DRUG EVALUATION Bifeprunox: a novel agent with partial properties at D2 and 5-HT1A receptors

Marie-Louise G Most second-generation, atypical, dopamine (DA) D2/5-HT2 blocking still Wadenberg induce extrapyramidal side effects (EPS) in higher doses. Weight gain and metabolic University of Kalmar, disturbances are also a problem, and negative and cognitive symptoms have not been Department of Natural Sciences, Norra Vagen 49, sufficiently addressed. The current brain DA mesolimbic hyperactive/mesocortical SE-391 82 Kalmar, Sweden hypoactive hypothesis of suggests that DA D2/5-HT1A receptor Tel.: +46 480 446 277; properties may be more efficacious with less side effects. DA D2 receptor partial Fax: +46 480 446 244; may stabilize a hyperactive/hypoactive DA condition. Additional 5-HT stimulation may marie-louise.wadenberg@ 1A hik.se enhance therapeutic efficacy and also improve EPS liability profile. In clinical trials in schizophrenic patients, the novel DA D2/5-HT1A partial agonist bifeprunox indeed demonstrates therapeutic efficacy, a safe EPS profile and appears beneficial regarding weight gain, prolactin, blood lipid and glucose levels and cardiac rhythm. The data on bifeprunox are promising and suggest that combined DA D2/5-HT1A partial agonism may well be important properties for future-generation antipsychotics.

Bifeprunox, a novel antipsychotic agent with a (DA D1, D2, D4, 5-HT2A/C, 5-HT1A, hista- so-called third-generation atypical pharmacolog- mine H1, α1, α2, cholinergic muscarinic recep- ical profile, is currently in clinical trials and tor affinity) and comparatively lower affinity for expected to launch as a schizophrenia therapy in the DA D2 receptor than traditional APDs. the American market sometime in 2007, and in produces good antipsychotic effect Europe in 2008. It is also being considered for with virtually no EPS in therapeutic doses, and treatment of bipolar disorder [101]. was therefore labeled atypical. Compared with traditional APDs, clozapine also shows superior Background therapeutic efficacy in treatment-resistant Schizophrenia affects around 1% of the general patients [2,3], beneficial effects against some population worldwide. The symptomatology aspects of cognitive impairment [4], and is supe- includes positive symptoms (e.g., hallucinations, rior to newer, atypical (second-generation) delusions and paranoia), negative symptoms APDs, such as , for preventing suicide (e.g., social withdrawal, poverty of speech, flat amongst patients with schizophrenia and affect), as well as features of cognitive impair- schizoaffective disorders [5]. This has created ment. The main pharmacological property and speculations in the drug development industry as therapeutic mechanism of action of traditional to which pharmacological properties may prima- antipsychotic drugs (APDs), such as rily be responsible for its unique efficacy and (Haldol®), is dopamine (DA) D2 receptor atypicality profile. Clozapine is, however, associ- Authorblockade. However, owing to high DAProof D2 ated with an increased risk for agranulocytosis, receptor occupancy in therapeutic doses, treat- and was even temporarily withdrawn from the ment with these drugs is frequently accompanied market due to a number of cases with fatal out- by disturbing extrapyramidal side effects (EPS), comes [6]. such as acute dystonia and parkinsonism, as well as endocrine effects such as increased prolactin Pathophysiology of schizophrenia levels. While effective against positive symptoms, The therapeutic efficacy of DA D2 receptor Keywords: bifeprunox, these drugs have, over time, proven to be less blocking traditional APDs suggested an overac- dopamine D2, partial efficacious against negative symptoms and cog- tivity of brain DA neural transmission in schizo- agonism, schizophrenia, nitive impairment, and may even worsen these phrenia (the dopamine hypothesis of serotonin (5-HT)1A, third-generation atypical symptoms. schizophrenia). However, while recent data antipsychotics The antipsychotic clozapine (Leponex®, Cloz- more directly point to a specific mesolim- aril®), a dibenzodiazepine that was introduced in bic/subcortical over-reactivity as part of 1967 [1], on the other hand, is pharmacologically responsible for the positive symptoms in schizo- different, with a multireceptor affinity profile phrenia [7], other data suggest that negative

10.2217/14796708.2.2.xxx © 2007 Future Medicine Ltd ISSN 1479-6708 Future Neurol. (2007) 2(2), xxx–xxx 1 DRUG EVALUATION – Wadenberg

