Title: Use Of Regularly Scheduled High Dose Intravenous
Methotrexate Therapy, With Interim Administration Of Immunomodulatory
Agents, To Treat Multiple Sclerosis And Other Diseases Of The Central
United States Patent: 6,903,100
Issued: June 7, 2005
Inventors: Rowe; Vernon D. (Kansas City, MO)
Assignee: MidAmerica Neuroscience Research Foundation
(Kansas City, MO)
Appl. No.: 128947
Filed: April 24, 2002
The present invention is directed to the treatment of multiple sclerosis
by periodically administering a high dose of methotrexate at a level
sufficiently high to cross the blood brain barrier. The methotrexate
administration is accompanied by leucovorin rescue of the periphery. The
high dose methotrexate is preferably administered at 1 to 4 month intervals.
The periodic high dose methotrexate treatment may be used in conjunction
with interim treatments using a therapeutic agent that is effective in
treating MS, but does not cross the BBB in cytotoxic amounts. It is
contemplated that the method of the present invention may be employed to
treat other non-infectious, non-neoplastic inflammatory conditions of the
Description of the Invention
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to the treatment of non-infectious, non-neoplastic
inflammatory conditions of the central nervous system using high dose
2. Description of Related Art
Multiple sclerosis (MS) is a demyelinating disease of the central nervous
system (CNS) with unknown cause and no known cure. Though single episodes of
demyelination can occur, once the disease is established in multiple sites
in the brain, spinal cord, and optic nerves, MS frequently follows a
clinically relapsing-remitting course while lesions in the CNS continue to
progress. During this phase, an immune mediated inflammatory response to
myelin antigens is thought to play a major role in the pathogenesis of
developing lesions. Then, in a clinically progressive phase, at least
fifty-five percent of patients worsen, with clinical relapses sometimes
punctuating their clinical decline.
The mechanism of tissue damage to the CNS is not known with certainty in the
progressive phase of MS. It is thought, however, that axonal damage, perhaps
through some type of immune mediation, is important in this phase of the
disease, though some axonal damage certainly occurs during the inflammatory
Perivascular infiltration of T lymphocytes and macrophages in brain lesions
is one of the characteristics of MS. Activation of myelin-reactive T cells
in the periphery is an early event in the MS process. These activated T
cells facilitate the production by B cells of antibodies against myelin, and
activate macrophages to attack oligodendrocytes in the CNS. The functions of
these immune cells are regulated by cytokines in autocrine and paracrine
fashions. Pro-inflammatory cytokines like IFN-γ, and TNF-α could have
disease-promoting roles in MS, whereas anti-inflammatory cytokines, like
IL-4, IL-10 and TGF-β, likely down-regulate the disease. The balance between
pro-inflammatory and anti-inflammatory cytokines may determine the outcome
of injury in MS.
Treatment options for patients with MS are limited. Currently, the primary
drugs used to treat MS are interferons and glatiramer acetate. These drugs
are marketed under the brand names AVONEX by Biogen, Inc.
(interferon-beta-la, recombinant), BETASERON by Berlex Laboratories, Inc.
(interferon-beta-1b, recombinant) and CAPOXONE by Teva Neuroscience, LLC
(copolymer-1, glatiramer acetate), and are often referred to as the "ABC"
treatments. Such treatments have been shown to slow, but not arrest, the
clinical course of progression in progressive MS. Thus, alternative, or
backup, treatment methods are needed.
Certain chemotherapeutic agents, such as methotrexate, mitoxantrone and
cyclophosphamide, have been used to treat MS. Although mitoxantrone and
cyclophosphamide have shown some efficacy against the progression of MS,
they do not cross the blood brain barrier (BBB) into the CNS and
mitoxantrone has limited lifetime use due to toxicity.
Methotrexate is an S-phase chemotherapeutic anti-metabolite, used for the
treatment of various neoplasms, particularly CNS lymphoma. Methotrexate is
also an anti-inflammatory agent and has been used for the treatment of
various autoimmune diseases, such as rheumatoid arthritis and psoriasis.
Methotrexate is a folate analogue which competitively binds and inhibits
dihydrofolate reductase (DHFR), and thus inhibits the synthesis of thymidine
and other compounds requiring methylation for their synthesis by inhibiting
the single carbon transfer necessary for their synthetic pathways.
Methotrexate also promotes the release of adenosine, and this mechanism may
be responsible for its anti-inflammatory activity.
