"There are about half a dozen other drugs that have given us positive signals in reducing cocaine use in double-blind, placebo-controlled trials," Vocci says. "We are in the process of doing confirmatory evaluations." The drugs include topiramate, modafinil, tiagabine, propranolol, ondansetron, naltrexone, and a combination of disulfiram and naltrexone. Many are existing CNS drugs that act on similar targets affected by drugs of abuse, or are useful in clinical populations where other conditions, such as depression, occur along with drug abuse.
For example, some antiepileptic drugs have multiple mechanisms of action and, in addition to controlling seizures, can reduce obsessive or compulsive thoughts that may be connected to treating drug craving, Vocci explains. Similarly, the anticonvulsant topiramate, sold by Johnson & Johnson as Topamax, causes weight loss and may affect other appetitive mechanisms.
Topiramate indirectly influences dopamine levels by activating -aminobutyric acid (GABA), an inhibitory neurotransmitter, and blocking glutamate, an excitatory neurotransmitter. According to NIDA, small-scale clinical studies have shown it helps cocaine-addicted individuals remain drug-free for three or more weeks-possibly enough time, when combined with behavior therapy, to offer a good chance for long-term cessation.
Modafinil, a drug that promotes wakefulness and is sold by Cephalon as Provigil, enhances glutamate levels. Animal studies have shown that repeated exposure to cocaine depletes glutamate in areas of the brain related to the development of addiction. And an increase in glutamate levels blocks cocaine self-administration in rats. University of Pennsylvania researchers have already reported positive clinical trial results, and results from a major trial are expected later this year, Vocci says.
Tiagabine, an anticonvulsant sold by Cephalon as Gabitril, is also being tested. The drug is a selective GABA reuptake inhibitor that increases GABA levels by selectively binding to GAT-1, the predominant GABA uptake transporter. If the company's products are found to work, Cephalon CEO Frank Baldino Jr. says it would be a "big step forward for drug abuse therapy" and one the company would support if it sees decent market opportunities.
Catalyst Pharmaceutical Partners (CPP) of Coral Gables, Fla., is developing vigabatrin for cocaine and other drug addictions. Vigabatrin, a -vinyl derivative of GABA, works by inhibiting the enzyme that breaks down GABA. The company licensed the compound from Brookhaven National Laboratory, which had conducted about a decade of addiction-related research. Sanofi-Aventis markets the drug as Sabril for epilepsy outside the U.S. CPP has completed two clinical trials in Mexico and has the go-ahead from FDA to begin a Phase I trial in the U.S.
There's clearly much more to treating addiction than simply blocking reward systems. Areas for discovery include finding existing or new compounds that modulate appetitive systems in the brain, Vocci says. Such systems, and the dopamine system is one of these, alert human beings to internal and external stimuli and shape behavior over time. "The stimuli of greatest importance are probably conditioned cues, mood and affect changes, drug priming, and stress," he explains. "So we are looking at medications that can block these processes."
A formerly dependent individual responds more strongly to an initial intake of a drug or alcohol than does a nondependent individual and thus is primed for further consumption. Animal and clinical studies have shown that dependent individuals also interpret stress almost as if it were a low drug dose that activates their dopamine systems. And stress, combined with a conditioned cue or trigger, can lead to relapse.
Drugs that might block priming include dopamine D3 receptor antagonists, D3 receptor partial agonists, cannabinoid antagonists, and narcotic antagonists, Vocci says, whereas antistress compounds include CRF antagonists, vasopressin 1B antagonists, orexin antagonists, and certain glutamate antagonists. "There are a host of approaches, and some companies are working with us right now at the preclinical and clinical pharmacology levels, and we're looking at moving into clinical studies."
