Crohns symposium mathew philps beyond biologicals

Drugs beyond Biologicals

Mathew PhilipPVS Memorial Hospital

Kochi

Drugs beyond current Biologicals

Mathew PhilipPVS Memorial Hospital

Kochi

Mucosal Healing

Introduction

• Need for new IBD drugs– Establishment of new goals in the management

(mucosal healing ) – Secondary failure to anti- TNF therapy (rate loss of

response is 10–20% /yr , withdrawal due to intolerance)

Therapeutic pipeline in CD

Therapeutic pipeline in UC

Outline

• Biosimilars• Biological agents in the pipeline• Therapeutic manipulation of the microbiota ?• Prognostic genomics in management ?

Biosimilars

Definition• Biosimilar is a copy version of an approved original

biologic medicine whose data protection has expired• Price reductions up to 80 %• Biosimilar could significantly differ from the

reference drug due to manufacturing processGuidelines (EMA and FDA) • Similarity between biosimilar and the reference

product in terms of quality, purity, safety and efficacy

Biosimilars

• Infliximab biosimilar (CT-P13, Inflectra®) vs infliximab for rheumatologic diseases

• Phase 1 RCT – Similar pharmacokinetics , efficacy and safety – require further investigation in IBD patients

• Phase III RCT in rheumatoid arthritis at 30 weeks – Equivalent efficacy – Comparable pharmacokinetic – Immunogenicity profile– Well tolerated– Safety profile

• Require further investigation in IBD patients

Park et al. 2013 Yoo et al. 2013

Biological agents in the pipeline

• Majority of new molecules for IBD aim to target T-cell activation, adhesion molecules or proinflammatory cytokines– Blockade of pro-inflammatory cytokines– Blockade of the downstream signaling pathways

mediated by cytokines– Smad7 antisense oligonucleotide

Blockade of pro-inflammatory cytokines

TNF-α • Targeting TNF through generation of a

polyclonal antibody response directly by the immune system of the patient

• TNF-Kinoid (TNF-K) is an immunotherapeutic composed of recombinant human TNF

• The administration of TNF-K prompts the production of neutralizing polyclonal antibodies against TNF

Delavallee et al. 2008


• Blocking TNF – Anti-TNF vaccination (in phase II trials in CD)– TNF gene silencing with small interfering RNA – TNF-neutralising nanobodies


HMPL-004• Andrographis paniculata extract• Reduce TNF and interleukin (IL)-1β , interferon

(IFN)-γ and IL-22 expression• Prevent experimental colitis by inhibiting T-cell

proliferation and Th1/Th17 response• HMPL-004 is currently being evaluated in two

phase III trials in CD and UC

Michelsen et al.2013; Sandborn et al 2013


IL-12/23• Share a common p40 subunit• IL-12 induce Th1 differentiation • IL-23 induce Th17 differentiation• Ustekinumab – monoclonal IgG1 antibody targeting

the p40 subunit of IL-12/IL-23• FDA and the EMA - Approved for psoriasis and

psoriatic arthritis • Induction and maintenance trial showed response in

moderate-to severe CD refractory to anti-TNFLeonardi et al. 2008; Papp et al. 2008;Gottlieb et al. 2009; Sandborn et al. 2012a


IL-13• Cytokine IL-13 belongs to the Th2 cytokine family

and activates JAK/STAT pathway• QAX576 in fistulizing perianal CD - result

pending• Tralokinumab in UC - no significant improvement• Anrunkinzumab(IMA-638) in UC – not significant• Anti- monoclonocal antibody against eotaxin-

1(Bertilimumab) in phase II trialsDanese et al. 2014


IL-6• Contributor of Th-17 differentiation• Increased levels associated with a more severe

form of IBD • Tocilizumab - blocks IL-6 receptor stopped after a

small pilot study in active CD• Phase II placebo-controlled• ANDANTE study - anti-IL-6 monoclonal antibody in

patients with active CD trial is ongoing

Ito et al. 2004; Singh et al. 2010

Anti-adhesion molecules

• Inflammatory process is characterized by leukocytic infiltration of the intestinal lamina propria

• Target strategies – Recruitment of leukocytes from circulation into

the site of inflammation – Could be a cornerstone to control the

inflammatory cascade

Lobaton et al. 2014


• Capture of leukocytes by the endothelium - L-selectin at the surface of leukocytes and their ligands (P and E-selectins) on endothelial cells

• Integrins - secondary adhesion molecules allow leukocytes to migrate through the vascular wall

• Chemokines released by T cells activate selectins and integrins

• Leucocytes also interact with chemokines through specific chemokine receptors (CCR)

Lobaton et al. 2014

Natalizumab

• Natalizumab is an IgG4 humanized monoclonal antibody that specifically antagonizes α4 integrin

• First developed in IBD showing efficacy for induction and maintenance of clinical remission in CD

• Cases of progressive multifocal leukoencephalopathy (PML) by JC virus reactivation slowed down further development

