Emerging drugs for schizophrenia: an update.

Review

Emerging drugs for schizophrenia: an update

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 09/25/14 For personal use only.

Luisa-Sophie K€oster, Maren Carbon & Christoph U Correll† †

The Zucker Hillside Hospital, Psychiatry Research, New York, NY, USA

1.

Background

2.

Medical need/existing treatment

3.

Current research goals

4.

Scientific rationale

5.

Competitive environment

6.

Potential development issues

7.

Conclusion

8.

Expert opinion

Introduction: Schizophrenia is one of the most serious mental disorders. Its treatment remains challenging, as existing antipsychotic antidopaminergic medications improve only/predominantly positive symptoms, agitation and aggression but have limited/insignificant efficacy for negative and cognitive symptoms, which strongly affect functional outcome. Therefore, new therapeutic agents are urgently needed that treat aspects of the spectrum of schizophrenia symptomatology and improve functional outcome. Areas covered: The authors review the mechanisms of action and key clinical results of drug development targets currently in Phase II and III clinical testing for schizophrenia. They further discuss potential barriers to the successful development of these targets and summarize the drug development status of emerging treatments for various aspects of schizophrenia. Expert opinion: Although modifications and variations of antidopaminergic mechanisms are expected to be successful, the added benefits will likely remain small, at least regarding enhanced efficacy for negative symptoms, cognition and functional outcomes. Greater innovation will likely come from further and deeper exploration of extra-dopaminergic mechanisms. Investment is needed to develop clinically meaningful animal paradigms probing the different symptom domains, to discover more efficient in vivo screening methods for novel drug targets, to optimize clinical trial design and trial conduct, and to parse the heterogeneous groups of schizophrenias into biologically more homogeneous subgroups. Keywords: agonist, antagonist, dopamine, mechanisms of action, medications, non-dopaminergic, psychosis, schizophrenia Expert Opin. Emerging Drugs [Early Online]

1.

Background

Schizophrenia, which affects ~ 1% of the world’s population, remains one of the most serious mental disorders that add substantial personal suffering and societal burden on healthcare provision [1,2]. The illness is characterized mainly by positive symptoms (hallucinations, delusions, disorganized speech/thought, disorganized behavior), negative symptoms (lack of motivation, drive, enjoyment, social interactions, gesturing/facial expressions, speech output) and cognitive impairment (deficits in attention, memory, executive functioning, grasp of social situations/ interactions). In the Global Burden of Disease Study 2010, schizophrenia ranked 16th world wide and 9th in North America regarding years lived with disability and was ranked as the illness with the highest disability weight among 289 studied diseases and injuries [3]. The treatment of schizophrenia remains challenging, as knowledge about its pathophysiology and subgrouping of this heterogeneous group of disorders is lacking [4]. In the second half of the twentieth century, as dopamine D2 receptor antagonists emerged as effective antipsychotic drugs, schizophrenia was conceptualized as a ‘dopamine-disorder’. Unfortunately, since their discovery in the 1950s, dopamine D2 blocking agents have remained the only approved and effective 10.1517/14728214.2014.958148 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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drug class for schizophrenia and related psychotic disorders [5]. The crucial role of dopaminergic neurotransmission in schizophrenia is still accepted, but therapy focusing on this one neurotransmitter system has not healed schizophrenia. While the striatal D2 receptor mediated hyper-dopaminergic state is likely related to positive symptoms (e.g., delusions and hallucinations), negative symptoms associated with disruption of normal emotions and behaviors are likely more related to a frontal, cortical D1 and subcortical dopamine receptor mediated deficit [6]. Additionally, accumulating evidence suggests that glutamatergic dysfunction may contribute to the pathogenesis of schizophrenia, negative symptoms, cognitive deficits and, possibly, also positive symptoms [7]. However, despite strong adverse effect on social and occupational outcomes [8], treatment options for negative and cognitive symptoms remain scarce. Limitations of current treatment options contribute to the significant economic burden of schizophrenia. For example, the overall cost of schizophrenia in the US in 2002 was estimated to be $62.7 billion [9]. There was a $22.7 billion excess of direct healthcare costs (out-patient care: $7.0 billion, medication cost: $5.0 billion, in-patient care: $2.8 billion, long-term care: $8.0 billion). The total direct non-healthcare excess costs, including living cost offsets, were estimated to be $7.6 billion. However, the total indirect excess costs were estimated at $32.4 billion. Overall, the indirect excess cost due to unemployment is the largest component of excess costs for patients with schizophrenia [9]. 2.

Medical need/existing treatment

Since discovery of chlorpromazine and its success in treating psychosis and related agitation/aggression in the early 1950s, the D2 receptor has been the one invariable target for effective antipsychotic drugs. During the past half century, numerous first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) with different formulations have been approved that have high or medium--to-low affinity for the D2 receptor and fully or partially block the actions of dopamine [10]. Although newer antipsychotics produce fewer extrapyramidal side effects (EPS), including potentially irreversible and socially stigmatizing involuntary movements, called tardive dyskinesia (TD) [11], they generally do not seem to be significantly more efficacious than FGAs. In particular, greater benefit regarding negative symptoms could not be shown when high FGA doses are avoided [12]. Nevertheless, SGAs have demonstrated higher efficacy compared to FGAs regarding relapse prevention and treatment continuation [13,14], yet both medication classes are heterogeneous. Further, safety and tolerability concerns regarding weight gain and metabolic side effects have risen that are more common with most SGAs and that can increase physical illness burden and shorten life expectancy [15,16]. As mentioned above, existing antipsychotic (predominantly antidopaminergic) medications are often effective for treating 2

positive symptoms and related agitation/aggression [4,12]. By contrast, current antipsychotics show rather limited efficacy for negative and cognitive symptoms, which strongly influence functional outcome [17]. Furthermore, in a substantial subgroup, even positive symptoms are resistant to currently available drugs [18]. Alternative strategies for the improvement of positive, negative and/or cognitive symptoms, involving either monotherapy with agents with non-dopaminergic molecular targets/mechanisms of action or augmentation of approved antipsychotics with additional medications have been tried, yet those have either failed or shown too inconsistent results to lead to regulatory approval (see below). Failed novel mechanism monotherapy approaches have included the metabotropic glutamate receptor 2/3 agonist pomaglumetad [19,20]. Failed or inconclusive augmentation strategies added to antipsychotics have included the addition of a second antidopaminergic drug [21,22], or addition of nonantidopaminergic medications. Augmentation strategies for positive symptoms have involved pro-glutamatergic agents, valproic acid [23], carbamazepine [24], lithium [25], lamotrigine [26], benzodiazepines [27], b blockers [28] and agents with anti-inflammatory properties [29,30]. Augmentation treatments for negative and/or cognitive symptoms included antidepressants [31-34], acetylcholinesterase inhibitors [35], omega-3 fatty acids [36], modafinil [37] and metabotropic glutamate [38] as well as NMDA receptor modulators [39,40]. To date, these strategies either failed or yielded unconvincing results, especially in larger samples. Therefore, there is an urgent need for new therapeutic agents that treat one or more components of the entire spectrum of symptomatology and functional impairments that are part of schizophrenia, without causing harmful side effects, especially in the neuromotor and cardiometabolic areas [41]. 3.

