Evrysdi

Evrysdi is a survival of motor neuron (SMN)2 pre-messenger ribonucleic acid (mRNA) splicing modifier designed to treat spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. Functional SMN protein deficiency is the pathophysiological mechanism of all SMA types. Evrysdi corrects the splicing of SMN2 to shift the balance from exon 7 exclusion to exon 7 inclusion into the mRNA transcript leading to an increased production in functional and stable SMN protein. Thus, Evrysdi treats SMA by increasing and sustaining functional SMN protein levels.In vitro and in vivo data indicate that risdiplam may cause alternative splicing of additional genes, including forkhead box protein M1 (FOXM1) and mitogen activated protein kinase activating death domain (MADD). FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse effects seen in animals.Risdiplam distributes evenly to all parts of the body, including the central nervous system (CNS) by crossing the blood brain barrier, and thereby leading to SMN protein increase in the CNS and throughout the body. Concentrations of risdiplam in plasma and SMN protein in blood reflect its distribution and pharmacodynamic effects in tissues such as brain and muscle.In all clinical trials, Evrysdi led to a consistent and durable increase in SMN protein with a greater than two fold median change from baseline within four weeks of treatment initiation as measured in blood. This increase in SMN protein was sustained throughout the treatment period of up to two years for infantile onset SMA and later onset SMA patients (see Section 5.1 Clinical trials).