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Social Media, Physicians, and
Patients with Multiple Sclerosis:
A Guide for the Perplexed
Andrew N. Wilner, MD, FACP, FAAN
Neurohospitalist
Department of Neurology
Lawrence and Memorial Hospital
New London, Connecticut
Please Answer the Following Questions

Are you “LinkedIn?”

Did you “Friend” anyone today?

Have you posted questions for your
fellow “Sermoans”?

Did you “tweet” this week?
Did You Answer Yes?
If you answered “Yes” to all 4 questions,
you can skip this presentation…if not,
please continue…
Social Media
The use of web-based technology to
facilitate interaction with others.
What Is Social Media?
“Media for social interaction, using highly
accessible and scalable publishing
techniques. Social media uses web-based
technologies to turn communication into
interactive dialogues…a blending of
technology and social interaction for the
co-creation of value.” –Wikipedia
Wikipedia, The Free Encyclopedia. Social media. Available at: http://en.wikipedia.org/wiki/Social_media.
Social Media—A Few Examples

Blogs

Twitter

Facebook, MySpace

Wikis

LinkedIn

YouTube

Sermo

Flickr, SmugMug
With permission from Solis B, et al. The conversation prism. Available at: http://www.theconversationprism.com.
Nicholas Kristof—New York Times
Columnist, February 2010
“I really think that [social media] is part of the
way that we are going to need to continue to
engage audiences, and I can engage dead white
men in my column and then I can engage
teenyboppers with my Facebook page…We
need to try to evolve, so that’s one reason why I
do shoot these videos for the [New York] Times’
website, why I blog, why I Twitter, why I
Facebook, why I have a YouTube channel.”
Williams A. Nicholas Kristof: newspaper columnist, globehopping dinosaur. Time Out New York. February 18-24, 2010.
Available at: http://newyork.timeout.com/articles/i-new-york/82860/nicholas-kristof-bold-questions.
Evolution of Health Information Sharing

Used to be 1-way (physician control)

Now “interactive”
– Physician-patient
– Patient-physician
– Patients-patient
How Health Information Was Shared
MD
Patient
Slide courtesy of Dr. Bryan Vartabedian.
How Health Information Is Shared
MD
ePatient
How Health Information Is Shared
ePatients
ePatient
Patient Blog on MS—Looks Official…
Learning to live with multiple sclerosis. Available at: http://learningtolivewithms.blogspot.com/.
The Social Media Revolution
How Is Its Use in Adults Growing?
2005
2009
Lenhart A. Adult and social network websites. January 14, 2009. Pew Internet & American Life Project. Available at:
http://pewinternet.org/Reports/2009/Adults-and-Social-Network-Websites.aspx.
Percentage of Adults Who Look Online
for Health Information
61%
Fox S. The social life of health information. January 14, 2009. Pew Internet & American Life Project. Available at:
http://pewinternet.org/~/media//Files/Reports/2009/PIP_Health_2009.pdf.
Health Information Sharing
The scale of health information sharing has
evolved from the doctor, patient, family, and
friends to MILLIONS OF PEOPLE IN THE
WORLD…
If Social Media Is a Fad, It’s a BIG One!

Facebook—500 million users1

Twitter—165 million users (90 million
tweets/day)2

LinkedIn—80 million users3
1. Facebook. Press room: people on Facebook. Available at: http://www.facebook.com/press/info.php?statistics.
2. Twitter blog. #newtwitterceo. October 4, 2010. Available at: http://blog.twitter.com/2010/10/newtwitterceo.html.
3. LinkedIn. Available at: http://www.linkedin.com/.
Patient with MS Communicates to the
WORLD on YouTube
Multiple sclerosis: CCSVI & liberation procedure NEWS. RADIO SHOW. THE END OF MS.
Available at: http://www.youtube.com/watch?v=_z8qJrH7VMU.
Twitter—The News in 140 Characters!
Multiple sclerosis: news and information on multiple sclerosis (MS). Available at: http://multiplesclerosis.comxa.com/.
MS Patient on CCSVI
Abbreviation: CCSVI, chronic cerebrospinal venous insufficiency.
Wheelchair kamikaze: the rants, ruminations, and reflections of a mad MS patient.
Available at: http://www.wheelchairkamikaze.com/.
MS Society Communicates Through
News Media
MS Society comments on CCSVI announcement live on Sky News.
Available at: http://www.youtube.com/watch?v=46Siaot1HL4.
American Academy of Neurology
Public Webinar on CCSVI

50 journalists on-site

4000 public attendees online who
submitted >700 questions

http://www.youtube.com/watch?v=W2ni
OdMGsJg
Abbreviation: CCSVI, chronic cerebrospinal venous insufficiency.
American Academy of Neurology National MS Society. CCSVI Web Forum Part 1 of 14. April 2010.
Available at: http://www.youtube.com/watch?v=W2niOdMGsJg.
US Hospitals on YouTube and Twitter
Bennett E. Hospital social network data and charts. Available at: http://ebennett.org/hsnl/data/.
How Will Social Media Impact My
Patient Care?
Positives

Patients will find
more information

Patients will share
information with
each other
Negatives

Patients will find
more
misinformation

Patients will share
more
misinformation with
each other
Where Are the Doctors?
MDs in Social Media Space
•
•
•
•
Late adopters
Time/impatience
Concerns over privacy, liability, and image
Physician usage of social media had grown
50% in the previous year, according to a June
2009 survey1
1. Massachusetts Medical Society. Social networking 101 for physicians. Available at:
http://www.massmed.org/Content/NavigationMenu2/ContinuingEducationEvents/NewCourses/SocialNetworking101forPhys
icians/ManagingTheRisksOfFacebookTwitterAndOtherSocialMedia/Managing_The_Risks_O.htm.
Advantages of Social Media