• FDA-approved for inducing and maintaining clinical response and remission in adult patients with moderate-to-severe CD after failure of anti-TNF inhibitors and only available in the USAGhosh et al. 2003 Van Assche et al. 2005

Vedolizumab

• Humanized monoclonal antibody • Inhibits binding of α 4β 7 integrin to the gut specific

intestinal mucosal address in MAdCAM-1• Effective in three phase II RCTs in UC and CD• Phase III trials • GEMINI I trial – UC – Effective in induction and durable clinical response and

mucosal healing • GEMINI II trial – CD– Not statistically significant for clinical response

Sandborn et al. 2013


• Etrolizumab - selectively binds the β 7 subunit of heterodimeric integrins α 4β 7 and α Eβ 7

• EUCALYPTUS trial – Clinical remission significant compared to placebo

• Phase III trials- results awaited


• Experimental drugs under trial• Anti-MadCAM-1 inhibitor in UC and CD • Anti-α 2β 1 integrin (vatelizumab)• FFA-2- G-protein-coupled receptor activated

by short chain fatty acid and implicated in the regulation of neutrophils activation and migration

Blockade of the downstream signalingpathways mediated by cytokines

JAK inhibitors• Janus kinase (JAK)1 and JAK3 are involved in the

transduction processes of the IL-2R and IL-6R • JAK inhibition potential therapeutic target in IBD • Tofacitinib is an oral JAK inhibitor of JAK1, JAK2

and JAK3 • Two JAK1 inhibitors currently evaluated – CD (GLPG0634) – UC (Peficitinib)

Coskun et al. 2013; Riese et al. 2010

Blockade of the downstream signalingpathways mediated by cytokines

Laquinimod• Synthetic orally administered molecule • Clinical efficacy in patients with multiple

sclerosis • T-cell shift into an anti-inflammatory

phenotype and a decrease of proinflammatory cytokines

Varrin-Doyer et al 2014

Smad7 antisense oligonucleotide

Smad7• Intracellular protein - binds to TGF-β 1

receptor preventing TGF-β 1-driven signaling• In CD, a defective activity of the suppressive

cytokine TGF-β 1 is often observed, due to increased levels of Smad7

Monteleone et al. 2012

Masitinib

• Mast cells proliferation/activation observed in IBD• Release histamine, tryptase, membrane-derived

lipid mediators and cytokines and growth factors including TNF, IL-4, IL-6, bFGF, VEGF and TGF-β

• Masitinib - potent and selective tyrosine kinase inhibitor that targets c-kit receptor (expressed by mast cells)

• Phase II trial is ongoing in patients with active CD

Beunk et al. 2013; Wernersson and Pejler, 2014

Other biological agents

• Aim to block the downstream signaling pathways mediated by cytokines

• Currently evaluated in phase II or phase III trials: – NNC 0142-0000-0002 (NKG2D)– SB012 (GATA-3)– VB-201 – DIMS0150 (TLRs) fingolimod – RPC1063 (sphingosine 1-phosphate 1 receptor)– GSK1399686 (ribosomal 50S subunit)

Current and novel biologics in IBD

Current and novel biologics

New strategies in the therapeuticmanipulation of the microbiome

• Comparison of clone libraries - statistically significant differences between the micro biotas of IBD vs. controls

• Subset of IBD patients - depletion of key commensal bacteria (Phyla Firmicutes and Bacteroidetes)

• Therapeutic manipulation of intestinal bacteria • Antibiotics, probiotics, prebiotics, diet and

combinations


• Rifaximin extended release• Faecal microbiota transplantation or faecal

bacteriotherapy• Some probiotics (eg VSL3 combination) maintain

antibiotic induced remission in relapsing pouchitis• High mucosal concentrations of Faecalibacterium

prausnitzii during resection associated with remission in patients with active CD requiring ileocaecal resection

Prantera Cet al 2012; Sokol et al 2008


• Faecal microbiota transplantation or faecal bacteriotherapy- a potential option in IBD

• Customised treatment approach based on analysis of an individual’s microbiota pattern

• Dietary approach as a therapeutic option to alter micro biota needs to be studied

Anderson JL 2012

Prognostic genomics in the management ofIBD

• Growing knowledge of the genetic makeup of IBD is creating an evolution in how IBD may be classified in the future

• Genetic analysis enable to prognosticate IBD• Mucosal gene signatures could predict

response to infliximab (95% sensitivity and 85% specificity)

Arijs I et al Gut 2009

Conclusions

• Biological therapies will be used selectively based on personalised benefit/risk assessment

• Choice of therapy depend on individual patient profiles, determined by reliable biomarkers and tissue signatures

• Beyond TNF blockers, anti-adhesion molecules appear to be the most promising drug

• Smad7 antisense oligonucleotide might open new therapeutic avenues for CD

Conclusions

• Biosimilars could have great potential in countries like India

• Altering the micro biota may be a more physiologic and sustained approach

• Genetic testing for classification, prognosis and therapy selection sounds promising

Thank You

Crohns symposium mathew philps beyond biologicals

Health & Medicine

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