Multiple Sclerosis Disease Modifying Therapies Update

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Practical Controversies in MS

Lucas McCarthy, MD, MSc Neurologist, Director MS Center Practical Controversies

How to approach common questions in the gray-zone of evidence- based practice?

Open cell phone or laptop to following link to participate in live questions

https://pollev.com/MSsummit

Practical Controversies in MS

• Misdiagnosis of MS

• Vitamin D testing / supplementation

• Use of complimentary / experimental treatments

• Treatment of Progressive MS

Updated 2017 McDonald MS Diagnostic Criteria

Easier to diagnosis = Easier to misdiagnose?

Lesions: ≥ 2 characteristic lesions (≥3mm) in ≥ 2 different locations

Symptoms: objective clinical evidence of at least 1 lesion

Relapse: ≥ 1 characteristic clinical attack

Changes over Time: ≥2 CSF Oligoclonal bands or >1 attack over time or new lesions over time (including enhancing and non-enhancing)

*No other reasonable diagnosis

Using 2017 Criteria compared with 2010 MS Criteria:

23-27% more patients diagnosed with MS at first attack

Previously needed to wait until MRI change or second attack Can make MS diagnosis easier now with 1st Attack and 1st MRI Earlier Diagnosis, Earlier Treatment, Lower Future Disability

© 2016 Virginia Mason Medical Center ECTRIMS 2018. Abstracts 139-142, presented October 11, 2018. Multiple Sclerosis Differential Diagnosis ExcludeAutoimmune Others:Infectious DiseasesGenetic that Mimic OtherMS Neurologic: HIV CADASIL Neoplasm (Glioma, Lymphoma) - Multiple Sclerosis Lyme MELAS Vitamin B12 or Copper deficiency - Neuromyelitis Optica Syphilis Neurofibromatosis Thiamine (B1) Deficiency - Autoimmune Encephalitis PML Porphyria Vascular Malformations - ADEM Tuberculosis Friedrich’s Ataxia Medication Effects (TNF-alpha) - Susac’s Syndrome Neuro-cysticercosis SCA Migraine Headache - Hashimoto’s Encephalitis Coccidiomycosis ALS / Motor Neuron Disease - CLIPPERS Cryptococcus Adult Onset Leukodystrophy: Compressive Myelopathy - CRION Brucellosis - Adreno-Leukodystrophy SSPE - Metachromatic Vascular: Systemic: HHV6 - Alexander’s Disease - Stroke - SLE (Lupus) Whipple’s Disease - Krabbe’s Disease - Amyloid Angiopathy - APS - Granulomatous Vasculitis - Sjogren’s - Primary CNS Angiitis - Sarcoidosis - Moya-Moya Disease - Behcet disease - Celiac disease Infiltrative: - Paraneoplastic - Langerhan’s Cell Histiocytosis - Lymphomatoid Granulomatosis - Erdheim-Chester Disease - HLH

Caution on Overdiagnosis for the sake of giving an answer:

“My radiologist said it could be MS”

“My symptoms fit perfectly with MS”

”I just want an answer…”

754 consecutive patients referred to an MS Center in the Netherlands:

67 % - MS or Probable MS (52% Definite, 15% Probable MS) 23 % - No Certain Diagnosis 7.7 % - Other Neurologic Disease • 2.2 % Ischemic Cerebrovascular Disease • 0.5 % Vasculitis • 0.4 % Multi-System Atrophy 1.3% - Other Demyelinating Disease

18% Misdiagnosed with MS on second opinion

Previously diagnosed MS patients did not fit criteria for MS when seen for second opinion at an MS specialty center (UCLA / Cedars- Sinai) Other Diagnosis: 1. Migraine headache (most common) 2. Radiologically Isolated Syndrome (RIS) 3. Cervical spinal stenosis 4. Peripheral Neuropathy 5. Optic Neuropathy © 2016 Virginia Mason Medical Center Kaisey et al. ECTRIMS 2018 MS Conference

Vitamin D and Multiple Sclerosis Vitamin D and MS

Cohort Evidence Low Vitamin D serum levels associates with increased prevalence of MS, MRI lesions and relapses in RRMS

“Correlation does not equal Causation”

Just because something is associated, does not make it causal.

