Potential SMA Therapy, RG7916, for Types 2 and 3 Advancing in Clinical Trial in Europe


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A Phase 2 clinical trial evaluating the efficacy and safety of RG7916 in children and adults with type 2 or 3 spinal muscular atrophy (SMA) has advanced into a second and possibly pivotal phase. The study is part of a development program jointly led by PTC Therapeutics, Roche and the SMA Foundation.

The SUNFISH trial (NCT02908685) consists of two parts: an exploratory dose-finding initial part that ran for 12 weeks  and a confirmatory part that will run for 24 months. This second part is randomized, double-blinded and placebo-controlled. Approximately 168 type 2 and 3 SMA patients, ages 2 to 25, are expected to enroll at sites in four European countries. When SUNFISH concludes in about two years, patients may continue in an open-label extension of this study.

An interim analysis from its first part demonstrated an exposure-dependent increase in the survival motor neuron (SMN) protein, which is deficient in these patients. RG7916 continues to be well-tolerated at all doses and no drug-related safety findings led to any patients withdrawing from part one.

RG7916 is an oral survival motor neuron 2 (SMN2) splicing modifier. Because SMA is caused by a defect in the SMN1 gene, the SMN2 gene has been explored as a potential replacement to guarantee the production of the SMN protein.

Messenger RNA (mRNA) is the molecule that guides protein formation. Pre-mRNA is a less developed version of mRNA. In order for pre-mRNA to become mRNA, the genetic material in pre-mRNA must be edited through a process called “splicing,” where some sections are removed.

To say that RG7916 is a splicing modifier means that it directly targets the underlying molecular deficiency of SMA by modulating SMN2 splicing to increase expression of full-length SMN2 mRNA from the SMN2 gene.

“We are excited to move RG7916 into the pivotal part of the SUNFISH trial,” Stuart W. Peltz, PhD, chief executive officer of PTC Therapeutics, said in a press release. “RG7916 resulted in a substantial increase in SMN2 protein production in SMA patients. We believe that a major advantage of RG7916 is that it is an oral drug that distributes throughout the body. This is important because the SMN protein is critical both in the CNS and peripheral tissues.”

RG7916 is also being investigated in babies with type 1 or infant-onset SMA in a Phase 2 trial called FIREFISH (NCT02913482). This study, running at sites in the U.S. and Europe, is currently recruiting infants ages 1 to 7 months old.

PTC Therapeutics and the SMA Foundation initially began working on this potential therapy in 2006, and Roche began to participate in 2011, when it acquired an exclusive worldwide license to this splicing program.  The U.S. Food and Drug Administration (FDA) designated RG7916 an orphan drug for the treatment of SMA in January 2017.

Initiation of the second part of SUNFISH triggered a $20 million milestone payment to PTC from Roche.