Current and Emerging Therapies Presented by: Dr. Kathryn Giles, MD - - PowerPoint PPT Presentation

Progress in MS: Current and Emerging Therapies

Presented by:

• Dr. Kathryn Giles, MD MSc FRCPC

The MS Society gratefully acknowledges the grant received from Biogen Idec Canada, which makes possible the Progress in MS: Current and Emerging Therapies session. The MS Society does not approve, endorse or recommend any specific product or therapy but provides information to assist individuals in making their own decisions.

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Today’s Discussion

• Treating MS
• Management of the Disease
• Questions & Answers

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Neuronal Damage Begins Prior to Clinical Presentation

Time (Years) Clinical Symptoms

Clinical Threshold Axonal Loss Demyelination

Clinically Isolated Syndrome

First Clinical Attack

Relapsing Remitting Secondary Progressive 3

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MS: Brain Volume and MRI Changes

Adapted from Goodkin DE. UCSF MS Curriculum. January 1999

Preclinical Relapsing Remitting Secondary Progressive C. I. S.

Time (Years)

Brain volume Relapses and Impairment MRI Burden of Disease

New lesions C.I.S., clinical isolated syndrome 4

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Disease Progression

• Over 20-25 years, 80-85% of MS will

progress from CIS to relapsing-remitting MS to secondary progressive MS

• IT IS IMPORTANT TO TREAT EARLY

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TREATING MS

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MS Treatment Requires a 3-Pronged Approach

• 1. Management of acute attacks
• 2. Management of symptoms
• 3. Management of underlying disease

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Management Options for Acute Attacks

Steroids

• I.V. (methylprednisolone 1 g daily x 3-5 days)
• High-dose oral (prednisone 1250 mg daily x 3-4 days)

Steroids do not alter course of MS; only the duration and severity of that attack

Morrow SH et al. Neurology 2004;63(6):1079-80.

Either is acceptable1 – Choice depends on regional facility and physician preference

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Management of Symptoms

• Depression
• Spasticity
• Bladder and bowel
• Pain
• Fatigue
• Mobility
• Sexual dysfunction

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Fampyra

• New mobility drug
• Can be used in both relapsing and progressive MS
• Increases walking speed
• Other effects – energy, cognition, stamina, arm function
• 30% are super-responders, 30% some response, 30% no

response

• Determine effectiveness in 2 weeks
• Common side effects (affect between 1 and 10 in every 100

patients): – Feeling unsteady, dizziness (risk of falling), headache, feeling, weak and tired, difficulty sleeping, anxiety, tremor (minor shaking), numbness or tingling of the skin, sore throat, shortness of breath, feeling sick (nausea), being sick (vomiting), constipation, upset stomach, back pain

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MANAGEMENT OF THE DISEASE

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Management of Disease

• Goals of First Line MS Therapy (Avonex,

Betaseron/Extavia, Copaxone, Rebif, Aubagio, Tecfidera)

– Reduce the frequency, severity and duration of relapses – Preserve cognitive function – Slow or delay accumulation of disability due to disease progression – Prevent development of new lesions as seen on MRI scans – Keep people with MS functioning normally

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Injectable First Line Therapy

• Avonex (interferon beta-1a), Betaseron

(interferon beta-1b), Copaxone (glatiramer acetate), Extavia (interferon beta-1b), Rebif (interferon beta-1a)

– Comparable effectiveness (30% reduction in relapse frequency and severity; 80% reduction in MRI activity; modest slowing of disability progression) – Differences in side effects and injection frequency – Choose according to lifestyle, and patient choice – Safe and years of experience

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Tecfidera: New Oral First Line Therapy

Tecfidera (BG-12; dimethyl fumarate)

• Oral

– Two pills, twice daily (120 mg) for a total of 480mg/day – One pill, taken twice daily (240 mg) for a total of 480mg/day

• Side effects in first month of treatment include flushing,

diarrhea, abdominal cramping, nausea

• Minimal monitoring
• Good early safety data
• Likely as (or more?) effective than standard injectable

drugs (49% relapse rate reduction; 90% reduction in MRI activity; slows disability progression over 2 years; reduction in brain atrophy; comparator arm with Copaxone in CONFIRM)

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– Daily oral agent, 14 mg pill once daily – Has recently obtained first line approval – Easy to use, easy to monitor and well-tolerated – Hair thinning, nausea, diarrhea – Possible effect on the developing fetus – women and men must use contraceptives – Need for washout if pregnancy or drug switch – Liver toxicity but otherwise good early safety – Effective (approximately equal to injectable DMT; 31% ARR reduction; 20% disability progression)

Second New Oral: Aubagio (teriflunomide)

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Second Line Therapies

Tysabri (natalizumab)

• Monthly infusion
• $$$$$, limited access
• PML (new JC virus testing and now titre

testing) – we can now manage risks

• Effective (68% relapse rate reduction; 90%

MRI activity reduction; slows disability progression)

• Well-tolerated

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Second Line Therapies

Gilenya (fingolimod)

• Daily oral agent
• $$$$, limited access
• Significant need for monitoring – macular

edema, cardiac, dermatalogic

• Effective (54% ARR reduction; 30%

progression; robust MRI effect)

• Immunosuppressant
• Limited safety data (varicella, zoster, macular

edema, cardiac effects, PML, malignancies)

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Second Line Therapies

Just Approved: Lemtrada (alemtuzumab)

– IV – human monoclonal antibody – Very easy to give – first treatment course is administered by intravenous infusion on five consecutive days, and the second course is administered on three consecutive days, 12 months later – Highly effective c/w Rebif 44 (68% reduction in relapse rate; decreased MRI activity and brain atrophy; trend to decreased disability) – Seems to have sustained benefit at three years in extension trials – Immunosuppressant – don’t know how long effects last – no way to reverse – Long-term monitoring required – ITP, serious infection, thyroid, kidney

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Pipeline: 1-3 Years

• Pegylated Interferon

– Monthly or bi-monthly injections – Similar effectiveness to Avonex

• Lingo

– May help remyelination and reverse previous injury

• Daclizumab

– Another monoclonal antibody – Infrequent IV injections

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• Disease Factors

— Severity of clinical disease (number and severity of attacks, EDSS score, cognitive function) — Appearance of MRI — Risk factors (age, gender) — Failure of first line DMT

• Patient Factors

— Age, gender, other health issues — Preference, lifestyle — Extended health plan, employment issues — Risk tolerance

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This Neurologist’s Approach to DMT: Old and New

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• Older DMT as First Line Therapy

— Young — Female, wanting to have children — Mild disease, and relatively inactive MRI — No extended health benefits — Risk averse

• New Orals as First Line Therapy

— Older, Males — More severe disease – Tecfidera over Aubagio — Preference, lifestyle, injection phobia — Extended health plan, employment issues — Risk tolerance

This Neurologist’s Approach to DMT: Old and New

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Realistic Treatment Expectations for All DMT, Both Old and New

• DMTs may:

— Delay progression to CDMS — Reduce the number and severity of acute attacks — Preserve ability to work, drive, and maintain and enjoy social relationships, leading to an improved quality of life — Slow down disease progression

• DMTs will not:

— Cure MS — Eliminate MS symptoms — Reverse existing damage to the CNS — Completely eliminate future disease

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Food For Thought:

• Orals:

— No more injections!!!!

• But:

— No DMT will cure MS or eliminate MS symptoms — We cannot compare agents one with another because of the design of clinical trials ( are new agents truly better?) — First line injectable therapies have over 20 years of safety data, and we understand the risks of adding in second line drugs when first line therapy fails — New agents have unknown risks

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THANK YOU