Transcript Looking Into the Crystal Ball

Looking Into the Crystal
Ball
Promising Research in Multiple
Sclerosis Treatment
What do we need to study in MS?







Why do people get MS?
Why do people get different types of MS?
Why does the course of MS vary so much?
What actual cells are abnormal in MS?
What are the protein targets in MS?
What parts of our brain or immune system can
we change to alter the course of MS?
How do we make life better for MS Patients?
Why do People get MS?
Genetics studies
 Environmental Studies

Genetic Studies
Twins studies- If one identical twin has MS,
the likelihood of the other getting it is 2535%. If one Fraternal Twin has MS, the
likelihood of the other getting it is only 2-3
%
20% of people with MS have a family
member with MS
Some ethnic groups seem to be less likely to
get MS than others- Asians
Genetic Studies
HLA- DR 2 gene is seen in about 60% of
people with MS
 Two other genes of the immune systemIL-2 Receptor and IL-7 Receptor genes
have a small association with MS
 Many other genes are likely to play a role
and are being studied at present
 Likely a risk factor based on more than
one genetic factor

Environmental Studies
Sunlight
 Epstein-Barr Virus
 Chlamydia Pneumoniae
 Radon?
 Vitamin D
 Other viruses and bacteria
 Other environmental proteins or chemicals

Why do people get different types
of MS?






Direct Brain studies
MRI studies
Blood Studies
Changes in the pattern of the spinal fluid in
more progressive MS
Comparing the severity of the course of the
disease to other measures
Finding better measures of disease progress
Direct Brain Studies
Samples of brains from MS patients studied to compare
the different types of brain lesions seen.
 4 different sub-types recognized
 Attempts to compare to clinical course are not yet
completely successful
 Some are also attempting to compare the MRI findings
of these types.
 Problems- MRIs aren’t as useful on people who have
died
 People who have biopsies done to diagnose their MS
have an unusual type of MS or a biopsy would not be
needed

MRI studies
MRI is a good tool to look at MS, but no
single MRI measure correlates well with
the clinical picture of MS (some people
with really bad looking MRIs have mild
disease and Vice-versa)
 New MRI techniques- MR Spectroscopy,
Magnetization Transfer Imaging,
Functional MRI, and other tools may help
measure disease activity in other ways.

Basic Science
Answering the questions of actual
molecular causes and activity in MS allows
for the identification of ways of changing
the disease
 Animal Models that we can manipulate
 Blood studies
 Tissue cultures
 DNA studies

What cells or parts of Cells are
abnormal in MS?
Inflammation- T cells and B cells and
adhesion Molecules
Oxidative Stress- Free radical production
Repair mechanisms
Early cell death
Loss of Axons- the role of myelin in
maintaining axons
What are the protein targets in MS
Different protein Targets in different types
of MS?
 The same target for everyone?
 Spreading of targets as the disease
progresses?

How can we alter the course of
MS?
Identifying target actions by the above
studies
 Developing drugs that alter the actions
uncovered by other studies
 Testing drugs in animal models and then
in humans
 Looking at the risk-benefit ratio of
different drugs.
 What about repair?

Phases of drug trials
Phase I- can this drug be safely given to people
or to people with this disease? Usually a small
study looking at safety only
 Phase II- finding a dose that can be given and
using a group of people to see if this looks as if
it might be effective
 Phase III- large controlled trial to determine if
this drug is actually beneficial in the disease
 Phase IV- testing of the drug after it is found to
be useful to understand better all the side
effects and uses of the drug

Drugs for RRMS in phase III trials
Cladribine
 Teraflunamide
 Fingolimod
 BG- 12
 Laquinimod
 Alemtuzumab (Campath)
 Combination Avonex and Copaxone

Cladribine
Oral Drug that blocks a certain type of Tcell
 Didn’t work in Secondary progressive MS
 Phase 3 trial ongoing in Relapsing MS
 Major risk of infection

Teriflunomide





Oral Medication with promising results in the
Phase II trials
Phase III study ongoing
Blocks the proliferation of Lymphocytes so that
the immune response is not as great to a given
protein
Similar to a drug given in Rheumatoid Arthritis
Concerns about Liver toxicity and infections
Fingolimod
Oral drug that prevents lymphocytes from
leaving the lymph nodes S-1P inhibitor
 Phase 2 trial with 50% reduction in clinical
disease activity
 Two Phase 3 trials are ongoing
 Safety concerns- heart block, melanoma,
retinal problems, asthma, increased risk of
infections, liver problems

