Discussing NEDA as an individualized treatment goal
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Discussing NEDA as an individualized treatment goal Presentation Transcript

  • 1. Discussing individualized treatment goals: the physician’s perspective Gavin Giovannoni Barts and The London
  • 2. Disclosures I have received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Almirall, BayerSchering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
  • 3. Definitions • DAF = disease activity free • NEDD (oncology) = No evident detectable disease • Minimal detectable disease • Biochemically detectable disease • PCR detectable disease • NEDA (MS) = No evident disease activity • T2T = treat-to-target (rheumatology) • Zeto = zero tolerance
  • 4. Conclusions / Questions – September 2012 • What should NEDA look like? • • • What about brain atrophy and CSF neurofilament levels? Should the definition be stage specific? • • • • We need to optimise the time fore re-base lining MRI when looking for a change; this will need to be agent specific. How do we deal with the difference between maintenance and induction therapies? • • • CIS/RRMS vs. R-SPMS vs. NR-SP/PPMS What do we do about post-inflammatory neurodegeneraton? What about the potential effects of superimposed accelerated ,or premature, aging? How do we define an appropriate baseline for comparison? • • Absence of any clinical and biomarker evidence of disease activity • Current definition = relapse, disease-progression, Gd-enhancing lesions and new T2 lesions Maintenance - absence of NEDA status indicated non-response Induction – absence of NEDA status indicates a time to retreat. How do we standardise (or improve) on the metrics?
  • 5. Teacher 38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London        Glatiramer acetate treatment for 3 years (good adherence and tolerance) Relapse with a mild left sensory loss Referred to me for a second opinion Switched to interferon β (intramuscular interferon β-1a; www.msdecisions.org.uk) Mild persistent flu-like side effects and lymphopenia 12/12’s neutralizing antibodies screen negative Volunteers for new research programme, which included a gadolinium-enhanced MRI protocol
  • 6. X Teacher 38-year-old teacher with relapsing–remitting MS  As a result of fatigue and cognitive problems she is forced to take early retirement  Although fully functional she develops depression and anxiety  In her spare time she spends a lot of time on the web and becomes an expert patient  Widely read  Net savvy; regular follower of www.ms-res.org
  • 7. NICE (UK) guidelines for the prescribing of natalizumab Natalizumab is recommended as an option for the treatment only of rapidly evolving severe relapsing–remitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared with a previous MRI. 1st-line or naïve MSers or 2nd-line (IFN-beta or GA failures) NICE - Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis; August 2007.
  • 8. NICE (UK) guidelines for the prescribing of fingolimod Fingolimod is recommended as an option for the treatment of highly active relapsing–remitting multiple sclerosis in adults, only if: 1. they have an unchanged or increased relapse rate or on-going severe relapses compared with the previous year despite treatment with beta interferon, and 2. the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme. NICE Fingolimod: final appraisal determination document; 16 March 2012 .
  • 9. The NICE (UK) relapsing MS DMT doughnut Natalizumab Highly-active or rapidly evolving severe RRMS Fingolimod Suboptimal responders? IFN β or GA Clinically active RRMS Clinically-inactive or MRI-active RRMS CIS RIS or asymptomatic MS CIS, clinically isolated syndrome; DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting MS. IFN β
  • 10. Relapsing-MS Rapidly-evolving severe Highly-active Active Inactive
  • 11. Bermel et al. Ann Neurol 2012. Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
  • 12. X Teacher
  • 13. X Teacher
  • 14. Questions: the Mser’s perspective To make an informed decision MSers need to ask and understand the following questions: 1. 2. 3. 4. 5. 6. 7. 8. Are you sure that you have MS? What types of MS do you have? What prognostic group do you fall into? What is the risk of not having any treatment? Do you have active MS? Am I eligible for treatment with a DMT? Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy? Do you understand the concept of treat-2-target of NEDA?
  • 15. Question: Are you sure that you have MS? • MS misdiagnosis rate of ~5%  CDMS 485/518 (94%) - SENSITIVITY = True+ve /(True+ve + False-ve) Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988 Jul;78(1):39-44. • MS mimics  NMO  Shimizu et al. IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology. 2010 Oct 19;75(16):1423-7.  Migraine  Kleinschmidt-DeMasters et al. PML complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005 Jul 28;353(4):369-74
  • 16. Question: what types of MS do you have? RRMS R-SPMS/NR-SPMS PPMS RPMS relapsing forms of MS vs. non-relapsing MS Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr;46(4):907-11.
