Current MS Treatments Yves Lapierre, MD Director Multiple Sclerosis Clinic INM/HNM Over the past 60 years and particularly since the 1960s, the combined efforts of many participants: - donors, MS Societies, - government agencies - MS clinic clinicians and scientists and pharmaceutical industry scientists - and all the study participants and patients have contributed to the emergence of new theories that led to new treatments. 1
The Past Jean-Martin Charcot described MS in 1868 He could not identify a cause but observed inflammation around blood vessels, loss of myelin, relative axon preservation and dissemination in the central nervous system. He also recognized the predominance of women, the age group, and the influence of stress and infections. Progression was deemed unavoidable and treatments disappointing:... need I say more about treatment. The time has not yet come when such a thing could be seriously considered. Today, 150 years later, we have developed and use epidemiology, (epi)genetics, molecular biology, immunology, experimental pathology and imaging. This is where we are now with regard to mechanisms and treatments. MS Treatments Treatment of attacks (relapses) Treatments for symptoms: spasticity, pain, sphincter problems, depression, etc. General measures: lifestyle, exercise, etc. Basic treatments 2
First-Generation Treatments Injections Avonex Betaseron/Extavia Copaxone Rebif INTERFERONS and GLATIRAMER ACETATE Properties of Interferons IFN Secreted naturally in the human body by many cells, including white blood cells. Cytokine (protein) interferes with virus replication, hence the term interferon, and with tumour growth. In medicine, 3 interferons are of interest:, and Beta-IFN: reduces harmful proinflammatory markers by stimulating suppressor lymphocytes. Also has a stabilizing effect on the blood-brain barrier (BBB) 3
Properties of Glatiramer Acetate (Copaxone) Polymer, combination of 4 amino acids that imitate a short sequence found in myelin basic protein Modulates the immune system to reduce bad lymphocytes (Th1) entering the central nervous system This reduces the number of attacks (29-32%), relapse severity and the number of new plaques on MRI Clinical Testing RRMS Annual Relapse Rate (2 years) Complications with Interferons Injectable Injection-site reactions (decreasing) Flu-like reactions (aches, etc., also decreasing) Headaches (in people prone to migraines) Monitoring Liver function and CBC, monthly X 6 then longer intervals Thyroid function Generally safe in the long term; liver, CBC 4
Complications with Glatiramer Acetate Injectable Injection-site reactions (slight) Systemic reactions: retrosternal tightening/pain, anxiety, 20-30 minutes, soon after injection in about 15% of patients always benign Lipoatrophy at injection sites, medium/long-term for a percentage of patients Allergy: rare/very rare Monitoring None Recently available Perfusion Tysabri (2006) Lemtrada (2013) Oral Gilenya (2011) Tecfidera (2013) Aubagio (2013) Basic Treatments: Second Generation MOST RECENT TREATMENTS Tysabri (natalizumab) 5
Tysabri (natalizumab) Monoclonal antibody binds to the alpha 4 integrin adhesion molecule and blocks the entry of lymphocytes into the central nervous system Approved for relapsing/remitting MS that is severe or resistant to other first-line treatments May be used as a first-line treatment in very severe cases AFFIRM and SENTINEL In these studies, Natalizumab reduced the number of relapses, the number of new plaques on MRI and delayed progression of the disease 68% fewer relapses and stable progression based on EDSS Can improve fatigue and attention disorders Adverse effects (non-pml): Allergy: infrequent (< 1%) Antibodies neutralize the drug (6%) Perfusion site reactions Liver enzymes occasionally high, require monitoring Jneurol, 18 mars 2009, Hutchinson. AFFIRM; n engl j med 354;9 2 mars, 2006 SENTINEL; n engl j med 354;9; march 2, 2006 TYSABRI: ANNUAL RELAPSE RATE 68% reduction compared to placebo Annual Relapse Rate (CI 95%) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.73 P<0.001 0.23 68% 0.78 P<0.001 0.27 66% Placebo n=315 TYSABRI n=627 0.67 P<0.001 0.20 70% 0.1 0.0 Years 0 2 Years 0 1 Years 1 2 Polman CH, et al. N Engl J Med. 2006;354:899 910; AFFIRM Study 6
