Phase 2 Clinical Test of Oral Compound Targeting Genetic Cause of SMA Starts in Europe

Özge Özkaya, PhD avatar

by Özge Özkaya, PhD |

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PTC Therapeutics has announced the initiation of a Phase 2 clinical trial to test the safety, tolerability, and efficacy of the small molecule RG7916 as a treatment for children and adults with type 2 and type 3 spinal muscular atrophy (SMA).

The trial, called SUNFISH (NCT02908685), currently recruiting patients in three European countries, is part of the SMA program initially developed by PTC in collaboration with the SMA Foundation (SMAF). The compound is being developed by Roche and overseen by a joint steering committee from PTC, Roche, and SMAF.

RG7916 is an oral compound targeting the underlying genetic cause of SMA. It modulates the splicing of the SMN2 gene to increase the production of SMN protein from this gene.

“We are excited to initiate clinical studies in SMA patients with RG7916 and advance our Spinal Muscular Atrophy program forward,” Stuart Peltz, PTC Therapeutics’ chief executive officer, said in a press release. “An oral small molecule splicing modifier has the potential benefit of systemic exposure to promote SMN protein in all affected organs and tissues. This attribute, along with an ease of administration, provides promise for this program to have a meaningful benefit for SMA patients.”

SUNFISH consists of two parts: one is 12 weeks long and aims to determine the compound’s optimal dose as well as to evaluate its safety, pharmacokinetics, and pharmacodynamics. It will conducted on approximately 36 patients with type 2 and type 3 SMA in a double-blind, placebo-controlled, and randomized manner, meaning that neither the patient nor the clinician will know who is taking the compound and who is taking placebo.

Once the optimal dose of RG7916 is determined, the second part of the trial, lasting 24 months, will begin. This will be a confirmatory study in approximately 150 patients with type 2 and type 3 SMA (ages 2–25), evaluating the efficacy of RG7916 compared to placebo. Part two will also be double-blind, placebo-controlled and randomized, and will be followed by an open-label extension study.

The company is also planning a clinical trial in infants with type 1 SMA in the coming months, called FIREFISH (NCT02913482). Like SUNFISH, this trial will also consist of two parts. In the first, the safety of RG7916 will be tested in at least eight infants (ages 1–7 months) with type 1 SMA for a minimum of four weeks, and the optimal dose will be determined. In the second part, the efficacy of the selected dose will be tested in 40 infants with type 1 SMA for 24 months. This trial will also be followed by an open-label extension study.

SMA is a rare genetic condition caused by a mutation in the SMN1 gene. This mutation leads to no SMN protein being produced from this gene at all. SMN is an essential protein for the survival of motor neurons. There is also a second gene called SMN2 in the human genome, from which some SMN protein can be produced. However, due to a splicing site on the SMN2 gene, the amount of SMN protein it produces is not sufficient. RG7916 modulates the splicing of the SMN2 gene to increase the production of SMN protein from it.

A Phase 1 clinical trial testing the safety and efficacy of RG7916 in healthy volunteers was recently completed and found that RG7916 was both well-tolerated and increased the production of the full-length messenger from the SMN2 gene.