A new insomnia treatment, approved by FDA July 22, is the first insomnia drug that was not designated a controlled substance by the Drug Enforcement Agency. Rozerem (ramelteon) is also the second sleep aid indicated for long-term use. Sepracor’s Lunesta (eszopiclone) was the first.

One of key questions about Rozerem is what its lack of a DEA warning will mean for the insomnia drug market.

    The fact that Rozerem is not controlled would not affect physicians’ prescribing behavior at all, predicted Dr. Clifford Massie of Chicago’s Suburban Lung Association. But he added that it might make a difference to patients with concerns about taking insomnia drugs.

    It will help eliminate patients’ fears of a stigma associated with sleep aids, Dr Rafael Pelayo of the Stanford Sleep Disorders Clinic said. This will make more people comfortable talking to their doctors or pharmacists about getting treatment, he continued.

    Pelayo attended an advisory board meeting for Rozerem at Takeda. He has also sat on advisory boards for competitor drugs Ambien and Lunesta.

    Both doctors said that Lunesta’s indication for long-term use would also make patients more comfortable with seeking treatment.

    “It’s good news for patients to know that insomnia has gotten safer,” Pelayo said.

New sleep drugs usually have variable results on patients, Massie said. He noted that many insomnia patients at specialty clinics have been on medication for so long that it is difficult to predict how their brains will a new receive treatment.

    But he noted concerns that Rozerem was too short acting to provide a full night of sleep.

    “What we really need is something that zonks people out for eight hours and then has no carry over,” Massie said.

    Pelayo wondered about the possibility of combining Rozerem with other insomnia therapies.

Rozerem has an affinity for two types of melatonin receptors, labeled MT1 and MT2, which are found in a part of the hypothalamus called the suprachiasmatic nucleus, or SCN, according to Phyllis Zee, an associate professor of neurology at Northwestern University’s Feinberg School of Medicine.

    The SCN functions as a master clock of circadian rhythms – the biological cycles that humans undergo on a 24-hour basis, Zee said. One of the master clock’s jobs is to produce a signal that keeps people awake during the daytime. The longer a person is awake, the stronger the signal, peaking at about 9 p.m. This acts to counteract the body’s natural drive for sleep.

    Without this signal people would be taking short naps every three or four hours, Zee explained. It allows people to consolidate their sleep at night.

    Although there is no direct proof, Zee indicated that experts believe Rozerem works by decreasing the rate at which the SCN fires off this signal. This is the same effect that melatonin has in controlled lab experiments, she said. But results of small studies on people using melatonin are not consistent with each other, she continued.

    Other insomnia drugs act on different sleep centers in the brain, located in both the hypothalamus and the cortex, Zee said. They interact with receptors for neurotransmitter GABA.

    Zee was an investigator for a multi-center clinical trial of Rozerem.

Articles

Experts offer their opinion on how Takeda's Rozerem, the first non-controlled sleep aid, will be received by doctors and patients.

Sleep Aid with Novel Mechanism Approved

Continuing its efforts to stay on top of the generic pharmaceutical industry, Teva Pharmaceutical Industries Ltd. purchased Ivax Corp. for $7.4 billion, July 25. According to Chief Executive Officer, Israel Makov, the acquisition will allow Teva to lead the industry “on a different scale,” both therapeutically and economically.

    Experts agree that this is a significant example of ongoing consolidation in the generics industry. By manufacturing the largest number of products, Teva is “going to be way up on top,” said Edward Thwaite, president of E.W.   Thwaite Associates Inc., a generics consulting firm.

    Including drugs manufactured by Ivax, Teva will now have an offering of more than 300 products, according to Makov. These are mostly generics but also include some branded drugs. The company’s pipeline will also be enlarged by the deal, he said during a conference call announcing the acquisition.

    Peter Young, president of specialist investment banking firm Young & Partners, said that that for some generics companies, consolidation can be beneficial if it leads to reduction in costs due to sales force and infrastructure and enhance the fullness of a company’s product portfolio. 

    These were all factors Teva executives emphasized when announcing the acquisition. Makov also cited expansion of research and development by eliminating duplication and using money more efficiently as a benefit of the acquisition.

    But Young disagreed with the idea that consolidation has benefits for the company’s research and development or regulatory sectors. 

    Young also asserted that remaining small could also be advantageous for some generic manufacturers. 

