EA042153B1 - METHODS FOR THE TREATMENT OF HETEROTOPIC OSSIFICATION - Google Patents

Description

Related Applications

This application under the Patent Cooperation Treaty claims priority over US Patent Application No. 62/347381, filed June 8, 2016, which is incorporated herein by reference in its entirety.

State of the art

Some patients with progressive fibrodysplasia ossificans (POF) experience muscle, tendon, and/or ligament involvement, such as soft tissue swelling and muscle necrosis, with mostly sudden onset of symptoms. These spontaneous lesions of muscles, tendons and/or ligaments, as well as injuries that result from trauma, can lead to heterotopic ossification and can be accompanied by unbearable pain and limit the functionality of the person having such a lesion. There are currently no approved treatments for muscle, tendon and/or ligament injury in subjects with POF that prevent heterotopic ossification.

The essence of the invention

The invention relates to a method for reducing heterotopic ossification in a human subject with progressive fibrodysplasia ossificans, said method comprising: (i) during a period when the subject is not experiencing any symptoms of an attack, orally administering to the subject palovarotene or a pharmaceutically acceptable salt thereof in an amount of 5 mg per day, and (ii) during the period when the subject is experiencing at least one attack symptom, oral daily administration to the subject of palovarotene or a pharmaceutically acceptable salt thereof in an amount of 20 mg for 28 days, and after 28 days, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 10 mg for a period of at least 56 days.

The invention also relates to a method for reducing heterotopic ossification in a human subject with progressive ossifying fibrodysplasia, where the subject weighs from 10 to 20 kg, and this method includes: (i) during the period when the subject does not experience any symptoms of an attack, oral daily administration to the subject 2.5 mg of palovarotene or a pharmaceutically acceptable salt thereof, and (ii) during the period when the subject is experiencing at least one symptom of an attack, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 10 mg for 28 days , and after 28 days oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 5 mg for a period of at least 56 days.

The invention also relates to a method for reducing heterotopic ossification in a human with progressive ossifying fibrodysplasia, where the subject weighs from 20 to 40 kg, and this method includes: (i) during the period when the subject does not experience any symptoms of an attack, oral daily administration to the subject palovarotene or a pharmaceutically acceptable salt thereof in an amount of 3 mg, and (ii) during the period when the subject experiences at least one symptom of an attack, oral daily administration to the subject of palovarotene or a pharmaceutically acceptable salt in an amount of 12.5 mg for 28 days, and after 28 days, oral daily administration to the subject of 6 mg of palovarotene or a pharmaceutically acceptable salt thereof for a period of at least 56 days. The invention also relates to a method for reducing heterotopic ossification in a human with progressive fibrodysplasia ossificans, comprising: (i) during the period when the subject does not experience any symptom of an attack, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 4 mg, and (ii) during the period when the subject is experiencing at least one symptom of an attack, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 15 mg for 28 days, and after 28 days, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in the amount of 7.5 mg for at least 56 days.

Description of graphic materials

In FIG. 1 is a graph showing the effects of seizures in a double blind study of 40 subjects.

In FIG. 2 is a graph showing the effects of seizures in an open-label study of 27 subjects.

In FIG. 3A and 3B are graphs showing a comparison of the volume of new heterotopic ossification in (i) episodic treatment of patients with POF (i.e. treatment only during periods of exacerbation and (ii) when using the treatment regimens of this invention, which include treatment for both a period of Patients in the placebo/no treatment group received a sugar-filled tablet or received nothing (28 patients) Patients in the PVO group only during the flare period received either 20 mg palovarotene (PVO) daily for 28 days followed by 10 mg PVO daily for 56 days (47 patients) or 10 mg PVO daily for 14 days followed by 5 mg PVO daily for 28 days (9 patients) Patients in the rest/flare PVO group received 5 mg PVO daily during the rest period and 20 mg PVO daily for 28 days (loading dose PO), followed by 10 mg PVO daily during those

- 1 042153 56 days (maintenance dose PO) after the onset of symptoms of an attack, i.e. the beginning of the exacerbation period (10 patients). In FIG. 3A shows the results of the three groups with two doses of PVO for the flare period only, and FIG. 3B shows the results of administering two doses of PVO only during the exacerbation period, as separate columns. In FIG. 3B demonstrates that doubling the amount of palovarotene administered only during periods of exacerbation had little effect on the amount of new heterotopic ossification (ie, 2.672 mm ³ vs. 2.216 mm ³ ). In contrast, the amount of new heterotopic ossification was drastically reduced when treatment included administering palovarotene during both the rest period and the exacerbation period (ie, 212 mm ³ ).

Detailed Description of the Invention

The present invention provides dosing regimens and pharmaceutical formulations for oral administration of palovarotene. Through these regimens, it is possible to reduce heterotopic ossification, reduce the number of seizures and/or reduce the severity of seizures in subjects suffering from progressive ossifying fibrodysplasia. The earlier clinical studies on the treatment of fibrodysplasia with palovarotene were designed to provide rescue therapy during periods of exacerbation with the assumption: (i) that new bone formation to a large extent would occur immediately after an attack; (ii) that treatment beginning within 7 days of the onset of an attack will be sufficient to reduce or prevent heterotopic ossification; and (iii) that treatment limited to periods of no more than 6 weeks will be sufficient to prevent heterotopic ossification. The rationale for treating seizures is based on the observation that POF is a chronic disease characterized by episodes of acute attacks that lead to the formation of new foci of heterotopic ossification and progressive disability. Alternating with periods of active attacks (i.e. periods of exacerbation), there are intervals of varying lengths of apparent non-exacerbation of the disease during which clinical symptoms do not occur and it is not known whether bone formation occurs or not.

These studies demonstrate that initiation of treatment within 7 days of the onset of an attack may be too late to significantly reduce heterotopic ossification, as bone formation may begin before the symptoms of an attack are recognized. In addition, the results of this study suggest that long-term treatment may be required to ensure that the subject benefits from palovarotene treatment at the onset of the bone formation process, during and after the onset of an attack. Finally, the results of this study demonstrate that short-term treatment (i.e., treatment limited to a 6-week period) may not be sufficient because in some patients, areas of new heterotopic ossification appeared after 6 weeks (but were not observed during the treatment period).

