Per Soelberg Sørensen

Transcription

1 Per Soelberg Sørensen Danish Multiple Sclerosis Center Department of Neurology Rigshospitalet, University of Copenhagen Copenhagen, Denmark Declared receipt personal compensation for serving on scientific advisory boards, steering committees or independent data monitoring boards for Biogen Idec, Merck, Novartis, Genzyme, Teva Pharmaceutical Industries Ltd., Glaxo SmithKlime, medday Pharmaceuticals and Forward Pharma. He declared receipt of honoraria from Biogen Idec, Merck, Teva Pharmaceutical Industries Ltd., Genzyme and Novartis. His department received support from Biogen Idec, Merck, Teva, Sanofi-Aventis, Genzyme, Novartis, Bayer, RoFAR, Roche, the Danish Multiple Sclerosis Society, the Danish Medical Research Council and the European Union Sixth Framework Programme

2 Selecting optimal therapy in relapsing MS: balancing efficacy and burden of therapy More effective, with limited burden More effective, but increased burden Efficacy: Relapses Disability MRI activity MRI atrophy Less effective, but limited burden Less effective, with increased burden Burden of Therapy: Convenience Monitoring Tolerability Safety 2 2

3 Evolution in disease-modifying drugs for relapsingremitting multiple sclerosis Fingolimod Teriflunomide Alemtuzumab Dimethyl fumarate 2000 Natalizumab Mitoxantrone Glatiramer acetate Interferon-beta (1b and 1a)

4 Disease-modifying drugs: Benefit/risk evaluation Established Inconveniences and Risks Convenience Monitoring Tolerability Safety Established Benefits efficacy Risk Minimization

5 Interferon-beta: benefit/risk evaluation Established Inconveniences and Possible Risks Injectables Frequent s.c. or i.m. injections Trivial side effects Flu-like symptoms (IFNβ) Injection site reactions Neutralizing Antibodies (NAbs) Established Benefits Moderate effect on disease activity (on average 30% reduction in relapse rate) Less effect on disability progression Excellent response in approximately 30% of patients No long-term safety concerns

6 Recommendations for Maximizing Tolerance and Safety of Interferon-beta Within 3 months CBC LFT MRI Counsel patients to Report adverse effects Use contraception Report pregnancy Prior to Initiating Initiation During Discontinuation Inform patients about possible adverse effects Treat flu-like symptoms with paracetamol or ibuprophen Measure NAbs after 6, 12 and 24 months Repeat NAb measurements if positive In case of confirmed high level NAbs switch to another therapy. With confirmed moderate level NAbs measure in vivo MxA response to IFN-beta Monitor CBC and LFT If LFT > 3 times upper normal level reduce dose or pause therapy Discontinue therapy if pregnancy occurs Switch to another therapy if unacceptable adverse effect MRI yearly Escalate therapy to a second-line therapy if suboptimal treatment response For alternative treatment: Direct switch to immunomodulator possible CBC: complete blood cell count; LFT: Liver function tests; MRI: Magnetic resonance imaging; NAbs: neutralizing antibodies; MxA: Myxovirus A

7 Glatiramer acetate: benefit/risk evaluation Established Inconveniences and Possible Risks Injectables Daily injections may decrease adherence Trivial side effects Injection site reactions Systemic reactions Established Benefits On average a moderate effect on disease activity (30% reduction in relapse rate) Less effect on disability progression Excellent response in approximately 30% of patients No long-term safety concerns

8 Recommendations for Maximizing Tolerance and Safety of Glatiramer Acetate Within 3 months CBC MRI Counsel patients to Report adverse effects Use contraception Report pregnancy Prior to Initiating Initiation During Discontinuation Inform patients about possible adverse effects Discontinue therapy if pregnancy occurs Switch to another therapy if unacceptable adverse effect MRI yearly Escalate therapy to a second-line therapy if suboptimal treatment response For alternative treatment: Direct switch to immunomodulator possible CBC: complete blood cell count; MRI: Magnetic resonance imaging;

9 Teriflunomide: benefit/risk evaluation Established Inconveniences and Possible Risks Adverse effects Diarrhoea and nausea Hair thinning ALT increase Potentially immunosuppressive properties Established Benefits Moderate effect on disease activity Moderate effect on disability progression Equal to IFN-β 1a SC One tablet daily

