ALCOHOLISM.
In contrast to the market for narcotic addiction therapies, Spectra Intelligence says the alcohol addiction medication market was just $125 million in 2005, but forecasts it to grow more than sixfold to $840 million by 2012. The small size today is despite a total potential market of 30 million or more people in the U.S., Europe, and Japan. Growth will come largely from the very recent launches of Vivitrol, developed by Alkermes and marketed by Cephalon, and of Campral, which has been gaining ground since FDA approved Forest Laboratories' version in 2004.
For about 45 years, the aversive agent disulfiram, sold by Odyssey Pharmaceuticals as Antabuse, was the only treatment. Today, some researchers consider it ineffective at best and often dangerous, as well as antiquated since it doesn't target known neurochemical mechanisms in alcohol addiction. Instead, it works by inhibiting aldehyde dehydrogenase, an enzyme that converts acetaldehyde to acetic acid, which leads to a buildup of acetaldehyde in the body. After taking disulfiram and then consuming alcohol, a person experiences nausea, flushing, headaches, and chest pains. The drug also can have more severe adverse effects, including death. Many patients simply stop taking it.
In 1994, an oral form of the opioid antagonist naltrexone, renamed ReVia, was approved by FDA for treating alcoholism; it is now sold as a generic drug under many different names. The drug's safety profile is good at lower doses, although it can cause liver failure at excessive doses and thus bears a warning on its label, which some in the field say has limited its use. It generally has been considered moderately effective in reducing drinking and cravings.
Alcohol dependence, with relapse rates of more than 75% after one year, and other addictions often require extended treatment and retreatment. Patient compliance is a serious issue with oral medications, according to David R. Gastfriend, Alkermes' vice president of medical affairs. "About 30 years ago, NIH issued a call for help to develop technologies for extended-release preparations," he says. With seed money from NIAAA and NIDA, Alkermes spent about six years developing Vivitrol, which was approved in April.
Vivitrol is naltrexone embedded in polymer microspheres for once-monthly intramuscular injection. Clinical studies have demonstrated that patients like the new formulation and can tolerate it and that its safety profile is good, he says. Results also show that Vivitrol helped decrease heavy drinking and prolong abstinence. In addition, the priming effect, which causes acute craving, is reduced. In clinical studies, patients used Vivitrol for at least six months, but in practice, a patient and physician will determine the duration of treatment.
FDA has approved Vivitrol for patients who have initiated abstinence, a group in which the drug has been found to work best and one consisting of individuals who essentially have chosen to address their dependence. It also is to be used in combination with psychosocial treatment. Although being abstinent or even entering treatment may be a hurdle, Gastfriend says, "the real message is that this is a potentially life-threatening disease, it's a medical condition, and it has to be taken seriously, and this is a serious medicine.
"We know that out of the 8 million or 9 million people in America with alcohol dependence, maybe 100,000 get medication, which is essentially nobody," he says, although about 2 million per year seek treatment. "Since 1935, at the outset of the Alcoholics Anonymous movement, we've had one major approach to treating alcohol dependence, and that is talking. And we have taken that, it seems, about as far as we are going to get with it," he says. He believes medications will be a crucial part of future treatment.
Although there are many different, rigorous approaches to behavioral or psychosocial therapy that all seem to do equally well, he says, "none of them stabilizes the chemical or neurological origins of this disease in the brain" as naltrexone is believed to do. "It's only through the science of neurotransmitter receptors that we are able to add another conceptual approach to stabilize the circuitry of reward systems in the limbic areas of the brain and address cognitive learning processes in the cortex for recovery."
Most physicians have approached addiction by prescribing abstinence, since they didn't favor "substituting dependence on one drug for another," Cephalon's Baldino remarks. "There's been a dearth of products and very low success rate for the abstinence route, and with a drug like Vivitrol, you really can improve today's standard of care." Cephalon intends to introduce Vivitrol first through addiction specialists to gain experience with them, then expand it to others, such as psychiatrists focusing on addiction, and eventually to primary care physicians.
"Primary care physicians will be an important audience because patients may be more likely to discuss their problems with them," he says. A recent clinical study, "Combining Medications and Behavioral Interventions for Alcoholism," or COMBINE, "really underscores the value of the combination of pharmacotherapy and psychosocial support," he says, and should help physicians realize that there is more they can do for patients. NIAAA recently issued guidelines supporting the combination of therapies.
Cephalon will offer a program called VIP3, or Vivitrol Information for Patients, Physicians & Providers, to integrate support services for all three groups as part of its commercialization strategy. Three years ago, it would have been extremely difficult to get doctors to consider using a pharmacotherapy, Baldino says, "but we're happy to have a new drug to launch into today's environment" that is more receptive to pharmacotherapy. In 2005, Cephalon signed a $490 million deal with Alkermes to market the drug.
"Large pharmaceutical companies historically have not gone into small emerging markets, which fortunately is good for smaller companies like us," he says. "The current alcohol dependence market is not an attractive market, and there are only a couple of players here." He believes, however, that if Vivitrol does well, it will spark the interest of other pharmaceutical companies, bring more investment in R&D, and eventually give patients more choices.
