Esbriet data show widening gap over competitors

InterMune’s long game looks like it will pay off. Data from its phase III Ascend trial of Esbriet in idiopathic pulmonary fibrosis (IPF) should be enough to win US backing, and with its nearest competitor, Boehringer Ingelheim, facing a potential cardiovascular signal Esbriet now has a better chance of living up to hefty expectations.

Detailed data released at the American Thoracic Society meeting gave fresh momentum to InterMune’s shares yesterday, after topline results had already spiced things up (InterMune draws up battle lines for IPF space following strong Esbriet data, February 26, 2014). With a filing coming within weeks, it is possible that by the end of the year US IPF patients could join those in Europe and Japan in having this treatment available to them.

Not taking no for an answer

InterMune designed Ascend after the FDA’s rejection of Esbriet in 2010, seeking a third pivotal trial because of mixed results in two earlier studies. The California-based group hoped to establish a mortality benefit as well as an improvement in lung function, as only the previous Capacity 2 trial had been able to do.

On lung function, the improvement was fairly decisive: a decline of 235ml compared with 428ml in forced vital capacity (FVC), a statistically significant difference over placebo at a p value of less than 0.0001. A secondary endpoint – patients with an FVC decline of 10% or more or dying – also came out on Esbriet’s side, with 17% of Esbriet’s patients reaching that combined endpoint and 32% of placebo patients, significant at p value of less than 0.0001. This measure was designed as a progression-free survival endpoint.

Overall survival was not statistically different, but the study was not powered to detect this, and the secondary endpoint of dyspnoea was not met. In a prespecified analysis of Ascend data pooled with the two Capacity trials survival endpoints look a little better, with statistically significant 48% reduction in the risk of any death and 68% reduction in the risk of respiratory death over more than 600 patients. As a retrospective analysis including data from older trials, those pooled survival data are likely to get a close examination from regulators.

In addition to these efficacy data, Esbriet also has three years of use in Europe and six in Japan, where it is marketed as Pirespa, so a sizable safety database has built up for the pill, which ought to increase regulators’ comfort. Esbriet’s adverse events profile looked little different in Ascend than in the Capacity trials, which will come as some relief to investors.

Regulatory view

A positive, but not unanimous, FDA advisory committee vote in 2010 suggests that another might not be needed, especially since this should be regarded as a resubmission with a six-month deadline. However, the possibility that Boehringer Ingelheim will be submitting the competing agent nintedanib raises the possibility that a meeting of the Pulmonary-Allergy Drugs Advisory Committee will be called in the same timeline, and that panellists will be asked to review Esbriet once again.

Shares in InterMune rose 13% to a three-year high of $38.92 yesterday after release of the data, valuing the company at nearly $4bn. Some of the value is no doubt built around the hope that the one-product group will be acquired, but it would be a decidedly more pricey transaction today than at the start of 2014, when InterMune had been struggling to grow sales into the triple-digit millions on European authorisation alone – 2014 sales are forecast to reach $135m, rising to $1.24bn in 2020, according to EvaluatePharma.

Giving InterMune a lift were comparatively disappointing data at ATS from nintedanib, which appeared weaker on efficacy, although none of these trials was head-to-head. Taken alone, the efficacy difference might not have been such a boost for InterMune if Boehringer’s two Inpulsis trials had not also revealed an imbalance in myocardial infarctions, 10 versus two in the placebo arms, and two MI deaths in the nintedanib groups versus one taking placebo. This finding prompted investigators to call for “further observations in larger cohorts”.

Esbriet looks like it will be headed for a US approval that many had hoped for in 2010, and if current forecasts are met InterMune could start generating sustainable profits in 2016. But the company has a short window to make back the more than $1bn in R&D expenditures it has accrued since its creation in 1999 before Esbriet's patent estate begins to erode in 2021.

To contact the writer of this story contact Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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