Finally, we did not observe adverse effects on the growth plate, as confirmed by knee and hand/wrist radiographs in children receiving short-term 6-week treatment; from which it can be concluded that longer treatment in children may be feasible.

The present invention can optimize earlier treatment protocols by (i) providing administration of palovarotene for an extended term (ie, daily) during periods of rest; (ii) increasing the dose level during periods of exacerbation after attacks; and (iii) increasing the timing of dosing during periods of exacerbation to reduce late-onset new heterotopic ossification. Treatment given daily during periods of rest (eg, 5 mg daily), with more intense treatment during attacks (eg, higher doses of 20 or 10 mg daily, for 84, 112, or 140 days after onset of an attack) may provide exposure to palovarotene throughout the course of the disease and may improve the efficacy of treatment in patients with POF.

The present invention provides dosing regimens and pharmaceutical formulations for oral administration of palovarotene.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans (also known as progressive myositis ossificans, a disease characterized by damage to muscle tissue), characterized by a period of rest and a period of exacerbation, while this method includes: (i) during the period of rest - daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 3±2 mg; and (ii) during the period of exacerbation - daily administration to the subject of an amount 2-6 times the amount administered daily during the rest period. In specific embodiments of the present invention, during an flare-up period, palovarotene or a pharmaceutically acceptable salt thereof is initially administered at a daily loading dose of 3.5 to 6 times the amount administered daily during the rest period, followed by a daily maintenance dose of more than 2 -3 times the amount administered daily during the dormant period. For example, the amount administered during the rest period may be 3±0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 12.5±1.0 mg

- 2 042153 per day and a daily maintenance dose of 6.0±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is between 20 and 40 kg. In another example, the amount administered during the rest period may be 4±0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 15±1.0 mg per day and a daily maintenance dose of 7. 5±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is between 40 and 60 kg. In another example, the amount administered during the rest period may be 5±0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 20±1.0 mg per day and a daily maintenance dose of 10 ±1.0 mg per day. Optionally, for this administration regimen, the weight of the subject is greater than 60 kg. In some embodiments of the invention, the amount administered during the rest period is 2±0.5 mg per day and the amount administered during the flare period comprises a daily loading dose of 10±1.0 mg per day and a daily maintenance dose of 5 ±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is less than 20 kg. In any of the above methods, the daily loading dose is administered over a period of 20 to 40 days (e.g., 24±4, 28±4, 32±4, 36±4 days, or 20, 21, 22, 23, 24, 25, 26 , 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 days). In specific embodiments of this invention, the daily maintenance dose is administered for at least a period of time from 14 to 84 days (for example, 21±7, 28±14, 42±14, 63±14, 72±12 days, or 52, 53, 54, 55, 56, 57, 58, 58, 60 or 84 days). Optionally, after 84 days, administration of the daily maintenance dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or continue administration of the maintenance dose until the symptoms of attacks or an attack do not weaken or stop. In specific embodiments of the invention, after 112 days, the daily maintenance dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience seizure or attack symptoms, or the maintenance dose is continued until until the symptoms of seizures or an attack subside or stop. In some embodiments of the present invention, a daily loading dose of 20 mg is administered for 28 days, a daily maintenance dose of 10 mg is administered for 56 days, and the amount administered during the rest period is 5 mg/day. In some embodiments of the present invention, a daily loading dose of 15 mg is administered for 28 days, a daily maintenance dose of 10 mg is administered for 56 days, and the amount administered during the rest period is 5 mg/day. Once the flare period has subsided, the subject may return to the dormant regimen at a lower dose level.

In one embodiment, this invention relates to a method of reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans, characterized by periods of rest and exacerbation, which method includes: (i) the introduction of 3.0+/-2.0 mg/day of palovarotene or its a pharmaceutically acceptable salt during periods of rest, and (ii) administering an amount between 10 mg/day of palovarotene or a pharmaceutically acceptable salt thereof and 20 mg/day of palovarotene or a pharmaceutically acceptable salt thereof within 84-140 days after the onset of the flare period.

In one embodiment, this invention relates to a method of reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by periods of rest and exacerbation, which method includes: (i) the introduction of 5 mg/day of palovarotene or its pharmaceutically acceptable salt during periods of rest, and (ii) administration of 20 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for 28 days, followed by administration of 10 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for 56 days after the onset of the flare period. In a further embodiment, the invention relates to a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by periods of rest and periods of exacerbation, said method comprising: (i) administering 5 mg/day of palovarotene or a pharmaceutically acceptable salt thereof during periods of rest and (ii) administration of 20 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for 28 days, followed by administration of 10 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for 84 days after the onset of the flare period. In yet another further embodiment, this invention relates to a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by periods of rest and periods of exacerbation, which method comprises: (i) administering 5 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for rest periods and (ii) administering 20 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for 28 days followed by 10 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for 112 days after the onset of the flare period.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of

