Current and future options of MS treatment Prof. Dr. Karl Vass, AKH Wien

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1 Current and future options of MS treatment Prof. Dr. Karl Vass, AKH Wien European Health Forum, Gastein 6 th October 2010

2 Multiple Sclerosis is the most common neurological disorder in young Caucasian adults 1 MS is a chronic autoimmune disease of the CNS MS affects up to 2.5 million people worldwide 1 Caucasians are at greater risk 2 60 to 140 per 100,000 for Northern EU, USA, Canada, Australia and New Zealand 100 per 100,000 in Austria up to 20 per 100,000 in Central and South America 5 per 100,000 in Asia Women are up to three times as likely to develop MS as men 3 MS generally affects people in the prime of their life onset typically begins between 20 to 40 years of age 4,5 Global prevalence of MS per 100,000 population 2 CNS, central nervous system; MS, Multiple Sclerosis 1. World Health Organization. Neurology atlas, 2004; 2. World Health Organization. Multiple sclerosis resources in the world atlas, 2008; 3. Whitacre CC et al. Science 1999; 4. Noseworthy JH et al. N Engl J Med 2000; 5. Confavreux C et al. Brain 1980

3 Multiple Sclerosis has a devastating impact on those affected MS is a chronic autoimmune disease associated with demyelination, axonal loss and progression of disability. Without treatment 50% of all patients are expected to need a cane to walk 10 to 15 years after onset of MS 1,2 50% of patients with progressive disease will need a cane to walk after only 5 years from onset 1,2 Cognitive ability may deteriorate early in the course of the disease, which has important implications for the employment prospects of patients with MS 3 6 MS is often associated with fatigue, pain, depression and anxiety 7 These co-morbidities often go unrecognized but are associated with significant health distress and contribute to patients fear regarding their future health and abilities 7 MS, Multiple Sclerosis 1. Confavreux C et al. Brain 1980; 2. Weinshenker BG et al. Brain 1989; 3. Achiron A and Barak Y. J Neurol Neurosurg Psychiatry 2003; 4. Rao SM et al. Neurology 1991; 5. Julian LJ et al. J Neurol 2008; 6. Rieckmann P. J Neurol 2004; 7. White CP et al. J Neurosci Nurs 2008

4 Multiple Sclerosis is a progressive disease with distinct stages

5 Multiple sclerosis leads to loss of myelinsheaths normal myelin myelin loss (demyelination)

6 Normal function of the nervous system Neuron Axon Synapse

7 Functional consequences of demyelination and axonal destruction intact myelin and intact axon impaired myelin yet intact axon destructed myelin and destructed axon

8 Approved DMTs for Multiple Sclerosis are all administered parenterally Agent Dosage Method Frequency* Betaseron (IFN beta-1b) 250 µg SC injection Every other day Avonex (IFN beta-1a) 30 µg IM injection Weekly Copaxone (glatiramer acetate) 20,000 µg SC injection Daily Mitoxantrone 12,000 µg/m 2 IV infusion Every 3 months Rebif (IFN beta-1a) 22 or 44 µg SC injection 3 times per week Tysabri (natalizumab) 300,000 µg IV infusion Every 4 weeks Extavia (IFN beta-1b) 250 µg SC injection Every other day DMT, disease-modifying therapy; IFN, interferon; IM, intramuscular; IV, intravenous; SC, subcutaneous *In USA only 8

9 Troublesome adverse effects of DMTs IFN beta is associated with flu-like symptoms following injection up to 75% of people will experience fever, headaches, fatigue, chills or arthralgia at some time point during treatment generally, flu-like symptoms subside over time although arthralgia and fatigue following injection can persist Injection-site reactions are very common >50% of patients receiving IFN beta will experience skin redness, local induration and pain, which tends to recover within days, but may also lead to skin necrosis up to 16% of patients receiving glatiramer acetate will experience injection-site reactions including pain, skin redness, pruritus, inflammation or lipoatrophy Injection site necrosis Injection site reaction Natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML) Mitoxantrone is associated with cardiotoxicity and acute leukaemia Injection site atrophy DMTs, disease-modifying treatments; IFN, interferon Walther EU and Hohlfeld R. Neurology 1999; Calabresi PA. Neurology 2002; Takahashi K. JMAJ 2004; Ellis R and Boggild M. Mult Scler 2009; Galetta SL and Markowitz C. CNS Drugs 2005; Johnson KP. Neurology

