2017-10-29 Conflicts of interest and funding Biologics I have - PDF document

2017-10-29 Conflicts of interest and funding Biologics I have received lecture fees from: Novartis and Thermo Fisher Scientific My research funding does not imply any conflicts of interest but I Biologic drugs with focus on allergy and asthma would like to take this opportunity to thank my funders:  Stockholm City Council  Her Royal Highness Crown Princess Lovisa research fund  Sachs´s Children and Youth Hospital Swedish Asthma and Allergy  Mjölkdroppen Foundation association  Åke Wiberg Foundation and  Hesselman´s Foundation Torsten Söderberg foundation   Frimurare Barnhuset Foundation  EAACI (Freemasons of Sweden) SFFA   Konsul Th C Bergh foundation Josef Brandström, MD  Swedish Medical Association  Research grant in memory of Kerstin (Stockholm section) Sachs' Children and youth Hospital, Södersjukhuset Hejdenberg Karolinska Institutet, Departement of clinical science and education,  The Samariten Foundation Södersjukhuset Josef Brandström 171006 josef.brandstrom@ki.se 2 Biopharmaceuticals  Biologic drugs Biologic drugs = Biological medicinal products  EU-definition: "a protein or nucleic acid – based pharmaceutical  Biologic drugs in asthma substance used for therapeutic or in vivo diagnostic purposes, which is produced by means other than direct extraction from a native (non- engineered ) biological source“  Biologic drugs (omalizumab) in food allergy  Monoclonal antibodies mAb omalizumab, infliximab….  Genetically engineered proteins Anakinra, etanercept… ( Re)defining biopharmaceutical Rader R Nature Biotech 2008 Josef Brandström 171006 Josef Brandström 171006 3 4 History >70 approved mAbs today Distribution of mAbs per main indication Onkology/hematology autoimmune/ auto- inflammatory Multiple Sclerosis Asthma infectious diseases Psoriasis Transplant Liu J. The history of mAb…Ann Med Surg 2014 Josef Brandström 171006 5 Josef Brandström 171006 6 1

2017-10-29 Pharmacodynamics Non-approved mAb  Bind cell-surface receptors  Several hundreds of registered non-approved mAb  Mostly for malignancies  Alters intracellular signaling and cytokine production  But also for  Alter cell adhesion/migration  Migraine  Bind malignant/infected cells  helping immune system in  Infections (gram-neg sepsis, S. Aureus, Influenza, rabies- clearing out malignant cells. Radioactive mAb! prophylaxis)  Inhibition of circulating molecules like cytokines,  Sciatica immunoglobulins  Diabetes type 1  Alzheimer´s disease  Antidotes: Bind toxins or drugs  Non-alcoholic Steatohepatitis (NASH)  …… Josef Brandström 171006 Josef Brandström 171006 7 8 What about the strange names? Omalizumab Target Oma-li-zu-mab -l(i)- Immune system All have a prefix: just a made up name -tox(a)- Toxin ipilimumab rituximab All have the – mab suffix = Monoclonal Anti-body -t(u)- Tumor Palivisumab ustekinumab -v(i)- Virus Pali-vi-su-mab What is in-between provides information about: Source of mab omalizumab target/indication and origin -o- Mouse -i- primate Trastuzumab -u- human Tras-tu-zu-mab -xi- chimer Rituximab or ri-tu-xi-mab -zu- humanized Obiltoxaximab Obil-toxa-xi-mab Josef Brandström 171006 Josef Brandström 171006 9 10 mAb targeting IgE Approved mAb in asthma and allergy Generic Trade- Year Indication(s) Type Effect name Appr. Omalizumab Xolair 2003 Asthma, Chronic Anti- ↓ IgE-ab spont. urtic. IgE Generic Name Indication Type Effect ↓ Fc ε RI omalizumab Xolair, Asthma, chronic Anti-IgE ↓ IgE-ab Ligelizumab ---------- No ? Anti-IgE More potent than 2003 spont urticaria omalizumab ↓ Fc ε RI mepolizumab Nucala eosinophilic Anti-IL 5 ↓ IL-5 stimulation of Antigen-binding IgE 2015 asthma (adults) eosinophils  ↓ production/ survival region of IgE Omalizumab reslizumab Cinqair eosinophilic Anti-IL 5 ↓ IL-5 stimulation of 2016 asthma (adults) eosinophils  C  3 Binds constant part of free ↓ production/ survival region IgE  non allergen specific dupilumab Dupixent Atopic dermatitis Anti-IL ↓ Interleukin 4 and 2017 (adults) 4/13 13 signaling blocking of IgE to Fc ε RI receptor interaction Hugo Farne. Anti-IL5 therapies for asthma. Arm J.P Pharmakinetics, pharmacodynamics...Ligelizumab, a Josef Brandström 171006 11 Josef Brandström 171006 12 Cochrane Systematic review sept 2017 novel high affinity anti-IgE....Clin Exp All 2014 2

