Looking Into the Looking Into the Crystal BallCrystal Ball

Promising Research in Promising Research in Multiple Sclerosis TreatmentMultiple Sclerosis Treatment

What do we need to study in What do we need to study in MS?MS?

Why do people get MS?Why do people get MS? Why do people get different types of MS?Why do people get different types of MS? Why does the course of MS vary so much?Why does the course of MS vary so much? What actual cells are abnormal in MS?What actual cells are abnormal in MS? What are the protein targets in MS?What are the protein targets in MS? What parts of our brain or immune system What parts of our brain or immune system

can we change to alter the course of MS?can we change to alter the course of MS? How do we make life better for MS How do we make life better for MS

Patients?Patients?

Why do People get MS?Why do People get MS? Genetics studiesGenetics studies Environmental StudiesEnvironmental Studies

Genetic StudiesGenetic StudiesTwins studies- If one identical twin has Twins studies- If one identical twin has

MS, the likelihood of the other MS, the likelihood of the other getting it is 25-35%. If one Fraternal getting it is 25-35%. If one Fraternal Twin has MS, the likelihood of the Twin has MS, the likelihood of the other getting it is only 2-3 %other getting it is only 2-3 %

20% of people with MS have a family 20% of people with MS have a family member with MSmember with MS

Some ethnic groups seem to be less Some ethnic groups seem to be less likely to get MS than others- Asians likely to get MS than others- Asians

Genetic StudiesGenetic Studies HLA- DR 2 gene is seen in about 60% of HLA- DR 2 gene is seen in about 60% of

people with MSpeople with MS Two other genes of the immune Two other genes of the immune

system- IL-2 Receptor and IL-7 Receptor system- IL-2 Receptor and IL-7 Receptor genes have a small association with MSgenes have a small association with MS

Many other genes are likely to play a Many other genes are likely to play a role and are being studied at presentrole and are being studied at present

Likely a risk factor based on more than Likely a risk factor based on more than one genetic factorone genetic factor

Environmental StudiesEnvironmental Studies SunlightSunlight Epstein-Barr VirusEpstein-Barr Virus Chlamydia PneumoniaeChlamydia Pneumoniae Radon?Radon? Vitamin DVitamin D Other viruses and bacteriaOther viruses and bacteria Other environmental proteins or Other environmental proteins or

chemicalschemicals

Why do people get different Why do people get different types of MS?types of MS?

Direct Brain studiesDirect Brain studies MRI studiesMRI studies Blood StudiesBlood Studies Changes in the pattern of the spinal fluid Changes in the pattern of the spinal fluid

in more progressive MSin more progressive MS Comparing the severity of the course of Comparing the severity of the course of

the disease to other measuresthe disease to other measures Finding better measures of disease Finding better measures of disease

progressprogress

Direct Brain StudiesDirect Brain Studies Samples of brains from MS patients studied to Samples of brains from MS patients studied to

compare the different types of brain lesions seen.compare the different types of brain lesions seen. 4 different sub-types recognized4 different sub-types recognized Attempts to compare to clinical course are not yet Attempts to compare to clinical course are not yet

completely successfulcompletely successful Some are also attempting to compare the MRI Some are also attempting to compare the MRI

findings of these types.findings of these types. Problems- MRIs aren’t as useful on people who Problems- MRIs aren’t as useful on people who

have diedhave died People who have biopsies done to diagnose their People who have biopsies done to diagnose their

MS have an unusual type of MS or a biopsy would MS have an unusual type of MS or a biopsy would not be needed not be needed

MRI studiesMRI studies MRI is a good tool to look at MS, but MRI is a good tool to look at MS, but

no single MRI measure correlates well no single MRI measure correlates well with the clinical picture of MS (some with the clinical picture of MS (some people with really bad looking MRIs people with really bad looking MRIs have mild disease and Vice-versa)have mild disease and Vice-versa)

New MRI techniques- MR New MRI techniques- MR Spectroscopy, Magnetization Transfer Spectroscopy, Magnetization Transfer Imaging, Functional MRI, and other Imaging, Functional MRI, and other tools may help measure disease tools may help measure disease activity in other ways.activity in other ways.

