Therapeutic Monoclonal Antibodies for Respiratory Diseases: Current Challenges & Perspectives March 31 - April 1, 2016

Home , Benralizumab, Bimagrumab, Gantenerumab, Ibalizumab, Obiltoxaximab, Solanezumab

Janice M. Reichert, Ph.D. Executive Director, The Antibody Society Editor-in-Chief, mAbs

1 Topics for discussion

 Overview of the antibody therapeutics clinical pipeline*  ‘Other’ disorders, incl. respiratory disorders  Antibodies recently approved or in regulatory review  Antibodies in clinical studies  Prospects for 2016

*Disclaimer: Commercial development; only public domain information known as of Feb 15, 2016 is included. It should be noted that frequent changes to the data occur over time.

2 3 Novel antibodies entering clinic* 120 102 100 81 80 66 54 60 50

0 2011 2012 2013 2014 2015 Year of first clinical study

*Commercial development only Antibodies in Phase 3 studies 60 53 50

39 40 33 29 30 26 25 25

20 Number of mAbs in Phase 3 Phase in mAbs of Number

0 2010 2011 2012 2013 2014 2015 2016 Year of article publication

Data from ‘Antibodies to watch’ articles published in mAbs. 5 First US or EU approvals of mAbs 11 10+ ? 10 9 8 7 6 5 4 3

Number of first approvals for mAbs for Number approvals of first 2 1 0 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 Year of first US or EU approval 16*

*Projected number of first approvals. Source: Table of antibodies approved or in review in the US or EU (antibodysociety.org) 6 Three approvals in 2016 so far…  Obiltoxaximab, targeting PA of B. anthracis exotoxin approved by FDA on March 18  ANTHIM® is indicated in adult and pediatric patients for treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate.  Ixekizumab, targeting IL-17A approved by FDA on March 22  Taltz® is indicated for treatment of adults with moderate-to-severe plaque psoriasis. A decision by the EC is pending.  Reslizumab, targeting IL-5 approved by FDA on March 23  Cinqair® is indicated for severe asthma in adults. A marketing application is undergoing review in the EU.

7 US or EU approvals in 2016?  6 more antibody therapeutics in regulatory review:  Atezolizumab, targeting PD-L1 for bladder cancer  Olaratumab, targeting PDGFRα for sarcoma  Immune-mediated disorders (e.g., psoriasis, RA, GvH)  Brodalumab, targeting IL-17R  Sarilumab, targeting IL-6R  Begelomab, targeting CD26  Bezlotoxumab, targeting C. difficile enterotoxin for prevention of infection recurrence Potential submissions in 2016?  Marketing applications for 9 mAbs may be submitted:  4 for cancer indications  Inotuzumab ozogamicin, targeting CD22  Durvalumab, targeting PD-L1 and tremelimumab, targeting CTLA4  Xilonix, targeting IL-1 α  Ocrelizumab, targeting CD20 for MS  Bimagrumab, targeting activing A receptor type IIB for sporadic inclusion body myositis  Ibalizumab, targeting CD4 for HIV infection  Benralizumab, targeting IL-5R for asthma, COPD  Lebrikizumab, targeting IL-13 for asthma mAbs in clinical studies 220 200 Non-cancer Cancer 180 82 160 105 140 120 100 80 60 136 98 40 40 20 0 17 Phase 1 Phase 2 Phase 3

Total pipeline = ~480 mAbs. Commercial development; Phase 1/2 included with Phase 2, Phase 2/3 included with Phase 3. Data known by Reichert Biotechnology Consulting LLC as of Feb 15, 2016.

10 Enhancement of functionality  Engineering of canonical antibodies  Glyco-engineering, protein engineering  Antibody-drug conjugates (ADCs)  Bispecific antibodies  Immunoconjugates  Fragments  Single-chain variable fragments, Fab, domain antibodies  Mixtures of antibodies Formats for all indications

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Phase 1 Phase 2 Phase 3 Canonical, full length ADC Bispecific Immunoconjugate Fragment Mixture

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Phase 1 Phase 2 Phase 3 Canonical, full length ADC Bispecific Immunoconjugate Fragments Mixtures

Notes: ‘Immunoconjugate’ includes immunocytokines, immunotoxins, radiolabeled antibodies; antibody component may be full length or fragment. ‘Fragments’ (e.g., scFv, Fab, nanobody) includes molecules that are less than full length and are otherwise unmodified (e.g., not bispecific or conjugated to another molecule). ‘Mixtures’ includes mixtures of two or more antibodies. Phase 1/2 studies were grouped with Phase 2; Phase 2/3 studies were grouped with Phase 3. 14 ‘Other’ therapeutic areas  mAbs for ‘other’ disorders comprise ~33% of the current pipeline (~160 of 480 mAbs)  Of the ~160 mAbs, the areas that include the largest number* of mAbs are:  Neurological (27 mAbs; 11 in Phase 2/3 or Phase 3 studies)  Cardiovascular / hemostasis (25 mAbs; 6 in Phase 3 studies)  Infectious disease (24 mAbs; 3 in Phase 3 studies)  Respiratory disease (22 mAbs, 4 in Phase 3 studies)