- 3 042153 house of exacerbation, while the specified method during the period of exacerbation includes: (i) administration to the subject of a loading dose in an amount of 9 to 21 mg of palovarotene or its pharmaceutically acceptable salt daily during the first period of time and (ii) after the first period of time daily administration to the subject of a maintenance dose of 40 to 60% of the amount administered in the loading dose. In some embodiments of this invention, the loading dose is 12.5±1.0 mg per day and the maintenance dose is 6.0±1.0 mg per day. Optionally, the weight of the subject is between 20 and 40 kg. In other embodiments of this invention, the loading dose is 15±1.0 mg per day and the maintenance dose is 7.5±1.0 mg per day. Optionally, the weight of the subject is between 40 and 60 kg. In some embodiments of this invention, the loading dose is 20±1.0 mg per day and the maintenance dose is 10±1.0 mg per day. Optionally, the subject's weight is greater than 60 kg. In any of the above methods, the loading dose is administered over a period of 20 to 40 days (e.g., 24±4, 28±4, 32±4, 36±4 days, or 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 days). In specific embodiments of this invention, the maintenance dose is administered over at least a period of time from 14 to 84 days (for example, 21±7, 28±14, 42±14, 63±14, 72±12 days, or 52, 53 , 54, 55, 56, 57, 58, 58, 60 or 84 days).). Optionally, after 84 days, the maintenance dose is continued for a further 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the maintenance dose is continued until the symptoms of an attack or attack subside. or won't stop. In specific embodiments of the present invention, after 112 days, the daily maintenance dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the maintenance dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing the severity of attacks or an attack of symptoms in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, while this method includes: (i) during the period of rest - daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in the amount 3±2 mg and (ii) during an aggravation period, daily administration to the subject of an amount 2-6 times the amount administered daily during the rest period. In specific embodiments of the present invention, during an flare-up period, palovaroten or a pharmaceutically acceptable salt thereof is initially administered at a daily loading dose of 3.5 to 6 times the amount administered daily during the rest period, followed by a daily maintenance dose of more than 2 -3 times the amount administered daily during the dormant period. For example, the amount administered during the rest period may be 3 ± 0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 12.5 ± 1.0 mg per day and a daily maintenance dose of 6 .0±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is between 20 and 40 kg. In another example, the amount administered during the rest period may be 4±0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 15±1.0 mg per day and a daily maintenance dose of 7 .5±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is between 40 and 60 kg. In yet another example, the amount administered during the rest period may be 5±0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 20±1.0 mg per day and a daily maintenance dose. 10±1.0 mg per day. Optionally, for this administration regimen, the weight of the subject is greater than 60 kg. In some embodiments of the present invention, the amount administered during the rest period is 2±0.5 mg per day and the amount administered during the flare period comprises a daily loading dose of 10±1.0 mg per day and a daily maintenance dose 5±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is less than 20 kg. In any of the above methods, the daily loading dose is administered over a period of 20 to 40 days (eg, 24±4, 28±4, 32±4, or 36±4 days). In specific embodiments of this invention, the daily maintenance dose is administered for at least a period of time from 14 to 84 days (eg, 21±7, 28±14, 42±14, 63±14, or 72±12 days). Optionally, after 84 days, the daily maintenance dose is continued for an additional 28 days if the subject continues to experience symptoms of an attack or attacks, or the maintenance dose is continued until the symptoms of an attack or attack subside or cease. In specific embodiments of the method, the number of seizures in the subject is reduced, or the frequency of seizures in the subject is reduced. Once the flare period has subsided, the subject may return to the dormant regimen at a lower dose level.

In one embodiment, this invention relates to a method of reducing attacks or an attack of symptoms in a subject with progressive ossifying fibrodysplasia, characterized by periods of rest and exacerbation, this method includes: (i) the introduction of 3.0+/-2.0

- 4,042,153 mg/day of palovarotene or a pharmaceutically acceptable salt thereof during rest periods and (ii) administering an amount between 10 mg/day of palovarotene or a pharmaceutically acceptable salt thereof and 20 mg/day of palovarotene or a pharmaceutically acceptable salt thereof for 84-140 days after the onset of the exacerbation period.

The present invention provides a method for reducing the frequency of seizures in a subject with progressive fibrodysplasia ossificans, characterized by a period of rest and a period of exacerbation, while this method includes: (i) during the period of rest - daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 3±2 mg and (ii) during an aggravation period, daily administration to the subject of an amount 2-6 times the amount administered daily during the rest period. In specific embodiments of the present invention, during an flare-up period, palovaroten or a pharmaceutically acceptable salt thereof is initially administered at a daily loading dose of 3.5 to 6 times the amount administered daily during the rest period, followed by a daily maintenance dose of more than 2 -3 times the amount administered daily during the dormant period. For example, the amount administered during the rest period may be 3 ± 0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 12.5 ± 1.0 mg per day and a daily maintenance dose of 6 .0±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is between 20 and 40 kg. In another example, the amount administered during the rest period may be 4±0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 15±1.0 mg per day and a daily maintenance dose of 7 .5±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is between 40 and 60 kg. In yet another example, the amount administered during the rest period may be 5±0.5 mg per day, and the amount administered during the flare period may include a daily loading dose of 20±1.0 mg per day and a daily maintenance dose. 10±1.0 mg per day. Optionally, for this administration regimen, the weight of the subject is greater than 60 kg. In some embodiments of the present invention, the amount administered during the rest period is 2±0.5 mg per day and the amount administered during the flare period comprises a daily loading dose of 10±1.0 mg per day and a daily maintenance dose 5±1.0 mg per day. Optionally, for this administration schedule, the weight of the subject is less than 20 kg. In any of the above methods, the daily loading dose is administered over a period of 20 to 40 days (eg, 24±4, 28±4, 32±4, or 36±4 days). In specific embodiments of this invention, the daily maintenance dose is administered for at least a period of time from 14 to 84 days (eg, 21±7, 28±14, 42±14, 63±14, or 72±12 days). Optionally, after 84 days, the daily maintenance dose is continued for an additional 28 days if the subject continues to experience symptoms of an attack or attacks, or the maintenance dose is continued until the symptoms of an attack or attack subside or cease. In specific embodiments of the method, the number of seizures in the subject is reduced, or the frequency of seizures in the subject is reduced. Once the flare period has subsided, the subject may return to the dormant regimen at a lower dose level.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, which method comprises: (i) during the period of rest, administering to the subject a first amount of a BMP signaling inhibitor daily, and (ii) during period of exacerbation - daily administration to the subject of an amount 2-6 times the amount administered daily during the rest period. In specific embodiments of the present invention, during the flare period, the BMP signaling inhibitor is initially administered at a daily loading dose of 3.5 to 6 times the amount administered daily during the rest period, followed by a daily maintenance dose of 2 to 3 times the amount administered daily during the dormant period. In some embodiments, the BMP signaling inhibitor is an activin receptor-like kinase 2 (ALK2) inhibitor. Specifically, the ALK2 kinase inhibitor is LDN-193189 (4-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone), LDN-212854 (5-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline), dorsomorphine (6[4-[2-(1-piperidinyl)ethoxy]phenyl ]-3-(4-pyridinyl)pyrazolo[1,5-a]pyrimidine), K02288 (3-[(6-amino-5(3,4,5-trimethoxyphenyl)-3-pyridinyl]phenol), DMH- 1 (4-[6-[4-1-methylethoxy)phenyl]pyrazolo[1.5a]pyrimidin-3-yl]quinoline) or ML-347 (5-[6-(4-methoxyphenyl)pyrazole[1.5 -a]pyrimidin-3-yl]quinolone).

