Summary: outcomes reported for zilurgisertib

In the 24-week double-blind period of PROGRESS, total new HO volume (new lesions plus expansion of existing lesions) decreased by a mean of 3.2 cm³ with zilurgisertib and increased by 24.6 cm³ with placebo. The registered primary endpoint, the proportion of participants with new HO lesions, was 1 of 32 (3.1%) with zilurgisertib and 5 of 30 (16.7%) with placebo (P=0.0986). Mean volume of new lesions was 0.003 cm³ with zilurgisertib and 6.57 cm³ with placebo, and mean annualized new flares were 2.34 and 4.55. No new lesions were reported in either group from Week 24 to Week 48 of the open-label extension. The effect of these radiographic changes on joint function, mobility, and survival has not been reported, and no consensus threshold defines a clinically meaningful reduction in new HO volume.

Labeled efficacy at Week 24: total new HO volume

“At Week 24, the mean change (SD) from baseline in total new HO volume was −3.2 cm³ (19.9) in the zilurgisertib group and +24.6 cm³ (51.9) in the placebo group, resulting in a Hodges-Lehmann treatment difference of −15.8 cm³ (95% CI: -32.1, -6.0).” (opens the prescribing information at this quote)

Registered primary endpoint and new lesion volume at Week 24

“At Week 24, 1 of 32 patients in the zilurgisertib group had new lesions versus 5 of 30 patients in the placebo group (primary endpoint, P=0.0986; Figure 2)” (opens the source at this quote in a new tab)
“Smaller new lesion volume (cm3) with ZGB vs PBO at Week 24 (mean [SD]): 0.003 [0.02] vs 6.57 [20.70]); P<0.0001” (opens the source at this quote in a new tab)
“Fewer mean (SD) annualized new flares by Week 24 with ZGB vs PBO (2.34 [6.06] vs 4.55 [7.71])” (opens the source at this quote in a new tab)

Durability through Week 48 of the open-label extension

“No patients had new lesions during the OLE period from Week 24 to 48” (opens the source at this quote in a new tab)
“From baseline to Week 24, total lesion volume decreased in the zilurgisertib group but increased in the placebo group, while from Week 24 to 48, total lesion volume decreased from baseline in both groups” (opens the source at this quote in a new tab)

Relation of new HO volume to function

“Currently, there is no consensus on a threshold for a clinically meaningful reduction in new HO volume in patients with FOP, and this warrants further research.” (opens the source at this quote in a new tab)
“reducing the volume of new HO over time may help slow the progression of functional disability, and preventing even small volumes of new HO in certain joints may be crucial for maintaining patients’ mobility and quality of life.” (opens the source at this quote in a new tab)

Disease course without disease-modifying therapy

“Most patients with FOP are confined to a wheelchair by the third decade of life and require lifelong assistance with activities of daily living. The median estimated life expectancy is 56 yr. Death often results from complications of thoracic insufficiency syndrome.” (opens the source at this quote in a new tab)

Atebrioz (zilurgisertib)

Expected outcomes of therapy