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Val Corrigall and Gabriel Panayi Academic Department of Rheumatology King’s College London

BiP/Rasolvir: from the bench ………. to the bedside. Val Corrigall and Gabriel Panayi Academic Department of Rheumatology King’s College London. From the bench ………………. BiP/Rasolvir TM. Human stress protein Produced in high yield and purity by recombinant technology Approved for human use

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Val Corrigall and Gabriel Panayi Academic Department of Rheumatology King’s College London

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  1. BiP/Rasolvir: from the bench ………. to the bedside Val Corrigall and Gabriel Panayi Academic Department of Rheumatology King’s College London

  2. From the bench ………………

  3. BiP/RasolvirTM Human stress protein Produced in high yield and purity by recombinant technology Approved for human use Successful conclusion Phase I/IIA Clinical Trial in patients with RA who had failed DMARDs and even biologics New biologic treatment for rheumatoid arthritis

  4. Unified Mode of Action BiP/Rasolvir works by modifying development from pre-cursor mononuclear cells of: • Antigen presenting cells to tolerising APC; • Osteoclasts: inhibiting development & activity; • Macrophage development deviated to anti-inflammatory function.

  5. Pre-clinical studies

  6. Protection BiP i.v Therapy BiP i.v or s.c bCII/IFA bCII/CFA day -7 0 21 24 70 arthritis Collagen-Induced Arthritis (CIA) model d0 d21 Dr Steve Thompson Prof Linda Myers

  7. 1μg Rasolvir™ was injected at onset of paw swelling Vehicle Control  Rasolvir™ 1μg IV Days after immunization A single low dose of Rasolvir™ “cured” arthritis in the CIA model.

  8. Saline control BiP/Rasolvir™ single IV injection

  9. Adoptive transfer therapy CIA model PBS or BiP (200μg sc) Spleen+LN cells from +/- BiP-treated mice d12 bCII + IFA bCII + CFA d0 d21 d24/25 arthritis

  10. Therapy CIA by adoptive transfer of lymphoid cells from BiP-treated mice Regulatory cells induced in the spleen/lymph node cell population (60% T cells) of the BiP-treated mouse suppress CIA. Immune cell development has been altered in the BiP treated mice to give long-term therapy in the absence of additional BiP Mean disease severity score Time (days) BiP-treated (■) 0r PBS-treated (●) lymphoid cells Brownlie,R.J.; Arthritis Rheum 54: 854-863. 2006

  11. In vivo pre-clinical studies

  12. Collaborative projecthTNFαtransgenic mouse Department of Internal Medicine and Institute for Clinical Immunology at the University of Erlangen-Nuremberg, Germany M Zaiss, J-P David and G Schett M Zaiss

  13. ip 10μg BiP Arthritis birth w11 w5 Experimental protocol Weekly monitoring Arthritis

  14. Body weight Grip strength Paw swelling 0 4 20 TNFtg control TNFtg + Bip 18 3 -1 [g] 16 2 Paw Swelling Arthritis Score Weight 14 -2 1 12 -3 0 10 6 7 8 9 10 11 12 6 7 8 9 10 11 12 6 7 8 9 10 11 Time [week] Time [week] Time [week] Clinical parameters (n=4 mice/group) * * * Single dose ip PBS or BiP (10μg/mouse) Wk 5

  15. Histology of the paw (n=4 mice/group)

  16. ip 250μg weekly anti-TNF Arthritis Weekly monitoring Arthritis • Anti -TNF blocks a ligand-receptor interaction Multiple doses of anti-TNF required for the same effect as single dose BiP Hence superiority of immunoregulation

  17. Conclusion from TNFtg mouse model: • BiP inhibits inflammation • BiP inhibits osteoclastogenesis • BiP inhibits pre-osteoclast and mature osteoclast function Rasolvir™ could protect patients from inflammation and bone loss

  18. In vivo pre-clinical studies

  19. Collaborative project Centre for Advanced Research of Biomedical EngineeringToin University, Yokohama, Japan K Yoshida and H Matsuno Human rheumatoid synovial membrane transplanted into SCID mice

  20. Xenogeneic SCID model Rheumatoid arthritis synovial membrane (RASM) transplanted into SCID mice Transplantation of RASM iv mouse BiP or HSA Mice killed SM transplants removed vascular anastomosis Wk0 Wk 4 Wk6 Histology ELISA Kaoru Yoshida,et al. Arthritis Research and Therapy 13:R149 2011

  21. Reduced Cellular infiltration of RASM transplants Control (HSA) BiP

  22. Immunohistological examination of transplants A single intravenous administration of BiP (10μg) into the SCID mouse suppresses inflammation in the human RASM explant Control (HSA) CD86 HLA-DR TNFα IL-6 BiP

  23. Conclusions from SCID xenogeneic model: • BiP inhibits cellular infiltration in human RA SM transplants. • BiP induces downregulation of inflammatory cytokines and cell surface molecules involved in antigen presentation

  24. Rasolvir™ resolves rheumatoid synovitis ............ To the bedside

  25. Clinical team GSTT GSTT Prof Gabriel Panayi The RAGULA Trial Dr Bruce Kirkham Dr Khal Chaabo BRC Gerry Trillana Quintiles Prof Tim Mant Dr Liz Allen Marco Da Sa

  26. First in Human, Randomised, Placebo Controlled, Double Blind, Single Escalating Dose, Phase I/IIa Study of BiP/Rasolvir in RA Infusion 3 months

  27. Primary Endpoint: Safety No serious adverse (SAE) or adverse events (AE) from treatment with BiP

  28. Secondary endpoint – Efficacy Disease Activity Score 28 (DAS28) > 5.1 active disease; <3.2 low disease activity; <2.6 remission Tertiary endpoint – serum biomarkers • C-reactive protein (CRP) • Vascular Endothelial Growth Factor (VEGF) • Interleukin-8 (IL-8)

  29. “Remission is an ambitious primary end point for RA clinical trials.” • Mack EE, Hsia E, Aletaha D (2016) Arth. Rheum, • doc: 10.1002/art.3945

  30. DAS28 response : 12 weeks post infusion

  31. Remission with anti-TNF biologics Data from clinical trials; at 6 months. • RA-ATTRACT: infliximab • placebo <1% • Infliximab 4-6% • GO-FORWARD: golilumab • placebo <3% • golilumab 13%

  32. Serum Biomarker: VEGF

  33. Future Plans • To develop BiP/Rasolvir as a new biologic for the treatment of: • RA • Other inflammatory joint diseases: JIA, ank spondylitis • Other inflammatory/autoimmune diseases: Crohn’s disease, Type I diabetes mellitus (prevention) • Prevention allograft rejection • Bone loss: systemic/localised

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