Methods for treating heterotopic ossification
Inventors
Desjardins, Clarissa • GROGAN, Donna Roy • PACKMAN, Jeffrey Neal • Harnett, Mark
Assignees
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Publication Number
US-12201614-B2
Publication Date
2025-01-21
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 document relates to reducing heterotopic ossification in a subject with fibrodysplasia ossificans progressiva by orally administering palovarotene in an oral daily dosing regimen that depends on whether the subject is experiencing a flare-up symptom or not. The regimen includes administering a low daily amount during periods when the subject is not experiencing any flare-up symptom, and administering a higher daily amount during periods when the subject is experiencing at least one flare-up symptom.
After a flare-up-associated period, the document provides a transition to a reduced maintenance daily amount for a period of at least 56 days. The document also defines determining that the subject is experiencing tolerance problems and reducing the dose of palovarotene administered to the subject.
The flare-up symptom is defined using a selectable list of flare-up symptoms, including swelling, pain, erythema, warmth, stiffness, and decreased range of motion. The dosing framework is weight-specific in dependent claims, and the document reports imaging-based outcomes indicating reduced new heterotopic ossification volume when dosing includes both quiescent and non-quiescent periods.
Claims Coverage
The independent claims are clm-00001, clm-00008, clm-00012, and clm-00015, each directed to reducing heterotopic ossification in fibrodysplasia ossificans progressiva using weight- and flare-up-period-dependent oral palovarotene dosing, followed by tolerance-driven palovarotene dose reduction. Across the independent claims, the main inventive features are a flare-up dependent dosing phase, a reduced maintenance phase after 28 days, and a tolerance-problems-driven dose reduction step, with weight ranges and specific dose amounts defining the dosing regimen.
Flare-up-dependent oral palovarotene dosing with quiescent low daily amount
During a period when the subject is not experiencing any flare-up symptom, orally administering daily to the subject an amount of palovarotene, or a pharmaceutically acceptable salt thereof, and during a period when the subject is experiencing at least one flare-up symptom, orally administering to the subject an amount of palovarotene, or a pharmaceutically acceptable salt thereof, daily for a period of 28 days.
Post-28-day reduced maintenance palovarotene dosing
After the period of 28 days, orally administering an amount of palovarotene, or a pharmaceutically acceptable salt thereof, daily for a period of at least 56 days.
Tolerance-problems determination and palovarotene dose reduction
Determining that the subject is experiencing tolerance problems, and reducing the dose of palovarotene administered to the subject.
Weight-range specific flare-up dosing regimen
Configuring the dosing regimen for a subject weighing from 10 to 20 kg, or from 20 to 40 kg, or from 40 to 60 kg, with corresponding daily palovarotene amounts during non-flare-up and flare-up periods and the corresponding reduced maintenance amount after the 28-day period.
Collectively, the independent claims cover a method that orally administers palovarotene based on flare-up presence, includes a defined 28-day flare-associated dosing followed by a reduced maintenance dosing for at least 56 days, and incorporates determining tolerance problems followed by reducing the palovarotene dose, with weight ranges and specific dose amounts used to define the dosing regimen.
Stated Advantages
Reduced new heterotopic ossification volume when dosing includes both quiescent and non-quiescent periods.
Documented Applications
Reducing heterotopic ossification in a subject with fibrodysplasia ossificans progressiva using flare-up dependent oral palovarotene dosing combined with quiescent and non-quiescent periods.
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