Atebrioz (zilurgisertib)

Zilurgisertib is an oral, selective inhibitor of wild-type and R206H-mutant ALK2, taken as 100 mg once daily. The efficacy evidence comes from Cohort 1 of PROGRESS (NCT05090891), a phase 2, randomized, double-blind, placebo-controlled trial in which 63 participants aged 12 years and older (28 adults and 35 pediatric participants aged 12 to 16 years) received zilurgisertib 100 mg (n = 32) or placebo (n = 31) once daily for 24 weeks, followed by an open-label extension of zilurgisertib.

The protocol-specified primary endpoint was the proportion of participants with new HO lesions at Week 24: 1 of 32 (3.1%) with zilurgisertib and 5 of 30 (16.7%) with placebo (P = 0.0986). The manufacturer states that the pivotal study “did not reach statistical significance on the primary endpoint”. The prescribing information establishes efficacy on a different measure, total new HO volume on whole-body CT excluding the head, which includes expansion of baseline HO as well as new discrete HO. At Week 24, the mean change from baseline in total new HO volume was −3.2 cm³ (SD 19.9) with zilurgisertib and +24.6 cm³ (SD 51.9) with placebo, a Hodges-Lehmann treatment difference of −15.8 cm³ (95% CI −32.1 to −6.0). An interim congress report states that no participant had new lesions from Week 24 to Week 48 of the open-label extension.

Adverse reactions in at least 10% of zilurgisertib-treated participants through Week 24 were headache (22% vs 16% with placebo), arthralgia (22% vs 10%), upper respiratory tract infection (22% vs 10%), epistaxis (13% vs 0%), and nausea (13% vs 3%); serious treatment-emergent adverse events occurred in 2 participants (6.3%) vs 3 (9.7%), and no adverse event led to dose reduction or discontinuation of zilurgisertib. The label carries one warning, embryo-fetal toxicity: zilurgisertib is contraindicated in pregnancy, pregnancy is to be excluded before initiation, and effective contraception is advised during treatment and for one week after the final dose. Mean serum iron, hemoglobin, and transferrin saturation increased relative to placebo and remained within the normal range, and through Week 100 the increases were “not associated with signs or symptoms of iron overload”. Iron deficiency anemia was reported in 3 zilurgisertib-treated participants. Rats given zilurgisertib for 6 months developed hepatic iron accumulation and basophilic foci of cellular alteration, and long-term carcinogenicity studies have not been conducted.