symptoms and cognitive disturbances may AstraZeneca’s atypical APD (ICI instead be due to a possibly parallel hypo- 204,636; Seroquel®), a dibenzothiazepine intro- dopaminergic state in prefrontal brain areas [8]. duced in the mid-1990s, is also on the market. This latter hypothesis is further supported by Quetiapine has a clozapine-like pharmacological findings suggesting a dysregulation of the profile, including low DA D2 receptor affinity and dopamine D1 receptor [9], known to be impor- high 5-HT2, α1 and histamine H1 receptor affin- tant for normal cognitive functions [10], and by ity. Its therapeutic profile is similar to clozapine, findings indicating a hypofunction of the gluta- with less EPS and prolactin elevation, but rela- matergic N-methyl-D-aspartate receptor [11] in tively high liability regarding weight gain, dyslipi- schizophrenic individuals as assessed postmor- demia, as well as a propensity to induce sedation, tem. Thus, current knowledge would suggest hypotension and, in some cases, syncope. that it might be more appropriate to think of Recently, focus has been on agonism/partial schizophrenia as a dual pathology disease. agonism at the 5-HT1A receptor [22]. Experimen- tally, 5-HT1A receptor stimulation produces a Antipsychotic drug development: preferential increase in prefrontal cortex DA overview of the market release [23], an effect that is expected to be benefi- Based on the hypothesis of a combined low DA cial against negative and cognitive symptoms in D2 and high 5-HT2 receptor affinity ratio as an schizophrenia. It is also possible that 5-HT1A important mechanism of action of clozapine receptor agonism may contribute both to a gen- [12], the second-generation, so-called atypical eral antipsychotic effect as well as a reduced EPS APDs such as (Risperdal®) [13] and liability [24–26]. Indeed, 5-HT receptors have 1A olanzapine (Zyprexa®) [14] were developed. been reported by some to be upregulated in fron- These drugs are an improvement in schizophre- tal cortex of schizophrenic individuals as deter- nia therapy, and EPS liability is often reduced. mined postmortem [27]. Some clinical This is most likely because additional 5-HT2 augmentation studies have reported ameliora- receptor blockage may allow for sufficient thera- tion of negative symptoms, and reduced inci- peutic efficacy at lower doses with subsequent dence of EPS with adjunctive treatment, with lower DA D2 receptor occupancy. Patients the 5-HT1A partial agonists or tandos- needing higher doses still show emerging EPS, pirone to haloperidol-treated schizophrenic indi- presumably because of a subsequent increase in viduals [28,29]. The fact that clozapine shows DA D2 receptor occupancy. Experimental data agonist properties at the 5-HT1A receptor may also support this notion [15–18]. thus contribute to some aspects of its superior 5-HT2 receptor blockade, in combination therapeutic profile [30,31]. with selective DA D2 receptor antagonists, has The novel APDs (Zeldox®, Geo- also been shown to increase prefrontal DA out- don®) [32] and (Abilify®) [33] include put as measured experimentally by in vivo 5-HT1A agonist, or partial agonist, properties. microdialysis in rats [19]. Nevertheless, treat- Ziprasidone was approved by the US FDA in ment-resistant patients, patients demonstrating 2001 for the treatment of schizophrenia, and is suicidal behavior, or pronounced negative available in intramuscular (for acute agita- and/or cognitive symptoms still do not always tion/aggression in schizophrenia) and oral respondAuthor optimally to treatment with the atypi- Proofforms. Ziprasidone is an antagonist at DA D2 cal APDs. Another serious concern with the and 5-HT2A receptors, the affinity for the atypicals, including clozapine, is their propen- 5-HT2 receptor being an order of magnitude sity to induce weight gain, as well as metabolic greater than that for the DA D2 receptor. In disturbances such as Type 2 diabetes, insulin addition, ziprasidone is an agonist at the resistance and dyslipidemia [20]. Both clozapine 5-HT1A receptor [34], and has less affinity than, and olanzapine show high liability in this for example, clozapine and olanzapine, for his- respect, while risperidone has a more beneficial tamine H1 receptors. Specific improvement of profile. Affinity for the histamine H1 receptor cognitive functions in clinically nonresponsive has been shown to be significantly correlated to patients [35], as well as efficacy against negative weight gain [21], but affinity for the 5-HT2C symptoms [36,37], by ziprasidone treatment have receptor subtype may also be a factor. Thus, in been reported. In a head-to-head comparison order to avoid such side effects, future APDs study with olanzapine, ziprasidone also showed should preferably be devoid of histamine H1 less propensity for weight gain, as well as a more receptor affinity. beneficial lipid profile than olanzapine [38].

