Medical Update Memo
Originally posted September
22, 2006
Updated November 3, 2006 and January 29, 2007
Summary
Results of a Phase II controlled clinical trial of oral fingolimod
(also known as FTY720) have been published in The New England
Journal of Medicine. The study found fingolimod significantly
reduced MS attack rates and signs of inflammation on MRI
scans. Fingolimod binds to a docking site (sphingosine-1-phosphate
receptor, or S1P receptor) on immune cells, including T cells
and B cells that have been implicated in causing nervous
system
damage in MS. The once-a-day pill induces them to remain
in lymph nodes, preventing these cells from migrating into
the
brain and spinal cord. A larger Phase III clinical trial
is underway at 125 centres worldwide, including 10 in Canada.
Results from the Phase III studies are needed before marketing
approval of fingolimod can be obtained. Novartis Pharmaceuticals
Corp is sponsoring the study.
Details
The results of the Phase II controlled clinical trial of oral
fingolimod (also known as FTY720) published recently in The
New England Journal of Medicine (2006;355(11):1124-1139)
by Ludwig Kappos, MD (University Hospital, Basel, Switzerland)
and colleagues were previously reported at medical meetings.
The investigators conducted a double-blind, placebo-controlled
study involving 255 participants with active, relapsing MS
at various study sites around the world, including Canada.
After six months, active inflammation on MRI scans was significantly
reduced in two groups receiving 1.25 mg or 5 mg of daily fingolimod,
versus those on placebo, and more people in the treatment group
versus placebo group stayed relapse-free. MS attacks were reduced
by more than 50 percent , as was the number of new active (enhancing)
MS lesions as shown on MRI scans. Fingolimod binds to a docking
site (sphingosine-1-phosphate receptor, or S1P receptor) on
immune cells, including T cells and B cells that have been
implicated in causing nervous system damage in MS. The once-a-day
pill induces them to remain in lymph nodes, preventing these
cells from migrating into the brain and spinal cord.
In a six-month extension of the original study, people in
the treatment groups continued on the same dose, and people
in the placebo group received either 1.25 mg or 5 mg of fingolimod.
In all, 227 people completed the extension study. The relapse
rate in placebo group participants switched to 1.25 mg was
reduced by seven percent, and in those switched to 5 mg,
it was reduced by 86 percent. Significant reductions in active
inflammation were seen on MRI scans in both groups formerly
on placebo. In groups continuing on fingolimod, relapse rates
and signs of active inflammation on MRI remained low.
In the original study, adverse events – mainly inflammation
of the nasal passages, breathing difficulties, headache,
diarrhea, and nausea – occurred more often in people
receiving 5 mg of fingolimod. A brain infection occurred
after 10 weeks of treatment in one person taking 5 mg, which
improved after treatment was withdrawn, but has resulted
in some neurological damage.
Adverse events were less frequent in the extension study,
and were mainly nasal inflammation, flu, and headache. Two
serious infections occurred, including facial herpes and
an infection of the colon. Other adverse events associated
with fingolimod were alterations in liver function, reduction
in heart rate after the first dose, decreases in blood cell
counts, and breathing difficulties.
In an accompanying editorial, Drs. Steffen Massberg and Ulrich
H. von Andrian (Harvard Medical School) comment on these
adverse events. They note that heart rate and breathing difficulties
are not surprising, because S1P is involved in the regulation
of heart rate and in the proliferation of cells in the airway.
Newer compounds that target specific docking sites of S1P
might help to avoid such side effects. “All inhibitors
of this pathway would need to be evaluated for their potential
to increase the patient’s susceptibility to infections,” the
authors caution.
A large-scale, Phase III study is underway that will eventually
involve 100 centres worldwide, although not all sites are
recruiting yet. The study is called FREEDOMS (FTY720 Research
Evaluating Effects of Daily Oral therapy in MS). This 24-month
study is comparing the safety and effectiveness of daily
treatment with 1.25 mg fingolimod, 0.5 mg fingolimod, or
inactive placebo in more than 2,000 people with relapsing-remitting
MS (a course of MS characterized by clearly defined flare-ups
followed by partial or complete recovery periods). The primary
outcome that will be measured is the reduction of relapse
rate, and secondary outcomes will include frequency of relapse,
disease activity on MRI scans, and time to progression of
disability. Results from such Phase III studies are needed
before Novartis could apply for marketing approval of fingolimod.
[With information from the National MS Society (USA)]
Canadian clinical trial sites
Dalhousie University, MS Research Unit, Halifax, Trudy
L. Campbell, 902-473-7947
Maisonneuve-Rosemont Hospital, Neurology Research Clinic,
Montreal, Dr. Jacques Lachapelle, 514-252-3400, #3298
Nepean Medical Centre, Ottawa, Isabelle D. Bedirian, Clinical
Trials Coordinator, 613-224-1223
Kingston General Hospital, MS Clinic, Kingston, Dr. Donald
G. Brunet or Vee McBride 613-548-2308
St. Michael's Hospital, Toronto, Dr. Paul O'Connor, 416-864-5830
University of Saskatchewan, Regina, Felix Veloso, Principal
Investigator 306-525-3586
University of British Columbia, Vancouver, Wendy Morrison,
Study Coordinator, 604-822-1756
ASK MS Information System Code: 1.4.1.75.b
National Research Department
National Marketing and Communications Department
Disclaimer
The Multiple Sclerosis Society of Canada is an independent,
voluntary health agency and does not approve, endorse or
recommend any specific product or therapy but provides
information to assist individuals in making their own decisions.
