|
By Timothy Tankosic, M.D.
According to the National Multiple Sclerosis Society, an
estimated 400,000 Americans have MS, and as many as 2.5
million people worldwide are affected with the disease.
Many important advances in the treatment of MS were
achieved since the early 1990s, when the first agents that
reduced the frequency of MS attacks through activities on
the immune system were introduced. The first of the
following U.S. FDA approvals occurred in 1993--
- Betaseron® (interferon beta-1b; Berlex,
Inc./Schering AG)
- Avonex® (interferon beta-1a; Biogen Idec, Inc.)
- Copaxone® (glatiramer acetate; Teva Pharmaceutical
Industries, Ltd.)
- Novantrone® (mitoxantrone; Serono International, SA)
- Rebif® (interferon beta-1a; Serono/Pfizer, Inc.)
Four of the drugs are approved for life-long use. The
exception is Novantrone, a cancer chemotherapeutic agent
associated with cardiotoxicity, which is restricted to
four (in-hospital) administrations per year for no more
than three years.
Most recently, Tysabri® (natalizumab; Biogen Idec and
Elan Corp.), a humanized MAb alpha-4 antagonist, was
approved by FDA for relapsing multiple sclerosis (November
2004). In February 2005 it was voluntarily suspended from
the U.S. market by the manufacturers, based on reports of
progressive multifocal leukoencephalopathy (PML), a rare
and potentially fatal, demyelinating disease of the CNS.
All ongoing clinical trials were halted. In August, the
companies reported results of a safety evaluation review
that found no new cases of PML among more than 2,000
patients treated for MS in clinical trials and in
commercial use, leaving the total at 3 (previously
reported) confirmed cases; 2 were fatal. Safety
evaluations in Crohn's disease and rheumatoid arthritis
are expected soon, as are submissions to regulatory
agencies. The companies, encouraged by the safety findings
to date, have initiated preliminary steps to restart
clinical trials in MS because of the "high unmet medical
need in MS and the therapeutic benefit we have seen with
Tysabri."
If approved, it is not clear how much of an impact
Tysabri would have on the treatment of MS. Before and
immediately after its approval, analysts had forecast
annual sales of $2 billion to more than $3 billion. One
analyst, Steven Harr of Morgan Stanley, suggests that
Tysabri will become a niche drug, with sales of about $500
million. In addition to fear about causing PML in
patients, he cites broader adverse events associated with
the drug, particularly opportunistic infections (which
might require monitoring), all of which are likely to be
closely scrutinized at FDA and of great interest to the
medical community. Biogen Idec reported to investors that,
in clinical trials, they found no significant differences
between subjects receiving Tysabri and those receiving
placebo.
Table 1 lists select recent events and drugs in
development for MS.
Table 1
|
Multiple
Sclerosis: Select Recent Events and Developmental
Drugs |
|
Compound |
Company |
Indication |
Mechanism of Action |
Development Status |
Comments |
|
Betaseron® (interferon beta-1b) |
Berlex,
Inc. (Montville, NJ)/Schering AG (Berlin, Germany) |
Relapsing MS |
Anti-inflammatory; Inhibitor of gamma interferon |
Phase IV
results positive (WW) |
Preliminary findings: safe for long term use; 16
years later follow-up of pivotal trial subjects |
| Tysabri®
(natalizumab) + Avonex® (interferon beta-1a) |
Biogen
Idec (San Diego, CA)/Elan Corp. (Dublin, Ireland) |
Relapsing MS |
Humanized MAb alpha-4 antagonist; Inhibits
adhesion molecules on immune cells preventing
migration into the brain + IFN-beta-1a |
Withdrawn (U.S., E.U.)
Phase III endpoint met (WW) |
Tysabri
was withdrawn in the U.S. and E.U. because of 3
cases of progressive multifocal
leukoencephalopathy in clinical trial subjects
receiving Tysabri + Avonex® (interferon beta-1a);
Phase III trial was a 3-year study |
| Sativex® |
GW
Pharmaceuticals Plc (Toronto, Canada)/Bayer AG
(Leverkusen, Germany) |
MS and
severe neuropathic pain |
Cannabis
extract; Mouth spray; Components include
tetrahydrocannabinol and cannabidiol |
Approved
(Canada)
Application requires new trial (U.K) |
Bayer
HealthCare will market; Appeal of denial of
approval for MS spasticity lost in the U.K.: new
trial required |
|
Teriflunomide (HMR1726) |
Sanofi-Aventis (Paris, France) |
MS |
Immunomodulator |
Phase
III (France) |
|
| Mylinax®
(cladribine, oral) |
Serono
International, SA (Geneva, Switzerland)/IVAX Corp.
(Miami, FL) |
MS |
Synthetic anti-neoplastic agent; Immunosuppressive |
Phase
III (U.S.) |
|
|
Fampridine-SR |
Acorda
Therapeutics (Hawthorne, NY) |
MS |
Selective neuronal potassium channel blocker |
Phase
III (U.S.) |
To
measure walking ability; Phase III trials for
spinal cord injury did not meet primary endpoints |
| MBP8298 |
BioMS
Medical Corp. (Edmonton, Canada) |
Secondary progressive MS |
Synthetic peptide; May induce or restore
immunological tolerance |
Phase
II/III trial initiated (Canada, U.K.) |
17 amino
acid sequence identical to a section of human
myelin basic protein |
|
Xaliproden (SR 57746) |
Sanofi-Aventis (Paris, France) |
MS |
Neurotrophic |
Phase II
(France) |
|
|
Laquinimod (SAIK-MS) |
Active
Biotech, AB (Lund, Switzerland) |
MS |
Affect
immune function |
Phase II
(Switzerland) |
Partnership agreement with Teva |
| Campath®
(alemtuzumab) |
Genzyme
Corp. (Cambridge, MA) |
MS |
Affect
immune function |
Phase II
(U.S.) |
Vs.
Rebif® (IFN-beta-1a) |
|
Daclizumab |
Protein
Design Labs, Inc. (Fremont, CA) |
MS |
Anti-CD25 binds IL-2 receptor |
Phase
I/II (U.S.) |
|
| N/A |
Serono
International, SA (Geneva, Switzerland) |
MS |
JNK
inhibitor |
Phase I
(U.S.) |
|
| AVE9897 |
Sanofi-Aventis (Paris, France) |
MS |
CCR1
antagonist |
Phase I
(France) |
|
|
Source: D&MD
This clinical
update on Tysabri and select developmental advances for
the treatment of multiple sclerosis was written by Timothy
Tankosic, M.D. He may be contacted via e-mail at
tt888@aol.com. |