2 Future Neurol. (2007) 2(2) futurefuture sciencescience ggrouproup Bifeprunox – DRUG EVALUATION

Intramuscular ziprasidone in acutely agitated cal/therapeutical profile. Thus, based on pre- patients showed a faster onset of effect and clinical behavioral and receptor occupancy superior tolerability compared with haloperidol data, it has been suggested that aripiprazole in [39]. The most frequent adverse events with clinically relevant doses mainly occupies DA ziprasidone appear to be dyspepsia, nausea, diz- D2 receptors, while significant 5-HT2 and ziness and somnolence [40], while ziprasidone 5-HT1A receptor occupancy by aripiprazole appears to have low liability for acute EPS, as occurs first at higher, not clinically relevant well as weight gain. However, prolonged QTc doses [43]. issues were of some concern with ziprasidone in the context of its introduction to the market. Partial agonism at the D2 receptor Ziprasidone is also now approved for acute & the dual pathology hypothesis treatment of mania associated with bipolar in schizophrenia disorder (for product summary, see [103]). It is becoming increasingly clear that the degree Aripiprazole was approved by the FDA in of cognitive impairment in schizophrenia is 2002 for the treatment of schizophrenia and is closely correlated to lifetime prognosis. There- available in tablets and oral solution. Aripipra- fore, antipsychotic drug development research zole has partial agonist properties at the 5-HT1A now focuses on drugs with cognitive enhancing receptor and is a less potent antagonist at the properties. With the current notion that a dual 5-HT2A receptor, has moderate affinity for hista- DA brain chemical pathology underlies schizo- mine receptors, but differs from ziprasidone in phrenia (see above), the ideal treatment could that it also has partial agonist properties at the be a compound with normalizing/stabilizing DA D2 receptor. With its combined DA properties. Hypothetically, that could possibly D2/5-HT1A receptor partial agonist properties, be accomplished with a partial DA D2 receptor aripiprazole could be considered a close prede- agonist [44]. A partial agonist is a drug that, cessor to bifeprunox. Aripiprazole appears to be despite its affinity for a certain receptor, is not effective in schizophrenia and schizoaffective dis- able to elicit a 100% tissue response, even at order, improve aspects of cognitive functioning higher doses. By occupying a certain percentage such as verbal skills, have few EPS adverse events of DA receptors, a partial agonist may act to and have a low propensity for weight gain or prevent excessive stimulation in brain areas with hyperprolactinemia [41]. hyperactive endogenous DA, while not causing In a head-to-head study with haloperidol, DA transmission blockage in hypodopaminer- aripiprazole showed equal therapeutic efficacy, a gic brain areas. Alternatively, partial agonists better EPS liability profile and no prolactin ele- being selective for DA autoreceptors exerting vation. There was no significant difference in negative feedback control on DA release/synthe- body weight changes between the two drugs and sis [45], may that way act as potential stabilizers placebo [42]. Adverse events for aripiprazole of dopamine dysregulation. In addition, partial include headache, nausea, vomiting, somno- agonists should be less likely to cause side effects lence, insomnia and akathisia. Cardiovascular due to their adaptive pharmacodynamic effects, such as increased QTc interval, may be property and subsequent flexibility. more of a concern with ziprasidone than with The idea of using DA receptor partial agonists Authoraripiprazole. Aripiprazole is also approved Proof for in the treatment of schizophrenia is not entirely acute treatment of mania in bipolar disorder (for new. A few DA partial agonists have already been product summary, see [103]). tried, with moderate success [46–48]. In this con- Taken together, ziprasidone and aripiprazole text, aripiprazole and bifeprunox (along with a show an advantage over other available APDs, pri- number of new drugs in development, such as marily regarding EPS liability, prolactin levels, and SLV313, and SSR 181507) represent a propensity for weight gain and metabolic side new class of DA partial agonists with a somewhat effects. However, these drugs have only been on modified pharmacological profile. the market for a few years, and more data are needed to accurately assess whether they are indeed Introduction to bifeprunox significantly superior to other available traditional, Chemistry as well as second-generation, atypical APDs. 1-(2-oxo-benzoxazolin-7-yl)-4-(3-biphe- In addition, it is not clear to what extent nyl)methylpiperazinemesylate (generic name 5-HT1A receptor agonism of these two novel bifeprunox or DU127090), with molecular for- APDs contributes to their pharmacologi- mula C24 H23 N3 O2, and molecular weight futurefuture sciencescience groupgroup www.futuremedicine.com 3 DRUG EVALUATION – Wadenberg

481.5 (bifeprunox mesylate) and 385.5 (base; Partial agonism/agonism properties by bife- Figure 1), is a novel/third-generation antipsy- prunox at DA D2 and 5-HT1A receptors, chotic in a series of 1-aryl-4-(biarylmethyl- respectively, has subsequently been confirmed in ene) developed by Solvay Pharma, several experimental studies [51,53–55]. with partial agonist properties at the DA D2 and Recently, bifeprunox was compared with arip- (partial) agonist properties at 5-HT1A receptors. iprazole for effects on rat ventral tegmental area (VTA) dopamine and dorsal raphe serotonin neu- Pharmacodynamics ronal activity, respectively [56]. Both bifeprunox Bifeprunox (DU127090) has high affinity (pKi (50–400 µg/kg intravenous [IV]) and aripiprazole 8.5) for DA D2 receptors. Its DA D2 receptor (200–500 µg/kg IV) dose-dependently inhibited affinity is similar to haloperidol and risperidone, the firing rate and suppressed bursting activity of but higher than that of clozapine or olanzapine. VTA DA cells. Similarly, both drugs significantly It also has high affinity for human (h)D3 (pKi reversed the suppressing effect of VTA DA cell-fir- 9.1), and hD4 (pKi 8.0) receptors, and for ing activity by the full DA D2 receptor agonist 5-HT1A receptors (pKi 8.2) [49,50,51]. In addi- . Both drugs also dose-dependently tion, it is virtually devoid of affinity for inhibited the firing rate of dorsal raphe 5-HT 5-HT2A/C receptors (compared with aripipra- cells, and this effect was prevented by treatment zole), α1 and α2 adrenoceptors, cholinergic mus- with the selective 5-HT1A carinic or histaminergic receptors [49]. In assays WAY-100635. Thus, bifeprunox (and aripipra- using hD2L-expressing cell lines, bifeprunox zole), also behave as combined partial D2/5-HT1A showed high affinity, but low efficacy (intrinsic receptor agonists in this experimental paradigm, activity), at DA D2 receptors, consistent with although aripiprazole was in general somewhat partial agonism [49]. This was further confirmed less potent. in vivo using microdialysis in freely moving rats. Taken together, a large body of data using dif- By measuring the synthesis rate of both ferent experimental paradigms consistently show dopamine and serotonin in the presence of aro- that bifeprunox displays a profile of high affinity matic decarboxylase inhibition, bifeprunox but low efficacy at the DA D2 receptor (consist- dose-dependently, but incompletely, increased ent with a partial agonist profile), and lower rat striatal L-3,4-dihydroxyphenylalanine accu- affinity and moderately high efficacy at the mulation, but decreased 5-HTP accumulation 5-HT1A receptor, indicative of a full agonist dose-dependently and maximally [52]. Compared profile as shown in some, but not all, models. with the DA D2 receptor antagonist haloperidol Experimental behavioral data suggest that mod- that maximally increases rat striatal L-3,4-dihy- ulation of DA D4 receptors may improve cognitive droxyphenylalanine accumulation, this would be functioning. Using functional assays at the human indicative of partial agonism by bifeprunox at DA D4.4 receptor, it was recently confirmed that DA D2 receptors. Similarly, compared with the bifeprunox exhibits potent partial agonist proper- selective 5-HT1A receptor agonist 8-OH-DPAT ties at hD4.4 receptors. Aripiprazole also exhibited that produces a maximal decrease in 5-HTP partial agonist properties at hD4.4 receptors but accumulation, these data would indicate full with lower potency, while typical and atypical agonism by bifeprunox at 5-HT1A receptors APDs tested behaved as antagonists [57]. regulatingAuthor 5-HT synthesis. Proof Experimental data on bifeprunox In the conditioned avoidance response (CAR) test Figure 1. Molecular structure of bifeprunox. with high predictive validity for antipsychotic activity, bifeprunox showed antipsychotic-like activity in rats at doses as low as 0.25 mg/kg, O potently reversed psychotic-like hyperactivity behavior induced by (PCP) in N O mice, and also potently antagonized D-ampheta- N N mine (0.5 mg/kg) induced hyperlocomotion in rats, while having no effect on baseline activity by itself in this dose range [58,59]. In addition, bife- prunox did not produce any signs of catalepsy (ED50 > 16 mg/kg) indicating a safe EPS liability profile [58,60].

