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    Personalizing treatment choice Personalizing treatment choice Presentation Transcript

    • Personalizing Treatment Choice International MS Physician Summit Prague, 22nd-23rd March 2014 Gavin Giovannoni Barts and The London
    • Disclosures Professor Giovannoni has 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, Bayer-Schering 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. Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni. Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation. I would like to acknowledge Mark Hughes, from Infusion, who helped me prepare some of my slides. Please note that Professor Giovannoni’s attendance at the 2014 MS Physician Summit, in Prague, was sponsored by Biogen-Idec.
    • Therapeutic Ideal Reliable long-term efficacy Maintaining QOL Maintaining independence Maintaining the ability to work No issue for pregnancy/fertility Maximum reduction of MS disease activity Maximum tolerability Maximum safety Ease of use Minor impact on everyday life QOL=quality of life.
    • Moving from Compliance to Concordance Requires a Culture Change Concordance modelCompliance model Prescriber decides diagnosis and treatment Prescriber’s task is to explain and instruct Patient’s task is to comprehend Successful outcome is compliance Prescriber and patient negotiate diagnosis and treatment Prescriber elicits, explains, persuades, and accommodates Patient explains, considers, and accommodates Successful outcome is a negotiated agreement Royal Pharmaceutical Society of Great Britain. From compliance to concordance: achieving shared goals in medicine taking. London, 1997.
    • Canada: Deciding on an MS Treatment Available from: mssociety.ca/en/pdf/EYO-ENG-web-2012.pdf. Accessed 13 March 2014.‎
    • Canada: Deciding on an MS Treatment Available from: mssociety.ca/en/pdf/EYO-ENG-web-2012.pdf. Accessed 13 March 2014.‎
    • UK: Deciding on an MS Treatment www.msdecisions.org.uk. Accessed 26 February 2014.
    • UK: Deciding on an MS Treatment www.msdecisions.org.uk. Accessed 26 February 2014.
    • Compliance Model “Trust me. I am the doctor”
    • Where are you on the diffusion curve? Giovannoni G et al. Lancet Neurol. 2006;5:887-894.
    • Patient FAQs Regarding the Impact of Therapy on Daily Life • What is MS? • Are you sure that I have MS? • What type of MS do I have? • What prognostic group do I fall into? • What is the risk of not being treated with a DMT? • Do I 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 no evident disease activity (NEDA)? • What about pregnancy? FAQ=frequently asked question; MS=multiple sclerosis; DMT= disease modifying therapy.
    • 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 findings/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 findings with large lesion load  Posterior fossa lesions  Brain atrophy  CSF positive for OCBs  Genomic factors (eg, ApoE4) MRI=magnetic resonance imaging; CSF=cerebrospinal fluid; OCB=oligoclonal bands; Apo=apolipoprotein. Adapted from Miller D et al. Lancet Neurol. 2005:4;281-288.
    • 0 10 20 30 40 50 60 70 80 0 5 10 15 20 PatientsConvertingtoEDSS‎≥3.0‎(%) Years 0 Lesions 1–3 Lesions 4–10 Lesions >10 Lesions 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. EDSS=Expanded Disability Status Scale. 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. Baseline Number of Brain Lesions Predicts Progression to EDSS ≥3.0 Queen Square Study
    • Question: What prognostic group do you fall into? Favourable Indeterminate Poor time Aim of treatment Giovannoni G. Barts & The London, UK, February 2014.
    • Question: What prognostic group do you fall into? Potential Consequences of the Disease
    • Question: Do You Have Active MS? vs 1 2 3 Clinical MRI Biomarkers Giovannoni G. Barts & The London, UK, February 2014.
    • Treatment Selection The individual MS patient: • MS prognosis • Life style and goals • Your goals for therapy Individual MS patient’s measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers? 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 adverse events • MRI • T2 & T1-Gd • Brain atrophy • Biomarkers • NAbs • CSF neurofilamentGd=gadolinium; NAb=neutralising antibody. Giovannoni G. Barts & The London, UK, February 2014. Define the individual MS‎patient’s‎disease Treatment failure? yes no Choose therapy Monitoring X Y Z
    • General Treatment Philosophy in 2008 Moderate Efficacy High Efficacy A B C D E Giovannoni G. Barts & The London, UK, February 2014.
    • Increasing Choice: the Escalation Ladder Moderate Efficacy Intermediate Efficacy High Efficacy Giovannoni G. Barts & The London, UK, February 2014.
    • A Conservative Alternative or, If Time=Brain, Is It Dangerous? CO-CZ-0056b N M YXModerate Efficacy Intermediate Efficacy High Efficacy A B C D E Giovannoni G. Barts & The London, UK, February 2014.
    • MS is an autoimmune disease hypothesis 15−20 year experiment “T2T-NEDA & early‎”‎ Question: Do you understand the difference between the treatment strategies of maintenance, escalation and induction therapy? What is your treatment philosophy? Maintenance-escalation vs induction Survival analysis T2T=treat-to-target; NEDA=no evidence of disease activity.