Current research goals

As predominantly antidopaminergic agents only effectively treat positive symptoms and aggression/agitation and have only minimal efficacy for negative and cognitive symptoms, mechanisms unrelated to D2 receptor hyperfunction need to be explored. These mechanisms may include either the dysfunction of other dopamine receptors, extra-dopaminergic neurotransmitter systems, or intracellular second messenger system pathways leading to differential gene expression processes [41-43]. Recently, a variety of new pharmacological approaches have emerged in schizophrenia in order to modulate dysfunctional neurotransmitter systems beyond the D2 receptor, and clinical testing has begun [44]. Several research goals exist (Table 1). These goals include broadening the scope of development from safe and tolerable antipsychotics to either true anti-schizophrenia medications that have enhanced efficacy for all relevant domains of schizophrenia or adjunctive agents that target cognitive or negative symptoms [45]. Likely, the latter is more realistic. Furthermore, positive and negative symptoms need to be efficiently controlled to achieve

Expert Opin. Emerging Drugs (2014) 19(4)


Table 1. Research goals and property targets for the development of ‘ideal’ new antipsychotic or antischizophrenia agents. Research goals and property targets for new antipsychotic or anti-schizophrenia agents Pharmacodynamic goals

Pharmacokinetic goals


Antidopaminergic, yet maintaining physiologic dopamine transmission Sole or additional non-dopaminergic therapeutic mechanism(s) Enhancing efficacy of antidopaminergic drugs Efficacy in antidopaminergic non-responders Minimal histaminergic blockade Minimal cholinergic blockade Minimal a-1 adrenergic blockade a-2 blocking effects Serotonin and/or noradrenaline reuptake inhibition Specific, salutary second messenger system effects Enhancing neurotrophic, neurogenic and/or anti-apoptotic factors Restoring satiety and metabolic signaling

Sufficiently broad efficacy-toxicity gap Fast onset of action No need for extensive/complicated titration, starting dose = working dose Long half-life Available in multiple formulations No rebound upon discontinuation/switch No need to be taken with food Not influenced by smoking Little to no effect on the metabolism of other medications Not influenced much by renal or hepatic dysfunction Blood levels reliably identifying therapeutic window

Efficacy goals

Safety/tolerability goals

Positive symptoms

Minimal/no extrapyrimidal side effects, akathisia, tardive dyskinesia Weight neutral/reversing abnormal weight Metabolically neutral/reversing abnormalities Minimal sedation Minimal anticholinergic effects Prolactin neutral/minimal sexual side effects/dysfunction No increased suicidality Little orthostasis No Qtc prolongation/pro-arrhythmogenic effects No blood dyscrasias Safe during pregnancy and development No need for blood monitoring Safe/tolerable across the entire age range

Negative symptoms Cognitive dysfunction Improving illness insight Anti-suicidal Effective for refractory illness Aggression/agitation/Impulsivity Mania Depressive symptoms/depression Anxiety/OCD symptoms Reducing smoking, substance craving/abuse Improvement of well-being and functional level Effective across the entire age range Adherence goals

Effectiveness goals

Once a day (or simple) dosing regimen, or once weekly Benign side-effect profile Subjectively acceptable to patients No food effect

Favorable risk:benefit profile High treatment acceptance/persistence Quality of life Level of functioning/recovery Subjective well-being Facilitation of long-term goals

Personalized care goals

Access goals

Availability of clinical and biological predictors of efficacy and tolerability for readily identifiable and meaningful patient subgroups Blood levels reliably identifying therapeutic window Drug-specific pharmacogenetic markers for efficacy and tolerability

remission (no more than mild symptom severity for ‡ 6 months), to protect against relapse and to achieve recovery (i.e., remission for at least 2 years with functional capacity in the areas of self-care, social interactions and education/ work) [46]. Ideally, new treatments would also overcome treatment resistance to currently available antipsychotics. All these efficacy gains should be achieved with acceptable safety and

Covered by health insurance

Affordable

tolerability profiles, although limited tolerability may be more acceptable for agents that are very effective for one of the currently unaddressed areas, such as negative symptoms, cognitive dysfunction or treatment resistance. Moreover, treatment options are needed that target specific patient subgroups [47]. While clinically scalable biomarkers of treatment response to individual medications would greatly


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Table 2. Pharmacodynamic mechanisms of neurotransmitter transmission modulation. Pharmacologic class Neutral receptor antagonists Full receptor agonists


Partial receptor agonists

Inverse receptor agonists Reuptake pump inhibitor Heteroreceptor Modulation

Positive allosteric modulators

Negative allosteric modulators

Mechanism No own activity at the receptor, but blockade of the receptor, such that the natural ligand cannot bind to the receptor Stimulation of the receptor in its physiologic direction Less than 50% intrinsic stimulatory activity at a receptor, while fully occupying the receptor, such that the natural ligand cannot bind to it Stimulation of the receptor in the opposite direction of the physiologic ligand Reduction of the activity of a reuptake pump Modulation of the activity of presynaptic heteroreceptors that are not specific to a certain neurotransmitter system, but that interact with various neurotransmitters, neuromodulators or neurohormones released from adjacent neurons or cells Potentiation of the response of the receptor to orthosteric agonists (that bind to the usual receptor site) by binding to a site other than the agonist Reduction of the activity of agonists in a noncompetitive fashion by binding to a site other than the agonist

enhance the management of schizophrenia and are even advanced by the FDA as potential marketable targets, to achieve truly personalized treatment for schizophrenia, a fuller understanding of underlying mechanisms of specific disease process and therapeutic and adverse responses is likely required. To achieve these goals, various pharmacologic avenues are pursued. In addition to traditional pharmacodynamic mechanisms, such as receptor agonism, partial agonism, antagonism or inverse agonism, or antagonism of reuptake pumps, newer approaches that are being tested include fine tuning of physiologic transmission, including heteroreceptor antagonism or inverse agonism and positive or negative allosteric modulation (Table 2) [48-52]. Furthermore, the potential of neuroprotective mechanisms is also explored (see below) [43]. 4.

Scientific rationale

Impaired neurotransmitter systems in schizophrenia

4.1

The supposed multilevel dysfunction underlying different dimensions of schizophrenia includes the interaction of the major central neurotransmitter systems apart from dopamine. The most important neurotransmitter pathways that offer starting points for pharmacological receptor modulation are briefly introduced below (Table 3). Dopamine receptor modulation Dopaminergic neurotransmission is crucial for motivation, pleasure, cognition, memory, learning, motor control and 4.1.1

4

Effect Decreased signaling towards neutral set point

Increased signaling above neutral set point Decreased signaling if basal activity is above the intrinsic activity Increased signaling if basal level is below the intrinsic activity Decreased signaling below neutral set point Increased signaling above neutral set point Fine tuning of signal transduction

Increased signaling above neutral set point in the presence of the natural ligand

Decreased signaling below neutral set point in the presence of the natural ligand

healthy endocrine functioning [53]. The supposed mechanism of action of antipsychotics is based on the hypothesis of reducing dopaminergic dysregulation involving excess dopaminergic activity in areas resulting in psychotic symptoms. The most recent understanding of the dopamine dysfunction [54,55] in schizophrenia suggests that hyperactivity of dopaminergic transmission of the associative striatum, the medial part of the striatum including the dorsal anterior striatum, is related to positive symptoms of psychosis. Antipsychotic-mediated blockade in this pathway can help reduce hallucinations, delusions and thought disorganization, the hallmark of psychosis. Disease-associated dysregulation in the limbic striatum, the dopaminergic mesolimbic pathway with projections from the ventral tegmental area of the midbrain to the ventral striatum including the nucleus accumbens, seems to be associated with primary negative symptoms and, possibly with depression [54,55]. Antidopaminergic medication-related blockade of this pathway can give rise to secondary negative symptoms [56]. Similarly, disease-associated dysregulation in or medication-induced blockade of the mesocortical pathway, dopaminergic projections from the ventral tegmental area to the cortex, has been associated with primary or secondary cognitive, negative and depressive symptoms [54,55]. Dopamine blockade in the nigrostriatal pathway, in particular those projecting from the substantia nigra in the midbrain to the dorsal posterior, sensorimotor striatum, which projects via the pallidum and thalamus to the motor cortex, is associated with neuromotor adverse effects [57]. Finally, blockade of the tuberoinfundibular pathway, the dopaminergic pathway of the



Table 3. Neurotransmitter/receptor targets and mechanisms of emerging agents in Phase II and III development for schizophrenia. Neurotransmitter/ receptor


Dopamine Dopamine D1 Dopamine D2

Mechanism

Target symptoms Undesired effects

Antagonism Antagonism

Psychosis Psychosis, aggression/agitation, Tics, OCD, EPS, Hyperprolactinemia

Partial agonism

Psychosis, aggression/agitation, Tics, OCD Psychosis

Established agent

First-generation antipsychotics, second-generation antipsychotic (SGAs) (except Aripiprazole) Aripiprazole

Emerging agent (main mechanism) Zicronapine Zicronapine

Cariprazine, brexpiprazole RP-5063, ITI-007 (pre- and postsynaptic) Cariprazine, brexpiprazole RP-5063

