SMA Program

Spinal Muscular Atrophy Program

PTC is committed to the development of treatments for rare and neglected disorders. Building on that commitment, PTC collaborated with the Spinal Muscular Atrophy Foundation in 2006 to utilize PTC’s Alternative Splicing technology platform to identify and develop new small-molecule therapeutics for use in the treatment or prevention of spinal muscular atrophy (SMA), a neuromuscular disease and the leading genetic cause of death among infants and toddlers.

In late 2011, Roche joined the collaboration to help further develop and commercialize compounds that has been identified from PTC’s efforts. Under the terms of the agreement, Roche gained an exclusive worldwide license to PTC's SMA program; PTC received $30 million as an upfront payment and may receive up to $460 million upon successful completion of certain development and commercialization milestones, and up to double-digit royalties on commercial sales. Clinical development is overseen by a joint steering committee comprised of members from Roche, PTC and the SMA Foundation.

Results of preclinical studies demonstrating that treatment with orally available splicing modifiers of the SMN2 gene starting early after birth prevented disease manifestations in mouse models of SMA were published in the journal Science on August 8, 2014. Scientists from Roche Pharma Research and Early Development (pRED), PTC Therapeutics, Inc., the SMA Foundation, the University of Southern California and Harvard University collaborated to demonstrate that continuous treatment of SMA mice with these compounds increased life span, normalized body weight, and prevented both disease-related motor dysfunction and neuromuscular deficits in a mouse model of SMA.

The researchers used chemical screening and optimization against proprietary assays developed at PTC to identify orally bioavailable small molecules that selectively modify the splicing of the SMN2 pre-mRNA to produce stable full length SMN protein. These splicing modifiers corrected the alternative splicing of the SMN2 gene and increased SMN protein levels in cultured cells obtained from SMA patients, including iPS cell-derived motor neurons. When evaluated in vivo, the SMN2 splicing modifiers penetrated into all tissues tested, including brain, spinal cord, and muscle; modified SMN2 alternative splicing toward the generation of the full length mRNA; and increased SMN protein production in the disease relevant tissues in two mouse models of SMA. As a result of the SMN protein increase, the compounds prevented the progression of the disease in a severe SMA mouse model. A Phase I clinical program to assess safety and tolerability with investigational compounds was initiated in early 2014.