Diarrhoea-Predominant IBS Market Firms Up

February 06, 2014 Therapeutic focus – Diarrhoea-predominant IBS market firms up

Jacob Plieth

US approval of Forest/Ironwood’s Linzess and the drug’s upcoming battle with Synergy Pharmaceuticals’ plecanatide put irritable bowel syndrome back on investors’ agenda, but such excitement had centred on the promise of treating the constipation-predominant form of the disease.

This week’s pivotal data for Furiex Pharmaceuticals’ eluxadoline – in diarrhoea-predominant IBS – has helped redress the balance and highlight a fairly compact industry pipeline (see table below). A couple of late-stage study readouts could bring new competitors Furiex’s way, though for now analysts are shying away from huge forecasts.

The opportunity for Furiex exists because there is only one US FDA-approved treatment for diarrhoea- predominant IBS (IBS-D) – Nestlé’s 5-HT3 antagonist Lotronex. However, this can only be used in women, and is restricted by side-effect issues.

In Europe no drug is approved for chronic use, though several are given for the acute treatment of the disease’s pain and spasms. Still, because the scientific basis of IBS is poorly understood, treatments tend to be symptomatic, and in fact Furiex’s two pivotal trials demonstrated strong activity in improving stool consistency and reducing abdominal pain – though this is an FDA-verified endpoint.

Moderate constipation

Eluxadoline works by activating mu opioid receptors and blocking delta opioid receptors, the theory being that the latter moderates constipation that might arise with activity at just the former. Furiex says it also acts locally in the gut, with very low oral bioavailability.

The private company Tioga Pharmaceuticals is developing asimadoline, a kappa opioid agonist licensed from Merck KGaA that recently completed a phase III study. Because of its poor ability to cross the blood–brain barrier, asimadoline is said to lack the psychotomimetic effects of centrally acting kappa agonists.

However, although a 596-patient phase II trial gave promising results, no data from phase III have been released yet. Tioga last raised cash back in April 2012.

Another threat to Furiex might come from Salix Pharmaceuticals’ Xifaxan. This antibiotic is marketed for travellers’ diarrhoea, and IBS-D represents a significant label expansion strategy; IBS-D is thought to represent around a third of all IBS cases, equating to a possible 15 million people in the US alone.

The logic of using an antibiotic lies in the theory that IBS is characterised by alterations in patients’ gut microflora, and along the same lines non-pharmaceutical treatment approaches include probiotics and dietary supplements.

Salix is awaiting the imminent readout of its phase III Target-3 trial, designed to provide data on how the agent should be used in re-treating patients with recurrent symptoms. This was undertaken to answer a US complete response letter in 2011, so the latest data represent Salix’s second shot at this market.

Indeed, setbacks have not been uncommon in this field; Solvay/Abbott’s cilansetron – like Lotronex this was a 5-HT3 antagonist – was dropped after a 2005 US non-approvable letter. 16% of Xifaxan’s $1.4bn forecast 2018 sales are expected to come from IBS-D, EvaluatePharma forecasts estimate.

The marketed ulcerative colitis drug mesalamine is also being investigated for IBS-D by several companies, including Salix.

5-HT3 mechanism still in play

Despite the drawbacks, the Lotronex concept of hitting 5-HT3 receptors is still being pursued, and the 5-HT3 antagonist ramosetron is marketed by Astellas for use specifically in men – albeit only in Japan. Lotus Pharmaceuticals’ OMS210 appears to be in a phase II study in Japan, while Forest’s Savella, a marketed fibromyalgia drug, had its phase II trial terminated after an adverse event.

Mid to late-stage industry projects for IBS-D

2018e sales 2018e Product Company Pharmacology class for IBS-D total sales Trial ID ($m) ($m)

Phase III

Xifaxan Salix Ansamycin 217 1,382 NCT01543178 (rifaximin) Pharmaceuticals

Tioga Asimadoline Kappa opioid agonist - - NCT01100684 Pharmaceuticals

Furiex Mu opioid agonist NCT01553747 Eluxadoline 272 272 Pharmaceuticals & delta antagonist NCT01553591

Lialda Shire / Cosmo Amino salicylic acid - 666 - (mesalamine) Pharmaceuticals

Phase II

Lyrica Pfizer (Mayo Clinic Alpha 2 delta ligand - 3,955 NCT00977197 (pregabalin) study)

5-HT Savella Forest Laboratories & norepinephrine - 109 NCT01471379 (milnacipran) reuptake inhibitor

Lotus OMS210 5-HT3 partial agonist - - - Pharmaceutical

Translocator protein ONO-2952 Ono Pharmaceutical 2 2 NCT01887002 ligand

Lexicon Tryptophan LX1033 - - NCT01494233 Pharmaceuticals hydroxylase inhibitor

Astellas Pharma / Bombesin-2 receptor ASP7147 Drais - - NCT01896583 antagonist Pharmaceuticals

Neurokinin-2 NCT00761007 Ibodutant Menarini - - antagonist NCT01303224

Apriso Salix Amino salicylic acid - 148 NCT01177410 (mesalamine) Pharmaceuticals

Salofalk Dr. Falk Pharma Amino salicylic acid - - - (mesalamine)

Source: EvaluatePharma

A related approach was being pursued by Lexicon Pharmaceuticals, which through LX1033 was using inhibition of tryptophan hydroxylase to reduce 5-HT production locally without affecting brain 5-HT levels. However, a hotly awaited phase II trial that read out in December failed to show significant improvements in stool consistency owing to a high placebo response.

The company insisted that further study was warranted, but subsequently implicated a broad round of cost savings and job cuts.

Other mid-stage approaches include Astellas Pharma’s bombesin-2 receptor antagonist ASP7147, whose phase II study could yield results late this year, and Ono Pharmaceutical’s translocator protein ligand ONO- 2952 (possible readout in 2015).

How soon Furiex has to face up to any of these challengers is probably not as pressing right now as the group’s need to raise cash; it ended the third quarter with $37m in the bank, and will owe Johnson & Johnson up to $45m in regulatory milestones on eluxadoline, which it hopes to file in June. At least the 130% share price jump it enjoyed on the phase III readout gave Furiex a market cap over $1bn, meaning that a raise might not prove too problematic. Still, the market reaction has yet to be backed up with sales forecasts, which for Furiex and others stand at fairly modest amounts.

In a disease that is not easy to characterise precisely, and whose symptoms can to some extend be targeted acutely, the trick will be to convince payers that an efficacious and relatively safe drug has real potential in the chronic setting.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter