Few new drugs are in clinical development for the treatment of Bipolar disorder. Most agents in clinical trials for this disorder (e.g., Bristol-Myers Squibb’s aripiprazole, Novartis’s oxcarbazepine, AstraZeneca’s quetiapine, Janssen’s risperidone, Ortho-McNeil’s topiramate, Pfizer’s ziprasidone) are already available in the major markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan) for the treatment of other psychiatric and neurological conditions and are readily used off-label for Bipolar disorder. Thus, they are discussed in the “Current Therapies” section.
Agents discussed in detail in the following sections, except pramipexole, are not available in any of the major markets. Although pramipexole is already on the market to treat Parkinson’s disease, this drug is covered as an emerging therapy because few physicians are aware of the drug’s potential to treat Bipolar disorder. Table 5 summarizes the drug therapies in development that will likely be used on- or off-label for Bipolar disorder.
Several other drugs are in early development for Bipolar disorder. Johnson & Johnson is actively recruiting Bipolar disorder patients to participate in efficacy and safety trials evaluating the use of R-209130 to treat Bipolar disorder depression; however, there are no publicly available data concerning these trials. Laxdale and Amarin have agents in development for Bipolar disorder: Amarin’s Lax-101 (Lyxia) and Laxdale’s LX-103/Lax-201 franchise. Information regarding Lax-101 in Bipolar disorder studies is limited; Laxdale’s LX-103 is only in preclinical trials for Bipolar disorder; and Lax-201 appears to be in development for major depressive disorder (in women) only.
Anticonvulsants in development for Bipolar disorder are D-Pharm’s DP-VPA, Novartis’s LIC-477 (licarbazepine), NPS Pharmaceuticals’ isovaleramide (NPS-1776), Shire Pharmaceuticals’ SPD-417, and Teva Pharmaceuticals/Acorda Therapeutic’s valrocemide (TV-1901, a derivative of valproic acid).
TABLE . Emerging Therapies in Development for Bipolar Disorder
|Compound||Development Phase||Marketing Company|
|United States||PR for indications other than Bipolar disorder||Pfizer|
|Europe||PR for indications other than Bipolar disorder||Pfizer|
|United States||PR||Shire Pharmaceuticals|
|United States||Ill for indications other than Bipolar disorder||Solvay/Wyeth|
|Europe||III for indications other than Bipolar disorder||Solvay/Wyeth|
|United States||R for indications other than Bipolar disorder||Eli Lilly|
|Europe||III for indications other than Bipolar disorder||Eli Lilly/Boehringer Ingelheim|
|Japan||III for indications other than Bipolar disorder||Eli Lilly/Shionogi|
|United States||II/III||Pfizer/Boehringer Ingelheim|
PR = Preregistered;
R = Registered.
Note: Development phase is based on databases such as R&D Focus, R&D Insight, Pharmaprojects, and the Investigational Drugs Database (IDdb3); periodicals such as Scrip, the FDC’s Pink Sheet, and Marketletter; company reports and press releases; and industry contacts.
Although not in development for Bipolar disorder, Pfizer’s pregabalin will enjoy a significant share of off-label use in Bipolar disorder because of its favorable side-effect profile.
Limited information is available concerning the agents in development. DP-VPA is in Phase I trials in Israel. LIC-477 was expected to enter Phase III trials in Europe in 2004, and although development for migraine and epilepsy continues, Bipolar disorder trials have stalled. Similarly, Bipolar disorder trials with isovalermide have stalled, while trials for migraine and epilepsy continue. Although Teva Pharmaceuticals and Acorda Therapeutics have entered into an agreement to codevelop and copro-mote valrocemide for Bipolar disorder, no data concerning clinical development for Bipolar disorder are publicly available. This section highlights pregabalin and SPD-417.
Mechanism Of Action
First- and second-generation anticonvulsants exert their effects via one of several principal mechanisms. The two most common are (1) inhibition of repetitive, high-frequency neuronal firing via blockade of voltage-dependent Na+ channels and (2) potentiation of postsynaptic inhibition mediated by neurotransmitters such as gamma-aminobutyric acid (gamma-aminobutyric acid). Researchers believe that several anticonvulsants function via similar mechanisms, even though they show remarkably different patterns of efficacy across individual patients. Such inconsistencies between scientific theory and clinical practice suggest these agents may act at one or more unknown targets in the central nervous system.
