Editor's note: Last week, BioWorld Insight looked at emerging treatments for inflammatory bowel disease. Part II of our dive into the gastrointestinal space focuses on irritable bowel syndrome.

Within the gastrointestinal (GI) space, inflammatory bowel disease (IBD) and its major constituents of ulcerative colitis and Crohn's disease remain bigger and easier targets for biopharma than irritable bowel syndrome (IBS) and related functional GI disorders, as evidenced by the number of drug trials sponsored by companies – approximately 800 in IBD compared to just over 100 targeting IBS, diarrhea-predominant IBS (IBS-D) and constipation-predominant IBS (IBS-C), according to Cortellis Clinical Trials Intelligence.

Those numbers belie the excitement and energy in the IBS community, however. As scientists learn more about the transmitters and receptors that line the epithelia of the GI tract, companies are translating those findings into drugs that block the chronic pain that is a hallmark of IBS and focusing on the larger role the gut plays in human health.

Examining how to treat diseases directly in the gut compared to systemic delivery was the premise for Ardelyx Inc., recalled Mike Raab, the company's president and CEO, whose tenure at Genzyme Corp. immersed him in the world of phosphate binders. The size of those polymeric molecules limited their applications, and the founders of Fremont, Calif.-based Ardelyx were optimistic they could build better therapies to target the channels and receptors lining the GI tract.

The team struck on the idea of blocking sodium-hydrogen exchanger 3 (NHE3), one of the main transporters responsible for maintaining the balance of sodium in the body, to treat constipation. In the course of their research, Ardelyx scientists did preclinical work to see if their lead compound, RDX5791, also known as tenapanor, showed a benefit in visceral hypersensitivity – the general increase in pain sensation common in people with IBS. (See BioWorld Today, Sept. 1, 2011.)

"We passed that test, and it looked phenomenal," Raab told BioWorld Insight. The company then moved RDX5791 into a phase IIa study in IBS-C and began to do work in models of kidney disease that led to a program in hyperphosphatemia for dialysis patients. The NHE3 inhibitor has since moved into late-stage studies in both indications. The mechanism is one of the most common that biopharmas are exploring in targeting IBS, as indicated in the chart below.

Like many biopharmas, Ardelyx has encountered challenges along the way. The company ran into a bit of a snag in the tenapanor phase IIb study in hyperphosphatemia, reporting higher than expected rates of diarrhea, but met its efficacy endpoint in IBS-C, now in a phase III program. (See BioWorld Today, Feb. 3, 2015.)

Last year, Ardelyx regained rights to its NHE3 sodium transporter portfolio, including lead candidate tenapanor, that were out-licensed in 2012 to Astrazeneca plc, of London, in a potential $272 million deal. The company paid for return of the assets at the same time it disclosed a private placement aiming to raise $77.8 million, sending its shares up 40 percent. (See BioWorld Today, Oct. 9, 2012, and June 4, 2015.)

At the time of the original Astrazeneca transaction, many big pharmas were departing GI, Raab said, but as new science emerges they're paying attention again – a factor that works in the favor of Ardelyx and other companies with late-stage IBS assets.

"Hundreds of millions of people are affected by the foods that we eat and the GI diseases that we're exposed to," he pointed out. "We're fortunate, with the work that we're doing, that the timing is good."

'Opportunity to leverage what we've learned so far'

Ardelyx wasn't taking a shot in the dark in IBS. The company was keenly aware of inroads another young biotech was making in the space. As Ardelyx was getting under way – the company was formed in 2007 – Ironwood Pharmaceuticals Inc., of Cambridge, Mass., was making its way to phase III trials with lead candidate Linzess (linaclotide) in IBS-C.

"As a small, private biotech company, we were paying attention to that," Raab admitted.

Linzess, a guanylate cyclase-C (GC-C) agonist currently approved to treat IBS-C and chronic idiopathic constipation (CIC) in adults, recently cleared 1 million patients after just four years on the market and is in development to treat opioid-induced constipation (OIC) and pediatric IBS-C/CIC and to prevent colon cancer. The drug and a follow-on, second-generation linaclotide colonic release program in IBS-C are partnered with Allergan plc, of Dublin, soon to be part of Pfizer Inc. – which, not coincidentally, recently pointed to GI as a primary area of interest. (See BioWorld Today, Aug. 31, 2012, and Nov. 24, 2015.)

Ironwood also has regional deals for Linzess with Astellas Pharma Inc., of Tokyo, and Astrazeneca's China unit. In January, at the J.P. Morgan Healthcare Conference in San Francisco, company officials laid out a strategy to build a sustainable commercial enterprise generating high-margin growth, with Linzess as its centerpiece. (See BioWorld Today, Jan. 13, 2016.)

