide in patients with relapsed or refractory DLBCL. 83 A total of 81 patients enrolled in
Ac

the study, with 68 available for efficacy assessment at the time of data cut-off. With a median observation
time of 8.3 months, the data showed an overall response rate of 49%, and a compete response in 31% of the
patients. The preliminary PFS rate at 12 months was 50.4% (95% confidence interval 40 - 67%) and the
preliminary median PFS had not been reached (95% confidence interval: 4.3 months-not reached). In
November 2018, MorphoSys indicated that they are in discussions with the FDA to evaluate possible paths to
market, including the possibility of an expedited regulatory submission and potential approval based
primarily on the L-MIND study. 84 MOR208 with bendamustine versus rituximab with bendamustine is being

21
evaluated in the Phase 2/3 B-MIND study (NCT02763319) of patients in patients with relapsed or refractory
DLBCL. The primary endpoint of the study is PFS and the primary completion date is March 2020.

Oportuzumab monatox (VB4-845, Vicinium™; Sesen Bio). This immunotoxin is composed of a recombinant
humanized antibody scFv targeting epithelial cell adhesion molecule (EpCAM) conjugated to Pseudomonas
aeruginosa exotoxin A. 85 Once bound to EpCAM expressed by cancer cells, oportuzumab monatox is
internalized into the cytoplasm, where it induces apoptosis. Oportuzumab monatox was granted US and EU

t
Orphan Drug designations in 2005, and FDA’s Fast Track designation for non-muscle invasive bladder cancer

ip
(NMIBC) that is unresponsive to treatment with bacillus Calmette-Guérin (BCG) in August 2018. 86 The
efficacy and tolerability of intravesical Vicinium™ is being evaluated in the open-label, multicenter Phase 3

cr
VISTA study (NCT02449239) of NMIBC patients previously treated with BCG. Enrollment was completed in
March 2018 with a total of 133 patients with high-grade NMIBC that is either carcinoma in situ (CIS) or

us
papillary with or without CIS, who have been previously treated with BCG. The primary endpoint is the
complete response rate in patients with CIS with or without papillary disease. In an analysis assessing pooled
CIS patients (n=77), Vicinium treatment resulted in a complete response rate of 42% at three months. 87
an
Sesen Bio expects to provide a six-month update from the VISTA study in December 2018, and is on track to
report 12-month VISTA study data in mid-2019. 88 Positive results could allow a BLA submission by the end of
M
2019.

TSR-042 (TESARO, Inc.). TESARO is developing anti-PD-1 mAb TSR-042 as a treatment for several types of
cancers. In October 2018, TESARO announced results from a Phase 1 dose escalation and cohort expansion
ed

study (GARNET; NCT02715284), which is intended to support a BLA submission to the FDA in 2019. 89 The
GARNET study is evaluating TSR-042 in patients with advanced solid tumors who have limited available
pt

treatment options. In the ongoing cohort expansion portion of GARNET, patients are administered TSR-042 at
a dose of 500 milligrams every 3 weeks for the first 4 cycles, and 1000 milligrams every 6 weeks thereafter in
ce

four cohorts: microsatellite instability high (MSI-H) endometrial cancer, MSI-H non-endometrial cancer,
microsatellite-stable endometrial cancer and non-small cell lung cancer. Among the 25 patients with MSI-H
endometrial cancer who had at least one post-baseline tumor assessment, one had a complete response and
Ac

12 had partial responses (including 1 unconfirmed response) by immune-related response evaluation criteria
in solid tumors (irRECIST) criteria. 89 Of the 13 responses, 12 are ongoing (92%), including three patients with
partial responses who have thus far received over 60 weeks of treatment with TSR-042. Three additional
patients (12%) had stable disease. TSR-042 is also being evaluated in the Phase 3 FIRST study (NCT03602859),
which is comparing platinum-based therapy with TSR-042 and niraparib versus standard of care platinum-
based therapy as first-line treatment of Stage III or IV non-mucinous epithelial ovarian cancer.

22
Enfortumab vedotin (ASG22ME; Seattle Genetics, Inc. / Astellas Pharma Inc.). This ADC directed against
nectin-4 is undergoing evaluation as a treatment for locally advanced or metastatic urothelial cancer. FDA has
granted enfortumab vedotin Breakthrough Therapy designation for this disease. Enfortumab vedotin as
monotherapy was evaluated at escalating doses in a Phase 1 study (NCT02091999) of 81 patients with locally
advanced or metastatic urothelial cancer. The results of the clinical study showed that, of 71 patients
evaluated for response, 41% had an objective response, including three (4%) complete responses and 26

t
(37%) partial responses. Disease control was achieved in 51 patients (72%), defined as the sum of patients

ip
achieving a complete response, partial response or stable disease. 90 Data from the study supported the start
of the pivotal single-arm, open-label, multicenter Phase 2 EV-201 study (NCT03219333), which is evaluating

cr
the safety and efficacy of enfortumab vedotin in patients with locally advanced or metastatic urothelial
cancer who previously received a checkpoint inhibitor (PD-L1 or PD-1) and either previously received

us
platinum-containing chemotherapy (Cohort 1) or are platinum-naïve and cisplatin-ineligible (Cohort 2). The
primary endpoint is the objective response rate, and secondary key outcomes measures include duration of
response, disease control rate, and PFS. Seattle Genetics and Astellas expect to report top-line data from the
an
EV-201 study in the first quarter of 2019. Positive data from this study could serve as the basis for a BLA
submission under the FDA’s accelerated approval pathway. 91 Enfortumab vedotin is also under evaluation in
M
the global Phase 3 EV-301 study (NCT03474107) in the same indication. The EV-301 study is intended to
support a broader global registration strategy and to serve as the confirmatory randomized trial in the US.
The estimated primary completion date is September 2021.
ed

Ublituximab (TG Therapeutics, Inc.) The glyco-engineered anti-CD20 antibody ublituximab is currently under
clinical investigation in a total of 5 late-stage clinical studies in cancer (CLL, non-Hodgkin’s lymphoma) and
non-cancer (multiple sclerosis) indications, with the most advanced being the studies for cancer. TG
pt

Therapeutics is awaiting pivotal data from all of them. In hematological malignancies, TG Therapeutics is
conducting three Phase 3 studies exploring the efficacy of ublituximab in combination with other anti-cancer
ce

agents. The UNITY-CLL Phase 3 study (NCT02612311) evaluated the combination of ublituximab and TGR-
1202, a PI3K delta inhibitor, versus anti-CD20 obinutuzumab plus chlorambucil in untreated and previously
Ac

treated CLL patients. The primary and secondary outcome measures are PFS and overall response rate,
respectively. TG Therapeutics had announced plans to prepare and potentially submit a marketing
application by the end of 2018, but, in September 2018, TG Therapeutics reported that an interim analysis of
the overall response rate in UNITY-CLL trial ‘could not be conducted at this time as the data were not
sufficiently mature to conduct the analysis.’ 92 The company will now focus on PFS data, with a readout
anticipated in 2019. Another Phase 3 study (NCT02301156) is comparing ublituximab in combination with
Ibrutinib to Ibrutinib alone in previously treated CLL patients. The primary outcome measures are overall

23
response rate and PFS. The estimated primary completion date is June 2019. The Phase 2/3 UNITY-NHL
(NCT02793583) study is evaluating ublituximab in combination with TGR-1202 with or without bendamustine
in 500 patients with previously treated non-Hodgkin’s lymphoma. Overall response rate is the primary
outcome measure and the estimated primary completion date is May 2019.

