Another Round of Trials for Vigabatrin

Firm secures funding for anti-craving tests.

A Florida pharmaceutical company has secured financing for additional testing of the anti-addiction drug vigabatrin, despite the drug’s poor performance in earlier trials. Patrick J. McEnany, chairman and CEO of Catalyst Pharmaceuticals (CPRX) in Coral Gables, said the company would continue developing CPP-109 , its version of vigabatrin, for the treatment of cocaine and methamphetamine addiction.

Vigabatrin garnered early publicity on the basis of early trials suggesting it might be effective against stimulant addiction. Unlike alcohol and heroin, cocaine and speed have proven particularly resistant to treatment with other drugs designed to diminish craving. A drug that effectively reduced craving in abstinent cocaine and methamphetamine addicts would open up a potentially large and lucrative market.

Catalyst said it raised $3.97 million in a recent common stock offering from a group of investors including Federated Kaufmann Funds. Catalyst owns exclusive licensing rights to several patents related to vigabatrin from Brookhaven National Laboratory, reports Genetic Engineering and Biotechnology News. The company also owns patents or patent applications in more than 30 countries. Catalyst recently acquired worldwide rights to a related patent held by Northwestern University.

Earlier, the U.S. Food and Drug Administration (FDA) had given Fast Track designation to vigabatrin. The drug increases brain levels of GABA, an inhibitory transmitter. However, CPP-109 failed in a mid-stage treatment for cocaine addiction. Brian Bandell of the South Florida Business Journal reported that during the 12-week study, the drug did not help addicts stay cocaine-free, compared to a placebo group. In July, the company’s stock was trading at a 52-week low of 39 cents.

Last week, Catalyst said its decision to renew testing and development efforts with vigabatrin was due to a reanalysis of data from the earlier test. The company said the review showed that overall test subject compliance rates during the clinical trial may have been as low as 40 %. The company also said that early results with methamphetamine addiction were promising, but not statistically significant due to the small number of test subjects.

Last year, there was also a flurry of interest in vigabatrin as a weight loss drug. (See my earlier post). The FDA has yet to approve the drug for use in the U.S., citing concerns about reports of retinal damage in patients overseas. Catalyst said it had not uncovered any clinically significant visual abnormalities in its CPP-109 testing programs.

Vigabatrin, or gamma vinyl-GABA, is marketed in Europe as Sabril, and has existing clinical uses for the treatment of specific types of epilepsy and infant spasms.

Graphics Credit: www.dosewatch.com


addiction drugs

Drug for Cocaine Addicts Causes Weight Loss

Is Vigabatrin the next big diet pill?

The U.S. Department of Energy's Brookhaven National Laboratory announced that obese rats lost weight on the experimental anti-cocaine drug vigabatrin, reinforcing the idea that certain forms of obesity--particularly binge eating--result from the same kinds of neurotransmitter disturbances that underlie vulnerability to addictive drugs like cocaine.

Amy DeMarco, lead author of the study, said in a press release from Brookhaven that the results "appear to demonstrate that vigabatrin induced satiety in these animals."

Earlier, the U.S. Food and Drug Administration (FDA) had given Fast Track designation to vigabatrin, an anticonvulsant, for evaluation as an anti-craving drug for cocaine and methamphetamine addiction. If successful, it would be the first medication ever approved for the treatment of addiction to stimulants. The FDA has yet to approve the drug for use in the U.S., citing concerns about reports of retinal damage in patients overseas.

First synthesized as a drug treatment for epilepsy in 1974, vigabatrin increases brain levels of the neurotransmitter GABA, an inhibitory compound also implicated in alcoholism. According to a press release from Ovation Pharmaceuticals, a marketer of the drug under the trade name Sabril, “Sabril may block the euphoria associated with cocaine administration in humans and may suppress craving by increasing brain levels of gamma-aminobutyric acid (GABA).” Increased brain levels of GABA, an inhibitory transmitter, result in higher levels of dopamine and serotonin. Catalyst Pharmaceutical Partners is also testing a version of vigabatrin called CPP-109.