Last week, Ironwood reported that 2015 U.S. net sales of Linzess, as provided by Allergan, increased approximately 53 percent, to $454.8 million, with the drug on track to exceed $1 billion in net sales by 2020. Largely on the strength of collaborative commercial arrangements for its single approved product, Ironwood's revenue increased more than 95 percent in 2015, to $149.6 million.

Linaclotide offers enormous potential for Ironwood, thanks to the drug's effect on intestinal pain fibers, according to Mark Currie, Ironwood's senior vice president, chief scientific officer and president of R&D. While the drug works throughout the intestines, the initial goal was to stimulate fluid secretion in the small intestines to improve constipation and then move to the large intestine to suppress pain.

"What we're trying to do in part of the life cycle management is to change the ratio a little bit," he told BioWorld Insight. "We're now developing formulations that will target much later release in the intestines so that we'll still have some positive impact on fluid secretions, but to a lesser degree, and have a stronger impact on decreasing pain in these patients."

The company also is advancing IW-9179 in functional dyspepsia and diabetic gastroparesis and IW-3718 in refractory gastroesophageal reflux disease, or GERD.

Ironwood's scientific and commercial thesis derive somewhat from the drug development arc in other indications, according to CEO Peter Hecht.

"We're the market innovators with Linzess" as the first GC-C agonist, he said, and despite the drug's rapid commercial trajectory, "it's very early days in this market," Hecht said.

"If you think about the very early days in the cholesterol market, when Merck brought in Mevacor, that was the first drug for lowering cholesterol in the blood and a great first product," he told BioWorld Insight. "Four or five years later, they brought Zocor into the market in the same indication. The two products, together, helped grow the franchise and grew the whole market. Similarly, with proton pump inhibitors for treating GERD, the first drug in was Astrazeneca's Prilosec, followed by the second-generation drug, Nexium, to co-exist in the same market. Each helped grow the other and bring more patients into the market."

With 40 million patients suffering from IBS or chronic constipation, "we see the opportunity to leverage what we've learned so far and bring further pain benefit to patients," Hecht added.

'The GI is like a sentinel'

And Ironwood isn't the only kid on the IBS block. In 2006, Sucampo Pharmaceuticals Inc., of Rockville, Md., gained approval for Amitiza (lubiprostone) in CIC in adults, followed by supplemental approvals in 2008 for IBS-C and in 2013 for OIC. (See BioWorld Today, May 1, 2008.)

Salix Pharmaceuticals Ltd., late of Raleigh, N.C., moved Xifaxan (rifaximin) over the goal line in 2010 to reduce the risk of overt hepatic encephalopathy. Last year, after a long and perilous clinical journey and the company's acquisition by Valeant Pharmaceuticals International Inc., of Laval, Quebec, the FDA expanded the Xifaxan label to include IBS-D. (See BioWorld Today, April 5, 2010, March 17, 2015, and May 29, 2015.)

At the same time, the agency approved Viberzi (eluxadoline), a locally acting mu opioid receptor agonist, delta opioid receptor antagonist and kappa opioid receptor agonist from Actavis plc (now Allergan), in IBS-D. Viberzi came to the Dublin-based company by way of its $28 billion takeover of Forest Laboratories Inc., which weeks earlier had purchased the drug's original developer, Furiex Pharmaceuticals Inc., for $1.1 billion in cash. (See BioWorld Today, April 29, 2014, and July 3, 2014.)

Other companies are being drawn into the space, in part, by the recognition that the GI tract is more fundamental to human health and disease than once believed, according to Jeremy Caldwell, executive vice president and chief scientific officer at Ardelyx.

"Historically, the GI was viewed as a passage tube that allowed ingested materials to be absorbed into the body for nourishment," Caldwell said. "We're now appreciating that the GI is much more of an active organ that communicates with all of the other organs in the system and instructs them in response to the immediate environment – whether nutrients, a pathogen or a toxic substance. In a way, the GI is like a sentinel that lets the body know what's coming."

For example, scientists are beginning to understand how foreign insults cause the GI to secrete cytokines and inflammatory signals that stimulate the immune system, he added. Short chain fatty acids that are produced by bacteria in the gut can activate GI receptors that, in turn, activate the immune system, essentially preparing it to counteract the infection that's attacked the gut.

"What we're doing at Ardelyx is taking advantage of the fact that the gut talks to, essentially, every other organ in the body and taking advantage of the mechanisms by which the GI transmits those signals to other organs," Caldwell explained. "We're able to address those same signals and transporters that are mediating signals from the gut. In many ways, our platform takes its cues from the GI."

Ardelyx also is beginning to take cues from the microbiome, which Caldwell called the "perfect complement" to the company's R&D efforts.

