Biosimilars and biologics – What does personalisation mean for you? Ian N Bruce Kellgren Centre for Rheumatology NIHR Manchester Biomedical Research Centre University of Manchester @Lupusdoc

Manchester University Hospitals NHS Trust and University of Manchester The Kellgren Centre for Rheumatology

Personalised Medicine Connective Tissue Diseases: an overview Biologics and Biosimilars: an overview Successes and Failures in SLE Is there a better way? Personalised Medicine

The Connective Tissue Diseases Systemic lupus erythematosus (SLE) Dermatomyositis/polymyositis (DM/PM) Sjogren’s syndrome Systemic sclerosis Limited Diffuse Anti-phospholipid syndrome (APS) ‘Overlap’ syndromes

Connective Tissue Disease Evolution Early life influences Autoantibodies Non-specific features Clinical diagnosis Genetic Susceptibility

Connective Tissue Diseases SLE APLS Sjogren’s MCTD Early ‘UCTD’ DM/PM Limited SSc Diffuse SSc

Clinical and serological spectrum SLE (dsDNA, Sm) APLS (aCL, LAC) Sjogren’s (Ro, La) Early ‘UCTD’ (ANA) MCTD (RNP) DM/PM (Jo-1, synthetases) Limited SS (Centromere) Diffuse SS (Topoisomerase 1, RNA polymerase)

Clinical manifestations Pathology SLE DM/PM Sjogren’s syndrome Scleroderma APS Vasospasm Raynaud’s ++ + +++ -

Clinical manifestations Pathology SLE DM/PM Sjogren’s syndrome Scleroderma APS Inflammation +++ ++ +/- - Fibrosis + Vasospasm Raynaud’s Thrombosis

Personalised Medicine Connective Tissue Diseases: an overview Biologics and Biosimilars: an overview Successes and Failures in SLE Is there a better way? Personalised Medicine

Typical ‘small molecules’ ‘Adalat’ Nifedipine

Typical ‘small molecules’ ‘Adalat’ Nifedipine ‘Adipine’ Nifedipress’ ‘Tensipine’… Nifedipine

Biologics A substance that is made from a living organism or its products. Biological drugs include antibodies, interleukins, and vaccines. Complex mixtures whose structure are not easily identified or characterized. Biologics can be composed of sugars, proteins or complex combinations of these substances.

Rituximab structure £££

Biosimilars A biosimilar is a biological medicine highly similar to another already approved biological medicine (the 'reference medicine').

Currently available Etanercept Enbrel Rituximab Mabthera Infliximab Remicade Adalimumab Humira Tocilizimab RoActemera

Currently available Etanercept Etanercept Benepali Enbrel Rituximab Mabthera Infliximab Remicade Adalimumab Humira Tocilizimab RoActemera Etanercept Benepali Rituximab Truxima, Rixathon, Reditux Infliximab Inflectra, Flixabi, Remsima Adalimumab Cyltezo, Exemptia Tocilizimab In development

Drivers for use High costs of originators Biosimilars Huge part of NHS budget Biosimilars 20-40% less expensive Similar efficacy and safety Provoke revision of originator costs as well ?Allows wider access to these therapies

Personalised Medicine Connective Tissue Diseases: an overview Biologics and Biosimilars: an overview Successes and Failures in SLE Is there a better way? Personalised Medicine

Licenced Medications for RA Other MOA biologics Steroids Classic DMARDS Leflunomide Gold MTX Biosimilars JAK-inhibitors Anti-TNF 1950’s 2000 2018

Licenced Medications for SLE Steroids Mepacrine Belimumab OHCQ 1950’s 2018

Licensed Medications Licensed for SLE Prednisolone Hydroxychloroquine Mepacrine Belimumab Unlicensed for SLE and other CTDs Azathioprine Methotrexate Cyclophosphamide Mycophenolate Rituximab Tacrolimus…..