Another approach is aimed at drugs that affect cognition. "Five or 10 years ago, I would have said these are a great idea, but we don't know much about drugs that would affect cognition in a way we want," Vocci comments. Now, drugs are emerging that can enhance cognition, increase attention, stop persistently recurring thoughts, increase inhibitory responses to stimuli, or decrease impulsiveness and risk-taking behaviors. Addressing these traits, which may be genetic or acquired through repeated drug abuse, is believed to be relevant to mitigating addictive behaviors, he says.
"When someone decides drug use is going to be an organizing principle of their life, they are addicted, and what you need to do is to alter their cognition in order to alter their behavior," Vocci explains. "There are cognitive behavioral therapies, and they may work in some of the population. But it's the others for whom we're looking for medications, because they are the ones that relapse and continue to use drugs."
As in nicotine addiction, vaccines are also in development. Celtic has in development a cocaine vaccine called TA-CD that consists of a cocaine derivative conjugated to a cholera-toxin protein. The company reported preliminary results this summer from two Phase II studies supported in part by NIDA. After the body develops antibodies, the rate at which cocaine can pass into the brain is blunted as long as the antibodies are present.
Studies performed at Columbia University nicely showed a reduction in cocaine's binding to dopamine transponders, O'Connor says. "If you get a reduction greater than about 45%, you actually blunt the euphoric effect." In clinical trials, patients with high antibody levels and reports of strongly diminished pleasure actually reduced their cocaine use, rather than trying to increase it to overcome the vaccine.
Whereas people addicted to nicotine may be able to remain abstinent after 12 weeks of treatment, the therapeutic window may be two to three years or longer for cocaine.
"We are discussing with NIDA-and planning to with FDA-the whole issue of what is a successful treatment for a patient addicted to cocaine," O'Connor says. "Obviously, the optimum goal would be that everyone would quit, but that may not be attainable, and what may be of real interest is that patients reduce their use of cocaine and become more productive members of society." Celtic anticipates having TA-CD in Phase III trials by late 2007.
"There are 300,000 to 400,000 people actively seeking help with their cocaine addiction in the U.S., but that probably only scratches the surface of whom you could access with an effective outpatient therapy," Celtic's Earl says. Estimates place the number closer to 10 million together in the U.S. and Western Europe where, he says, it is a rapidly growing problem and high on government and law enforcement agendas. "Our expectation is that when an effective product becomes available the uptake will be pretty rapid," Earl says.
Celtic has arrangements for manufacturing the vaccine and envisions finding a larger company to commercialize it. "At the appropriate time, we will auction our programs to an appropriate universe of big pharma companies positioned to make the best of them in the marketplace," says Stephen Evans-Freke, Celtic's managing general partner. He expects interest will be high, since the "major pharmaceutical companies have only very recently woken up to the scale of the medical need and therefore the commercial opportunity in treating drug addiction."
Other medications being tested for cocaine and for methamphetamine addictions include selegiline, used to treat Parkinson's disease; baclofen, used for muscle spasms; and ondansetron, which prevents nausea during chemotherapy. Methamphetamine has an even greater effect on dopaminergic systems than cocaine, and there are reportedly an estimated 350,000 heavy users in the U.S. alone. The smoking-cessation medication bupropion has recently been found to reduce drug use and craving in low-to-moderate methamphetamine users, or those who use the drug fewer than 18 days per month, Vocci says.
InterveXion Therapeutics in Little Rock, Ark., has received a $3 million grant from NIDA that is helping the firm prepare for clinical testing of monoclonal antibody (mAb) treatments. "We expect to meet with FDA just after the first of the year and hopefully start clinical trials as soon as next June," says President and CEO R. Barry Holtz. The company's first candidate for testing, InterveXin-PCP, targets phencyclidine (PCP) abuse and is to be followed soon after by InterveXin-METH for treating methamphetamine abuse.