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, said method comprising: (i) during the period of rest, administering to the subject daily palovarotene or a pharmaceutically acceptable salt thereof in an amount of 5 mg, and (ii) during the period of exacerbation, daily administration to the subject of 20 mg of palovarotene or a pharmaceutically acceptable salt thereof for 28 days, followed by daily administration of 10 mg of palovarotene to the subject

- 5 042153 or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the 10 mg daily dose is continued for an additional 28 days (i.e., 84 days in total) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until the symptoms of attacks or the attack will not weaken or stop. In some embodiments of the invention, after 84 days have elapsed, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days have elapsed, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans, characterized by a period of rest and a period of exacerbation, and the weight of the subject is from 10 to 20 kg, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in an amount of 2.5 mg and (ii) during the period of exacerbation - daily administration to the subject of 10 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration to the subject of 5 mg of palovarotene or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the 5 mg daily dose is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the 5 mg dose is continued until the symptoms of an attack or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days, the daily 5 mg dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 5 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the daily 5 mg dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 5 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans, characterized by a period of rest and a period of exacerbation, and the weight of the subject is from 20 to 40 kg, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in an amount of 3 mg and (ii) during the period of exacerbation - daily administration to the subject of 12.5 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration to the subject of 6 mg of palovarotene or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the 6 mg daily dose is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the 6 mg dose is continued until the symptoms of attacks or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days have elapsed, the daily 6 mg dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 6 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the 6 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 6 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans, characterized by a period of rest and a period of exacerbation, and the weight of the subject is from 40 to 60 kg, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in an amount of 4 mg and (ii) during the period of exacerbation - daily administration to the subject of 15 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration to the subject of 7.5 mg of palovarotene or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the dose of 7.5 mg is continued until until the symptoms of seizures or an attack subside or stop. In some embodiments of the present invention, after 84 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the administration of a dose of 7.5 mg until the symptoms of attacks or an attack weaken or stop. IN

- 6 042153 specific embodiments of this invention, after 112 days, the daily dose of 7.5 mg is continued for another 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the dose is continued 7 .5 mg until seizure or attack symptoms subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, and the weight of the subject is 60 kg or more, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in an amount of 5 mg and (ii) during the period of exacerbation - daily administration to the subject of 20 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration to the subject of 10 mg of palovarotene or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until the symptoms of an attack or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days have elapsed, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, the method comprising: (i) during the period of rest, administering to the subject daily palovarotene or a pharmaceutically acceptable salt thereof in an amount of 4 mg, and (ii) during the flare period, administering to the subject 15 mg of palovarotene or a pharmaceutically acceptable salt thereof daily for 28 days followed by daily administration to the subject of 7.5 mg of palovarotene or a pharmaceutically acceptable salt thereof for at least 56 days. Optionally, after 56 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the dose of 7.5 mg is continued until until the symptoms of seizures or an attack subside or stop. In some embodiments of the present invention, after 84 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the administration of a dose of 7.5 mg until the symptoms of attacks or an attack weaken or stop. In specific embodiments of this invention, after 112 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the administration of a dose of 7.5 mg until the symptoms of attacks or an attack weaken or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans, characterized by a period of rest and a period of exacerbation, and the weight of the subject is from 10 to 20 kg, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in an amount of 1 mg and (ii) during the period of exacerbation - daily administration to the subject of 7.5 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration to the subject of 3 mg of palovarotene or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the 3 mg daily dose is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the 3 mg dose is continued until the symptoms of attacks or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days have elapsed, the daily 3 mg dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 3 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the 3 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 3 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans, characterized by a period of rest and a period of exacerbation, and the weight of the subject is from 20 to 40 kg, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutical use

- 7 042153 lemoy salt in the amount of 2.5 mg and (ii) during the period of exacerbation - daily administration to the subject of 10 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration of 5 mg of palovarotene or its pharmaceutically acceptable salt to the subject for at least 56 days. Optionally, after 56 days, the 5 mg daily dose is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the 5 mg dose is continued until the symptoms of attacks or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days, the daily 5 mg dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 5 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the 5 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 5 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive ossifying fibrodysplasia characterized by a period of rest and a period of exacerbation, and the weight of the subject is from 40 to 60 kg, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in an amount of 3 mg and (ii) during the period of exacerbation - daily administration to the subject of 12.5 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration to the subject of 6 mg of palovarotene or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the daily maintenance dose is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or continue with a dose of 6 mg until the symptoms of an attack or an attack will not weaken or stop. In some embodiments of the present invention, after 84 days, the daily 6 mg dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 6 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the daily 6 mg dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 6 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, and the weight of the subject is 60 kg or more, while this method includes: (i) during the period of rest - daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in the amount of 4 mg and (ii) during the period of exacerbation - daily administration to the subject of 15 mg of palovarotene or its pharmaceutically acceptable salt for 28 days, followed by daily administration to the subject of 7.5 mg of palovarotene or its pharmaceutically acceptable salt for at least 56 days. Optionally, after 56 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 84 days) if the subject continues to experience symptoms of an attack or attacks, or the dose of 7.5 mg is continued until until the symptoms of seizures or an attack subside or stop. In some embodiments of the present invention, after 84 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the administration of a dose of 7.5 mg until the symptoms of attacks or an attack weaken or stop. In specific embodiments of this invention, after 112 days, the daily dose of 7.5 mg is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the administration of a dose of 7.5 mg until the symptoms of attacks or an attack weaken or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, said method comprising: (i) during the period of rest, administering to the subject daily palovarotene or a pharmaceutically acceptable salt thereof in an amount of 5 mg, and (ii) during the flare period, administering to the subject 10 mg of palovarotene or a pharmaceutically acceptable salt thereof daily for at least 56 days. Optionally, after 56 days, the 10 mg daily dose is continued for an additional 28 days (i.e., 84 days in total) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until the symptoms of attacks or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days have elapsed, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or seizures

- 8 042153 weaken or not stop. In specific embodiments of the present invention, after 112 days, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, said method comprising: (i) during the period of rest, administering to the subject daily palovarotene or a pharmaceutically acceptable salt thereof in an amount of 5 mg, and (ii) during the flare period, daily administration to the subject of 15 mg of palovarotene or a pharmaceutically acceptable salt thereof for 28 days followed by daily administration of 10 mg of palovarotene or its pharmaceutically acceptable salt to the subject for at least 56 days. Optionally, after 56 days, the 10 mg daily dose is continued for an additional 28 days (i.e., 84 days in total) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until the symptoms of attacks or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days have elapsed, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