Two Phase 3 studies (ULTIMATE 1, NCT03277261 and ULTIMATE 2, NCT03277248) are evaluating the efficacy
and safety of ublituximab compared to teriflunomide in 440 patients with relapsing multiple sclerosis. For

t
both studies, the primary outcome measure is annualized relapse rate and the estimated primary completion

ip
date is March 2021.

cr
Outlook for the near future
Medical care of patients will likely be strongly influenced by the increased number and variety of

us
antibody therapeutics that may be approved in the near future. This is especially the case for cancer patients,
who may soon have a substantially larger number of antibody immune checkpoint modulators and ADCs
available to them. Of the 33 antibody therapeutics currently in late-stage clinical development for cancer, 11
an
modulate immune checkpoints and 8 are ADCs. Of the immune checkpoint modulators, ‘antibodies to watch’
include anti-CTLA4 tremelimumab (AstraZeneca), anti-PD-1 spartalizumab (Novartis), anti-PD-1 BCD-100
(Biocad), and radiolabeled anti-B7-H3 omburtamab (Y-mAbs Therapeutics), which are all being evaluated in
M
clinical studies with primary completion dates in late 2018 and in 2019. Looking further into the future,
results from studies of antibodies targeting immune checkpoints other than CTLA4, PD-1 and PD-L1 are
eagerly anticipated. Results of the Phase 3 study (NCT02951156) of the CD137/4-1BB agonist utomilumab
ed

(PF-05082566, Pfizer) in combination regimens in patients with relapsed or refractory diffuse large B-cell
lymphoma may be available near the study’s primary completion date of March 2020. In addition, results of
pt

the Phase 2/3 study (NCT03470922) of anti-LAG3 relatlimab (Bristol-Myers Squibb) combined with nivolumab
versus nivolumab in patients with previously untreated metastatic or unresectable melanoma may be
ce

released near the study’s primary completion date of July 2020.

ADC ‘antibodies to watch’ include mirvetuximab soravtansine (ImmunoGen), trastuzumab

duocarmazine (Synthon BioPharmaceuticals), and depatuxizumab mafodotin (Abbvie). Mirvetuximab
Ac

soravtansine, an ADC that targets α-folate receptor 1, is undergoing evaluation in the Phase 3 FORWARD I
study (NCT02631876) of patients with folate receptor alpha-positive advanced epithelial ovarian cancer,
primary peritoneal cancer or fallopian tube cancer. This study has a primary completion date in November
2018, and top-line results from the study are expected in the first half of 2019. The safety and efficacy of anti-
HER2 trastuzumab duocarmazine (Synthon BioPharmaceuticals) is being evaluated in the Phase 3 TULIP study
(NCT03262935) of patients with human epidermal growth factor receptor 2 (HER2)-positive unresectable
locally advanced or metastatic breast cancer. This study has a primary completion date in May 2019.

24
Trastuzumab duocarmazine was granted a Fast Track designation for treating patients diagnosed with HER2-
positive metastatic breast cancer that has progressed during or after at least two HER2-targeting treatment
regimens for locally advanced or metastatic disease, or progressed during or after [ado-]trastuzumab
emtansine treatment. The anti-epidermal growth factor receptor ADC depatuxizumab mafodotin is being
evaluated as a treatment for glioblastoma in two Phase 3 studies, NCT03419403 and NCT02573324, with
primary completion dates in September 2019 and March 2020, respectively. In addition, anti-DLL3

t
rovalpituzumab tesirine (AbbVie) is undergoing evaluation in three Phase 3 studies of small cell lung cancer

ip
(SCLC) patients, TAHOE (NCT03061812), MERU (NCT03033511) and M16-292 (NCT03334487), with primary
completion dates in September 2019, November 2019, and September 2020. However, AbbVie announced in

cr
March 2018 that they will not seek accelerated approval for rovalpituzumab tesirine in third-line
relapsed/refractory SCLC based on the magnitude of effect across multiple parameters in the Phase 2 TRINITY

us
study.93

We anticipate that a sufficient number of the ~ 225 antibody therapeutics in Phase 2 studies will
an
transition to late-stage studies to keep the total number in the range of 50-65 in 2019 and beyond. For
example, the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of anti-IL-6
clazakizumab for the treatment of chronic active antibody-mediated rejection in kidney transplant recipients
M
is due to start in March 2019, and Phase 3 studies to investigate the efficacy and safety of UB-421
monotherapy as substitution for stable antiretroviral therapy in HIV-1 infected adults (NCT03149211) and
UB-421 in combination with optimized background therapy regimen in patients with multi-drug resistant HIV-
ed

1 infection (NCT03164447) are due to start in July and September 2019, respectively. We look forward to
documenting progress made with these and other ‘antibodies to watch’ in the next installment of this article
series.
pt
ce

Acknowledgements
The authors thank Mrinalini (Mini) Muralidharan for preparation of the figures, Vandna Prasad Rath, Hanson
Wade, for providing access to the Beacon Targeted Therapies database, and Rob Jones, Craic Computing LLC,
Ac

for providing access to the Therapeutic Antibody Database.

Disclosure Statement
The authors declare no conflicts of interest.

25
References
1. The Royal Swedish Academy of Sciences. Scientific Background on the Nobel Prize in Chemistry 2018:
Directed Evolution Of Enzymes And Binding Proteins.
https://www.nobelprize.org/uploads/2018/10/advanced-chemistryprize-2018.pdf
2. Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the
virion surface. Science 1985;228(4705):1315-1317. DOI: 10.1126/science.4001944.
3. Scott JK, Smith GP. Searching for peptide ligands with an epitope library. Science 1990;
249(4967):386-90.

t
4. Frenzel A, Schirrmann T, Hust M. Phage display-derived human antibodies in clinical development

ip
and therapy. MAbs. 2016;8(7):1177-1194.
5. Nixon AE, Sexton DJ, Ladner RC. Drugs derived from phage display: from candidate identification to

cr
clinical practice. MAbs. 2014;6(1):73-85.
6. The Royal Swedish Academy of Sciences. The Nobel Prize in Physiology or Medicine 2018.
NobelPrize.org. Nobel Media AB 2018. Fri. 26 Oct 2018.

us
https://www.nobelprize.org/prizes/medicine/2018/summary/.
7. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the
immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887-95.
an
8. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade.
Science. 1996;271(5256):1734-6.
9. Donini C, D'Ambrosio L, Grignani G, Aglietta M, Sangiolo D. Next generation immune-checkpoints for
cancer therapy. J Thorac Dis. 2018;10(Suppl 13):S1581-S1601. doi: 10.21037/jtd.2018.02.79.
M
10. Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC. Monoclonal antibody successes in the clinic. Nat
Biotechnol. 2005;23(9):1073-8.
11. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for
investigational drugs. Nat Biotechnol. 2014;32(1):40-51. doi: 10.1038/nbt.2786.
ed

12. Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs 2018; 10(2):183-203. doi:
10.1080/19420862.2018.1415671.
13. Reichert JM. Antibodies to watch in 2017. MAbs 2017; 9(2):167-181. doi:
pt

10.1080/19420862.2016.1269580.
14. Reichert JM. Antibodies to watch in 2016. MAbs 2016; 8(2):197-204. doi:
10.1080/19420862.2015.1125583.
ce

15. Reichert JM. Antibodies to watch in 2015. MAbs 2015; 7(1): 1-8. doi:
10.4161/19420862.2015.988944.
16. Reichert JM. Antibodies to watch in 2014. MAbs 2014; 6(1):5-14. doi: 10.4161/mabs.27333.
17. Reichert JM. Which are the antibodies to watch in 2013? MAbs 2013; 5(1):1-4. doi:
Ac

10.4161/mabs.22976.
18. Reichert JM. Which are the antibodies to watch in 2012? MAbs 2012; 4(1):1-3. doi:
10.4161/mabs.4.1.18719.
19. Reichert JM. Antibody-based therapeutics to watch in 2011. MAbs 2011; 3(1):76-99.
20. Reichert JM. Antibodies to watch in 2010. MAbs 2010; 2(1):84-100.
21. US Food and Drug Administration. FDA approves novel preventive treatment for migraine. May 17,
2018 press release.
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm608120.htm?utm_campaig
n=05172018_PR_FDA%20approves%20migraine%20prevention%20treatment&utm_medium=email
&utm_source=Eloqua.