Dopamine D3

Partial agonism

Serotonin Serotonin 5-HT1a

Partial agonism

Serotonin 5-HT1B

Partial agonism

Serotonin 5-HT2a

Antagonism

Psychosis, depression, anxiety Psychosis, depression, anxiety Psychosis, anti EPS

Inverse Agonism

Psychosis, anti EPS

Antagonism Antagonism Reuptake inhibition

Depression Depression Depression, anxiety

Uptake inhibition

Depression

Neboglamine

Positive allosteric modulation

Positive and negative symptoms, anxiety

ADX-71149

Agonism (noncompetitive GLYCINT1 inhibitor) Positive allosteric modulate at glycine side

Negative symptoms, cognition

Bitopertin

Agonism

Cognition

ABT-126

Agonism

Cognition, negative symptoms

Encenicline, ABT-126

Antagonism

Negative symptoms, cognition Psychosis Negative symptoms, cognition

OMS-824 PF-2545920 GWP-42003 SAM-101 (Combination of Mincocyline and antipsychotic drugs) ALKS-3831 (ALKS-33: ‘samidorphan’ plus olanzapine)

Serotonin 5-HT6 Serotonin 5-HT7 Serotonin Adrenergic a adrenergic Glutamate Metabotropic (m)glutamate recepetor2 (mGluR2) NMDA

Acetylcholine M1/M4 muscarinic Acetylcholine receptor (nAChr) a7 Nicotinergic acetylcholine (a7nACh) Others Phosphodiesterase 10A (PDE10A) Cannabinoid-1 Minocycline

Antagonism Neuroprotection

µ-opioid receptor

Antagonism

Aripiprazole, lurasidone, ziprasidone

Brexpiprazole RP-5063, eltroprazine Eltroprazine

SGAs (except amisulpride)

Zicronapine, brexpiprazole MT-210 ITI-007 Pimavanserin RP-5063 RP-5063, AVN-211 RP-5063 ITI-007

Asenapine Lurasidone Quetiapine

Neboglamine

Reduced weight gain than olanzapine monotherapy

EPS: Extrapyrimidal side effects; OCD: Obsessive compulsive disorder.


5



hypothalamus, disinhibits the dopamine-facilitated reduction in prolactin secretion in the anterior pituitary gland, leading to sexual and reproductive system dysfunction, including amenorrhea and galactorrhea [58]. The above indicates that dopamine transmission needs to be preserved in certain areas of the brain, whereas others require attenuation to reduce psychotic symptoms. Mechanisms that can help counter unopposed dopamine blockade and allow antipsychotic efficacy while limiting antidopaminergic side effects include a low D2 occupancy over the full therapeutic dose range (e.g., clozapine, quetiapine), partial D2 agonism (e.g., aripiprazole) and indirect augmentation of dopamine activity by muscarinic and histaminic blockade (e.g., chlorpromazine, clozapine, olanzapine, quetiapine), or modulation of serotonin receptors (SGAs) [48,53]. Serotonin receptor modulation Due to the close serotonin-dopamine interaction, serotonergic receptors have long been among the primary pharmacological targets for schizophrenia [59]. 5-HT2A antagonism can increase dopaminergic transmission in the nigrostriatal pathway and reduce EPS risk. By increasing the release of dopamine in the prefrontal cortex, serotonin receptor modulation could theoretically improve negative symptoms and cognitive impairment. However, SGAs with potent 5-HT2A antagonism do not have convincingly greater efficacy for negative and cognitive symptoms or lower risk for EPS-related, secondary negative and cognitive symptoms, which are generally more likely with FGA that lack clinically relevant 5-HT2A blockade. Moreover, pimavanserin, a selective 5-HT2A antagonist was unable to treat positive symptoms in the absence of dopamine blockade, at least in schizophrenia [60]. Partial agonism at prefrontal 5-HT1A receptors has been associated with reduced anxiety and depression and possibly improved cognitive ability. The 5-HT1A partial agonist, buspirone, showed ability to enhance cognition in patients on stable antipsychotic medication [61]. Based on these findings, compounds possessing 5-HT1A agonism combined with D2 like receptor antagonism are being developed as potential antipsychotics (Table 3). Modulation of the 5-HT2C receptor might be of interest, as this G-protein-coupled receptor is expressed by gabaergic, glutamatergic and dopaminergic neurons and may thus modulate multiple neurotransmitter systems involved in schizophrenia symptoms [62]. The selective 5-HT2C receptor agonist, vabicaserin, showed efficacy at 200 mg using olanzapine as an active comparator for positive symptom and the Clinical Global Impressions Scale (CGI), whereas 400 mg did not differ from placebo [63]. The distribution and high affinity of certain SGAs (e.g., clozapine, olanzapine) as well as antidepressants (e.g., amoxapine, amitriptyline) to the 5-HT6 receptor suggest that 5-HT6 ligands may have a therapeutic role in conditions such as schizophrenia and depression [64]. Moreover, 5-HT6 receptor antagonists have been implicated in preclinical models of 4.1.2

6

cognition [65]. Similarly, certain SGAs (e.g., amisulpride, risperidone) and antidepressants (e.g., maprotiline, mianserin) bind with high affinity to 5-HT7 receptors, which have a role in depression as well as in learning and in memory [64]. NMDA receptor modulation Non-competitive NMDA-receptor (NMDA-R) antagonists, such as ketamine and phencyclidine, can provoke schizophrenia-like symptoms in healthy individuals [66] and schizophrenia patients [67], including psychosis, negative symptoms and attention and memory problems. These effects led to the hypothesis that NMDA-R hypofunction may be involved in the pathophysiology of schizophrenia [68]. The NMDA-R is a specific type of an inotropic glutamate receptor. Activation of the NMDA-R via glutamate requires co-activation by two ligands: glutamate and either D-serine or glycine [69]. NMDAR antagonism leads to cortical excitation, likely due to reduced excitation of inhibitory interneurons, which is hypothesized to result in psychotic symptoms. As glutamate is the most abundant excitatory neurotransmitter, direct, unselective stimulation of inotropic NMDA receptor would involve a plethora of unwanted central effects. Interventions via the metabotropic subtypes of glutamate receptors, and glycine-transport inhibition can be more titrated and specific. Since glycine transporters can remove glycine that is being therapeutically increased, glycine transporter-1 inhibitors are tested to increase local synaptic levels of glycine. In animal models and human studies, sarcosine, a naturally occurring substance, improved negative symptoms [40], supporting the potential utility of glycinetransporter 1 inhibitors. 4.1.3

Phosphodiesterase 10 inhibitors Phosphodiesterase (PDE-10a) inhibitors attenuate the inactivation of the second messenger cAMP and cGMP. PDE-10a is especially expressed in the medium spiny neuron of the basal ganglia, suggesting relevant regional specificity. Data suggest that PDE-10a inhibition leads to potentiation of dopamine D1 receptor signaling and concomitant inhibition of dopamine D2 transmission [70]. Consequently, antipsychotic and procognitive effects have been suggested and were confirmed in rodent and primate models [71]. 4.1.4

Cannabinoid receptor modulation Consuming cannabis is a risk factor for developing psychosis or schizophrenia [72]. Accumulating evidence suggests an imbalance of the endocannabinoid system in schizophrenia, including cannabinoid-1 (CB-1) receptors and anandamide, an endocannabinoid transmitter involved in pain regulation, mood and cognition [73]. Thus, pharmacological modulation of the endocannabinoid system represents an intriguing new therapeutic target for schizophrenia [74]. Relevance of the cannabinoid receptor system in schizophrenia is highlighted by a recent, small 4-week, double-blind, active-controlled trial of cannabidiol (a cannabis extract devoid of CB-1 receptor interaction) that showed equal efficacy compared to amisulpride in 4.1.5



patients with acutely exacerbated schizophrenia. Cannabidiol was well tolerated and clinical improvement correlated significantly with increased serum anandamide levels [75]. Cholinergic neurotransmission Both, central muscarinic acetylcholine receptor (mAChR) and nicotinic achetylcholine recepotor (nAChR) agonists have improved cognitive function in healthy individuals and schizophrenia patients [76]. Due to the ubiquitous nature of the cholinergic system, clinical efficacy can only be achieved with agents presenting very high receptor selectivity. The M1/M4 mAChR agonist xanomeline demonstrated antipsychotic potency as well as cognitive improvement compared to placebo in a small pilot study but was associated with gastrointestinal adverse effects [77]. Further clinical development of this compound was unsuccessful. To date, no other agents modulating the muscarinic acetylcholine receptor are in advanced clinical testing for schizophrenia. Nicotinic a-7 agonism is also implicated in the modulation of many cognitive functions. Therefore, nicotinic a-7 agonists have been tested as adjuncts to antipsychotics to improve cognitive impairment associated with schizophrenia or Alzheimer’s disease. In schizophrenia, preclinical, genetic and postmortem studies demonstrated altered nAChR levels and function [10]. For example, EVP-6124, a nAChR agonist, is currently tested in a Phase II trial for the indication of schizophrenia.


