They acknowledge that varenicline is associated with higher smoking cessation rates and represents a new class of drug that offers clinicians a pharmacological alternative with a mode of action different from that of NRTs or bupropion. But they also note that "clearly, quitting smoking, even with pharmacological and behavioral assistance, is extremely difficult. Patients currently cannot and probably never will simply be able to 'take a pill' that will make them stop smoking."
This isn't stopping other drug developers from trying. Sanofi-Aventis' rimonabant, which blocks the cannabinoid CB1 receptor, is considered a promising candidate. Although the company recently received positive responses from regulators for the drug, trade-named Acomplia, as a weight management treatment, neither U.S. nor European regulators have given it the go-ahead for smoking cessation. It is also being investigated as a treatment for alcohol dependence.
In addition to other cannabinoid CB1 receptor antagonists, compounds under study include the anticonvulsant topiramate, opioid antagonist naltrexone, and antidepressant fluoxetine, as well as a nicotinic partial agonist, dianicline, by Sanofi-Aventis and a glycine antagonist for preventing relapse by GSK. Addex Pharmaceuticals has been testing a dopamine D1 receptor antagonist, but its current clinical status is unclear.
San Diego-based Somaxon Pharmaceuticals has completed a Phase II clinical study of oral nalmefene, an opioid receptor antagonist already used intravenously for reversing the effects of opioids after anesthesia or overdose. It has licensed the compound from Biotie Therapies in Finland for smoking cessation and impulse control disorders, such as pathological gambling.
Yaupon Therapeutics, created in 2002 by two University of Kentucky professors and pharmaceutical industry executive Robert Alonso, is studying nornicotine, a tobacco alkaloid structurally similar to nicotine except it lacks one methyl group. "Nornicotine is very different from nicotine in terms of its pharmacology and pharmacokinetics," says Peter Crooks, Yaupon's chief scientific officer and pharmaceutical sciences professor at the University of Kentucky. Although it would work like an NRT, the drug acts on receptor subtypes different from those that respond to nicotine to partially stimulate dopamine release and has a longer half-life and better side-effect profile.
"We've determined that one particular optical isomer of nornicotine appears to be most effective as a potential smoking cessation agent," Crooks adds. "And we've managed over the past year to come up with a very nice chemical method to inexpensively produce the desired pure enantiomer." The company is conducting toxicity tests and has received a National Institutes of Health grant that should allow it to begin Phase I clinical testing early next year.
Tackling the problem differently are a few companies developing nicotine vaccines. Nicotine is a small molecule that easily passes to the brain undetected by the immune system. The vaccines typically combine a nicotine derivative and protein carrier to stimulate the immune system to produce nicotine antibodies. The antibodies soak up nicotine in the bloodstream, prevent it from reaching receptors in the brain, and thereby block its effect. While this eliminates the pleasurable reward, as well as nicotine's addictive reinforcing effects, a vaccine isn't expected to ease withdrawal.
Nabi Biopharmaceuticals has been working with NIDA to develop and test NicVax, which consists of a nicotine-like molecule conjugated to recombinant exotoxin protein A from Pseudomonas aeruginosa. Preclinical studies have shown that the blocking effect works, while Phase I studies found the vaccine to be highly immunogenic and safe. The company has completed two Phase II trials on different formulations and began a Phase IIb, placebo-controlled study at nine sites in May. The study includes behavioral support and is designed to demonstrate proof-of-concept and determine optimal doses.
Even in Phase II trials not designed to show efficacy, smokers taking the highest dose of NicVax achieved a 33-40% quit rate versus 9% for placebo with mild to moderate side effects and none of the typical withdrawal symptoms, explains Thomas E. Rathjen, Nabi's vice president for investor relations. Nabi attributes the latter effect to a very small amount of nicotine still getting to the brain and moderating withdrawal while not eliciting a pleasurable response.
Unlike medications that a patient can stop taking, a vaccine "takes the control of the therapy away from the patient," Rathjen points out. After four or five shots over about three months, sufficient antibody levels develop and persist for 12 or more months. The 12-month mark seems to be critical, he adds, because if smokers get that far smoke-free, they have a 70-75% chance of remaining so. And although patients may smoke, the antibodies can't be overcome with any reasonable amount of relapse smoking. Boosters are also a possibility for continued treatment.
If all goes well, Nabi anticipates it could start Phase III studies in the second half of 2007. The company has been discussing appropriate end points for late-stage trials with regulators, Rathjen says, and already manufactures the vaccine at commercial scale in its Boca Raton, Fla., facility. Plans are to look for a pharmaceutical partner to market the vaccine through primary care physicians. In March, FDA granted NicVax fast-track approval status, designed to facilitate the development and expedite review of products for unmet medical needs.
Similarly, Switzerland-based Cytos Biotechnology is developing Cyt002-NicQb, consisting of nicotine attached to a viruslike particle called Qb. The company says its vaccine is safe, well-tolerated, and highly immunogenic. In a Phase II dose-ranging study, the company saw a 42% long-term abstinence rate among a subgroup of patients with high antibody levels compared with 21% for the placebo group. Since lower antibody levels weren't effective, Cytos has been optimizing the formulation and dosage to achieve high levels in as many patients as possible in future studies.
Meanwhile, Celtic Pharmaceutical Holdings, an investment firm that acquired Xenova in September 2005, launched a Phase II placebo-controlled, multicenter trial of Xenova's nicotine vaccine, TA-Nic, in the U.K. in May and will begin a Phase IIa/IIb study in the U.S. this fall, says Patrick C. O'Connor, Celtic's managing director of clinical development. TA-Nic uses a nicotine derivative coupled to a recombinant nontoxic B subunit of cholera toxin. It has been shown to be immunogenic and safe in Phase I trials and gave indications of increased quit rates.