AFFIRM: Lasting Improvement of Disability in Patients with Highly Active MS and EDSS 2.0* Cumulative Probability of Sustained Improvement 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 With Natalizumab, >1 in 3 patients improved in 2 years Boosted probability of improvement 143% Adjusted HR = 2.43 (95% CI: 1.02 5.77) P=0.045 Natalizumab 35.5% Placebo 15.4% 0 12 24 36 48 60 72 84 96 108 120 In weeks since onset Number of Patients at Risk Placebo 40 35 33 31 31 Natalizumab 103 82 72 71 66 *Sustained improvement: 1.0-point reduction in EDSS score; highly active MS ( 2 relapses reported in the year before study entry and 1 gadolinium-enhanced lesion at the time of study entry). EDSS=Expanded Disability Status Scale; HR=hazard ratio; CI=confidence interval; MS=multiple sclerosis. Phillips JT et al. Mult Scler. 2011;17:970-979; Munschauer F et al. Presented at AAN; April 25 May 2, 2009; Seattle, WA. P06.131. 19 64% Free of clinical MS activity 71% No Relapses 95% No Gd+ Lesions AFFIRM: Natalizumab Increased the Percentage of Patients Without Clinically Active MS and No MRI Activity 37% No MS Activity 58% No Activity on MRI 84% No Progression 58% No T2 Lesions Patients Free of Activity for 2 Years Placebo (n=304) 7% P<0.0001 Natalizumab (n=600) 37% P<0.0001, natalizumab vs placebo, for all individual and combined disease measures. MRI=magnetic resonance imaging; Gd+=gadolinium-enhancing. Havrdová E et al. Lancet Neurol. 2009;8:254-260. 20 1.49 1.43 STRATA: Low Annual Relapse Rate up to 4 Years Consistent with the AFFIRM Study Rate Originally Placebo Originally Natalizumab Unadjusted Annual Relapse Rate 0,71 n=381 n=707 n=381 n=707 n=328 n=641 Stop / Suspend Treatment n=385 0,31 n=709 n=282 n=584 Originally Placebo then on Natalizumab n=249 n=528 n=244 n=519 n=203 n=456 n=385 n=709 0.20 0,22 0,17 0,22 0,22 0,21 0,21 0,17 0,16 0 0,14 0,13 0,11 0,11 Years 1 Year 2 Years 3 Years 4 Years 5 *Includes data on patients dosed with natalizumab; includes all available on-treatment relapse data. Goodman A et al. Presented at ECTRIMS; October 19 22, 2011; Amsterdam, Netherlands. P981. 21 Sept. 2012 7
Overall safety Overview of Clinical Trials Adverse effects are generally slight and resolve spontaneously: Headaches, fatigue, urinary infections, arthralgias, flu-like symptoms, etc. Serious adverse effects are comparable to placebo Low rate of serious hypersensitivity reaction (1.1%) No high risk of cancer or depression Infections Rare cases of PML and other opportunistic infections Some herpes zoster infection/reactivation cases Stoppage due to adverse effects comparable in groups 4% placebo, 6% Natalizumab AE=adverse event; PML=progressive multifocal leukoencephalopathy. Polman CH et al. N Engl J Med. 2006;354:899-910; Rudick RA et al. N Engl J Med. 2006;354:911-923; Yousry TA et al. N Engl J Med. 22 2006;354:924-933. LL Educational resource provided in response to unsolicited request (Content current 10/17/2012) MOST RECENT TREATMENTS Lemtrada (alemtuzumab) 8
