[Author: Lynda Williams, senior medwireNews reporter]
Palovarotene therapy reduces heterotopic ossification (HO) in children and adults with fibrodysplasia ossificans progressiva (FOP), indicates the third interim analysis of the MOVE trial, conducted after at least 18 months of follow-up.
“Post hoc analyses showed evidence for efficacy in the reduction of new HO in FOP, although there was a high risk of PPC [premature physeal closure] in skeletally immature patients,” the team reports in the Journal of Bone and Mineral Research.
The international phase 3 open-label study recruited people aged 4 years or older with FOP who had been free from flare-up symptoms for at least 4 weeks, say Robert Pignolo (Mayo Clinic, Rochester, Minnesota, USA) and co-authors.
The participants were given oral palovarotene 5 mg/day with a switch to a more intensive 12-week treatment cycle at the onset of an eligible flare-up, defined as one or more symptoms consistent with prior flare-up, such as pain, swelling, redness, and stiffness, or after a “substantial high-risk traumatic event.”
This flare-up treatment cycle consisted of palovarotene 20 mg/day for 4 weeks followed by 10 mg/day for 8 weeks (dose adjusted for pediatric patients with less than 90% skeletal maturity) and an option to continue at this dosage until flare-up resolution. In addition, flare-up therapy could be restarted following further new flare-up locations, marked worsening of the initial flare-up, or new trauma, the investigators say.
The study focused on the 97 participants (mean age 14.6 years, 52.6% male) who carried the ACVR1 R206H pathogenic variant and had undergone low-dose whole-body computed tomography HO volume measurement at baseline and on at least one further occasion.
These patients were compared with 101 participants of the Natural History Study of FOP (NHS; mean age 17.3 years, 55.4% male) who had received standard care.
The majority of both groups were ambulant at baseline (88.9 vs 87.4%) and could carry out activities of daily living with some help (64.6 vs 54.1%), but some patients used a wheelchair (25.3 vs 30.6%) or required complete help with activities (10.1 vs 11.7%).
Pignolo and co-workers explain that MOVE was paused after the 12-month interim analysis showed no difference between the patient groups in the primary efficacy endpoint of annualized change in new HO volume using a Bayesian compound Poisson model (BcPM) with square-root transformation to “mitigate the high variability in new HO volumes” in the NHS cohort.
The independent data monitoring committee recommended the trial should continue and at the current post-hoc interim analysis at 18 months, BcPM with transformation continued to show no significant difference in the annualized volume of new HO with palovarotene versus standard of care (65.4% probability of reduction in new HO).
However, MOVE participants were undergoing scans every 6 months versus every 12 months in the NHS group, and the model did not account for negative changes in the annualized HO volume.
When the researchers accounted for the difference in scan scheduling, there was a 16.0% reduction in the square-root transformed new HO volume with palovarotene and a 90.7% probability of a reduction in new HO.
And when BcPM fitted a 36.0% reduction in non-transformed mean annualized volume of new HO to account for bias caused by negative HO values there was a 99.4% probability of reduction in new HO with palovarotene treatment, and analysis of the raw data for the annualized volume of new HO indicated there was a 60.0% reduction in volume of new HO.
In addition, when considering only the 39 patients who transferred from NHS to MOVE, patient-level analysis indicated that palovarotene was associated with a 54% reduction in average annualized new HO volume compared with standard care.
Pignolo et al also report that the palovarotene-treated patients had less variability in their annualized net change in HO volume than controls and were more likely to have a reduction in their annualized measured volume of HO (28.9 vs 5.0%).
Furthermore, patients given palovarotene were less likely to have experienced catastrophic new HO than their NHS counterparts at both 12 months and at the last assessment, and this was true when using new HO thresholds of greater than 30, 50, or 100 x 103 mm3 of new HO.
The researchers observe that, as expected, there was no difference in functional endpoints, or physical and mental endpoints between the two patient groups after 18 months.
At data cutoff, 34.3% of the 99 patients who comprised the principal safety set had received at least 12–18 months of palovarotene and 51.5% had done so for at least 18–25 months, with an average exposure of 3141 mg and flare-up dosing used in 70 cases.
All patients experienced at least one treatment-emergent adverse event (TEAE) and 97.0% at least one retinoid-associated TEAE, the investigators report. These were mild, moderate, and severe in 32.3%, 45.5%, and 22.2% of cases and were most commonly skin complaints, such as dry skin (68.7%) or lips (46.5%) and alopecia (34.3%), and musculoskeletal events, such as arthralgia (33.3%).
Patients were more likely to require dose reduction for TEAEs during flare-up dosing than during chronic dosing (40.0 vs 11.1%).
Of concern, 36.8% of the 57 patients aged less than 14 years at baseline experienced partial or complete PPC (n=20) or an epiphyseal disorder (frayed metaphyseal edge; n=1). Eighteen of the PPC cases occurred during treatment and two at 115 and 305 days after discontinuation.
The researchers therefore conclude: “Given the potential risk of long bone growth inhibition, particularly in very young children (<8 years of age for girls and <10 years of age for boys), extremely careful consideration of the benefits and risks should be made when deciding whether to treat growing children with palovarotene.”
Further longer term follow-up for AEs is required, they add.
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