Wider audience

Low cost

Instantaneous communication

Easy updating

Interactive—“Web 2.0”

Self-education
4: Individuals – email lists
3: Closed networks – MySpace, Facebook
2: Open networks – blogs, feeds, YouTube
1: Mainstream media – press, influencers
Armano D. Influence ripples. Available at: http://darmano.typepad.com.
How You Can Use Social Media to
Improve Your Practice

Patient education

Promote your practice

Recruit patients for clinical trials

Cultivate professional relationships
Blog
Put a stake in the ground
Slide courtesy of Dr. Bryan Vartabedian.
Do Physicians
Have an
Obligation to Be
in the Online
Space?
KevinMD.com. Available at: http://www.kevinmd.com/blog/2009/08/delayed-vaccine-schedule-dangerous.html.
Visit This Blog's Front Page
Neuro Notes
Zamboni "Venous Insufficiency" Theory of Multiple Sclerosis−Red
Flags Warn of Thin Ice
Andrew Wilner, MD, Neurology, 11:28PM Apr 14, 2010
Here in Canada, ice hockey is big sport. But everyone knows you
don't go skating on the pond when the ice is thin. At the request
of the National Multiple Sclerosis (MS) Society, the AAN hosted
a prime time press conference to create a venue where the
controversial theory that "chronic cerebrospinal venous
insufficiency" (CCSVI) is the etiology of MS could be discussed
by its leading proponent, Paolo Zamboni, MD, Director, Vascular
Diseases Center, University of Ferrara, Italy, Robert Zivadinov,
MD, PhD, Director of the Buffalo Neuroimaging Analysis Center,
Buffalo, NY, Andrew Common, MD, Radiologist in Chief, St.
Michaels Hospital, University of Toronto, Ontario, CA, and
Aaron Miller, MD, Professor of Neurology and Director of the MS
Center at Mount Sinai, NY, NY, and Chief Medical Officer of the
Medscape
Blogs. NeuroMS
Notes.Society.
Zamboni "venous insufficiency" theory of multiple sclerosis−red flags warn of thin ice.
National
Available at: http://boards.medscape.com/[email protected]@.29fccf6a!comment=1.
Blog
Slide courtesy of Dr. Bryan Vartabedian.
Opportunities for Self-Education

MedPage Today

Medscape

Sermo

Twitter

YouTube
Physician Education
Projects In Knowledge. Multiple sclerosis tool kit: diagnosing and understanding cognitive dysfunction. Available at:
http://www.projectsinknowledge.com/neurology/multiple-sclerosis_1.cfm?jn=2008.
Disadvantages of Social Media

Information chaos!

Misinformation abounds

Communication “too easy”−just a
click…

Lack of patient/physician boundaries…

“Private” information becomes “public”
Do Not Practice Medicine!
“New communication technologies must
never replace the crucial interpersonal
contacts that are the very basis of the
patient-physician relationship.”
–AMA Guidelines for Physician-Patient Electronic
Communications
American Medical Association. Guidelines for physician-patient electronic communications. Available at: http://www.amaassn.org/ama/pub/about-ama/our-people/member-groups-sections/young-physicians-section/advocacyresources/guidelines-physician-patient-electronic-communications.shtml.
Staying Safe on Social Networks

Never discuss patients by name

Do not communicate with patients regarding
clinical care

Block patients from personal Facebook
pages

Patients, boss, future employer, in-laws, will
read everything you write

Be nice—avoid negative comments about
your hospital, colleagues, and patients!

Don’t be anonymous—take responsibility for
your words
Just Like a Tattoo…
Available at: http://www.tattoo-designs-free.com/heart.html.
It Seemed Like a Good Idea at the
Time…

Everything you write on the internet is
“engraved in stone” in the internet “cloud”

Don’t say anything you wouldn’t want to read
in the newspaper

Self-censorship is a good thing…

Take a “time out” before you hit “SHARE” or
“SEND”! (Pause before you post)
Do’s and Don’ts of Social Media

Educate patients

Educate yourself

Promote awareness
(advertise)

Build relationships

Be polite

Do NOT practice
medicine

Do NOT socialize with
patients—respect
boundaries!

Never discuss patients
by name—HIPAA1

Don’t say anything
online you might regret
later
1. Health Insurance Portability and Accountability Act, 1996. Available at:
http://www.cms.gov/HIPAAGenInfo/02_TheHIPAALawandRelated%20Information.asp#TopOfPage.
Answers to the 4 Questions:

Are You “LinkedIn?”—business

Did you “Friend” anyone today?—
Facebook

Have you posted questions for your
fellow “Sermoans”?—clinicians

Did you “tweet” this week?—Twitter
Learn More About Social Media

Social Networking 101 for Physicians—
Massachusetts Medical Society CME
Program1

Guidelines for Physician-Patient
Electronic Communications—AMA2
1. Massachusetts Medical Society CME Program. Available at:
http://www.massmed.org/AM/Template.cfm?section=Communication4&Template=/CM/HTMLDisplay.cfm&Content
ID=32899.
2. American Medical Association. Available at: http://www.ama-assn.org/ama/pub/about-ama/our-people/membergroups-sections/young-physicians-section/advocacy-resources/guidelines-physician-patient-electroniccommunications.shtml.
Thanks for Listening!
The End
Using Current Treatments to
Optimize Patient Outcomes
Jack N. Ratchford, MD
Assistant Professor of Neurology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Topics