Basic ScienceBasic Science Answering the questions of actual Answering the questions of actual

molecular causes and activity in MS molecular causes and activity in MS allows for the identification of ways of allows for the identification of ways of changing the diseasechanging the disease

Animal Models that we can manipulateAnimal Models that we can manipulate Blood studiesBlood studies Tissue culturesTissue cultures DNA studiesDNA studies

What cells or parts of Cells are What cells or parts of Cells are abnormal in MS? abnormal in MS?

Inflammation- T cells and B cells and Inflammation- T cells and B cells and adhesion Moleculesadhesion Molecules

Oxidative Stress- Free radical Oxidative Stress- Free radical production production

Repair mechanismsRepair mechanismsEarly cell deathEarly cell deathLoss of Axons- the role of myelin in Loss of Axons- the role of myelin in

maintaining axonsmaintaining axons

What are the protein targets in What are the protein targets in MSMS

Different protein Targets in different Different protein Targets in different types of MS?types of MS?

The same target for everyone?The same target for everyone? Spreading of targets as the disease Spreading of targets as the disease

progresses?progresses?

How can we alter the course of How can we alter the course of MS?MS?

Identifying target actions by the Identifying target actions by the above studiesabove studies

Developing drugs that alter the Developing drugs that alter the actions uncovered by other studiesactions uncovered by other studies

Testing drugs in animal models and Testing drugs in animal models and then in humansthen in humans

Looking at the risk-benefit ratio of Looking at the risk-benefit ratio of different drugs.different drugs.

What about repair?What about repair?

Phases of drug trialsPhases of drug trials Phase I- can this drug be safely given to Phase I- can this drug be safely given to

people or to people with this disease? people or to people with this disease? Usually a small study looking at safety onlyUsually a small study looking at safety only

Phase II- finding a dose that can be given Phase II- finding a dose that can be given and using a group of people to see if this and using a group of people to see if this looks as if it might be effectivelooks as if it might be effective

Phase III- large controlled trial to determine Phase III- large controlled trial to determine if this drug is actually beneficial in the if this drug is actually beneficial in the diseasedisease

Phase IV- testing of the drug after it is Phase IV- testing of the drug after it is found to be useful to understand better all found to be useful to understand better all the side effects and uses of the drugthe side effects and uses of the drug

Drugs for RRMS in phase III Drugs for RRMS in phase III trialstrials

CladribineCladribine TeraflunamideTeraflunamide FingolimodFingolimod BG- 12BG- 12 LaquinimodLaquinimod Alemtuzumab (Campath)Alemtuzumab (Campath) Combination Avonex and CopaxoneCombination Avonex and Copaxone

CladribineCladribine Oral Drug that blocks a certain type Oral Drug that blocks a certain type

of T-cellof T-cell Didn’t work in Secondary progressive Didn’t work in Secondary progressive

MSMS Phase 3 trial ongoing in Relapsing MSPhase 3 trial ongoing in Relapsing MS Major risk of infectionMajor risk of infection

TeriflunomideTeriflunomide Oral Medication with promising results in Oral Medication with promising results in

the Phase II trials the Phase II trials Phase III study ongoingPhase III study ongoing Blocks the proliferation of Lymphocytes so Blocks the proliferation of Lymphocytes so

that the immune response is not as great to that the immune response is not as great to a given proteina given protein

Similar to a drug given in Rheumatoid Similar to a drug given in Rheumatoid ArthritisArthritis

Concerns about Liver toxicity and infectionsConcerns about Liver toxicity and infections

FingolimodFingolimod Oral drug that prevents lymphocytes Oral drug that prevents lymphocytes

from leaving the lymph nodes S-1P from leaving the lymph nodes S-1P inhibitorinhibitor

Phase 2 trial with 50% reduction in Phase 2 trial with 50% reduction in clinical disease activity clinical disease activity