"The real downfall for a lot of people is not actually stopping, even though they go through an acute withdrawal phase; it's when they subsequently take the first cigarette and it feels so good," O'Connor says. The idea is that by raising antibody levels slowly, people will get less pleasure out of smoking and be able to quit. "But then, if they do relapse, they won't get that huge reinforcement from the first cigarette, because the antibodies would mop up the nicotine and not allow it to get into the brain," he says.
"There is a major gap in the market for something more effective, and the scale of the problems related to smoking is so huge that anything remotely useful in helping people to quit and stay quit is clearly going to find a place," says Michael Earl, Celtic's managing director for commercialization. "But I don't think there will be a magic bullet that solves everybody's problems." He anticipates further development will explore how vaccines, counseling, and other pharmacotherapies work alone or together for patient management.
DRUG ADDICTION.
New doors may be opening as well for pharmacotherapies to treat addictions to other drugs, such as heroin, cocaine, and methamphetamine. For more than 30 years, methadone maintenance therapy has been the leading treatment method. Methadone is a long-acting, synthetic opiate administered orally to prevent withdrawal, block the effects of illicit opioid use, and diminish craving. Patients stabilized on this sustained-agonist therapy can function normally. Mallinckrodt Pharmaceutical is the leading bulk producer of the generic drug.
"There are probably about 250,000 people on methadone," NIDA's Vocci says. "But there's an estimated 1 million heroin addicts in the U.S. and anywhere between 1.5 million and 4 million people who have a problem with prescription opiates." The system, he believes, is constrained by limited public funding and access to treatment clinics. Europe, meanwhile, has an estimated 1.1 million intravenous drug users, 70% of whom are said to be untreated.
For about 10 years starting in 1993, methadone wasn't alone; levo-alpha-acetylmethadol was available, but then Roxane Laboratories ceased making it following reports of severe adverse events. Naltrexone, a synthetic opiate antagonist originally marketed by DuPont as Trexan in 1984 but is now off-patent, can be used after a patient undergoes opiate detoxification. It blocks the effects of self-administered opiates, so it can prevent relapse. It also is used to reverse acute opiate overdose. Other drugs used for detoxification and withdrawal are clonidine and lofexidine.
Without effective counseling or monitoring, patient compliance with addiction therapies can be a problem. To improve compliance, several companies are creating new formulations. DrugAbuse Sciences (DAS), based in Paris, has a sustained-release form of naltrexone for once-monthly injection. The company has it in Phase II clinical trials for opioid dependence and in Phase III for alcohol dependence. DAS and Titan Pharmaceuticals both are developing sustained-release buprenorphine. Titan expects to begin a Phase II clinical trial of its six-month version soon, while DAS anticipates starting a Phase I trial by 2007 for its once-per-month form.
Approved in the U.S. in 2002, buprenorphine was the first new treatment to arrive in more than a decade. Like methadone, it is a substitution therapy with the potential for abuse, although it has weaker opiate effects. It blocks cravings and can prevent withdrawal. In different regional markets, Schering-Plough and Reckitt Benckiser sell an oral form as Subutex and an oral combination of buprenorphine and naloxone as Suboxone.
Opioids attach to opioid receptors in the brain, spinal cord, and gastrointestinal tract and block the transmission of pain and cause neurotransmitter release in the brain's reward center. Buprenorphine acts as a partial agonist at the µ-opioid receptor and an antagonist at the -opioid receptor subtypes. The structufrally similar compounds naloxone, nalmefene, and naltrexone have antagonistic effects at various µ-, -, and -opioid receptors (Chemistry Today 2006, 24, 54) and thereby block the neurochemical reward and reinforcement system.
The combination of drugs in Suboxone is designed to minimize misuse. Naloxone is ineffective when taken orally, but it attenuates buprenorphine's agonist effect when Suboxone is abused by injection. According to an article in the July 22 issue of the Lancet, Subutex smuggled in from Europe-it was first approved in France in 1996-has become a major drug of abuse in Russia. In late July, European regulators recommended marketing approval for Suboxone.
In Europe, the prescription of opioids by doctors for treating addictions is less restricted than it is in the U.S. When the U.S. Congress passed the Drug Addiction Treatment Act (DATA) in 2000, it brought about a major change for patients in that treatment could take place in the privacy of a doctor's office rather than a rehabilitation clinic. The act allows certified physicians to prescribe certain controlled substances approved by FDA for the treatment of addictions.
Subutex and Suboxone are currently the only drugs qualified under DATA. A recent study reported in the New England Journal of Medicine (2006, 355, 365) found that office-based treatment combining Suboxone and brief counseling was effective in substantially reducing drug use in about 40-50% of patients.
No drugs have been approved for cocaine addiction, despite it being a large problem, although a significant number of candidates have been and continue to be tested (Eur. J. Pharmacol. 2005, 526, 101). For several years, NIDA has aggressively pursued this area and, more recently, methamphetamine abuse, Vocci says.
In 1990, NIDA set up its Medications Development Division to address the need for such pharmacotherapies. Its approach has been to support and coordinate the testing of marketed medications, whose properties suggest they might be effective, as a rapid and less expensive route to new treatments, as well as the discovery and investigation of new compounds. About 65 existing medications have been tested and more than 3,000 compounds identified and evaluated.
Disulfiram, one of the few existing pharmacotherapies for alcohol dependence, has given the most consistent and reproducible results in cocaine studies, Vocci says. It works as an aversion therapy, because its interaction with alcohol produces undesirable physical effects. In cocaine users, disulfiram produces an unpleasant sense of hyperstimulation, likely attributable to enhanced dopamine activity. Cocaine is believed to act as a dopamine-reuptake inhibitor, and disulfiram inhibits dopamine -hydroxylase, which metabolizes dopamine.
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