Pfizer’s pregabalin is a single-isomer gamma-aminobutyric acid agonist. This analogue of gamma-aminobutyric acid, a follow-up to Pfizer’s gamma-aminobutyric acid agonist gabapentin, is in clinical studies for epilepsy, neuropathic pain, generalized anxiety disorder, fibromyalgia, and social anxiety disorder (SAD). In 2003, Pfizer submitted a new drug application (NDA) to the FDA seeking approval for pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy and herpes zoster; generalized anxiety disorder; and as adjunctive therapy for partial seizures in patients with epilepsy. In 2004, the Committee for Proprietary Medicinal Products adopted a positive opinion recommending marketing authorization of pregabalin in the European Union (EU) for the treatment of neuropathic pain and for use as adjunctive therapy in epilepsy. There are no known plans for Pfizer to file for approval for the treatment of Bipolar disorder, but the agent will likely be used off-label to treat Bipolar disorder.
Pregabalin is believed to have a biochemical function similar to that of gabapentin, although the latter’s precise mechanism of action is not known. Both agents are structural analogues of the inhibitory neurotransmitter gamma-aminobutyric acid and, as such, probably enhance the inhibition of neuronal depolarization by some influence on the neurotransmitter. However, gabapentin is not metabolically converted to gamma-aminobutyric acid or a gamma-aminobutyric acid agonist and does not inhibit gamma-aminobutyric acid uptake or degradation. Likewise, research has not shown that pregabalin interacts with neurotransmitter receptors or has any direct action on sodium and calcium channels. Gabapentin and pregabalin may also modulate the excitatory effects of glutamate, based on the observation that both agents enhance the activity of glutamic acid decarboxylase (an enzyme involved in the degradation of glutamate).
No studies have been published regarding the efficacy of pregabalin for the treatment of Bipolar disorder. Two open-label trials have shown gabapentin to be efficacious in the treatment of Bipolar disorder, although a Pfizer-sponsored double-blind trial showed gabapentin to be no more efficacious than placebo. Despite these data, gabapentin may have a role as an adjunctive therapy, particularly in patients with comorbid anxiety disorder or substance abuse. Pregabalin will also likely play an adjunctive therapy role in the treatment of Bipolar disorder.
Researchers have found pregabalin to have virtually no hepatic elimination; approximately 99% of the drug is excreted renally in its unchanged form. This feature is similar to gabapentin, which, unlike lithium, does not require monitoring of its plasma concentrations. Pregabalin also has good oral bioavailability and an elimination half-life of six hours, a quality that will allow less frequent dosing. To date, side effects related to pregabalin have been mild and central nervous system -related.
As mentioned previously, gabapentin is considered less effective than other mood stabilizers, yet it offers a significant advantage in its enhanced tolerability and reduced risk of drug interactions compared with other agents. If pregabalin can match gabapentin’s safety and side-effect profile and offer improved efficacy and more convenient dosing, the drug could truly distinguish itself in the Bipolar disorder market.
In early 2004, Shire Pharmaceuticals filed an NDA with the FDA for SPD-417 (Bipotrol), a formulation of carbamazepine, for the treatment of Bipolar disorder mania. Other than dosing and pill size, there are few differences between SPD-417 and the already marketed extended-release carbamazepine (Shire’s Carbatrol). However, SPD-417 is in development specifically for the treatment of Bipolar disorder and will be marketed, at launch, for the treatment of Bipolar disorder; as a result, this drug may gain a significant share in the Bipolar disorder market.
SPD-417’s mechanism of action is similar to carbamazepine’s. Carbamazepine blocks voltage-sensitive sodium channels and acts on potassium channels to increase potassium conductance. It also affects a number of neurotransmitter systems implicated in the pathophysiology of mood disorders. Specifically, carbamazepine alters neurotransmission mediated by adenosine, dopamine, norepinephrine, serotonin, acetylcholine, gamma-aminobutyric acid, glutamate, substance P, and aspartate.