26
22. Teva Pharmaceutical Industries Ltd. Teva Announces U.S. Approval of AJOVY™ (fremanezumab-vfrm)
Injection, the First and Only Anti-CGRP Treatment with Both Quarterly and Monthly Dosing for the
Preventive Treatment of Migraine in Adults. September 14, 2018 press release.
http://ir.tevapharm.com/phoenix.zhtml?c=73925&p=irol-newsArticle&ID=2367592.
23. Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang
R, Ma Y, Aycardi E. Effect of Fremanezumab Compared With Placebo for Prevention of Episodic
Migraine: A Randomized Clinical Trial. JAMA. 2018;319(19):1999-2008. doi:
10.1001/jama.2018.4853.
24. Eli Lilly and Company. Lilly's Emgality™ (galcanezumab-gnlm) Receives U.S. FDA Approval for the

t
Preventive Treatment of Migraine in Adults. September 27, 2018 press release.

ip
https://investor.lilly.com/news-releases/news-release-details/lillys-emgalitytm-galcanezumab-gnlm-
receives-us-fda-approval.
25. Kyowa Hakko Kirin Co. Ltd, Kyowa Kirin International PLC, Ultragenyx Pharmaceutical Inc. Kyowa Kirin

cr
and Ultragenyx Announce Crysvita® (burosumab) Receives Conditional Marketing Authorisation in
Europe for the Treatment of X–Linked Hypophosphatemia in Children. February 23, 2018 press
release. www.kyowa-kirin.com/news_releases/2018/pdf/e20180223_01.pdf.

us
26. Insogna KL, Briot K, Imel EA, Kamenický P, Ruppe MD, Portale AA, Weber T, Pitukcheewanont P,
Cheong HI, Jan de Beur S, Imanishi Y, Ito N, Lachmann RH, Tanaka H, Perwad F, Zhang L, Chen CY,
Theodore-Oklota C, Mealiffe M, San Martin J, Carpenter TO; AXLES 1 Investigators. A Randomized,
Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23
an
Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res.
2018 Aug;33(8):1383-1393. doi: 10.1002/jbmr.3475.
27. US Food and Drug Administration. FDA approves first therapy for rare inherited form of rickets, x-
linked hypophosphatemia. April 17, 2018 press release.
M
https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm604810.htm
28. Shire plc. Shire Announces FDA Approval of TAKHZYRO™ (lanadelumab-flyo), a First-of-its-Kind mAb
Preventive Treatment for Hereditary Angioedema. August 23, 2018 press release.
https://www.shire.com/en/newsroom/2018/august/4fhgmy
29. Sanofi. Cablivi™ (caplacizumab) approved in Europe for adults with acquired thrombotic
ed

thrombocytopenic purpura (aTTP). September 3, 2018 press release.

http://www.news.sanofi.us/2018-09-03-Cablivi-TM-caplacizumab-approved-in-Europe-for-adults-
with-acquired-thrombotic-thrombocytopenic-purpura-aTTP
30. Scully M, Cataland S, Peyvandi F, Coppo P, Knoebl P, Kremer Hovinga JA, Metjian A, de la Rubia J,
pt

Pavenski K, Callewaert F, et al. Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3

Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.
59th Annual Meeting of the American Society of Hematology, Atlanta, GA, USA, December 12, 2017.
ce

https://www.ablynx.com/uploads/events/ca854140-58c3-4357-9695-4b81c1996c75-
12dec2017_caplacizumabherculesash_final.pdf
31. US Food and Drug Administration. FDA approves treatment for two rare types of non-Hodgkin
lymphoma. August 8, 2018 press release.
Ac

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm616176.htm
32. Beck A, Reichert JM. Marketing approval of mogamulizumab: a triumph for glyco-engineering. MAbs.
2012;4(4):419-25. doi: 10.4161/mabs.20996.
33. Pastan I, Onda M, Weldon J, Fitzgerald D, Kreitman R. Immunotoxins with decreased immunogenicity
and improved activity. Leuk Lymphoma. 2011;52 Suppl 2:87-90. doi:
10.3109/10428194.2011.573039.
34. Kreitman RJ, Dearden C, Zinzani PL, Delgado J, Karlin L, Robak T, Gladstone DE, le Coutre P, Dietrich S,
Gotic M, Larratt L, Offner F, Schiller G, Swords R, Bacon L, Bocchia M, Bouabdallah K, Breems DA,
Cortelezzi A, Dinner S, Doubek M, Gjertsen BT, Gobbi M, Hellmann A, Lepretre S, Maloisel F, Ravandi
F, Rousselot P, Rummel M, Siddiqi T, Tadmor T, Troussard X, Yi CA, Saglio G, Roboz GJ, Balic K,

27
 Standifer N, He P, Marshall S, Wilson W, Pastan I, Yao NS, Giles F. Moxetumomab pasudotox in
relapsed/refractory hairy cell leukemia. Leukemia. 2018;32(8):1768-1777. doi: 10.1038/s41375-018-
0210-1.
35. Regeneron Pharmaceuticals, Inc. FDA Approves Libtayo® (cemiplimab-rwlc) as First and Only
Treatment for Advanced Cutaneous Squamous Cell Carcinoma. September 28, 2018 press release.
https://investor.regeneron.com/news-releases/news-release-details/fda-approves-libtayor-
cemiplimab-rwlc-first-and-only-treatment
36. US Food and Drug Administration. FDA approves new HIV treatment for patients who have limited
treatment options. March 6, 2018 press release.

t
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm599657.htm

ip
37. Emu B, Fessel J, Schrader S, Kumar P, Richmond G, Win S, Weinheimer S, Marsolais C, Lewis S. Phase
3 Study of Ibalizumab for Multidrug-Resistant HIV-1. N Engl J Med. 2018;379(7):645-654. doi:
10.1056/NEJMoa1711460.

cr
38. US Food and Drug Administration. TROGARZO™ (ibalizumab-uiyk) prescribing information.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761065lbl.pdf
39. Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaçi D, Nograles K, Mehta A, Cichanowitz N, Li Q,

us
Liu K, La Rosa C, Green S, Kimball AB. Tildrakizumab versus placebo or etanercept for chronic plaque
psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials.
Lancet. 2017 Jul 15;390(10091):276-288. doi: 10.1016/S0140-6736(17)31279-5.
40. Blauvelt A, Reich K, Papp KA, Kimball AB, Gooderham M, Tyring SK, Sinclair R, Thaçi D, Li Q,
an
Cichanowitz N, Green S, La Rosa C. Safety of tildrakizumab for moderate-to-severe plaque psoriasis:
pooled analysis of three randomized controlled trials. Br J Dermatol. 2018;179(3):615-622. doi:
10.1111/bjd.16724.
41. US Food and Drug Administration. FDA approves first treatment specifically for patients with rare
M
and life-threatening type of immune disease. November 20, 2018 press release.
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626263.htm
42. Immunomedics. Corporate overview. September 2018. https://www.immunomedics.com/wp-
content/uploads/2018/09/Corporate-Presentation-September-2018.pdf
43. Alexion Pharmaceuticals. FDA Accepts Priority Review of ALXN1210 as a Treatment for Patients with
ed

