FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP)
An ultra-rare genetic disorder that causes progressive heterotopic ossification (HO)1,2
Affecting 1 in every million people, fibrodysplasia ossificans progressiva (FOP) is characterized by malformation of both big toes, heterotopic ossification, and flare-ups. As HO progresses, ribbons, sheets, and plates of heterotopic bone replace skeletal muscles and connective tissues.1,2
Tiwari et al. Cureus. 2018;10(7):e2955. Used with permission under Creative Commons CC BY 3.0 license.
This illustration was co-created with people living with FOP.
FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP)
An ultra-rare genetic disorder that causes progressive heterotopic ossification (HO)1,2
Affecting 1 in every million people, fibrodysplasia ossificans progressiva (FOP) is characterized by malformation of both big toes, heterotopic ossificiation, and flare-ups. As HO progresses, ribbons, sheets, and plates of heterotopic bone replace skeletal muscles and connective tissues.1,2
Tiwari et al. Cureus. 2018;10(7):e2955. Used with permission under Creative Commons CC BY 3.0 license.
This illustration was co-created with people living with FOP.
How heterotopic ossification (HO)
forms in FOP
FOP is caused by a point mutation (R206H) in ALK2/ACVR1, a gene in the bone morphogenetic protein (BMP) pathway, which is critical in skeletal formation and repair.3,4
- In FOP, inflammations trigger hyperactivation of the already active ALK2/ACVR1 receptor. Inflammation also triggers the secretion of several ligands5
- Through the binding of BMP-signaling ligands (including Activin A), BMP/ALK2 signaling is further increased5,6
- The downstream effect of ALK2/ACVR1 receptor hyperactivity results in the activation of Smad 1/5/8 through phosphorylation5,6
- Activation of Smad 1/5/8 results in the expression of genes that promote differentiation of progenitor cells to chondrogenic cells, rather than soft or connective tissue5,6
How heterotopic ossification (HO) forms in FOP
FOP is caused by a point mutation (R206H) in ALK2/ACVR1, a gene in the bone morphogenetic protein (BMP) pathway, which is critical in skeletal formation and repair.3,4
Irreversible HO can form with or without flare-ups1,7-9
FOP flare-ups can be unpredictable, with 61% of flare-ups occurring without an identified cause.7
Flare-ups are often precipitated by10-12:
| Soft-tissue injury | Viral infection | Falls |
| Intramuscular injections | Muscular stretching | Fatigue |
| Soft-tissue injury | Muscular stretching |
| Intramuscular injections |
Falls |
| Viral infection | Fatigue |
Refer to the International Clinical Council’s guidelines on how to avoid triggering a flare-up.1
Flare-ups are painful, recurrent episodes of soft-tissue swelling, common in FOP10
Flare-ups can transform soft tissues into irreversible HO that spans the joints, locking them in place.10
Early identification of flare-ups is critical10
Major symptoms experienced during a flare-up include7,†:
Swelling
Pain
Reduced movement
Stiffness
Warmth (in the affected area)
†SOHONOS has not been demonstrated to have an impact on the symptoms of a flare-up.
Swelling
Pain
Reduced movement
Stiffness
Warmth (in the affected area)
†SOHONOS has not been demonstrated to have an impact on the symptoms of a flare-up.
Consider discussing possible signs of flare-ups with your patients.
Slowing the accumulation of new HO is crucial to inhibit cumulative disability1,7-9,11
IMPORTANT SAFETY INFORMATION
WARNING: EMBRYO-FETAL TOXICITY and PREMATURE EPIPHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS
- SOHONOS is contraindicated in pregnancy. SOHONOS may cause fetal harm. Because of the risk of teratogenicity and to minimize fetal exposure, SOHONOS is to be administered only if conditions for pregnancy prevention are met.
- Premature epiphyseal closure occurs in growing pediatric patients treated with SOHONOS, close monitoring is recommended.
Contraindications
SOHONOS is contraindicated in patients during pregnancy, or with a history of allergy or hypersensitivity to retinoids, or to any component of SOHONOS. Anaphylaxis and other allergic reactions have occurred with other retinoids.
Warnings and Precautions
- Embryo-Fetal Toxicity: SOHONOS can cause fetal harm and is contraindicated during pregnancy. SOHONOS is a retinoid which is associated with birth defects in humans. Advise females of reproductive potential to use an effective method of contraception at least 1 month prior to treatment, during SOHONOS treatment and for 1 month after the last dose. If a pregnancy occurs during treatment, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity. Inform patients not to donate blood during SOHONOS treatment and for 1 week following discontinuation.
- Premature Epiphyseal Closure in Growing Pediatric Patients: SOHONOS can cause irreversible premature epiphyseal closure and potential adverse effects on growth. In clinical studies, premature epiphyseal closure occurred with SOHONOS treatment in growing pediatric patients with FOP. Monitoring of linear growth is recommended in growing pediatric patients. Prior to starting treatment with SOHONOS, all growing pediatric patients should undergo baseline assessment of skeletal maturity and continued monitoring until patients reach skeletal maturity or final adult height. If a patient exhibits signs of premature epiphyseal closure or adverse effects on growth based on clinical or radiologic evaluations, further evaluation may be required, including an assessment of the benefits and risks of continued treatment, or temporary or permanent discontinuation of SOHONOS until the patient achieves epiphyseal closure and skeletal maturity.