A multicenter, randomized, double-blind trial (n = 204) compared SPD-417 (400-1,600 mg/day) with placebo in patients experiencing manic or mixed episodes and diagnosed with DSM-IV Bipolar disorder. The primary measure of efficacy was change from baseline to last observation in the YMRS total score. Secondary measures of efficacy were responder rate (percentage of patients with at least a 50% reduction on YMRS scores from baseline to last observation) and change from baseline to last observation in CGI and HAM-D scores. At the end of the three-week trial, patients receiving SPD-417 had greater reductions in YMRS total scores than did patients receiving placebo. SPD-417 also yielded greater improvement in CGI scores when compared with placebo; however, there were no differences in HAM-D scores between treatment groups. In the SDP-417-treated group, patients were more likely to experience adverse events such as dizziness, nausea, somnolence, vomiting, dyspepsia, dry mouth, pruritis, and speech disorder.
Antipsychotics are increasingly becoming part of the Bipolar disorder treatment regimen. Although many antipsychotics are in development (Dainippon Pharmaceutical’s blonanserin, Sumitomo Pharmaceuticals’ SM-13496, Johnson & Johnson’s paliperidone, Vanda Pharmaceutical’s iloperidone, Lundbeck’s Lu-31-130, and Merck’s ACR-16), Organon’s asenapine and Solvay’s bifeprunox hold the most promise for the treatment of Bipolar disorder.
Mechanism Of Action
Atypical antipsychotics are serotonin-dopamine antagonists — that is, they act at both dopamine and serotonin receptors. One notable characteristic shared by all atypical antipsychotics is that they have much reduced or no motor side effects, such as extrapyramidal symptoms, compared with typical antipsychotics. Theoretically, this effect could be the result of blockade of both 5-HT2A receptors and D2 receptors. This serotonin blockage prevents dopamine from being released in the mesolimbic dopamine pathway; hyperactivity of dopamine in this area is associated with extrapyramidal symptoms.
In 2003, Organon and Pfizer entered into an agreement for the exclusive worldwide development and commercialization of asenapine (ORG-5222) as a potential treatment for schizophrenia and Bipolar disorder. Under the terms of the agreement, Pfizer and Organon will collaborate on the clinical development and manufacturing of asenapine and copromote the product in the United States, Europe, Japan, and other markets. Asenapine is in Phase III in the United States and Europe for schizophrenia and Bipolar disorder.
Asenapine has high affinity for 5-HT2A, 5-HT2C, Dl, D2, HI, and alpha-1-adrenergic receptors and moderate affinity for alpha-2-adrenergic, 5-HT1A, and 5-HT1B receptors. Unlike clozapine (and olanzapine), it has negligible affinity for D4 and muscarinic receptors.
Evidence from the schizophrenia trials and of relevance to Bipolar disorder treatment is asenapine’s side-effect profile. At the fall 2003 financial analyst meeting, Organon presented consolidated data from three Phase II studies that suggested asenapine significantly reduces the positive and negative symptoms of schizophrenia. Consolidated data from these three studies also suggest that asenapine’s tolerability is similar to that of risperidone. The incidence of extrapyramidal symptoms was similar at the study end among asenapine-, risperidone-, and placebo-treated patients. The mean increase in body weight from baseline at six weeks was approximately 0.5 kg (1.1 lb) for asenapine, 1.9 kg (4.18 lb) for risperidone, and 0.3 kg (0.66 lb) for placebo. The fact that the weight gain associated with asenapine was similar to that of placebo and lower than that of risperidone is impressive; unfortunately, the statistical significance of these data was not presented. The percentage of patients with QTc prolongation ( > 450m/sec) was approximately 9% for asenapine, 17% for risperidone, and 10% for placebo. Organon also claims that asenapine did not significantly increase glucose and prolactin levels. No further details were released.
Solvay and Lundbeck are jointly developing and marketing bifeprunox (DU-127090) for schizophrenia. Lundbeck has marketing rights in Europe, while Solvay, along with Wyeth, will be codeveloping and marketing bifeprunox in the United States and Japan. Bifeprunox is in Phase I trials in Europe and the United States for Parkinson’s disease and Phase III trials for schizophrenia.