Clinical trials using low-dose methotrexate (7.5 mg/week), administered
orally, in progressive MS, have been shown to impact the course of
progressive MS with minimal toxicity. This treatment option has been widely
adopted in the United States for MS patients in the progressive phase who
are developing upper extremity dysfunction. Some MS centers empirically
treat refractory patients with higher doses (15 mg or 20 mg) orally once a
week. However, when administered orally, the serum level of methotrexate is
not sufficient to cross the BBB in cytotoxic amounts. Thus, while oral
methotrexate treatments show mild improvement in upper extremity strength in
MS patients, a need remains for a treatment that arrests or reverses the
progression of the disease.
Methotrexate has been given intravenously in high enough doses to cross the
blood-brain barrier (BBB) and enter the CNS. The peripheral bone marrow,
immune system, gastrointestinal endothelium and other vital rapidly dividing
tissues can be rescued by an inhibitor of methotrexate, such as leucovorin,
which does not penetrate the BBB. The safety of high dose methotrexate
therapy with leucovorin rescue has been demonstrated. For example, clinical
trials using high dose methotrexate (8 g/m2), administered via a
four hour intravenous (IV) infusion, with leucovorin rescue, have shown
promising results in treating CNS lymphomas with low toxicity. High dose
methotrexate (2.5 g/m2) sporadically administered via IV
infusion, with leucovorin rescue, has similarly shown no significant
toxicity. Further, it is believed no cumulative deficit from repeated
treatments has been reported.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to the treatment of non-infectious,
non-neoplastic inflammatory conditions of the CNS by periodically
administering a high dose of methotrexate at a level sufficiently high to
cross the BBB. Preferably, this periodic high dose treatment is used in
conjunction with interim treatments using a therapeutic agent that does not
cross the BBB.
In one aspect of the present invention, a high dose of methotrexate is
periodically administered to a patient suffering from MS. The periodic high
dose methotrexate treatments preferably are supplemented with regular
interim treatments using one or more therapeutic agents administered at a
level which has therapeutic value in treating MS, but is insufficient to
cause the agent to cross the BBB. In any case, the periodic high dose
methotrexate treatment must be combined with rescue of the periphery using
leucovorin or other methotrexate inhibitor. It has been found that
administration of such a treatment regimen to patients with worsening
symptoms of progressive MS halted the deterioration of the symptoms in every
patient treated, and in some patients, actually resulted in an overall
improved score on the multiple sclerosis functional composite (the "MSFC"),
a standard clinical outcome measurement for MS.
It is believed that by crossing the BBB and entering the CNS, methotrexate
is able to inhibit the mechanism of tissue damage to the CNS in a manner
that cannot be achieved with therapeutic agents that do not cross the BBB.
Specifically, it is believed that the methotrexate enters the CNS and is
able to suppress destructive immune elements resident there, effectively
clearing out the CNS of such destructive immune elements. For long-term
benefits, the high dose methotrexate must be periodically administered to
prevent the destructive inflammatory process from resuming between
treatments. Intervals between periodic high dose methotrexate treatments are
preferably between about one (1) and about four (4) months, more preferably
between about one (1) and about (3) months, and most preferably about two
(2) months. The level of methotrexate administered is preferably high enough
to achieve cytotoxic levels in the CNS, but low enough to minimize toxicity.
The interim treatments suppress the peripheral immune system between the
periodic high dose treatments, thereby further inhibiting the resumption of
disease progression. The interim treatments are preferably administered at a
dose which has therapeutic value. The interim treatments preferably employ
an immunomodulatory agent, such as interferon, glatiramer acetate, low dose
oral methotrexate or others.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENT
The present invention provides a method for treating MS, and other
non-infectious, non-neoplastic inflammatory conditions of the CNS, by
periodically administering a high dose of methotrexate in an amount
sufficient to cross the BBB. It is believed the high dose methotrexate
purges the CNS of immune cells responsible for the destructive inflammatory
process involved in disease formation, thereby inhibiting progression of the
disease. However, left unchecked, destructive immune cells from the
peripheral immune system will ultimately cross the BBB and repopulate the
CNS. Thus, sporadic high dose methotrexate treatments can allow the
accumulation of destructive immune cells in the CNS between treatments,
which prevents long term inhibition of the disease. By periodically purging
the CNS of the destructive immune cells, the periodic high dose treatments
of the present invention prevent the disease from progressing and thereby
provide long term inhibition of the disease.
The high dose treatments preferably are periodically administered at
intervals sufficient to purge the CNS of destructive immune cells and
prevent progression of the disease between treatments. The term
"periodically" as used herein means that high dose treatments are repeated
at regular intervals, as opposed to being repeated, if at all, at sporadic,
unscheduled intervals. Preferably high dose treatments are periodically
administered at intervals between about one (1) to about four (4) months,
more preferably about one (1) to about (3) months, and most preferably the
interval between treatments is about (2) months. Most preferably the
intervals between treatments are uniform.
