Antibody Engineering & Therapeutics

December 14, 2017

Janice M. Reichert, Ph.D.

Executive Director, The Antibody Society

Editor-in-Chief, mAbs

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The Antibody Society

• The Antibody Society is a non-profit trade association

representing individuals and organizations involved in

antibody R&D

• We pursue initiatives intended to broadly benefit the

field of antibody R&D, e.g.,

• INN source infix issue

• Development metrics

• Standards for next-generation sequencing data (Adaptive

Immune Receptor Repertoire Community)

• We engage in activities that broadly benefit our

members, such as education and publishing, and help

to organize conferences

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Topics for discussion

• Newly on the market (or soon to be)

• Recent first approvals for antibody therapeutics

• Antibodies in regulatory review

• Antibodies in late-stage clinical development

• Possible near-term marketing application submissions

(details in supp. slides)

• Near-term study primary completion dates (supp. slides)

• Antibody therapeutics development metrics

• Data collected

• Success rates

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First US or EU approvals of mAbs

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Year of first US or EU approval

*Projected number of first approvals. Table of approvals and antibodies in review at antibodysociety.org

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10 first US or EU approvals in 2017

• Sarilumab (Kevzara)

• Targets IL-6R; US and EU approved for rheumatoid arthritis

• Brodalumab (Siliq, Lumicef)

• Targets IL-17RA; US and EU approved for plaque psoriasis

• Guselkumab (Tremfya)

• Targets IL-23p19; US and EU approval for plaque psoriasis

• Dupilumab (Dupixent)

• Targets IL-4Ra; US and EU approval for atopic dermatitis

• Ocrelizumab (Ocrevus)

• Targets CD20; US for multiple sclerosis; EC decision pending

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Ten first approvals in 2017… (cont.)• Benralizumab (Fasenra)

• Targets IL-5a; US approval for asthma, EC decision pending

• Emicizumab (Hemlibra

• Targets Factor Ixa, X; US approval for hemophilia A, EU review

• Avelumab (Bavencio)

• Targets PD-L1; US and EU approval for Merkel cell carcinoma

• Durvalumab (Imfinzi)

• Targets PD-L1; US approval for urothelial carcinoma, EU review

• Inotuzumab ozogamicin (Besponsa)

• Targets CD22; US and EU approval for acute lymphoblastic leukemia

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Nine first EU or US approvals in 2018?

• Ibalizumab, targeting CD4 for drug resist. HIV infection

• Priority review; Breakthrough Therapy, US orphan designations

• PDUFA date Jan 3, 2018

• Burosumab, anti-FGF23 for X-linked hypophosphatemia

• Breakthrough Therapy designation in US;

• PDUFA date Apr 2018

• Tildrakizumab, targeting IL-23p19 for plaque psoriasis

• Caplacizumab, targeting von Willebrand factor for acquired

thrombotic thrombocytopenic purpura

• Positive Phase 3 results released in Oct 2017; FT, but no BLA

yet

Source: antibodysociety.org

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1st EU or US approvals in 2018? • Erenumab, targeting CGRP receptor for prev. of migraine

• Fremanezumab, targeting CGRP for migraine prevention

• Galcanezumab (LY2951742), IgG4 targeting CGRP for

migraine prevention

• Fast track designation for treatment of cluster headache, with

Phase 3 trial results expected in 2018

• Romosozumab, targeting sclerostin for osteoporosis

• Heart-related side effects observed in Phase 3 study

• Complete response letter requesting additional clinical data from

Phase 3 studies (ARCH and BRIDGE) in July 2017

• Mogamulizumab, targeting CCR4 for cutaneous T cell lymphoma

Source: antibodysociety.org

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mAb pipeline

260 250

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0255075

100125150175200225250275

Phase 1 Phase 2 Late-stage study

Total pipeline = ~560 mAbs. Commercial development; Phase 1/2 included with Phase 2, Phase 2/3 included with

Phase 3. Tables of mAbs in Phase 3 available at www.antibodysociety.org and in ‘Antibodies to watch in 2018’ paper

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Antibodies in late-stage studies*

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2010 2011 2012 2013 2014 2015 2016 2017 2018#

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Year of article publication

* Data from ‘Antibodies to watch’ articles published in mAbs; #: projection

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First applications submitted in late

2017 or during 2018?

