6. Current Treatment Considerations

At the present time, there are limited treatments for FOP. The disorder’s rarity, variable severity, and fluctuating clinical course pose substantial uncertainties when evaluating experimental therapies.

In evaluating each treatment, we have focused on the known mechanism of action of the drug as it relates to the proposed pathogenesis of FOP. Consideration for use of each medication was made based on current regulatory approval, or if no approval, balancing the clinical uncertainty of each agent when used to treat FOP against the compassionate need to control the disabling symptoms of the disease adequately and safely, especially during flare-ups. Each pharmacologic agent was classified into one of four categories based on Phase 3 clinical trial results and approved use, experimental or anecdotal experience with the drug, as well as knowledge of each drug’s safety profile.

Regulatory-approved: Medications that have been approved by at least one regulatory authority (e.g., U.S. Federal Drug Administration, or FDA).

Examples: Chronic and episodic use of palovarotene (SohonosTM)

Class I: Medications that have been widely used to control symptoms of acute flare-ups in FOP (swelling and pain), or chronic arthropathy - with generally minimal side effects.

Examples: Short-term use of high-dose corticosteroids, and use of non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors.

Class II: Medications that have theoretical application to various aspects of FOP, are approved for the treatment of other disorders, and have limited and well-described effects.

Examples: Leukotriene inhibitors (Montelukast), mast cell stabilizers (Cromolyn), aminobisphosphonates (Pamidronate; Zoledronate), specific tyrosine kinase inhibitors (Imatinib), Janus kinase inhibitors (Tofacitinib), or IL-1β inhibitors (Canakinumab).

Class III: Investigational and new drugs

Examples: Selective ACVR1/ALK2 signal transduction inhibitors, monoclonal antibodies targeting Activin or MMP-9.

PHYSICIANS TREATING PATIENTS WHO HAVE FOP SHOULD KEEP IN MIND THAT NONE OF THESE MEDICATIONS (OR ANY OTHER MEDICATIONS TO DATE) HAVE BEEN PROVEN TO ALTER THE NATURAL HISTORY OF FOP

We emphasize that this report reflects the authors’ experience and opinions on the various classes of symptom-modifying medications and is meant only as a guide to this controversial area of therapeutics. Although there are common physical features shared by every person who has FOP, there are differences among individuals that may alter the potential benefits or risks of any medication or class of medications discussed here. The decision to use or withhold a particular medication must ultimately rest with an individual patient and his or her physician.

Class I Medications can be considered for acute flare-ups involving the major joints of the major appendicular skeleton, the immediate use of prednisone at a dose of 2 mg/kg/day (up to 100 mg) can be considered as a single daily dose for a maximum of four days. For maximal beneficial effect, the prednisone should be started within 24 hours of the onset of a flare-up, which corresponds to the earliest phase of acute and intense lymphocytic infiltration into skeletal muscle. If the flare-up is more than two days old, prednisone is generally less effective. If the flare-up responds to the medication but recurs when the prednisone is discontinued, a repeat 4-day course with a subsequent 10-day taper can be considered. Prednisone should generally not be used for flare-ups on the chest or trunk, as it is difficult to judge the exact onset of a new flare-up. Prolonged or chronic use of corticosteroids is of no benefit, may accelerate heterotopic ossification (HO), is harmful systemically, and should not be considered. Furthermore, suppression of the pituitary-adrenal axis is likely to occur with chronic or long-term use and can have long- term harmful effects. The use of prednisone is meant only to suppress or abort the early inflammatory events of an acute FOP flare-up, and potentially suppress the subsequent death of skeletal muscle in the earliest stages of an FOP flare-up.

When prednisone is discontinued (or if a flare-up existing for more than 48 hours is being considered for treatment), symptomatic treatment may be considered with a non-steroidal anti-inflammatory agent. A cyclooxygenase-2 (COX-2) inhibitor can be used instead of a traditional NSAID (Table 1). As with all non- steroidal anti-inflammatory medications, gastrointestinal precautions should prevail. If long-term use of the COX-2 inhibitors is considered, serum liver and kidney function tests should be monitored. COX-2 inhibitors should be used with caution in FOP patients with a history of cardiovascular disease or in older FOP patients who are severely immobilized or completely non-ambulatory.

Class II Medications can be considered with caution, at the physicians’ discretion.

Class III Medications are under development, being tested in clinical trials and are not yet available for general use.