Alemtuzumab: Active Mechanism Can Explain Rebalancing of the Immune System Alemtuzumab is a monoclonal antibody that, by selectively targeting the CD52 antigen, depletes the T and B lymphocytes in the blood 1-3 ; this is followed by a distinctive repopulation pattern that is thought to rebalance the immune system 2,3. These pharmacodynamic variations may partially explain its effect on multiple sclerosis (MS) 4. Selection Depletion Repopulation The mechanism for the therapeutic effects of alemtuzumab in MS is unclear. 1. Fox EJ. Expert Rev Neurother 2010; 10:1789-1797; 2. Jones JL et al. Brain 2010:133; 2232-2247; 3. Cox AL et al. Eur J Immunol 2005:35; 3332-3342; 4. Données internes de Genzyme Corporation. Alemtuzumab is thought to rebalance the immune system in remitting-relapsing MS Cible les lymphocytes T et B Atténue l inflammation dans la SEP Diminue l activité de la maladie dans la SEP The exact active mechanism of alemtuzumab is unclear. 1. Fox EJ. Expert Rev Neurother 2010; 10(12):1789-1797; 2. Jones JL et al. Brain 2010:133(pt 8); 2232-2247; 3. Cox AL et al. Eur J Immunol 2005;35(11); 3332-3342; 4. Données internes de Genzyme/sanofi, Cambridge, MA. Annual Relapse Rate (Main Coparameter) 0.6 CARE-MS I IFNß-1a sc 0.7 Relapse reduction: 54.9% p<0.0001 Alem. 12 mg 0.6 CARE-MS Il 0.7 Relapse reduction: 49.4% p<0.0001 Adjusted ARR (95% CI) 0.5 0.4 0.3 0.2 0.1 0.39 0.18 0.754 Adjusted ARR (95% CI) 0.5 0.4 0.3 0.2 0.1 0.52 0.26 0.754 0 Years 0 2 0 Years 0 2 Alem.=alemtuzumab; ARR=annual relapse rate; CI= confidence interval; IFNß-1a s.c.=interferon beta-1a subcutaneous 1. Coles AJ et al. ECTRIMS 2011; 2. Cohen JA et al. AAN 2012. 9
Common Side Effects of Lemtrada Most patients treated with Lemtrada experience side effects during the infusion or within the next 24 hours For most people, reactions are mild, but severe reactions may occur Your health professional can prescribe medications to help limit Lemtrada s side effects, including: Methylprednisolone (1,000 mg) for the first three 3 days of each cycle Acyclovir (200 mg) twice a day or the equivalent the first day of each cycle and for at least 1 month Antihistamines and/or antipyretics Reserved for the use of Canadian health professionals Common Side Effects of Lemtrada The most common side effects of Lemtrada are: Headaches and dizziness Skin rash, hives and itching Fever Nausea and vomiting Difficulty sleeping Lemtrada Safety: Autoimmune Side Effects Serious and fatal autoimmune conditions have arisen during clinical trials and after 5 years of follow-up Autoimmune side effects are disorders that occur when the organism is attacked by its own immune system Lemtrada may cause your immune system to attack parts of your body, including blood, thyroid and kidneys. Lemtrada s serious autoimmune side effects may include: Idiopathic thrombocytopenic purpura (ITP causing a low blood platelet count): serious but diagnosable and treatable, < 1 % Thyroid disorders, always treatable, approximately 19% Kidney disease: serious, 0.3% Other blood disorders (in rare cases) Reserved for the use of Canadian health professionals 10
DRUGS IN PILL FORMAT Gilenya (Fingolimod) HO HO NH 2 Gilenya (Fingolimod) S1P1 receptor inhibiter Active mechanism Redistributes lymphocytes from blood to lymphatic organs. Penetrates the CNS, acts on neurons. Possible direct regenerative effect on oligodendrocytes Administration Oral pill 0.5 mg, once a day Horga A, Montalban X. Expert Rev Neurotherapeutics. 2008; 8:699 714 Blood FTY720 Inhibits Lymphocyte Transmigration out of Lymph Nodes Efferent Lymph Normal Lymphocytes circulate freely between blood and the efferent lymph Blood Lymph Node The lymph node s endothelial barrier allows lymphocytes to transmigrate out of the node Efferent Lymph FTY720 Lymphocytes remain trapped in the lymph node when the endothelial barrier constricts Lymph Node Restriction of the endothelial barrier by continuous FTY720 stimulation of the S1P 1 receptors in the node s endothelium prevents lymphocyte migration out of the nodes. 11