4.1.6

Antioxidant, anti-inflammatory and/or neuroprotective agents

4.1.7

Minocycline, a semi-synthetic second-generation tetracycline antibiotic has shown neuroprotective effects in animal models of schizophrenia [78]. Minocycline has antioxidant, anti-inflammatory and neuroprotective properties, possibly via nitric oxide synthase inhibition, inhibition of microglial activation and antiapoptotic function [44]. Given these properties, minocycline has emerged as a potential adjunctive treatment and independent clinical testing has begun, showing mixed results across four randomized controlled trials [30]. When combined in a metaanalysis, the mean weighted effect size (ES) for total psychopathology was 0.22, which was not significant (95% CI: -0.39 to 0.82). SAM-101, a combination of minocycline with existing antipsychotic drugs, is in advanced clinical testing (see Section 4.7). Further investigations of anti-inflammatory/neuroprotective agents as adjunctive agents include NSAIDs, the neuroprotective protein davunetide, essential fatty acids, estrogens and N-acetylcysteine (NAC). Although no Phase II or III studies are currently registered for any of these agents, recent metaanalyses showed small or insignificant effects of these adjunctive agents for total psychopathology, positive and/or negative symptoms. Efficacy for positive symptoms in mostly small studies was found for NSAIDs (possibly with efficacy for aspirin but not Cox-2 inhibitors [79] and especially in first-episode patients) [29], estrogens and NAC [30], whereas davunetide and essential fatty acids estrogen failed to separate from placebo.

5.

Competitive environment

Despite the urgent need for new treatments for schizophrenia, there have not been any approved agents with a mechanism not involving antidopaminergic properties since the discovery of chlorpromazine. Although schizophrenia occurs in only 1% of the population, its economic burden is enormous, justifying novel and expensive treatments if they alter the outcomes and/or disease trajectory in clinically significant ways. Moreover, sales of individual antipsychotics reached up to $5 -- 6 billion annually. This high sales potential is due to the varying efficacy of SGAs for conditions that are more common than schizophrenia, including bipolar mania, irritability associated with autism and, especially, depressive disorders insufficiently responding to first-line antidepressant treatments. Additionally, off-label prescribing for aggression associated with disruptive behavior disorders or dementia, obsessive compulsive disorder, anxiety disorders, post-traumatic stress disorder and insomnia [80] further increased sales of agents developed originally as antipsychotics for schizophrenia. However, while in the past small chemical modifications of existing mechanisms/agents were successfully approved, there seems to be a shift across regulatory environments towards favoring novel mechanisms or, at least, the requirement of documented added benefits over existing medications. In addition to the pursuit of novel agents and mechanisms, fixed-dose combinations of existing treatments and new routes of administration, such as transdermal applications and longacting injectable formulations, are being developed. All targets for schizophrenia that are currently tested in Phase II and III are listed in Table 4 together with their mechanisms of action. Dopamine receptors Mechanisms beyond an unselective D2 antagonism are promising; the goal is to normalize abnormal striatal neurotransmission, while maintaining/improving dopaminergic neurotransmissions in other brain regions (see Section 3.1.1). Emerging drugs distinguish from existing drugs by involving D3 and D4 receptors, as well as partial agonism on the D2 or D3 receptor, postsynaptically and/or presynaptically. 5.1

D1 agonism The D1-mediated cortical hypodopaminergic state likely underlies cognitive impairment in schizophrenia. Nevertheless, clinical testing of the D1 receptor agonist dihydrexine failed to show positive effects for cognition [81]. At present, no other D1 agonists are in late clinical testing. 5.1.1

D2/D3 partial agonism: cariprazine, brexpiprazole

5.1.2

To date, aripiprazole is the only FDA approved D2 partial agonist. Clinically, D2 partial agonism has proven to be associated with relatively low levels of EPS and prolactin, or even reductions in prolactin across the dose range. Cariprazine


7

8

Addex and Ortho-McNeil (Johnson & Johnson) Alkermes

Novartis

ADX-71149 (JNJ-40411813)

AQW-051


Aivneuro Chugai (Roche)

Dainippon Sumitomo Pharma

Otsuka

Gedeon Richter

PsychoGenics

AVN-211 Bitopertin (RG-1678; RO-4917838)

Blonanserin (transdermal patch) DSP-5423P Brexpiprazole (OPC-34712)

Cariprazine (RGH-188)

Eltoprazine (PGI-256)

3-(trans-4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)cyclohexyl)- 1,1-dimethylurea hydrochloride Piperazine, 1-(2,3-dihydro1,4-benzodioxin-5-yl)- [CAS]

Dodecanoic acid, [7-[4-[4-(2,3-dichlorophenyl)1-piperazinyl]butoxy]-3,4-dihydro-2-oxo- 1(2H)-quinolinyl] methyl ester NR [4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl] [5-methanesulfonyl-2-((S)2,2,2-trifluoro-1-methylethoxy) phenyl]methanone Cycloocta[b]pyridine, 2-(4-ethyl1-piperazinyl)-4-(4-fluorophenyl)5,6,7,8,9,10-hexahydro- [CAS] 2(1H)-Quinolinone, 7-[4-(4-benzo[b]thien-4-yl1-piperazinyl)butoxy]-

10H-Thieno(2,3-b)(1,5) benzodiazepine, 2-methyl4-(4-methyl-1-piperazinyl)[CAS] + Morphinan3-carboxamide, 17(cyclopropylmethyl)-4,14-dihydroxy-6-oxoNR

NR

Chemical name

Major depressive disorder Schizophrenia Alzheimer’s disease PTSD Anxiety, unspecified ADHD Schizophrenia Psychosis, bipolar Major Depression Depression, bipolar ADHD Schizophrenia Dyskinesia, levodopa-induced PD

Schizophrenia

Schizophrenia Schizophrenia OCD

Schizophrenia PD Dyskinesia, levodopa-induced Alzheimer’s disease Schizophrenia

Schizophrenia

Schizophrenia

Schizophrenia

Indication

Phase III Phase III Phase III Phase III Phase III Phase II Pre-registration Pre-registration Phase III Phase II Phase II Phase II Phase II Phase II

Phase II

Phase II Phase III Phase II

Phase II Phase II Phase II Not reported Phase III

Phase II

Phase II

Phase II

Stage of development

5-HT1A (partial) agonist 5-HA1B (partial) agonist

D2 partial agonist D3 partial agonist

D2 (partial) agonist D3 (partial) agonist 5-HT1A agonist 5-HT2A antagonist

D2 antagonist 5-HT2 antagonist

5-HT6 antagonist Glycine transporter 1 inhibitor

D2 agonist 5-HT1A agonist 5-HT2A antagonist

a7 neuronal nicotinic agonist

a7 nicotinic agonist Neuronal nicotinic agonist Glutamate-2 receptor positive allosteric modulator Opioid mu (µ) antagonist plus olanzapine

Receptor/mechanism of action

ADHD: Attention deficit hyperactivity disorder; D: Dopamine; HD: Huntington’s disease; HT: Hydroxytryptamine; NR: Not reported; OCD: Obsessive compulsive disorder; PD: Parkinson’s disease; PDE: Phosphodiesterase.