Current disease-modifying treatment
options

Head-to-head clinical trials

High-risk clinically isolated syndrome
treatment trials

Managing breakthrough disease

Individualizing MS care

Technology for MS patients and
clinicians
FDA-approved Disease-Modifying MS
Treatments
Brand Name
Generic Name
Dose
Year Approved
Betaseron*
SC IFN β-1b
0.25 mg SC qod
1993
Extavia†
SC IFN β-1b
0.25 mg SC qod
2009
Avonex‡
IM IFN β-1a
30 mcg IM weekly
1996
Rebif§
SC IFN β-1a
44 mcg SC tiw
2002
Glatiramer acetate
20 mg SC daily
1996
Tysabri‡
Natalizumab
300 mg IV monthly
2004, 2006
Novantrone§
Mitoxantrone
12 mg/m2 IV q3mo
2000
Fingolimod
0.5 mg PO daily
2010
Copaxone¶
Gilenya†
Abbreviations: IFN, interferon; IM, intramuscular; IV, intravenous; PO, by mouth; SC, subcutaneous.
*Bayer Healthcare Pharmaceuticals Inc., Montville, NJ; †Novartis Pharmaceuticals Corporation, East Hanover, NJ;
‡Biogen Idec Inc., Cambridge, MA; §EMD Serono, Inc., Rockland, MA; ¶TEVA Neuroscience, Inc, Kansas City, MO.
Drugs@FDA. Available at: http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/.
Graphic courtesy of Dr. Jack Ratchford.
Recent Head-to-head Trials

REGARD1

BEYOND2

BECOME3

TRANSFORMS4
Abbreviations: BECOME, Betaferon vs Copaxone in MS with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints; BEYOND,
Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose; REGARD, Rebif vs Glatiramer Acetate in Relapsing MS
Disease; TRANSFORMS, TRial Assessing injectable InterferoN vS FTY720 Oral in RrMS.
1. Mikol DD, et al. Lancet Neurol. 2008;7:903-914. 2. O'Connor P, et al. Lancet Neurol. 2009;8:889-897. 3. Cadavid D, et al.
Neurology. 2009;72:1976-1983. 4. Cohen JA, et al. N Engl J Med. 2010;362:402-415.
REGARD




Patients: relapsing-remitting MS; IFNβ and glatiramer
acetate treatment naive
Design: 96-week, randomized, open-label, SC IFN β-1a
vs glatiramer acetate
Outcome: time to 1st relapse, MRI
Results
–
–
–

No significant difference in time to 1st relapse
No difference in number or change in volume for T2
lesions
Fewer gadolinium-enhancing lesions in the SC IFN β-1a
group
Comments: similar efficacy; less activity than expected
in the study population
Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
BEYOND

Patients: early, treatment-naive relapsing-remitting
MS

Design: randomized to SC IFN β-1b 500 mcg (higher
dose), 250 mcg (standard dose), or glatiramer acetate

Outcome: relapse rate, disability progression

Results: no differences

Comments: same efficacy for glatiramer acetate, SC
IFN β-1b, and double-dose SC IFN β-1b; implies a
ceiling effect with IFN β
O'Connor P, et al. Lancet Neurol. 2009;8:889-897.
BECOME

Patients: relapsing-remitting MS or high-risk
clinically isolated syndrome; treatment naive

Design: SC IFN β-1b vs glatiramer acetate
with monthly 3 Tesla MRI using triple-dose
gadolinium

Outcome: number of new or enhancing MRI
lesions

Result: no difference in MRI or clinical
activity
Cadavid D, et al. Neurology. 2009;72:1976-1983.

Comment: more evidence of similar efficacy
TRANSFORMS

Patients: relapsing-remitting MS; treatment naive or
treatment experienced

Design: 1 year, double blind, fingolimod vs IM IFN β-1a

Outcome: relapse rate, MRI, disability

Results: lower relapse rate for fingolimod, better MRI
results, no effect on disability

2 deaths with high-dose fingolimod (disseminated
varicella zoster virus and herpes simplex virus
encephalitis), other adverse events include liver function
test abnormalities, first dose bradycardia/atrioventricular
block, macular edema, infections, etc
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
Fingolimod

First FDA-approved oral diseasemodifying MS medication

Reduced relapse rate, development of
new MRI lesions, and disability accrual
in trials1,2
1. Cohen JA, et al. N Engl J Med. 2010;362:402-415.
2. Kappos L, et al. N Engl J Med. 2010;362:387-401.
Fingolimod

Potential side effects
– Increased risk of lower respiratory infections,
possible increased risk of serious herpes simplex
virus or varicella zoster virus infections
– First dose bradycardia or arrhythmia
– Liver function test elevations
– Macular edema
– Dyspnea, drop in diffusion capacity
– Elevated blood pressure
Cohen JA, et al. N Engl J Med. 2010;362:402-415. Kappos L, et al. N Engl J Med. 2010;362:387-401. Gilenya [PI]. East
Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010.
Fingolimod

Which patients should be considered
for its use?
– Probably as effective or more effective
than current first-line treatments, but risks
appear to be higher
– Approved as a first-line treatment,1 but
best use may be patients with active MS
who fail an injectable treatment or who
cannot tolerate injectable medications
1. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010.
Disease-Modifying Treatment in HighRisk Clinically Isolated Syndrome
Study Name
Drug
Entry Criteria
Results
CHAMPS/CHAMPIONS1,2
IM IFN β-1a
30 mcg weekly
≥2 MRI lesions
Lower rate of MS diagnosis
at 3 years (35% vs 50%)
and 5 years (36% vs 49%)
ETOMS3
SC IFN β-1a
22 mcg weekly
(low-dose SC
IFN β-1a)
≥4 MRI lesions OR 3
lesions if 1 enhancing or
infratentorial
Lower rate of MS diagnosis
at 2 years (34% vs 45%)
BENEFIT4,5
SC IFN β-1b
250 mcg qod
≥2 MRI lesions
Lower rate of MS diagnosis
at 2 years (28% vs 45%);
decreased disability
development
PreCISe6
Glatiramer
acetate 20 mg
SC daily
≥2 lesions
Lower rate of MS diagnosis
1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Kinkel RP, et al. Neurology. 2006;66:678-684. 3. Comi G, et al.
Lancet. 2001;357:1576-1582. 4. Kappos L, et al. Neurology. 2006;67:1242-1249. 5. Kappos L, et al. Lancet. 2007;370:389397. 6. Comi G et al. Lancet. 2009;374:1503-1511.
Graphic courtesy of Dr. Jack Ratchford.
Managing Breakthrough Disease

