[Author: Laura Cowen]
Experimental data suggest that the tyrosine kinase inhibitor saracatinib may be a candidate for the treatment of fibrodysplasia ossificans progressiva (FOP), via its inhibition of activin receptor-like kinase (ALK)2.
Alex Bullock (University of Oxford, UK) and colleagues believe their in vitro and in vivo studies show that “[r]epositioning saracatinib for FOP offers an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition.”
They explain that ALK2 is a type I bone morphogenetic protein (BMP) receptor kinase that is encoded by the ACVR1 gene. Mutations in this gene are responsible for all cases of FOP, making the ALK2 pathway a therapeutic target for FOP.
In the current study, Bullock and team screened a library of small-molecule kinase inhibitors that have previously been tested in clinical trials to determine whether any were active against ALK2.
They report in JCI Insight that the dual SRC/ABL inhibitor saracatinib had the strongest activity against ALK2, and that the inhibition was 30 times more selective for BMP than for transforming growth factor (TGF)-β signaling pathways with ALK5 receptors, when tested in the C2C12 cell line.
This selectivity was confirmed in zebrafish embryos where saracatinib induced dorsalization, a developmental phenotype that is highly specific for BMP inhibition. Furthermore, this dorsalized phenotype increased in severity with increasing saracatinib doses.
To evaluate the therapeutic potential of saracatinib, the investigators tested saracatinib in ACVR1Q207D-transgenic mice, which provide a model of heterotopic ossification (HO). They found that after treatment at a dose of 25 mg/kg per day for 28 days, the mice demonstrated significantly improved range of motion, and markedly reduced HO at the site of ACVR1Q207D activation compared with mice treated with a vehicle control.
In a second mouse model, ACVR1R206H, which more accurately represents FOP disease, 28 days of saracatinib (25 mg/kg per day) protected the mice against HO for up to 90 days, with only mild loss of motion developing between days 60 and 90 after treatment completion.
“These initial results confirmed that saracatinib attenuates HO mediated by dysregulated Acvr1R206H signaling in vivo and may be an effective transient therapy following acute trauma, as supported by the prolonged protection observed after treatment withdrawal and the lack of rebound ossification,” Bullock et al remark.
They also note that the treatment was well-tolerated and did not appear to impact neonatal growth, which “suggests that its application to FOP could be extended beyond the prophylactic treatment of acute episodes of HO.”
The authors conclude: “Based on the evidence of target engagement and efficacy in preclinical models at doses equivalent to or lower than those previously tolerated in humans, a phase II clinical trial using 100 mg/[day] has been launched to explore the use of saracatinib as prophylaxis for FOP progression.”
They add that “if saracatinib is sufficiently tolerable, its chronic use for the long-term suppression of ACVR1R206H activity might be a promising option for maintaining optimal control of FOP disease, suppressing its progression even in the absence of flares or acute episodes, and potentially preventing flares altogether.”