The high dose methotrexate is administered by IV infusion at a dosage
sufficient to cross the BBB and enter the CNS at a cytotoxic level.
Preferably the dose is between about 0.5 and about 4.0 g/m2, more
preferably between about 1.0 and about 4.0 g/m2, and most
preferably is about 2.0 g/m2. However, lower doses of
methotrexate may be used to achieve the effect of a high dose treatment if
combined with agents and/or treatments which lower the BBB. After
administration of the high dose methotrexate, the peripheral bone marrow,
immune system, gastrointestinal endothelium and other vital rapidly dividing
tissues can be rescued by an inhibitor of methotrexate, such as leucovorin,
which does not penetrate the BBB in a sufficient amount to inhibit the
action of the methotrexate within the CNS.
In a particularly preferred embodiment of the present invention, the
periodic high dose methotrexate treatments are combined with interim
treatments using an immunomodulatory agent that has therapeutic value in
treating MS, but does not cross the BBB. The interim treatments serve to
modulate the peripheral immune system between high dose treatments. More
specifically, the interim treatments, given regularly, presumably suppress
the peripheral immune system, and reduce the rate that cells of the immune
system cross the BBB into the CNS.
The interim treatments may employ any therapeutic agent that has therapeutic
value in treating MS, provided the agent does not cross the BBB in a
cytotoxic amount. Preferably the therapeutic agent is an immunomodulatory
agent and more preferably is selected from the group consisting of
interferon, glatiramer acetate and oral methotrexate. When oral methotrexate
is employed as the interim immunomodulatory agent, it is preferably
administered at a dosage in the range of 5.0 to 20 mg per week, more
preferably 7.5 to 16 mg per week, and most preferably 10 mg per week. Other
immunomodulatory agents may be administered at dosages suitable for the
treatment of relapsing MS, as can be determined by one in the art.
Preferably the interim therapeutic agent may be administered outside of a
The present invention requires that the therapeutic agent be administered at
a level which has therapeutic value in treating MS, but is insufficient to
cause the agent to cross the BBB in a cytotoxic amount. For some therapeutic
agents, no dosage level would be sufficient to cause the agent to cross the
BBB due to the molecular weight of the agent. Thus, the interim
administration of an agent in relatively high doses is contemplated by the
invention, provided that a cytotoxic amount of the agent does not cross the
BBB after administration. As used herein the term "low dose" encompasses any
dose of a therapeutic agent wherein the agent does not cross the BBB in a
cytotoxic amount after administration. Further, although it is contemplated
that some interim therapeutic agent may cross the BBB consistent with the
present invention, provided it is less than a cytotoxic amount, it is
preferred that none of interim therapeutic agent crosses the BBB.
The following example more fully illustrates the present invention:
Ten patients of relapsing progressive MS were treated with bimonthly high
dose intravenous methotrexate with leucovorin rescue, combined with interim
treatment with low dose immunomodulatory agents. Patients included in the
study had a confirmed diagnosis of secondary progressive MS and at least a
three-month history of worsening symptoms. The characteristics of patients
enrolled in this study are summarized in Table 1.
|Summary of Patients Enrolled in Methotrexate Treatment
||A, B, C,
|*A: interferon beta 1a;
|B: interferon beta 1b;
|C: glatiramer acetate;
|M: oral methotrexate.
Methotrexate treatments were given every 2 months for up to 6 treatments.
Methotrexate was administered by IV at a dosage of 1 g/m2 for the
first three treatments. The drug was well tolerated at dose of 1 g/m2
and some of the patients' MSFC scores improved significantly after 3
treatments. The patients were then switched to doses of 2 g/m2 of
methotrexate for three subsequent treatments. Methotrexate was given after
hydration and alkalization, with urine pH 7.0 or greater. The infusion was
followed by continued hydration for several hours.
Each methotrexate treatment was followed by intravenous leucovorin rescue
with 50 mg leucovorin eight hours after the start of the methotrexate
infusion. Oral leucovorin (25 mg) was administered every 6 hours for a total
of 12 doses after intravenous leucovorin rescue, and the serum methotrexate
level measured. If necessary oral leucovorin was continued until the serum
level reached 0.05 μM.
At the time of study entry, all patients were being treated, with interferon
(AVONEX® or BETA-SERON®), glatiramer acetate (COPAXONE®), or oral
methotrexate. These medications were continued between treatments.
The safety results demonstrate that the treatment is safe. No hematological
toxicity was observed. Five patients experienced some nausea with
methotrexate treatment, easily treated with Zofran, a standard anti-emetic.