The present invention provides a method for reducing heterotopic ossification in a subject with progressive fibrodysplasia ossificans characterized by a period of rest and a period of exacerbation, said method comprising: (i) during the period of rest, administering to the subject daily palovarotene or a pharmaceutically acceptable salt thereof in an amount of 5 mg, and (ii) during the flare period, administering to the subject 10 mg of palovarotene or a pharmaceutically acceptable salt thereof daily for 28 days followed by daily administration to the subject of 10 mg of palovarotene or a pharmaceutically acceptable salt thereof for at least 56 days. Optionally, after 56 days, the 10 mg daily dose is continued for an additional 28 days (i.e., 84 days in total) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until the symptoms of attacks or the attack will not weaken or stop. In some embodiments of the present invention, after 84 days have elapsed, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 112 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop. In specific embodiments of the present invention, after 112 days, the 10 mg daily dose is continued for an additional 28 days (i.e., a total of 140 days) if the subject continues to experience symptoms of an attack or attacks, or the 10 mg dose is continued until until the symptoms of seizures or an attack subside or stop.

In any of the above methods, the subject may be an adult. Alternatively, the subject may be a child or adolescent who has not reached 90% skeletal maturity.

In any of the above methods, the method may further comprise administering an antihistamine agent to the subject (eg, topically or systemically).

In any of the above methods, the method may further include applying an emollient to the subject's skin.

In any of the above methods, the method may further comprise administering a corticosteroid agent to the subject (eg, topically or systemically).

In this context, the term heterotopic ossification or HO refers to the presence of bone in soft tissues where bone is normally absent. HO may be due to progressive fibrodysplasia ossificans, a rare genetic disorder.

As used herein, the term reduction in seizure frequency refers to a reduction in the number or frequency of seizures in subjects treated with palovarotene using the methods described herein compared to untreated subjects.

In this context, the term rest period refers to periods of time during which a subject with POF does not experience a period of exacerbation.

As used herein, the term flare-up period refers to periods of time during which a subject with POF experiences an attack or is at risk of heterotopic ossification triggered by an attack or surgery.

In this context, the term reduction in seizure severity refers to the average reduction in the intensity of one or more symptoms of an attack in subjects treated with palovarotene using the methods described herein, compared with subjects

- 9 042153 not receiving treatment.

In this context, the term reduction in heterotopic ossification refers to the average reduction in the amount of bone formed, or the number of sites where bone is formed, in the soft tissues of subjects treated with palovarotene using the methods described herein, compared with untreated subjects.

In this context, the term attack refers to symptoms associated with local inflammation at the anatomical site where HO begins to form. In subjects with POF, a local attack is characterized by swelling, pain, erythema, fever, stiffness, and limited range of motion that precedes overt bone formation. Such local inflammation and initial stages of injury may be associated with the presence and accumulation of innate immune cells, including mast cells, which are believed to play an important role in inducing and initiating the process of HO formation. As a consequence, the current standard of care for patients with POF is to administer systemic corticosteroids no more than 24 hours after the onset of an attack, with treatment continued for several days to reduce inflammation and pain. However, corticosteroids have not been shown to completely prevent HO. Seizures are often caused by trauma and may include, for example, seizures following surgery to remove bone from soft tissue in a subject with POF. The methods described herein may be suitable for the treatment of patients with POF after surgery.

I. Progressive ossifying fibrodysplasia (POF).

Presented in this invention, the scheme of administration of palovarotene reduce muscle damage and heterotopic ossification in a subject with POF. Palovarotene (also called 4-[(1E)-2-[5,6,7,8tetrahydro-5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-2-naphthalenyl]ethyl ] benzoic acid) is a selective retinoic acid receptor gamma (RARy) agonist having the structure

O

In some embodiments of this invention, palovarotene is administered to a subject with POF in accordance with the administration schemes described herein. POF is a rare, severely disabling disease characterized by painful, recurrent episodes of soft tissue swelling (attacks) and abnormal heterotopic ossification (HO) in muscles, tendons, and ligaments. Seizure symptoms, progression, and frequency in patients with POP are well documented (e.g., Pignolo, R.J. et al. J. Bone Miner. Res. 31, 650-656 (2016)).

In some embodiments of the present invention, the lesions occur in early childhood and result in progressive ankylosis of the large joints, followed by loss of motion. The prognosis of the disease is poor with an average life expectancy of 40 years. POF is caused by an activating mutation in the bone morphogenetic protein (BMP) type I receptor or activin receptor 1A (ACVR1), also known as the activin-like kinase 2 type 1 receptor (ALK2). Most patients with POF have the same point mutation, R206H, referred to as classic POF, although about 3% of patients have other mutations in the same gene. The prevalence is estimated at about 1 in 2 million individuals, without any geographic, ethnic, racial, or gender differences. Heterotopic ossification is an episodic and cumulative pathological condition that lasts throughout life, as a result of which segments, plates and strips of additional bone form throughout the body and pass through the joints, gradually limiting movement. Rapidly growing bone spurs are known to protrude through the skin, causing pain and risk of infection. Asymmetric HO in the chest and subsequent contralateral growth can lead to rapid progression of spinal deformity and cause thoracic insufficiency syndrome. Ankylosis of the temporomandibular joints leads to severe dental caries and malnutrition.

As described in Example 3, the presence of muscle necrosis detected by imaging techniques may indicate an increased risk of HO formation. In addition, the presence of significant muscle necrosis in some patients observed with imaging studies performed within 7 days of the onset of symptoms of an attack suggests that the process that will eventually lead to the formation of a new HO site may begin before when the onset of clinical symptoms becomes known. Based on these observations, in some embodiments of the present invention it may be useful to provide doses in the absence of an attack in order to provide exposure to palovarotene at the beginning of the process and before the onset of clinical symptoms.

In some embodiments of the present invention, periods of seizure activity alternate with intervals of varying lengths of apparent absence of disease exacerbation without overt clinical symptoms.

- 10 042153 symptoms.