Low Vitamin D levels also correlate with risk for: • Colon cancer, Breast cancer, Prostate cancer, Type 1+2 Diabetes; Cardiovascular Disease; Dementia; Osteoperosis; Depression; Schizophrenia; Rheumatoid Arthritis

Normal Vit D

50 nmol/L = Low Vit D 20ng/mL

BENEFIT trial. early or delayed start of interferon beta-1b.

Each 10 ng/mL higher Vit D level was associated ~32% reduced risk of a subsequent contrast-enhancing lesion over 5 years (IRR=0.68, 95% CI [0.54, 0.86], p=0.001)

Vitamin D has anti-inflammatory actions in vitro1 - enhanced Th2 and decreased Th1 cytokine production - dendritic cell effects - enhanced macrophage phagocytosis

In experimental autoimmune encephalitis (EAE)2 • pre-induction treatment prevents disease development • Post-induction treatment ameliorates disease activity

Genetic association of SNPs with Vitamin D and MS

1Smolders et al. Neuroimmunol 2008 2Vieth R. Am J Clin Nutr 1999

Prior lower dose trials did not show significant benefits

Larger trials have been and are being done

Lets look at some – trend toward benefit, low risk for harm

Largest high dose Vitamin D trial to date: SOLAR trial: Smolders et al. “Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a”. ECTRIMS 2016

229 MS patients Taking Interferon β-1a sc already Age 18 - 55 Vitamin D levels < 150nmol/ml (60ng/ml) Randomized to 14,000IU D3 (VigantOL Oil) vs. placebo 48 Weeks duration *reported but unpublished

Poor recruitment – reduced study duration from 96 to 48 week *Primary Endpoint: % Disease Activity Free (NEDA) No relapses, no EDSS progression, no new or enhancing lesions

Vitamin D3 Placebo Endpoint 14,000 Difference P Value (n = 116) (n = 113) *Disease 37.2 35.3 1.9% 0.912 Activity Free (%) Relapse Free (%) 78.8 75.0 3.8% Annualized 0.28 0.41 31.7% 0.165 Relapse Rate New/Active MRI 1.09 1.49 32% 0.0005 Lesions (mean) Results Reported : https://clinicaltrials.gov/ct2/show/results/NCT01285401

Camu et al. Cholecalciferol supplementation in relapsing multiple sclerosis patients treated with subcutaneous interferon beta-1a: a randomized, controlled trial. ECTRIMS 2016. Abstract P750

129 pts, randomized placebo controlled trial; 2 year duration 100,000IU D3 q2 weeks (7,143IU / day) + IFNB-1a

No significant benefit for Relapses (ARR 0.34 vs. 0.45, p = 0.38)

Subgroup analysis: per protocol, completers (90 out of 129): - ARR reduction – RR 0.40, p = 0.011 - New T2 lesions – RR 0.23, p < 0.001 *reported but unpublished - New T1 lesions – RR 0.22, p = 0.001 © 2016 Virginia Mason Medical Center data Vitamin D Supplementation Trials

Koduah et al. Vitamin D supplementation in multiple sclerosis: primary efficacy endpoint and safety of a randomized, controlled, double-blind phase II trial (EVIDIMS). ECTRIMS 2018.

EVIDIMS trial - German multicenter RCT

Patients: 53 pts with CIS or MS on IFNB-1b

Intervention: equivalent to 10,200 IU vs. 200 IU D3 Daily x 18mo

Primary Outcome: New T2 lesions – no significant difference

*reported but unpublished

Jagannath VA et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev. 2018 Sep 24

12 RCTs including 933 subjects in years 2010 – 2017 *included SOLAR trial

464 in vitamin D group, 469 in comparison groups

No Significant Differences:

Annualized Relapse Rate (ARR) - difference = -0.05 (-0.17 to 0.07) from five trials; 417 participants

EDSS – mean difference = -0.25, (-0.61 to 0.10) from five trials; 221 participants

MRI Gad enhancing lesions – difference = 0.02, (-0.45 to 0.48) two trials; 256 participants

1. Jagannath VA et al. Cochrane Database Syst Rev. 2018 Sep 24 “evidence suggests no benefit of vitamin D for patient‐important outcomes among people with MS”

2. McLaughlin et al. J Neurol. 2018 “No statistically significant difference was seen for any of the outcome measures. There were non-significant trends in favour of vitamin D for all outcome measures”

3. Zheng et al. Mult Scler Relat Disord. 2018 Jul “Our findings suggest that vitamin D appeared to have no therapeutic effect on EDSS score or ARR in the patients with MS.”

