[Author: Laura Cowen]
Treatment with the retinoic acid receptor (RAR)-gamma agonist palovarotene may prevent heterotopic ossification (HO) during a fibrodysplasia ossificans progressiva (FOP) flare-up, phase 2 study data suggest.
Although the findings were not statistically significant, “they support further evaluation” of the drug in larger studies, report Frederick Kaplan (The University of Pennsylvania, Philadelphia, USA) and co-authors in the Journal of Bone and Mineral Research.
Kaplan et al explain that RAR-gamma agonists prevent HO via downregulation of the bone morphogenic protein signaling pathway that ultimately leads to pre-chondrogenic mesenchymal stem cells being redirected from an osteoblast fate to a non-osseous soft tissue fate.
They tested the efficacy of palovarotene for the prevention of HO in a group of 40 patients aged 7 to 53 years who reported at least two current flare-up symptoms (pain, soft tissue swelling, decreased range of motion, stiffness, redness, or warmth).
The participants were randomly assigned to receive oral palovarotene 10 mg daily for 2 weeks followed by 5 mg for 4 weeks (palovarotene 10/5 mg; n=21), palovarotene 5 mg daily for 2 weeks followed by 2.5 mg for 4 weeks (palovarotene 5/2.5 mg; n=9), or placebo (n=10) and were then followed-up for a further 6 weeks after the end of treatment.
The first patient was enrolled in July 2014 and the last patient completed the trial in May 2016.
The researchers found that, at 6 weeks, 100% of patients in the palovarotene 10/5 mg group, 88.9% of those in the palovarotene 5/2.5 mg group, and 88.9% in the placebo group responded to the treatment, defined as having no or minimal new HO at the flare-up body region by plain radiograph.
At 12 weeks, the corresponding proportions were 95.0%, 88.9%, and 77.8%.
There were no significant differences among the three groups at either timepoint, but the researchers suggest that the high proportion of responders in the placebo group indicates that using plain radiographs for assessment “was not sufficiently sensitive to measure the presence or amount of new HO at the flare-up body region.”
When the team reviewed computed tomography (CT) images, and/or plain radiographs, taken at week 12, they found that the proportion of flare-ups with new HO at the flare-up body region was numerically lower in the palovarotene 10/5 mg group than in the placebo group, at 15.0% versus 40.0%. By contrast, the incidence in the palovarotene 5/2.5 mg group of 44.4% was similar to that with placebo.
CT scans also revealed that the least-squares mean volume of new HO among all patients at week 12 was 79.0% lower with palovarotene 10/5 mg versus placebo and 92.7% lower with palovarotene 5/2.5 mg versus placebo (3.8 and 1.3 versus 18.0 × 103 mm3, respectively) but again, the differences were not statistically significant.
The fact that the mean volume of new HO increased at the flare-up body region in both palovarotene groups in the 6 weeks following treatment cessation, suggests that “outcomes may be optimized by increasing dose and treatment duration,” Kaplan and colleagues remark.
Indeed, they add that this finding “informed decisions for palovarotene dosing during the [ongoing] open-label extension” of the trial, which they say has also shown “promising trends.”
The researchers also assessed the safety of palovarotene and found that the drug was “well-tolerated.”
All participants experienced at least one treatment-emergent adverse event (AE), most commonly dry skin and lips. Just four patients experienced serious AEs, including two “condition aggravated” cases and one instance of myoclonus that were possibly related to treatment. No patients discontinued treatment or required dose reduction as a result of toxicity but one patient receiving palovarotene 10/5 mg required a treatment interruption due to a transient, asymptomatic mild increase in lipase levels that were deemed “probably related” to the study drug.
Kaplan et al conclude: “Although inconclusive, the data presented here suggest that high-dose RAR-[gamma] agonist treatment during a flare-up may be beneficial in patients with FOP.”
“Based on these data, palovarotene was advanced in the FOP clinical program,” they add.