PPARγ agonists for treatment of multiple sclerosis
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Publication Number
US-9867816-B2
Publication Date
2018-01-16
Expiration Date
Abstract
Methods of treatment of multiple sclerosis (MS) with PPARγ agonists, and in particular with the compound of formula (I) known as INT131:
Core Innovation
The patent describes use of the selective PPARγ modulator INT131, also identified as compound (I), to treat multiple sclerosis, including prevention and treatment of relapses in patients with MS. It further positions the treatment as addressing grey matter atrophy and neuroprotection against MS progression, including primary progressive MS and relapsing/remitting MS.
The problem addressed is acute neuroinflammation associated with MS relapse activity, including relapse rates and CNS leukocyte infiltration. The patent uses an experimental autoimmune encephalomyelitis (EAE) model as a rationale, reporting reduced relapse rates and decreased acute CNS leukocyte infiltration, including CD45-positive leukocytes.
To support CNS delivery and timing, the patent provides pharmacokinetic/bioavailability data for INT131 using radiolabeled [3H]INT131. The data are described as showing BBB penetration and time-dependent accumulation in brain/spinal cord versus blood, with delayed CSF accumulation consistent with BBB transport.
Claims Coverage
The independent claim covers treating grey matter atrophy in a patient in need by administering INT131, compound of formula (I), at regular dosing intervals with a therapeutically effective amount. Across dependents, the claim set refines the regular dosing interval and specifies therapeutically effective amounts in milligrams.
Treating grey matter atrophy with regular dosing of compound (I)
A method of treating grey matter atrophy in a patient in need thereof comprising administering to said patient at regular dosing intervals a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
Once-daily regular dosing interval
The method comprising administering the pharmaceutical composition with a regular dosing interval of once per day.
Therapeutically effective amount of about 1 to about 3 milligrams
The method comprising administering a therapeutically effective amount of the compound of formula (I) ranging from about 1 to about 3 milligrams.
Daily dose options of about 1 mg or about 3 mg
The method wherein the therapeutically effective amount is about 1 milligrams per day or about 3 milligrams per day.
Daily dose of about 1 milligram
The method wherein the therapeutically effective amount is about 1 milligrams.
Overall claim coverage centers on administering compound of formula (I), INT131, in a pharmaceutical composition to treat grey matter atrophy using regular dosing intervals. Dependent coverage specifies once-daily dosing and quantifies the therapeutically effective amount in the range of about 1 to about 3 milligrams, including about 1 mg/day and about 3 mg/day, with an additional dependent refinement to about 1 milligram.
Stated Advantages
Reduced relapse rates in the EAE model.
Decreased acute CNS leukocyte infiltration, including CD45-positive leukocytes.
BBB penetration with time-dependent accumulation in brain/spinal cord.
Delayed CSF accumulation consistent with BBB transport.
Expected sparing of gray matter/thalamus atrophy.
Neuroprotection against MS progression.
Documented Applications
Treating grey matter atrophy in a patient in need using INT131 (compound of formula (I)) administered at regular dosing intervals.
Treating multiple sclerosis, including prevention and treatment of relapses, in primary progressive MS and relapsing/remitting MS (RRMS) contexts.
Rationale evaluation in an experimental autoimmune encephalomyelitis (EAE) mouse model, assessing relapse rates and acute CNS leukocyte infiltration (CD45+).
Supporting CNS delivery assessment using radiolabeled [3H]INT131 measurements (brain/spinal cord vs blood and delayed CSF accumulation) described as consistent with BBB transport.
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