Challenges of defining breakthrough

Options
1. Switch to a different injectable medication
2. Change to natalizumab or fingolimod
3. Add or substitute an off-label treatment
(eg, pulse steroids, oral
immunosuppressants, cyclophosphamide,
rituximab)
4. Clinical trial
Individualizing MS Care


1 approach may not work for everybody
Recognizing bad prognostic signs1-3
–
–
–
–
–
–
–
–
Patients with cerebellar signs or corticospinal tract
signs at onset
Polysymptomatic onset
Frequent relapses
Poor recovery from relapses
African American
Male
Brain atrophy or many T1 hypointensities on MRI
Progressive onset
1. Langer-Gould A, et al. Arch Neurol. 2006;63:1686-1691. 2. Kister I, et al. Neurology. 2010;75:217-223.
3. Bakshi R, et al. Arch Neurol. 2008;65:1449-1453.
Individualizing MS Care
Rethinking Current Treatments


Threshold for escalating treatment
should be lower in patients who are
doing poorly
Consider agents with different modes of
action
– Induction therapy with mitoxantrone or
cytotoxic agents followed by maintenance
therapy with an immunomodulatory agent

Biomarkers may be useful to detect
patients in need of more aggressive
early treatment
Mitoxantrone Induction Therapy

Case series of 100 patients1
–
–
Patients: aggressive relapsing-remitting MS (RRMS);
treatment naive or treatment experienced
Design: monthly mitoxantrone (20 mg) and
methylprednisolone (1 g) for 6 months


73 patients received maintenance therapy within 6 months
following induction: mitoxantrone q3mo (n = 21), IFN-β
(n = 25), azathioprine (n = 15), methotrexate (n = 7), or
glatiramer acetate (n = 5)
Trial of glatiramer acetate maintenance after
mitoxantrone induction vs galtiramer acetate alone2,3
–
–
Patients: RRMS
Design: 12 months glatiramer acetate (20 mg/d) following 3
monthly mitoxantrone infusions (12 mg/m2) or 15 months
glatiramer acetate alone (20 mg/d)
1. Le Page E, et al. J Neurol Neurosurg Pyschiatry. 2008;79:52-56. 2. Vollmer T, et al. Mult Scler.
2008;14:663-670. 3. Arnold DL, et al. J Neurol. 2008;255:1473-1478.
Other Induction Therapies


High-dose cyclophosphamide induction1
–
Patients: aggressive relapsing-remitting MS (RRMS); treatment
naive or treatment experienced
–
Design: 2-year open-label trial in 9 patients; high-dose
cyclophosphamide (50 mg/kg/d IV) for 4 consecutive days,
followed by granulocyte colony-stimulating factor (filgrastim)
Autologous stem cell transplantation2
–
Patients: RRMS; treatment experienced
–
Design: phase I/II study

Peripheral blood hematopoietic stem cells mobilized with
cyclophosphamide (2 g/m2 IV) followed by filgrastim

Mobilized cells collected by apheresis

Conditioning regimen: cyclophosphamide (200 mg/kg IV) in 4 equal
fractions plus alemtuzumab or rabbit antithymocyte globulin

Cells reinfused 36 hours after completion of cyclophosphamide
1. Krishnan C, et al. Arch Neurol. 2008;65:1044-1051. 2. Burt RK, et al. Lancet Neurol. 2009;8:244-253.
Technology for MS Patients

Many MS patients are savvy internet
users

Increasingly, patients are using social
media to get information about their MS
and communicate with peers
– >20,000 MS patients use PatientsLikeMe1
(www.patientslikeme.com)
– MS World is the official chat service and
bulletin board for the National MS Society2
(www.msworld.org)
1. The PatientsLikeMe Multiple Sclerosis Community. Available at: http://www.patientslikeme.com/multiplesclerosis/community. 2. MSWorld.org. Available at: http://www.msworld.org/.
Technology for MS Patients
Online symptom surveys for patients

Can be used to screen for problems and
be shared with a healthcare
professional

https://www.mymshealth.org
My MS Health. Available at: https://www.mymshealth.org/.
Technology for MS Clinicians

Clinical prediction tool
– Gives predictions of relapse rate, Expanded
Disability Status Scale, and time to progression
for the subsequent 2 years based on individual
characteristics1
– https://www.slcmsr.net/public/login.jsp

iPoint of Care-MS
– A “widget” on a desktop computer or iPhone that
allows one to quickly search for relevant
resources2
– http://ms.ipointofcare.org/Default.aspx
1. Daumer M, et al. BMC Med Inform Decis Mak. 2007;7:11.
2. Multiple Sclerosis. iPointOfCare. Available at: http://ms.ipointofcare.org/TherapeuticAreas.aspx?ctrl=FAQs&type=MS.
Technology for MS Clinicians

Resource Detectives
– An online tool to find local resources for
patients (eg, physical therapy, legal advice,
clinical trials)
– www.resourcedetectives.org

Consortium of MS Centers website
– Consensus guidelines and other resources
– www.mscare.org

National MS Society website
– Many resources for MS clinical care and
research
– www.nationalmssociety.org
Future Directions in MS Therapy:
Are Neurologists Becoming
Immunologists Online?
Augusto A. Miravalle, MD
Assistant Professor of Neurology
University of Colorado, Denver
Aurora, Colorado
Overview

Understand basic mechanisms of action
underlying selected current and
experimental therapies for MS

Review efficacy and safety data on
emerging MS therapies

Understand potential risk and benefits
of social media and technology in the
care of MS patients
Definitions

