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IPF grabs headlines at American Thoracic Society conference

pharmafile | July 21, 2014 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | IPF, ats, ats 2014, brett wells, idiopathic pulmonary fibrosis, san diego, thoracic society

Just prior to landing in San Diego it was somewhat disconcerting to see fire spreading across the terrain and huge patches of scorched earth, as the county witnessed a dramatic wildfire that led to 30,000 acres of land going up in smoke.

As residents in some parts of San Diego itself struggled to breathe, it was rather ironic that in a nearby location the pharma industry was also hosting the biggest respiratory event of the year: and Pharmafile was on site to witness the new and exciting research in this area.

The American Thoracic Society (ATS) was founded in 1905 when a small group of doctors decided the best way to highlight care for tuberculosis patients was to share their experiences and discoveries.

Now going for more than a century the ATS has matured into an international society with over 15,000 members who all work to improve health worldwide by enhancing research, clinical care and public health in respiratory disease, sleep disorders and critical illness.

The annual conference remains a magnet to pharma and service companies alike, who get together to discuss/report/promote data and offerings related to tuberculosis, asthma, COPD, lung cancer, sepsis, acute respiratory distress, and sleep apnea, among other diseases.

Walking around the event floor you can expect to see several 3D displays and devices containing media content awaiting your interaction, all from a variety of firms vying for attendees’ attention.

Admittedly, it’s an impressive display and whilst it’s tempting to be easily distracted also by massage chairs or Boehringer’s chocolate brownies (I did like the British tea stand the best myself) – there is serious research to viewed and interpreted.

Asthma and COPD

My first port of call was to Bing Yao, who works for MedImmune as senior VP of R&D and respiratory, inflammation and autoimmunity, about why he was there.

He tells me: “We are pioneering innovative research and exploring novel molecular pathways in respiratory disease, one of our core therapeutic areas. Our approach leverages AstraZeneca and MedImmune’s combined expertise in monoclonal antibody research with our broad experience in drug development.”

Yao goes on: “The data we presented at ATS showed promising safety and efficacy outcomes for our severe asthma biologics, benralizumab and tralokinumab. We’re encouraged by these data, as they suggest we are closer to addressing a significant unmet need and providing important therapeutic options for patients.”

Asked about what’s next for benralizumab and tralokinumab and when they expect them to be filed, Yao says ongoing trials for benralizumab will help them determine whether it reduces the number of exacerbations in patients with severe asthma that remains uncontrolled.

For COPD, he explains: “We anticipate moving benralizumab into Phase III later this year. Tralokinumab should move into Phase III development for asthma later this year as well, and we’ll be able to provide more details once the first patient is dosed in this programme.”

Yao adds that tralokinumab is also in an ongoing mid-stage study for patients with mild to moderate idiopathic pulmonary fibrosis (IPF) – and it is this disease that becomes the focal point of the event.

Idiopathic pulmonary fibrosis

After an hour at the conference it becomes clear as to what areas are ‘trending’ the most within the respiratory world this year, and the buzz word on many lips was IPF.

The condition is probably most known for taking the lives of cult actor Marlon Brando and US stuntman Evel Knievel, and at the patient level it is a debilitating and fatal lung disease that presents few treatment options.

Characterised by a progressive decline in lung function, the term pulmonary fibrosis means ‘scarring of lung tissue’ and is the cause of worsening dyspnea (shortness of breath). Fibrosis is associated with a poor prognosis, and the term ‘idiopathic’ in medical jargon simply means ‘unknown origin’, because the cause of pulmonary fibrosis is still a mystery for researchers.

Whilst the origins of IPF are unknown this has not stopped pharma from seeking to treat it, and the drugs market for this disease whilst small, is certainly growing.

The first treatment to gain approval for the condition was InterMune’s Esbriet (pirfenidone), which received European approval for mild-to-moderate IPF in 2011. It was also given an orphan drug status meaning it has an extended patent life, and therefore extended protection against generics.

But InterMune has had a much more difficult path in gain regulatory approval in the US after the FDA knocked the drug back in 2011, asking the firm for more trial data.

Despite the setback InterMune pushed on and the firm hopes to be finally back on track with the agency, after presenting new and positive data at ATS from its Phase III ASCEND trial which showed it could help patients breathe better with its medicine.