10 Recommendations for Maximizing Tolerance and Safety of Teriflunomide Within 3 months CBC LFT MRI Negative pregnancy test before initiation of therapy in women with child-bearing potential Counsel patients to Report symptoms of infection Report adverse effects Use contraception/avoid pregnancy Prior to Initiating Initiation During Discontinuation Inform patients about possible adverse effects inform about teratogenicity Inform patients about the need of contraception/ avoidance of pregnancy Monitor LFT every 2 weeks for 6 months If patients want to become pregnant, wait 2 years or until plasma level is <0.02 mg/l - alternatively treat with cholestyramine or active charcoal for 11 days If pregnancy occurs counsel patient about the possibly of induced abortion MRI yearly Switch to another therapy if unacceptable adverse effect Escalate therapy to a second-line therapy if suboptimal treatment response CBC: complete blood cell count; LFT: Liver function tests; MRI: Magnetic resonance imaging; For alternative treatment: Direct switch to immunomodulator possible

11 Dimethyl Fumarate: benefit/risk evaluation Established Inconveniences and Possible Risks Adverse effects Flushing Abdominal pain Administered as two tablets daily Low risk of PML Established Benefits Robust effect on disease activity Moderate effect on disability progression Numerically but not statistically significant better than GA

12 Recommendations for Maximizing Tolerance and Safety of Dimethyl Fumarate Within 3 months CBC MRI Negative pregnancy test before initiation of therapy in women with child-bearing potential Counsel patients to Report symptoms of infection Report symptoms of any disease worsening Report adverse effects Use contraception/avoid pregnancy Prior to Initiating Initiation During Discontinuation Inform patients about possible adverse effects including rare PML Pregnancy counselling Treat flushing with acetylsalicylic acid Monitor lymphocyte count every 3 months If lymphocyte count < 0.5 x10 9 /l for 6 months, discontinue therapy temporarily MRI yearly Switch to another therapy if unacceptable adverse effect Escalate therapy to a second-line therapy if suboptimal treatment response For alternative treatment: Direct switch to immunomodulator possible CBC: complete blood cell count; MRI: Magnetic resonance imaging; PML: Progressive multifocal leukoencephalitis

13 Fingolimod: Risks/Inconveniences>Benefits Established Inconveniences and Possible Risks Adverse effects Bradycardia, A-V block Retinal edema Infections: dermatomal zoster Infrequent severe adverse effects Serious infections: disseminated varicella, herpes encephalitis Skin cancers Single case of PML Established Benefits Superior to IFN-β 1a Large effect on disease activity Moderate effect on disability progression One tablet daily 13

14 Recommendations for Maximizing Tolerance and Safety of Fingolimod Within 3 months before Tx: CBC LFT and bilirubin levels MRI ECG Ophthalmologic exam in high-risk patients Negative pregnancy test before initiation of therapy in women with child-bearing potential VZV antibody measurement; VZV vaccination if no VZV antibodies Counsel patients to: Report symptoms of infection Report symptoms of any disease worsening Avoid live attenuated vaccines Use contraception/avoid pregnancy Perform: Ophthalmologic exam 3 4 months after starting Tx Spirometry and DLCO when clinically indicated Monitor liver function and blood pressure Prior to Initiating Initiation During Discontinuation CAVE drugs: antiarrhythmics; Ca ++ - channel blockers and β- blockers; inhibitors of CYP3A4-mediated metabolism (avoid, if possible; consult SPC) Pregnancy counselling Inform about possible side effects, including rare PML Baseline pulse and blood pressure Observe all patients for 6 hours with ECG monitoring If symptomatic, extend monitoring and observe until symptoms resolve Tx stopped 1 day in weeks 1-2; > 7 days in weeks 3-4; or > 14 days after week 4: repeat Tx initiation phase Switch to another therapy, if unacceptable adverse effect Switch therapy to another second-line therapy, if suboptimal treatment response 2 months from Tx discontinuation: Monitor for infections Counsel on need for contraception For alternative treatment: 6-week wash-out CBC: complete blood cell count; LFT: Liver function tests; MRI: Magnetic resonance imaging; ECG: Electrocardiography; VZV: Varicella-Zoster virus; CYP: ; SPC: ; DLCO: ; Tx: 14

15 Natalizumab: Benefits>risks/inconveniences Established Inconveniences and Possible Risks Intravenous infusions Rare infusion reactions Rare NAbs Infrequent severe adverse effects PML in 2:1000 per year (after 2 years) Established Benefits Profound effect on disease activity Significant effect on disability progression Improves QoL Good cost-effectiveness Risk stratication for PML possible 15