Paroxysmal Nocturnal Hemoglobinuria (PNH) in the US. August 20, 2018 press release.
http://ir.alexion.com/news-releases/news-release-details/fda-accepts-priority-review-alxn1210-
treatment-patients
44. Alexion Pharmaceuticals. Alexion Announces Positive Top-Line Results Showing Successful Phase 3
pt

Clinical Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Patients with Paroxysmal

Nocturnal Hemoglobinuria (PNH). March 15, 2018 press release. https://news.alexion.com/press-
release/product-news/alexion-announces-positive-top-line-results-showing-successful-phase-3-cl.
ce

45. AbbVie. AbbVie Submits Biologics License Application to U.S. FDA for Investigational Treatment
Risankizumab for Moderate to Severe Plaque Psoriasis. April 25, 2018 press release.
https://news.abbvie.com/news/abbvie-submits-biologics-license-application-to-us-fda-for-
investigational-treatment-risankizumab-for-moderate-to-severe-plaque-psoriasis.htm.
Ac

46. Gordon KB, Strober B, Lebwohl M, Augustin M, Blauvelt A, Poulin Y, Papp KA, Sofen H, Puig L, Foley P,
Ohtsuki M, Flack M, Geng Z, Gu Y, Valdes JM, Thompson EHZ, Bachelez H. Efficacy and safety of
risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two
double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet.
2018;392(10148):650-661. doi: 10.1016/S0140-6736(18)31713-6.
47. Amgen and UCB. Amgen And UCB provide update on regulatory status of EVENITY™ (romosozumab)
in the US. July 16, 2017. https://www.amgen.com/media/news-releases/2017/07/amgen-and-ucb-
provide-update-on-regulatory-status-of-evenity-romosozumab-in-the-us/.
48. Amgen and UCB. Amgen And UCB resubmit biologics license application (BLA) For EVENITY™
(romosozumab) to the US FDA. July 12, 2018 press release. https://www.amgen.com/media/news-

28
 releases/2018/07/amgen-and-ucb-resubmit-biologics-license-application-bla-for-evenity-
romosozumab-to-the-us-fda/.
49. Zhang H, Deng M, Lin P, Liu J, Liu C, Strohl WR, Wang S, Ho M. Frontiers and Opportunities: Highlights
of the 2nd Annual Conference of the Chinese Antibody Society. Antib Ther. 2018 Sep;1(2):65-74. doi:
10.1093/abt/tby009.
50. Zhang T, Song X, Xu L, Ma J, Zhang Y, Gong W, Zhang Y, Zhou X, Wang Z, Wang Y, Shi Y, Bai H, Liu
N, Yang X, Cui X, Cao Y, Liu Q, Song J, Li Y, Tang Z, Guo M, Wang L, Li K. The binding of an anti-PD-
1 antibody to FcγRΙ has a profound impact on its biological functions. Cancer Immunol
Immunother. 2018;67(7):1079-1090. doi: 10.1007/s00262-018-2160-x.

t
51. Beigene Ltd. BeiGene Announces Acceptance of New Drug Application for Anti-PD-1 Antibody

ip
Tislelizumab in Hodgkin’s Lymphoma in China. August 31, 2018 press release.
http://ir.beigene.com/phoenix.zhtml?c=254246&p=irol-newsArticle&ID=2365642.
52. Innovent Biologics (Suzhou) Co. Ltd. Innovent Biologics Announces the Study Result of its Anti-

cr
PD-1 Antibody in Hodgkin Lymphoma May 17, 2018 press release.
http://innoventbio.com/en/#/news/102.
53. LSK BioPharma, Jiangsu Hengrui Medicine. LSK BioPharma and Jiangsu Hengrui Medicine

us
Announce Global Clinical Collaboration to Evaluate the Combination of Anti-Angiogenesis and
Immuno-Oncology Therapy for Patients with Advanced Hepatocellular Carcinoma (HCC).
October 21, 2018 press release. http://lskbiopharma.com/lsk-biopharma-and-jiangsu-hengrui-
medicine-announce-global-clinical-collaboration-to-evaluate-the-combination-of-anti-
an
angiogenesis-and-immuno-oncology-therapy-for-patients-with-advanced-hepatocellular/.
54. Wang C, Liu Y, Nie J, Shen L, Yang Q, Han W. Safety and efficacy of decitabine-primed anti-PD-1
(SHR-1210) treatment in patients with relapsed/refractory classical Hodgkin lymphoma. 2018
American Society of Clinical Oncology meeting abstract.
M
https://meetinglibrary.asco.org/record/162336/abstract.
55. Zhou C, Gao G, Wu F, Chen X, Li W, Xiong A, Su C, Cai W, Ren S, Jiang T, Wang Y, Kang X, Wang Q.
A phase Ib study of SHR-1210 plus apatinib for heavily previously treated advanced non-
ed

squamous non-small cell lung cancer (NSCLC) patients. 2018 American Society of Clinical
Oncology meeting abstract. https://meetinglibrary.asco.org/record/160803/abstract.
56. Xu JM, Zhang Y, Jia R, Yue CY, Chang L, Liu RR, Zhang G, Zhao CH, Zhang YY, Chen CX, Wang Y, Yi
X, Hu Z, Zou JJ, Wang QR. Anti-PD-1 Antibody SHR-1210 combined with Apatinib for Advanced
pt

Hepatocellular Carcinoma, Gastric or Esophagogastric Junction Cancer: An Open-label, Dose

Escalation and Expansion Study. Clin Cancer Res. 2018 Oct 22. pii: clincanres.2484.2018. doi:
10.1158/1078-0432.CCR-18-2484.
ce

57. Fang W, Yang Y, Ma Y, Hong S, Lin L, He X, Xiong J, Li P, Zhao H, Huang Y, Zhang Y, Chen L, Zhou
N, Zhao Y, Hou X, Yang Q, Zhang L. Camrelizumab (SHR-1210) alone or in combination with
gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1
trials. Lancet Oncol. 2018 Oct;19(10):1338-1350. doi: 10.1016/S1470-2045(18)30495-9.
Ac

58. Huang J, Xu B, Mo H, Zhang W, Chen X, Wu D, Qu D, Wang X, Lan B, Yang B, Wang P, Zhang H,

Yang Q, Jiao Y. Safety, Activity, and Biomarkers of SHR-1210, an Anti-PD-1 Antibody, for Patients
with Advanced Esophageal Carcinoma. Clin Cancer Res. 2018;24(6):1296-1304. doi:
10.1158/1078-0432.CCR-17-2439.
59. Mo H, Huang J, Xu J, Chen X, Wu D, Qu D, Wang X, Lan B, Wang X, Xu J, Zhang H, Chi Y, Yang Q,
Xu B. Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1
antibody in advanced solid tumours: a dose-escalation, phase 1 study. Br J Cancer.
2018;119(5):538-545. doi: 10.1038/s41416-018-0100-3.
60. Scurci I, Martins E, Hartley O. CCR5: Established paradigms and new frontiers for a 'celebrity'
chemokine receptor. Cytokine. 2018;109:81-93. doi: 10.1016/j.cyto.2018.02.018.

