ATL1102, an antisense drug to CD49d, the alpha chain of VLA-4, has been evaluated in a Phase II study in nine non-ambulant patients with Duchenne muscular dystrophy (DMD) at the Murdoch Children’s Research Institute. All patients (12 to 18 years of age) were dosed with ATL1102 once weekly at 25mg s.c. for 24 weeks. Eight of the patients were on standard of care corticosteroid treatment. ATL1102 was shown to be safe, and modulated CD49d+ lymphocytes, and stabilized upper limb muscle function, strength, and fat fraction.
Post-hoc analysis of plasma from the study assessed ATL1102’s effects on proteomics as measured by the Somascan® assay, a large scale, aptamer-based assay, using normalized relative fluorescence units (nRFU). Parametric mixed effect longitudinal analysis was conducted to determine the average percent change over time, p-value and Benjaminin-Hochberg false discovery rate (FDR) adjusted p-value.
At 24 weeks, statistically significant mean decreases of Thrombospondin-1 (-49.3%) and increases of LTBP4 (20.7%), BMP5 (46.2%) and BMP6 (34.4%) were observed compared to baseline levels (FDR p-value <0.0005). Compared to a healthy adult control, nRFU baseline levels of LTBP4, BMP5 and BMP6 were below average, and ATL1102 treatment modulated each to nearer the external control mean.
ATL1102 increase of LTBP4, which sequesters TGF-beta, and ATL1102 decrease of Thrombospondin-1, which activates TGF-beta, suggest potential for reduced TGF-beta associated fibrosis.
ATL1102 increases of BMP5 and BMP6, ligands of the TGF-beta superfamily of proteins, with a role in cartilage and bone formation, suggest a potential for improved bone density. Serum BMP6 levels are reportedly associated with improved elbow flexion in DMD patients.
The effects on these proteins and others detected relevant to immune response, muscle and bone physiology may have a role in the observed ATL1102 function and strength stabilization and MRI benefits in the non-ambulant patients in the Phase II DMD study.