Therapeutic Monoclonal Antibodies for Respiratory Diseases: Current Challenges & Perspectives March 31 - April 1, 2016 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 40 20 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 10 0 2010 2011 2012 2013 2014 2015 2016 Year of article publication Data from ‘Antibodies to watch’ articles published in mAbs. 5 10 11 Number of first approvals for mAbs of mAbs US or EU approvals First 0 1 2 3 4 5 6 7 8 9 the US or EU (antibodysociety.org) or US the in or in review approved of antibodies Table Source: approvals. number of first *Projected 97 98 99 00 01 02 Year of first US EUor approval of first Year 03 04 05 06 07 08 09 10 11 12 13 14 15 10+ ? 6 16* 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 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. Formats for cancer only 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 28.