Bifeprunox acts as a dopamine D2 and 5-HT1A partial agonist. Its affinity for D2 receptors is comparable to that of haloperidol and risperidone and superior to that of clozapine and olanzapine. The drug also has a high affinity for D3 and D4 receptors. Like aripiprazole, bifeprunox has a partial agonist effect at 5-HT1A receptors and no affinity for muscarinic or noradrenergic alpha-2 receptors; unlike aripiprazole, it has virtually no affinity for 5-HT2A and 5-HT2C, noradrenergic alpha-1, or histaminergic receptors.
The developer’s announcements of clinical data suggest that bifeprunox has good efficacy with limited side effects. According to a Solvay press release dated June 3, 2004, bifeprunox has shown efficacy in patients with schizophrenia and does not cause weight gain or increase prolactin. Moreover, the agent has a favorable lipid profile, does not cause QTC prolongation, extrapyramidal symptoms are comparable to placebo, and there is no evidence of glucose dysregulation.
Agents in development with potential for treating Bipolar disorder depression are GlaxoSmithKline’s GW-353162 and GW-273293, Eli Lilly’s duloxetine, Repligen’s RG-2133, Wyeth’s desvenlafaxine, and Pfizer/Boehringer Ingelheim’s pramipexole (Mirapex). Because pramipexole is not an antidepressant, this agent is discussed in the section “Dopamine Agonists.”
Repligen’s RG-2133 is a pro-drug of uridine. This agent is not discussed in detail because publicly available trial data are limited to a company press release describing data from a Phase I (n = 19), open-label trial evaluating RG-2133’s efficacy in treating major depression and Bipolar disorder. Results from this trial found the drug to be safe and unlikely to induce mania.
GlaxoSmithKline has an array of agents used on- and off-label for Bipolar disorder depression: bupropion, lamotrigine, and lithium. Because of the successful sales of these agents in the Bipolar disorder market, the company may launch another agent that will be used on- or off-label for Bipolar disorder depression, but which agent is unclear. GW-320659 (manifaxine), a norepinephrine/dopamine reuptake inhibitor; GW-273293, a sodium-channel blocker; and GW-353162, a norepinephrine/dopamine reuptake inhibitor, have all been in development for Bipolar disorder. Development of GW-320659 and GW-353162 for Bipolar disorder appears to have been discontinued. GW-273293 remains in preclinical development for Bipolar disorder. GW-353162 is still in development (Phase II) for major depression and appears to have properties similar to those of bupropion, so it will likely be used heavily off-label for the treatment of Bipolar disorder depression.
Mechanism Of Action
Selective serotonin reuptake inhibitors (Selective serotonin reuptake inhibitors), the agents in the antidepressant class most often prescribed, act by selectively inhibiting the presynaptic reuptake of serotonin (5-HT) while exerting little effect on norepinephrine or dopamine uptake. After a serotonergic neuron fires, 5-HT is normally transported back into the presynaptic neuron for repackaging and subsequent rerelease. Selective serotonin reuptake inhibitors block the reuptake mechanism and consequently increase the level of 5-HT in the synaptic space surrounding the neuron. The excess 5-HT activates all 5-HT receptors, both pre- and postsynaptically. Selective serotonin reuptake inhibitors’ activation of the anxiogenic postsynaptic 5-HT2A receptors may explain the initial increase in anxiety that Selective serotonin reuptake inhibitors cause in some patients, as well as the sexual side effects associated with this class of drugs. Citalopram and escitalopram show the greatest selectivity for serotonin over norepinephrine, followed by sertraline, paroxetine, fluvoxamine, and fluoxetine, in that order.
Like the Selective serotonin reuptake inhibitors, the serotonin-norepinephrine reuptake inhibitors inhibit the serotonin reuptake transporter, and, like the older tricyclic antidepressants, they inhibit the norepinephrine reuptake transporter. However, the serotonin-norepinephrine reuptake inhibitors are considered an improvement over the tricyclic antidepressants because they do not affect the histamine, acetylcholine, and adrenergic receptors and therefore do not cause the severe weight gain, dry mouth, and hypotension associated with tricyclic antidepressants. Because serotonin-norepinephrine reuptake inhibitors act on both serotonergic and noradrenergic systems, they are also called noradrenergic and specific serotonergic antidepressants. Venlafaxine is more potent in inhibiting serotonin than in inhibiting norepinephrine. Conversely, milnacipran is twice as potent in inhibiting norepinephrine reuptake as it is in inhibiting serotonin reuptake; hence, the drug is sometimes referred to as a norepinephrine/serotonin reuptake inhibitor.