Annual Relapse Rate 0.4 0.3 0.2 0.1 FREEDOMS (phase III study) Main Criterion: Annual Relapse Rate 54% vs 60% vs placebo placebo p < 0.001 p < 0.001 0.40 0.18 0.16 0 Placebo (n = 418) Fingolimod 0.5 mg (n = 425) Fingolimod 1.25 mg (n = 429) ARR was also reduced both in patients never treated and in patients who previously took an IMD (p < 0.01 for all comparisons) ITT Population Binomial regression model adjusted by treatment group, country, number of relapses in the previous two years and for EDSS at onset ARR, annual relapse rate; IMD, immunomodulator Fingolimod Side Effects Fingolimod may: Cause a reversible bradycardia (3.5% v. 1.0% with placebo) We must observe all patients for 6 hours after the first dose Cause macular edema (0.4% v. 0.1% with placebo) We must perform an ophthalmic evaluation 3 to 4 months after beginning treatment Footnote: UO = Undesirable occurrence; VZV = varicella zoster virus Health Canada Drug Product Database Available at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php Consulted on April 1, 2011 EI = événement indésirable; VZV = virus varicelle-zona Santé Canada. Base de données sur les produits pharmaceutiques. Disponible au : http://webprod.hc-sc.gc.ca/dpd-bdpp/language-langage.do?url=t.search.recherche&lang=fra. Consulté le 1 er avril 2011. Fingolimod Side Effects Increase in liver enzymes (3.3% v. 0.2% with placebo) We must monitor transaminase and bilirubin levels before treatment every three months during the first year and periodically thereafter Slight increase in the risk of lower respiratory infections (0.5% v. 0.2% with placebo) and herpes virus (8.7% v. 7.9% with placebo) We need to check the CBC and VZV serostatus before starting treatment 12
FREEDOMS (phase III) Security : Summary Cardiovascular Bradycardia was frequent, but usually asymptomatic, transient and self-limiting Atrioventricular blocks were uncommon, usually asymptomatic, transient and self-limiting Both events were seen following administration of the first dose of fingolimod A mild increase (1-3 mmhg ) in blood pressure was observed Infections Overall incidence of infections, including herpesvirus infections, was similar in all three groups Lower respiratory tract infections (bronchitis and pneumonia) occurred more frequently in the fingolimod groups compared with placebo The reduction in peripheral lymphocyte count was not associated with an increase in infections Macular edema 7 cases reported, all in the fingolimod 1.25 mg group The majority occurred within the first 3 months of treatment and resolved after study drug discontinuation Neoplasms Malignant neoplasms reported in 4 patients receiving fingolimod 0.5 mg, 4 patients receiving fingolimod 1.25 mg, and 10 patients in the placebo group The study findings do not suggest an increased risk of cancer with the use of fingolimod S1P 1, sphingosine 1-phosphate receptor subtype 1 DRUGS IN PILL FORMAT Tecfidera (dimethyl fumarate) BG 12: Define Study BG 12/dimethyl fumarate (new generation) Neuroprotection and anti-inflammatory effects Activates the Nrf2 transcription factor pathway that has neuroprotective effects (stimulates the Antioxidant Response Element pathway) Inhibits some cytokines and adhesion molecules 13