Meta-analysis Serious Adverse Events – difference = 1%, (-3% to 4%) Minor Adverse Effects – difference = 2%, (-2% to 6%)

Cost of Testing: Vit D-25(OH)- $96 (range $33 – $231)1

IOM Report 2011: • >4000IU D3 daily supplement not recommended • levels >50–60 ng/mL should be avoided • “are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly”

1Healthcarebluebook.com; Accessed 3/2019; 2NIH Office of Dietary Supplements © 2016 Virginia Mason Medical Center https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ Vitamin D Status Institute of medicine Endocrine society Vitamin D status “Deficient” – ≤ 20 ng/mL (≤ 50 nmol/L) “Insufficient” – 21–29 ng/mL “Sufficient” 20 ng/mL (50 nmol/L) ≥ 30 ng/mL “Ideal” – 40–60 ng/mL Considered “safe” – ≤ 100 ng/mL (≤ 250 nmol/L)

Daily vitamin D intake recommendations (upper limit recommendation) Children 600 IU/day (2500–3000 IU/day) 600–1000 IU/day (4000 IU/day) Adults 600 IU/day (4000 IU/day) 1500–2000 IU/day (10,000 IU/day) 800 IU/day for seniors

VIDAMS trial: Vitamin D to Ameliorate MS Ellen Mowry, MD at Johns Hopkins; Recruiting 2012 – 2019

Patients: 172 pts with RRMS; age 18 – 50, EDSS ≤ 4

Intervention: 600 IU vs. 5,000 IU D3 + Glatiramer Acetate

Primary outcome: Relapses

Secondary outcomes: MRI lesions, EDSS, brain volume, OCT, LCVA

Do not recommend supplements until more evidence - pros: saves costs and unnecessary supplementation - cons: risk ‘missing out’ on treatment if beneficial

’Blindly’ recommend supplements to all e.g. 2,000IU D3 daily (200% RDA for adults) - pros: saves costs of testing, possible benefits for multiple diseases - cons: unnecessary for those not deficient?, cost of supplements

Test Vitamin D levels and Supplement if lower than ’goal’ - pros: avoids unnecessary supplementation - cons: costs of labs (not covered) and supplements, unclear if

Off Label Use of Experimental Complimentary MS Disease Modifying Therapy Repairing / Preventing MS Damage?

Current MS Drugs prevent but do not likely help with repair damage or slow inactive degeneration

Many off-label medications and supplements have been studied

Some may recommend these therapies to their patients before tertiary studies are done

Off label medications or Supplements Under Investigation for MS Repair / Slowing Degeneration:

• Biotin • Clemastine • Simvastatin • Alpha Lipoic Acid

High dose Biotin (MD1003) for improvements in Progressive MS First trial in France in 154 patients, progressive MS, 12 month trial 12.6% had improvements in disability at 1 year 11.9% disability improvement at 1 year extension (PBO->Biotin)

Other Progressive MS Trials

Switched to MD1003 (Biotin) Worse Disability

Placebo group

MD1003 (Biotin) Group

100,000mcg Biotin (proprietary) TID vs. Placebo

Patients with primary or secondary progressive MS

Add on therapy to current stable Disease Modifying MS Medication

Typical dosing OTC – 5,000mcg Biotin Daily

Safety is good compared to placebo, can cause Blood Test Abnormalities (e.g. Thyroid studies, Troponin)

A repurposed non-prescription sedating anti-histamine (similar to Benadryl in mechanism of action)

Clemastine studied for repair of Optic Nerve damage in MS

A repurposed non-prescription anti-histamine for MS?