    • Increasing Personalization: Matching Efficacy to Disease Activity Moderate Efficacy Intermediate Efficacy High Efficacy Ongoing activity but low concern Ongoing activity but high concern Poor (active disease) Indeterminate (active disease) Favourable (active disease) Giovannoni G. Barts & The London, UK, February 2014.
    • An Aggressive Disease Requires a Strong Medicine Moderate Efficacy Intermediate Efficacy High Efficacy Giovannoni G. Barts & The London, UK, February 2014.
    • Treat-to-Target: No Evidence of Disease Activity
    • Herd Immunity Not immunised but still healthy Immunised and healthy Not immunised, sick and contagious http://en.wikipedia.org/wiki/Herd_immunity. Accessed 7 March 2014.
    • A Hypothetical Population of Newly Diagnosed People with CIS/MS CIS=clinically isolated syndrome.
    • Hypothetical Long-term Outcomes Under the Current Treatment Paradigm Giovannoni G. Barts & The London, UK, February 2014.
    • Hypothetical Long-term Outcomes Under the T2T-NEDA Paradigm Giovannoni G. Barts & The London, UK, February 2014.
    • Question: What about pregnancy? 14. How do you treat hyperemesis gravidarum during pregnancy? 15. Should I continue taking my other drugs for my MS symptoms during pregnancy? 16. What is the best treatment strategy for my MS? Should I go onto a DMT and get my MS under control before starting a family or should I start my family first? 17. What is the best treatment strategy for my MS to maximise my chances of having a family and keeping my MS under control? 18. How will having neutralizing anti-IFN beta antibodies affect my baby? 19. Can I have in vitro fertilization? Will the drugs that are used to induce ovulation affect my MS? 20. What dose of vitamin D do you advise during pregnancy? 21. Are oral contraceptives safer for my MS? Which contraceptive do you recommend? 1. Does MS affect my fertility? 2. Will pregnancy affect the course of my MS? 3. Will I be able to breast feed after delivery? 4. How long before I fall pregnant must I stop my DMT? 5. If I fall pregnant on a DMT will this affect the baby? 6. Can I breast feed on my DMT? 7. Will I be able to be a good parent if I become disabled from my MS? 8. If I become disabled or unemployed as a result of MS will I be able to support my children? 9. What is the risk of my children getting MS? 10. Can I do anything to prevent them from getting MS? 11. Am I more likely to need an assisted delivery because I have MS? 12. Will I be able to have a normal vaginal delivery? 13. Will I be able to have an epidural during labour?
    • Considerations for Women of Childbearing Potential Interferon β • In monkeys, increased rate of abortion. No malformations in surviving animals • Initiation of treatment is contraindicated during pregnancy Glatiramer acetate • Animal studies are insufficient with respect to effects on pregnancy; embryonal/foetal development, parturition, and postnatal development • Contraindicated during pregnancy Natalizumab • Studies in guinea pigs and monkeys showed no evidence of teratogenic effects or effects on growth of offspring • Should not be used during pregnancy unless the clinical condition of the woman requires treatment with natalizumab Fingolimod • Animal studies have shown reproductive toxicity, including foetal loss and teratogenicity • While on treatment, women should not become pregnant; if pregnancy occurs, discontinuation of fingolimod is recommended Animal studies, Clinical recommendations Data from summary of product of characteristics (SmPC) for each therapy.
    • Considerations for Women of Child-bearing Potential Teriflunomide • Embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range • Contraindicated in pregnancy • Patient advised to contact physician if pregnancy is suspected; institution of accelerated elimination may decrease risk to foetus Alemtuzumab • Dosing mice for 5 days during gestation resulted in significant increases in dead or resorbed conceptuses and reduction in viable foetuses • Placental transfer and potential pharmacologic activity observed • Contraception advised during treatment and for 4 months following • Should be administered during pregnancy only if the potential benefit justifies the potential risk to the foetus • Thyroid disease poses special risks in women who are pregnant (potential miscarriage, foetal effects such as mental retardation and dwarfism,‎transient‎neonatal‎Graves’‎disease) Dimethyl fumarate • No malformations have been observed at any dose in rats or rabbits • Should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus Animal studies, Clinical recommendations Data from summary of product of characteristics (SmPC) for each therapy.
    • Key Takeaways • There is a large gap between the therapeutic ideal and reality • How are you going to close this gap? • By practicing the concordance model? • By being ready to answer your patients questions? • We need to find balance between therapeutic objectives and patient needs (benefit-risk assessment) • What are your therapeutic objectives? • Patient and physician perception of burden of therapy may differ • Treatment philosophies vary widely • Principal patient considerations impacting on treatment choice and adherence are • Pregnancy • Route of administration • Dosing frequency • Cognitive level • Depression • Belief in medicine/concept of disease (patient vs doctor) • Understanding that effectiveness varies between individuals