29
61. CytoDyn Inc. CytoDyn’s PRO 140 (leronlimab) HIV Monotherapy Trial Results Show 92% Responder’s
Rate at 700 mg Dose. November 13, 2018 press release. https://www.cytodyn.com/media/press-
releases/detail/297/cytodyns-pro-140-leronlimab-hiv-monotherapy-trial.
62. Novartis. New analysis of Novartis Phase III brolucizumab (RTH258) data reinforces superior
reduction of retinal fluid, a key marker of disease activity in nAMD. September 22, 2018 press
release. https://www.novartis.com/news/media-releases/new-analysis-novartis-phase-iii-
brolucizumab-rth258-data-reinforces-superior-reduction-retinal-fluid-key-marker-disease-activity-
namd.
63. Novartis. Two-year data for Novartis brolucizumab reaffirm superiority versus aflibercept in reducing

t
retinal fluid in patients with nAMD. October 27, 2018 press release.

ip
https://www.novartis.com/news/media-releases/two-year-data-novartis-brolucizumab-reaffirm-
superiority-versus-aflibercept-reducing-retinal-fluid-patients-namd.
64. Alder Biopharmaceuticals. Alder BioPharmaceuticals® Reports Third Quarter 2018 Financial and

cr
Operating Results. November 5, 2018 press release. https://investor.alderbio.com/news-
releases/news-release-details/alder-biopharmaceuticalsr-reports-third-quarter-2018-financial.
65. Alder Biopharmaceuticals. Transforming the Prevention Treatment Paradigm for Migraine Patients.

us
November 5, 2018 corporate presentation.
https://investor.alderbio.com/index.php/encrypt/files?file=nasdaq_kms/assets/2018/11/06/3-08-
52/Corporate%20Deck%20November%205th%20FINAL%20FINAL.pdf&file_alias=18416.
66. Alder Biopharmaceuticals. Alder BioPharmaceuticals® Presents New One-Year Data for Eptinezumab
an
from PROMISE 1 Phase 3 Trial Demonstrating Long-Term Efficacy in Episodic Migraine. June 29, 2018
press release. https://investor.alderbio.com/news-releases/news-release-details/alder-
biopharmaceuticalsr-presents-new-one-year-data-eptinezumab.
67. Alder Biopharmaceuticals. Alder BioPharmaceuticals® Presents New Six-Month Data for Eptinezumab
M
Demonstrating Improvement in Efficacy in PROMISE 2 Phase 3 Trial for Chronic Migraine. June 29,
2018 press release. https://investor.alderbio.com/news-releases/news-release-details/alder-
biopharmaceuticalsr-presents-new-six-month-data.
68. Horizon Pharma. An Overview of Thyroid Eye Disease (TED) and Teprotumumab Clinical Data.
October 4, 2018 corporate presentation. http://ir.horizon-pharma.com/static-files/c153d2c9-fae6-
ed

4e3b-ab18-7e8485e2c2d4.
69. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, Smith WR, Panepinto JA,
Weatherall DJ, Costa FF, Vichinsky EP. Sickle cell disease. Nat Rev Dis Primers. 2018 Mar 15;4:18010.
doi: 10.1038/nrdp.2018.10.
pt

70. Kutlar A, Kanter J, Liles DK, Alvarez OA, Cançado RD, Friedrisch JR, Knight-Madden JM, Bruederle A,
Shi M, Zhu Z, Ataga KI. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell
disease: A SUSTAIN study analysis. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308
ce

71. Novartis. Novartis analysis shows crizanlizumab (SEG101) increased the number of patients free of
sickle cell pain crises vs placebo during SUSTAIN study. October 9, 2018 press release.
https://www.novartis.com/news/media-releases/novartis-analysis-shows-crizanlizumab-seg101-
increased-number-patients-free-sickle-cell-pain-crises-vs-placebo-during-sustain-study
Ac

72. Chugai Pharmaceutical Co., Ltd. Chugai Presents Results from Phase III Study of Satralizumab in
NMOSD at ECTRIMS 2018. October 15, 2018 press release. https://www.chugai-
pharm.co.jp/english/news/detail/20181015120001_561.html.
73. Denk F, Bennett DL, McMahon SB. Nerve Growth Factor and Pain Mechanisms. Annu Rev Neurosci.
2017;40:307-325. doi: 10.1146/annurev-neuro-072116-031121.
74. Pfizer Inc., Eli Lilly and Company. Pfizer And Lilly Announce Positive Top-Line Results From Phase 3
Trial Of Tanezumab For The Treatment Of Osteoarthritis (OA) Pain. July 18, 2018 press release.
https://www.pfizer.com/news/press-release/press-release-
detail/pfizer_and_lilly_announce_positive_top_line_results_from_phase_3_trial_of_tanezumab_for
_the_treatment_of_osteoarthritis_oa_pain.

30
75. Eli Lilly and Company. Form 10-Q Quarterly Report for the quarter ended June 30, 2018.
https://www.sec.gov/Archives/edgar/data/59478/000005947818000188/lly-6302018x10q.htm.
76. SehnLH, KamdarM, Herrera AF, McMillan A, Flowers C, Kim WS, Kim TM, Ozcan M, Trněný M,
Demeter J, Hertzberg M, Salles G, Davies A, Hirata J, Cheng J, Ku G, Matasar M. Adding polatuzumab
vedotin (POLA) to bendamustine and rituximab (BR) treatment improves survival in patients with
relapsed/refractory DLBCL: results of a Phase 2 clinical trial. 23rd Congress of the European
Hematology Association, June 16, 2018; Stockholm, Sweden.
https://www.primeoncology.org/app/uploads/hematology-updates-stockholm-2018-dlbcl-s802-
sehn.pdf

t
77. Roche. Roche Virtual Late Stage Pipeline Event 2018. September 13, 2018 corporate presentation.

ip
https://www.roche.com/dam/jcr:8142e2f9-9525-4a8f-ad1f-d5f605e36991/en/irp20180913.pdf
78. Sanofi. Q3 2018 Results. October 31, 2018 corporate presentation, slides 38, 41.
https://www.sanofi.com/-/media/Project/One-Sanofi-Web/Websites/Global/Sanofi-

cr
COM/Home/en/investors/docs/Q-
R/Q3_2018_Final_Slides.pdf?la=fr&hash=1746EC206B1D3AEB873C251D8512A5F62C28AE10
79. Richardson PG, Attal M, Campana F, Le-Guennec S, Hui AM, Risse ML, Corzo K, Anderson KC.

us
Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in
relapsed/refractory multiple myeloma: ICARIA Phase III study design. Future Oncol. 2018
May;14(11):1035-1047. doi: 10.2217/fon-2017-0616.
80. Novartis AG. Q2 2018 Results. July 18, 2018 investor presentation, slides 36, 37, 81.
an
https://www.novartis.com/sites/www.novartis.com/files/q2-2018-ir-presentation.pdf.
81. Novartis. Q2 results confirm full year guidance. Strong pipeline results underpin potential of several
highly innovative products. July 18, 2017 press release. https://www.novartis.com/news/media-
releases/q2-results-confirm-full-year-guidance-strong-pipeline-results-underpin-potential.
M
82. Kellner C, Zhukovsky EA, Pötzke A, Brüggemann M, Schrauder A, Schrappe M, Kneba M, Repp R,
Humpe A, Gramatzki M, Peipp M. The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces
natural killer cell-mediated lysis of acute lymphoblastic leukemia cells from pediatric and adult
patients. Leukemia. 2013 Jul;27(7):1595-8. doi: 10.1038/leu.2012.373.
83. Morphosys. MorphoSys Reports Updated Data from L-MIND Study of MOR208 plus Lenalidomide in
ed

