Learn how research on RAR gamma agonists motivated the palovarotene clinical trials  

Dr. Pacifici, what year did you identify the roles and action of retinoid in skeletal development and growth? How did it make you feel when you heard the clinical trial, based on your research finding, was advancing?

I started working on retinoids in skeletal development many years ago. While I was a faculty member at the University of Rome Medical School, I published a paper in 1980 showing for the first time that the natural endogenous retinoid called retinoid acid (RA) was able to potently inhibit chondrogenic cell differentiation and cartilage formation, while it had no effect or stimulating effects on other types of differentiating cells, such as muscle cells. Because HO in FOP starts with formation of cartilage which is then replaced by bone, it was clear back then already that RA could be used therapeutically to block cartilage formation in pathological conditions.

Natural retinoids such as RA are very potent and act on all the different types of nuclear RARs - RAR alpha, RAR beta and RAR gamma - and thus, could elicit unwanted side effects if used as therapeutic drugs. To improve and overcome this potential obstacle, several pharmaceutical companies back in the 80’s and 90’s produced synthetic retinoids that structurally resemble natural retinoids but are selective for the different RARs.

We and others had shown that RAR alpha is first expressed at the early stages of chondrogenic cell differentiation and is then replaced by expression of RAR gamma. To test whether RAR-selective drugs could serve as possible treatments against HO, I directed one of my lab technicians, Ms. Tiffany Morrison, to test RAR alpha agonists in an animal model of non-congenital HO. The results obtained in mid-2000 were extremely encouraging and showed for the first time that these drugs could indeed prevent HO formation by blocking BMP signaling. These studies were followed up and expanded subsequently, leading to our paper in Nature Medicine in 2011 in which we showed that RAR gamma agonists, including palovarotene, were more potent than alpha agonists and were able to very effectively block HO in an animal model of FOP. This seminal publication attracted significant attention and inspired the creation of Clementia Pharmaceuticals, the company that is sponsoring one of the current FOP clinical trials. Laboratory scientists all dream of contributing to medicine and creating novel treatments for diseases, particularly diseases as severe as FOP is. Thus, I regard myself extremely fortunate to have been able to fulfill this dream.

I am doubly fortunate that in my research work I have been focusing also on Multiple Osteochondroma (MO). Despite being caused by mutations in genes totally different from ACVR1, MO shares several general pathogenic steps with FOP. In particular, the osteochondromas start with cartilage formation followed by bone formation, just like HO. We anticipated that retinoid agonists could represent a therapeutic for MO as well and had shared these ideas with Clementia several years ago. In 2017, we reported for the first time that osteochondroma formation is caused by excessive BMP signaling, just like HO in FOP, and that blocking this pathway represents an effective therapeutic tool against MO. I was exceedingly happy when Clementia launched a phase 2 clinical trial last year to test palovarotene for the treatment of MO patients. Thus, my work has led to the identification of palovarotene which is being tested as a treatment of two distinct pediatric disorders: FOP and MO.

Learn more about the Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of Philadelphia (CHOP).