Therapy Focus – Phase III proves tough for IPF

Analysis

2014 finally saw the approval of the first agents able to slow the progression of idiopathic pulmonary fibrosis (IPF): Roche’s Esbriet and Boehringer Ingelheim’s Ofev. However, despite these successes in the notoriously difficult indication, the search for a cure continues and the late-stage pipeline is depressingly barren. With the termination of Gilead’s phase II study of simtuzumab and AstraZeneca's tralokinumab trial in January chances of more approvals in the near future are becoming slimmer.

The launches of Esbriet and Ofev caused a “seismic change” in the field of IPF, Dr Toby Maher, a leading specialist in IPF and consultant respiratory physician at Royal Brompton Hospital, told EP Vantage. Prior to the release of these drugs patients with the disease had an average life expectancy of three years post-diagnosis. But these agents are not by any means perfect.

Although they do represent the first effective pharmacological options in the indication, the drugs only slow the inevitable decline in lung function seen in IPF patients, and the only treatment to offer improvement in patients remains lung transplant. Esbriet and Ofev also have significant side-effects, with diarrhoea, nausea and vomiting being common for both drugs. Unfortunately for patients, a look at the industry pipeline for IPF shows that there are no new projects for the indication beyond phase II.

Select phase II trials in idiopathic pulmonary fibrosis
Project Company Pharmacology class 2020e sales ($m) Enrolment NCT ID
STX-100 Biogen Anti-avb6 integrin MAb 60 40 NCT01371305
FG-3019 FibroGen CTGF MAb 50 136 NCT01890265
BMS-986202 Bristol-Myers Squibb LPA1 antagonist 47 135 NCT01766817
SAR156597 Sanofi IL-4 & IL-13 MAb 43 300 NCT02345070
FG-3019 Bristol-Myers Squibb CTGF MAb - 136 NCT01890265
AF-219/ RG1646 Roche P2X3 antagonist - 50 NCT02502097
Lebrikizumab Roche IL-13 MAb - 304 NCT01872689
MN-001 MediciNova PDE3 & PDE4 & 5-LO inhibitor - 15 NCT02503657
AF-219/ RG1646 Afferent Pharmaceuticals P2X3 antagonist - 50 NCT02502097
PRM-151 IV Promedior MREG differentiation inducer - 117 NCT02550873

Design and fall

Progress in the field has also been slow. Several of these treatments, including Biogen’s STX-100 and Fibrogen’s FG-3019, have remained in phase II since EP Vantage last reviewed this space in early 2012, having suffered multiple pushbacks to their completion dates (Therapeutic focus – IPF pipeline fills up as opportunity callsFebruary 15, 2012).

According to Dr Maher trial design has long been a problem in the indication. “The biggest issue is in early phase studies and the endpoint you use for short proof-of-concept or a [phase] IIb dose-ranging study. That is why there is a bit of a bottleneck of dozens of potential compounds that people are looking at but no easy way to get through to later phase studies.” Given the lack of effective short-term endpoints many companies may not be willing to invest in the long running-trials that are necessary to prove efficacy so early in the pipeline.

Many treatments such as Celgene’s CC-930, J&J’s CNTO-888 and Novartis’s QAX576 have all fallen by the wayside in past few years, abandoned in phase II. The last of these was an inhibitor of IL-13 – a pharmacological approach still being pursued by Roche,Sanofi and up until recently Astra - who will no doubt hope to fare better. The completion dates for these ongoing trials are due May 2017 and July 2017 respectively.

The latest in the series of casualties in the indication were Gilead’s simtuzumab and AstraZeneca's tralokinumab  – in January this year the companies pulled the plug on their respective 500 and 176-patient phase II trials. Gilead's cancellation was due lack of efficacy and Astra have yet to disclose.

This bleak view of the pipeline may change during 2016 with results expected to read out for tralokinumab, BMS-986202, STX-100, FG-3019, MN-001 and AF-219, barring any further setbacks to trial dates.

Targets of choice

The majority of the therapies still in the clinic fall into one of two modes of action: either targeting inflammation pathway components, or those involved in fibrosis. The idea of inflammation processes being viable targets for treatments in IPF has been a contentious one up until fairly recently, as Dr Maher explained. “Over the last 10 years we have denied there is any inflammatory component to IPF, but I think as our understanding of inflammation and immune dysregulation has improved, people have stopped being as dogmatic about that.”

Dr Maher went on to say “we have perhaps underappreciated the role of inflammatory cells in the pathogenesis of the disease”, and several drug developers look as if they agree. Roche, Astra and Promedior are all trialling drugs thought to alter macrophage activity in some way.

Whilst both Esbriet and Ofev are anti-fibrotic drugs, the mechanism of the former is still unknown. Dr Maher stated the current suspicion is that “from a mechanism point of view [the two drugs] are probably not absolutely distinct”. This could be one of the reasons why, according to Dr Maher, the currently available drugs “aren’t natural bedfellows” in terms of combination treatment. However, this has not deterred either Roche or Boehringer from running studies looking into the safety of this combination – both are due to read out in early 2017.

Pulling up the ladder

Esbriet and Ofev have also increased the difficulty for those hoping to follow in their footsteps to approval, as it is now no longer possible to do placebo-controlled trials, on ethical grounds. The nature of the disease also means patients already receiving Esbriet or Ofev might be unwilling to gamble on switching to a new experimental treatment, leaving only the newly diagnosed as potential trial candidates.

Alongside this extra complication, developers that manage to take their product through to phase III will also have to bear the expense of having to include the existing treatments in their trial design as comparators. These additional hurdles could give bigger companies such as Boehringer and Roche an edge in pursuing this indication.

Whilst it seems unlikely there will be any new products launching into the IPF market for several years, 2016 will hopefully yield some clues as to which treatments might go the distance. 

*Article updated to reflect AstraZeneca's trial termination.

To contact the writer of this story email Edwin Elmhirst at news@epvantage.com or follow @EPVantage on Twitter

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