In a patient with POF, heterotopic ossification (HO) can be measured using a variety of techniques known in the art, including, but not limited to, low-dose CT scan imaging, magnetic resonance imaging (MRI), and radiological imaging. . One of the clinically significant indicators of HO in POF is the proportion of seizures in a patient without new HO, the number of seizures or periods of exacerbation experienced by the patient over a certain period of time, which do not lead to the formation of new areas of heterotopic ossification.

II. Pharmaceutical composition and composition.

For administration to a subject, palovarotene may be presented in pharmaceutically acceptable compositions. These pharmaceutically acceptable compositions include palovarotene and one or more pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions may be formulated for administration in solid or liquid form.

Palovarotene can be administered in a neutral form (ie free base or zwitterionic neutral form). Optionally, palovarotene can be administered in the form of a pharmaceutically acceptable salt, such as non-toxic acid addition salts or metal complexes, which are commonly used in the pharmaceutical industry. Examples of acid addition salts that can be used in the methods of this invention include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic or trifluoroacetic acid or the like; polymeric acids such as tannic acid, carboxymethyl cellulose or the like; and an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid or the like. Metal complexes that can be used in the methods of this invention include, among others, calcium, zinc and iron.

In some embodiments of this invention, a pharmaceutical composition comprising palovarotene is formulated for oral administration. In some embodiments of this invention, the pharmaceutical composition is formulated by combining palovarotene with one or more pharmaceutically acceptable carriers and excipients. Such carriers and excipients make it possible to formulate a pharmaceutical composition in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions for oral administration by a subject.

In some embodiments of this invention, pharmaceutical compositions for oral administration are obtained by mixing palovarotene and one or more pharmaceutically acceptable carriers and excipients. Suitable carriers and excipients include, but are not limited to, fillers such as sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). In some embodiments of this invention, such a mixture is optionally crushed and additional substances are optionally added. In some embodiments of this invention, pharmaceutical compositions are formulated to produce tablets or dragees. In some embodiments of this invention, disintegrating agents (eg, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate) are added.

When palovarotene is administered orally, the pharmaceutical composition containing palovarotene may be in unit dosage form (eg, liquid or solid unit dosage form). The concentration and/or amount of palovarotene in the formulation may vary depending on, for example, the dose of palovarotene administered to the body and the frequency of administration.

III. Therapy and doses.

Palovarotene can be administered to a subject with POF whether or not the subject is experiencing an attack. For example, administering doses during the non-seizure period (ie, administering palovarotene during rest periods) can provide the subject with palovarotene exposure when the seizure process begins and before the onset of clinical symptoms. In some embodiments of this invention, palovarotene can be administered to a subject with POF during an extended term (eg, continuous daily treatment during periods of rest and periods of exacerbation). In some embodiments of the present invention, palovarotene may be administered to a subject with PF for an extended term (e.g., extended daily treatment during periods of rest and periods of exacerbation), and the dose of palovarotene may be increased during attacks (e.g., acute daily treatment during periods of exacerbation, or during the period after the onset of the aggravation period from 84 days to 112 or 140 days, during which there is a risk of further heterotopic ossification).

- 11 042153

The end of the exacerbation period is characterized by a decrease in the risk of heterotopic ossification in some cases 84 days after the start of treatment during the exacerbation period, i.e. 84 days after the onset of symptoms of an attack. If the patient experiences persistent symptoms of an attack, treatment during an exacerbation can be extended, for example, for another 28 or 56 days. During the flare period, the subject may be treated with higher daily doses of palovarotene (ie, loading doses and/or maintenance doses). At the end of the flare period, the subject may return to treatment with lower daily doses of palovarotene administered during rest periods. Determining when to switch from flare-up doses to resting doses, i.e. at the end of an exacerbation period depends on and may be determined by the symptoms experienced by the subject, and this determination may be made in consultation with the subject's health care professional or the patient himself. According to the administration regimens of the present invention, a subject may return to a flare dose level after the subject has been symptom free for at least 2, 3, 4, or 5 consecutive weeks.

In some embodiments of the invention, 5 mg daily is administered to the subject during rest periods, 20 mg daily is administered for 28 days after the onset of the flare period, followed by 10 mg daily for 56 days, and back to 5 mg daily if the patient no longer experiencing any symptoms of an attack. Optionally, treatment with 10 mg per day may be extended for an additional 28 or 56 days if the patient is still experiencing symptoms of an attack (ie, the period of exacerbation persists).

The palovarotene regimens of this invention include administering a higher dose as a loading dose after the onset of an exacerbation phase, such as 20 mg/day for 28 days, followed by a maintenance dose, such as 10 mg/day for 56 days, and administering more low dose during rest periods, eg 5 mg/day. Adult loading doses for use in the treatment regimens of this invention range from 15 to 20 mg/day and may be adjusted depending on the weight of the patient or the tolerance of the patient to palovarotene. Adult maintenance doses for use in the treatment regimens of this invention range from 7.5 to 10 mg/day and may be adjusted depending on the weight of the patient or the tolerance of the patient to palovarotene.

In some embodiments of this invention, palovarotene is co-administered with one or more other pharmaceutical agents, including, but not limited to, glucocorticoids for control of seizure symptoms, non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, leukotriene inhibitors and mast cell stabilizers, aminobisphosphonates, and imatinib mesylate (see Briggs et al., Expert Opinion on Orphan Drugs 3:1137-1154 (2015) and Kaplan et al., Clin Proc Intl Clin Consort FOP 4:1 - 100 (2011)). In some embodiments of this invention, such one or more other pharmaceutical agents are intended to treat the same disease or condition as palovarotene. In some embodiments of this invention, such one or more other pharmaceutical agents are intended to treat a disease or condition other than palovarotene. In some embodiments of this invention, one or more other pharmaceutical agents are intended to treat the undesirable effect of palovarotene. In some embodiments of this invention, palovarotene and one or more other pharmaceutical agents are administered simultaneously. In some embodiments of this invention, palovarotene and one or more other pharmaceutical agents are administered at different times. In some embodiments of this invention, palovarotene and one or more other pharmaceutical agents are prepared together in one composition. In some embodiments of this invention, palovarotene and one or more other pharmaceutical agents are prepared separately.

Typically, palovarotene is administered in unit dosage form (eg, tablets, capsules, etc.). In some embodiments of this invention, palovarotene is administered at a dose selected from 1.5, 2, 2.5, 3, 4, 5, 6, 7.5, 10, 12.5, 15, or 20 mg.