4 Future Neurol. (2007) 2(2) futurefuture sciencescience ggrouproup Bifeprunox – DRUG EVALUATION

In vivo striatal DA D2 receptor occupancy by above 5 mg/kg. In addition, bifeprunox bifeprunox in rats has been reported to be more (0.1–10 mg/kg) alone reversed haloperidol than 90% at 0.25 mg/kg (the minimum effective (2.5 mg/kg) induced catalepsy [67]. dose in the CAR test). The DA D2 occupancy of In behavioral models for cognitive distur- bifeprunox was long-lasting, presumably because bances and negative symptoms in schizophrenia, of slow receptor off-rate rather than an accumula- bifeprunox (0.04–2.5 mg/kg) reversed apomor- tion of bifeprunox in the brain. Despite the high phine-induced sensorimotor gating deficits (dis- DA D2 receptor occupancy, no catalepsy was ruption of prepulse inhibition [PPI]), as did observed, even at high doses (>16 mg/kg), which aripiprazole (at doses of 0.04 or 10 mg/kg, but most likely can be explained by the partial ago- not in doses between those two) [68]. Contrary to nism at the DA D2 receptor in combination with aripiprazole, which reversed social interaction the 5-HT1A agonism of bifeprunox Table 1 [61]. deficits induced by PCP in rats (at 0.04 or In rats with unilateral lesions by 6-hydroxy- 0.16 mg/kg), bifeprunox (0.01–0.63 mg/kg) dopamine of dopaminergic input to the stria- failed to do so [69]. However, in a recent study tum, DA agonists cause contralateral turning both bifeprunox (0.16 mg/kg) and aripiprazole due to stimulation of lesion-induced supersensi- (0.16 mg/kg) reversed PCP-induced deficits in tive receptors. Bifeprunox also causes contralat- working, as well as reference, memory in rats. eral turning in such animals Bifeprunox had minimal (detrimental) effects by (ED50 = 0.026 mg/kg), indicative of DA ago- itself, while aripiprazole, according to the nist properties of bifeprunox [62], while in the authors, showed more detrimental effects of its apomorphine-induced climbing test in mice, own [70]. bifeprunox acted as a partial DA agonist by Finally, bifeprunox has also demonstrated inhibiting this effect (ED50 = 0.14mg/kg orally) , as well as anxiolytic, effects [66]; (ED50 = 0.5mg/kg intraperitoneally) [63,64]. experimentally in rats [60,71]. Further indications of a safe EPS liability pro- In summary, experimentally, bifeprunox pro- file of bifeprunox comes from studies in Cebus duces antipsychotic-like effects in several animal monkeys previously sensitized to neuroleptics. models for antipsychotic activity, has little or no Thus, bifeprunox (0.125–50 mg/kg orally) pro- propensity to induce EPS, and appears to have duced only mild dystonia and parkinsonian efficacy in some animal models of cognitive dis- symptoms in these monkeys. Furthermore, these turbance. Bifeprunox also shows antidepres- symptoms came to a plateau at a low dose and, in sant/anxiolytic effects in animal behavioral contrast to for example haloperidol, decreased models. with higher doses [65]. In this study, bifeprunox also had positive effects in these animals on reac- Pharmacokinetics tivity and alertness to the environment, suggesting Available data on the pharmacokinetics of bife- socially enhancing properties that may be benefi- prunox are incomplete. Thus, there are currently cial against negative symptoms and cognitive no published data available on the absorption, impairment in schizophrenia. distribution and metabolism/elimination prop- Data from recent studies strongly suggest that erties of bifeprunox. the 5-HT1A agonistic property of bifeprunox In a study evaluating methods to determine Authorcontributes to its favorable EPS profile. Thus,Proofthe protein binding of bifeprunox in one plasma using the catalepsy bar test bifeprunox, at least sample, it is stated that bifeprunox is an apolar up to 10 mg/kg, did not produce catalepsy in basic compound with relatively high protein mice. Aripiprazole, by comparison, produced lit- binding. Plasma concentrations are in the lower tle or no catalepsy up to 40 mg/kg in the same ng/ml range [72]. A pharmacokinetic/pharmaco- study. However, in the presence of the selective dynamic model based on the preclinical data on 5-HT1A receptor antagonist WAY 100635 bifeprunox obtained in the CAR test and the in (2.5 mg/kg), bifeprunox produced significant vivo DA D2 occupancy data (see above), suggests catalepsy in the mice already at doses around that a clinically effective steady-state plasma con- 0.1 mg/kg. For aripiprazole, an upward shift in centration of bifeprunox would be around dose–esponse was seen in the presence of WAY 5–10 ng/ml [61]. In a study using the positron 100635 [66]. This was also seen in rats where emission tomography technique, the correlation bifeprunox, while not producing any catalepsy between DA D2 occupancy, dose and plasma by itself, in the presence of WAY 100635 concentration of bifeprunox was investigated in (0.63 mg/kg) produced significant catalepsy six healthy human male subjects. The DA D2 futurefuture sciencescience groupgroup www.futuremedicine.com 5 DRUG EVALUATION – Wadenberg

