Pharmacotherapy Update Multiple Sclerosis

Transcription

1 Pharmacotherapy Update Multiple Sclerosis Yolande Hanssens SIG Leader Medicine Information Hamad Medical Corporation Pharmacy Department - Clinical Service Unit Doha - Qatar Heidelberg/October 2017 Pharmacotherapy Update Multiple Sclerosis Introduction Classification Therapeutic management of RRMS* Disease Modifying Drugs (DMDs) Patient tailored treatment Special patient groups Summary & take home messages *RRMS = Relapsing Remitting Multiple Sclerosis 1

2 MS - Intro Progressive, chronic idiopathic autoimmune driven disorder of the nervous system widespread inflammation affecting the brain and spinal cord plaques (MRI) Unpredictable Symptoms from numbness and tingling to blindness and paralysis Age 20-50, M:2F, genetic factors? North Europeans? > 2.3 million No cure MS Classification Relapsing-Remitting MS (RRMS) About 85% Secondary-Progressive MS (SPMS) Symptoms worsen more steadily over time, with or without the occurrence of relapses and remissions. RRMS SPMS at some point Primary-Progressive MS (PPMS) About 10% slowly worsening symptoms from the beginning, with no relapses or remissions Progressive-Relapsing MS (PRMS) About 5% steadily worsening disease state from the beginning, with acute relapses but no remissions, with or without recovery Hooper K. Managing Progressive MS. New York, NY: National Multiple Sclerosis Society; Multiple Sclerosis: Just the Facts New York, NY; National Multiple Sclerosis Society;

3 Types of MS at Diagnosis MS International Federation; Clinical Evolution TIME WINDOW to START TREATMENT RIS = Radiological Isolated Syndrome CIS = Clinical Isolated Syndrome RRMS = Relapsing Remitting MS R-SPMS = Relapsing Secondary Progressive MS SPMS = Secondary Progressive MS 3

4 Therapeutic Management No Cure DMDs for RRMS Mode of Action & Major Adverse Events Documented Treatment Effects Patient Tailored Therapy Special Patient groups & Overall Pharmaceutical Care Considerations DMD = Disease modifying Drug RRMS = Relapsing Remitting MS Ocreluzimab i.v EDDS = Expanded Disability Status Scale MSFC = Multiple Sclerosis Functional Composite NEDA = No Evidence of Disease Activity 4

5 DMDs for RRMS Interferon β (Rebif, Betaseron, Avonex, Plegridy ) Glatiramer acetate (Copaxone ) Teriflunomide (Aubagio ) Dimethyl fumarate (Tecfidera ) Fingolimod (Gilenya ) Natalizumab (Tysabri ) Alemtuzumab (Lemtrada ) Ocrelizumab (Ocrevus ) DMD = Disease modifying Drug RRMS = Relapsing Remitting MS MOA - unknown Interferon β (PEG)Interferon Beta-1a IM (Avonex ) & SubQ (Rebif, Plegridy ) Chinese hamster ovary cells Interferon Beta-1b SubQ (Betaseron ) E coli 5

6 Interferon β - Concerns Related to adverse effects Anaphylaxis/hypersensitivity reactions Autoimmune disorders Bone marrow suppression Flu-like symptoms Hepatic effects obtain liver function tests at 1, 3, and 6 months post therapy initiation and periodically thereafter. Injection site reactions Neuropsychiatric disorders Thrombotic microangiopathy Glatiramer Acetate MOA - thought to induce and activate T-lymphocyte suppressor cells specific for a myelin antigen & to interfere with the antigen-presenting function of certain immune cells opposing pathogenic T-cell function SubQ - 20 mg once daily OR 40 mg 3x/week 6

7 Glatiramer - Concerns Related to adverse effects Hypersensitivity reactions Immune response Lipoatrophy including skin necrosis Systemic reactions anxiety, chest pain, constriction of the throat, dyspnea, flushing, palpitations, urticaria usually self-limited and transient generally occur several months after initiation of treatment. Teriflunomide MOA - immunomodulatory agent that inhibits pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects - may reduce the number of activated lymphocytes in the CNS PO 7 to 14 mg once daily 7

8 Teriflunomide - Concerns Related to adverse effects Dermatologic reactions: Cases of serious skin reactions, including cases of Stevens-Johnson syndrome and fatal toxic epidermal necrolysis have been reported with teriflunomide Hepatotoxicity - [US Boxed Warning] Hypersensitivity reactions - Anaphylaxis and severe allergic reactions may occur Hypertension Infections Interstitial lung disease Malignancy Pancreatitis Peripheral neuropathy Renal effects - Transient acute renal failure Teriflunomide - Concerns Other Drug elimination procedure - up to 2 years to reach low levels of teriflunomide metabolite serum concentrations. drug elimination procedure using cholestyramine or activated charcoal for more rapid elimination BUT return of disease activity Teriflunomide is also found in semen Immunizations - before initiating therapy 8