*excludes some Phase 1 studies of only healthy volunteers

15 Recently approved or in review  Cardiovascular / hemostasis  Alirocumab and evolocumab for high cholesterol indication, idarucizumab for reversal of dabigatran anticoagulant activity approved in 2015 in US, EU  Infectious disease  Obiltoxaximab, 2016 approval for inhalation anthrax in US  Bezlotoxumab, prevention of C. difficile infection recurrence in US and EU review  Respiratory disease  Mepolizumab, asthma indication approved in 2015 in US, EU  Reslizumab, 2016 approval in US for asthma; review in EU Complete list on website of The Antibody Society (www.antibodysociety.org) 16 Neurological indications: Ph3  Anti-nerve growth factor mAbs  Fulranumab, fasinumab, tanezumab  Phase 3 studies in pain due to osteoarthritis of knee or hip, low back pain  Anti-calcitonin gene-related peptide / receptor mAbs  ALD403, AMG334, LY2951742, TEV48125  Phase 3 studies in migraine prevention, episodic cluster and chronic headache  Anti-amyloid mAbs  Aducanumab, crenezumab, gantenerumab, solanezumab  Phase 3 studies in Alzheimer’s disease

17 CV / hemostasis: Phase 3  6 mAbs in Phase 2/3 or 3 studies  Bococizumab, targeting PCSK9 for high cholesterol  Roledumab, targeting Rhesus D for Rh disease  NEOD001, targeting amyloid for primary systemic amyloidosis  Lanadelumab, targeting plasma kallikrein for hereditary angioedema attacks  Caplacizumab, VH-VH (Nanobody) targeting von Willebrand factor for thrombotic thrombocytopenic purpura  Emicizumab, bispecific targeting Factor IXa and Factor X for hemophilia A

18 Infectious disease  3 mAbs in Phase 3 studies  Anti-CCR5 PRO140 and anti-CD4 ibalizumab for human immunedeficiency virus (HIV) infection  Anti-RSV F protein REGN2222 for prevention of respiratory syncytial virus (RSV) infection  mAbs in Phase 1 and 2 studies for potential prevention or treatment of infection with:  HIV, RSV, influenza, Ebola virus, Hep B virus, Staphylococcus aureus

19 Respiratory disease: Phase 3  Benralizumab, targeting IL-5 receptor for asthma and chronic obstructive pulmonary disease  Dupilumab, targeting IL-4 receptor alpha, blocks interleukin-4 and interleukin-13 from binding the receptor, for asthma  Lebrikizumab, targeting IL-13 for asthma  Tralokinumab, targeting IL-13 for asthma

20 Types in the clinic  ~90% of mAbs for ‘other’ TAs in clinical studies are conventional IgG1, IgG2, IgG4 or IgM that may have been Fc or glycoengineered  Mechanisms of action include receptor or ligand blockade, i.e., interference of signal transduction  ~10% are non-conventional, including  7 bispecific mAbs  7 fragments (domain, nanobody, scFv, Fab)  4 mixtures of 2 or 3 mAbs

21 22 Near-term 1st approvals: ‘Other’ TAs  Bezlotoxumab for prevention of C. difficile infection recurrence (PDUFA date July 23, 2016) Possible entry into reg. review

 ‘Other’ TA mAbs now in Phase 3 that may transition to first regulatory review in 2016:  Anti-activin A receptor type IIB bimagrumab for sporadic inclusion body myositis  Anti-CD4 ibalizumab for HIV infection  Anti-IL-5R benralizumab for asthma  Anti-IL13 lebrikizumab for severe asthma

24 Phase 3 antibodies to watch  Total of 8 antibodies for ‘other’ TAs have Phase 3 primary completion dates in 2016  Pain: anti-NGF fasinumab, fulranumab; anti-CGRP LY2951742  High cholesterol: anti-PCSK9 bococizumab  Rh disease: anti-RhD roledumab  RSV infection: REGN222/SAR438584  HIV infection: ibalizumab  Osteoporosis: anti-sclerostin romosozumab

25 Conclusions  Increase in number of mAbs in clinical studies expected to drive trend toward first approvals for ~6- 8 new mAbs per year (or more)  Sustainability of approval trend depends on verification of expected increases in potency of engineered antibodies, antibody-drug conjugates and bispecific antibodies (esp. in oncology) and validity of the novel targets  Unmet medical need should be reduced and patient choices for antibody therapeutics should increase in the next ~ 8 years (ave. time of clinical phase)

26 Thank you!

Janice M. Reichert, Ph.D. Executive Director, The Antibody Society Editor-in-Chief, mAbs [email protected] www.antibodysociety.org

27 The Antibody Society sponsors