Aggressive Lymphoma (r/r DLBCL). March 13, 2018. https://www.morphosys.com/media-

investors/media-center/morphosys-reports-updated-data-from-l-mind-study-of-mor208-plus.
84. Morphosys. MorphoSys AG Announces Third Quarter 2018 Results. November 5, 2018.
https://www.morphosys.com/media-investors/media-center/morphosys-ag-announces-third-
pt

quarter-2018-results .
85. Biggers K, Scheinfeld N. VB4-845, a conjugated recombinant antibody and immunotoxin for head and
neck cancer and bladder cancer. Curr Opin Mol Ther. 2008;10(2):176-86.
ce

86. Sesen Bio. Sesen Bio announces Vicinium granted Fast Track designation by FDA for treatment of
non-muscle invasive bladder cancer. August 09, 2018 press release. https://sesenbio.gcs-
web.com/news-releases/news-release-details/sesen-bio-announces-vicinium-granted-fast-track-
designation-fda.
Ac

87. Sesen Bio. Phase 3 Registration Trial for Non-Muscle Invasive Bladder Cancer Achieves 42% Complete
Response Rate at Three Months in Carcinoma in Situ Patients. May 21, 2018 press release.
https://sesenbio.gcs-web.com/news-releases/news-release-details/phase-3-registration-trial-non-
muscle-invasive-bladder-cancer.
88. Sesen Bio. Sesen Bio Reports Third Quarter 2018 Financial Results and Planned VISTA Trial Readouts.
November 8, 2018 press release. https://sesenbio.gcs-web.com/news-releases/news-release-
details/sesen-bio-reports-third-quarter-2018-financial-results-and.
89. TESARO, Inc. TESARO Announces Data Presentations at ESMO 2018 Congress. October 20, 2018.
http://ir.tesarobio.com/news-releases/news-release-details/tesaro-announces-data-presentations-
esmo-2018-congress-0.

31
 90. Seattle Genetics, Inc. Seattle Genetics and Astellas Announce Updated Enfortumab Vedotin Phase 1
Data in Metastatic Urothelial Cancer at 2017 ASCO Annual Meeting. June 5, 2017 press release.
http://investor.seattlegenetics.com/news-releases/news-release-details/seattle-genetics-and-
astellas-announce-updated-enfortumab.
91. Seattle Genetics, Inc. Seattle Genetics and Astellas Announce Progress in Enfortumab Vedotin
Urothelial Cancer Clinical Development Program. October 25, 2018 press release.
http://investor.seattlegenetics.com/news-releases/news-release-details/seattle-genetics-reports-
third-quarter-2018-financial-results.
92. TG Therapeutics. TG Therapeutics Announces Update Regarding UNITY-CLL Phase 3 Trial. September

t
25, 2018 press release. http://ir.tgtherapeutics.com/news-releases/news-release-details/tg-

ip
therapeutics-announces-update-regarding-unity-cll-phase-3.
93. AbbVie. AbbVie Announces Results from Phase 2 Study Evaluating Rovalpituzumab Tesirine (Rova-T)
for Third-Line Treatment of Patients with DLL3-Expressing Relapsed/Refractory Small Cell Lung

cr
Cancer. March 22, 2018 press release. https://news.abbvie.com/news/abbvie-announces-results-
from-phase-2-study-evaluating-rovalpituzumab-tesirine-rova-t-for-third-line-treatment-patients-
with-dll3-expressing-relapsedrefractory-small-cell-lung-cancer.htm.

us
List of Figures and Tables
an
Figure 1. Number of antibody therapeutics entering first-in-human studies per year, 2005-2017.
Green bars, all antibody therapeutics. Blue bars, antibody therapeutics for non-cancer indications only. Red
bars, antibody therapeutics for cancer only. Dotted lines, 2-year moving averages. Totals include only
M
antibody therapeutics sponsored by commercial firms; those sponsored solely by government, academic or
non-profit organizations were excluded.
ed
pt
ce
Ac

32
 t
ip
cr
us
an
M
Figure 2. Clinical phase transition and
a approval success ratess for antibodyy therapeuticss that entered clinical
study during 2000-200 09.
Green baars, all antibody therapeuttics. Blue barss, antibody th herapeutics foor non-cancerr indications oonly. Red
ed

bars, antibody therapeutics for can ncer only. Coh

horts included d only antibo
ody therapeuttics sponsored d by
commerccial firms; tho ose sponsored d solely by go
overnment, accademic or no on-profit orgaanizations weere
excludedd. Number of molecules that entered clinical study d during 2000-0 09: all, n=357;; non-cancer only,
o
n=181; caancer only, n==176. Final faates (approvaal or termination) are know wn for 76%. M MAbs that had d advanced
pt

to Phase 1/2 were classified as Phaase 2; mAbs that had advanced to Phasse 2/3 were cllassified as Ph hase 3.
Two mAb bs with first aapprovals outside the US/EEU regions (itaalizumab (Alzzumab) and R Rabishield appprovals in
ce

India) weere classified as Phase 3. PPhase transitio

on percentages were calcu ulated as folloows: the num
mber of
antibodyy therapeuticss that compleeted a given p phase and transitioned to tthe next was divided by th he
arithmetic difference between thee number thatt entered the phase and th he number th hat remained in the
phase at the time of the calculation. Phase transitions occurring between n clinical studies conductedd world-
Ac

wide werre included. Approval

A succcess were deffined as a firstt US or EU ap
pproval; suppllemental app provals
were nott included. Ab bbreviation RR, regulatory review.

33
 t
ip
cr
us
an
M

Figure 3. Clinical phase transition and

a approval success ratess for antibodyy therapeuticss that entered clinical
study during 2005-201 14.
ed

Green baars, all antibody therapeuttics. Blue barss, antibody thherapeutics fo

or non-cancerr indications oonly. Red
bars, antibody therapeutics for can ncer only. Coh horts included
d only antibo
ody therapeuttics sponsored d by
commerccial firms; tho ose sponsoredd solely by goovernment, accademic or no on-profit orgaanizations weere
excludedd. Number of molecules that entered clinical study d during 2005-114: all, n=569;; non-cancer only,
o
pt

n=295; caancer only, n==274. Final faates (approvaal or termination) are knowwn for 58%. MAbs
M that had
d advanced
to Phase 1/2 were classified as Phaase 2; mAbs that had advanced to Phasse 2/3 were cllassified as Ph hase 3.
Two mAb bs with first aapprovals outside the US/EEU regions (itaalizumab (Alzzumab) and R Rabishield appprovals in
ce

India) weere classified as Phase 3. Phase

P transitio
on percentages were calcu ulated as follo
ows: the nummber of
antibodyy therapeuticss that compleeted a given p phase and transitioned to tthe next was divided by th he
arithmetic difference between thee number thatt entered the phase and th he number th hat remained in the
Ac

phase at the time of the calculation. Transitionss occurring beetween clinicaal studies con nducted world-wide
were inclluded. Approval success w were defined aas a first US o
or EU approvaal; supplemen ntal approvalss were not
included. Abbreviation RR, regulato ory review.