• 8 for non-cancer indications: lanadelumab, crizanlizumab,

ravulizumab, eptinezumab, risankizumab, satralizumab,

brolucizumab, PRO140

• 4 for cancer indications: sacituzumab govitecan,

moxetumomab pasudotox, cemiplimab, ublituximab

• See supplemental slides posted in presentations section

at www.antibodysociety.org and ‘Antibodies to watch in

2018’, soon to be posted in the Latest articles section of

the mAbs website, for details

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Drug development metrics

• Assess performance of the pharmaceutical industry, and

serve as benchmarks for individual companies

• Success rates are useful for setting expectations for

clinical development of drugs, e.g.,

• Phase transition and approval success rates

• Phase 1 to 2, Phase 2 to 3, Phase 3 to reg. review;

overall rate from Phase 1 to approval

• Global, US or EU approvals

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Data collected

• Top-level data on all commercially sponsored antibodies

currently in clinical study and those that entered clinical

study during 2000-2016, but were terminated

• Name(s) and company

• Molecular characteristics (sequence source, isotype,

any modifications, target)

• Clinical development data (dates of transitions,

indications of studies)

• First regulatory review (focus on EU and US)

• First marketing approval (focus on EU and US)

• As of Oct 1, 2017, dataset includes over 950 molecules

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Rates comparison

Sources: 1. Hay et al Nat Biotechnol 2014; 2. Society est. 9/05/17

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Phase 1 to 2 Phase 2 to 3 Phase 3 to RR RR to approval Phase 1 to approval

Biologics (1) All mAbs, '00-09 (3)

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Study start 2000-09, US/EU approvals

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Phase 1 to 2 Phase 2 to 3 Phase 3 to RR RR to approval Phase 1 to approval

00-09, all Cancer only Non-cancer only Unmod., full-length, non-murine

# of molecules: 00-09, all, n=358; Cancer only, n=176; Non-cancer only, n=182; Unmod., full-length, non-murine, n=265.

Final fates (approval or termination) are known for 71%. Three approvals outside the US/EU regions (mogamulizumab approval in

Japan, italizumab and Rmab approvals in India) classified as Phase 3

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Study start 2005-14, US/EU approvals

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Phase 1 to 2 Phase 2 to 3 Phase 3 to RR RR to approval Phase 1 to approval

00-09, all Cancer only Non-cancer only Unmod., full-length, non-murine

# of molecules: 05-14, all, n=566; Cancer only, n=270; Non-cancer only, n=296; Unmod., full-length, non-murine, n=426. Final fates

(approval or termination) are known for 47%. Three approvals outside the US/EU regions (mogamulizumab approval in Japan,

italizumab and Rmab approvals in India) classified as Phase 3

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To conclude…• Number of mAbs in late-stage clinical studies expected

to drive trend toward first approvals for ~6-9 new mAbs

per year (or more) into the future

• 2018 will be an active year! Currently watching:

• 11 applications in US or EU regulatory review

• 12 possible marketing application submissions (8 non-cancer,

4 cancer)

• 19 antibodies with top-level Phase 3 results expected (10

non-cancer, 9 cancer)

• Success rates for antibody therapeutics development

holding at relatively high levels (20-24%, P1-approval)

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Support provided by…

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Support also provided by…

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Please join us!www.antibodysociety.org

Janice M. Reichert, Ph.D.

Executive Director, The Antibody Society

Editor-in-Chief, mAbs

janice.reichert@antibodysociety.org

Tables of approved antibody therapeutics, antibodies

in regulatory review and Phase 3 can be found in the

Members Only section

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8 first applications submitted in

late 2017 or during 2018?

• 3 for cardiovascular/hemostasis disorders

• 1 for pain indications

• 2 for immune-mediated disorder

• 1 for ophthalmic indication

• 1 for infectious disease

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CV / hemostasis1. Lanadelumab (DX-2930), targeting plasma kallikrein for

hereditary angioedema attacks

• Positive results in Phase 3 HELP study

• Breakthrough therapy and Fast Track designations, EU and US orphan designations

• Shire plans to submit a BLA by late 2017 or early 2018, MAA in H1 2018

2. Crizanlizumab (SEG101), targeting CD62 (aka P-selectin) for sickle cell pain crises caused by vaso-occlusion

• Positive Phase 2 results reported in Dec 2016

• US and EU orphan designations

• Crizanlizumab was discussed with health authorities, and based on their feedback Novartis expects to submit for regulatory approval in the US in 2018. This assumes successful PK/PD comparability study to final manufacturing process

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CV / hemostasis (cont.)

