ATL1102, an antisense drug to the CD49d alpha chain of adhesion molecule VLA-4, has been evaluated in a Phase II study in nine non-ambulant patients with Duchenne muscular dystrophy (DMD). Patients (12 to 18 years) 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 performance of upper limb PUL2.0 muscle function, grip and pinch strength, and MRI fat fraction.
Analysis of plasma from the patients assessed ATL1102’s effects via proteomics using the Somascan® aptamer-based assay, 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 increases of sVCAM-1 (18.0%), LTBP4 (20.7%), , BMP5 (46.2%), BMP6 (34.4%) and IGF-I (18.8%) and decreases of Thrombospondin-1 (-49.3%) were observed compared to baseline levels (FDR p-value <0.0005). Compared to healthy adult controls, nRFU baseline levels of sVCAM-1, LTBP4, BMP5 and BMP6 were below average, and Thrombospondin-1 above average and ATL1102 treatment modulated each to nearer the external control mean.
ATL1102 effects on sVCAM-1, LTBP4 which sequesters TGF-beta, and Thrombospondin-1 which activates TGF-beta, both genetic modifiers of disease progression and fibrosis in DMD may have a role in the observed ATL1102 function and strength stabilization and MRI benefits in the non-ambulant patients. ATL1102 increases of BMP5 and BMP6, with roles in cartilage and bone formation suggest a potential for reduced osteoporosis. ATL1102 increases of IGF-I suggest a potential for increasing linear growth.
These proteins involved in muscle and bone physiology and linear growth can be important in osteopenia and growth retardation presenting in DMD patients, exacerbated by corticosteroids, and treatment with ATL1102 may improve patient outcomes.