1. 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

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

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

4. 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

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

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

7. 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)

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

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

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

11. Typical ‘small molecules’
‘Adalat’
Nifedipine

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

13. 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.

14. Rituximab structure
£££

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

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

17. 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

18. 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

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

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

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

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

23. 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

24. Targeting B cells
6= Belimumab

25. 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

26. 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:

27. Targeting B cells
1= Rituximab

28. 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

29. 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

30. 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:

31. 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

32. 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)

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” patients
NICE reserves the right to withdraw approval for belimumab after this additional analysis is completed.

36. 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

37. 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

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

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

40. Our best biologics only work in about half of patients

41. 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

42. Predictors of Response to Belimumab
Van 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. 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

45. 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

46. 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.

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

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

49. 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

50. 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)

51. 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

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