Table 1. Effects of bifeprunox compared with aripiprazole on CAR (MED)/D2 occupancy (%), and threshold for catalepsy. Drug CAR (MED mg/kg, sc) D2 occupancy (%) Catalepsy (ED50 mg/kg, sc) Bifeprunox 0.25 >90 >16 Aripiprazole 2.5 >90 >20 MED: Minimum effective dose; sc: Subcutaneous. Adapted from [61]. occupancy in these subjects was dose-related, In the USA, a Phase II trial was initiated in with a 90% DA D2 occupancy observed at bife- January 2006. This is a randomized, dou- prunox greater than 10 mg. A higher dose ble-blind, placebo-controlled study to assess the (20 mg) did not further increase DA D2 occu- tolerability/efficacy of bifeprunox in schizo- pancy, suggesting a plateau in DA D2 occupancy phrenic, schizoaffective or bipolar patients. The at 10 mg. Thus, bifeprunox would be expected study is set for 2 months, with an optional to show antipsychotic effect at doses producing 26-week open-label extension, with the aim of 90% D2 occupancy (i.e., doses ≥10 mg). Plasma achieving the ‘shortest tolerated titration dosing’ half-life was reported to be 9 h, but DA D2 to a dose of 40 mg/day. In June 2006, Wyeth was occupancy 24 h after administration was still at reported to be planning to file an FDA approval 79%. Contrary to most antipsychotics, prolactin and commercial launch of bifeprunox for the levels actually decreased (2.5% of baseline at treatment of schizophrenia sometime in 2007 10 mg). There were no clinically relevant [101]. An NDA was submitted to FDA in October changes in ECG or vital signs measures [73–75]. 2006 by Solvay [101; J Arnt, Personal Communication]. At the American College of Neuropsychophar- Clinical efficacy: completed & ongoing macology meeting in December 2006, additional clinical trials data from completed clinical trials with bifepru- Bifeprunox is currently the lead compound of nox became available. In a 6-week, randomized, four of Solvay’s new investigational antipsychotic double-blind, placebo-controlled study, using ris- drugs, which all have a similar pharmacological peridone (6 mg/day) as an active reference, bife- profile. The other drugs are SLV-310, SLV-313 prunox (30 or 40 mg/day) was evaluated against and SLV-314. If successful in clinical trials, it placebo in schizophrenic patients experiencing will be marketed worldwide by Lundbeck A/S acute exacerbations. Safety and tolerability of and by Solvay Pharmaceuticals and Wyeth in the bifeprunox was also evaluated. The total number USA, Canada, Mexico and Japan. of subjects was 599, the study was run in 38 cent- In a placebo-controlled Phase II trial in ers and 40% of subjects completed the study. Pri- schizophrenic patients to assess an appropriate mary outcome measure was change in Positive dose range, bifeprunox showed therapeutic and Negative Symptom Scale (PANSS) total score efficacy and was also well tolerated. The inci- (baseline to end point), using last observation car- dence of EPS was similar to placebo. In addi- ried forward (LOCF). In addition, EPS, weight tion, bifeprunox showed little propensity to gain, lipid profile and serum prolactin were mon- produceAuthor weight gain, did not increase prolactin Proofitored. Bifeprunox 30 mg, but not 40 mg, was levels, had no adverse effects on blood lipids or superior to placebo in reduction of total PANSS glucose levels, and did not show QTc score. This was also true for risperidone (6 mg). prolongation [104]. Most common adverse events with bifeprunox Based on these promising findings, a larger (30 or 40 mg) were gastrointestinally (GI)-related European Phase III trial was initiated in Septem- (e.g., constipation, nausea, vomiting, anorexia, ber 2003 by Solvay and Lundbeck A/S [101,105]. dyspepsia). EPS signs in patients on bifeprunox The launch in the European market was initially were lower than with risperidone treatment. Bife- set to 2007. However, in January 2006, H Lund- prunox also caused significant weight loss com- beck A/S announced that the review of clinical pared with placebo, while patients on risperidone data regarding bifeprunox has led to a delayed experienced weight gain. There was also a signifi- submission of a registration dossier in the Euro- cant (vs placebo) decrease in plasma prolactin lev- pean Union, to 2008, “depending on the com- els in patients on bifeprunox, as well as a decrease pletion of additional Phase III comparative in nonfasting plasma glucose, total serum choles- clinical work” [101]. terol and triglycerides [76].

