IPF: The Game Is On, The Game Is Changing …

Until recently, we have had very little to offer patients with Idiopathic Pulmonary Fibrosis (IPF).  The disease is on the increase, tends to affect men in their late middle age, and has a prognosis worse than most cancers (50% of patients will die within three years of diagnosis).

The approach to the patient with presumed IPF, appears primitive compared to the sophisticated approach to the cancer patient. No-one would treat a cancer patient without a biopsy, but only a tiny minority of IPF patients undergo lung biopsy because of the morbidity and mortality associated with this surgical procedure; as a result, most patients receive a diagnosis of IPF on the basis of a history and typical CT scan results. There is a wealth of drugs on offer for the patient with cancer, but until now, there has been limited and conflicting evidence that any drug can alter the course of IPF. 

Until now  ……….  Last week at the American Thoracic Society, new data was released from a number of clinical trials that are published in the latest edition of the New England Journal of Medicine, the most established and reputable international medical journal. 

The studies published included the INPULSIS™-1 and -2 trial (Nintedanib, previously BIBF-1120 in IPF) and the ASCEND trial (Pirfendione in IPF).

Nintedanib is an investigational small molecule tyrosine kinase inhibitor in development by Boehringer Ingelheim for IPF.  It targets growth factors, which have been shown to be potentially involved – the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR).

The two Phase 3 INPULSIS™ Trials of Nintedanib involved a total of 1,061 people with mild to moderate IPF treated for 52 weeks, and showed that Nintedanib reduced the lung function decline compared to placebo. The studies did not follow enough patients for long enough to comment on effects on mortality, but there was a trend towards reduced death rates in the Nintedanib group. The most frequent adverse event was diarrhoea, affecting 61.5% of patients on Nintedanib. 

However, before we get too excited, the patients in INPULSIS™ all had reasonable lung function (average lung capacity was 80% of that predicted and around 2700mls); the lung volume lost in the treated group over a year was 114ml compared with 228ml in the untreated group.  We are talking about small volumes, 114ml ~4% of the total lung volume saved over a year – or the same volume as one third of a can of coke out of a total of nearly 3 x 1 litre bottles. Will this translate into a serious impact on exercise ability and life expectancy?  Will there be effects on mortality given that there were no effects on acute exacerbation frequency? What will be the effect on patients with moderate to severe disease, the ones that are not caught early and perhaps have more progressive, aggressive disease?

The ASCEND trial was the fourth Phase 3 study to look at the effect of Pirfenidone (Esbriet) in 555 patients with IPF.  The American FDA has not licensed this drug, thought to act by inhibiting TGF β1, because the results of the first three trials in IPF were mixed. In the ASCEND trial, Pirfenidone reduced the one year rate of decline in FVC, with evidence, from pooling data from all four studies, that it may also reduce mortality. The patients in ASCEND had worse disease than in INPULSIS™ which may explain why they declined more quickly. Pirfenidone saved ~140mls of lung function per year.

Tempering the enthusiasm of the positive studies, is the realisation that the drugs didn’t make people feel better, stop disease progression, cure the disease or reverse the fibrotic damage – the ultimate therapeutic goals.  Coming with these sobering thoughts was the report of PANTHER-IPF.  Disappointingly, N-acetylcysteine or NAC was shown not to slow the rate of decline in FVC (although it may reduce the toxicity of prednisone and Azathioprine in IPF). However, one drug did offer some promise. FibroGen presented their Phase 2a study of FG-3019, an investigational monoclonal antibody that inhibits connective tissue growth factor (CTGF).  The trial recruited 37 patients with mild to moderate IPF of whom 33 completed 48 weeks of treatment. After 48 weeks of treatment, 12 of the 33 patients (36%) had improved fibrosis (unheard of in IPF before now) and two patients had stable fibrosis. This means that 14 patients (42%) had improved or stable fibrosis, improved lung function and felt better. Eighteen of the 33 patients continued FG-3019 treatment for a second year, and four continued to improve, but the rest worsened.

So where does that leave the patient with IPF and his clinician as the nihilistic approach begins to disperse?  What should we do with the mounting evidence that immunomodulation (with Cyclophosphamide and Rituximab) although beneficial in inflammatory pulmonary fibrosis (PF), such as that associated with rheumatoid arthritis and scleroderma, may increase mortality in IPF?  

More than ever before, we believe that it is essential to make a confident diagnosis in all patients with PF, to separate out those with IPF from those with inflammatory pulmonary fibrosis, and, in many cases, this requires a biopsy of the affected lung.   Our own work establishing non-invasive bronchoscopic cryoscopic lung biopsy to rigorously identify those with IPF, from those with other forms of PF, is set to be a game changer.

Breathing Matters has funded the research that has set the stage for a full application to the NIHR for a proper study on the role of cryoscopic lung biopsy (CLB) in the management of PF of unknown cause. It no longer seems fanciful to imagine a time when a patient with PF will be worked up with a scan and a CLB that will provide an individualised diagnosis; this result will guide the clinician on how best to manage their patient.

 

Although we are behind our cancer colleagues, (the standard of diagnosis and treatment options that they offer their patients is superior to that offered to patients with PF), the distance is closing, and it will not be long before they feel our toes on their heels!   The game is on……!