The weight loss study involved 50 genetically obese lab animals, and 50 normal animals. Each of the animals was given doses of vigabatrin or placebo for forty days. At the end of that period, the obese animals had lost 19 per cent of their body weight, while the non-obese animals lost from 12 to 20 per cent of their weight.

Brookhaven senior scientist Stephen Dewey, who did much of the early work on vigabatrin, said: "The fact that these results occurred in genetically obese animals offers hope that this drug could potentially treat severe obesity." In the lab press release, Dewey also observed that "This would appear to be true even if the obesity results from binge eating, as this disorder is characterized by eating patterns that are similar to drug-taking patterns in those with cocaine dependency."

Perhaps. But ten years ago, the research community was just as enthusiastic when a serotonin-boosting diet pill called Redux (dexfenfluramine) won full FDA approval in 1996. Redux was the first drug ever approved in the U.S. for the long-term treatment of obesity. But the euphoria didn’t last long. By the time Redux made the cover of Time, researchers were already rumbling about continued reports of high toxicity and hypertension in rat studies. Concerns about pulmonary hypertension arose, and in August, 1997, doctors at the Mayo Clinic in Minnesota reported serious heart valve abnormalities in 24 women taking the "phen-fen" combination.

A month later, at the FDA’s request, phen-fen and Redux were permanently pulled off the market.

Graphics Credit: SheKnows.com

Drugs for Cocaine Addiction

Researchers target GABA, noradrenaline.

According to Catalyst Pharmaceutical Partners, a company conducting research on drugs for the treatment of addiction, "The U.S. Food and Drug Administration has recognized that cocaine addiction is a 'serious, life-threatening condition for which there is no current drug treatment,' and the National Institute on Drug Abuse (NIDA) has stated that finding a pharmacological treatment for cocaine addiction is their number one research priority."

Other researchers view it differently, however. Allan Parry, a drug counsellor in Liverpool, U.K., told New Scientist that such work was "only likely to be relevant to a tiny minority of people. People often give up cocaine because their lifestyle changes or they just grow up."

Fighting fire with fire--using drugs to treat drug addiction--will likely remain a controversial approach for years to come.

What is the rationale for the use of drugs in the treatment of drug addiction? There are two basic approaches. Scientists look for medications that help patients initiate abstinence, and they look for drugs that help prevent relapse once the patient has achieved abstinence. The categories are not hard and fast. For example, a drug that effective reduces the reinforcing effects of cocaine by reducing the intensity of withdrawal can theoretically perform both functions at once. On the other hand, a drug that blunts the euphoric effects of cocaine--a drug that takes away the best of the buzz, no matter how much cocaine is ingested--can also succeed at the twin tasks of abstinence initiation and relapse prevention.

The search for medications with which to treat cocaine addiction has been in progress much longer than equivalent efforts aimed at methamphetamine addiction. One research target of long standing is modafinil, an odd-duck drug sold as Provigil for the treatment of narcolepsy. A mild stimulant, modafinil does a little bit of everything, pharmacologically tweaking dopamine, noradrenaline, anandamide and GABA receptor systems. Perhaps for this reason, the drug seemingly has been tried for almost everything, from Alzheimer's to atypical depression to jet lag. The U.S. military has reportedly shown some interest in it.

According to published research by Kyle M. Kampman in the June 2008 Addiction Science and Clinical Practice (PDF), modafinil-treated human subjects used less cocaine than placebo-using counterparts did in several recent small-scale studies. "In a double blind pilot trial with 62 cocaine-dependent patients, those who received modafinil submitted more cocaine-metabolite-free urine samples than placebo-treated patients (42 vs. 22 percent; Dackis et al., 2005)."

Propranolol, better known as the beta-blocker Inderal, works primarily by suppressing adrenaline and noradrenaline levels. In human studies to date, propranolol has shown itself most effective with the most severely cocaine-addicted patients. Studies by Kampman have shown that propanolol-treated patients stay in treatment longer than patients in control groups do.

Specific research on relapse prevention strategies has focused on GABA-enhancing drugs that inhibit cocaine reinforcement by secondarily blocking the dopamine surge characteristic of cocaine intoxication. In addition to vigabatrin, discussed in the previous post, topiramate is another particularly well-suited candidate for relapse prevention. Known as Topamax, and prescribed for seizures and migraines, the drug has shown early promise: "In a 13-week, double-blind, placebo-controlled pilot trial of topiramate involving 40 cocaine-dependent patients.... more of those on topiramate achieved at least 3 weeks of continuous abstinence (59 vs. 26 percent)."

Surprisingly, the granddaddy of all anti-addiction drugs--Antabuse--has made a comeback as a subject of study for cocaine addiction, even though it has never been spectacularly effective in its original application as a relapse prevention drug for alcoholics. Disulfiram, as it is known chemically, causes unpleasant physical sensations, including vomiting, when combined with even small amounts of alcohol. It does so by inhibiting the enzymes responsible for degrading alcohol. Even a little becomes too much. In similar fashion, disulfiram retards the breakdown of cocaine, leading to extremely high levels that induce paranoia and anxiety rather than a pleasurable, if extreme, high. At least four published trials have demonstrated reduced cocaine use in disulfiram-treated patients, according to Kampman's paper . One important downside to using Antabuse for cocaine addiction is that serious complications might occur if alcohol is added to the mix.

Finally, and still well into the future, is the prospect of relapse prevention therapy by means of a vaccine--an entirely different mechanism of approach. Research has shown that it is possible to produce "cocaine-specific antibodies that bind to cocaine molecules and prevent them from crossing the blood-brain barrier, thereby blunting the drug's euphoric and reinforcing effects," Kampman's paper asserts. A vaccine called TA-CD has tested well in preliminary studies.

No Pill for Stimulant Addiction

Meth and cocaine continue to elude researchers.

Despite promising trials of several compounds, methamphetamine addiction remains largely impervious to anti-craving pills and other forms of drug treatment. According to a paper in the June issue of Addiction Science and Clinical Practice, "currently, no medications are approved by the FDA for the treatment of stimulant dependence. However, recent advances in understanding... have allowed researchers to identify several promising candidates."

The paper's author, Dr. Kyle Kampman of the University of Pennsylvania School of Medicine and Treatment Research Center, notes that "the demand for treatment for cocaine dependence remained roughly level from 1992 to 2005, while the demand for treatment for amphetamine dependence increased about eight-fold." (See chart above).

As I wrote earlier ("FDA Puts Coke/Meth Treatment on Fast Track"), the U.S. Food and Drug Administration (FDA) in January gave Fast Track designation to vigabatrin, sold as Sabril by Ovation Pharmaceuticals. Ovation is collaborating with the NIDA on Phase II studies to evaluate the safety of Sabril, with Phase III trials scheduled for the end of this year.

Vigabatrin, an anti-epilepsy drug called Gamma-vinyl-GABA, or GVG for short, showed early promise for use with cocaine addicts in a 60-day study and appears to increase GABA transmission. GABA has an inhibitory effect on dopamine and serotonin release.

Another entry in the vigabatrin sweepstakes, Catalyst Pharmaceuticals, is also testing its version of the drug, dubbed CPP-109, for the treatment of methamphetamine addiction in Phase II double-blind, placebo-controlled studies. Patrick J. McEnany, chief executive officer of Catalyst, commented, "We are excited to follow up on our cocaine trial with the initiation of our second, large-scale U.S. Phase II trial with CPP-109, this time as a potential treatment for methamphetamine addiction. As with cocaine, we believe that CPP-109 may offer the potential to provide patients suffering from methamphetamine addiction, as well as the physicians and clinicians that treat them, with a safe and effective pharmacotherapy option."

What, in essence, are such pills designed to accomplish? The primary avenue of research has centered upon medications that decrease the addict's experience of withdrawal and craving. According to Kampan, "several studies have demonstrated that patients who experience severe cocaine withdrawal symptoms... are twice as likely to drop out of treatment and less likely to attain abstinence in outpatient programs."

