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 ID: 1045231
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1. Biosimilars and biologics – What does personalisation mean for you?Ian N BruceKellgren Centre for RheumatologyNIHR Manchester Biomedical Research Centre University of Manchester @Lupusdoc
2. Manchester University Hospitals NHS Trust and University of ManchesterThe Kellgren Centre for Rheumatology
3. Personalised MedicineConnective Tissue Diseases: an overview Biologics and Biosimilars: an overviewSuccesses and Failures in SLEIs there a better way?Personalised Medicine
4. The Connective Tissue DiseasesSystemic lupus erythematosus (SLE)Dermatomyositis/polymyositis (DM/PM)Sjogren’s syndromeSystemic sclerosisLimited Diffuse Anti-phospholipid syndrome (APS)‘Overlap’ syndromes
5. Connective Tissue Disease EvolutionGenetic Susceptibility
6. Connective Tissue DiseasesSLESjogren’sDiffuseSScDM/PMLimited SSc APLSMCTDEarly‘UCTD’
7. Clinical and serological spectrumSLE(dsDNA, Sm)Sjogren’s(Ro, La)Diffuse SS(Topoisomerase 1, RNA polymerase)DM/PM(Jo-1, synthetases)Limited SS(Centromere) APLS(aCL, LAC)MCTD(RNP)Early‘UCTD’(ANA)
8. Clinical manifestationsPathologySLEDM/PMSjogren’s syndromeSclerodermaAPSVasospasmRaynaud’s+++++++-
9. Clinical manifestationsPathologySLEDM/PMSjogren’s syndromeSclerodermaAPSInflammation+++++++++/--Fibrosis++++++++-VasospasmRaynaud’s+++++++-Thrombosis+++/-+/-++++
10. Personalised MedicineConnective Tissue Diseases: an overview Biologics and Biosimilars: an overviewSuccesses and Failures in SLEIs there a better way?Personalised Medicine
11. Typical ‘small molecules’ ‘Adalat’Nifedipine
12. Typical ‘small molecules’ ‘Adalat’Nifedipine‘Adipine’ Nifedipress’ ‘Tensipine’…Nifedipine
13. BiologicsA 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.
14. Rituximab structure£££
15. BiosimilarsA biosimilar is a biological medicine highly similar to another already approved biological medicine (the 'reference medicine').
16. Currently available Etanercept EnbrelRituximab MabtheraInfliximab RemicadeAdalimumab HumiraTocilizimab RoActemera
17. Currently available Etanercept EnbrelRituximab MabtheraInfliximab RemicadeAdalimumab HumiraTocilizimab RoActemera Etanercept BenepaliRituximab Truxima, Rixathon, RedituxInfliximab Inflectra, Flixabi, RemsimaAdalimumabCyltezo, ExemptiaTocilizimab In development
18. Drivers for useHigh costs of originatorsHuge part of NHS budgetBiosimilars20-40% less expensiveSimilar efficacy and safetyProvoke revision of originator costs as well?Allows wider access to these therapies
19. Personalised MedicineConnective Tissue Diseases: an overview Biologics and Biosimilars: an overviewSuccesses and Failures in SLEIs there a better way?Personalised Medicine
20. Licenced Medications for RA1950’s2018SteroidsGoldClassic DMARDSMTXLeflunomide2000Anti-TNFOther MOA biologicsBiosimilarsJAK-inhibitors
21. Licenced Medications for SLE1950’s2018SteroidsOHCQMepacrine Belimumab
22. Licensed MedicationsLicensed for SLEPrednisoloneHydroxychloroquineMepacrineBelimumabUnlicensed for SLE and other CTDsAzathioprineMethotrexateCyclophosphamideMycophenolate RituximabTacrolimus…..