9 Dimethyl fumarate MOA - believed to result from its anti-inflammatory and cytoprotective properties via activation of the Nrf2* pathway PO 120 mg BID; after 7 days to 240 mg BID *Nrf2 = nuclear factor (erythroid-derived 2)-like 2 Dimethyl fumarate - Concerns Related to adverse effects Dermatitis/irritation Flushing Gastrointestinal events Hepatotoxicity Hypersensitivity reactions- Anaphylaxis and angioedema may occur after the first dose or at any time during treatment Lymphopenia Proteinuria Progressive multifocal leukoencephalopathy (PML) - 9

10 Dimethyl fumarate - Concerns Related to adverse effects Dermatitis/irritation Flushing Gastrointestinal events Hepatotoxicity Hypersensitivity reactions Lymphopenia Proteinuria Progressive multifocal leukoencephalopathy (PML) associated with persistent (>6 months) lymphopenia, with a majority of cases occurring in patients with lymphocyte counts <500/mm 3 and anti-jcv (John Cunningham virus) antibody >0.9 withhold therapy immediately at the first sign or symptom suggestive of PML (eg, progressive weakness on one side of the body or clumsiness of limbs; vision disturbances; mental status changes) and perform a diagnostic evaluation (MRI findings may appear before clinical signs/symptoms). Fingolimod MOA Sphingosine 1-Phosphate (S1P) Receptor Modulator; blocks the lymphocytes' ability to emerge from lymph nodes the amount of lymphocytes available to the central nervous system is decreased reduces central inflammation. PO 0.5 mg PO once daily 10

11 Fingolimod- Concerns Related to adverse effects Atrioventricular (AV) block Bradycardia Cryptococcal infections Hepatic effects Herpes infection Hypersensitivity reaction Hypertension Immune suppression Macular edema Malignancy Neurotoxicity Progressive multifocal leukoencephalopathy (PML) Respiratory effects QT prolongation Fingolimod- Concerns Other specific warnings/precautions Discontinuation of therapy rebound syndrome may occur within 4 to 16 weeks of stopping fingolimod treatment in patients with multiple sclerosis of varying severity and duration relapses have occurred despite the initiation of other diseasemodifying therapies Rebound symptoms: back and extremity pain, confusion, constipation, diplopia, facial muscle spasms, fatigue, increased leg weakness, nausea, paraparesis and paresthesias 11

12 Natalizumab Alemtuzumab Ocrelizumab Monoclonal Antibodies with different MOA IV with different treatment schedules Natalizumab : 300 mg every 4 weeks Alemtuzumab : 12 mg daily for 5 consecutive days (total 60 mg), followed 12 months later by 12 mg daily for 3 consecutive days (total 36 mg); total duration of therapy: 24 months Ocrelizumab : 300 mg on day 1, 300 mg 2 weeks later and 600 mg once every 6 months Natalizumab Alemtuzumab Ocrelizumab Monoclonal Antibodies with different MOA Need for pre-medication methylprednisolone (1000 mg IV) 30 minutes prior to each infusion an antihistamine (eg, diphenhydramine) 30 to 60 minutes prior each infusion may also consider premedication with paracetamol assess for infection; delay administration for active infection monitor patient during (and after) infusion 12

13 Natalizumab, Alemtuzumab Ocrelizumab - Concerns Related to adverse effects Hepatotoxicity Herpes infection & other infections Hep B reactivations Hypersensitivity reaction/antibody formation Immune reconstitution inflammatory syndrome (IRIS) Malignancy Lab test abnormalities Progressive multifocal leukoencephalopathy (PML) Auto-Immune effects Bone marrow suppression GI toxicity Ocreluzimab i.v EDDS = Expanded Disability Status Scale MSFC = Multiple Sclerosis Functional Composite NEDA = No Evidence of Disease Activity 13

14 Overview of the efficacy of MS therapies currently available: NEDA # at 2 years Trial Study drug % patients achieving NEDA # Comparator % patients achieving NEDA # OPERA I 1*** Ocrelizumab 48 sc IFN β-1a 29 OPERA II 1*** Ocrelizumab 48 sc IFN β-1a 25 CARE-MS I 2* Alemtuzumab 39 sc IFN β-1a 27 AFFIRM 3*** Natalizumab 37 Placebo 7 FREEDOMS 4** Fingolimod 33 Placebo 13 CARE-MS II 5*** Alemtuzumab 32 sc IFN β-1a 14 DEFINE 6* Dimethyl fumarate 28 Placebo 15 TEMSO 7** Teriflunomide 22.9 Placebo 14.3 Data cannot be directly compared between trials because of different study designs and/or populations P-value study drug vs comparator; *<0.05; **<0.001; ***< Traboulsee A et al. Neurology 2016;86 [PL02.004]; 2. Cohen AJ et al. Lancet 2012;380: ; 3. Havrdova E et al. Lancet Neurol 2009;8:254 60; 4. Bevan CJ, Cree BAC. JAMA Neurol 2014;71:269 70; 5. Coles AJ et al. Lancet 2012;380: ; 6. Giovannoni G et al. Neurology 2012;78 [PD5.005]; 7. Freedman M et al. Neurology 2012;78 [PD5.007] # NEDA = No Evidence of Disease Activity 14