    “Much of generic pharma is regional,” he said, referring especially to companies’ sales and regulatory functions. “So the benefit of being global might not be as strong as in other industries.”

    What’s more, Young said, for companies that are very strong in one therapeutic niche, consolidation might not bring any benefits. As and example, he compared a luxury car company, such as Porsche, with a lot of revenue from very strong niche market, with a mainstream car company, Ford, which is being weakened by global competitors. Porsche would have nothing to gain by acquiring Ford, he indicated.

    Young believes that consolidation in the generics industry would have only a modest impact on pricing for customers. 

    “You’d have to have a lot of people merging before the level of competition would go down,” he said.

    But Thwaite disagreed. A large company with a diverse product portfolio and pipeline will have more pull with customers, including wholesalers, warehousing chains, mail order companies and managed care companies, he said.

    “Every customer has got to deal with them, whether they want to or not,” Thwaite said.

Teva's recent purchase of Ivax has analysts wondering where the push for bigger and more global generic manufacturing companies will take the industry.

Teva Advances Generics Consolidation with Ivax Purchase

The Central American Free Trade Agreement, which narrowly passed the House in an early morning vote last week, has various industry and advocacy groups arguing about how its intellectual property regulations compare with current domestic laws. 

The Generic Pharmaceutical Association supported the agreement but lobbied for changes in specific elements of the intellectual property rules, which it believes give unfair advantage to brand drug producers. The association objects to the provisions that allow patent extensions that compensate for time spent in the approval process because these extensions do not specify time limits. 

    “We want to ensure that the extension does not exceed what is available in the U.S., at this time,” spokeswoman Andrea Hofelich said.

    Generic manufacturers are also concerned that CAFTA’s five-year market exclusivity period could be applied separately in every country, allowing manufacturers to delay applying in one country until the exclusivity period has already ended another country.

Another GphA complaint is that the agreement does not allow generic companies to begin marketing a drug until any potential lawsuits have been resolved, unlike the provisions of the Hatch-Waxman Act. This would allow brand companies to have “de facto patent extensions,” during the period that the suit is unsettled, according to the association. Hofelich described this as a potential way for pharma companies to “game” the system and prevent the entry of generic drugs.

    Asia Russell, spokeswoman for HIV/AIDS advocacy group Health GAP, is concerned that CAFTA will retroactively affect domestic policy. And she expressed fear that the agreements intellectual property provisions would “ratchet up protections even here at home,” through international harmonization.

Although generics manufacturers say that the CAFTA intellectual property protections are more stringent than domestic standards, brand pharma companies say the agreement brings Central American countries in line with United States law.

    According to a PhRMA statement, CAFTA “will considerably upgrade the level of IP protection in the region. Provisions on data protection, patent term restoration, linkage and patentability will provide a better framework for investment and improve patient’s access to medicines.”

    According to Stan Lovenworth, partner at Dewey Ballantine LLP, the agreement puts Central America in line with the United States.

    “I don’t think that it changes the basic world-wide pattern,” he said.

    Joseph McKinney, director of the McBride Center of International Business at Baylor University’s Hankamer School of Business, agreed. CAFTA provides a stable framework for protecting intellectual property that is uniform throughout the region and does not change as individual governments change, he explained. He also noted that it strengthens enforcement of counterfeiting and intellectual property violations.

    “The pharmaceutical industry is one of those that will benefit from the agreement,” McKinney said. Although he admitted that there is “certainly a concern on the part of generic manufacturers.”

Russell believes that CAFTA protections are not just stronger than domestic laws but also more stringent than WTO standards and the Doha declaration. She is concerned that this will have a negative impact on public health in Central American countries.

    “CAFTA is a major step backwards for public health and access to affordable medicines in Central America,” she said.

    Lovenworth argued that public health and intellectual property rights do not have to be mutually exclusive.

    “A way should be found to preserve both,” he said. “[A] way to deal with developing world health problems that isn’t stopping protections of intellectual property. I don’t think you need to sacrifice the protections that bring new drugs to the world.”

    He asserted that the solution to the problem was intricately linked with issue of when, if ever, compulsory licensing is appropriate for public health reasons.

Generics manufacturers, public health advocates and Big Pharma square off over the implications of the Central American Free Trade Agreement.

Pharmaceutical Executive-08-02-2005

Sleep Aid with Novel Mechanism Approved

Teva Advances Generics Consolidation with Ivax Purchase

CAFTA Intellectual Property Provisions Stir Controversy