Initially, Holtz explains, the company will investigate the treatment of acute cases using passive or nonimmunogenic mAbs to bind with high affinity to, and thereby neutralize, the drug of abuse. The technology came out of the laboratory of S. Michael Owens, professor of pharmacology and toxicology at the University of Arkansas for Medical Sciences and director of the UAMS Center for Alcohol & Drug Abuse. He also serves as InterveXion's chief scientific officer.
"It's important to detoxify patients proactively in the emergency room," Holtz says, "because, for example, the problem with methamphetamine is that it binds permanently to receptors in the brain and destroys them. So there is no recovery." Long term, methamphetamine use alters activity in the dopamine systems associated with motor control and verbal learning, as well as affecting areas of the brain connected to emotion and memory.
After several years of preclinical work, the company is producing the antibodies in an alfalfa-based system with the help of Medicago in Quebec. "In the long run, this should reduce costs quite a bit," Holtz explains, especially in methamphetamine cases where patients often have very high levels of the drug in their bodies and large amounts of antibody will be needed. Because of the long half-life of the mAbs, the therapy will also be used to help recovering addicts overcome their dependence and to prevent or reduce adverse effects in chronic users.
Meanwhile, DAS has advanced anti-cocaine and anti-methamphetamine antibodies as far as preclinical development. It has put these products on hold, however, as it works on other products. One of these is DAS-431, a dopamine D1 receptor agonist licensed from Abbott Laboratories in 2000. Abbott tested the compound in Phase IIa studies for cocaine addiction and saw positive results, according to DAS, which expects to begin Phase IIb studies in 2007.
Yaupon Therapeutics, meanwhile, has funding from NIDA and anticipates starting Phase II studies of the dopamine-modulating agent lobeline for treating methamphetamine addiction in early 2007. Preclinical studies have found lobeline to be effective in animal models and that it also protects dopamine-producing neurons. Like Yaupon's other drug candidates, lobeline is a plant alkaloid; the compound comes from the Indian tobacco plant and has been known for centuries.
"It was defined as a nicotinic receptor agonist in most of the old literature," explains University of Kentucky professor of pharmaceutical sciences and Yaupon founder Linda Dwoskin. "From our data, however, we figured out that in the central nervous system it's actually acting as a nicotinic receptor antagonist." She notes that lobeline's use as a smoking cessation agent had been studied decades earlier without definitive results.
"We've also looked at interactions with dopaminergic systems and found that lobeline is a potent inhibitor of the vesicular monoamine transporter 2, which is the protein that stores dopamine in vesicles for release," Dwoskin adds. As such, it functions to antagonize the effects of amphetamine stimulants and prevents the amphetamine-induced release of dopamine. It does so by binding noncompetitively at an allosteric site, and because of this mechanism, its effect can't be overridden by increased intake of the drug of abuse.
Phase I work was carried out through a clinical trials agreement with NIDA. "They have helped us tremendously in getting this compound into the clinic," Crooks says. "It's a partnership that has really provided a lot of basic support that normally you wouldn't expect to have when commercializing a product on your own." Crooks and Dwoskin's work has continued in the synthesis and development of lobeline analogs to both test the target mechanism and find more selective and novel inhibitors.
"The mechanisms of drug abuse and treatment are complex, and I don't know that we are going to be able to find any one medication that works," Vocci says. "Most of the time in CNS pharmacology, it seems like the 'dirty' drugs with multiple mechanisms work best." Then, once effective pharmacotherapies are found, the task is to reduce side effects. "For example, newer selective serotonin reuptake inhibitor antidepressants don't work any better than the old tricyclics, but they do have fewer risks," he adds. And, in treating drug abuse, as for other disorders, combinations of medications may play a role.
The market for narcotic addiction therapies is about $440 million and is not expected to grow between now and 2012, on the basis of current therapeutics, reports Spectra Intelligence. The entrance of any one new medication, especially one that creates a new market sector around cocaine dependency, could be a significant boost. If approved, for example, products with the potential of $300 million to $400 million in annual sales include TA-CD and long-acting buprenorphine.
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