Staff Writer

With $2.3 million in seed funding in hand, Arginetix Inc. is conducting preclinical studies to advance its small-molecule arginase inhibitors in the crowded fields of pulmonary arterial hypertension (PAH) and erectile dysfunction (ED).

The Baltimore-based start-up owes its beginnings to scientific co-founders David Christianson of the University of Pennsylvania and Dan Berkowitz of Johns Hopkins University. Their labs established preclinical proof of concept for arginase inhibition in PAH, ED, asthma and atherosclerosis. Data published in The American Journal of Physiology - Heart and Circulatory Physiology demonstrated that, in a mouse model of ED, treatment with an arginase inhibitor restored the intracavernosal pressure of aged mice to the level of young mice without affecting young mice.

Such research caught the eye of Gary Lessing, a former investment banker and biotech executive who was then serving as entrepreneur-in-residence for Red Abbey Venture Partners.

Lessing said he was "excited about the attractiveness of arginase as a target" as well as the preclinical proof-of-concept established by the scientists. He worked with Red Abbey's incubator arm, Acidophil LLC, to found the company in December 2007 and took the reins as president and CEO.

Acidophil provided an undisclosed amount of initial funding to carry Arginetix through 2008 while it licensed the arginase inhibitor program from the University of Pennsylvania and started working on pharmacokinetic, toxicology and other traditional biotech studies that hadn't yet been done by the academic founders. Then in late 2008, Arginetix raised $2.3 million in a seed round co-led by Quaker BioVentures and MedImmune Ventures, with participation by Red Abbey, Maryland Health Care Product Development Corp. and Acidophil.

Lessing now is looking to raise a $20 million Series A round that would carry Arginetix into Phase II proof-of-concept studies with ABH, its lead small-molecule arginase inhibitor.

While other biotechs have worked on arginine as a target, Lessing said he doesn't know of anyone else working on its enzyme, arginase. Inhibiting the enzyme increases production of nitric oxide, which is critical for cell signaling, and reduces the production of reactive oxygen, which can damage cells. Additionally, arginase inhibition can decrease levels of ornithine, a molecule that contributes to hyperplasia and fibrosis.

Lessing noted that arginase inhibition is a "more elegant way of trying to impact these pathways" than targeting arginine directly.

Therapeutic applications may include PAH, ED, asthma, atherosclerosis and cancer. Arginetix plans to focus internally on PAH and ED, for starters.

In PAH, existing treatments include endothelin receptor antagonists like Tracleer (bosentan, Actelion Ltd.) and Letairis (ambrisentan, Gilead Sciences Inc.); prostacyclins like Ventavis (iloprost, Actelion Ltd.), Flolan (epoprostenol sodium, GlaxoSmithKline plc) and Remodulin (treprostinil, United Therapeutics Inc.); and phosphodiesterase-5 (PDE-5) inhibitors like Revatio (sildenafil, Pfizer Inc.).

Even more competition is on the way, with Pfizer conducting Phase III trials of PF-1228305 (Thelin), an endothelin receptor antagonist that was the subject of three approvable letters before Pfizer acquired its developer, Encysive Pharmaceuticals Inc. (See BioWorld Today, Feb. 21, 2008.)

Yet Lessing maintained that PAH still represents "a significant unmet need" and noted that none of the existing drugs address the role of nitric oxide in the disease. As such, Arginetix's ABH could be complementary to the existing treatments, he said.

The scenario is similar in ED, where PDE-5 inhibitors like Viagra (sildenafil, Pfizer Inc.) and Cialis (tadalafil, Eli Lilly and Co.) rule the market and Vivus Inc.'s fast-acting avanafil is in Phase III.

Lessing referenced statistics claiming that about half of men with diabetes have erectile dysfunction and tend to be less responsive to PDE-5 inhibitors than nondiabetic men. He sees ABH as an option for those patients, but he also sees a "strong rationale" for combining arginase inhibitors with PDE-5 inhibitors.

"PDE-5 inhibitors stabilize cyclic GMP," while arginase inhibitors act on nitric oxide to increase levels of cyclic GMP, making the PDE-5 inhibitors more effective, Lessing explained.

Arginetix is advancing ABH through pharmacokinetic, toxicology and drug profiling studies. An investigational new drug application is slated for filing around 2010.

Although potential partners already have initiated discussions with Arginetix, Lessing said the company does not have a "strong desire" to partner right now. "We need to advance the research work further," he said - but Lessing added the company is always open to discussions.