Little left to lift spirits in IPF field

For sufferers of idiopathic pulmonary fibrosis (IPF) the news of a cure or even an effective treatment appears to get bleaker and bleaker every day. Yesterday, the findings of a small study using Pfizer’s Revatio to alleviate symptoms of the lung disease did little to dispel the gloom after it failed to improve the distance walked by patients in six minutes.

The disappointment of trying to using Revatio in this hard to treat disease follows a decision earlier this month by the FDA not to approve one of the brightest hopes in the space, InterMune’s pirfenidone, despite an earlier positive recommendation from an advisory committee (Intermune left gasping by FDA rejection of pirfenidone, May 5, 2010). This big setback came hot on the heels of Actelion’s Tracleer also stumbling and falling in March after it failed to meet its primary endpoint of a reduction in time to disease worsening or death (Actelion stopped in its tracks with negative Tracleer data, March 1, 2010). 

Yesterday, a detailed review of the results of the negative Build-3 trial at the American Thoracic Society conference confirmed the initial results that Tracleer failed to show a statistically significant reduction in the time to the disease worsening or death. Further hammering nails into the coffin of the drug in this indication were the revelations that a subgroup analysis of the results also failed to show any statistcally significant benefits while the drug also showed worrying levels of liver toxicity.

Narrowing field

Prior to this there had been real hopes that either Tracleer, or more particularly pirfenidone, which could now face lengthy additional trials, might become an effective treatment for the disorder that usually kills within five years of diagnosis. But what the setbacks do is leave what was already a very slender pipeline looking even narrower as can be seen from the table below.

The next two biggest hopes, macitentan and Letairis/Volibris, are both endothelin receptor antagonists (ERAs). Unsuprisingly, following the failure of Tracleer in IPF, Actelion has refocused its efforts in the space on macitentan, which the company believes will not only have greater efficacy than its older sibling, but should also overcome some of the liver toxicity issues associated with Tracleer.

What the market and patients will now be waiting for is the phase II trial Music to report to back up these claims. Data are expected in the second half of 2011 and will be examined closely, especially as some in the market believe that that the failure of Tracleer could cast doubt on the whole ERA approach to IPF.

While expectations for macitentan are relatively modest, if the data are positive it could provide Actelion with a huge boost given the drug’s long patent life and the paucity of available products.

As for Letairis/Volibris, the drug from Gilead and Glaxo, it could be distinguished from macitentan in that rather than being a dual ERA it is a selective one. What will determine whether this approach is the right one will be the results from the Artemis trial, which will have its final read out in 2012.

New approaches

Of the other earlier stage treatments in the pipeline using novel approaches including Novartis’ monoclonal antibody QAX576 and mondoBiotech’s Aviptadil, there is little data available making it hard to speculate if these could be next great hopes.

As such, although it has not formally been recognised as a treatment for IPF some hope can be taken from this week’s trial results using Revatio, which is a lower dose form of vasodilator Viagra. Although it did not improve walking ability it did score well on secondary endpoints including forced vital capacity and arterial oxygen saturation, as well as quality of life improvements and shortness of breath.

The trial was, however, relatively small at 180 patients so conclusions should not be drawn from the secondary endpoints, but investigators from the National Heart, Lung and Blood Institute and the Cowlin Fund of Chicago Community Trust who conducted the trials said that further, larger studies could be warranted to explore these improvements.

The study might also help off-label use of Revatio in IPF, which is already approved in pulmonary arterial hypertension, potentially boosting sales of the drug which are due to hit $445m in 2011 before it loses patent protection in the following year.

IPF pipeline
Annual sales WW ($m)
Status Product Company Pharmacological Class 2010 2012 2014 2016
Marketed/Filed Pirespa/Pirfenidone Shionogi/InterMune TNFa inhibitor  60  484  926  1350
Phase III Letairis/Volibris Gilead Sciences/GlaxoSmithKline Endothelin A receptor antagonist  396  642  825  751
Phase II Macitentan Actelion Endothelin receptor antagonist  -  -  124  236
GS 6201 Gilead Sciences Respiratory agent  -  -  -   -
QAX576 Novartis Anti-IL-13 Mab  -  -  -   -
Aviptadil mondoBIOTECH Vasoactive intestinal peptide  -  -  -   -
Phase I Tyvaso United Therapeutics Prostacyclin analogue  20  237  316  393
CC-930 (JNK 930) Celgene JNK inhibitor  -  -  -   -
GC-1008 Genzyme Anti-TGF-beta MAb  -  -  -   -

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