Licensed/NICE approved SLE Trial Summaries Agent Primary Endpoint Secondary Outcomes Comments Belimumab  Licensed/NICE approved Atacicept X Ph III reported Anifrolumab 2nd Ph III Nov 2018 Baricitinib Ph III planned Epratuzumab Withdrawn Rituximab (EXPLORER) No further trials Rituximab (LUNAR) - Tabalumab  / X Blisibimod Sifalimumab Development stopped

Targeting B cells 6= Belimumab

Belimumab Trials: BLISS-52 and BLISS-76 Response Rates at Week 52 Navarra Lancet 2011, page 725, table 2; PI page 13, table 3 Patients Meeting Primary Endpoint at Week 52 in 2 Phase III Trials 44% vs 58% Δ = 14% 33.5% vs 43.2% Δ = 9.6% P<0.05 BOTH trials Van Vollenhoven EULAR abstract, Results line 4; PI page 13, table 3 Van Vollenhoven EULAR abstract, Table 1st row 867 patients 819 patients

Belimumab subcutaneous trial Belimumab 200mg by weekly s/c injection SRI4 Response: 61.4% vs 48.4% OR (95%CI) =1.65 (1.25, 2.25) Probability of severe flare: HR (95%CI) = 0.51 (0.35, 0.74) Stohl W et al Arthritis Rheum 2017;69: 1016-27

Targeting B cells 1= Rituximab

EXPLORER Trial: Rituximab in SLE 257 patients randomised P=0.975 % patients No Clinical Response Partial Clinical Response Major Clinical Response MCR+PCR Merrill JT et al Arthritis Rheum 2010 Jan;62(1):222-33 28

Response to rituximab in Lupus Nephritis patients -28 proliferative LN -15 membranous LN patients Improvements in proteinuria in LN patients with either proliferative or membranous LN Jonsdottir T et al Rheumatology, 2010;49:1502

Early Responses in UK Lupus Register (BILAG-BR) 178 pts with 6 month follow-up: Response: loss of all BILAG A and B scores to ≤ 1 B with no new A/B scores in other organs 49% response at 6 months +5-6% no flare with steroid reduction Major clinical response at 6 mths 33 (18.4%) of patients McCarthy E et al Rheumatology 2018;57:470-479

NHS England Policies NHS England Interim Guidance for RTX (2013) Allows off-licence use NICE Approved Belimumab (2016) Managed Access Scheme** Specialised Rheumatology Centres Register patients in BILAG Biologics Register

Interim Policy for Rituximab in SLE (2013) ‘Refractory disease’: SLE diagnosis Persistently Active Disease (BILAG A x 1 or 2 Bs OR SLEDAI >6) Failure to be controlled on 2 or more ‘standard’ agents inc MMF or Cyclophosphamide. Unacceptably high-dose of corticosteroids on a regular basis to control disease (> 10 mg prednisolone daily)  This population should be: Offered clinical trials Registered on a national safety register (BILAG BR)

Belimumab Approval in UK (2016) An add-on treatment for active autoantibody-positive SLE in adults only if all of the following apply: Evidence for serological disease activity (defined as positive anti-double-stranded DNA and low complement) AND a SELENA-SLEDAI score ≥ 10 despite standard treatment; Treatment is continued beyond 24 weeks only if the SELENA-SLEDAI (SLEDAI –2K) score has improved by 4 points or more; Under the conditions for data collection, monitoring, patient consent, cost to the NHS, and review by NICE as laid out in sections 5 and 6 of the full guidance document (BILAG registry).

Belimumab Approval in UK (2016) An add-on treatment for active autoantibody-positive SLE in adults only if all of the following apply: Evidence for serological disease activity (defined as positive anti-double-stranded DNA and low complement) AND a SELENA-SLEDAI score ≥ 10 despite standard treatment; Treatment is continued beyond 24 weeks only if the SELENA-SLEDAI (SLEDAI –2K) score has improved by 4 points or more; Under the conditions for data collection, monitoring, patient consent, cost to the NHS, and review by NICE as laid out in sections 5 and 6 of the full guidance document (BILAG registry).