However, questions remain about the safety of vigabatrin. Although available abroad, it is not approved for use in the U.S., due to an association with serious visual effects after long-term use. The use of vigabatrin for stimulant addiction, if approved, might require associated eye examinations.

Buproprion, a drug that has shown some promise in the treatment of cocaine addiction, is also a candidate for meth addiction. The drug inhibits the reuptake of dopamine, thus allowing more dopamine to circulate in the brain. In addition, there are plans to test other drugs being investigated for cocaine craving, such as topiramate and modafinil.

According to the 2005 SAMHSA Survey on Drug Use and Health, an estimated 10.4 million people age 12 or older (4.3 percent of the population) have tried methamphetamine at some time in their lives. Approximately 1.3 million reported past-year methamphetamine use, and 512,000 reported current (past-month) use. Approximately 535,000 patients sought treatment for methamphetamine and other stimulant abuse in 2006.

Next post: Drugs for cocaine craving

Photo Credit: National Drug Intelligence Center

dopamine

FDA Puts Coke/Meth Treatment on Fast Track

Sabril may block cravings for stimulants.

The U.S. Food and Drug Administration (FDA) has given Fast Track designation to vigabatrin, an anticonvulsant marketed as Sabril, for evaluation as an anti-craving drug for cocaine and methamphetamine addiction. If approved, it would be the first medication ever approved for the treatment of addiction to stimulants.

The Fast Track designation at the FDA is intended to speed up the evaluation of drug treatments aimed at life-threatening disorders for which no current treatments exist. A 2006 study by the Substance Abuse and Mental Health Services Administration estimated that there were more than one million cocaine and methamphetamine addicts in the U.S.

First synthesized as a drug treatment for epilepsy in 1974, Sabril increases brain levels of the neurotransmitter GABA, an inhibitory compound also implicated in alcoholism. According to a press release from Ovation Pharmaceuticals, a marketer of the drug, “Sabril may block the euphoria associated with cocaine administration in humans and may suppress craving by increasing brain levels of gamma-aminobutyric acid (GABA).” Catalyst Pharmaceutical Partners has also announced plans to proceed with Sabril testing.

Ovation is collaborating with the NIDA on Phase II studies to evaluate the safety of Sabril, with Phase III trials scheduled for the end of this year. FDA has never approved the drug for use in the U.S., citing concerns over retinal damage in patients overseas.

Earlier animal testing and two limited early-stage studies on human addicts in 2003-2004 have convinced the company that Sabril diminishes cravings for stimulants. It may also blunt the euphoric effect of meth and cocaine. "This is unheard of in addiction treatment," Stephen Dewey of the Brookhaven National Laboratory, a member of an earlier vigabatrin study team, told New Scientist in 2003. "There are no medicines that are effective at blocking cocaine craving in addicts."

Writing in the November 2004 issue of Synapse, Jonathan D. Brodie and colleagues at the New York University School of Medicine reported that “A rapid elevation in nucleus accumbens dopamine characterizes the neurochemical response to cocaine, methamphetamine, and other drugs of abuse. CITE Previously, we demonstrated that this response and associated behaviors are attenuated or even blocked by Vigabatrin, an antiepileptic drug and an irreversible inhibitor of GABA-transaminase."

However, the New Scientist also reported that many doctors who work with cocaine addicts were skeptical. "Cocaine is a recreational drug. The vast majority of people who take cocaine or crack want to continue doing so," said Allan Parry, a drug counselor in Liverpool, UK. "So in that sense this work is only likely to be relevant to a tiny minority of people. People often give up cocaine because their lifestyle changes or they just grow up."

Ovation said it was “pleased that the FDA has recognized the significant need for effective treatment options to address stimulant addiction, which is a major public health problem.”

Since there are no FDA-approved medications for cocaine or methamphetamine addiction, current treatment strategy centers on cognitive and behavioral approaches.