Meanwhile, Finnish biotech company Biotie Therapies is testing an oral form of nalmefene for alcohol dependence and for impulse disorders. "Opiate receptor antagonism has a solid base in treating dependence disorders," Biotie CEO Timo Veromaa says, "and nalmefene has a better bioavailability than naltrexone, is longer lasting, and does not have the liver toxicity issues." Side effects are those common to the overall class of opiate antagonists, he adds.
The company has been working for several years to show the drug's efficacy in reducing heavy drinking, rather than achieving or maintaining abstinence. "We have taken a completely new look at this and devised a clinical development program from the opposite viewpoint," Veromaa explains, since he says results for abstinence-oriented therapies have largely been extremely poor and relapse rates very high.
Unlike other therapies, Biotie's nalmefene has been designed to be used on demand. "Patients are advised to take one tablet per day as needed, when drinking is imminent-and these people know when they are going to drink," Veromaa says. "Because nalmefene takes away the craving, it leads to the ability to resist urges to drink excessively." In one large, late-stage clinical trial, nalmefene reduced heavy drinking by almost 50%.
"We have completed two Phase III clinical studies and are now going into the registration phase in Europe for alcohol dependence," Veromaa says. Approval is anticipated first in the U.K. in 2007, followed by other European countries in 2008. Biotie will manufacture the drug. It has signed on Britannia Pharmaceuticals as a marketing partner for the U.K. and Ireland and is finding others in other markets outside the U.S. Somaxon Pharmaceuticals has licensed North American rights to nalmefene but is not yet pursuing it for alcohol dependence.
Forest Laboratories' business model is to look for products in areas of unmet medical need, where the mechanisms are unique, or where there may be some distinct safety or efficacy advantage, explains Jeffrey M. Jonas, Forest executive vice president and medical officer. The company licensed Campral from Merck KGaA in Europe and has been marketing it in the U.S. since 2004. How the drug works in alcohol dependence is not well understood, but it is thought to modulate glutamatergic activity, possibly reducing glutamate levels and alcohol withdrawal symptoms.
"It's believed that alcoholics develop compensatory mechanisms in the brain because of chronic alcohol use, and when alcohol is removed, they develop cravings due to changes in the neurochemistry," Jonas says, "and somehow Campral stabilizes the neurochemistry." The drug, given as two 333-mg tablets twice daily, is to be used along with psychosocial therapy in patients who have been abstinent. Jonas says that taking a medication routinely may actually be positive for patients "for whom having a reconfirmation of treatment is important in acknowledging their illness."
Results from clinical trials suggest that after as long as a year patients that had used Campral were about two or three times more likely to achieve complete abstinence than those on placebo, Jonas explains, "and we think that's a meaningful effect." In contrast to pharmacotherapies and clinical trials targeting a reduction in drinking, Jonas says, "we have to believe that the ability to sustain abstinence is probably the gold standard for treating alcoholism."
The results of the COMBINE study, published in the May 3 issue of JAMA, have sparked a great deal of discussion. NIAAA launched the 1,400-patient multicenter study in 2001 to identify the most effective treatments for alcohol dependence. In addition to naltrexone, the study included acamprosate and a combination of the two drugs, all given along with medical management or behavioral support. Acamprosate had been widely studied and used in Europe since 1989, where the vast majority of clinical studies have shown it helps individuals maintain abstinence, before being approved on the basis of these data in the U.S.
Although treatment using naltrexone performed slightly better than placebo in the study, acamprosate alone or in combination with naltrexone, did not-much to many people's surprise (J. Am. Med. Assoc. 2006, 295, 2075). The trial has raised differing views about study design, including questions around population differences in determining efficacy and applicability to real-world settings. Maybe most important, it highlights the challenge in finding effective treatments.
"Alcoholism is a difficult illness to treat," Jonas says. "It is a very complicated mix of psychological drives and physiologic drives." This often makes it difficult for medications to show an effect, which makes treatment for this kind of disorder daunting and, in turn, makes the impact of these drugs somewhat less dramatic. Further complicating matters, patients also often have a gamut of psychosocial problems and coexisting conditions, such as depression and anxiety.
It's not unusual to find that a drug may work in some trials and not in others, and the reason why isn't always clear, says Raye Z. Litten, coleader of NIAAA's medications development team and COMBINE's government director. And all medications don't work in all patients. "We know, for example, that acamprosate and naltrexone don't work for everyone, but that doesn't mean they don't help some people," he says. The institute is still conducting an exploratory analysis of the COMBINE data to see whether they can identify who did and didn't respond.
"If you could predict the population a drug would work in, you would undoubtedly see a better effect and more consistent results," Litten says, "and be able to deliver medications in a more effective, more reliable, and safer manner." The need for personalized treatment is evident in alcohol dependence, according to NIAAA researchers whose work has helped determine that complex mechanisms underlie the disease, which likely is not a single disorder but many with common defining features.
