Drug Firms Vie to Develop More Effective Antipsychotics

Along with numerous interviews, an extensive review by Psychiatric News of documents from numerous sources, including the U.S. Food and Drug Administration (FDA), industry analysts, and pharmaceutical companies, revealed that more than two dozen pharmaceutical companies are involved in the race to develop at least 40 new antipsychotic medications.

However, regulators, analysts, and the pharmaceutical industry agree that only a handful of those drugs will ever make it all the way through the“ pipeline” to reach the pharmacy shelf. The Pharmaceutical Research and Manufacturers of America, the professional trade association that represents U.S. pharmaceutical research and biotechnology companies, estimates that for every 5,000 new chemical compounds evaluated for possible development as a human medication, only five go on to enter clinical trials in humans. Of those five drugs, only one will win the FDA's marketing approval.

The drug development process involves many stages, from discovery and preclinical testing through phase III clinical trials in patient volunteers (see chart on page 29. The process can take 10 to 15 years and cost hundreds of millions of dollars.

Of the 40 or so developmental antipsychotic medications working their way through the pipeline, only two are new formulations of existing approved medications: an intramuscular depot injectable formulation of olanzapine (Zyprexa) and a sustained-release formulation of quetiapine (Seroquel).

Analysts expect a new drug application (NDA) to be filed with the FDA later this year for the sustained-release quetiapine, while an NDA for the depot olanzapine is likely at least a year to 18 months out. Little information was available in the public domain for either product. However, analysts question how well a once-a-month injectable olanzapine will fare, given the drug's side-effect profile.

The remaining candidates under development are all what the FDA designates as “new chemical entities” (NCEs). While several of the NCEs are related to or derived from approved medications, all NCEs possess unique chemical structures that have not previously been approved for human use. Nevertheless, analysts agreed, all of the antipsychotics in late stages of development are “me-too” drugs—their mechanisms of action are the same as existing drugs.

To date, only one NDA for an NCE antipsychotic medication has been filed with the FDA. That NDA, for Johnson & Johnson's paliperidone ER tablets—a derivative of the company's risperidone (Risperdal)— was submitted November 29, 2005, and is expected to be ruled on by FDA regulators by the end of 2006. An NDA for a paliperidone depot injectable is expected to be filed this year.

Company documents and analysts describe paliperidone as a metabolite of risperidone that possesses at least equal efficacy while boasting an improved safety profile.

The extended-release formulation of paliperidone uses the patented OROS technology of sustained release, resulting in more consistent blood levels of medication over the 24 hours between daily dosings. The depot formulation, Grady commented, “is said to be every six- to 12-week dosing. We're bullish on that; we think that would be very attractive.” But, Grady added, a dosing interval of that length could also be a liability. The profile of the drug, she said, “will have to be just right. Physicians are going to have to be able to not be scared of [depot paliperidone].”

“Key [antipsychotics] to watch out for in the near future,” said Emma Travis, a senior CNS analyst with Datamonitor, “are the launch of Solvay/Wyeth's bifeprunox and Organon/Pfizer's asenapine” (see chart page 25.

Bifeprunox is a partial dopamine agonist/antagonist and serotonin agonist, similar to aripiprazole (Bristol-Myers Squibb's Abilify).

“This one is interesting,” Grady said, “because it is only the second drug with this mechanism of action to get to the market. That is clearly an opportunity.”

Solvay, which developed the drug and licensed U.S. marketing rights to Wyeth, said in a November 29, 2005, press release, that “additional phase III comparative clinical work” would be required “to satisfy European Union requirements.” The company said the European regulatory filing is now planned for 2008. However, in the same press release, the company said “Solvay and U.S. partner Wyeth Pharmaceuticals are continuing to assess and analyze the clinical study data with respect to a U.S. filing in 2006.” Incidentally, Solvay has three additional antipsychotics in earlier stages of clinical development.

The second highly anticipated drug is asenapine, which was developed by Organon and licensed to Pfizer. An Organon statement on the asenapine development program noted in March that phase III clinical trials were on target to be completed in late 2006, with an expected NDA in early 2007. Asenapine is described as an “atypical antipsychotic with a unique receptor signature” involving antagonism at serotonin, dopamine type 2, and adrenergic receptors. The drug's interaction with serotonin receptors is said to be stronger than any of the currently marketed antipsychotics, with only minimal interaction with muscarinic receptors.