23. SLE Trial SummariesAgentPrimary EndpointSecondary OutcomesCommentsBelimumabLicensed/NICE approvedAtaciceptXPh III reported AnifrolumabX2nd Ph III Nov 2018BaricitinibPh III plannedEpratuzumabXXWithdrawnRituximab (EXPLORER)XNo further trialsRituximab (LUNAR)X-No further trialsTabalumab / X-WithdrawnBlisibimodXXWithdrawnSifalimumab-Development stopped
24. Targeting B cells 6= Belimumab
25. Belimumab Trials: BLISS-52 and BLISS-76 Response Rates at Week 52Patients Meeting Primary Endpoint at Week 52 in 2 Phase III Trials33.5% vs 43.2%Δ = 9.6%44% vs 58%Δ = 14%867 patients 819 patientsP<0.05 BOTH trials
26. Belimumab subcutaneous trial Stohl W et alArthritis Rheum 2017;69: 1016-27SRI4 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)Belimumab 200mg by weekly s/c injection
27. Targeting B cells1= Rituximab
28. EXPLORER Trial:Rituximab in SLENo ClinicalResponsePartialClinical ResponseMajorClinicalResponseMCR+PCRP=0.975% patientsMerrill JT et alArthritis Rheum 2010 Jan;62(1):222-33257 patients randomised
29. Response to rituximab in Lupus Nephritis patientsJonsdottir T et alRheumatology, 2010;49:1502 Improvements in proteinuria in LN patients with either proliferative or membranous LN-28 proliferative LN-15 membranous LNpatients
30. Early Responses in UK Lupus Register (BILAG-BR) McCarthy E et alRheumatology 2018;57:470-479 Major clinical response at 6 mths33 (18.4%) of patients 49% response at 6 months+5-6% no flare with steroid reduction178 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
31. NHS England Interim Guidance for RTX (2013) Allows off-licence use NICE Approved Belimumab (2016)Managed Access Scheme**Specialised Rheumatology CentresRegister patients in BILAG Biologics RegisterNHS England Policies
32. Interim Policy for Rituximab in SLE (2013)‘Refractory disease’: SLE diagnosisPersistently 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)
33. 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).
34. 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).
35. 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” patientsNICE reserves the right to withdraw approval for belimumab after this additional analysis is completed.
36. To examine the safety and ‘real-world’ effectiveness of biological therapies in the management of lupus in the UK, compared to standard therapiesBILAG Biologics RegisterAim
37. Observational Cohort StudyGroup 1: Patients with lupus starting biologic therapyGroup 2: Patients with lupus starting a new standard therapyInformation from patients in Group 1Information from patients in Group 2COMPAREInformation collected by the hospital team for at least 3 years0 months6 months12 monthsAnnual questionnaires for at least 2 more years
38. How are doing in with biologics in SLE (SSc and other CTDs)? Could do better!!
39. Personalised MedicineConnective Tissue Diseases: an overview Biologics and Biosimilars: an overviewSuccesses and Failures in SLEIs there a better way?Personalised Medicine
40. Our best biologics only work in about half of patientswww.benlysta.co.uk
41. MMFCyclophosHCQAnti-B cellPrecision MedicineDifferent people respond differently to treatmentPrecision medicine = the right treatment for the right person at the right time PRISMSteroids
42. Predictors of Response to BelimumabVan Vollenhoven et al Ann Rheum Dis 2012;71:1343–1349
43. Anifrolumab Trial (an anti-interferon drug)Furie R et al Arthritis Rheum 2017; 69: 376–386
44. RituximabSystematic ReviewDisease-related factors:clinical phenotype and severitybaseline anti-ENA antibodies and anti-Ro antibodiesInterleukin (IL) 2/21 SNPspost-RTX complete B cell depletionearlier B cell repopulationPirone et alSemin Arth Rheum Jul 2017
45. Connective Tissue Diseases (CTDs)Myositis (IIM)Scleroderma (SSc)SLESjogren’s syndrome (SS)MCTD(mixed)UCTD(undifferentiated)Shared clinical features = shared pathology?Molecular taxonomy of disease
46. Genetic Factors Shared Across DiseasesBarturen G et al. Nature Rev Rheum. 2018;14: 75.3212239154191826RASScSLESjogren’s Syndrome
47. Lupus Extended Autoimmune Phenotype (LEAP) Study1 clinical feature of connective tissue diseaseand1 relevant autoantibodyN=164
48. Interferon Gene Scores in CTDs+ve(38%)-ve(62%)
49. CTD management New treatments have been slow to developSome have evidence to support their useVery difficult health funding environmentBiosimilars are providing ‘competition’ in the market and drive down costsObservational Registers:Assesses ‘real world’ effectiveness and safetyHelps support access to treatmentHelps build the evidence base
50. CTD management Most treatments have ~40-50% response rateSignificant overlap in the underlying mechanisms of these conditionsWe need to better understand subsetsWithin a particular conditionAcross related conditions (shared inflammatory drive)
51. Ben ParkerJohn ReynoldsTracy BriggsSahena HaqueHector ChinoyAriane HerrickEoghan McCarthyEllen BruceFiona StirlingManchester Biomedical Research CentreAcknowledgementsBILAG GroupUK Rheumatologists and NephrologistsPatientsParticipantsAdvice on studies
52. “I saw the crescent…, you saw the whole of the moon”