6 Future Neurol. (2007) 2(2) futurefuture sciencescience ggrouproup Bifeprunox – DRUG EVALUATION

Furthermore, in a 6-week, randomized, dou- deterioration and also a shorter time to deterio- ble-blind, placebo-controlled study, again using ration, compared with the bifeprunox arm. Bife- risperidone (6 mg/day) as an active reference, prunox also showed significant advantage (over bifeprunox (5, 10 or 20 mg/day) was evaluated in placebo) for changes in PANSS total score. Both a dose-finding study against placebo in schizo- doses of bifeprunox were safe and well tolerated phrenic patients experiencing acute exacerba- with a beneficial side-effect profile. Patients on tions. EPS, weight gain, lipid profile and serum bifeprunox also showed improved individual prolactin were also monitored. The total number records on metabolic parameters – in particular of subjects were 589 (18–65 years old), the study regarding weight and lipids [79]. involved 37 centers, and 44% of subjects com- A study with preferential focus on the meta- pleted the study. Withdrawal from study due to bolic profile of bifeprunox was also presented. lack of efficacy was 15% (bifeprunox 20 mg) ver- The study was based on integrated safety analy- sus 7% (risperidone 6 mg). The primary outcome ses from four 6-week, double-blind trials and measure was change in PANSS total score (base- one 6-month, randomized, double-blind trial. A line to end point) using LOCF. Bifeprunox total of 1995 subjects from the 6-week trials, and (20 mg) showed significant reduction of PANSS 497 from the 6-month trial, were included. The total score (vs placebo). Risperidone was also study concludes that pooled data of metabolic effective. EPS signs were similar to placebo. All results from these trials suggest that treatment doses of bifeprunox caused significant weight loss, with bifeprunox is associated with a reduced risk as well as significant decrease in nonfasting cho- of metabolic complications such as weight gain, lesterol and triglyceride levels. Serum prolactin dyslipidemia and glucose dysregulation [80]. was also significantly (vs placebo) decreased, and A summary of clinical data is presented in no changes in ECG profile were observed [77]. Table 2, [105]. Further clinical trials planned for A third 6-week, randomized, double-blind, bifeprunox are listed in Table 3. placebo-controlled, parallel-group efficacy and Bifeprunox was also earlier considered for the safety study in schizophrenic patients (604 treatment of Parkinson’s disease (PD). Clinical patients, in 32 centers) with acute exacerbations trials in Europe for PD have been mentioned in using bifeprunox (20 or 30), and with olanzap- an earlier review on bifeprunox [81]. However, ine (15 mg/day) as an active reference, also there is currently no reliable information availa- showed a reduction by bifeprunox in PANSS ble on the status of bifeprunox in this respect. In total score (baseline to end point) using LOCF. the primate 1-methyl-4-phenyl-1,2,3,6-tetrahy- However, the effect of bifeprunox in this trial did dropyridine (MPTP) model of PD, however, not reach statistical significance (vs placebo). bifeprunox (1 mg/kg) reversed MPTP-induced Olanzapine showed significant therapeutic effect hypomotility and disability. The effect of bifepru- (vs placebo). Safety data indicated that bifepru- nox was proportional to its intrinsic activity at nox was safe and well tolerated, as well as being DA D2 receptors and, according to the investiga- associated with a beneficial metabolic profile (vs tors, suggestive of antiparkinsonian effects [82]. placebo). The completion rate was 48 and 47%, for bifeprunox 20 and 30 mg, respectively [78]. Safety & tolerability Data on long-term efficacy and safety of bife- In clinical trials, bifeprunox (20, 30 or 40 mg) has Authorprunox were also presented. The study wasProof a been reported to be well tolerated, with no clini- 6-month, randomized, double-blind, paral- cally relevant changes in electrocardiogram profile lel-group, placebo-controlled trial in patients or vital signs measures. Bifeprunox also displays a with stable schizophrenia (≥2years) with fixed safe EPS liability profile. Incidence of EPS was in doses (20 or 30 mg) of bifeprunox. A total of general similar to placebo. Prolactin levels follow- 497 subjects in 35 centers (six countries) were ing bifeprunox treatment were reported to recruited, out of which 36.5% (biferunox decrease rather than the opposite. Compared with 20 mg) and 32.6% (biferunox 30 mg) com- earlier atypical APDs, bifeprunox appears to have pleted the study. The primary end point was a safer liability profile regarding weight gain and time from randomization to deterioration. Meta- markers for metabolic syndrome. Thus, bifepru- bolic syndrome parameters were measured in a nox did not produce weight gain, and had no subset of patients. Patients on bifeprunox (20 or adverse effects on blood lipids or glucose levels in 30 mg) showed significantly longer time to dete- clinical trials completed at this point in time. rioration (vs placebo) with LOCF. In the placebo Most common adverse events with bifeprunox arm, there were in general more patients showing were GI-related (e.g., constipation, nausea, futurefuture sciencescience groupgroup www.futuremedicine.com 7 DRUG EVALUATION – Wadenberg [76] [77] [78] [79] [80] Ref. 1995 (from (from 1995 the 6-week trials); the (from 497 trial) 6-month 604 n 588 497 599

