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January 28, 2000
Summary: On January 28, 2000, an advisory panel for the U.S. Food
and Drug Administration recommended that the FDA approve Novantrone®
(mitoxantrone for injection concentrate) to slow worsening of neurologic
disability in secondary-progressive and relapsing-remitting forms of multiple
sclerosis:
- The panel recommended that if approved, intravenous infusions of Novantrone®
should only be used in individuals with normal cardiac function, every
three months at a dose of 12mg/m2.
- Use of Novantrone will require cardiac monitoring when the cumulative
dose exceeds 100 mg/m2, and may be limited to a total dose of 140 mg/m2.
Additional monitoring for immune function will likely be suggested.
- Although the FDA is not required to follow the advisory panel's advice,
it generally does. The drug agency's decision is expected in the near
future.
- According to an Immunex spokesperson, the annual price of Novantrone
to slow worsening of neurologic disability in secondary-progressive
and relapsing-remitting MS would be approximately $3,000.
Details: On January 28, 2000, an advisory panel for the U.S. Food
and Drug Administration recommended that the FDA approve Novantrone®
(mitoxantrone for injection concentrate, distributed by Immunex Corporation,
Seattle) to slow worsening of neurologic disability in secondary-progressive
and relapsing-remitting forms of multiple sclerosis. (Secondary-progressive
MS begins with clearly defined flare-ups, or relapses, with recovery,
followed by progression with or without occasional relapses. Relapsing-remitting
MS involves clearly defined disease relapses with full recovery or with
sequelae (resulting conditions) and residual deficit upon recovery.)
The panel's decision was based on review of a series of clinical studies
on Novantrone conducted over the past ten years in Europe and Canada,
which demonstrated benefit in slowing progression of disability and reducing
accumulation of new lesions in the brain, detected by magnetic resonance
imaging (MRI).
Novantrone is a potent immune suppressing agent that is approved by the
FDA for use in adult myeloid leukemia and for pain associated with certain
forms of prostate cancer. It has multiple modes of action, including inhibition
of proliferation (division) of cells, suppression of immune-system B cells
and helper T cells, and modulation of other immune cells and substances.
Background Studies
The first studies of Novantrone related to MS began in the late 1980s
in laboratory rodents with the MS-like disease EAE, including studies
funded by the National MS Society. Clinical studies in MS began as small,
uncontrolled trials in Europe, also in the late 1980s. Using a variety
of dosages, and studying both relapsing-remitting and progressive forms
of MS, these studies suggested that Novantrone might slow disease progression.
This led to a larger, placebo-controlled, double-blinded clinical study
in 17 centers in 4 European countries involving 194 individuals who were
randomly assigned to one of three treatment groups (low dose --5 mg/m2;
high dose --12 mg/m2; and inactive placebo). Individuals with documented
secondary-progressive MS, with or without relapses, and with modest to
moderate disability (EDSS 3-6), were enrolled. The treatment was delivered
by an intravenous infusion, once every three months for 24 months. Changes
in brain lesions, as determined by annual MRIs, were monitored in over
half of the participants.
At the end of two years significantly fewer high-dose treated patients
than placebo patients showed deterioration in disability of 1 point on
the EDSS rating scale. There was also a statistically significant reduction
in the number of relapses requiring corticosteroid treatment. After an
addition year of post-treatment "follow-up," 17% of the treatment group
deteriorated 1 point on the EDSS compared to 44% of the placebo group,
and there was a 65% reduction in annual relapse rate. Finally, in those
individuals that had annual MRI brain scans, those on Novantrone showed
trends toward reduced accumulation of new lesions.
A second study focusing primarily on MRI was done in 5 French clinical
centers in individuals with highly active MS - with significant progression
of disability and/or 2 or more acute attacks in the previous 12-month
period. Twenty-two of the individuals in the study were given 20 mg/m2
Novantrone monthly by intravenous infusion plus 1 gm/month intravenous
steroids, for 6 months; 22 received monthly steroids only. At the end
of the study, there were significantly lower numbers of active inflammatory
lesions in the brains of Novantrone plus steroid-treated patients compared
with steroid-treated patients alone, and also a slower progression of
disability and reduced relapse rate.
Safety and Side Effects
Short-term safety and tolerability of Novantrone in the MS studies appear
to be acceptable. In all, 603 individuals with MS have been treated in
clinical trials with Novantrone. Among the more common side effects seen
in the two major controlled studies were nausea, hair loss, urinary and
upper respiratory tract infections, and menstrual disorders (in females).
However, dose-related cardiac toxicity has been reported with Novantrone
in cumulative doses exceeding 130-140 mg/m2, primarily in cancer patients.
Although no clinically significant cardiac toxicity was seen in these
MS trials, they studies have been only 2 years or less in duration and
the cumulative dose of Novantrone was less than 100 mg/m2. Longer-term
safety in MS, particularly its impact on cardiac function, has not been
examined.
Next Steps
Although the FDA is not required to follow the advisory panel's recommendations,
it generally does. The FDA should reach a decision about specific details
of labeling of Novantrone in the near future. The panel recommended that
if approved, intravenous infusions of Novantrone should only be used in
individuals with normal cardiac function, every three months at a dose
of 12mg/m2. Use of Novantrone will require cardiac monitoring when the
cumulative dose exceeds 100 mg/m2, and may be limited to a total dose
of 140 mg/m2. Additional monitoring for immune function will likely be
suggested.
While Novantrone may provide an important management agent for disease
progression, because of the dose-related toxicity, it cannot be used without
close monitoring. Additional data will be needed to determine the optimal
use of this medication.
According to an Immunex spokesperson, the annual price of Novantrone
to slow worsening of neurologic disability in secondary-progressive and
relapsing-remitting MS would be approximately $3,000.
Individuals interested in the use of Novantrone in MS should consult
their personal physicians and contact Immunex Corporation at 1-800-IMMUNEX
(1-800-466-8639).
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