  • 17. Question: what prognostic group do you fall into? Good prognosis Poor prognosis                Young Female sex “Unifocal” onset Isolated sensory symptom (optic neuritis, sensory) Full recovery from attack Long interval to second relapse No disability after 5 years Normal MRI / low lesion load No posterior fossa lesions No brain atrophy CSF negative for OCBs         Older age of onset Male sex “Multifocal“ onset Efferent system affected (motor, cerebellar, bladder) Partial or no recovery from a relapse High relapse rate in the first 2 years Disability after 5 years Abnormal MRI with large lesion load Posterior fossa lesions Brain atrophy CSF positive for OCBs Genomic factors (e.g. ApoE4) Adapted from Miller et al., Lancet Neurology 2005: 4; 281-288
  • 18. Baseline number of brain lesions predicts progression to EDSS Score ≥3.0 Queen Square Study The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study. The exact relationship between MRI findings and the clinical status of the patient is unknown. Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503; Brex PA et al. N Engl J Med. 2002;346:158-164.
  • 19. Question: what prognostic group do you fall into? Favourable Indeterminate Poor time Aim of treatment
  • 20. Question: What is the risk of not having any treatment? Utility EDSS and utilitya show a significant inverse relationship1,b EDSS Status  MS is one of the most common causes of neurological disability in young adults 2  Natural history studies indicate that it takes a median time of 8, 20 and 30 years to reach the irreversible disability levels of EDSS 4, 6 and 7, respectively3  Up to 75% increased annualized divorce rate4  Life expectancy is reduced by 5-10 years5  7.5x greater than suicide rate than the general population6  2 out of 3 patients with RRMS were unemployed due to the disease7 aUtility measures are derived from EQ-5D using the EuroQoL instrument. from Orme et al 2007. Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5. 1.Orme M et al. Value In Health. 2007;10:54-60. 2.WHO. 2008.[TK] 3. Confavreaux, Compston. 2005.[TK] 4. Coles et al. 2001.[TK] 5. Confavreaux, Vukusic. 2006.[TK] 6. Sadovnick et al. Neurology 1991;41:1193-6. 7. Morales-Gonzales. Mult Scler. 2004;10:47-54. bAdapted
  • 21. Question: do you have active MS? 1 Clinical vs. 2 MRI 3 Biomarkers
  • 22. Question: am I eligible for treatment with a DMT? • • • • MSer Neurologist Payers Regulator
  • 23. Question: Am I eligible for treatment with a DMT?
  • 24. Question: Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy? What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “T2T-NEDA & early ” MS is an autoimmune disease hypothesis 15-20 year experiment
  • 25. Treatment Selection Define the individual MSer’s disease Individual Mser’s measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers? Choose therapy X Y yes no Monitoring Treatment failure? The individual Mser: • MS prognosis • Life style and goals • Your goals for therapy Z Therapy: • Maintenance vs. Induction • Moderate efficacy (1st-line) • Intermediate efficacy (2nd-line) • High-efficacy (3rd-line) Monitoring: • Clinical • Relapse • Disability progression • Risk profile for serious AEs • MRI • T2 & T1-Gd • Brain Atrophy • Biomarkers • NABs • CSF NF
  • 26. Treatment Ladder 3rd-line X 1st-line A 1st-line E 1st-line B 1st-line D 1st-line C 2nd-line M 2nd-line N 3rd-line y
  • 27. A population approach: arguing by analogy
  • 28. Relapsing-MS Rapidly-evolving severe Highly-active Active Inactive
  • 29. RES HA Active Inactive
  • 30. A population of newly diagnosed CISers/MSers
  • 31. Long-term outcomes under the current Rx paradigm
  • 32. Long-term outcomes under the T2T-NEDA paradigm
  • 33. T2T-NEDA diffusion curve • • • • MSer Neurologist Payers Regulator Giovannoni & Cutter; Lancet Neurol 2006; 5: 887–94.
  • 34. Conclusions / Questions - December 2013 1. 2. 3. 4. 5. 6. 7. 8. 9. What should NEDA look like? Should the definition be stage specific? What do we do about post-inflammatory neurodegeneraton? What about the potential effects of superimposed accelerated , or premature, aging? How do we define an appropriate baseline for comparison? How do we deal with the difference between maintenance and induction therapies? How do we standardise (or improve) on the metrics? How do we communicate these concepts to our colleagues and more importantly MSers? How can we facilitate the adoption of the T2T-NEDA paradigm?