2017-10-29 Omalizumab for asthma in adults Omalizumab; shortcomings in asthma and children. Rebecca Normansell et al. 2014  No significant difference in discontinuation of oral corticosteroids! OR 95% CI Absolute risk reduction  Little or no effect on lung function Exacerbations 0.42-0-6 0.55 10 % Placebo 26%, Omalizumab 16% During week 16-60 of omalizumab  High IgE or body weight might disqualify from treatment Hospitalization 0.06-0.42 0.16 2.5 %  Cost-effectiveness? Placebo 3 %, Omalizumab 0.5 % During week 16-60 of omalizumab Complete steroid withdrawal 2-3.13 2.5 19 % Placebo 21 %, Omalizumab 40% within 6~months Daily inh. corticosteroid dose -118 µg (minus 84 ug to minus 154 µg) Normansell R et al. Omalizumab for asthma in adults and children. Cochrane Syst rev. 2014 Tianwen Lai et al. Long-term efficacy and safety of omalizumab in Safe and no reports of anti-drug antibody development patients with persistent uncontrolled allergic asthma: a systematic review and meta-analysis. Scientific reports 2015 Josef Brandström 171006 Josef Brandström 171006 13 14 Cost-effectiveness Why is omalizumab not effective sometimes?  There is no definitive cut-off for when a drug is considered cost- effective. UK guidelines ~ € 20k  100k depending on disease  Is the asthma IgE-driven?  Unknown reasons Author/year/country Patients Cost per Author's Conclusion  Doses are individualized; can they still be to low? QUALY  Since omalizumab does not remove all IgE; patients Brown / 2007 /Canada Uncontrolled severe € 821.000 Cost effective asthma with a high proportion of disease-relevant s-IgE might Wu / 2007 / USA Severe persistent Not cost-effective for not respond to treatment € 821.000 asthma most patients The size of the disease relevant IgE-ab fraction in relation to Dewilde / 2006 / Swed Uncontr. severe asthma € 56.000 May be cost-effective total-IgE predicts the efficacy of anti-IgE (Xolair) treatment . Johansson S.G.O, Nopp A et al. Allergy 2009 Dal Negro / 2011 / Italy Severe and resistant € 26.000 Positive effects asthma justifies price Tianwen Lai et al. Long-term efficacy and safety of Josef Brandström 171006 Josef Brandström 171006 15 16 omalizumab…meta -analysis. Scientific reports 2015 Ligelizumab vs. omalizumab (mild asthma) effect on allergen induced bronchial reactivity “Anti - IgE 2.0” Generic name Indication Type Effect Omalizumab Xolair Asthma,spont. urtic. Anti-IgE ↓ IgE- ab, ↓ Fc ε RI Ligelizumab ------- Asthma? Anti-IgE More potent than omalizumab Median PC 15 increased 16-fold in ligelizumab vs. 5-fold in omalizumab (p=0.1). Gavreau G. Efficacy and safety of…ligelizumab versus omalizumab and Gavreau G. Efficacy and safety of…ligelizumab versus omalizumab and Josef Brandström 171006 17 Josef Brandström 171006 18 placebo in inhibiting allergen-induced early asthmatic responses. JACI 2016 placebo in inhibiting allergen-induced early asthmatic responses. JACI 2016 3