- Mucocutaneous Adverse Reactions: Dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation (skin peeling), and dry eye occurred in 98% of patients treated with SOHONOS. SOHONOS may contribute to an increased risk of skin and soft tissue infections, particularly paronychia and decubitus ulcer, due to a decreased skin barrier from adverse reactions such as dry and peeling skin. Some of these adverse reactions led to dose reductions which occurred more frequently during flare-up dosing suggesting a dose response relationship. Prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions are recommended (e.g., skin emollients, sunscreen, lip moisturizers, or artificial tears). Some may require dose reduction or discontinuation. Photosensitivity reactions (e.g., burning, erythema, blistering) involving areas exposed to the sun have been associated with the use of retinoids and may occur with SOHONOS. Precautionary measures for phototoxicity are recommended (use of sunscreens, protective clothing, and use of sunglasses).
- Metabolic Bone Disorders: Retinoids are associated with bone toxicity, including reductions in bone mass and spontaneous reports of osteoporosis and fracture. In FOP clinical studies, SOHONOS resulted in decreased vertebral bone mineral content and bone density, and an increased risk of radiologically observed vertebral fractures in treated patients compared to untreated patients. Periodic radiological assessment of the spine is recommended. Retinoids have been associated with hyperostotic changes (bone spurs) and calcification of tendons or ligaments may occur with SOHONOS.
- Psychiatric Disorders: New or worsening psychiatric events were reported with SOHONOS including depression, anxiety, mood alterations, and suicidal thoughts and behaviors. There is a relatively high background prevalence of psychiatric disorders in untreated patients with FOP. Monitor for development of new or worsening psychiatric symptoms during treatment with SOHONOS. Individuals with a history of psychiatric illness may be more susceptible to these adverse effects. Patients and/or caregivers should contact their healthcare provider if new or worsening psychiatric symptoms develop during treatment with SOHONOS.
- Night Blindness: This may be dose-dependent, making driving a vehicle at night potentially hazardous during treatment. Advise patients to be cautious when driving or operating any vehicle at night and seek medical attention in the event of vision impairment.
Adverse Reactions
The most common adverse reactions (≥ 10%) are dry skin, lip dry, arthralgia, pruritus, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation (skin peeling), nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral edema, and fatigue.
Drug Interactions
- CYP3A4 inhibitors may increase SOHONOS exposure. Avoid concomitant use of strong or moderate CYP3A4 inhibitors, as well as grapefruit, pomelo or juices containing these fruits.
- CYP3A4 inducers may decrease SOHONOS exposure. Avoid concomitant use of strong or moderate CYP3A4 inducers.
- The use of both vitamin A and SOHONOS at the same time may lead to additive effects. Concomitant administration of vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids must be avoided due to risk of hypervitaminosis A.
- Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. Avoid coadministration of SOHONOS with tetracycline derivatives.
Use in Specific Populations
- Pregnancy: SOHONOS is contraindicated during pregnancy. Obtain a negative serum pregnancy test within 1 week prior to SOHONOS therapy and periodically, as needed, over the course of treatment with SOHONOS and 1 month after treatment discontinuation unless patient is not at risk of pregnancy. If pregnancy occurs during treatment with SOHONOS, stop treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for evaluation and advice.
- Lactation: Advise females that breastfeeding is not recommended during treatment with SOHONOS, and for at least 1 month after the last dose.
- Females and Males of Reproductive Potential: Advise females of reproductive potential to use effective contraception at least 1 month prior to and during treatment, and for 1 month after the last dose unless continuous abstinence is chosen.
- Pediatric Use: All growing pediatric patients should undergo baseline assessment of growth and skeletal maturity before starting treatment and continued clinical and radiographic monitoring every 6-12 months until patients reach skeletal maturity or final adult height.
- Renal or Hepatic Impairment: Use of SOHONOS in patients with severe renal impairment, or with moderate or severe hepatic impairment is not recommended.
INDICATION
SOHONOS™ is indicated for the reduction in volume of new heterotopic ossification in adults and pediatric patients aged 8 years and older for females and 10 years and older for males with fibrodysplasia ossificans progressiva (FOP).
Please see full Prescribing Information, including BOXED WARNING.
References: 1. Baujat G, Choquet R, Bouée S, et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis. 2017;12(1):123. 2. Pignolo RJ, Hsiao EC, Baujat G. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J Rare Dis. 2021;16(1):350. 3. Pignolo RJ, Hsiao EC, Al Mukaddam M, et al. Reduction of new heterotopic ossification (HO) in the open-label, phase 3 MOVE trial or palovarotene for fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res. 2023;38(3):381-394. 4. Pignolo RJ, Pacifici M. Retinoid agonists in the targeting of heterotopic ossification. Cells. 2021;10:3245. 5. Lin H, Shi F, Gao J, Hua P. The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator. Biosci Rep. 2019;39(8):BSR20190377. 6. Culbert AL, Chakkalakal SA, Theosmy EG, Brennan TA, Kaplan FS, Shore EM. Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells. 2014;32(5):1289-1300. 7. Pignolo RJ, Bedford-Gay C, Liljesthröm M, et al. The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment. J Bone Miner Res. 2016;31(3):650-656. 8. Di Rocco M, Baujat G, Bertamino M, et al. International physician survey on management of FOP: a modified Delphi study. Orphanet J Rare Dis. 2017;12(1):110. 9. Pignolo RJ, Baujat G, Brown MA, et al. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis. 2019;14(1):98. 10. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev. 2013;10 Suppl 2(0 2):437-448. 11. SOHONOS Full Prescribing Information. Cambridge, MA: Ipsen Biopharmaceuticals, Inc; August 2023. 12. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011;6:80.