Belimumab Approval in UK (2016) Managed Access Agreement (MAA) between NICE, the University of Manchester (acting on behalf of BILAG), Lupus UK, NHS England and GSK. A real-world research study to collect additional data on belimumab as part of the NHS England ‘commissioning with evaluation’ process. Only Specialised Rheumatology Centres who are contributing to the BILAG Biologics Registry (BILAG-BR) can access funding for belimumab as part of the NICE guidance.   Funding is limited to a maximum of 300 “responder” patients NICE reserves the right to withdraw approval for belimumab after this additional analysis is completed.

BILAG Biologics Register Aim To examine the safety and ‘real-world’ effectiveness of biological therapies in the management of lupus in the UK, compared to standard therapies

Observational Cohort Study Information from patients in Group 1 Group 1: Patients with lupus starting biologic therapy 0 months 6 months 12 months Annual questionnaires for at least 2 more years Information collected by the hospital team for at least 3 years COMPARE Group 2: Patients with lupus starting a new standard therapy Information from patients in Group 2

How are doing in with biologics in SLE (SSc and other CTDs)? Could do better!!

Personalised Medicine Connective Tissue Diseases: an overview Biologics and Biosimilars: an overview Successes and Failures in SLE Is there a better way? Personalised Medicine

Our best biologics only work in about half of patients www.benlysta.co.uk

Different people respond differently to treatment Precision Medicine Different people respond differently to treatment Precision medicine = the right treatment for the right person at the right time MMF Steroids Cyclophos HCQ PRISM Anti-B cell

Predictors of Response to Belimumab Van Vollenhoven et al Ann Rheum Dis 2012;71:1343–1349

Anifrolumab Trial (an anti-interferon drug) Furie R et al Arthritis Rheum 2017; 69: 376–386

Rituximab Systematic Review Disease-related factors: clinical phenotype and severity baseline anti-ENA antibodies and anti-Ro antibodies Interleukin (IL) 2/21 SNPs post-RTX complete B cell depletion earlier B cell repopulation Pirone et al Semin Arth Rheum Jul 2017

Connective Tissue Diseases (CTDs) Myositis (IIM) Scleroderma (SSc) SLE Sjogren’s syndrome (SS) MCTD (mixed) UCTD (undifferentiated) Shared clinical features = shared pathology? Molecular taxonomy of disease

Genetic Factors Shared Across Diseases Sjogren’s Syndrome SSc SLE RA 19 4 32 39 2 8 1 12 2 6 15 Barturen G et al. Nature Rev Rheum. 2018;14: 75.

Lupus Extended Autoimmune Phenotype (LEAP) Study 1 clinical feature of connective tissue disease and 1 relevant autoantibody N=164

Interferon Gene Scores in CTDs +ve (38%) -ve (62%)

CTD management New treatments have been slow to develop Some have evidence to support their use Very difficult health funding environment Biosimilars are providing ‘competition’ in the market and drive down costs Observational Registers: Assesses ‘real world’ effectiveness and safety Helps support access to treatment Helps build the evidence base

CTD management Most treatments have ~40-50% response rate Significant overlap in the underlying mechanisms of these conditions We need to better understand subsets Within a particular condition Across related conditions (shared inflammatory drive)

Acknowledgements BILAG Group UK Rheumatologists and Nephrologists Ben Parker John Reynolds Tracy Briggs Sahena Haque Hector Chinoy Ariane Herrick Eoghan McCarthy Ellen Bruce Fiona Stirling BILAG Group UK Rheumatologists and Nephrologists Patients Participants Advice on studies Manchester Biomedical Research Centre

you saw the whole of the moon” “I saw the crescent…, you saw the whole of the moon”