34
 t
ip
cr
us
an
M

Figure 4. Clinical phases for antibody therapeuttics in develop

pment.
o November 2018. Totals include only antibody therapeutics spo
Data as of onsored by coommercial firm ms; those
ed

sponsoreed solely by government, aacademic or n non-profit orgganizations w

were excludedd. Phase 1/2 inncluded
with Phase 2; late-stagge studies incclude pivotal Phase 2, Phase 2/3 and Ph hase 3. Tabless of mAbs in llate-stage
studies are available aat www.antibbodysociety.org.
pt
ce
Ac

35
 t
ip
cr
us
an
M

Figure 5. Antibodies to
o watch in 20
010-2019.
Data from
m ‘Antibodiess to watch’ arrticles publish
hed in mAbs. 2019 data as of November 2018. Totalss include
ed

only antibody therapeeutics sponsoored by comm mercial firms; those sponsoored solely byy governmentt, academic
or non-profit organizaations were excluded. Tables of mAbs in n late-stage studies
s are avvailable at
www.anttibodysocietyy.org.
pt
ce
Ac

36
 Ac
ce
pt
ed
M
an
us
cr
ip

37
t
 Table 1. Antibody therapeutics granted first approvals in the European Union or the United States during
2018*

International non- Brand Date of first Date of first

proprietary name# name Target; Format Indication first approved EU approval US approval
Erenumab Aimovig CGRP receptor; Human Migraine prevention 7/26/2018 5/17/2018
IgG2
Fremanezumab Ajovy CGRP; Humanized IgG2 Migraine prevention In review 9/14/2018

t
Galcanezumab Emgality CGRP; Humanized IgG4 Migraine prevention Nov. 2018 9/27/2018

ip
Burosumab Crysvita FGF23; Human IgG1 X-linked hypophosphatemia 2/19/2018 4/17/2018
Lanadelumab Takhzyro Plasma kallikrein; Human Hereditary angioedema Nov. 2018 8/23/2018
IgG1 attacks

cr
Caplacizumab Cablivi von Willebrand factor; Acquired thrombotic 8/31/2018 In review
Humanized Nanobody thrombocytopenic purpura
Mogamulizumab Poteligeo CCR4; Humanized IgG1 Mycosis fungoides or Nov. 2018 8/8/2018

us
Sézary syndrome
Moxetumomab Lumoxiti CD22; Murine IgG1 dsFv Hairy cell leukemia NA 9/13/2018
pasudodox immunotoxin
Cemiplimab Libtayo PD-1; Human mAb Cutaneous squamous cell In review 9/28/2018
an
carcinoma
Ibalizumab Trogarzo CD4; Humanized IgG4 HIV infection In review 3/6/2018
Tildrakizumab Ilumetri, IL-23 p19; Humanized Plaque psoriasis 9/17/2018 3/20/2018
M
Ilumya IgG1
Emapalumab Gamifant IFNγ; Human IgG1 Primary hemophagocytic In review 11/20/2018
lymphohistiocytosis
Data available as of November 30, 2018. *Biosimilar products were excluded. #INN assigned by the World
ed

Health Organization; US product names in alphabetical order are burosomab-twza, cemiplimab-rwlc, emapalumab-
lzsg, erenumab-aooe, fremanezumab-vfrm, galcanezumab-gnlm, ibalizumab-uiyk, lanadelumab-flyo,
mogamulizumab-kpkc, moxetumomab pasudotox-tdfk, tildrakizumab-asmn. Abbreviations: CD, cluster of
differentiation; CGRP, calcitonin gene-related peptide; dsFv, disulfide-stabilized variable fragment; EU
pt

European Union; FGF23, fibroblast growth factor 23; IgG, immunoglobulin G; NA, not applicable; PD-1
programmed cell death 1; US, United States.
ce
Ac

38
 Table 2. Investigational antibody therapeutics in regulatory review in the European Union or the United
States*

International
non-proprietary Brand name Status in Status in
name proposed Target; Format Indication EU US
Sacituzumab TROP-2; humanized IgG1
govitecan (Pending) ADC Triple-negative breast cancer NA In review
Ravulizumab Paroxysmal nocturnal
(ALXN1210) (Pending) C5; humanized IgG2/4 hemoglobinuria In review In review

t
Risankizumab (Pending) IL-23 p19; Humanized IgG1 Plaque psoriasis In review In review

ip
Osteoporosis in
Sclerostin; Humanized postmenopausal women at
Romosozumab EVENITY IgG2 increased risk of fracture In review In review

cr
Data available as of November 30, 2018. *Antibody therapeutics not previously approved in the EU or US for
any indication; biosimilar products were excluded. Abbreviations: ADC, antibody-drug conjugate; EU,

us
European Union; C5, complement component 5; IgG, immunoglobulin G; IL, interleukin; NA, not applicable;
TROP-2, trophoblast cell-surface antigen 2; US, United States.
an
M
ed
pt
ce
Ac

39
Table 3. Investigational monoclonal antibodies in late-stage clinical studies for non-cancer indications
Primary sponsoring INN or code Molecular Target(s) Most Pivotal Phase 2, Phase
company name format advance 2/3 or 3 indications
d phase

Omeros Corporation OMS721 Human mAb MASP-2 Phase 3 Atypical hemolytic uremic

t
syndrome

ip
Novartis Ligelizumab Human IgG1 IgE Phase 3 Chronic spontaneous
urticaria

cr
Bioverativ Sutimlimab, Humanized C1s Phase 3 Cold agglutinin disease
BIVV009 mAb
Regeneron Evinacumab Human mAb Angiopoietin- Phase 3 Homozygous familial

us
Pharmaceuticals like 3 hypercholesterolemia
Novartis Crizanlizumab Humanized CD62 (aka P- Phase 3 Sickle cell disease
IgG2 selectin)
an
UCB Bimekizumab Humanized IL-17A, F Phase 3 Ankylosing spondylitis,
IgG1 psoriasis
Biocad BCD-085 Humanized IL-17 Phase 3 Ankylosing spondylitis,
M
mAb psoriasis
AstraZeneca/ Tralokinumab Human IgG4 IL-13 Phase 3 Atopic dermatitis
MedImmune LLC
ed

Novartis Ianalumab Human IgG1 BLyS/BAFF/TACI Phase Autoimmune hepatitis

(VAY736) /BCMA 2/3
receptor
pt

R-Pharm Olokizumab Humanized IL-6 Phase 3 Rheumatoid arthritis

IgG4
AstraZeneca/ Anifrolumab Human IgG1 IFN a, b, ω Phase 3 Systemic lupus
ce

MedImmune LLC receptor 1 erythematosus

Genentech Etrolizumab Humanized a4-b7/ aE-b7 Phase 3 Ulcerative colitis; Crohn's
IgG1 integrin disease
Ac

receptor
Boehringer Ingelheim BI655130 Human IgG1 IL-36R Phase Ulcerative colitis
2/3
Eli Lilly & Co. Mirikizumab Humanized IL-23p19 Phase 3 Ulcerative colitis,
IgG4 psoriasis
Shire SHP-647 Human IgG2 Mucosal Phase 3 Ulcerative colitis; Crohn's
addressin cell disease
adhesion