Two Phase 3 trials are ongoingTwo Phase 3 trials are ongoing Safety concerns- heart block, melanoma, Safety concerns- heart block, melanoma,

retinal problems, asthma, increased risk retinal problems, asthma, increased risk of infections, liver problemsof infections, liver problems

BG00012BG00012 Oral drug similar to a psoriasis drug Oral drug similar to a psoriasis drug

called Fumadermcalled Fumaderm Phase 2 trial was promising- showed Phase 2 trial was promising- showed

a reduction in inflammatory activity a reduction in inflammatory activity by 68% by MRIby 68% by MRI

Phase 3 trial is ongoing- compares Phase 3 trial is ongoing- compares BG12 with copaxone and placeboBG12 with copaxone and placebo

Concerns about Kidney and liver Concerns about Kidney and liver function and low blood countsfunction and low blood counts

LaquinimodLaquinimod Oral drug that acts as an Oral drug that acts as an

immunomodulator. immunomodulator. Mechanism of action isn’t certainMechanism of action isn’t certain Phase 2 trial showed a reduction of Phase 2 trial showed a reduction of

active lesions by 50% and new lesions by active lesions by 50% and new lesions by 44%44%

Phase 3 trial ongoingPhase 3 trial ongoing Side effect profile is fairly mild at Side effect profile is fairly mild at

present, but some concern about Liver present, but some concern about Liver problems or low blood countsproblems or low blood counts

Combi-RXCombi-RX Does combining Copaxone and Does combining Copaxone and

interferon work better than either interferon work better than either drug alone?drug alone?

Study to compare Avonex to Study to compare Avonex to Copaxone to both drugs combinedCopaxone to both drugs combined

No placebo Group, but everyone No placebo Group, but everyone takes injections for bothtakes injections for both

Alemtuzumab (Campath)Alemtuzumab (Campath) IV drug given for 5 days once a year.IV drug given for 5 days once a year. Phase II trial showed a reduction in Phase II trial showed a reduction in

relapses of about 70% compared to relapses of about 70% compared to RebifRebif

Risk of Grave’s DiseaseRisk of Grave’s Disease Risk of ITPRisk of ITP Risk of unusual infectionsRisk of unusual infections Not useful in SPMSNot useful in SPMS

RRMS drugs in Phase II trialsRRMS drugs in Phase II trials CDP 323CDP 323 Rituximab/ OcrelizumabRituximab/ Ocrelizumab DaclizumabDaclizumab EstriolEstriol

CDP 323CDP 323 VLA-4 inhibitorVLA-4 inhibitor Likely to work like Tysabri to Likely to work like Tysabri to

decrease influx of inflammatory cells decrease influx of inflammatory cells into the nervous system.into the nervous system.

Initial studies are promisingInitial studies are promising Phase II trial open to RRMS or SPMS Phase II trial open to RRMS or SPMS

with Relapseswith Relapses

DaclizumabDaclizumab Antibody against the IL-2 ReceptorAntibody against the IL-2 Receptor Conflicting studies- phase I open Conflicting studies- phase I open

label with the IV form looks a little label with the IV form looks a little more promising than the the Phase II more promising than the the Phase II trial with the subcutaneous injectiontrial with the subcutaneous injection

RituximabRituximab An antibody against the B cells- used An antibody against the B cells- used

in a lot of different autoimmune in a lot of different autoimmune diseasesdiseases

Phase II trial showed a major reduction Phase II trial showed a major reduction in active lesions compared to placeboin active lesions compared to placebo

The humanized version of the drug, The humanized version of the drug, Ocrelizumab is now in Phase II testingOcrelizumab is now in Phase II testing

EstriolEstriol Because it is well known that pregnant Because it is well known that pregnant

women do better than normal during women do better than normal during their pregnancy, studies into different their pregnancy, studies into different estrogens have begun.estrogens have begun.

