The 28 day round-up

Despite the rumblings of layoffs, downturns, redundancies and bailouts, February seems to have been a good month for drug approvals globally. Following are some noteworthy developments.

-Matrix Labs received the first and only World Health Organization (WHO) approval for Lopinavir/Ritonavir Tablets, 200 mg/50 mg. Matrix's version of this product is heat-stable and affordable, making it practical for distribution and use in warm climates. A WHO approval indicates that a drug meets international safety, efficacy and manufacturing quality standards. With such status, Matrix can sell the treatment in most countries outside the United States and Europe. The company's emphasis on producing affordable products has allowed it to drive down the average annual cost per patient of effective therapies. Approximately 30% of HIV/AIDS patients in the developing world depend on Matrix's ARV products.

- The US FDA has approved ATryn® (Antithrombin [Recombinant]) for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. The GTC Bio & Ovation Pharma collaboration is the first ever transgenically produced therapeutic protein and the first recombinant antithrombin approved in the U.S. Along with the approval of ATryn, the FDA’s Center for Veterinary Medicine also approved GTC’s New Animal Drug Application, the first of its kind for the regulation of a genetic construct stably integrated into the genome of genetically engineered animals. This is now required for a recombinant technology used to develop transgenic animals, such as the goats that produce recombinant antithrombin.

-Good news for patients with osteoarthritis of the knee. The FDA has finally approved Genzyme's Synvisc-One which could potentially change the face of viscosupplementation therapy. Viscosupplementation is a procedure in which hyaluronic acid or a derivative such as hylan G-F 20 is injected into the knee joint to replace synovial fluid that typically becomes degraded in patients with osteoarthritis. Synvisc-One is an important therapy for OA of the knee because it delivers long-term pain relief (upto 6 months) through a single injection without the systemic side effects that can be caused by steroids and anti-inflammatory medication.

-Over 5 million gout patients with hyperuricemia have a new treatment option for the first time in 40 years. Teijin Pharma's new molecular entity, Febuxostat, is licensed to Takeda for marketing in the US where it will be available as ULORIC.

- The European Commission has granted marketing authorisation for Servier's Valdoxan(R) /Thymanax(R) (agomelatine), the first melatonergic antidepressant for the treatment of adult patients with major depressive episodes. Valdoxan is the first antidepressant with melatonin receptor (MT1) and (MT2) agonist properties and 5-hydroxytryptamine (serotonin) receptor 2C (5-HT2C) antagonist properties. This unique receptor profile of Valdoxan allows for the first time the restoration of the circadian rhythms of depressed patients. Valdoxan's mechanism of action is unlike those of the commonly-prescribed antidepressants, the SSRIs and SNRIs, as Valdoxan exerts its antidepressant efficacy without having an impact on serotonin levels.

-Dapoxetine has received marketing authorisation in Finland and Sweden for the on-demand treatment of premature ejaculation (PE) in men 18-64 years of age

-A big bump for companies in Canada, as some potential major earners received approval. The 44 NOC's issued by Health Canada included- Lilly's Cymbalta for Generalized Anxiety Disorder; Schering Plough's much anticipated contraceptive NuvaRing; Shire's Vyvanse for ADHD; Wyeth's antidepressant Pristiq; and a new indication for Avastin by Roche. The increasing number of drug submissions in Canada is a sign that manufacturers now consider the Canadian market to be substantial and profitable enough to hit those earning targets despite price controls, a public payer system, and generics friendly IP laws.

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Dapoxetine: The Final Blockbuster?

Janssen-Cilag (a Johnson & Johnson company) announced on Feb 10 that it had received regulatory approval in Finland and Sweden for its dapoxetine drug Priligy™. These approvals follow the December 2008 decentralised marketing authorisation procedure adopted by seven European Union countries: Sweden, Austria, Finland, Germany, Spain, Italy and Portugal. The two Scandinavian countries can now boast another claim to fame: being the first nations to offer their men an approved treatment for Premature Ejaculation (PE).

Dapoxetine hydrochloride is a novel, selective serotonin reuptake inhibitor (SSRI) compound that last made headlines in 2005 when the US FDA declined to approve the drug for PE. The reasons cited back then were lack of sufficient evidence and side effect issues. Dapoxetine has now been extensively evaluated in five randomised, placebo-controlled Phase III clinical trials involving more than 6,000 men with PE and their partners. More details about that here. J&J hopes that their comprehensive trial programme pays dividends, and has applied for market authorization in the other 5 European nations with a decentralized system as well as 10 other countries, including Canada, Australia, Mexico and Turkey. Successful approval in these markets may well mean that it is only a matter of time before the FDA is faced with a second review of dapoxetine.

So why the big fuss you ask? Well, according to a well publicized 2005 study in the Journal of Sexual Medicine, PE is the most common male sexual dysfunction affecting between 20-30% of males (It just so happens that the study was funded in part by J&J and its subsidiary Alza). Nonetheless, it is a legitimate condition that millions suffer from, and at a time when pipelines can no longer cater to blockbuster categories, J&J finds itself sitting on a golden cash cow. The US erectile dysfunction (ED) market (Viagra, Cialis and Levitra) was $3.4 billion in 2007 and continues to grow; according to industry analysts, the market for PE drugs is estimated to be as large as the erectile dysfunction market. In contrast to ED, which is more prevalent in men over 50, PE is a problem encountered by sexually active men of all ages. Importantly, there is no major competition being faced as both Pfizer & GSK abandoned their candidate drugs after the FDA rejection in 2005. A Massachusetts company – NeuroHealing Pharmaceuticals- has a d-modafinil (of Provigil fame) isomer in development for PE, but they don’t expect to commence clinicals until early 2010.

Even more astonishing (and a testament to J&J’s superior deal-making capacity) is that the rights to dapoxetine were bought for a meager $65 million. Dapoxetine (originally known as LY 210448) was one of David Wong’s creations (others include Prozac, Cymbalta, Stattera) in the late 80’s when Eli Lilly actively began pursuing the depression market. However, after several failures, Lilly sold the patent to J&J in 2003 subsequent to their purchase of Alza. Although it is known that high serotonin levels do play a major factor in lengthening ejaculatory response, off label use of currently approved SSRI’s in treating PE have been largely discouraged due to the side effects such as ED, loss of libido, nausea, serotonin syndrome, and increased suicide risk. The beauty of dapoxetine however, is its very short half life of 1.2 hours, meaning men can take the medication on demand with low risk of accumulation.

Whether dapoxetine is effective or if it will be a successful product are no longer valid questions. In a post Viagra world, it is almost certain that it will achieve near-cult status. The real question is whether dapoxetine’s success will be its eventual downfall. Not unlike the COX drugs, the potential for flagrant prescribing of dapoxetine is high. Combined with what will certainly be a high rate of abuse, it will be interesting to see what medical precautions & dispensing limitations are placed. One thing is for sure, a dapoxetine tragedy can not be blamed solely on the manufacturer. This time around, the entire medical community will have to shoulder the responsibility.

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