Alkermes

Aripiprazole lauroxil (ALKS-9070) extendedrelease formulation

ALKS-3831 (Fix-dose combination olanzapine + ALKS 33 = samidorphan)

AbbVie

Company

ABT-126

Compound

Table 4. Emerging drugs in Phase II and III development for schizophrenia (in alphabetical order).



GW Pharmaceuticals

Intra-Cellular Therapies ITI

Mitsubishi Tanable Pharma Rottapharm Madaus

GWP-42003

ITI-007

MT-210 (CYR-101)

Pfizer

PF-2545920 (MP-10) is the lead in a series of PDE 10 (PDE XA) inhibitors Pimavanserin tartrate (ACP-103)


Reckitt Benckiser

Rovi Pharmaceutical

Risperidone RBP-7000 (sustained-released formulation)

Risperidone-ISM (using in-situ microparticle)

4H-Pyrido[1,2-a]pyrimidin-4-one, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]6,7,8,9-tetrahydro-2-methyl 4H-Pyrido[1,2-a]pyrimidin-4-one, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-

(E)-2-((6-methoxy-2-methylquinolin-4-yl)thio)-N’-(3,4,5-trimethoxybenzylidene)acetohydrazide 2-[4-(1-Methyl-4-pyridin-4-yl-1Hpyrazol-3-yl)-phenoxymethyl]QUINOLINE Urea, N-[(4-fluorophenyl) methyl]-N-(1-methyl-4-piperidinyl)-N’-[[4-(2methylpropoxy) phenyl]methyl]-, (2R,3R)2,3-dihydroxybutanedioate (2:1)

N1-(4,4-Dimethylcyclohexyl)-Lisoglutamine

Benzo[b]thiophene-2-carboxamide, N-(3R)-1-azabicyclo[2.2.2] oct-3-yl-7-chloro-, hydrochloride (1:1)

Chemical name

Schizophrenia

Schizophrenia

Schizophrenia HD Psychosis, bipolar PD Psychosis, PD Alzheimer’s disease Dyskinesia, levodopa-induced Insomnia Psychosis, Alzheimer’s disease Schizophrenia Schizophrenia

Schizophrenia HD

Schizophrenia Addiction, cocaine

Schizophrenia Colitis, ulcerative Steatohepatitis Schizophrenia Alzheimer’s disease Insomnia Depression, unspecified Schizophrenia

Schizophrenia Alzheimer’s disease

Indication

II II II II II II II II

Phase II

Phase III

Phase II

Phase II Phase II Discontinued Phase III Phase III Phase II Phase II Phase II Phase II Phase II

Phase II Phase II

Phase II Phase II

Phase Phase Phase Phase Phase Phase Phase Phase

Phase III Phase III


5-HT2A antagonist D2 antagonist

5-HT2A antagonist D2 antagonist D4 antagonist a adreno antagonist 5-HT2A antagonist D2 antagonist

5-HT2A inverse agonist

PDE-10 Inhibitor

5-HT2A antagonist 5-HT uptake inhibitor D2 agonist D antagonist 5-HT2A antagonist Sigma-2 antagonist Glycine NMDA-associated agonist Adrenergic transmitter uptake inhibitor PDE-10-Inhibitor

Cannabinoid receptor agonist

a7 nicotinic agonist



PharmaNeuro-Boost

PNB-02 (Fix-dose combination: pipamperone + risperidone)

ACADIA

Omeros

OMS-824

Neboglamine (XY-2401; nebostinel)

Forum

Company

Encenicline hydrochloride (EVP-6124)

Compound

Table 4. Emerging drugs in Phase II and III development for schizophrenia (in alphabetical order) (continued).



9

SAM-101 (Combination of Mincocyline and antipsychotic drugs) Zicronapine (LU-31-130)


5-HT2A antagonist 5-HT2c antagonist D1 antagonist D2 antagonist Phase III Schizophrenia Lundbeck

Piperazine, 4-[(1R,3S)-6-chloro2,3-dihydro-3-phenyl-1H-inden1-yl]-1,2,2-trimethyl-

Schizophrenia XTL Biopharmaceuticals

Phase II

Schizophrenia Reviva Pharmaceuticals

6,7,8,9-tetrahydro-2-methyl[CAS] RP-5063 (RP-5000)

Company

Chemical name

Indication

Phase II


10

Compound

Table 4. Emerging drugs in Phase II and III development for schizophrenia (in alphabetical order) (continued).



D2 partial agonist D3 partial agonist D4 partial agonist 5-HT1A partial agonist 5-HT2A partial agonist 5 -HT6 antagonist 5-HT7 antagonist Protein 30S ribosomal subunit inhibitor


(pre-registered) acts as a D3-preferring D2/D3 receptor partial agonist. Notably, the D3 receptor is an autoreceptor that controls the phasic, as opposed to the tonic, activity of dopamine neurons, which is proposed to mediate behavioral abnormalities elicited by glutamate/N-methyl-D-aspartic acid receptor blockade [82]. Two positive Phase III trials in acute schizophrenia have been announced in press releases by Forest Laboratories. In one fix-dose study, 617 adults were randomized to receive double-blinded cariprazine 3 mg/day, cariprazine 6 mg/day, aripiprazole 10 mg/day or placebo for 6 weeks. Statistically significant improvements of the Positive and Negative Syndrome Scale (PANSS) total score were observed in both cariprazine arms (3 mg/day: -6.0, p = 0.0044 and 6 mg/day: -8.8, p < 0.0001) and with aripiprazole compared to placebo treatment. The change from baseline PANSS total score was statistically significant at every time point, starting at week 1 with the 6-mg/day cariprazine group and at week 3 with the 3-mg/day group. In a second, fixedflexible dose study, 446 adults were randomized to receive cariprazine 3 -- 6 mg/day, cariprazine 6 -- 9 mg/day or placebo for 6 weeks. Again, compared to placebo statistically significant improvements of the PANSS total score were found in both cariprazine dose groups (3 -- 6 mg/day: -6.8, p = 0.0029 and 6 -- 9 mg/day: -9.9, p = 0.0001). Statistically significant change from baseline was achieved at week 1 for the cariprazine 6 -- 9 mg/day group and at week 2 onwards the for the cariprazine 3 -- 6 mg/day group. Most common adverse effects of caripirazine were akathisia, headache, insomnia, restlessness and EPS [82]. With brexpiprazole, developed by Otsuka, another D2 partial agonist emerges (currently under review by the FDA). Brexpiprazole is considered a pharmacologic successor of the much prescribed aripiprazole, whose patent life will expire in the US in April 2015. In the development of brexpiprazole, the attempt was made to reduce the D2 partial agonist activity of aripiprazole and to slightly increase the histaminergic blockade in order to attenuate akathisia/restlessness and insomnia effects. To our knowledge, no results of the three Phase II clinical studies in schizophrenia have been published or announced, so far. However, positive results were already presented for major depressive disorder (MDD) [83]. FDA submission of brexpiprazole in monotherapy for schizophrenia and as an adjunct to antidepressants for MDD occurred in July 2014 [84].

Novel and/or specific dopamine and serotonin receptor modulation: RP-5063, zicronapine, ITI-007

5.2

Beyond postsynaptic dopamine modulation, SGAs have added blockade or partial agonist activity at various serotonergic receptors and/or blockade at the a2 adrenergic autoreceptor [48]. In order to minimize weight gain, metabolic adverse effects, sedation and anticholinergic effects, newer SGAs as well as emerging targets have less pronounced antagonism at H1 and muscarinergic receptors.




