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Alfredo Ribeiro-da-Silva, MD, PhD

Modulation of NGF levels as a treatment for arthritis pain. Alfredo Ribeiro-da-Silva, MD, PhD. Alan Edwards Centre for Research on Pain Department of Pharmacology & Therapeutics Department of Anatomy & Cell Biology. What is situation now. Rheumatoid arthritis

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Alfredo Ribeiro-da-Silva, MD, PhD

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  1. Modulation of NGF levels as a treatment for arthritis pain Alfredo Ribeiro-da-Silva, MD, PhD Alan Edwards Centre for Research on Pain Department of Pharmacology & Therapeutics Department of Anatomy & Cell Biology

  2. What is situation now • Rheumatoid arthritis • Symptomatic treatment (analgesics) • Disease-modifying drugs including biologics • Results far from optimal • Osteoarthritis • Analgesics • Non-pharmacological interventions • Results far from optimal

  3. Where does the pharmaceutical industry stand regarding drug development for arthritis? • Rheumatoid arthritis • Development of new biologics - example Pfizer’s Xeljanz (Tofacitinib) – licensed in US but not EU • Osteoarthritis • Clinical trials with anti-NGF antibodies (suspended in 2010 based on safety concerns, supposed to re-start in the fall of 2013 with lower doses and more restricted selection of patients).

  4. Anti-NGF antibodies in patients with osteoarthritis • No studies with anti-nerve growth factor (NGF) antibodies in rheumatoid arthritis. Why? • Studies showing beneficial effects of anti-NGF in patients with osteoarthritis: • N. E. Lane, T. J. Schnitzer, C. A. Birbara, M. Mokhtarani, D. L. Shelton, M. D. Smith, and M. T. Brown. Tanezumab for the treatment of pain from osteoarthritis of the knee.N.Engl.J.Med. 363 (16):1521-1531, 2010. • E. L. Spierings, J. Fidelholtz, G. Wolfram, M. D. Smith, M. T. Brown, and C. R. West. A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee. Pain, 2013, in press. • M. T. Brown, F. T. Murphy, D. M. Radin, I. Davignon, M. D. Smith, and C. R. West. Tanezumab reduces osteoarthritic hip pain: Results of a randomized, double-blind, placebo-controlled phase 3 trial. Arthritis Rheum, 2013, in press. • Antibodies quite good at reducing pain in osteoarthritis and can be given each 8 weeks only

  5. Issues with the use of anti-NGF antibodies in arthritis patients • Risk of acceleration of the pathology. • Some patients on antibodies required emergency joint replacement surgery • Above issue led to temporary suspension of clinical trials in 2010 • Possibility that NGF has functions in bone that should not be suppressed • Will the antibodies ever be mainstream therapy for osteoarthritis? Likely will always have a black label.

  6. Why antagonize Nerve Growth Factor? • NGF originally discovered as factor essential for survival of sensory and sympathetic neurons. • However, it was later found that NGF plays major role in nociceptor sensitization after tissue injury in adults • Indeed, NGF could be described as a pain producing substance • Clinical trials of NGF as a treatment for Alzheimer’s disease cancelled because patients had pain

  7. How does NGF induce pain? • Besides the neurotrophic factor functions, NGF is a key upstream modulator of expression and sensitization neurotransmitters, receptors and ion channels expressed in nociceptive afferents • NGF expressed by inflammatory cells such as eosinophils, lymphocytes, macrophages and mast cells following injury • NGF is upregulated in animal models of inflammation and in models of inflammatory arthritis

  8. How does NGF induce pain (2)? • NGF skin injection causes fast sensitization of nociceptors both in rodents an humans (1 and 3 hrs respectively) • NGF acts on the high affinity trkA receptors expressed by mast cells and other inflammatory cells and leads to release of inflammatory mediators and cytokines • NGF also sensitizes directly primary afferents through trkA receptors • Important mechanism is a sensitization of TRPV1 (capsaicin) channels

  9. How does NGF induce pain (3)? • Changes in gene transcription in DRG • NGF bound to trkA is internalized in primary afferents and causes transcription changes in DRG neurons (increase in synthesis of substance P, CGRP, TRPV1, trkA, BDNF, etc) • Increased release of substance P and CGRP in periphery leads to neurogenic inflammation and further activation of inflammatory cells and NGF synthesis • Increased activity of peptidergic afferents in spinal cord leads to central sensitization • Increased levels of NGF lead to abnormal fibre sprouting (including sympathetic sprouting)

