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Pharma Two B taking ‘synergistic’ approach in pursuit of 505(b)(2) approval

Published in Scrip Magazine by Donna Young, April 22nd 2011
Israeli start-up Pharma Two B has taken the concept of synergism seriously, from the eclectic group of scientists and managers it has brought together under one roof, to its fixed-dose combination strategy of drug development, to the approval pathway it plans to seek in gaining the US FDA’s OK-505 (b)(2), a hybrid route to approval that is increasingly growing more popular in the US because of the costs saved and time reduced in getting medicines to the marketplace.

Pharma Two B’s executives combined years of drug R&D and marketing experience, said CEO Dr. Nurit Livnah, add up to over 100, which she noted is not bad for a young company.

Indeed, the firm’s chairman, Ehud Marom, served as an executive in Israel role at Israeli generics drug major Teva Pharmaceuticals, where he helped bring the immunomodulator multiple sclerosis drug Copaxone (glatiramer) to the market. He was also CEO at Gamida-Cell and held positions at several other Israeli-based drug companies, including Peptor, a biotech firm where Dr. Livnah also spent several years – first as head of chemistry and later as vice-president of R&D.

She also served as director of research at Develogen after it merged with Peptor in 2001, and was previously vice-president of R&D at Proteologics before joining Pharma Two B when the company was formed in 2008.

Pharma Two B’s other executives also bring several years of diverse R&D management and marketing experience to the table, Dr. Livnah told Scrip. The Rehovot, Israel- based company’s main focus is developing fixed-dose combinations based on lower doses of FDA-approved drugs with complementary biological mechanisms, which she said leads to a synergistic effect that results in significantly increased therapeutic activity.

That synergistic effect, Dr. Livnah said allows for lowering the doses of the active ingredients, which provides for an improved safety profile with fewer adverse effects. That effect is augmented by a sustained release profile, permitting the combination drug to have longer therapeutic activity in the body, she added.

On the one hand, Pharma Two B’s fixed-dose combination approach is “innovative”, with “clinical and commercial value”, while on the other, it saves time, money and other resources in R&D, clinical trials and the regulatory process, she insisted.

Pursuing fixed-dose combinations of already approved agents also will permit the company to use the FDA’s 505(b)(2) approval pathway, which is sort of a hybrid of the new drug application (NDA) and the abbreviated NDA.

The 505(b)(2) pathway, which was established under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly known as the Hatch-Waxman Act, was created to encourage drug makers to develop new medicines using already approved agents. Under 505(b)(2), manufacturers can rely on data not developed by the applicant or for which the applicant has not obtained a right of reference, such as published literature or the FDA’s findings of safety and effectiveness for an approved drug.

There were 31 applications approved in fiscal year 2008 under 505(b)(2), with another 35 approved in FY 2009, while 29 gained approval in FY 2010 under the pathway. FDA spokeswoman Karen Mahoney told Scrip.
Prior to the FDA Amendments Act of 2007, which required the FDA to report on the 505(b)(2) pathway to Congress, the agency did not track or report the numbers of approvals of those types of applications, she noted.

But the less risky pathway is becoming increasingly appealing for drug makers, such as Depomed, which gained approval in January of its once-daily oral formulation of gabapentin drug Gralise as a treatment for postherpetic neuralgia, and Bio Delivery Sciences International, which is seeking approval under 505(b)(2) for its investigational opioid dependence drug BEMA Buprenorphine / Naloxone.

DR Nurit Livnah and Ehud Marom

Pharma Two B also has found that route a desirable path to take, and plans to pursue it for the company’s experimental fixed-dose combination drug P2B 001, which currently is under development for Parkinson’s disease, a central nervous system disorder characterized by tremors and difficulty with movement, walking and coordination, Dr. Livnah said. She noted that Parkinson’s affects about four million people worldwide and is most common in the elderly, with the incidence of the condition increasing due to the aging population.

Parkinson’s, a progressive disease, occurs when the nerve cells in the brain that make dopamine, which helps to control muscle movement, are slowly destroyed for unknown reasons, leading to a loss of muscle function.

The current “gold standard” of treatment for Parkinson’s is levodopa, also known as L-dopa, which is converted to dopamine in the brain, Dr. Livnah noted. But although L-dopa is effective in treating the disease, it comes with severe adverse effects, mostly notably dyskinesia, an inability to control muscles, often resulting in uncontrolled flailing of the arms and legs and other rapid and repetitive motions, she said. L-dopa also can cause arrhythmia, low blood pressure, breathing disturbances and adverse gastrointestinal effects. The drug also requires dosage adjustments with continuous use.

“There is a clear, unmet need for a longer term treatment of the disease”, Dr. Livnah said.

Pharma Two B’s P2B 001, which is formulated for sustained-release and designed to effectively treat Parkinson’s disease in doses that are significantly lower than existing effective treatments, could delay the inevitable administration of L-dopa, giving patients more time of effective treatment, with fewer adverse effects, she maintained.

In a chronic disease, such as Parkinson’s, where the treatment duration is long and a medication’s dosages need to be constantly increased because of disease progression, “it may be a huge benefit to be able to start treatment with very low doses, and keep the patient on a safe, yet highly effective treatment for as long as possible, before having to either go to higher doses, or move to harsher drugs”, Dr. Livnah said.

P2B 001’s two undisclosed active ingredients currently are used in treating Parkinson’s but work in two different ways and are not effective enough on their own low doses, she noted. Pharma Two B, however, has found a way to combine the two agents to increase their “dopaminergic” effect, Dr. Livnah said.

Most Parkinson’s drugs attempt to regulate the dopamine signal transduction, degradation or reuptake process, or stimulate the dopamine receptors. But Pharma Two B takes a different approach with P2B 001 by intervening with two different pathways, rather than one, and which complement each other’s activity, Dr. Livnah said.

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