RP-5063 by Reviva Pharmaceuticals was developed as a dopamine-serotonin system stabilizer with partial agonism of D2 D3, D4, 5-HT1A and 5-HT2A receptors and additional antagonism of the 5-HT6 and 5-HT7 receptors. In a multi-centre, global Phase II study, 234 patients with acutely exacerbated schizophrenia or schizoaffective disorder were randomized in a 3:3:3:2:1 ratio to once daily RP-5063 at 15, 30 or 50 mg/day, placebo or aripiprazole 15 mg/day. Broad efficacy (defined as ‡ 20% improvement of baseline PANSS total score and a two-point improvement on the Clinical Global ImpressionsSeverity scale was present in 46% of patients on RP-5063 15 mg/day, 32% on RP-5063 at 30 mg/day and 33% on 50 mg/day, compared with 19% of patients on placebo. Notably, there were no differences relative to placebo regarding body weight, lipids and blood glucose after 4 weeks of RP-5063 reatment [85]. Zicronapine is a tetracyclic azepine with affinity for the 5-HT2A/2C as well as D1/D2 receptors, developed by Lundbeck. In an exploratory, placebo-controlled Phase II study, 280 patients were randomized in a 2:1 ratio to zicronapine (3, 5, 7 and 10 mg/day) or placebo for 8 weeks. The primary focus of this trial was safety and tolerability measured by adverse effects, clinical safety laboratory tests and metabolic parameters. Secondary outcomes included PANSS and CGI-S and CGIImprovement (CGI-I) scores. At 7 mg/day and 10 mg/day, significant reductions in PANSS total score were reported, while CGI results and ES s were not mentioned [86]. In a second, 12-week, randomized, double-blind Phase IIb trial with 93 patients, zicronapine 5 -- 7 mg/day was compared with olanzapine 10 -- 15 mg/day. The primary outcomes included the PANSS total score, secondary outcome included CGI-S/I and Calgary Depression Scale for Schizophrenia scores. Comparable PANSS score reductions were shown for both active drugs (Lundbeck 18 December 2009). Zicronapine was safe and tolerable in both studies. Results of another 6-month, fixed-dose (7.5 mg/day), risperidone-controlled, Phase III trial in 160 patients have not been published, but further Phase III studies of zicronapine are planned according to a latest press release [87]. Combining novel modulation of the dopamine system in combination with different serotonin functions is targeted by Intra-Cellular Therapies with its drug ITI-007. ITI-007 is an orally available, potent 5-HT2A receptor antagonist, dopamine receptor phosphoprotein modulator and serotonin reuptake inhibitor. ITI-007 modulates phosphoprotein signaling pathways downstream of dopamine receptors, acting simultaneously as a postsynaptic dopamine D2 receptor antagonist and as a presynaptic dopamine D2 receptor partial agonist with mesolimbic/mesocortical selectivity in vivo [88]. Additionally, ITI-007 also indirectly modulates glutamatergic activity by increasing the phosphorylation of the NR2B, or GluN2B, subunit of NMDA channels, exerting this activity apparently only in extrastriatal dopamine-rich brain regions (e.g., the nucleus accumbens). Its high 5-HT2a/D2 ratio that provides dose-dependent engagement of D2 and 5-HT2a and the

presynaptic partial D2 agonism may imply utility in different neuropsychiatric indications at different dose levels. In a Phase IIb, randomized, double-blind, placebo- and activecontrolled trial, 335 patients with acutely exacerbated schizophrenia were randomized to receive one of four treatments for 4 weeks: 60 mg/day ITI-007, 120 mg/day ITI007, 4 mg/day risperidone or placebo in a 1:1:1:1 ratio for 28 days. The primary end point was the change from baseline to day 28 in the PANSS total score. Results in 311 analyzed patients demonstrated that patients treated with ITI-007 60 mg/day experienced a mean 13.2 point reduction in the PANSS total score compared to a mean reduction of 7.4 points in patients on placebo (p = 0.017) for an antipsychotic ES of 0.4. ITI-007 120 mg/day did not separate from placebo, but risperidone did, with a similar ES s as ITI-007 60 mg/day. However, in a post-hoc analysis, unlike risperidone, ITI-007 improved the PANSS negative symptom subscale score with an ES of 0.34 in a subgroup of patients with prominent negative symptoms at baseline. Similarly, unlike risperidone, ITI-007 at 60 mg/day did not worsen certain negative symptoms, such as blunted affect and it improved the PANSS prosocial factor with a larger ES than risperidone (0.6 vs 0.4). Finally, at 60 and 120 mg/day, ITI-007 was associated with adverse effects that were generally comparable to placebo, except for greater sedation, which was highest with ITI 120 mg/day. Moreover, ITI-007 showed a favorable profile compared to risperidone regarding prolactin, extrapyramidal adverse effects and several metabolic adverse effects [89,90].

Serotonin receptors: eltroprazine, pimavanserin, MT-210, AVN-211

5.3

Eltroprazine, a piperazine derivate, is in development by PsychoGenics to treat cognitive impairment associated with schizophrenia. It acts as a partial 5-HT1A/2B receptor agonist, which suggests that eltroprazine may be useful for normalizing prefrontal cognitive abilities, reducing aggression and impulsivity, and improving cognitive function in schizophrenia. Eltroprazine (unknown dose taken orally over 8 weeks) was tested adjunctively with antipsychotics in a Phase II, randomized, double-blind, placebo-controlled parallel trial in 50 adults with schizophrenia. The primary outcome was the MATRICS Consensus Cognitive Battery (MCCB), administered at baseline and monthly. Although the estimated completion date of this trial was in 2012 [91], no results have been published so far. Additionally, eltroprazine was tested for treatment of ADHD and dyskinesia in Parkinson’s disease. It was well tolerated; the most common treatment emergent adverse events were gastrointestinal [92]. Pimavanserin, a selective 5-HT2a/2c inverse agonist has been tested by Acadia as an add-on agent to antipsychotics for additional antipsychotic activity. In a 6-week, placebo-controlled, Phase II trial, 423 patients with chronic schizophrenia experiencing an acute exacerbation were randomized to receive 2 mg/day risperidone + placebo, 2 mg/day risperidone + 20 mg/


11



day pimavanserin, 6 mg/day risperidone + placebo, 2 mg/day haloperidol + 20 mg/day pimavanserin or 2 mg/day haloperidol + placebo [60]. In this study, a sub-effective risperidone dose of 2 mg/day combined with 20 mg/day pimavanserin aiming to increase 5-HT2A receptor blockade resulted in significantly greater efficacy than 2 mg/day risperidone + placebo at study end point (-23.0 vs -16.3; p = 0.007). In addition, faster onset of action, measured by a ‡ 20% reduction in PANSS total score after 2 weeks, was demonstrated for the 2 mg/day risperidone + 20 mg/day pimavanserin group compared to both risperidone + placebo groups: 2 mg/day risperidone + 20 mg/ day pimavanserin 62.3%; 6mg/d risperidone + placebo 42.0% (p = 0.01) and 2 mg/day risperidone + placebo 37.7% (p = 0.002). At the 6-week end point, 2 mg/day risperidone + 20 mg/day pimavanserin versus effective dose 6 mg/day risperidone showed equal efficacy and no difference in EPS, but less weight gain (p = 0.05) and hyperprolactinemia (p = 0.0004). 2 mg/day haloperidol + placebo and 2 mg/day haloperidol + 20 mg/day pimavanserin were not significantly different from each other regarding efficacy, but haloperidol combined with 20 mg/day pimavanserin had marginally fewer EPS at endpoint measured by the Simpson Angus Scale (0.3 vs 0.6; p = 0.07) [60]. These results suggest that pimavanserin may be able to enhance efficacy only of subtherapeutic doses of risperidone, enabling a dose-dependent sparing of antidopaminergic adverse effects. However, different from psychosis associated with schizophrenia, pimavanserin has been superior in monotherapy to placebo regarding psychosis associated with Parkinson’s disease [93]. MT-210, developed by Mitsubishi Tanabe, uses a novel approach involving the combination of 5-HT2A and sigma-2 antagonism. According to a press release, in a double-blind, randomized, placebo-controlled study including 100 patients with schizophrenia or schizoaffective disorder, MT-210 demonstrated a significant reduction of negative symptoms (measured by PANSS) and improvement in cognition (measured by Brief Assessment of Cognition in Schizophrenia Instrument) without providing further details about study duration or ESs [94]. Another approach is the small-molecule 5-HT6 antagonist, AVN-211, under development by Avineuro, aiming at cognition improvement in schizophrenia. In a double-blind, placebo-controlled Phase IIa pilot study, 42 patients on stable antipsychotic therapy were randomized to 4 mg/day AVN211 or placebo for 4 weeks. Treatment effects were measured using common clinical rating scales (e.g., PANSS, CGI-S) and the attention tests: Digit Symbol Coding, Schulte Tables, Continuous Attention Task and Subtest VIII of Wechsler Adult Intelligence Scale (WAIS). At the end point, a near-significant reduction in the PANSS positive subscale (p = 0.058) and in the CGI-S (p = 0.0068) were demonstrated. The attention tests were not different at study endpoint, except for the subtest VIII of the WAIS, which favored AVN-211 (p = 0.02) [95]. As per a press release, Avineuro Pharmaceuticals, Inc., plans to start additional clinical trials with AVN-211 in Alzheimer’s disease [96]. 12