10 Unmet needs in multiple sclerosis New treatments that Have improved efficacy and are well tolerated Target both inflammation and neurodegeneration; promote remyelination and repair Are conveniently administered Are effective in PPMS Treat the chronic symptoms of MS, particularly fatigue Improve patient adherence Increased recognition of co-morbid and chronic symptoms that affect QoL In MS, there is a need for... Individualized treatment Biomarkers for disease progression and treatment response Greater understanding and discussion of patient perceptions Greater interactions between patients, physicians, caregivers and other medical staff Better techniques for early diagnosis MS, Multiple Sclerosis; PPMS, primary progressive Multiple Sclerosis; QoL, quality of life 10

11 There is a need for Multiple Sclerosis treatments that can be administered orally All currently approved disease-modifying therapies are administered parenterally long-term injection therapies impose a burden on patients and may lead to reduced compliance 1 skin reactions to injectable disease-modifying therapies are relatively common and include exacerbation of underlying skin disease 2,3 difficulties with self-injection (e.g. inability to self-inject) are common 5,6 patients may suffer from fear of injections 1. Cohen BA and Rieckmann P. Int J Clin Pract 2007; 2. Samuel L and Lowenstein EJ. J Drugs Dermatol 2006; 3. Johnson KP et al. Neurology 1995; 4. Frohman EM et al. Mult Scler 2004; 5. Cox D and Stone J. J Neurosci Nurs 2006; 6. Mohr DC et al. Mult Scler

12 Conclusions DMTs represented an important therapeutic advance, as they were the first drugs to modify the course of MS Current (typically first-line) DMTs are administered parenterally, from once-daily to once-weekly main effect is reducing the incidence of relapses (~30% vs placebo), but the effect on delaying disease progression is less clearly shown are associated with a number of drug-specific side-effects including flu-like symptoms and injection-site reactions Natalizumab (typically a second-line DMT) reduces the incidence of relapses (68% vs placebo) and delays the progression of disability. It is associated with an increased risk of PML (actuarial incidence: 1 in 1000) Hence, there is a need to Improve EFFICACY Improve TOLERABILITY Improve CONVENIENCE Identify new MODES of ACTION In general, an improved balance between efficacy and safety is required DMTs, disease-modifying treatments; MS, Multiple Sclerosis; PML, progressive multifocal leukoencephalopathy Noseworthy et al. N Engl J Med 2000; Compston and Coles. Lancet 2002; Polman CH and Uitdehaag BM. Lancet Neurol 2003; Kappos L et al. J Neurol

13 Future directions Introduction of new therapies that: have significantly greater efficacy with manageable safety are neuroprotective and promote endogenous repair can be administered in convenient regimens, e.g. orally treat primary progressive multiple sclerosis (PPMS) improve compliance and adherence preserve immuno-competence Identification and validation of a simple, practical, reproducible and inexpensive biomarker Methods of diagnosing and treating MS associated symptoms such as fatigue, cognitive impairment and depression Provision of support functions for all patients 13

14 Many novel Multiple Sclerosis products are anticipated to be launched in the near future and beyond Oral fingolimod (S1P receptor modulator) BG-12 (dimethyl fumarate) Teriflunomide (pyrimidine synthesis inhibitor) Ocrelizumab (anti-cd20) Alemtuzumab (depletion of CD4+ and CD8+ T cells) Pegylated interferon beta-1a (immunmodulator) Firategrast (alpha-4 integrin antagonist) Laquinimod* (immunoregulatory drug) Daclizumab (anti-cd25, increase natural killer cells) Ofatumumab (anti-cd20) Cladribine (antineoplastic purine analogue) BAF (S1P receptor modulator) MS vaccines Oral drug submitted TV-1102 (antisense inhibitor of CD49d) PI-2301 (immunomodulatory drug) Phase III (relapsing MS) Phase II (relapsing MS) Rituximab (anti-cd20) *Exact mechanism of action not yet elucidated. Note timing estimates for product approval are based on clinical trial data from clinicaltrials.gov and standard industry assumptions in MS development MS, Multiple Sclerosis; S1P, sphingosine 1-phosphate

15 Future directions Elucidation of the pathogenesis of MS and its sub-types may offer unique perspectives for development of new therapies Therapies with new mechanisms of action / routes of administration are hoped to improve the balance between efficacy, convenience and safety / tolerability New therapies will aim to decrease the burden of administration-related adverse events and / or anxiety Well-tolerated disease modifying drugs that delay the progression of disability will represent a significant advance in the treatment of MS The ultimate goal of drug development for MS remains the identification of compounds that reverse underlying disease pathology MS, Multiple Sclerosis