Only one patient experienced Grade I renal toxicity after one treatment,
whose 2-week follow up creatinine clearance was within acceptable limits and
the next treatment was given. No alopecia was noted.
Five samples of cerebrospinal fluid (CSF) were analyzed for methotrexate,
representing several patients and several time points after methotrexate
infusion of 2 g/m2. The results established that methotrexate
did, in fact, cross the BBB in cytotoxic amounts.
The clinical outcome was determined by MSFC scores at baseline and at two
months follow up visits after each treatment. The MSFC is a clinical outcome
measure, which measures three clinical functions involving hand dexterity,
walking, and cognition. Two tailed paired t-test was used to compare the
results of MSFC.
Clinical assessment with MSFC scores showed significant improvement after
treatment. After one year of treatment, the overall MSFC scores of all the
patients showed some increase. The MSFC results, including the three
subtests, are shown in Table 2.
|Characteristics of Individual Patients and
|Effect of Methotrexate on MSFC
|The patients are listed in decreasing order of improvement as
measured by the MSFC. For all the changes, >+0.1 were considered as
improvement "(+)", <-0.1 were considered as worsening "(-)" and
between -0.1 and +0.1 were considered as unchanged "(o)".
|The 9-HPT: nine-hole peg test; 25-ft walk: timed 25-ft walk; PASAT:
Paced Auditory Serial Addition Test.
As can be seen from Table 2, the overall MSFC scores of the patients
before treatment ranged from -5.83 to +0.44. The maximum increase was +1.28
while the minimum increase was +0.08. The extent of increase did not seem to
correlate with MSFC baseline, the duration of MS or other agents used
between treatment in this small study. Due to variation between each
examination, changes less than 0.1 were considered as unchanged. Thus, seven
patients improved and three patients were unchanged on their MSFC after one
year of treatment. This is particularly significant, in that all patients
had been worsening for at least three months prior to treatment.
Although examination of the subtests showed various results, for each
individual patient, at least one subtest of MSFC was improved after
treatment. For the nine-hole peg test (arm function), 8 patients improved, 1
patient showed a minor worsening and 1 was unchanged. In the timed 25-ft
walk (leg function), 2 patients showed improvement, 1 had a slight worsening
and the other 7 remained unchanged. In the PASAT (cognitive function), 6
patients improved, 2 turned worse and the other 2 remained unchanged. In
summary, analyzing the patients together, there was significant improvement
in mean overall MSFC and nine-hole peg scores after methotrexate treatment
(p<0.05). The improvement was not significant in the 25-ft walk and PASAT
The method of the present invention has been shown to stop the progression
of MS in subjects suffering from progressive MS. Methotrexate is the
preferred therapeutic agent, due to its ability to cross the BBB without
disruption of the BBB. Further, methotrexate is inexpensive compared to
current MS treatments, is relatively non-toxic when accompanied by
leucovorin rescue, and has no established cumulative effects from repeated
treatments. Thus, unlike other chemotherapeutic agents employed for the
treatment of MS that have limited lifetime use because of toxicity,
methotrexate may be administered in high doses over a long period of time.
In view of the success of the treatment regime employed in this study for
treating MS, it is contemplated that the same methodology may be valuable in
treating other non-infectious, non-neoplastic, inflammatory diseases of the
CNS, such as amyotrophic lateral sclerosis (ALS), vasulitis, sarcoid, and
the like. Further, it is contemplated that other agents that can be
administered at a level sufficient to cross the BBB, and do not produce
unacceptable toxicity when administered periodically at such level, may be
employed in the present invention.
From the foregoing it will be seen that this invention is one well adapted
to attain all ends and objectives herein-above set forth, together with the
other advantages which are obvious and which are inherent to the invention.
Since many possible embodiments may be made of the invention without
departing from the scope thereof, is to be understood that all matters
herein set forth or shown in the accompanying drawings are to be interpreted
as illustrative, and not in a limiting sense.
While specific embodiments have been shown and discussed, various
modifications may of course be made, and the invention is not limited to the
specific forms or arrangement of parts and steps described herein, except
insofar as such limitations are included in the following claims. Further,
it will be understood that certain features and sub-combinations are of
utility and may be employed without reference to other features and
sub-combinations. This is contemplated by and is within the scope of the
Claim 1 of 42 Claims
1. A kit for treating a non-infectious non-neoplastic inflammatory
condition of the central nervous system of a human host having a blood
brain barrier comprising:
a dosage of intravenous methotrexate sufficient to cross the blood brain
barrier at a cytotoxic level; and
a plurality of dosages of a second therapeutic agent which has therapeutic
value in treating a condition of the central nervous system.
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