(above) (above; As in Rapaport Rapaport As in et al. Metabolic profile Rapaport As in et al. applies to all doses) three in Improvement individual metabolic parameters (weight gain, lipids) loss, Weight lipid decreased levels & glucose

l of Medicine, St Louis, USA. (above) . (above) USA; Irvine, California of University France; Nantes, of University at As in Rapaport As in Rapaport et al Adverse events As in Rapaport et al. or (20 Bifeprunox 30 mg) safe and well tolerated Constipation, vomiting, nausea, anorexia, dyspepsia

ngeles, USA; Washington University Schoo Bifeprunox is associated with reduced risk reduced with is associated Bifeprunox as weight such complications metabolic of gain,dyslipidemia, glucose dysregulation PANSS total scores reduced by both doses reduced total scores PANSS vs not significant (but bifeprunox of levels, prolactin decreased placebo), ECG profile normal Bifeprunox (30Bifeprunox vs superior significantly mg) total score) in PANSS (change placebo levels prolactin decreased EPS, no Results Results superior vs mg) significantly (20 Bifeprunox no total score), in PANSS (change placebo normal levels, prolactin decreased EPS, ECG profile vs time to deterioration longer Significantly less both doses); (bifeprunox placebo on bifeprunox; deteriorated patients total scores in PANSS advantage significant vs placebo changes 20 or 30 or 20 mg/day 30 or 40 or 30 mg/day Bifeprunox dose Bifeprunox 10 or 5, 20 mg/day Bifeprunox 20 or 30 mg (fixed dose) Author Proof, H Lundbeck A/S, and Wyeth Research, in collaboration with researchers d, USA; Cedars–Sinai Medical Center, Los A Los USA;Center, d, Cedars–Sinai Medical (above) Bifeprunox (above) et al. et al. The safety The study integrated metabolic (pooled analyses four 6-week, from data) and one trials, double-blind randomized, 6-month, trial double-blind 6-week, randomized, randomized, 6-week, placebo- double-blind, controlled As in Rapaport Trial design Trial As in Rapaport randomized, 6-month, parallel-group, double-blind, placebo-controlled out by Inc. Solvay Pharmaceuticals

et al. et al. et al. et al. et al. (2006) (2006) centers) (35 Table 2. Summary of data from clinical trials on bifeprunox. 2. Summary of data from Table Authors Rapaport Casey Barbato Bourin Shapiro (2006) centers) (38 (2006) centers) (32 (2006) centers) (37 ECG:Electrocardiogram; EPS:Extrapyramidal Positiveand side negative effects; PANSS: symptomscale. Studies were carried Portlan University, Science Oregon Health and

8 Future Neurol. (2007) 2(2) futurefuture sciencescience ggrouproup Bifeprunox – DRUG EVALUATION

Table 3. Clinical trials currently planned for bifeprunox. Trial Status Switch study of existing atypical antipsychotics to bifeprunox Not yet recruiting Progressively decreasing titration schedules of bifeprunox in subjects with schizophrenia or bipolar disorder Recruiting Open-label extension study of bifeprunox in schizophrenia Not yet recruiting Study evaluating bifeprunox in patients with schizophrenia Not yet recruiting Study comparing bifeprunox with risperidone in the treatment of outpatients with schizophrenia:weight gain Not yet recruiting being the primary end point Treatment of elderly subjects with psychosis and behavioral disturbances associated with dementia of the Recruiting Alzheimer’s type Taken from [102]. vomiting, anorexia and dyspepsia). These events levels and QTc interval. Contrary to second-gen- did not display dose-dependence in the 6-week eration atypical APDs, bifeprunox shows a bene- trials, but showed a more dose-dependent profile, ficial profile regarding weight gain and markers with an incidence of 5% in the 6-month trial. for metabolic syndrome that are also similar to aripiprazole. Clinical data on antipsychotic effi- Regulatory affairs cacy of bifeprunox also appear promising. How- Bifeprunox is not yet approved for use in any ever, currently most clinical data are available country. only as preliminary reports presented as abstracts at scientific meetings. Needless to say, Conclusion peer-reviewed articles would provide a clearer Preclinical and clinical studies suggest that APDs picture of the status of bifeprunox as an antipsy- with combined DA D2/5-HT1A partial agonist chotic. Further (Phase II–III) studies directly properties, such as aripiprazole and bifeprunox, designed to compare the clinical efficacy of bife- may have an advantage over second-generation, prunox with that of second-generation atypical mainly DA D2/5-HT2 receptor blocking, atypi- APDs, as well as with aripiprazole, remain to be cal APDs. Thus, bifeprunox displays antipsy- performed/published, before it is possible to chotic-like effects in animal models for assess the full therapeutic efficacy profile of bife- antipsychotic activity, a safe EPS liability profile, prunox in schizophrenia. In addition, informa- activity in some models of cognitive disturbance tion on pharmacokinetic properties of and antidepressant/anxiolytic-like effects in ani- bifeprunox is still not available. mal behavioral models. In clinical trials in schizophrenic patients, Future perspective bifeprunox (20 or 30 mg) showed significant Atypical APDs such as clozapine, risperidone therapeutic efficacy compared with placebo as and olanzapine act on several target sites. In measured by changes in PANSS total score as addition, their mechanism of action is often primary outcome measure and was well tolerated that of an antagonist, thereby limiting their Authorwith most common adverse events Proofbeing pharmacological flexibility/adaptability. Most GI-related. The EPS profile was similar to pla- atypicals still also come with some serious cebo. Contrary to second-generation atypical adverse events such as induction of agranulocy- antipsychotics, bifeprunox did not produce tosis, weight gain, metabolic syndrome and weight gain, and had no adverse effects on blood cardiovascular effects. Furthermore, therapeu- lipids or glucose levels. In addition, bifeprunox tic response/efficacy varies and is often far from did not increase prolactin levels. There were also optimal. Partial DA D2/5-HT1A agonists like no adverse effects on cardiac rythm. aripiprazole and bifeprunox represent a new In summary, data on bifeprunox are consist- class (third-generation) of APDs, that are mov- ent with what could be anticipated from a com- ing away from the multireceptor, mainly antag- pound with combined DA D2/5-HT1A partial onistic affinity profile represented by, for agonist properties. Clinical data on bifeprunox example, clozapine and olanzapine. Given the so far indicate that bifeprunox compares favora- current notion of a dual pathology in schizo- bly with aripiprazole on safety and tolerability phrenia (as outlined above), partial DA D2 markers such as EPS liability, effects on prolactin agonists, with or without additional 5-HT1A

