Methods for treating heterotopic ossification
Inventors
Desjardins, Clarissa • GROGAN, Donna Roy • PACKMAN, Jeffrey Neal • Harnett, Mark
Assignees
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Publication Number
US-12138245-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The invention features dosing regimens and pharmaceutical formulations for oral administration of palovarotene. The dosing regimens can reduce heterotopic ossification, reduce the number of flare-ups, and/or reduce the severity of flare-ups in subjects suffering from fibrodysplasia ossificans progressiva.
Core Innovation
The invention describes a method of reducing heterotopic ossification in a subject with fibrodysplasia ossificans progressiva by orally administering palovarotene, or a pharmaceutically acceptable salt thereof, in a regimen that depends on whether the subject is experiencing flare-up symptoms. The method distinguishes dosing during a period when the subject is not experiencing any flare-up symptom from dosing during a period when the subject is experiencing at least one flare-up symptom.
The regimen sets palovarotene daily amounts based on subject weight ranges and flare-up state, including lower daily dosing during non-flare periods and higher daily dosing during flare-up periods. After an initial flare-up dosing period of 28 days, the method provides a lower daily palovarotene dose for at least 56 days, and the lower daily dose continues for extended durations beyond the baseline minimum when flare-up symptoms persist.
The disclosed approach is grounded in the problem that flare-up treatment initiated after symptom onset may be too late, and that prolonged dosing incorporating quiescent and non-quiescent periods is used to reduce new heterotopic ossification volume. The document indicates that a regimen combining a chronic quiescent dosing phase with a prolonged non-quiescent flare-related dosing phase markedly reduces heterotopic ossification volume versus placebo, untreated, or non-quiescent-only regimens, with described imaging outcomes.
Claims Coverage
The document provides three independent claims directed to reducing heterotopic ossification in subjects with fibrodysplasia ossificans progressiva, with each independent claim specifying weight range selection and a flare-up-state-specific oral palovarotene dosing schedule. The main inventive features are the weight-based dosing groups, the two-stage dosing structure, and the specified dosing amounts and durations.
Weight-based palovarotene dosing with flare-up state
Administering palovarotene, or a pharmaceutically acceptable salt thereof, orally according to a regimen that distinguishes a period when the subject is not experiencing any flare-up symptom from a period when the subject is experiencing at least one flare-up symptom, with dosing continuing after the flare-up period.
2.5 mg then 10 mg for 28 days followed by at least 56 days of 5 mg (10 to 20 kg)
For a subject weighing from 10 to 20 kg, administering 2.5 mg daily during a period with no flare-up symptoms, administering 10 mg daily for 28 days during a period with at least one flare-up symptom, and after the 28 days, administering 5 mg daily for a period of at least 56 days.
3 mg then 12.5 mg for 28 days followed by at least 56 days of 6 mg (20 to 40 kg)
For a subject weighing from 20 kg to 40 kg, administering 3 mg daily during a period with no flare-up symptoms, administering 12.5 mg daily for 28 days during a period with at least one flare-up symptom, and after the 28 days, administering 6 mg daily for a period of at least 56 days.
4 mg then 15 mg for 28 days followed by at least 56 days of 7.5 mg (40 to 60 kg)
For a subject weighing from 40 kg to 60 kg, administering 4 mg daily during a period with no flare-up symptoms, administering 15 mg daily for 28 days during a period with at least one flare-up symptom, and after the 28 days, administering 7.5 mg daily for a period of at least 56 days.
Across the independent claims, the claim coverage centers on reducing heterotopic ossification in fibrodysplasia ossificans progressiva subjects by orally administering palovarotene using a weight-based regimen that changes daily dose depending on whether flare-up symptoms are present, followed by a lower-dose post-flare period of at least 56 days.
Stated Advantages
Reduces heterotopic ossification in a subject with fibrodysplasia ossificans progressiva.
Documented Applications
Treatment method for reducing heterotopic ossification in a subject with fibrodysplasia ossificans progressiva using oral palovarotene dosing based on quiescent versus flare-up periods.
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