BioWorld Today Contributing Writer

With $9 million raised to date and nine compounds in clinical and preclinical development, P2D Bioscience Inc. already has traction in its efforts to advance product candidates for central nervous system and pulmonary disorders, including attention deficit/hyperactivity disorder (ADHD), obesity, anxiety, depression, Alzheimer's disease, traumatic brain injury and chronic obstructive pulmonary disease.

Even better for the Cincinnati-based company, most of the money raised since its launch in 2005 has come from government and foundation grants, according to Frank Zemlan, the company's CEO and co-founder. P2D harkens back to the moniker Phase 2 Discovery, one of Zemlan's previous biotech start-ups, which subsequently outlicensed a proprietary Phase III-ready insomnia drug.

The company's lead compounds are dopamine transport inhibitors designed to overcome the addictive side effects and cardiovascular risks of currently marketed stimulants for ADHD, including Ritalin (methylphenidate, Novartis AG), Concerta (a different formulation of methylphenidate, Johnson & Johnson) and Adderall XR (d-amphetamine, Shire plc).

P2D has developed two benztropine derivatives, PD2005 and PD2007, that have shown a higher affinity for the dopamine transporter than conventional drugs. Their parent compound, benztropine, is an FDA-approved drug that's been used for more than 40 years and has demonstrated safety in multiple human studies, according to Zemlan.

"Our DAT inhibitors were developed at [the National Institutes of Health], and we licensed them in from the NIH to start the company," he told BioWorld Today.

"Our drugs are not addicting, for good reason: They don't have rapid onset, which is less than one minute for amphetamine. Ours take 10 minutes." P2D's compounds also have a safer cardiovascular profile, Zemlan said.

In June, the NIH awarded P2D $1.5 million to develop PD2007 through investigational new drug application safety and toxicity studies, which are under way.

"We have a lot of irons in the fire, but this drug is on the front burner," Zemlan said, adding that the company is seeking co-development partners for Phase I and IIa studies.

With its superior safety profile in comparison to amphetamines, PD2005 also is being evaluated in the treatment of obesity and diabetes.

The benztropine derivative's primary mechanism of action is the same as other anti-obesity drugs, including sibutramine (Meridia, Abbott) and fenfluramine (Pondimin, Wyeth) – yanked from the market years ago – and newer candidates Contrave (naltrexone/bupropion, Orexigen Therapeutics Inc.) and Qnexa (phentermine/topiramate, Vivus Inc.), which are in regulatory limbo due to cardiovascular and other safety concerns. (See BioWorld Today, June 6, 2011.)

Benztropine derivatives work primarily by increasing energy expenditure, and the weight is lost from body fat, not lean body mass – a significant clinical advantage, Zemlan said. Efficacy studies have demonstrated that PD2005 significantly decreased body weight in preclinical obesity models. In addition, benztropine derivatives lower triglyceride levels and improve the body's sensitivity to insulin.

P2D has several other promising candidates. PD9475, also under development for the treatment of ADHD, is a betahistine that is a potent antagonist at the histamine H3 autoreceptor. That compound has completed a Phase Ib study, and data analysis is under way, Zemlan said.

The company is making progress on a selective RAC GTPase inhibitor, PD3766, for the treatment of chronic inflammatory respiratory disorders, including chronic obstructive pulmonary disease and asthma. The company recently received a $320,000 grant from the National Heart, Lung and Blood Institute to further the compound's development.

"This is a very new target, and we have the only drug for that target," Zemlan said.

Further down the road are additional candidates for obesity and diabetes as well as applications for several of its compounds in Alzheimer's disease and traumatic brain injury.

P2D also recently inked a license to investigate the use of the EGFR inhibitor Tarceva (erlotinib, Astellas Pharma Inc. and Roche AG) for stem cell mobilization to treat seriously ill cancer patients, according to Zemlan.

Although most of its compounds remain in early preclinical development, the company has attracted a steady stream of grants. When seeking to raise private capital, however, the company hit a brick wall in the U.S. Consequently, P2D turned to investors in India, where three of its 12 employees are located, and that has proven to be a winning strategy.

"We have money to go through most of the investigational new drug application process" for PD2007, and "we're expanding now to get additional investors," Zemlan said. "The sweet spot for early outlicensing is Phase II, where you've demonstrated human safety as well as efficacy. That's our plan for '07, so we're looking for partners in India to work with us to do the Phase I and IIa studies, and that is looking pretty promising."

P2D conducts much of its drug synthesis, early pharmacokinetic and screening development in India and has a joint agreement with an Indian company, which Zemlan declined to name, to co-develop a TNF-alpha inhibitor. Zemlan expects to add another six employees – mostly in the U.S. – as the company moves into pre-IND work for PD2007.

Zemlan has no interest in competing with large pharmas, however.

"My background is in early stage drug development, not in marketing," he said. "Our model is to develop a compound to Phase IIa, then go out and license it."