Capsules containing tiny enterosoluble DMF pills Monomethyl Fumarate (MMF) Dimethyl Fumarate (DMF) and the Fumarates Fumaric Acid Dimethyl Fumarate Dawson K et al. Presented at CMSC; May 27 30, 2009; Atlanta, GA, USA. S71. 40 H Fumaric acid is a natural molecule, essential for oxidative respiration (Krebs/citric-acid cycle). Dimethyl fumarate is formulated as oral, enterosoluble microcrystals contained in a capsule. Dimethyl fumarate is quickly converted presystemically into monomethyl fumarate (MMF). DEFINE (Determination of the Efficacy and Safety of Oral Fumarate IN RElapsing-Remitting MS) Phase III randomized, double-blind, placebo-controlled clinical trial: 2 years, multisite, 1234 patients Assessed the efficacy and safety of BG-12 compared to placebo in patients with remitting-relapsing MS 2 BG-12, 240 mg twice daily (BID) and 3 times daily (TID) reduced: Risk of attack by 49% and 50%, respectively (P<0.0001) Annual relapse rate was 53% and 48% (P<0.0001) Disability progression was 38% (P=0.0050) and 34% (P=0.0128) BG-12 significantly reduced lesions on MRI after 2 years (MRI group): Gadolinium-enhancing (Gd+) lesions New/expanding T2 lesions New T1 hypointense lesions 2 Gold et al. ECTRIMS 2011 (oral presentation #95). Integrated Analysis: Annual Relapse Rate and Percentage of Relapsed Patients DMF bid=43% reduction of risk, P 0.0001 DMF tid=47% reduction of risk, P 0.0001 0.437 49% reduction vs placebo P 0.0001* 49% reduction vs placebo P 0.0001* 0.280 0.251 Placebo DMF bid DMF tid BL Study Time (weeks) 42 Integrated ITT population; only relapses confirmed by the INEC are included in the analysis. *P value based on Poisson regression (due to underdispersion using negative binomial distribution) adjusted for baseline EDSS score ( 2.0 vs >2.0), study, region, number of relapses in the 1 year prior to study entry, and baseline age (<40 vs 40 years); P value based on Cox proportional hazards model; Kaplan-Meier estimate of the proportion of subjects relapsed within 2 years. Gold R et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. S151. 14
GI Adverse Effects in the First 3 Months of Treatment with 240 mg BID Adverse Effects. chez 769 patients. Abdominal Pain Nausea/ Vomiting Diarrhea All cases, n 121 120 78 Severity, n (%) Slight Moderate Severe 68 (56) 42 (35) 11 (9) 65 (54) 49 (41) 6 (5) 49 (63) 26 (33) 3 (4) Symptom therapy n (%) 46 (38) 39 (33) 20 (26) Resolved, n (%) 113 (93) 114 (95) 75 (96) denominator for percentages; patients may have experienced more than one event; events may have resolved at any time during the study. GI events included the preferred terms in the level 2 subordinate standardized MedDRA queries gastrointestinal nonspecific inflammations or gastrointestinal nonspecific symptoms and therapeutic procedures. Bar-Or A et al. Presented at Latin-American Congress of Multiple Sclerosis; November, 28 30, 2012; Rio de Janeiro, Brazil. 43 44 Conclusions Dimethyl fumarate mainly acts via the Nrf2 pathway, which governs antiinflammatory and cytoprotective responses to oxidative stress. Efficacy results for DMF bid and tid were largely comparable. Compared to placebo, DMF bid significantly reduced disease activity, clinically and on MRI, and improved quality-of-life parameters. All causes considered, the incidence of serious or less serious adverse effects and stopping medication because of adverse effects were similar for the both the placebo and DMF groups. However, the most noteworthy adverse effects of the drug were flushing on the face and arms with itching and gastrointestinal events. Incidence peaked in the first months of the study, then decreased. Adverse effects were mostly considered slight or moderate; only 3% and 4%, respectively, of patients stopped the treatment because of flushing and GI symptoms. Nrf2=nuclear factor (erythroid-derived 2)-like 2; Keap1=kelch-like ECH-associated protein. Linker RA et al. Brain. 2011;134:679-692; Scannevin R et al. J Pharmacol Exp Ther. 2012;341:274-284. Fox R et al. N Engl J Med. 2012;367:1087-1097; Gold R et al. N Engl J Med. 2012;367:1098-1107; Gold R et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. S151; Kappos L et al. Presented at AAN; March 16 23, 2013; San Diego, CA. S41.005; Kita M et al. Presented at AAN; March 16 23, 2013; San Diego, CA. P07.092; Havrdova E et al. Presented at AAN; March 16 23, 2013; San Diego, CA. P07.106; Selmaj K et al. Presented at ECTRIMS; October 10 13, 2012; Lyon, France. P484 DRUGS IN PILL FORMAT Teriflunomide (Aubagio) 15