16 Risk stratification in daily clinical practice JCV Ab JCV Ab+ Tx-naïve patients Breakthrough disease patients High JCV Ab index No previous IS Low JCV Ab index No previous IS Previous IS Rx Natalizumab Use other Rx Rx Na or consider other Rx Use other Rx 6 monthly JCV Ab test After 1 year JCV Ab Continue NaTx JCV Ab+ Recommend other Rx Switch to other Rx Consider other Rx 6 monthly JCV Ab test After 2 year JCV Ab Continue Na Tx JCV Ab+ Recommend other Rx Switch to other Rx Recommend other Rx JCV Ab: John Cunningham virus antibodies; Ab =antibody negative; Ab+=antibody positive; IS: Immunosuppressant therapy; Tx=treatment; Rx=prescription; Na=natalizumab. JCV Ab- JCV Ab+ low index JCV Ab+ high index In all JCV Ab+ patients reconsider natalizumab therapy efficacy of natalizumab Risk assessment in the individual patient with continued Rx Efficacy and risk of alternative treatments

17 Recommendations for Maximizing Tolerance and Safety of Natalizumab Within 3 months before Tx: CBC MRI JCV Ab test Counsel patients to: Report symptoms of infection Report symptoms of any disease worsening Encourage caregiver to report changes in behavior or cognition Use contraception/avoid pregnancy Prior to Initiating Initiation During Discontinuation Inform patients about possible adverse effects including risk of PML Use PML risk stratification Discontinue if hypersensitivity reactions occur Anti-natalizumab Ab testing after 3, 6 and 12 months or if there is ongoing infusion reactions. Cease therapy if test is positive JCV Ab test every 6 months in Ab patients Monitor liver function tests as appropriate MRI yearly If PML is suspected, stop natalizumab, perform MRI and CSF qpcr for JC virus Switch to another therapy if unacceptable adverse effect Switch therapy to another second-line therapy if suboptimal treatment response For alternative treatment: Direct switch to immunomodulator possible Washout prior to immunosuppression, case by case evaluation MRI before start of other treatment CBC=complete blood count; MRI: Magnetic resonance imaging; JCV Ab: John Cunningham virus antibodies; PML: Progressive multifocal leukoencephalitis; Ab: Antibodies; CSF: Cerebrospinal fluid; qpcr: quantitative real-time PCR

18 Alemtuzumab: Benefits>risks/inconveniences Established Inconveniences and Possible Risks Infusion associated reactions Infections Immune thrombocytopenic purpura Immune thyroid disorders Immune nephropaties Cytopenias Established Benefits Robust effect on disease activity and disability progression Infrequent administration Long-lasting efficacy Superiority to IFN-β 1a sc 18

19 Recommendations for Maximizing Tolerance and Safety of Alemtuzumab Within 3 months before Tx: CBC, serum creatinine, urinalysis Thyroid function tests MRI Screening for TB (if indicated) Screening for HBV and/or HIV (if indicated) Screening for VZV antibodies VZV vaccination if no VZ antibodies Negative pregnancy test before initiation of therapy in women with child-bearing potential Counsel patients to: Report symptoms of infection Report signs of bruising, bleedings or petechiae Avoid live attenuated vaccines Use contraception/avoid pregnancy until 4 months after treatment Perform: Monthly CBC, creatinine, urinanalysis Thyroid function tests every 3 months HPV screening annually for female patients. Prior to Initiating Initiation During Discontinuation Inform patients about possible adverse effects Pregnancy counselling (potential adverse fetal outcomes) Antihistamines, corticosteroids and antipyretics prior to infusion Administer corticosteroids first 3 days Pulse and blood pressure monitoring after infusion Oral anti-herpes medication for at least 1 month Tx: ; CBC=complete blood count; MRI: Magnetic resonance imaging; TB: Tuberculosis; HBV: Hepatitis B virus; HIV: Human VZV=varicella-zoster virus; Tx=treatment. 4 years from last treatment: Monitor for infections Monthly CBC, se-creatinine, urinanalysis Thyroid function tests every 3 months For alternative treatment: Only sparse data available; IFN-beta and glatiramer acetate probably safe

20 Thank you for your attention 20

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22 Thank you for your attention 22