A mouse study with Estriol, an estrogen A mouse study with Estriol, an estrogen found in high quantities in pregnant found in high quantities in pregnant women showed a good effectwomen showed a good effect

Phase II trial in combination with Phase II trial in combination with Copaxone is ongoingCopaxone is ongoing

Secondary Secondary Progressive MS Progressive MS

ABT-874—antibody that inhibits certain protiens that promote immunity. Now in phase II trial in SPMS

MBP8298—synthetic protein fragment or peptide may make immune system tolerant of myelin. Phase II/III study in SPMS is underway

Primary Progressive MSPrimary Progressive MS Rituximab trial did not show any Rituximab trial did not show any

significant difference, but some hint significant difference, but some hint that certain subgroups of PPMS might that certain subgroups of PPMS might benefitbenefit

Fingolimod trial started in PPMSFingolimod trial started in PPMS

How do we make life better for How do we make life better for MS Patients?MS Patients?

Symptomatic TreatmentsSymptomatic Treatments RehabilitationRehabilitation New devices to improve mobility New devices to improve mobility

FampridineFampridine Known as 4 amino Pyridine or 4-AP, this Known as 4 amino Pyridine or 4-AP, this

drug is believed to improve function drug is believed to improve function through the damaged parts of the through the damaged parts of the brain.brain.

Recent study showed an improvement Recent study showed an improvement in walking speed in about 40% of peole in walking speed in about 40% of peole who tried itwho tried it

Presently being presented to the FDA Presently being presented to the FDA for possible approvalfor possible approval

Provigil and R-ModafanilProvigil and R-Modafanil Some suggestion of assistance in Some suggestion of assistance in

fatiguefatigue We plan to study it in cognitive We plan to study it in cognitive

function in the near future.function in the near future.

RehabilitationRehabilitation Many ongoing studies to evaluate Many ongoing studies to evaluate

exercise for MS patientsexercise for MS patients Cognitive re-training studiesCognitive re-training studies Walk-aideWalk-aide New electronic walking devices used New electronic walking devices used

for paraplegic patientsfor paraplegic patients

Future directions of Future directions of ResearchResearch

Repair and regeneration of new Repair and regeneration of new myelinmyelin

Stop the ongoing degeneration and Stop the ongoing degeneration and atrophy and preserve dying cellsatrophy and preserve dying cells

Find more specific ways to block the Find more specific ways to block the immune response in MS onlyimmune response in MS only

Stem CellsStem Cells Some types of stem cells can be used Some types of stem cells can be used

to replace the bone marrow if a to replace the bone marrow if a person undergoes chemotherapy and person undergoes chemotherapy and has her own Bone marrow wiped out. has her own Bone marrow wiped out.

Commonly done in cancer patients, Commonly done in cancer patients, but with a lot of toxicity and riskbut with a lot of toxicity and risk

Studied in severe, rapidly worsening Studied in severe, rapidly worsening MSMS

Mesenchymal Stem CellsMesenchymal Stem Cells This is a technique of taking bone This is a technique of taking bone

marrow stem cells from a person, marrow stem cells from a person, changing them by growing them in changing them by growing them in culture, and and the n injecting them culture, and and the n injecting them back into the blood of a person with back into the blood of a person with MS. MS.

May alter the immune response to May alter the immune response to change the course of MS, possibility of change the course of MS, possibility of also aiding in repairalso aiding in repair

Stem Cell RepairStem Cell Repair One of the most exciting theories is to use One of the most exciting theories is to use

stem cells for repair- encourage the cells to stem cells for repair- encourage the cells to become a new cell that will replace a become a new cell that will replace a damaged cell- new myelin producing cells, or damaged cell- new myelin producing cells, or new brain cellsnew brain cells

Need to find ways to stimulate the proper Need to find ways to stimulate the proper types of cells, get the cells to right places in types of cells, get the cells to right places in the brain, encourage them to actually replace the brain, encourage them to actually replace the damaged cells, and to stop growing when the damaged cells, and to stop growing when they are at the right density.they are at the right density.

Lots of research needs to be done to figure out Lots of research needs to be done to figure out how this would best be used.how this would best be used.

What to know about clinical What to know about clinical trialstrials

Placebo ControlPlacebo Control Need for comparisons and clinical Need for comparisons and clinical

accuracyaccuracy Trying a drug that might not workTrying a drug that might not work Unforeseen side effects Unforeseen side effects