"The disease phenotype is a product of the interaction of genes and the environment," says Markus Heilig, chief of the Laboratory of Clinical & Translational Studies at NIAAA. At one extreme, people have a genetic susceptibility, and progress is being made in identifying genetic variations. At the other, the disease is shaped by environmental factors. "What people fail to appreciate is that the major environmental factor is alcohol itself," he adds. Cycles of intoxication and withdrawal over a sufficiently long time trigger neuroadaptive changes.
Thus, in very simple terms, neurochemical imbalances that manifest as the same apparent dependence on alcohol can arise from either genetics or environment, or actually a combination of both sources. Neuroadaptive and genetically susceptible individuals, and others in between, react differently to alcohol, to factors such as stress, and to pharmacotherapies. Understanding and identifying these mechanisms and their manifestations has implications for both finding drugs and the patients in which they'll work and may even influence clinical trial design.
For example, a genetic variation found in the µ-opioid receptor enhances the pleasurable effects of alcohol, Heilig says. "And blocking that receptor would be expected to have more of an effect in people with that variation than in others." Pharmacogenetic data-namely, a predictive positive therapeutic response to naltrexone-have emerged to support this hypothesis, he adds. Similarly, a hallmark of some neuroadaptive alcoholics is a hyperglutamatergic state; acamprosate reverses the effect in alcohol-dependent animals but has no effect in those not adapted to alcohol.
"We have right now about six to seven preclinically very well-validated targets" that have fulfilled specific requirements, Heilig says. "They have to be compounds that either already have properties that are useful for clinical development or that we can hopefully optimize to that stage, and there needs to be a serious pharmaceutical company willing to support development." It can be difficult to find partners for off-patent drugs, even when the compounds hold promise or NIAAA assumes the development risk, because they offer no earning potential.
Nevertheless, interest on the part of pharmaceutical companies is increasing for a number of reasons, says Mark Egli, coleader of the NIAAA medications development team, including companies' need for new products and the size of the potential market. They also are attracted to new animal models for evaluating compounds based on a significantly improved understanding of the mechanisms of alcohol dependence and addiction in general, he says. As proof of companies' growing interest, one can look back 10 years when no major company had any large-scale clinical trials under way in this area; since then there have been at least a dozen.
NIAAA itself has more than 50 clinical trials under way for alcohol dependence and related conditions. It has been exploring existing medications, such as topiramate, gabapentin, valproate, ondansetron, baclofen, aripiprazole, memantine, and rimonabant. It also has been investigating new compounds targeting opioid, serotonin, GABA, dopamine, glutamate, cannabinoid, CRF, adenosine, and neuropeptide Y receptors. Egli has coauthored two recent reviews on the subject with Heilig (Pharmacol. Ther. 2006, 111, 855) and with Litten and others (Expert Opin. Emerging Drugs 2005, 10, 323).
Clearly, when it comes to alcohol dependence, it's not all about dopamine. "Dopamine is a very important neurotransmitter that's involved in many aspects of behavior, and it got a lot of attention because of its role in reinforcement and reward," Egli says. "It's certainly part of the equation, but because alcohol affects so many systems in the body, and because there is no one single receptor to target, finding drugs that work may be more complex than for other addictions."
"Before naltrexone and acamprosate were approved, many people were saying we'd never get a drug through FDA because there was no receptor to target," Litten says. Both drugs are now approved in about 29 countries. "Maybe it's a small step in curing alcoholism, but it's certainly a big step for researchers," he says. It demonstrates both the progress in basic science over the past 10 to 15 years and the possibility for success in development and approval. Work is expected to continue on establishing targets, validating models, and finding genetic markers.
NIAAA is taking steps to address development issues. "We are finalizing the formation of an integrated medication development program here at the institute," Willenbring says. "For a long time, we have been funding extramural research, but now we are more systematically providing a certain set of services and strategies that we hope will serve as a complement to industry." The idea is to facilitate early-stage clinical development and proof-of-concept stages and not replicate industry's capabilities in either drug discovery or large-scale efficacy and safety trials.
NIAAA also is hoping to access libraries of compounds at pharmaceutical companies. "We're in dialogue with various pharmaceutical companies about compounds they have but aren't going to pursue, or they'll come to us because they believe something might be effective," Willenbring explains. The institute then might conduct preclinical research and even initial clinical trials with the hope of having something to hand back that a company will want to develop further.
Willenbring believes there will be considerable advances in pharmacotherapy. "There are so many potential targets, which is both good and bad news," he says. "It means there are a lot of opportunities, but it also means we are unlikely to find a single medication that's going to make a really big difference because the disease is so complex." Instead, at least near term, successful treatment strategies will probably involve medications with multiple actions or multiple medications as doctors learn more about what is available, is effective, and works best for their patients.
In the past, addiction treatment has been handled largely by specialists rather than within general health care, but there aren't that many specialists, and awareness about pharmacological approaches has been limited. Marketing has also been lackluster, and thus there's been little market penetration. "One of the biggest problems we have is that the drugs are not being used because we don't have the infrastructure set up to provide treatment," Willenbring says. Although there are expectations for another six or more new addiction medications within the next 10 years, it will require change to make these treatment options available.
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