futurefuture sciencescience groupgroup www.futuremedicine.com 9 DRUG EVALUATION – Wadenberg

Executive summary Mechanisms of action

• Bifeprunox is a partial agonist at the dopamine D2 receptor and a (partial) agonist at serotonin (5-HT)1A receptors. • As partial agonists, by virtue of their definition, are flexible/adaptive to brain tissue/neurotransmitter conditions, these properties in combination are expected to optimize overall therapeutic response in schizophrenic individuals, and at the same time minimize the risk of side effects. Pharmacokinetic properties • Available data on the pharmacokinetics of bifeprunox are incomplete. • Bifeprunox is an apolar basic compound with relatively high protein binding. • Plasma concentrations are in the lower ng/ml range. • A pharmacokinetic/pharmacodynamic modeling of preclinical data on bifeprunox suggests that a clinically effective steady-state plasma concentration of bifeprunox would be around 5-10 ng/ml. • Plasma half-life is 9 h. Clinical efficacy • A positron emission tomography study showed that D2 occupancy in six healthy human male subjects was dose-related with a 90% D2 occupancy observed at bifeprunox greater than or equal to 10 mg. • The D2 occupancy 24 h after administration was still fairly high (79%). • Bifeprunox would be expected to show antipsychotic effects in the clinic starting at doses producing 90% D2 occupancy (i.e., ≥10 mg). • In a placebo-controlled Phase II trial in schizophrenic patients to assess an appropriate dose range, bifeprunox showed therapeutic efficacy. • Further data on clinical efficacy of bifeprunox were recently made available from three 6-week, randomized, double-blind, placebo-controlled trials, together involving a total of 1792 schizophrenic individuals experiencing acute exacerbation. Two of these studies demonstrated statistically significant therapeutic efficacy (change in Positive And Negative Symptom Scale [PANSS] total score) versus placebo by bifeprunox 20 or 30 mg/day. The third trial showed a reduction in PANSS total score by bifeprunox (20 or 30 mg) versus placebo that, however, did not reach statistical significance. • A 6-month randomized, double-blind, parallel-group, placebo-controlled trial with a total of 497 patients with stable schizophrenia demonstrated that bifeprunox (20 or 30 mg) significantly prolonged time to deterioration compared with placebo. Bifeprunox also showed significant advantage (over placebo) for changes in PANSS total score, and more patients in the placebo arm showed deterioration compared with patients in the bifeprunox arm. Safety & tolerability • Bifeprunox was shown to be well tolerated. • Most common adverse events with bifeprunox (30 or 40 mg) were gastrointestinal-related (e.g., constipation, nausea, vomiting, anorexia and dyspepsia). • The incidence of extrapyramidal side effects was similar to placebo. • Bifeprunox showed little propensity to produce weight gain. • Bifeprunox did not increase prolactin levels. • Bifeprunox had no adverse effects on blood lipids or glucose levels. • Bifeprunox did not show QTc prolongation. Drug interaction • Information on drug interactionsAuthor are not yet available. Proof Dosage & administration • Dosage of bifeprunox is expected to be in the range of 20 to 30 mg. • Formulation is expected to be in the form of tablets.

(partial) agonistic properties, may well, the right DA D2/5-HT1A affinity and context, the idea of compounds with by virtue of their DA stabilizing proper- efficacy balance for optimal therapeu- tissue sensitive, brain chemical stabi- ties, prove to be more efficacious and tic effect/fewer side effects. Along lizing properties appears to be a have a significantly reduced side effect another line, further research on the promising lead. liability profile, in particular with addi- molecular basis behind the brain Acknowledgements tional 5-HT1A agonism. pathology in schizophrenia may hold The work to fine-tune future APDs important answers that are sure to be I would like to thank Drs Jørn Arnt, Peter Hertel will, among other things, most likely helpful in optimizing the design of and Rolf Feenstra for valuable information via per- include the challenge to find out just novel antipsychotic molecules. In that sonal communication.

10 Future Neurol. (2007) 2(2) futurefuture sciencescience ggrouproup Bifeprunox – DRUG EVALUATION

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