Immunosuppressive therapies
– Cause generalized immune suppression
– Limited therapeutic potential due to systemic effects

Immunomodulatory therapies
– Do not cause generalized immune suppression
– Shift the immune response from proinflammatory
(Th1)
to more beneficial anti-inflammatory (Th2) response

Protective/repair therapies
– Desirable to support neural regeneration and inhibit
neural degeneration
– Effective strategy in MS, as disease is diagnosed
Treatment Algorithms for MS
Treatment for MS can follow 1 of 2 principal
algorithms

Induction algorithms concentrate all
therapeutic efforts on the early phases of the
disease, which ultimately defines prognosis

Escalation algorithms begin with the safest
treatments and move on to more aggressive
therapies only in the event of treatment
failure
Treatments for MS

Current first-line treatments for MS are
typically monotherapies, but disease activity
is insufficiently controlled by these
treatments in some patients

Second-line monotherapies are limited and
associated with greater safety concerns

Alternatively, combination therapy with
established drugs can improve clinical
efficacy while managing the potential for
adverse events

Who are the candidates for emerging
therapies?

Will emerging therapies be used as part
of combination therapy?
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T-cell NK cells
CD 25
T-cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T-cell
ODC
Lymphocyte-targeted therapies
T-cell
Fingolimod
Dimethyl fumarate
T-cell T-cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T-cell
CD 52
B-cell
B-cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Fingolimod
Mechanism of Action

Fingolimod targets receptors for sphingosine 1phosphate (S1P), a signaling lipid released at sites of
inflammation

S1P receptors are found on the surface of newly
generated T-cells and promote T-cell migration from
lymphatic organs to peripheral sites of inflammation

T-cells that have fingolimod bound to receptors do
NOT egress

Fingolimod is lipid-soluble and readily permeates the
blood brain barrier to enter the central nervous
system
Rammohan KW, et al. Neurology. 2010;74:S47-S53.
Fingolimod
Mechanism of Action
Multiple Sclerosis
• Traps circulating
LN
lymphocytes in
peripheral LN
• Reduces T-cell
infiltration in the
CNS
S1P receptor
T-cell
Fingolimod-P
• Internalizes S1P1 blunting
response to chemotactic
signals
• Blocks lymphocyte egress from
LN while sparing immune
surveillance by peripheral
memory T-cells
Fingolimod
Abbreviations: CNS, central nervous system; LN, lymph node; S1P, sphingosine 1-phosphate.
Rammohan KW, et al. Neurology. 2010;74:S47-S53.
Graphic courtesy of Dr. Augusto Miravalle.
Fingolimod
Clinical Experience

Phase II trial in relapsing-remitting MS patients1
–
–

Doses 1.25 and 5 mg
Significantly reduced the number of new focal
inflammatory lesions (by 80%) and relapse rates (by
50%) compared with placebo
Phase III trial (TRANSFORMS)2
–
–
–
–
–
12 months
Doses 0.5 and 1.25 mg
Comparing fingolimod with once-weekly IFN -1a
Significant reduction of relapse rate and MRI activity
2 fatalities related to varicella zoster virus and herpes
simplex virus encephalitis infections
1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. Cohen JK, et al. N Engl J Med. 2010;362:402-415.
Fingolimod
Clinical Experience

Phase III trial (FREEDOMS)
– 24 months
– Doses 0.5 and 1.25 mg
– Reduced annualized relapse rates by 54% and
60%, respectively
– Reduced accumulation of disability on both
doses
– 30% reduction in the rate of brain volume loss at
6 months of therapy
Kappos L, et al. N Engl J Med. 2010;362:387-401.
Fingolimod
Safety and Pharmacokinetics

Safety
– Potential adverse effects (as observed in phase II and III clinical
trials for MS) include1-3
Lymphopenia
Transient but significant decrease in heart rate
following administration
Infection
Hepatotoxicity
Bradycardia
Skin and breast cancers
Increased airway resistance
Death due to herpes encephalitis
Macular edema
Death due to disseminated varicella infection

Pharmacokinetics
– Serum half-life is 7 days4
– Reduces peripheral lymphocyte counts for up to 24 hours following
administration4
1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. Cohen JK, et al. N Engl J Med. 2010;362:402-415. 3. Kappos L,
et al. N Engl J Med. 2010;362:387-401. 4. Brown BA, et al. Ann Pharmacother. 2007;41:1660-1668.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T-cell NK cells
CD 25
T-cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T-cell
ODC
Lymphocyte-targeted therapies
T-cell
Fingolimod
Dimethyl fumarate
T-cell T-cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T-cell
CD 52
B-cell
B-cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Cladribine
Mechanism of Action




Cladribine exploits the specific enzymatic degradation of
deoxynucleotides in lymphocytes
Most cells do not rely on adenosine deaminase (ADA) to
degrade deoxyadenosine phosphate, because of high levels
of deoxynucleotidase (5-NTase), a dephosphorylating
enzyme
Lymphocytes do rely on ADA to degrade deoxyadenosine
phosphate, because of low levels of 5-NTase
Since cladribine is resistant to ADA, and lymphocytes have
low levels of 5-NTase, cladribine results in the
accumulation of deoxyadenosine nucleotides in
lymphocytes
Leustatin [PI]. Raritan, NJ: Ortho Biotech Products, LP; 2007.
Cladribine
Clinical Experience


Phase III trial (CLARITY)1
– In patients with relapsing-remitting MS
– Compared with placebo, significant reduction in
 Relapse rate (by 55%–58%)
 Disability progression (by 31%–33%)
 Number of gadolinium-enhancing active T2
lesions (by 73%–88%)
Phase III trial (ORACLE MS)2
– In patients with clinically isolated syndrome
– Currently under way
1. Giovannoni G, et al. N Engl J Med. 2010;362:416-426; 2. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00725985.
Cladribine
Safety and Pharmacokinetics