There is now, however, a new contender to the throne in the shape of Boehringer’s Inpulsis (nintedanib) that is yet to gain approval in any market, but has been accepted for an accelerated review from both the FDA and the EMA, meaning it could be available from early 2015.

But as there is currently only one drug on the market – and only in Europe – it quickly became clear that there is an urgent need for drugs that can at the least slow disease progression, with a hope for a future outright cure seemingly still some way off.

The symptoms of IPF mean it is often misdiagnosed – generally being confined to the common ailments of coughing and fatigue – although it is known that the disease actually affects more men than women. It also predominately affects older adults, namely between 50 and 70 years of age, and especially those with a history of smoking.

At one of many media events I had the opportunity to hear from patients suffering with IPF. Some might find the appearance of sufferers at such an occasion to be distasteful (albeit an increasingly common occurrence in pharma), but it did paint a moving and very visual portrayal of why there is such a need for new medicines and positive action.

And of these new drugs Inpulsis is one of the first to show progress in slowing the disease’s ability to restrict patient breathing. The data at ATS showed that when compared to placebo, it could slow IPF progression by around 50 per cent.

Study investigator Professor Luca Richeldi tells Pharmafile that the results were not surprising, but certainly welcomed: “I was optimistically expecting these results,” he explains. “In all of the trials, all the results go in the same direction. It means you feel confident providing the drug to patients.”

When asked whether he expects to see a lot of calls for early access to the drug on compassionate grounds, as has happened with new drugs such as Gilead’s hep C pill Sovaldi (sofosbuvir), he says: “A huge amount. My expectation will be there. But I want to underscore the fact that we’re not preventing anything, rather slowing disease progression.”

Boehringer was of course not the only pharma firm present at ATS with an IPF data offering and given its European approval, InterMune’s Esbriet is the clear market leader. Data from its ASCEND trial also showed its strong hand helping the breathing in patients.

InterMune has also taken the unusual move to give its medicine to some US patients at no cost, a decision that may help kick-start sales of its product prior to approval.

It has also been earning plaudits from the research community as the drug recently made it onto the prestigious UK Prix Galien award shortlist, the winner of which will be declared in October. This prize is awarded to the firm that has produced the most innovative new medicine of the past two years, and Esbriet is believed to be among the top contenders.

Manageable disease goals

Pharmafile spoke to InterMune spokesman Jim Goff about ATS 2014 and the excitement around IPF.

“We have attended ATS over much of the past decade, participating in a range of symposiums and poster sessions primarily on IPF. The conference is an important venue to discuss new findings in pulmonary research with an interested and engaged audience. In particular, this year’s conference provided new and promising research about treatment options for patients with IPF.”

Goff adds: “As there is a significant unmet need for patients with IPF, we were pleased that IPF was in the spotlight at this year’s conference.” When suggested it was looking like a two-horse race between Inpulsis and Esbriet in the disease setting, Goff couldn’t be drawn on any potential winner though.

“These were not head-to-head studies, and it would therefore not be appropriate to compare the two data sets,” he explains. What is up for discussion of course is any potential for eradicating the high mortality rate associated with IPF.

“Although we cannot predict if or when a cure for IPF may be developed, one goal might be that IPF one day becomes a chronic, manageable disease rather than a rapidly lethal disease, similar to the progress that has been made in the treatment of HIV or other lethal diseases,” Goff says.

And the issue of mortality is vitally important, as what’s most striking about IPF is that there are fewer treatments and higher rates of death than better known conditions such cancer. Given the seriousness of the disease, I ask Goff why is it that there is seemingly so little awareness around the lung disease.

He suggests: “Awareness is a significant issue for many orphan diseases, including IPF – a disease that is more rapidly lethal than some cancers, including breast, ovarian and colorectal cancers. In other rare or orphan diseases, the availability of a new therapy often helps increase disease awareness.”

He points out that prior to Esbriet, there were no approved therapies for IPF in Europe or Canada, and there are currently no FDA-approved therapies in the US, meaning awareness across the pond is even lower.

These drugs are certainly no cure and no one at ATS was under any illusion that there were meant to be: but easing the symptoms and attempting to reduce mortality – whilst also increasing awareness of IPF – was the key for researchers this year, and in that regard the conference was a success.

Brett Wells

Pharmafocus had its accommodation and flights for the event paid for by Boehringer Ingelheim