Upcoming events – Translarna's turn in cystic fibrosis and brodalumab's approval tardiness


Welcome to your weekly digest of approaching regulatory and clinical readouts. PTC Therapeutics 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 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.

Consensus for the project once peaked at $1bn by 2022, according to EvaluatePharma, but it now sits at $405m, with $129m allocated to cystic fibrosis.


After a positive advisory committee the US regulator extended brodalumab’s potential approval date from November to February, saying it needed more time to discuss its risk-management program. The Valeant project comes with suicide risks, something that led to Amgen and Astrazeneca dropping it (FDA experts back brodalumab, with warnings, July 20, 2016).

If it is launched the psoriasis biological will be the third IL-17-targeting antibody to market behind Novartis’s Cosentyx and Lilly’s Taltz. The last two have warnings about serious infections, but nothing about psychiatric risk.

Brodalumab sales are forecast to reach $370m by 2022 according to consensus from EvaluatePharma, which pales in comparison to Novartis and Lilly’s projects.The market is becoming increasingly crowded, with IL-23 MAbs such as J&J’s guselkumab also set to enter, and even with its upcoming approval brodalumab is languishing behind.

Late-stage psoriasis biologicals
Global sales for psoriasis
Product MAb mechanism Company Psoriasis launch 2016 2022e
Marketed Stelara Anti-IL-12 & IL-23 Johnson & Johnson Dec 2008 2,961 4,677
Cosentyx Anti-IL-17A Novartis Feb 2015 889 3,012
Taltz Anti-IL-17A Lilly Apr 2016 115 1,265
Filed Guselkumab Anti-IL-23 Johnson & Johnson Dec 2017 - 1,172
Brodalumab Anti-IL-17 Valeant Jun 2017 - 370
Phase III Risankizumab Anti-IL-23 AbbVie Dec 2018 - 509
Tildrakizumab Anti-IL-23 p29 Merck & Co Mar 2018 - -
Project Trial ID
Translarna ACT CF NCT02139306

To contact the writer of this story email Joanne Fagg in London at joannef@epvantage.com or follow @ByJoFagg on Twitter

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