"We're beginning to understand, through collaborators and publications, how the microbiome and the metabolites it creates are able to promote a disease state and how many of the receptors in the gut have evolved to interact with the metabolites of the microbiome to create the symbiosis that exists today," he said. Caldwell cited, as one example, a study published this month that suggested that the composition of the microbiome influenced whether animals infected with the malaria parasite developed severe disease. (See BioWorld Today, Feb. 9, 2016.)

Studies of microbiome suggest IBS drugs have room to run

The dazzling growth in the study of the human microbiome has significant implications for therapeutics targeting the gut – especially IBS, where the cause remains unknown, and related conditions.

Synthetic Biologics Inc., of New York, founded in 2001 as Adeona Therapeutics Inc., is focusing on therapies to protect the gut microbiome. In January, the company said the second phase II trial of SYN-010, its IBS-C candidate, met its primary endpoint, with top-line data from patients who completed the second trial showing a statistically significant decrease in methane production over 12 weeks of treatment, measured from the beginning of the first phase II study (study 1). Top-line data from the second phase II also showed improvements in secondary efficacy endpoints, including a statistically significant reduction in the mean IBS symptom severity score from study 1 baseline. The firm has launched preparations for a phase III program of SYN-010, a modified-release formulation of lovastatin lactone designed to reduce methane production in the intestine.

Last year, Synergy Pharmaceuticals Inc., of New York, reported that its wholly owned drug, plecanatide, met the primary endpoint in the first of two pivotal phase III studies, in CIC, laying the groundwork for an NDA filing, which came in January. The drug, an analogue of the naturally occurring human peptide, uroguanylin, also is in a phase III program in IBS-C.

The company declined to talk with BioWorld Insight about its development efforts, but last week Synergy disclosed a collaboration with Bind Therapeutics Inc., of Cambridge, Mass., on research to engineer accurins from Bind that incorporate Synergy's uroguanylin analogues to explore the potential targeting of GC-C receptors expressed on tumors, particularly gastrointestinal malignancies.

And earlier this month, Redhill Biopharma Ltd., of Tel Aviv, completed a first-in-human pharmacokinetic study of Bekinda (RHB-102) in a 12-mg formulation to support a planned phase II study to treat IBS-D. The company has a phase III study of Bekinda, dosed at 24 mg, under way in acute gastroenteritis and gastritis, with top-line results expected in the second half of 2016.

'It's been an amazing transformation'

Among the other companies with IBS programs include Enterome Bioscience SA, Medicinova Inc. and Velicept Therapeutics Inc., (See BioWorld Today, Dec. 18, 2015.)

And beyond IBS, IBS-C and IBS-D, dozens of biopharmas are directly targeting CIC, OIC and related indications, including GERD and gastroparesis. For example, in 2014, Nektar Therapeutics Inc.'s Movantik (naloxegol), a peripherally active mu-opioid receptor antagonist partnered with Astrazeneca plc, of London, entered the space as an oral treatment for OIC in adults with chronic noncancer pain. (See BioWorld Today, Sept. 17, 2014.)

Last week, Shionogi & Co. Ltd. said it plans by midyear to file applications in the U.S. and Japan for naldemedine to treat OIC. The Osaka, Japan-based pharma reported data from the pivotal phase III COMPOSE I study at the American Academy of Pain Medicine 2016 meeting in Palm Springs showing that once-daily treatment with the oral, peripherally acting mu-opioid receptor antagonist improved OIC compared to placebo in patients with chronic noncancer pain.

Among its handful of additional assets, Ardelyx also has a TRG5 agonist, RDX009, in preclinical studies in a range of GI indications and expects to file an investigational new drug application by year-end.

And last week, Ironwood reported data from a phase Ia study of IW-1701, its soluble guanylate cyclase (sGC) stimulator, that demonstrated the expected cardiovascular pharmacodynamic effects, proof of mechanism for sGC stimulation, a dose range that was well tolerated in healthy volunteers as a single dose and a pharmacokinetic profile suitable for once-daily dosing. Although the company hasn't selected a lead indication, the agent has therapeutic potential in vascular and fibrotic diseases such as congestive heart failure and diabetic nephropathy as well as certain orphan diseases. The company has a second sGC stimulator, IW-1973, that reported similar phase Ia findings, and both candidates are expected to report phase Ib findings by year-end.

"We're seeing so many drugs come out in this space," Ironwood's Currie said. "It's been an amazing transformation, and it's opened people's eyes to see how broad the opportunity is. There's a rebirth of real innovation in functional GI disorders."

Ardelyx – and the industry in general – have "hardly scratched the surface" in IBS and other functional GI diseases, Raab agreed. By targeting the gut locally and specifically, "there's an awful lot we think we can do while avoiding systemic toxicity from traditional small molecules."

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