In some embodiments of this invention, the dose can be administered at intervals ranging from more than once a day (for example, twice a day or three times a day) to once a day for as long as necessary to maintain the desired effect.

Examples

Example 1. Seizure outcomes.

Sixty-seven attacks were treated: 40 double-blinded (10 subjects received placebo, 9 subjects received palovaroten 5 mg once daily for 2 weeks, then 2.5 mg once daily for 4 weeks). weeks and 21 subjects received palovarotene 10 mg once daily for 2 weeks, then 5 mg once daily for 4 weeks); and 27 subjects received palovarotene unblinded. Sixty-one of these 67 seizures have available post-baseline imaging (on a low-grade CT scan).

- 12 042153 dose). The results of the relevant studies are summarized in FIG. 1 and 2.

New HO sites were observed in 14 of 61 attacks, ten in a double-blind study and four in an open-label extension study. Most of these attacks (10 out of 14) resulted in new HO patches at the end of the 6-week treatment (Day 42), and four attacks resulted in new HO patches at the end of the 6-week follow-up period (Day 84).

EXAMPLE 2 Palovarotene Administration Schedule for a Cohort of Adult Patients.

The adult patient cohort includes individuals who have achieved at least 90% skeletal maturity regardless of age. Individuals in the adult cohort received palovarotene (neutral form) 5 mg once daily as treatment outside of an attack (eg, during periods when there were no symptoms of an attack). This administration schedule ensured that subjects were exposed to palovarotene early in the development of the HO process, prior to the onset of clinical symptoms.

Individuals in the adult cohort who experienced an attack received an increased dose of palovarotene 20 mg once a day for 28 days, then 10 mg once a day for at least 56 days (total of 3 months of treatment) . Treatment was extended in 4-week increments if an attack continued beyond the initial 3 months. When the seizure subsided, subjects returned to the non-seizure dose of 5 mg. Ten individuals received this treatment (resting/flare PVO treatment: 5 mg PVO daily during the rest period and 20 mg PVO daily for 28 days (loading dose PO) followed by 10 mg PVO daily for 56 days (maintenance). dose PO) after the onset of symptoms of an attack). Outcomes were compared between those individuals who received sugar-filled tablets or no treatment (placebo/no treatment, 28 patients) and those who received either 20 mg palovarotene (PVO) daily for 28 days followed by 10 mg PVO daily for 56 days (47 patients) or 10 mg PVO for 14 days followed by 5 mg PVO for 28 days (9 patients) during the flare period (i.e. the PVO flare only group in Fig. 3A).

Evaluation of new HO in the attack area was performed using X-ray diagnostics, while low-dose CT imaging was used for secondary image evaluation. Interpretation of radiographs and computed tomography included an assessment of the absence or presence of a new GO in the attack area compared to the original image and the volume of a new GO, if the latter is present. Performing both X-ray and CT scans of the attack area allowed us to choose the most appropriate method for assessing HO, assisting in the development of subsequent studies. To ensure consistency and standardization, images were assessed for the presence or absence of HO using two independent procedures, both of which were blinded to treatment group information. During the initial reading, two musculoskeletal radiologists independently compared the original and post-original images within the same imaging modality.

Volume of new heterotopic ossification (HO), i.e. HO that occurred during the flare period was assessed 12 weeks after treatment initiation for the flare period only treatment group and 12 weeks after the start of the 20 mg/day PO loading dose in the rest period/flare period treatment group. These data suggest that the rest period/flare period treatment regimen further inhibits new bone formation after attacks. Compared to the placebo/no treatment group, patients in the Flare Only group experienced a 75% reduction in mean bone formation (new HO) and patients in the Rest/flare group experienced a decrease in mean bone formation (new HO). GO) by 97% (see Fig. 3A and 3B). These data also demonstrate that the resting/flare period treatment regimens of the present invention significantly reduce mean bone volume formation (new HO) compared to the flare only treatment regimen (i.e., to treat seizures in subjects only).

Example 3. Scheme of administration of palovarotene for a cohort of children.

The pediatric cohort includes individuals under 18 years of age who have not reached 90% skeletal maturity as determined by hand/wrist radiographs. Individuals in the cohort of children who have an attack receive palovarotene (neutral form) at a dose of 20 mg once a day (or an equivalent weight equivalent dose, as shown in Table 1) for 28 days, then - 10 mg once a day per day (or equivalent weight-adjusted dose as shown in Table 1) for at least 56 days (a total of 3 months of treatment). Treatment may be extended in 4-week increments if an attack continues beyond the initial 3 months. In addition to treatment after the onset of symptoms of an attack, i.e. during an exacerbation period, children may be treated for a long time with a dose of 2.5-5 mg of palovarotene once a day during the rest period (i.e. when the patient does not experience symptoms of an attack or does not experience symptoms of an attack for at least last, e.g. 2, 4, 6, 8 weeks or 84 days).

- 13 042153

Table 1

Weight-adjusted dose levels for pediatric patients (under 18 years of age and skeletal maturity < 90%)

Weight group (< 90% skeletal maturity) Daily loading dose during exacerbation (DL) Daily Maintenance Dose PO Daily dose at rest (RD) 10 to < 20 kg 10 mg 5 mg 2.5 mg 20 to < 40 kg 12.5 mg 6 mg 3 mg 40 to < 60 kg 15 mg 7.5 mg 4 mg >60 kg 20 mg 10 mg 5 mg

Example 4 Safety Results.

The overall incidence of adverse events in the double-blind study described in Example 1 was 97.1% (33 out of 34 subjects with available safety data) with a dose-dependent increase in the treatment groups. Dose-dependent increases in the frequency and severity of retinoid-associated adverse events were also observed. Most retinoid-associated adverse events were severe or moderate. The most commonly reported adverse events overall were dry skin (58.8%) and dry lips (32.4%). For this reason, the dose was not reduced and the treatment was not stopped.

The results were similar in the open study (described in example 1), in which the overall incidence of adverse events was 92.3% (12 of 13 subjects). Retinoid-associated adverse events were reported in all subjects, with the majority of these being mild (69.2%) in severity. The most commonly reported adverse events overall were dry skin (69.2%) and itching (61.5%). For this reason, the dose was not reduced and the treatment was not stopped.