Glutamate receptors: ADX-71149, bitopertin, RG-1678

5.4

Currently, ADX-71149, under development by Addex for the treatment of schizophrenia, anxiety and depression, is the only selective modulator of the metabotropic glutamate2 (mGLu2) site that is under development for schizophrenia after Lilly had negative results from a large Phase III development program for the mGLu2/3 agonist pomaglumetad [19,20]. ADX-71149 was tested in patients with schizophrenia in two different designs. In part A, 15 drug-naive subjects with subacute psychosis received ADX-71149 50 mg/day titrated up to 150 mg/day open label for 12 weeks. In part B, 92 subjects on stable antipsychotic treatment with residual positive symptoms (n = 25), predominant negative symptoms (n = 47) or insufficient response to clozapine (n = 20), received adjunctive ADX-71149 50mg, 150mg or placebo. In part B, the primary end point regarding safety and tolerability was apparently met, and 50 mg/day was reported to be effective in patients with negative symptoms [97,98]. After the glycine transporter-1 (GlyT-1) reuptake inhibitor Org-25935 used adjunctively with antipsychotics was unsuccessful in treating persistent negative symptoms [99] and after the termination of Phase II clinical trial programs of other GlyT-1 inhibitors (AMG-747, PF-03463235 and PF-02545 920) [100] bitopertin (RG-1678) is the only GlyT-1 (reuptake inhibitor that was tested in Phase II or III for schizophrenia. In a large, 8-week, double-blind, Phase IIb study, 323 patients with persistent, predominant negative symptoms were randomized to bitopertin 10, 30, 60 mg/day or placebo. The primary outcome was change in the PANSS negative factor score. At least, in per protocol (but not ITT) analyses, bitopertin was associated with a significant reduction in negative symptoms at 10 mg/day (p = 0.049) and 30 mg/day (p = 0.03), but not with 60 mg/day. In addition, a significantly higher response rate and a trend towards improved functioning were demonstrated in the 10 mg/day bitopertin group compared to placebo [101]. However, results were only positive in per protocol analyses and not in intent-to-treat analyses. On the basis of these Phase IIb trial results, an impressively large, placebo-controlled Phase III trial program was started. This Phase III program included 6 adjunctive trials, three 24-week trials for patients with persistent, predominant negative symptoms and three 12-week trials for patients with suboptimally controlled positive symptoms, each with exploratory end points at 52 weeks. Further, a Phase II/III study testing bitopertin as monotherapy for patients with acute exacerbation of schizophrenia was also conducted [102]. According to recently published papers and presented posters, bitoperin at 5, 10 and 20 mg/day was well tolerated, but two completed adjunctive treatment trials in patients with predominant negative symptoms [103,104] and one completed adjunctive treatment trial in patients with sub-optimally controlled positive symptoms were negative [105]. Of the remaining three adjunctive treatment trials, two were discontinued for futility in interim analyses [106]. In only one recently completed




trial in patients with residual positive symptoms, the 10-mg arm separated significantly from placebo regarding the PANSS positive score, which was the primary outcome [106]. In addition, the only monotherapy Phase II/III trial that compared bitopertin 10 and 30 mg/day with placebo in 301 patients with suboptimally controlled positive symptoms and that included olanzapine as an active control was a failed trial, as neither bitopertin nor olanzapine separated from placebo on the primary end point, PANSS total score, after 4 weeks of treatment [107]. Another agent, neboglamine (XY-240), a glycine site positive allosteric modulator, is under development by Rottapharm Madaus. As per Rottapharm Madaus, the Phase II study was designed, but is currently on hold. PDE inhibitors: OMS-824, PF-2545920 PF-2545920 (MP-10) failed to show efficacy as a monotherapy in patients with acute exacerbation of schizophrenia [108]. After terminating a placebo-controlled Phase II trial of the PDE-10a inhibitor PF-2545920 (MP-10) in February 2008, Pfizer is currently testing PF-2545920 in the adjunctive treatment of out-patients with sub-optimally controlled symptoms of schizophrenia [109]. OMS-824, currently in Phase II testing by Omeros, represents the second PDE-10 inhibitor still in clinical testing for schizophrenia. The company reported first results regarding safety, tolerability and pharmacokinetics. Results showed that tolerability and pharmacokinetics of OMS-824 were not affected by concomitant antipsychotic treatment, and OMS824 was well tolerated even at high plasma levels. Future Phase II and III trials may evaluate OMS-824 as a monotherapy and as adjunctive treatment for cognitive impairment, acute exacerbation of symptoms, and/or inadequate response to antipsychotic medications in schizophrenia [110]. 5.5

Cannabinoid-1 antagonists: GWP-42003 According to GW-Pharmaceuticals’ website, GWP-42003, a cannabinoid, has shown notable antipsychotic effects in accepted pre-clinical models of schizophrenia and also demonstrated the ability to reduce characteristic movement disorders induced by currently available antipsychotic agents [111]. Recently, GWPharmaceuticals announced an ongoing Phase IIa, 6-week, placebo-controlled trial using the cannabinoid GWP-42003 adjunctively with ongoing antipsychotic treatment in schizophrenia. The primary outcome is PANSS total score change; secondary outcomes include quality of life and cognition as well as safety and tolerability of GWP-42003. This study is expected to enroll approximately 80 patients with an estimated completion date in the second half of 2015 [112]. 5.6

prospective, randomized, double-blinded, placebo-controlled Phase IIa trial in 70 schizophrenia patients, SAM-101 met the end points of improving cognitive status, minimizing negative symptoms and reducing antipsychotic-related weight gain without providing more detailed information [113]. a-7 nicotinic receptor agonists: encenicline, AQW-051, ABT-126

5.8

Currently, three a-7 nicotinic receptor agonists are in advanced stages of clinical testing for schizophrenia, encenicline (EVP-6124), AQW-051 and nelonicline (ABT-126). While safety and tolerability testing is complete for all three agents, no results are available yet for AQW-051 [114] and nelonicline (ABT-126) [115], although a Phase IIb study was recently completed for nelonicline. Encenicline (EVP-6124) by Forum (former Envivo) Pharmaceuticals works by sensitizing the a-7 nicotinic receptor to its naturally occurring ligand. In a recent proof-of-concept, randomized placebo-controlled trial in 21 patients on stable SGA treatment, EVP-6124 was well tolerated and showed positive, and in some cases, dose-dependent effects on several EEG responses, especially Mismatch Negativity and P300 potentials. Benefits were also found in cognitive tests that measured non-verbal learning, memory and executive function [116]. In a 3-month, Phase IIb trial of 319 patients on stable SGAs, two doses of EVP-6124 (0.3 and 1 mg/day) were evaluated. The primary outcome for all patients was the Overall Cognition Index (OCI) from the CogState testing battery and Trails 2 and 4 of the Neuropsychological Test Battery (NTB), with PANSS scores being a secondary outcome. Subjects in the US (n = 151) were also evaluated with the Schizophrenia Cognition Rating Scale (SCoRS) and the MATRICS Consensus Cognitive Battery (MCCB). Improvement of general cognition, measured by the OCI plus Trails 2 and 4 of the NTB, was demonstrated for the 0.3 mg/day EVP-6124 group compared to placebo (p = 0.034), mainly due to beneficial effects on visual learning, visual attention and social cognition. This positive effect was supported by a strong trend for improved cognition on the MCCB for the 1-mg/day EVP-6124 group. Significant effects on clinical function, measured by the SCoRS Interviewer Rating was shown for the 1-mg dose group (p = 0.011) versus placebo. In addition, improvement of PANSS negative symptom score was demonstrated for the 1-mg/day dose group (p = 0.028) at 3 months [117,118]. In contrast to these encouraging results, the previously tested a-7 nicotinic receptor agonists, TC-5619 by Targacept, failed to repeat positive results of a proof-of-concept study on cognition and negative symptoms in the following Phase IIb trial, leading to termination of the program [119]. Fixed-dose strategies and new routes of administration: risperidone RBP-7000, risperidone ISM, aripiprazole lauroxil, blonanserin, PNB-02, ALKS-3831