3. ALXN1210, targeting C5 for paroxysmal nocturnal

hemoglobinuria and atypical hemolytic uremic syndrome

• 2 Phase 3 studies in PNH with primary completion dates of

Dec 2017 and Mar 2018; 2 Phase 3 studies in aHUS with

primary completion dates in Dec 2017 and Dec 2018

• Orphan designations in EU and EU for PNH

• 2018 BLA submission planned

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PainAnti-calcitonin gene-related peptide mAb for migraine

prevention

4. Eptinezumab (ALD403), IgG1

• Positive results from Phase 3 PROMISE 1 study

• BLA may be submitted by end of 2018

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Immune-mediated disorders

5. Risankizumab (ABBV066, BI655066), targeting IL-23 p19

subunit for psoriasis

• 4 Phase 3 studies in psoriasis with primary completion dates

Nov 2016 – Mar 2017; data may be released in 2017

• BLA submission for psoriasis planned in 2018, with launch

expected in 2019

• 3 Phase 3 studies in Crohn’s disease not yet recruiting; US

orphan designation for CD in pediatric patients

6. Satralizumab (SA237), IgG2 targeting IL-6R for neuromyelitis

optica (NMO) and NMO spectrum disorder

• 2 Phase 3 studies, primary completions in July and Oct 2018

• Application submission anticipated in 2018 (as per Roche

pipeline)

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Ophthalmic

7. Brolucizumab, scFv targeting VEGF-A for

neovascular age-related macular degeneration

• Positive results from Phase 3 HAWK and HARRIER studies

• Brolucizumab enables much higher concentrations of

antibody in the eye than approved therapies. Given the

complexity of the formulation, Novartis has invested to

ensure a competitive, low cost of goods formulation over the

past 18 months to maximize long term value. Novartis

expects to complete the pharmacokinetic study with the final

manufacturing process to enable filing in 2018.

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Infectious disease

8. PRO140, IgG4 targeting CCR5 for HIV infection

• Two Phase 2/3 studies with primary completion dates in Oct and

Dec 2017

• Fast Track designation

• Cytodyn expects to submit rolling BLA; company has meeting

with FDA on Oct 12, 2017 purpose of the meeting will be to

address open issues set forth in an FDA memorandum

regarding the adequate number and type of evaluable patients

required for efficacy and safety necessary to support the filing of

a Biologics License Application

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2017/8 Phase 3 results for 10 mAbs

• 1 for ophthalmic indication

• 3 for cardiovascular/hemostasis disorders

• 3 for neurological disorders (pain, Alzheimer’s disease)

• 3 for immune-mediated diseases

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Ophthalmic: Antibody to watch

1. Lampalizumab (RG7417, FCFD4514S), Fab

targeting Factor D

• NCT02247531 Spectri and NCT02247479 Chroma

studies are evaluating lampalizumab administered

intravitreally to patients with geographic atrophy

secondary to age-related macular degeneration

• Primary endpoint was not met in Spectri study

• Primary completion date of Chroma study is Nov 2017

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CV / hemostasis: Abs to watch

2. Roledumab (LFB-R593), targeting Rhesus D for Rh

disease

• Phase 2/3 NCT02287896 active, not recruiting patients;

primary completion date in November 2017

3. NEOD001, targeting amyloid for AL amyloidosis

• VITAL amyloidosis study has primary completion date in

January 2018

• Fast track designation for the potential treatment of AL

amyloidosis

• Topline results in the Phase 2b PRONTO study (129

patients) expected in the second quarter of 2018

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CV / hemostasis (cont.)4. Emapalumab (NI-0501), targeting IFN gamma for primary

hemophagocytic lymphohistiocytosis

• Condition characterized by the overwhelming activation of

normal T lymphocytes and macrophages, invariably leading

to clinical and hematologic alterations and death in the

absence of treatment

• PRIority MEdicines (PRIME), orphan designations in EU

• Breakthrough therapy, rare pediatric disease, orphan

designations in US

• Phase 2/3 study has primary completion date in December

2017

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Pain: Antibodies to watch

Anti-nerve growth factor mAbs for pain due to osteoarthritis of

knee or hip, low back pain

5. Fasinumab (REGN475/SAR164877), IgG4

• Phase 2/3 primary completions: Jun 2017, Sep 2019

• Phase 3 primary completions: Feb 2018, Mar 2019, Aug 2020

• Phase 3 NCT03285646 study not yet recruiting

6. Tanezumab (PF-04383119), IgG2

• 7 Phase 3 studies recruiting, 1 Phase 3 study not yet

recruiting; NCT02528253 primary completion date in Nov

2017, other Phase 3 studies with primary completion dates in

May 2018 and Sep 2018

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Alzheimer’s disease: Ab to watch

7. Gantenerumab (RO4909832), targeting amyloid-b

• Phase 3 NCT02051608 study in patients with mild

Alzheimer’s disease initiated in March 2014 has primary

completion date in July 2018

• Phase 3 NCT01224106 study in patients with prodromal

Alzheimer’s disease initiated in November 2010 has primary

completion date in July 2020; 105 mg and 225 mg SC

doses are being evaluated

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Immune-mediated disorders:

Antibodies to watch

8. Etrolizumab targeting β7 subunit of α4β7 and αEβ7

integrin heterodimers for ulcerative colitis

• 2 Phase 3 studies, primary completions in March 2018

9. Anifrolumab, targeting type-I IFN receptor subunit 1 for

systemic lupus erythematosus

• 2 Phase 3 studies, primary completions in Jul, Sep 2018

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4 application sub in 2017/8?

