A Journey through Anti-Inflammatory Drug Discovery
Dr John Unitt
ELRIG Networking Events - Nottingham June 13th 2019
Enabling Success www.sygnaturediscovery.com Outline
Future • What’s inflammation? • Drug Discovery Trends and Landmarks • Current Challenges and the Future
2 What is inflammation?
• Part of body’s response to insult and initiation of healing process • Causes . Wound . Infection . Auto-immune • Original characterised by Celsus 50 AD . Pain, swelling, heat, redness, immobility • Phases 1. Acute 2. Chronic 3. Resolution • Overlap with immunology . Immuno-inflammation
3 Acute Inflammation
4 Chronic Inflammation
Chronic Mediators Tissue Neutrophils Damage Th1 Antibodies M1 Inflamed Site Auto-immunity • Genetics – defective immune regulation genes polymorphisms (e.g. HLA) Intensity Treg • Auto-antibodies M1 M2 • Environment & infection Activation Lipoxins • Gender, diet….. Resolution Trigger Time
5 Auto-immune diseases Rheumatoid Arthritis
From RAAID
6 Inflammation under pins nearly all diseases
No. of projects in Discovery Phase Linked to Inflammation?
7 Outline
Future • What’s inflammation? • Drug Discovery Trends and Landmarks • Current Challenges and the Future
8 Small Molecules to Biologics
FDA Anti-inflammatory Drug Approvals Key cytokines Anti-TNFa (1990s) Antibodies (1986) Recombinant Proteins (1980s) Disease understanding NSAIDs Th17 (2005) - pathogenic Steroids Treg (2000) - suppressive
Still unmet needs
9 Signs and Symptoms to Disease Modifying
• Signs and symptoms . NSAIDs . Steroids • Disease modifying . Immune cell anti-proliferatives o Methotrexate, leflunomide… . Anti-cytokines o Humira (anti-TNFα) o Benlysta (anti-BAFF) o IL-1, IL-6, IL-12/23, IL-17 o CD20 (B cells) o CD3 (T cells) o JAK inhibitors . Increase in efficacy & permanence
10 Steroids HO HO O O Glucocorticoid Receptor Agonists H
• Nuclear hormone receptor H H Cortisone (1950) O • Cortisone . Highly efficacious . Systemic side effects OH O O HO • Topical delivery H O . Inhaled H Budesonide (1981) H o O . Skin Budesonide o Dexamethasone (1958) Side effects Anti- Diabetes Inflammatory F • Dissociated (SEGRAs) F F Sundahl et al. (2015) Pharm. Ther. 152:28 H . Separate good (anti-inflammatory) from F abs N N side effects (diabetogenic etc.) OH . Shown in vitro, but not in vivo O . Still some discovery effort on going………… Mapracorat
11 Non-steroidal ant-inflammatory drugs NSAIDs • Aspirin/Ibuprofen/Indomethacin (Pre-1970s) O . Anti-inflammatory, but limited by GI side effects (R) • Mechanism identified by John Vane (1970s) OH
• COX1 and COX2 (1988) Ibuprofen . COX1: housekeeper/constitutive . COX2: inducible, pro-inflammatory . Go for COX-2 selective! • Vioxx – first COX-2 selective O O . Increase cardiac AEs . Withdrawn from market • Roles of COX-1 and 2 . Further research O S • Protection of gastric damage O . NO-NSAIDs Vioxx . Local NO delivery
12 Anti-Cytokine Biologicals
• Auto-immune disease therapies . Driven by increase in disease understanding . Biological drug capability • Key cytokine inhibition . Highly efficacious . Multiple targets . Now top selling drugs • Still room for improvement . Confounded by complex disease polygenetics and environment factors . Patient response rates roughly….. Koenders (2015) TIPS o 1/3 respond o 1/3 don’t respond o 1/3 respond then lose efficacy . Infection and malignancy due to chronic use NRDD (2018) 17: 231
13 JAK Kinase Inhibitors
N N N O • 4 JAK kinases N
. JAK1, 2, 3 and Tyk2 N N H • Key players in major cytokine signalling pathways Tofacitnib(2017) . Pathogenic Th17 IL-17/IL-23
F F • Tofacitinib – Pan JAK inhibitor F . Efficacious, but CV AEs via JAK 2 (EPO) NH
• Push for more selectivity O HN N . Phase II – Filgotinib – JAK 1 selective N . Decernotinib - JAK 3 selective N N • Similar efficacy and adverse effects to anti-TNFα H Decernotinib (in Dev.) • JAK selectivity profile v. efficacy relationship still remains to be defined Khan (2016) Immunopharmacology. 93
14 Outline
Future • What’s inflammation? • Drug Discovery Trends and Landmarks • Current Challenges and the Future
15 Inflammasome BRDs Inhibitors STATs STING TLRs Phenotypic Various GPCRs…….
16 Inflammasome Inhibitors
• Family of intracellular multiprotein complexes . Makes pro-inflammatory IL-1/IL-18 . Activated by non-infectious agents o Less risk of infection (c.f. other anti-cytokines) . Supported by human monogenetic diseases OH • Pfizer 1990s . CP-456773 (from phenotypic hit) O . Inflammasome (2015) O S O • Canakinumab IL-1 inhibition HN . Clinical cancer and CV benefit O HN . Multiple indications • New target with broad application
17 Inflammasome Inhibitors
2016 2018 Clinical safety and efficacy?
Other inflammasomes & disease indications? 2016 2019 IFM Quatro
2016
18 Challenges
• Current therapies are highly effective . BUT need continuous use and have increased risk of malignancy/infection • Can we cure and/or prevent autoimmune diseases? . What initiates autoimmune disease? o Most current drugs target later stage disease and not initiation . Predictive biomarkers of onset? o Early signals prior to disease symptoms -> early intervention and prevention • Need to induce remission in all patients . Only achieved in a minority at the moment . Why do some patients not respond? o Need greater understanding of disease heterogeneity o Personalised medicines – patient specific
19 Reset the Treg/Th17 balance Future Ex vivo Treg efficacious in AI disease
IL-1 Resolvins Angiogenesis Auto-immune Lipoxins Pro-oxidant Initiation DNA damage Cancer Pro- Initiation resolution Gut microbiome modulators Anti-TNFα More Immuno- for IBD +Synoviocyte Combination Microbiome Inflammation +Angiogenesis Therapies • Pre- and Pro-biotics • Healthy microbiome Immuno- Epigenetics Metabolism Acidosis Metabolic enzymes Neuro- Development of autoimmunity Active metabolites Inflammation HDAC, BET, Demethylase Modulate immune cells e.g. increased Treg generation & function Microglia CNS access Abs small molecules 20 Outline
Future • What’s inflammation? • Drug Discovery Trends and Landmarks • Current Challenges and the Future
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