  10. Why antagonize NGF? • Animal experiments have shown fundamental difference in role of NGF in growth and differentiation and the role in the adult nervous system • In adult animals the NGF-trkA signalling becomes a major player in both acute nociception and in chronic pain • Antagonizing the NGF-trkA signalling makes sense to control pain • This can be achieved by using anti-NGF antibodies or blocking trkA either with ligands or with antibodies • If anti-trkA antibodies are used, only the effects mediated through trkA are antagonized (not those mediated through the low affinity p75 receptor)

  11. Animal studies using anti-NGF antibodies • In polyarthritis induced by CFA injected in vein of the tail, anti-NGF antibodies reversed hyperalgesia (Shelton et al., Pain 116 (1-2):8-16, 2005). • In a mouse CFA-induced monoarthritis model, the use of an antibody of those in clinical trials (tanezumab) led to suppression of sprouting in bone and joints and alleviation of pain (Ghilardi at al., Arthritis Rheum 64 (7):2223-2232, 2012). • We will focus on this second paper

  12. Study from Mantyh’s lab • Anti-NGF antibodies administered i.p. to mice (at 4 hours and 5, 10, 15, 20, and 25 days post-CFA injected in knee joint • Treatment did not improve CFA induced alterations in joint. • Treatment did not affect inflammatory markers Ghilardi at al., Arthritis Rheum 64 (7):2223-2232, 2012

  13. Study from Mantyh’s lab (2) • Anti-NGF treatment did not prevent CFA-induced proliferation of blood vessels • It did not prevent inflammatory cell infiltration either Ghilardi at al., Arthritis Rheum 64 (7):2223-2232, 2012

  14. Study from Mantyh’s lab (3) • Anti-NGF antibodies prevented fibre sprouting in joint Ghilardi at al., Arthritis Rheum 64 (7):2223-2232, 2012

  15. Study from Mantyh’s lab (behaviour) • Anti-NGF treatment ameliorated pain-related behaviour and limb use • No negative effects on bone or joint structure were observed that could explain the acceleration of pathology observed in some patients Ghilardi at al., Arthritis Rheum 64 (7):2223-2232, 2012

  16. Study from our lab • In this study, we used a different approach to reduce endogenous NGF levels in an experimental model of arthritis (monoarthritis of the ankle in rat) • Used a subtler way to modulate endogenous NGF levels • Our objective was just to bring back to normal the abnormally elevated NGF levels in arthritis

  17. a2-antiplasmin X Adapted from Bruno & Cuello, PNAS, (2006)

  18. Experimental designs for α2-antiplasmin administration on CFA-induced allodynia and hyperalgesia • Early administration 1 α2-AP α2-AP Tissue collection for IHC and WB CFA CFA • Delayed administration 3d test 7d test 1d test 14d test pre- test 1 week 2 weeks 3d test 7d test pre- test 1d test 14d test 2 3 weeks 4 weeks

  19. Early α2-antiplasmin administration alleviated the CFA-induced allodynia and hyperalgesia Heat Hyperalgesia Mechanical allodynia Cold allodynia *Longo G., *Osikowicz M., Liu H., Cuello A.C., Ribeiro-da-Silva A. To be submitted

  20. Early α2-antiplasmin administration normalized the abnormally elevated levels of mature NGF induced by CFA but did not affect proNGF levels CFA+ a2-AP CFA+ a2-AP CFA+V A B CFA+V mNGF 14 kDa proNGF 40 kDa 42 kDa beta-actin 42 kDa beta-actin Sham Sham

  21. Delayed α2-antiplasmin administration alleviated the CFA-induced allodynia Heat Hyperalgesia Mechanical allodynia Cold allodynia Osikowicz, Longo et al., To be submitted

  22. Delayed α2-antiplasmin administration also normalized the abnormally elevated levels of mature NGF induced by CFA but did not affect proNGF levels CFA+ a2-AP CFA+ a2-AP A B CFA+V CFA+V 40 kDa proNGF mNGF 14 kDa beta-actin 42 kDa beta-actin 42 kDa Sham Sham Osikowicz, Longo et al., To be submitted

  23. α2-antiplasmin reversed the skin sympathetic fiber sprouting associated with inflammatory arthritis Osikowicz, Longo et al., To be submitted

  24. Conclusions from our study • Our study provides novel evidence suggesting that inflammatory pain associated with arthritis can be managed by reducing the abnormally elevated mNGF levels. • Indeed, normalizing the abnormally elevated levels of mature NGF produced some alleviation of CFA-induced hypersensitivity to mechanical and thermal stimuli in rats and blocked the abnormal fibre sprouting.

  25. Acknowledgements • Geraldine Longo • Maria Osikowicz • Claudio Cuello • Gary J. Bennett • MITACS Accelerate program • Pfizer Canada • Louise and Alan Edwards Foundation

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