Therapeutic focus - Behind Tracleer pulmonary fibrosis pipeline is a trickle

Analysis

For sufferers of idiopathic pulmonary fibrosis (IPF) treatment options are limited, at best the symptoms of the chronic and debilitating lung condition can be managed. Therefore there are high hopes for a handful of therapies in late and mid-stage development.

IPF has proven itself a hard target in the past, and although the research pipeline is not huge with some novel compounds in the clinic the chance of something starting to show efficacy in actually modifying the disease is improving. As the table below shows the first product to reach the US market for this specific indication is likely to be InterMune’s pirfenidone; the FDA is due to make a decision on the immunosuppressant by May 4. However, amongst the novel approaches the endothelin antagonists Tracleer and Letairis will be next to generate pivotal results, and considering this class of drug accounts for a large proportion of the late-stage pipeline, both physicians and patients will be hoping for good news.

Thin pipeline

Corticosteroids and immunosuppressants are often used as a treatment for IPF, but beyond having a lung transplant the condition cannot be reversed, at best the symptoms can be managed, as far as is possible. The main symptom of IPF is shortness of breath that gradually gets worse, and the exact cause is unknown, although it is thought that smoking or exposure to pollutants, viral infections or even gastroesophageal reflux disease could be involved.

It used to be thought that inflammation led to scarring and fibrosis, but because treatments that reduce inflammation are not always effective this hypothesis is under question. Some experts believe it could be caused by damaged alveoli cells trying to heal themselves, and that this process becomes out of control, causing the fibrosis.

For a disorder that kills around half of the people who contract it in the first three years, the disease does not have a particularly rich research and development pipeline, however. EvaluatePharmalists nine drugs that have progressed to human stage testing, with evidence of recent clinical work being conducted. Many are also in trials for other conditions such as pulmonary hypertension or scleroderma.

Included in that number is two drugs already on the market for pulmonary hypertension: Actelion’s Tracleer, which generates more than $1bn in sales, and Tyvaso, an inhaled version of the injection treatment Remodulin.

Pirfenidone is already on the market in Japan to treat IPF, marketed as Pirespa by Shionogi since October 2008. It was the first drug approved to specifically treat IPF anywhere in the world.

InterMune owns rights to the drug elsewhere and it is currently under review by the FDA. Approval would not only be a big event for IPF patients, as a relatively small company the product could prove transformative for InterMune. But even with priority review status at the FDA, pirfenidone was one of the big drugs that failed to launch as analysts had forecast in 2009, with a resulting 16% downgrade of consensus sales forecasts in 2014 from $917m in February 2009 to the current $768m (Failure to launch for 2009’s big hopes, January 15, 2010).

Dominant class

If pirfenidone, a TNF-alpha, is leading the way, it is closely followed by three endothelin receptor antagonists in phase III and II. Leading the charge is the endothelin A and B receptor antagonist Tracleer, now nearing the release of phase III data (Event – Actelion hoping new data will build on Tracleer, January 13, 2010).

Behind the closely watched Tracleer in phase III is Letairis, an endothelin A receptor antagonist to which Gilead Sciences has rights in the US and GlaxoSmithKline, as Volibris, in the rest of the world. Gilead’s ARTEMIS-IPF study is still enrolling patients, with a goal of 600 subjects at 193 study locations and an estimated study completion date of December 2012, according to www.clinicaltrials.gov. That trial will measure time to death or disease progression, as well as the proportion of patients with disease progression at 48 weeks.

The drug is already on the market in pulmonary hypertension; consensus forecasts shows worldwide sales of the drug rising from $129m in 2008 to $950m in 2014.

Actelion is taking a second IPF shot on goal with macitentan, the third endothelin receptor antagonist in the pipeline. The Swiss company began a phase II trial in May 2009 with an estimated 156 patients to test improvement in forced vital capacity over 12 months as a primary endpoint, and time to disease progression or death over three years as secondary endpoints, according to clincialtrials.gov. That trial is expected to end in March 2010 for the primary endpoint and March 2012 for the secondary endpoint.

With so much emphasis on the endothelin receptor agonists in the IPF pipeline, many will be hoping for successful Tracleer trials. If the data disappoints, it may cast doubt on the usefullnes of this class in this disease, leaving only a thin trickle in the IPF pipeline.

Earlier stage

Gilead also is taking a second shot with GS 6201, listed as being in phase II trials, although little information is available on the compound.

Novartis is testing the effectiveness of its anti IL-13 monoclonal antibody, QAX 576, in a phase II study with 31 patients. Investigators are testing the hypothesis that IPF patients experience increased IL-13 production and that QAX576 will reduce that production, according to clinicaltrials.gov.

Lastly, aviptadil has been trialled in IPF, but looks unlikely to turn into a promising late stage candidate anytime soon. In 2006, Biogen Idec bought rights to the drug, a vasoactive intestinal peptide, from mondoBiotech in pulmonary arterial hypertension, and the option over rights in three other respiratory indications, including IPF. However, little information on the progress of the drug has been revealed by either company in the last couple of years, and no studies are listed on clinicaltrials.gov.

A couple of earlier, novel stage candidates are also in the pipeline, a JNK inhibitor from Celgene and an anti-TGF beta Mab, fresolimumab, from Genzyme; the latter appears to be in active development although whether it will progress forward in this indication remains to be seen.

IPF Pipeline Annual sales WW (across all indications - $m)
Status Product Company Pharmacological Class 2010 2012 2014
Marketed/Filed Pirespa/Pirfenidone Shionogi/InterMune TNFa inhibitor 96 511 838
Phase III Tracleer Actelion Endothelin A & B receptor antagonist 1,629 1,961 2,150
Letairis/Volibris Gilead Sciences/GlaxoSmithKline Endothelin A receptor antagonist 432 696 950
Phase II Macitentan Actelion Endothelin receptor antagonist - - 62
GS 6201 Gilead Sciences Respiratory agent - - -
QAX576 Novartis Anti-IL-13 Mab - - -
Aviptadil mondoBIOTECH Vasoactive intestinal peptide - - -
Phase I Tyvaso United Therapeutics Prostacyclin analogue 64 199 338
CC-930 (JNK 930) Celgene JNK inhibitor - - -
GC-1008 Genzyme Anti-TGF-beta MAb - - -

Source: EvaluatePharma

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