Safety
– Infection is the chief safety concern1

In clinical trials, adverse events included2
Headaches
Lymphopenia, neutropenia, leukopenia
Nasopharyngitis
Herpes zoster infections
Upper respiratory tract infections
Malignancies (melanoma, ovarian cancer,
metastatic pancreatic carcinoma, and
choriocarcinoma)
Nausea

Pharmacokinetics
– Serum half-life of 6–8 hours3
– Immunosuppression maintained for at least 6–12 months3
1. Cohen JA. Arch Neurol. 2009;66:821-828. 2. Giovannoni G, et al. N Engl J Med. 2010;362:416-426. 3. Leist TP, et al.
Curr Med Res Opin. 2007;23:2667-2676.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T-cell NK cells
CD 25
T-cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T-cell
ODC
Lymphocyte-targeted therapies
T-cell
Fingolimod
Dimethyl fumarate
T-cell T-cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T-cell
CD 52
B-cell
B-cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Teriflunomide
Mechanism of Action
An inhibitor of the mitochondrial dihydroorotate
dehydrogenase (DHODH), an enzyme crucial to pyrimidine
synthesis
• Activated lymphocytes
depend on de novo
pyrimidine synthesis
• Depletion could
-
Inhibit immune-cell
proliferation
-
Impair phospholipid
synthesis and protein
glycosylation in immune
cells
Reprinted from Tallantyre E, et al. The International MS Journal. 2008;15:62-68 with permission from Cambridge Medical
Publications (CMP).
Teriflunomide
Clinical Experience

Phase II trial1
– Patients with relapsing forms of MS
– Received placebo, teriflunomide 7 mg or 14 mg a day for 36 weeks
– Significant reduction in the number of T1- and T2-enhancing lesions
vs placebo

Phase II trials of combination therapy with IFN- and with
glatiramer acetate are currently under way2-4
1. O'Connor PW, et al. Neurology. 2006;66:894-900. 2. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00475865. 3. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00489489.
4. ClinicalTrials.gov. 2010. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00811395.
Teriflunomide
Clinical Experience

Phase III trial (TEMSO)1
–
–

A 2-year, double-blind, placebo-controlled study
examining relapse rate in relapsing MS; recently
completed1
Other phase III trials in relapsing MS (TOWER,
TENERE) currently under way2,3
Phase III trial (TOPIC)4
–
A 2-year, double-blind placebo-controlled study in
clinically isolated syndrome; currently under way
1. ClinicalTrials.gov. 2010. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00134563. 2. ClinicalTrials.gov. 2010.
Available at: http://www.clinicaltrials.gov/ct2/show/NCT00751881. 3. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00883337. 4. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00622700.
Teriflunomide
Safety and Pharmacokinetics

Safety
– Adverse effects in clinical trials included1,2
Nasopharyngitis
Nausea
Alopecia
Diarrhea
Limb pain
Hepatic necrosis and pancytopenia (patients with
rheumatoid arthritis)
Arthralgia
Increase in liver enzymes
– Contraindicated in women of childbearing age1,2

Pharmacokinetics
– Mean plasma half-life is 15–18 days2
1. Cohen JA. Arch Neurol. 2009;66:821-828. 2. Tallantyre E, et al. Int MS J. 2008;15:62-68.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T cell NK cells
CD 25
T cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T cell
ODC
Lymphocyte-targeted therapies
T cell
Fingolimod
Dimethyl fumarate
T cell T cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T cell
CD 52
B cell
B cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Daclizumab
Mechanism of Action
A humanized monoclonal antibody targeting
CD25 receptors1

Inhibits proliferation and activation of T-cells, including
autoreactive T-cells1

Promotes expansion of CD56+ natural killer (NK) cells;
mechanism unknown2

In clinical trials, expanded CD56+ NK cells were
capable of killing autoreactive CD4+ and CD8+ T-cells
and were correlated with clinical outcome3,4
1. Lutterotti A, et al. Lancet Neurol. 2008;7:538-547. 2. Buttmann M, et al. Expert Rev Neurother. 2008;8:433-455.
3. Bielekova B, et al. Arch Neurol. 2009;66:483-489. 4. Bielekova B, et al. Proc Natl Acad Sci U S A. 2006;103:5941-5946.
Daclizumab
Clinical Experience

Phase II trial (CHOICE)1
– Investigated daclizumab as an add-on therapy in
patients with relapsing-remitting MS
– In the high-dose group, daclizumab produced a
significant 72% reduction in new or enlarged
gadolinium-enhancing lesions on MRI scans over a 6month period vs placebo
– No differences in annualized relapse rates between the
study arms

Additional phase II and phase III studies are ongoing24
1. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 2. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00390221. 3. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00870740.
4. ClinicalTrials.gov. 2010. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01064401.
Daclizumab
Safety and Pharmacokinetics

Safety
– The most common and serious adverse effects in clinical
trials were1


Cutaneous reactions more frequently observed with daclizumab
than placebo (44% vs 39%)

Severe infections more frequently observed with daclizumab
than placebo (7% vs 3%)
Pharmacokinetics
– Serum half-life approximately 20 days2
1. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 2. Buttmann M, et al. Expert Rev Neurother. 2008;8:433-455.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T cell NK cells
CD 25
T cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T cell
ODC
Lymphocyte-targeted therapies
T cell
Fingolimod
Dimethyl fumarate
T cell T cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T cell
CD 52
B cell
B cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Rituximab
Mechanism of Action

A chimeric monoclonal antibody targeting
CD20 receptors1

Causes selective B-cell destruction1

Thought to have a therapeutic effect in MS,
where localized B-cell expansion in the central
nervous system is associated with
inflammation1
1. Lutterotti A, et al. Lancet Neurol. 2008;7:538-547.
Rituximab
Clinical Experience