15 Comi G, Radaelli M, Soelberg Sorensen P. Lancet 2017;389:

16 Switching Therapy &Wash-Out Periods Required for Treatment Switch in MS Patients Treatment 1 Treatment 2 Wash-Out IFN 1 or GA 2 Any Drug No wash-out required Any Drug IFN or GA No wash-out required Teriflunomide Dimethyl Fumarate Fingolimod Natalizumab Fingolimod Natalizumab Alemtuzumab Fingolimod Natalizumab Alemtuzumab Teriflunomide Natalizumab Alemtuzumab Fingolimod Teriflunomide Dimethyl Fumarate accelerated elimination procedure or 3.5 months until lymphocytes level returns to normal levels until lymphocytes level returns to normal levels (1 to 2months) 1-3 months 1 IFN = Interferon; 2 GA = Glatiramer Acetate Michel L, et al. Update on treatments in multiple sclerosis. Presse Med

17 Treatment decisions for RRMS are multifactorial: Need for Systematic Approach Patient & Disease Profile Therapy Issues Patient Preferences Geographic & Economic Factors Age, gender, family status Disease activity/disease type Stage of disease Treatment history Comorbidities & concurrent treatment Efficacy Safety Tolerability Administration (route/frequency) Monitoring requirements & frequency of monitoring Sociodemographic profile (lifestyle, work status, family status) Convenience Risk tolerance Likelihood of adherence Access to medication Approved usage Cost Female Pregnancy Lactation Shared Decision & Patient Tailored Treatment MS & Pregnancy Effects of pregnancy on MS Rate of relapse especially during 3 rd trimester Rate of relapses in first 3 months post partum Before 1 st Trim 2 nd Trim 3 rd Trim 1 st 3 months post Confavreux C et al. NEJM. 1998: Vukusic S et al. Brain. 2004:

18 MS & Pregnancy Effects of pregnancy on MS No acceleration in the rate of disability or disease progression postpartum Epidural anesthesia Breastfeeding No adverse event on rate of relapse or progression of MS Confavreux C et al. NEJM. 1998: Vukusic S et al. Brain. 2004: MS & Pregnancy MS does not seem to impair fertility Effect of Assisted Reproductive Technology (ART)? risk of MS disease activity? Roles of extra hormones (GnRH agonist, FSH, progesterone) or rapid changes in hormone levels Hellwig K, Correale. J Clin Immunol. 2013: Correale J et al. Ann Neurol. 2012: Voskuhl RR. Ann Neurol. 2012:631 18

19 MS & Pregnancy Effect of MS on Pregnancy Outcomes rate of caesarian delivery Lower infant birth weight No in complications ectopic pregnancies birth defects spontaneous abortions MS in offspring : 2.5% (single MS) vs 30.5% (dual MS) Kelly VM et al. Neurology. 2009: Dahl J et al. Neurology. 2005: Mueller BA et al. Am J Obstet Gynecol. 2002: Ebers G. Lancet Neurol. 2008: MS & Pregnancy Treatment of RRMS during Pregnancy To stop or NOT to stop? Washout period DMD Glatiramer acetate Interferons Dimethyl fumarate Natalizumab Fingolimod Alemtuzumab Teriflunomide* Washout period none zero to one month zero to one month one to three months two months three to four months washout protocol using po cholestyramine or activated charcoal (<0.02mg/ml) *Also found in semen 19

20 Safety during pregnancy of drugs used to treat RRMS Category B - No evidence of human risk in controlled studies Glatiramer acetate Category C - Risk cannot be ruled out Alemtuzumab Dimethyl fumarate Fingolimod Interferon beta-1a (Avonex, Rebif ) Interferon beta-1b (Betaseron ) Natalizumab Category X - Contraindicated in pregnancy Teriflunomide Modified from: Damek DM, Shuster EA, Mayo Clin Proc 1997; 72:977 (UptoDate-SEP2017) MS & Breastfeeding Effect of breastfeeding on MS None Effect of MS on breastfeeding Meds! Interferon β and glatiramer acetate OK? Others to avoid Coyle PK. Continuum (Minneap Minn). 2014:42-59 Hale TW et al. Breastfeed Med. 2012:

21 Conclusions Management of patients with MS/RRMS is very complex Early treatment influences the course over time There is a clear difference in safety profile among the current DMDs The risk-benefit ratio needs to be individualized Baseline assessment and monitoring are required for most of the DMDs in MS Teratogenicity & carcinogenicity are important factors in the choice of DMD Cost 21