How Do Retinoic Acid Receptor Gamma Agonists Work?

Retinoic acid receptor gamma (RAR-G) agonists are a novel class of medications used to treat fibrodysplasia ossificans progressiva (FOP), an extremely rare genetic disorder that causes abnormal bone growth in place of connective tissues such as muscle, tendons and ligaments. Palovarotene, with the brand name of Sohonos, is the first drug of this class to be approved by the FDA in August 2023.

Fibrodysplasia ossificans progressiva (FOP) is a disorder caused by mutations in the ACVR1/ALK2 gene which encodes activin A receptor type 1 (ACVR1)/activin-like kinase 2 (ALK2) proteins. ACVR1/ALK2 is a protein belonging to a family of proteins known as bone morphogenetic protein (BMP) type I receptor that stimulates cartilage forming cells (chondrocytes) to mature into bone cells.

Most of the skeletal bones are formed from cartilage tissue through BMP signaling. Normally, BMP signaling is turned off at the appropriate time. Gain-of-function mutation in the ACVR1/ALK2 causes excessive BMP signaling which makes normal connective tissue gradually turn into bone tissue (heterotopic ossification). The abnormal bone growth results in restricted mobility, bone deformities and severe disability.

Retinoid acid receptor gamma agonists selectively bind to RAR-G receptors, protein particles that are expressed in chondrocytes and chondrogenic cells. RAR-G agonists, by binding to RAR-G receptors, interfere with the BMP/ALK2 signaling and decrease the consequent conversion of cartilage into bone.

Retinoic acid receptor gamma agonists are oral capsules used to reduce the formation of heterotopic ossification in adults and children aged 8 years and above for females and 10 years and above for males with fibrodysplasia ossificans progressiva.

Side effects of retinoic acid receptor gamma agonists include the following:

• Premature cessation of bone growth (epiphyseal closure)
• Dry skin
• Itching (pruritus)
• Rash
• Skin peeling (exfoliation)
• Skin redness (erythema)
• Hair loss (alopecia)
• Dry lips
• Dry eyes
• Hypersensitivity reaction
• Swelling of extremities (peripheral edema)
• Joint pain (arthralgia)
• Pain in extremities
• Headache
• Back pain
• Musculoskeletal pain
• Muscle pain (myalgia)
• Fatigue
• Nausea
• High level of triglycerides in blood (hypertriglyceridemia)
• Elevation of liver enzyme ALT
• Loss of bone mineral density
• Radiological vertebral fractures

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of retinoic acid receptor gamma agonists include:

• palovarotene
• Sohonos