Teriflunomide Active mechanism Administration Clinical studies Inhibits proliferation of rapidly dividing cells by inhibiting pyrimidine synthesis. Possible preference for T cells Oral pill once a day:14 mg TENERE (vs Rx44); TOPICS (SCI study); TEMSO; phase III placebocontrolled study; Phase II GA additive and IFN additive Studies ended ~ 2012 Tallantyre E et al. Int MS J. 2008; 15:62 8 Not approved by Health Canada AUBAGIO MD (Teriflunomide) Active Mechanism in MS According to research, AUBAGIO acts differently from other current MS treatments AUBAGIO blocks reproduction of overactive immune cells that may be responsible for inflammation in MS For illustration only. The exact active mechanism in AUBAGIO s therapeutic effect in MS is unknown. Reference: AUBAGIO Monograph. USE RESERVED FOR HEALTH PROFESSIONALS 47 Efficacy of AUBAGIO MD (teriflunomide): Annual Relapse Rate Clinical Trial 1: TEMSO Relapse rate decreased 31% in patients receiving a 14-mg dose of AUBAGIO, compared to controls. Clinical Trial 2: TOWER Relapse rate decreased % 36% in patients receiving a 14-mg dose of AUBAGIO, Reduction of relapses compared to controls. Reference: AUBAGIO Monograph. USE RESERVED FOR HEALTH PROFESSIONALS 48 16
Efficacy of AUBAGIO MD (teriflunomide): Number of New Lesions Clinical Trial 1: TEMSO The 14-mg dose of AUBAGIO reduced the number of brain lesions by 80% compared to placebo 1. AUBAGIO Monograph. USE RESERVED FOR HEALTH PROFESSIONALS 49 Most Frequent Adverse Effects of AUBAGIO MD (teriflunomide) Adverse effects in 5% of patients reported with 14 mg AUBAGIO at a rate 1% higher than placebo AUBAGIO 14 mg Adverse Effects (n = 786) Infections and Infestations Flu 9.2% Sinusitis 6.0% Placebo (n = 806) 7.4% 3.8% Blood and lymphatic system disorder Neutropena 6.9% 1.6% Nervous system disorder Paresthesia 8.4% 7.1% Gastrointestinal events Diarrhea (caused dropouts: 0.3%/0.8% in TEMSO/TOWER trials) Nausea Upper abdominal pain 14.4% 12.3% 5.6% 7.8% 7.8% 4.3% Skin and subcutaneous tissue Alopecia (caused dropouts: 1.4%/1.6% in TEMSO/TOWER trials) Acne 14.1% 5.0% 4.3% 3.3% Tests and analyses Elevated alanine aminotransferase levels (caused dropouts: 2.2 %/2.4 % in TEMSO/TOWER trials) This list of adverse effects is not exhaustive. For any unexpected effects that occur during treatment with AUBAGIO, contact your physician or MS One on One program nurse. 14.0% 7.7% 50 New Treatments 5 new treatments have appeared since 2010. In placebo-controlled studies and others using an active comparator, the results suggest, and in many cases confirm, greater efficacy for most of the new products. Aubagio, an oral treatment, is as effective as the first generation treatments. The adverse-effect profiles of the new drugs are very different from the previous drugs and require different monitoring, in some cases much more intensive. Given these differences, every drug must be prescribed after appropriate education and discussion with the health care team, and based on the disease type and severity, previous treatments, comorbidities, lifestyle, preferences, refunds, etc. 17
Summary In recent decades, tremendous progress has been made in MS research but much remains to be done. Challenges: the cause(s), control of all forms of the disease, the cure?, rehabilitation, remyelination, stem cells, prevention Since1995, 12 basic treatments have been introduced and progress continues Thank You 18