Phase II trial (HERMES)1,2
– Patients with relapsing-remitting MS
– Resulted in reduction of mean number of gadolinium-enhancing
lesions (by 91%) and relapse rate (by 58%) vs placebo

Phase II/III (OLYMPUS)3
– Patients with primary-progressive MS
– Appeared to have efficacy only in young patients and those with
signs of active inflammation on MRI scans

Phase I/II (RIVITaLISe)4
– Patients with secondary-progressive MS
– Initiated in September 2010
1. Hauser SL, et al. N Engl J Med. 2008;358:676-688. 2. Buttmann M, et al. Expert Rev Neurother. 2008;8:433-455.
3. Hawker K, et al. Ann Neurol. 2009;66:460-471. 4. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT01212094.
Rituximab
Safety and Pharmacokinetics

Safety
– Long-term safety profile has yet to be established1


5 cases of progressive multifocal encephalopathy reported in patients
with rheumatoid arthritis or systemic lupus erythematous receiving
rituximab in conjunction with other immunosuppressants1,2

Other adverse events included infusion reactions, chills, pruritis,
pyrexia,
throat irritation, urinary tract infections, and sinusitis3,4
Pharmacokinetics
– Flexible or fixed dosing1

375 mg/m² given weekly for 4 weeks

2 grams divided in 2 infusions of 1 gram each, 2 weeks apart
– Serum half-life approximately 19 days1
– Following administration of 2 grams of rituximab, CD19-positive Bdepleted
and remain
undetectable
for up to 6
1. Buttmann cells
M, et al. are
Expertrapidly
Rev Neurother.
2008;8:433-455.
2. FDA. 2009.
Available at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm187791.htm.
3. Hauser
months3
SL, et al. N Engl J Med. 2008;358:676-688. 4. Hawker K, et al. Ann Neurol. 2009;66:460-471.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T-cell NK cells
CD 25
T-cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T-cell
ODC
Lymphocyte-targeted therapies
T-cell
Fingolimod
Dimethyl fumarate
T-cell T-cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T-cell
CD 52
B-cell
B-cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Ocrelizumab

Humanized monoclonal antibody targeting
CD19+ B-cells.

Recent phase II clinical trials using
ocrelizumab (2000 mg; 600 mg) vs placebo
showed 96% reduction on number of MRI
lesions, as well as 80% reduction on
annualized relapse rate

Safety profile was limited to infusion-related
events (43%), mild infections, and systemic
inflammatory response syndrome
Kappos et al. Efficacy and Safety of Ocrelizumab in Patients with RRMS: Results of a Phase II Randomized
Placebo-Controlled Multicenter Trial. ECTRIMS 2010.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T-cell NK cells
CD 25
T-cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T-cell
ODC
Lymphocyte-targeted therapies
T-cell
Fingolimod
Dimethyl fumarate
T-cell T-cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T-cell
CD 52
B-cell
B-cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Alemtuzumab
Mechanism of Action

A humanized monoclonal antibody targeting cells
expressing CD52 receptors1
– CD52 is a glycoprotein of unknown function, expressed on Tand B-cells, monocytes, and eosinophils1

Alemtuzumab causes rapid immune cell depletion
(2 days) mediated by complement-mediated lysis and
antibody-dependent cellular cytotoxicity2,3

Following treatment
– CD4+ T-cells are depleted for 60 months (median)
– B-cells and monocytes are depleted for 3 months (median)
Abbreviation: PBMC, peripheral blood mononuclear cell.
1. Lutterotti A, et al. Lancet Neurol. 2008;7:538-547. 2. Buttmann M, et al. Expert Rev Neurother. 2008;8:433-455.
3. Cohen JA. Arch Neurol. 2009;66:821-828.
Alemtuzumab
Clinical Experience

Phase II trial1
– Patients with relapsing-remitting MS
– Compared with conventional IFN-β therapy, significant
benefit in


Disability progression

Relapse rate

T2 hyperintense lesion volume change

Brain volume
Phase III trials2,3
– 2 trials (CARE-MS I, CARE-MS II) for the treatment of RRMS
currently under way
1. CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801. 2. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00530348. 3. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00548405.
Alemtuzumab
Safety and Pharmacokinetics

Safety
– Common and serious adverse events in clinical trials included1-3
Infusion-related events (fever, rigors, nausea)
Immune thromocytopenic purpura (ITP)
Cytokine release syndrome
Autoimmune disorders
Transient thrombocytopenia
– As a result of several cases of ITP, including 1 fatal case, a patient
monitoring program was instituted for the remainder of the phase II
trial1
– The most serious observed adverse event was autoimmunity, with
autoimmune thyroid disorders affecting 23%–30% of patients in
clinical trials1,2

Pharmacokinetics
– Serum half-life of approximately 8 days3
– Suppressed B-cells and monocytes for 3 months, CD4+ T-cells for
61Trial
months,
and
CD8+
for 30 months
following
infusion3
1. CAMMS223
Investigators.
N Engl
J Med.T-cells
2008;359:1786-1801.
2. Cohen JA.
Arch Neurol. 2009;66:821-828;
3. Buttmann M, et al. Exp Rev Neurother. 2008;8:433-455.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T cell NK cells
CD 25
T cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T cell
ODC
Lymphocyte-targeted therapies
T cell
Fingolimod
Dimethyl fumarate
T cell T cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T cell
CD 52
B cell
B cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtsey of Dr. Augusto Miravalle.
Laquinimod
Mechanism of Action
An immunomodulator derivative of linomide1

Anti-inflammatory properties of laquinimod are attributed
to
– Effects on MHC-II gene transcription
– Stimulation of neurotrophins and neurotrophic factor
– Activation of anti-inflammatory pathways
– Promotion of apoptosis in CD8+ and B-cells
– Inhibition of CD14+ and natural killer cells