Example 5 Growth Plate Evaluation.

The effect of palovarotene on the growth plate was evaluated. Daily administration of palovarotene caused regression of histological growth plate anomalies and shortened long bones, which was observed in Prrx1-R206H mice. In this model, histological analysis revealed a significant decrease in the height of the hypertrophic zone of the growth plate, which is mainly responsible for the lengthening of the tubular bone. Administration of palovarotene inhibited the growth of tubular bones and virtually normalized growth plate organization and matrix deposition in Prrx1-R206H mice. These results suggest opposite effects of palovarotene on the growth plate in normal and mutant (ACVR1 R206H) cells and tissues. The adverse effects of palovarotene in wild-type mice contrast with the positive effects seen in FOP mice.

Example 6 Alternative Administration Schemes.

For individuals experiencing tolerance problems, an alternative de-escalation regimen can be used, as indicated in table. 2 and 3. Dose level at rest (RR) is administered continuously during the rest period (eg, when the patient is not experiencing seizures, or to individuals who have not experienced symptoms of an attack for at least 4 consecutive weeks). Dose level in the period of exacerbation (PO) is administered during the period of exacerbation. An exacerbation loading dose (FR) is administered within 20 to 40 days (eg, 21 to 30 days or 28 days) after the onset of an attack (eg, within 7 days after the patient has one or more symptoms of an attack ). The maintenance dose level of PO is administered immediately after the loading dose of PO for a period of at least 56 days, which period may increase in increments of 4 weeks, for example 4, 8 or 12 weeks, and be greater than 56 days, if the symptoms of an attack in a patient persist until the relief of symptoms of an attack.

table 2

Dose levels for adult patients

Adult weight group (> 18 or < 18 s > 90% maturity skeletal system) Daily loading dose during exacerbation (DL) Daily Maintenance Dose PO Dose at rest (PP) Standard Adult Dose 20 mg 10 mg 5 mg De-escalation Dose for adults 1 15 mg 10 mg 5 mg De-escalation Adult Dose 2 10 mg 10 mg 5 mg De-escalation Adult Dose 3 15 mg 7.5 mg 4 mg

- 14 042153

Table 3

Weight-adjusted dosing schedules for children (up to 18 years of age and <90% skeletal maturity)

Group by weight (< 90% maturity skeletal system) Daily loading dose during exacerbation (DL) Daily Maintenance Dose PO Daily dose at rest (RD) 10 to < 20 kg Scheme 10 mg 5 mg 2.5 mg 10 to <20 kg De-escalation scheme 7.5 mg 3 mg 1 mg 20 to < 40 kg Scheme 12.5 mg 6 mg 3 mg 20 to < 40 kg De-escalation scheme 10 mg 5 mg 2.5 mg 40 to < 60 kg Scheme 15 mg 7.5 mg 4 mg 40 to < 60 kg De-escalation scheme 12.5 mg 6 mg 3 mg > 60 kg Scheme 20 mg 10 mg 5 mg >60 kg De-escalation scheme 15 mg 7.5 mg 4 mg

Other embodiments of the invention

Although the invention has been described in connection with its specific embodiments, it should be understood that it may be subject to further modifications, and this application is intended to cover any changes, uses or adaptations of this invention, following, in most cases, the principles of this invention. , and the inclusion of such departures from this description is known or common practice in the art to which this invention pertains, and may be applied to the general features set forth above.

All publications, patents, and patent applications are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application were expressly and specifically indicated to be incorporated by reference in their entirety.

Other embodiments of this invention are given in the following claims.

Claims (10)

CLAIM 1. A method of reducing heterotopic ossification in a human subject with progressive fibrodysplasia ossificans, said method comprising: (i) during a period when the subject is not experiencing any symptoms of an attack, oral administration to the subject of palovarotene or a pharmaceutically acceptable salt thereof in an amount of 5 mg per day, and (o) during the period when the subject experiences at least one symptom of an attack, oral daily administration to the subject of 20 mg of palovarotene or a pharmaceutically acceptable salt thereof for 28 days, and after 28 days, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 10 mg for a period of at least 56 days. 2. The method according to claim 1, characterized in that the weight of the subject is 60 kg or more. 3. A method of reducing heterotopic ossification in a human subject with progressive fibrodysplasia ossificans, wherein the subject weighs between 10 and 20 kg, said method comprising: (i) during a period when the subject is not experiencing any symptoms of an attack, oral daily administration of palovarotene to the subject or its pharmaceutically acceptable salt in an amount of 2.5 mg, and (and) during the period when the subject experiences at least one symptom of an attack, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 10 mg for 28 days, and after 28 days oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 5 mg for a period of at least 56 days. 4. A method for reducing heterotopic ossification in a human with progressive fibrodysplasia ossificans, wherein the subject weighs between 20 and 40 kg, said method comprising: (i) during a period when the subject is not experiencing any symptoms of an attack, oral daily -15042153 administering to the subject palovarotene or its pharmaceutically acceptable salt in an amount of 3 mg, and (ii) during the period when the subject experiences at least one symptom of an attack, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 12.5 mg within 28 days, and after 28 days oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 6 mg for a period of at least 56 days. 5. A method of reducing heterotopic ossification in a human with progressive fibrodysplasia ossificans, comprising: (i) during a period when the subject does not experience any symptom of an attack, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 4 mg, and (ii) in during the period when the subject experiences at least one symptom of an attack, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 15 mg for 28 days, and after 28 days, oral daily administration to the subject of palovarotene or its pharmaceutically acceptable salt in an amount of 7, 5 mg for at least 56 days. 6. The method according to claim 5, characterized in that the weight of the subject is from 40 to 60 kg. 7. The method according to any one of claims 1 to 6, wherein the period of at least 56 days is a period of 56 days. 8. The method of any one of claims 1 to 7, wherein the amount administered over a period of at least 56 days is administered daily for an additional 28 days if the subject continues to experience at least one attack symptom. 9. The method according to any one of claims 1 to 8, further comprising administering to the subject an antihistamine agent, optionally the antihistamine agent is administered topically or systemically; or further comprising applying an emollient agent to the subject's skin. 10. A method according to any one of claims 1 to 9, wherein at least one attack symptom is selected from edema, pain, erythema, fever, stiffness, and limited range of motion.