Hopeful new clinical trails for nonsense mutations

Translarna’s Turn In Cystic Fibrosis And Brodalumab’s Approval Tardiness


Welcome to your weekly digest of approaching regulatory and clinical readouts. PTC Therapeutics (NASDAQ:PTC) is awaiting data in the first quarter with its transcription modulator Translarna in nonsense mutation cystic fibrosis. Questions abound on its regulatory path in Duchenne muscular dystrophy, so the company needs to diversify its pipeline.

After a three-month extension, Valeant (NYSE:VRX) should know the US decision on brodalumab in psoriasis by February 16. With uncertainties around the project’s safety and its late-entrant status the commercial potential remains modest (see table below).

Latest indication

ACT CF is a 48-week, placebo-controlled Phase III trial of Translarna in 208 patients aged six or older with a nonsense mutation in the CFTR gene (known as nmCF), which is responsible for 10% of cystic fibrosis cases worldwide. Sufferers do not produce any functional CFTR protein and generally have a more severe form of the disease than patients with other mutations.

Participants received Translarna three times a day or placebo, and the primary endpoint is absolute change in FEV1. The protocol initially looked at relative change, but was amended in line with trials of other approved therapies. Secondary measures include pulmonary exacerbations, and data are expected in the current quarter.

Relative change in FEV1 was the primary endpoint in a previous Phase III trial, but this was missed by the intent-to-treat population. A subgroup analysis showed a positive difference in patients who were not using chronic inhaled aminoglycosides such as tobramycin, suggesting that this interferes with Translarna’s mechanism of action. The ACT CF study excludes patients who have chronically used aminoglycosides within four months before screening.

Increased creatinine concentrations, an indicator of acute kidney injury, occurred in 15% of patients in the active group compared with <1% of placebo recipients, a signal that will need to be closely watched.

In its main indication, Duchenne muscular dystrophy, Translarna has faced an uphill battle for approval. It received a refuse-to-file letter from the FDA, and the regulators rejected PTC’s appeal last October. It is faring slightly better in Europe with a conditional approval, but a permanent approval and any change of heart from the FDA is seemingly dependent on new data, which will likely not be available until 2021.

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