As a consequence, there is cytokine balance in favor of
anti-inflammatory Th2/Th3 cytokines, with suppression of
proinflammatory and cytokine related genes2
1. Cohen JA. Arch Neurol. 2009;66:821-828. 2. Yang JS, et al. J Neuroimmunol. 2004;156:3-9.
Laquinimod
Clinical Experience

Phase II trial1
– Patients with relapsing-remitting MS (RRMS)
– Significant decreases in the number of active lesions vs placebo
– No significant difference in relapses or disability progression vs
placebo

Phase IIb trial2
– Patients with RRMS
– Daily dose 0.6 mg
– Significantly reduced MRI disease activity (cumulative number of
gadolinium-enhancing lesions) by 60% vs placebo

Phase III trials3,4
– 2 trials (ALLEGRO, BRAVO) for the treatment of RRMS currently
under way
1. Polman C, et al. Neurology. 2005;64:987-991. 2. Comi G, et al. Lancet. 2008;371:2085-2092. 3. ClinicalTrials.gov. 2010.
Available at: http://www.clinicaltrials.gov/ct2/show/NCT00509145. 4. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00605215.
Laquinimod
Safety and Pharmacokinetics

Safety
– Serious adverse events included Budd-Chiari syndrome and
menometrorrhagia with myofibroma1
– Other adverse events included arthralgia, eye pain, chest
pain, menstrual disorders, and mild dose-dependent
increases in liver enzymes1,2

Pharmacokinetics
– Based on preclinical animal studies, high oral bioavailability,
and low total clearance rate3
1. Comi G, et al. Lancet. 2008;371:2085-2092. 2. Polman C, et al. Neurology. 2005;64:987-991. 3. Preiningerova J. Expert
Opin Investig Drugs. 2009;18:985-989.
Elevated CD56Bright
Daclizumab
Nonspecific immune modulation
Laquinimod
Dimethyl fumarate (BG00012)
T-cell NK cells
CD 25
T-cell
IL4, NT3, BDNF
Immune sequestration
Fingolimod
T-cell
ODC
Lymphocyte-targeted therapies
T-cell
Fingolimod
Dimethyl fumarate
T-cell T-cell
A
Cell proliferation
Cladribine
Teriflunomide
MØ
Antibody-dependent cell lysis
Alemtuzumab
Rituximab
Ocrelizumab
T-cell
CD 52
B-cell
B-cell
CD 20
BBB
Abbreviations: A, astrocytes; BBB, blood brain barrier; BDNF, brain-derived neurotrophic factor; IL-4, interleukin 4; MØ,
macrophages; NT3, neurotrophin-3; ODC, oligodendrocytes.
Graphic courtesy of Dr. Augusto Miravalle.
Dimethyl Fumarate (BG00012)
Mechanism of Action

Activates nuclear factor E2-related factor 2 (Nrf2) transcriptional
pathway1
Nrf2
•
•
•
•
•
•

Detox enzymes
Antioxidant enzymes
NADPH generating enzymes
GSH biosynthesis enzymes
Chaperones
Ubiquitination/proteasome
NFkB
•
•
•
Proinflammatory cytokines
Leukocyte adhesion molecules
Lymphocyte activation
May also provide a neuroprotective effect by inducing phase II
detoxification genes2,3
–
Eg, NAD(P)H:quinone oxidoreductase-1 (NQO-1)
Abbreviations: GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate; NFκB, nuclear factor κB.
1. Cohen JA. Arch Neurol. 2009;66:821-828. 2. Rammohan KW, et al. Neurology. 2010;74:S47-S53. 3. Wierinckx A, et al. J
Neuroimmunol. 2005; 266:132-143.
Graphic courtesy of Dr. Augusto Miravalle.
Dimethyl Fumarate (BG00012)
Clinical Experience

Phase IIb trial1
– Patients with relapsing-remitting MS
– Significant reduction of new gadoliniumenhancing lesions
– No significant effect on relapse rate

Phase III trials
–
2 trials (DEFINE, CONFIRM) are currently under way2,3
1. Kappos L, et al. Lancet. 2008 25;372:1463-1472. 2. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00420212. 3. ClinicalTrials.gov. 2010. Available at:
http://www.clinicaltrials.gov/ct2/show/NCT00451451.
Dimethyl Fumarate (BG00012)
Safety and Pharmacokinetics

Safety
– The most commonly observed adverse effects in clinical trials
were1
Flushing
Diarrhea
Headache
Pruritis
Nasopharyngitis
Abdominal pain
Nausea

Pharmacokinetics
– Serum half-life of dimethyl fumarate approximately 12 minutes2
– Serum half-life of active metabolite approximately 36 hours2
– Biologic effects are estimated to last even longer2
1. Kappos L, et al. Lancet. 2008 25;372:1463-1472. 2. Lee D-H, et al. Int MS J. 2008;15:12-18.
Social Media in MS
Definition

Social media is the integration of social interaction,
technology, and medicine

Some examples of social media include
– Communication

Blogs

Social networking
– Collaboration/education

Wikipedia

Social bookmarking

Ratings
Communication

Patients-to-patients blogs
– Benefits

Helpful for patients to share and discuss with similar communities daily
life problems

Share symptoms, concerns, and questions on treatment options
– Risks


Potential for assuming that shared answers and advice are based on
scientific evidence
Physicians-to-patients blogs
– Benefits

Facilitate access to answers to common questions
– Risks

Use of this method for emergent-urgent health-related issues

Lack of confidentiality
Collaboration/Education

Physicians-to-physicians blogs
– Benefits

Rapid access and dissemination of information from experts across
geographies and specialties

Improve practice management

Collaborate on difficult case presentations

CME
– Risks


Usually no peer-to-peer review and poor editorial oversight
Networking
– Benefits

Build a referral base or network

Expand your interactions

Search for colleagues
– Risks

Privacy
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