1. Sacituzumab govitecan, humanized anti-Trop-2 antibody

conjugated to SN38• Immunomedics announced that they were on track to submit a BLA for

accelerated approval of sacituzumab govitecan as third-line treatment for

mTNBC by the end of March 2018

• Fast track designation

2. Moxetumomab pasudotox, dsFv immunotoxin targeting

CD22 for hairy cell leukemia

• Phase 3 primary completion date May 24, 2017

• US orphan designation for hairy cell leukemia

• AstraZeneca estimates BLA filing date in 2018

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4 application sub in 2017/8? (cont.)

3. Cemiplimab (REGN2810), targeting PD-1

• NCT02760498, a potentially pivotal Phase 2 study, is enrolling patients

with metastatic cutaneous squamous cell carcinoma (CSCC) and

locally advanced and unresectable CSCC; initiation was Mar 2016 and

primary completion date is May 2019

• Breakthrough therapy designation for CSCC

• Phase 3 studies in cervical cancer and NSCLC, with primary

completion dates of May 2020 and Nov 2021, respectively

• Pending data results, the companies (Regeneron and Sanofi)

anticipate submitting a BLA for cemiplimab in Q1 2018

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4 application sub in 2017/8? (cont.)

4. Ublituximab (LFB-R603, TGT-1101), mAb targeting

CD20 produced in low fucose (YB2/0 cell line) for chronic

lymphocytic leukemia

• Positive results from Phase 3 GENUINE study

(NCT02301156) in CLL; Phase 3 UNITY-CLL study

(NCT02612311) has primary completion date in Sep 2018

• TG Therapeutics 2017 milestones include meeting with FDA

to review the GENUINE Phase 3 data and discuss suitability

for filing for accelerated approval.

• Two Phase 3 studies in multiple sclerosis also recruiting

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2018 Phase 3 results expected for

9 mAbs1. Tremelimumab, targeting CTLA4, evaluated in combo with

durvalumab

• Phase 3 MYSTIC study in NSCLC did not meet primary

endpoint; Phase 3 ARCTIC and NEPTUNE studies in NSCLC

have primary completion dates in Nov 2017 and Oct 2018

• Phase 3 Kestrel (1st-line HNSCC), Phase 3 Eagle (2nd-line

HNSCC) studies with data expected in Feb and Mar 2018,

respectively

• Phase 3 NCT02516241 study in urothelial cancer has a

primary completion date in April 2018

• Phase 3 HIMALAYA study in unresectable hepatocellular

carcinoma not yet recruiting as of Oct 10

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Phase 3 results (continued)

2. Isatuximab (SAR650984), targeting CD38 for plasma cell

myeloma

• Phase 3 NCT02990338 study has primary completion

date in May 2018

3. Carotuximab, targeting CD105 (aka endoglin) for

angiosarcoma

• Phase 3 NCT02979899 study (TAPPAS) has primary

completion date in Sep 2018

• US orphan drug for the treatment of soft tissue sarcoma;

fast track designation, but in renal cell cancer

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Phase 3 results (cont….)

4. BCD-100, targeting PD-1 for melanoma

• Phase 2/3 NCT03269565 (MIRACULUM) study has

primary completion date in Aug 2018

5. Camrelizumab (SHR-1210), targeting PD-1

• Phase 3 NCT03099382 study in esophageal carcinoma

and Phase 2/3 NCT02989922 study in hepatocellular

carcinoma have primary completion dates in June and

Dec 2018, respectively

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Late-stage ADCs

6. Glembatumumab vedotin, ADC targeting gp NMB for

metastatic gpNMB over-expressing triple-negative BC

• Pivotal Phase 2 METRIC study has primary completion date

in December 2017

• Fast track designation for gpNMB+ breast cancer

7. Mirvetuximab soravtansine (IMGN853), ADC targeting

folate receptor alpha for FRa+ adv. ep. ovarian cancer,

primary peritoneal or fallopian tube cancer

• Phase 3 FORWARD I study has primary completion date in

November 2018

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Late-stage immunoconjugates

8. Oportuzumab monatox, PE-scFv targeting EpCAM for

bladder cancer

• Phase 3 has primary completion date in Dec 2018

9. L19IL2/L19TNF, scFvs targeting fibronectin extra-domain

B conjugated to either IL2 or TNF, evaluated as a

mixture, for melanoma

• Phase 3 study has primary completion date in Dec 2018

• Patients will receive multiple intratumoral

administrations into all injectable cutaneous,

subcutaneous, and nodal tumors of a mixture of L19IL2

and L19TNF once weekly for up to 4 weeks