40
 molecule

AstraZeneca/ Tezepelumab Human IgG2 Thymic stromal Phase 3 Severe uncontrolled

MedImmune LLC lymphopoietin asthma
CytoDyn Leronlimab Humanized CCR5 Phase HIV infection
(PRO140) IgG4 2/3
GC Pharma Lenvervimab Humanized Hepatitis B virus Phase Hepatitis B virus-
(GC1102) IgG1 surface antigen 2/3 associated liver

t
transplant

ip
Biogen Aducanumab Human IgG1 Amyloid beta Phase 3 Alzheimer's disease
Genentech Crenezumab Humanized Amyloid beta Phase 3 Alzheimer's disease

cr
IgG4
Hoffmann-La Roche Gantenerumab Human IgG1 Amyloid beta Phase 3 Alzheimer's disease

us
Hoffmann-La Roche Faricimab Bispecific VEGF-A, Ang2 Phase 3 Diabetic macular edema
CrossMab
Novartis Brolucizumab Humanized VEGF-A Phase 3 Neovascular age-
scFv
an related macular degenera
tion
Viela Bio Inebilizumab Humanized CD19 Phase Neuromyelitis optica and
M
IgG1 2/3 neuromyelitis optica
spectrum disorders
Chugai Satralizumab Humanized IL-6R Phase 3 Neuromyelitis optica and
Pharmaceuticals/ IgG2 neuromyelitis optica
ed

Roche spectrum disorders

Horizon Pharma USA Teprotumumab Human IgG1 IGF-1R Phase 3 Thyroid eye disease
pt

Alder Eptinezumab Humanized CGRP Phase 3 Episodic migraines

Biopharmaceuticals IgG1
Regeneron Fasinumab Human IgG4 Nerve growth Phase 3 Pain due to osteoarthritis
ce

Pharmaceuticals factor of knee or hip, low back

pain
Pfizer; Eli Lilly & Tanezumab Humanized Nerve growth Phase 3 Pain due to osteoarthritis
Ac

Company IgG2 factor of knee or hip, low back

pain, cancer pain due to
bone metastasis

Data available as of November 30, 2018. Abbreviations: BAFF, B-cell activating factor; BCMA, B-cell maturation
antigen; BLyS, B lymphocyte stimulator; CGRP, calcitonin gene-related peptide; MASP-2, mannose-binding
protein-associated serine protease 2; TACI, transmembrane activator and CAML interactor; IGF-1R, insulin-
like growth factor-1 receptor; VEGF, vascular endothelial growth factor.

41
Table 4. Investigational monoclonal antibodies in late-stage clinical studies for cancer indications
Primary sponsoring INN or code Molecular Target(s) Most Pivotal Phase 2,
company name format advanced Phase 2/3 or 3
phase indications

TG Therapeutics Ublituximab Chimeric IgG1 CD20 Phase 3 Chronic

lymphocytic
leukemia

t
ip
ADC Therapeutics Sarl Loncastuximab Humanized IgG1 CD19 Pivotal Diffuse large B-
tesirine ADC Phase 2 cell lymphoma

cr
Hoffmann-La Roche Polatuzumab Humanized IgG1 CD79b Phase 3 Diffuse large B-

us
vedotin ADC cell lymphoma

Pfizer Utomilumab
an
Human IgG2 4-1BB Phase 3 Diffuse large B-
(CD137) cell lymphoma
M

MorphoSys XMAB-5574, Humanized IgG1 CD19 Phase 2/3 Diffuse large B-

MOR208 cell lymphoma
ed

Sanofi Isatuximab Humanized IgG1 CD38 Phase 3 Multiple myeloma

pt

Jiangsu HengRui Camrelizumab Humanized IgG4 PD-1 Phase 3; Hodgkin's

Medicine Co., Ltd regulatory lymphoma,
review in hepatocellular
ce

China carcinoma

Actinium I-131-BC8, Murine IgG1, CD45 Phase 3 Ablation of bone

Ac

Pharmaceuticals Iomab-B radio-labeled marrow prior to

hematopoietic
cell
transplantation in
AML patients

42
Tracon Carotuximab Chimeric IgG1 Endoglin Phase 3 Angiosarcoma

Alphamab Oncology KN035 mAb, single PD-L1 Phase 3 Bile tract

domain carcinoma

Viventia Bio Oportuzumab Humanized scFv EpCAM Phase 3 Bladder cancer

monatox immunotoxin

t
Bio-Thera Solutions BAT8001 Humanized IgG1 HER2 Phase 3 Breast cancer

ip
ADC

Synthon (vic- Humanized IgG1 HER2 Phase 3 Breast cancer

cr
Biopharmaceuticals )trastuzumab ADC
BV duocarmazine

us
MacroGenics Margetuximab Chimeric IgG1 HER2 Phase 3 Breast cancer

Daiichi Sankyo Trastuzumab Humanized ADC HER2 Phase 3 Breast cancer,

deruxtecan HER2+ gastric or
an
gastroesophageal
junction
adenocarcinoma
M

Five Prime Bemarituzumab Humanized IgG1 FGFR2b Phase 3 Gastric and

ed

Therapeutics, Zai Lab gastro-esophageal

Limited junction
adenocarcinoma
pt
ce

Astellas Zolbetuximab, Chimeric IgG1 Claudin-18.2 Phase 3 Gastric and

claudiximab gastro-esophageal
junction
adenocarcinoma
Ac

43
Gilead Sciences Andecaliximab Humanized IgG4 MMP9 Phase 3 Gastric cancer or
gastroesophageal
junction
adenocarcinoma

AbbVie Depatuxizumab IgG1 ADC EGFR Phase 2b/3 Glioblastoma

mafodotin

t
Y-mabs Therapeutics Naxitamab Humanized mAb GD2 Phase 3 High risk

ip
neuroblastoma
and refractory

cr
osteomedullary
disease

us
Bristol-Myers Squibb Relatlimab (BMS- Human mAb LAG-3 Phase 2/3 Melanoma
986016) an
Biocad BCD-100 Human mAb PD-1 Phase 2/3 Melanoma

Novartis Spartalizumab, Humanized IgG4 PD-1 Phase 3 Melanoma

PDR001
M
Philogen SpA L19IL2 + L19TNF scFv conjugates Fibronectin Phase 3 Melanoma
extra-
domain B
ed

Y-mAbs Therapeutics 131I- Murine mAb, B7-H3 Phase 2/3 Neuroblastoma

omburtamab radiolabeled central nervous
system/
leptomeningeal
pt

metastases
ce

BeiGene Tislelizumab Humanized mAb PD-1 Phase 3; Non-small cell

Ac

(BGB-A317) regulatory lung cancer,

review in Hodgkin's
China lymphoma

Innovent Biologics IBI308 Human mAb PD-1 Phase 3; Squamous cell

(Suzhou) Co. Ltd. regulatory non-small cell
review in lung cancer
China

44
CStone CS1001 Human PD-L1 Phase 3 Non-small cell
Pharmaceuticals lung cancer

AstraZeneca/ Tremelimumab Human IgG2 CTLA4 Phase 3 Non-small cell

MedImmune LLC lung, head &
neck, urothelial
cancer

t
Tesaro, Inc. TSR-042 Humanized mAb PD-1 Phase 3 Ovarian cancer

ip
ImmunoGen Mirvetuximab IgG1 ADC Folate Phase 3 Ovarian cancer
soravtansine receptor 1

cr
AbbVie Rovalpituzumab Humanized IgG1 DLL3 Phase 3 Small cell lung
tesirine ADC cancer

us
Seattle Genetics Enfortumab Human IgG1 ADC Nectin 4 Phase 3 Urothelial cancer
vedotin an
Data available as of November 30, 2018. Abbreviations: ADC, antibody drug conjugate; CTLA-4, cytotoxic T-
lymphocyte–associated antigen 4; DLL3, delta-like protein 3; EGFR, epidermal growth factor receptor;
EpCAM, epithelial cell adhesion molecule; FGFR2, fibroblast growth factor receptor 2; HER2, epidermal
growth factor receptor-2; MMP-9, matrix metallopeptidase 9; PD-1, programmed cell death 1; PD-L1,
M
programmed death ligand.
ed
pt
ce
Ac

45