BG00012
Oral drug similar to a psoriasis drug called
Fumaderm
 Phase 2 trial was promising- showed a
reduction in inflammatory activity by 68%
by MRI
 Phase 3 trial is ongoing- compares BG12
with copaxone and placebo
 Concerns about Kidney and liver function
and low blood counts

Laquinimod
Oral drug that acts as an
immunomodulator.
 Mechanism of action isn’t certain
 Phase 2 trial showed a reduction of active
lesions by 50% and new lesions by 44%
 Phase 3 trial ongoing
 Side effect profile is fairly mild at present,
but some concern about Liver problems or
low blood counts

Combi-RX
Does combining Copaxone and interferon
work better than either drug alone?
 Study to compare Avonex to Copaxone to
both drugs combined
 No placebo Group, but everyone takes
injections for both

Alemtuzumab (Campath)
IV drug given for 5 days once a year.
 Phase II trial showed a reduction in
relapses of about 70% compared to Rebif
 Risk of Grave’s Disease
 Risk of ITP
 Risk of unusual infections
 Not useful in SPMS

RRMS drugs in Phase II trials
CDP 323
 Rituximab/ Ocrelizumab
 Daclizumab
 Estriol

CDP 323
VLA-4 inhibitor
 Likely to work like Tysabri to decrease
influx of inflammatory cells into the
nervous system.
 Initial studies are promising
 Phase II trial open to RRMS or SPMS with
Relapses

Daclizumab
Antibody against the IL-2 Receptor
 Conflicting studies- phase I open label
with the IV form looks a little more
promising than the the Phase II trial with
the subcutaneous injection

Rituximab
An antibody against the B cells- used in a
lot of different autoimmune diseases
 Phase II trial showed a major reduction in
active lesions compared to placebo
 The humanized version of the drug,
Ocrelizumab is now in Phase II testing

Estriol
Because it is well known that pregnant
women do better than normal during their
pregnancy, studies into different estrogens
have begun.
 A mouse study with Estriol, an estrogen
found in high quantities in pregnant
women showed a good effect
 Phase II trial in combination with
Copaxone is ongoing

Secondary
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 MS
Rituximab trial did not show any
significant difference, but some hint that
certain subgroups of PPMS might benefit
 Fingolimod trial started in PPMS

How do we make life better for MS
Patients?
Symptomatic Treatments
 Rehabilitation
 New devices to improve mobility

Fampridine
Known as 4 amino Pyridine or 4-AP, this
drug is believed to improve function
through the damaged parts of the brain.
 Recent study showed an improvement in
walking speed in about 40% of peole who
tried it
 Presently being presented to the FDA for
possible approval

Provigil and R-Modafanil
Some suggestion of assistance in fatigue
 We plan to study it in cognitive function in
the near future.

Rehabilitation
Many ongoing studies to evaluate exercise
for MS patients
 Cognitive re-training studies
 Walk-aide
 New electronic walking devices used for
paraplegic patients

Future directions of Research
Repair and regeneration of new myelin
 Stop the ongoing degeneration and
atrophy and preserve dying cells
 Find more specific ways to block the
immune response in MS only

Stem Cells
Some types of stem cells can be used to
replace the bone marrow if a person
undergoes chemotherapy and has her own
Bone marrow wiped out.
 Commonly done in cancer patients, but
with a lot of toxicity and risk
 Studied in severe, rapidly worsening MS

Mesenchymal Stem Cells
This is a technique of taking bone marrow
stem cells from a person, changing them
by growing them in culture, and and the n
injecting them back into the blood of a
person with MS.
 May alter the immune response to change
the course of MS, possibility of also aiding
in repair

Stem Cell Repair
One of the most exciting theories is to use stem
cells for repair- encourage the cells to become a
new cell that will replace a damaged cell- new
myelin producing cells, or new brain cells
 Need to find ways to stimulate the proper types
of cells, get the cells to right places in the brain,
encourage them to actually replace the damaged
cells, and to stop growing when they are at the
right density.
 Lots of research needs to be done to figure out
how this would best be used.

What to know about clinical
trials
Placebo Control
 Need for comparisons and clinical accuracy
 Trying a drug that might not work
 Unforeseen side effects