“What is interesting about asenapine— which has specifically been referred to as `clozapine-like, without the side effects'— is that Organon developed the drug, then Pfizer signed on to market it,” Grady told Psychiatric News. Considering that Pfizer already markets ziprasidone (Geodon), and the market is already highly competitive with well-established drugs, Grady added, “what is it about asenapine that made Pfizer so interested?”

Several other antipsychotics appear to be in late-stage development, two of which have been available in other countries for years.

Lundbeck's sertindole (Serdolect), a serotonin/dopamine/alpha-adrenergic antagonist, was reintroduced in the European market in December 2005. The drug was pulled from the market in 1998 after reports of QTc prolongation and subsequent sudden cardiac death. Lundbeck completed additional safety testing of the drug in 5,000 patients after the drug was pulled off the market, bringing the total clinical trial database to 17,000 patients.

Lundbeck has said it intends to launch the product in the United States; however, the company's president and CEO, Claus Braestrup, noted in May 2005 that the company would “have to wait a couple of years before we will be in a position [to address previously discussed FDA concerns], and we have not made any predictions or expectations” regarding when an NDA might be filed.

A second drug, also available in Europe and available in Japan since 1982, is Orion Pharmaceutical's zotepine (Zoleptil). As of last summer, analysts said the company was exploring a U.S. market launch, however this could not be confirmed.

A third drug in late-stage development is Corcept Therapeutics' glucocorticoid type II receptor (GR-II) antagonist, mifepristone (Corlux).

The drug is better known for its ability to block estrogen and its controversial marketing as the “morning-after pill” method of contraception. The drug is currently in phase III testing in patients with psychotic major depression, and because no other drug is marketed as an approved treatment for psychotic depression, the FDA has designated mifepristone for psychotic depression as an “orphan drug” and granted Corcept's request for designation of fast-track status. Once an NDA is filed, fast-track status commits the FDA to an accelerated approval timeline.

The remaining drug known to be in late-stage development is iloperidone, which was developed by Novartis Pharmaceuticals in the early 1990s. Said to have longer occupancy and higher affinity for serotonin receptors than dopamine receptors, iloperidone was expected to have moderate efficacy while offering a lower liability for extrapyramidal symptoms.

Similar to ziprasidone, however, the drug appeared to be associated with potential prolongation of the QTc interval. Novartis discontinued development of the compound and later sold the rights to Titan Pharmaceuticals. Titan then licensed the drug to Vanda Pharmaceuticals for phase III clinical testing. If or when an NDA might be filed with the FDA is unknown.

At least four other NCEs are in mid-stage development and show promise for final approval. Each drug is in phase II clinical trials; therefore, none is likely to be the subject of an NDA filing before the end of 2007 or into 2008. Organon is developing an AMPAkine modulator, designated ORG 24448, which was given the generic name farampator. Japan's Dainippon Sumitomo Pharmaceuticals is testing blonanserin (Lonasen), a new serotonin/dopamine/adrenergic antagonist, and has partnered with Merck in the United States on another developmental antipsychotic, lurasidone, a serotonin/dopamine antagonist SGA. Finally, ocaperidone, another risperidone derivative on which Johnson & Johnson discontinued development in 1994, has been licensed to Neuro3D for further development.

A number of other putative antipsychotics that appear to be truly novel compounds are in early development. Some interact with the tachykinin receptor NK3, while others target melatonin receptors or are CRF modulators. Drugs are also in the pipeline targeting cannabinoid receptors, nicotinic acetylcholine receptors, glutamate and NMDA receptors, and highly specific subsets of dopamine, serotonin, and/or noradrenergic receptors.

In addition, one company (Acadia Pharmaceuticals) is specifically chasing the efficacy of clozapine with a direct metabolite of the drug, known as ACP-104 or N-desmethylclozapine. The compound is said to maintain clozapine's relatively higher efficacy, but is less likely to mirror its well-documented adverse effects.

Overall, however, it is difficult at best to guess which—if any—of these drugs in the earlier stages of development has significant potential.

“There are certainly a lot of drugs in development,” concluded Grady. Any that come to market, she added, provide another option to help patients. “But honestly, as far as late-stage products,” she said,“ there isn't anything that is really impressive—and when I say that, what I mean is nothing that is truly novel, different, or has the potential to change the face of treatment for schizophrenia.” ▪