Merck & Co. Inc.'s new billion-dollar collaboration with Bayer AG threw a spotlight on drugs capable of amping up concentrations of the messenger molecule cyclic guanosine monophosphate (cGMP) to impact cardiovascular and gastrointestinal diseases. Now Bayer, Ironwood Pharmaceuticals Inc. and others are leveraging expertise built on the way to gaining FDA approval for drugs in the space to expand their use.

The only two FDA-approved drugs capable of modulating cGMP, Bayer's Adempas (riociguat) and Ironwood's Linzess (linaclotide), do so in different ways. Both impact targets in the guanylate cyclase family and both are showing potential for interesting new applications.

Adempas targets soluble guanylate cyclase (sGC), the only known nitric oxide receptor in the human body. Nitric oxide activates soluble guanylate cyclase, which in turn kicks off production of cGMP, relaxing arteries and thereby increasing blood flow and decreasing blood pressure. The FDA approved Adempas to treat two forms of pulmonary hypertension in October 2013, making it the first drug in its class to be approved to treat pulmonary arterial hypertension (PAH) and the first drug of any class to be shown to be effective for patients with chronic thromboembolic pulmonary hypertension.

Ironwood's Linzess (linaclotide), on the other hand, selectively activates guanylate cyclase C (GC-C), a receptor found almost exclusively in the membrane of cells lining the inner surface of intestinal tissue. In August 2012, it became the first and only GC-C activator approved by the FDA to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C), easing abdominal pain in the latter, and netting 2013 sales of about $119 million. Now Ironwood is pursuing an expanded indication for Linzess in opioid-induced constipation (OIC).

The company is also developing another GC-C activator, IW-9179, to treat functional dyspepsia and gastroparesis. But there's much more opportunity to be realized in regulating cGMP, Ironwood's chief scientific officer, Mark Currie, told BioWorld Insight. "In our mind, there are very few regulators that have this kind of utility," he said.

Currie and his team now are advancing preclinical molecules that target sGC in a bid to address indications beyond the gastrointestinal space. They expect to initiate their first sGC clinical study in the first half of 2015, prioritizing evaluation of application in PAH and other cardiovascular indications.

By looking at ways to optimize the half-life and volume of distribution of molecules targeting sGC, Currie's team is on the path to finding ways to deliver a controlled day-long lowering of blood pressure and, in other cases, diminish fibroblast proliferation in the treatment of pulmonary, liver and kidney fibroses. They're also looking at ways to cross the blood-brain barrier to impact Alzheimer's disease and improve memory, he said.

SHARING RISKS AND REWARDS

Despite the promise of sGC modulators, major development efforts and clinical programs will be required to realize their potential. That's where the Bayer-Merck deal comes in. Both companies have been working on sGCs for years. Underscoring Bayer's desire to defray the major costs it will face developing Adempas and other sGCs for new indications, this month it struck a deal giving Merck full commercialization rights for Adempas outside the Americas, half the profits for its phase II sGC, vericiguat, and optionally half of any profit from several other sGCs the companies plan to co-develop. In exchange, Merck will shoulder half the development costs for those new drugs.

For the potential rewards Adempas and the other sGCs offer, Merck agreed to pay Bayer $1 billion up front and up to an additional $1.1 billion if Adempas and the other sGCs hit certain sales milestones. In addition to contributing its cash and one phase I compound, the Whitehouse Station, N.J.-based company also brings serious credibility in the cardiovascular market to the table. (See BioWorld Today, May 7, 2014.)

Importantly for both, Bayer's vericiguat, an investigational sGC it's developing in two phase IIb studies in an indication it's calling "worsening chronic heart failure," is included in the deal. Merck's lengthy experience selling cardiovascular treatments in the U.S. market could be a boon for Bayer, noted Bayer CEO Marijn Dekkers, during a conference call discussing the deal.

"The significant expertise that Merck has built as a top five global player in the cardiovascular area, and its strong presence in the large U.S. market, make Merck a partner of choice for our current and future sGC program," he said.

Without doubt, having a partner to foot the cost of what Dekkers called "a significant and comprehensive" phase III trial of vericiguat next year will help, too.

For vericiguat and other potential investigational sGC modulators, Bayer will lead the commercialization outside the Americas while Merck will lead commercialization in the Americas. Both companies will have the option to co-promote Adempas and the follow-on sGC modulators in each others' territories.

Meanwhile, Leverkusen, Germany-based Bayer already is looking for ways to expand riociguat's use. It's preparing to run phase II trials studying the drug's impact in pulmonary hypertension (PH) associated with interstitial idiopathic pneumonia, diffuse systemic sclerosis, cystic fibrosis and the rare Raynaud's disease.

The partners also are testing two more compounds in phase I, an unnamed Bayer sGC stimulator in development as a treatment for resistant hypertension and Merck's MK 8892 for PH and heart failure. A second Bayer compound is part of the deal, but is still preclinical.

MORE IN PLAY

Innovation alone won't make drugs targeting guanylate cyclases successful, of course. In PAH, for example, Adempas already has competition from Actelion Pharmaceuticals Ltd.'s Opsumit (macitentan), an oral version of Actelion's Tracleer (bosentan) that was approved in October 2013 for PAH. United Therapeutics Corp.'s Remodulin (treprostinil) is creating competition for Adempas, too. But clearly there's plenty of commercial and clinical interest carrying cGMP modulators ahead.

New York-based Synergy Pharmaceuticals Inc. is developing plecanatide, a drug targeting GC-C to treat the same indications as Linzess. The company intends to initiate pivotal phase III trials with IBS-C patients in the second half of 2014. It's additionally developing a GC-C agonist it calls SP-333 for the treatment of OIC and ulcerative colitis. (See BioWorld Today, Nov. 13, 2013.)

Tokyo-based Astellas Pharma Inc., Ironwood's development and marketing partner in Japan, also is working on sGCs and has built an extensive patent position in the space, but with very different chemistry than Ironwood's, Currie said.

"I think it's a natural progression as you see advances in these area that once you're able to bring clear benefit to patients," he said, "there will continue to be innovations."