Tricyclic antidepressants block the synaptic reuptake of serotonin and norepinephrine to varying degrees. They have little effect on dopamine but they are potent blockers of muscarinic, histaminergic HI, and alpha-1-adrenergic receptors.
Second-generation antidepressants, which were launched in the 1980s, resulted from an effort to improve the pharmacological profiles of the first-generation antidepressants, the tricyclic antidepressants. Tricyclic antidepressants are effective in treating most forms of depression, but their mechanism of action — blockage of histaminergic, muscarinic, and alpha-1-adrenergic receptors — causes a wide array of side effects. Second-generation antidepressants are more receptor-specific — that is, they have less effect at receptors responsible for many of the side effects associated with tricyclic antidepressants. Several different mechanisms of action characterize second-generation antidepressants: some block norepinephrine uptake, some block dopamine uptake, and some block serotonin reuptake.
Eli Lilly is developing duloxetine for the treatment of major depression and urinary incontinence. In September 2003, Lilly received an approvable letter from the FDA for the treatment of stress urinary incontinence, and in October 2003, the company received a second approvable letter (the first letter was received in September 2002) for the treatment of depression. The FDA requested additional studies from Lilly before final approval of duloxetine to treat stress urinary incontinence, but it did not request additional studies to treat depression. In June 2004, however, the FDA extended the action date for issuing final approval of duloxetine to allow itself more time to go through recently submitted analyses of existing trial data. Approval of duloxetine was expected to be delayed until Lilly’s plants in Indianapolis passed inspection by the FDA, but in late 2003, the agency informed Lilly that the company’s injectable and dry products facilities in Indianapolis had reached a level of compliance that allows preapproval site inspections for products under review. The FDA gave duloxetine final approval in August 2004.
In Europe, where the drug will be comarketed with Boehringer Ingelheim, duloxetine is registered for the treatment of depression; it was approved for stress urinary incontinence in August 2004. In Japan, where the drug is being jointly developed with Shionogi, duloxetine is in Phase III studies for depression.
Like all serotonin-norepinephrine reuptake inhibitors, duloxetine acts on both serotonergic and noradrenergic systems; studies by Eli Lilly demonstrate that duloxetine inhibits serotonin and norepinephrine equally.
Duloxetine appears to be equal to fluoxetine in efficacy and tolerability. In one eight-week, double-blind, multicenter study, patients (n = 173) with major depression (DSM-IV criteria) were given 40-120 mg per day of duloxetine, 20 mg per day of fluoxetine, or placebo. The primary measure of efficacy was a reduction in the 17-item HAM-D for depression. At end point, duloxetine was significantly better than placebo and fluoxetine. Furthermore, duloxetine-treated patients showed greater, statistically significant improvement on the 17-item HAM-D anxiety subscale relative to fluoxetine-treated patients. In this same trial, duloxetine’s side effects were similar to fluoxetine’s: duloxetine -and fluoxetine-treated patients reported similar frequency of nausea, dry mouth, insomnia, and sexual dysfunction.
Duloxetine will not offer any advantages over currently available drugs in the area of sexual dysfunction. Because of duloxetine’s mechanism of action, which is similar to that of venlafaxine, the compound is likely to cause sexual dysfunction and to share venlafaxine’s delayed onset of action. In a long-term study that measured improvement of sexual dysfunction in patients receiving duloxetine or paroxetine, rates of acute sexual dysfunction were similar in paroxetine- and duloxetine-treated patients, and both groups had rates significantly higher than patients treated with placebo, as measured by the Arizona Sexual Experience questionnaire (ASEX). However, responses to certain questions on the ASEX showed that 70.9% of patients receiving duloxetine experienced improvement over time in sexual function while only 57.6% of patients taking paroxetine experienced improvement.