Clemastine studied for remyelination of Optic Neuritis in MS

Small Pilot Trial – 50 patients (25 on drug, 25 on placebo)

Small significant improvement in VEP electrical response (1.7ms speed improvement, average speed ~105ms)

Ongoing Larger trial - NCT02521311 ReCOVER Trial, 90 pts, Acute Optic Neuritis, Clemastine vs. Placebo 3 months of treatment, then monitoring for 9 months © 2016 Virginia Mason Medical Center Green et al. Lancet, 10/2017 Simvastatin for MS

MS STAT Trial N=140, SPMS 18-65 yrs old EDSS 4.0 – 6.5 no relapses or steroid use in 3 months No DMT use in last 6 months Simvastatin 80mg vs. Placebo

• Relative Brain Atrophy reduced by 43% vs. Placebo

• Absolute Brain Atrophy Rate reduced by 0.25%/year • 0.28% in Simvastatin vs. 0.58% in Placebo per year, p = 0.003

MS STAT2 Trial – ongoing (NCT03387670) 1180 patients, 40 vs. 80mg vs. Placebo x 35 months; no DMT use

SPMS aged 40–70 years

Enrolled in a single center, (OHSU)

2-year, double-blind, randomized trial

1,200 mg LA daily vs placebo

Annualized Brain Volume Loss

LA -0.21% Placebo -0.65%

COMPARISONS:

MS STAT Trial -0.28 % vs. -0.58%

FREEDOMS Trial -0.37% vs. -0.67% 68% reduction in annualized percent change in brain volume (slowed decline) © 2016 Virginia Mason Medical Center Spain et al. Neurol Neuroimmunol Neuroinflamm 2017 Use of Experimental Therapy

Ongoing placebo controlled clinical trials: • Biotin • Simvastatin • Alpha Lipoic Acid • Clemastine

Equipoise – uncertainty of differences, null hypothesis

Use of off-label therapies outside of clinical trials

Treatment of Secondary Progressive MS

*timely updates Treatment of Secondary Progressive MS

Secondary Progressive MS Progression of clinical disability from MS unrelated to clinical relapses after an initially relapsing course

Differentiate progressive MS in two groups:

ACTIVE MS – with relapses and new lesions vs. INACTIVE MS – without relapses or new lesions

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278–86. © 2016 Virginia Mason Medical Center Treatment of Secondary Progressive MS

Should we consider starting or changing a DMT in patients with INACTIVE secondary progression of clinical disability?

Inflammation

Regeneration

Relapsing Remitting MS Time Secondary Progressive MS

FDA approval for Siponimod (Mayzent®), to treat relapsing forms of MS including secondary progressive MS with active disease

No first dose monitoring required for patients without pre-existing cardiac disease (AV Block, h/o MI, CHF)

Genetic testing recommended for CYP2C9, modulated dosing and exclusions based on genotype

Titration dosing for initiation

EXPAND Trial 2017

Siponimod is a selective S1P1 and S1P5 receptor modulator Similar to Fingolimod (Gilenya), a non-specific S1P receptor modulator

Inclusion: • 18-60yrs old with SPMS (progression ≥2yrs in-between relapses or without relapses, no relapse within 3 months) • Moderately disabled (EDSS 3.0 – 6.5, ambulate with walker >20m) • 1,651 patients - randomized 2:1 Siponimod to placebo

EVOLVE Trial Very active patients in trial:

• 21% with Gad+ enhancing lesions at baseline

• 36% with clinical relapses in last 2 years

• 22% never treated with prior DMT

EXPAND Trial Subgroup HR (95% CI)

No Relapses in prior 2 yrs 0.87 (0.68 - 1.11) Relapses in prior 2yrs 0.67 (0.49 - 0.91) -- recent relapses No Gad+ lesions at baseline 0.87 (0.68 - 1.11) Gad+ lesions at baseline 0.64 (0.42 - 0.95) -- recent new lesions

MS Duration since first symptoms < 10 yrs 0.77 (0.61 - 0.97) -- earlier onset diasease 10-20yrs 0.82 (0.66 - 1.02) 20-30yrs 0.88 (0.59 - 1.31)