5.9

Antioxidant, anti-inflammatory and/or neuroprotective agents: minocycline (SAM-101)

5.7

SAM-101 is a lead candidate under development by XTL Biopharmaceuticals that combines minocycline with existing antipsychotic drugs. The company announced that in a

In March 2014, Janssen announced that the independent data safety monitoring board discontinued its pivotal Phase III


13



trial comparing 3-monhtly injections of paliperidone palmitate with placebo injections, after conducting a planned interim analysis after 60% (42 events) of projected relapses had occurred [120]. The interim analysis showed that 3monthly paliperidone injections significantly separated from placebo regarding the primary outcome, time to impending relapse. Paliperidone palmitate 3-month formulation utilizes Alkermes’ proprietary NanoCrystal technology, which enables solubility of poorly water-soluble compounds. The submission of the final study data to the FDA is expected to occur by the end of 2014. Additionally, novel delivery methods of sustained released formulations of risperidone are tested by Reckett Benckiser (RB-7000) and Rovi Pharmaceuticals (Risperidione ISM). RB-7000 is a long acting administration of risperidone administered once monthly by subcutaneous injection [121]. Currently, a Phase III double-blind, placebo-controlled, multi-centre study evaluates safety and tolerability of risperidone 90mg and 120mg versus placebo in 339 subjects with acute schizophrenia [122]. Rovi Pharmaceutical develops a long-acting injectable formulation of risperidone, for the treatment of schizophrenia, using its ISM (in situ microparticle) delivery system. Due to the company’s website, this formulation promises less variability, enhanced stability and a decreased number of needed doses of the active principle. Data of the Phase I trial suggest sustained delivery of risperidone after the first injection, allowing once-monthly injections without the need of supplementary oral risperidone in the first weeks [123]. Safety, tolerability and pharmacokinetics are currently tested in a Phase II trial [124]. Alkermes recently presented results of a 12-week, Phase III, multi-centre, double-blind, placebo-controlled trial of aripripazole lauroxil (ALKS-9070), a long-lasting injectable formulation of a prodrug of aripiprazole. 623 acutely exacerbated and hospitalized patients with schizophrenia were randomized to once-monthly intramuscular injections of aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg or a matching placebo injection of either high volume or low volume. Patients received a 3-week cotreatment with oral aripiprazole. Results demonstrated statistically and clinically significant placeboadjusted mean reductions from baseline in PANSS total scores (aripiprazole lauroxil 441 mg: -10.9 points, p < 0.001; aripiprazole lauroxil 882 mg: -11.9 points, p < 0.001). Moreover, both dose groups had significantly greater reductions in CGI-I scores compared to placebo (p < 0.001). Alkermes plans to submit a New Drug Application (NDA) to the US FDA in the third quarter of 2014 [125]. While Otsuka and Lundbeck already have the 1-monthly injectable formulation approved for the maintenance treatment of schizophrenia, the two companies submitted data from a 12-week trial in acutely exacerbated, hospitalized patients with schizophrenia in April 2014 to obtain the indication for acute treatment of schizophrenia. The study demonstrated efficacy of aripirazole once monthly on the primary end point of PANSS total score (p < 0.0001), as well as on the key secondary 14

end point of CGI-S score change (p < 0.0001). The three most common adverse events reported by patients receiving Abilify Maintena were weight gain, headache and akathisia [126]. Dainippon Sumitomo announced planning a Phase II study of DSP-5423P, a transdermal patch formulation of the SGA blonanserin, a 5-HT2A/D2 antagonist approved in Japan. To our knowledge, no results have been published so far [127]. Furthermore, testing is ongoing for fix-dose strategies. PNB-02 is a fix-dose combination of pipamperone and risperidone tested in a clinical Phase I/IIa proof of concept by PharmaNeuro-Boost [128]. ALKS-3831 combines the novel µ-opioid receptor antagonist samidorphan with olanzapine, aiming for less weight gain and other metabolic factors in comparison to olanzapine alone. Results are expected in the first half of 2015 [129]. Alkermes is also initiating another Phase II study of ALKS-3831 in patients with schizophrenia and comorbid alcohol use [130].

Potential additional targets: NBI-98854, oxytocin, erythropoetin 5.10

Additional targets in clinical testing to treat schizophrenia associated symptoms are the vesicular monoamine transporter 2 inhibitor (VMAT2) NBI-98854 for the indication of TD and oxytocin nasal spray for the indication of impaired social cognition in schizophrenia. NBI-98854 is under development by Neurocrine Biosciences. Its properties as a highly selective VMAT2 inhibitor may allow the regulation of dopamine release levels during dopaminergic neurotransmission, while at the same time having little impact on other monoamines, aiming the reduce ‘off target’ side effects. According to the company’s website, 109 patients with moderate-to-severe TD and schizophrenia or schizoaffective disorder received the capsule formulation of NBI-98854 in a Phase IIb, 6-week, randomized-controlled trial. The dosing was either 50 mg/ day of NBI-98854 for 6 weeks, 100 mg/day for the initial 2 weeks fallowed by 50 mg/day for the final 4 weeks or placebo for 6 weeks. The impact on dyskinesia was assessed with the Abnormal Involuntary Movement Scale. The 50-mg/day group did not reach statistical significance for the primary end point at week 6, but the 100 mg/day, showed a statistically and clinically meaningful reduction in TD symptoms at week 2 (the end of the 100mg interval, no ES given). NBI-98854 was generally safe and well tolerated. A second trial including 32 patients showed inconsistent effects, and further investigation is planned [131]. Nasal oxytocin may represent an important new adjunctive treatment option for patients with schizophrenia [132]. While in healthy volunteers single-dose intranasal oxytocin was associated with increased interpersonal trust, eye contact, emotion recognition, theory of mind and social reciprocity, in patients with chronic schizophrenia higher plasma levels of oxytocin were associated with less severe positive symptoms in women and better pro-social function in both sexes [44]. Clinical




testing of this compound has begun. A pilot 6-week randomized study of oxytocin (n = 14) on social cognition and social skills in schizophrenia showed improvements in fear recognition (p = 0.05), self-reported perspective taking (p = 0.03) and negative symptoms (p = 0.002) in the treatment group [133]. According to clinicaltrials.gov, large clinical testing of oxytocin in schizophrenia is ongoing. The effect of erythropoietin (EPO) in schizophrenia has been tested in several studies. A qualitative review of 78 studies suggests that several potential cerebral effects of EPO may be useful in treatment of schizophrenia, including neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood--brain barrier permeability, effects on oxidative stress and neurogenesis. In contrast, the potential severe side effects (e.g., increased risk of thrombosis and cancer) could severely limit clinical use, but further study is needed [134]. 6.

Potential development issues

Since the introduction of chlorpromazine, D2 receptor modulation has remained the only successful target for the development of antipsychotics. Given the lack of deeper understanding of the complete and heterogeneous pathophysiology of schizophrenia with an unknown relationship between clinical phenotypes and biological underpinnings as well as drug mechanisms, it remains unclear, which pharmacologic mechanism of action(s) will provide the highest level of efficacy, while avoiding serious side effects. Animal models are lacking that closely resemble schizophrenia and its clinical phenotypes and domains, further hampering drug development. Until the goal of dissecting the syndrome and symptom domains of schizophrenia into biological entities has been achieved, the rational development of antipsychotics or antischizophrenia medications with mechanisms other than antidopaminergic action will remain challenging. The same is true for the much needed identification of biomarkers that would ideally enable dividing patients with schizophrenia into meaningful etiological and pathophysiological subgroups, which could be matched more closely by mechanisms of actions of novel medications. In addition to this overarching shortcoming regarding the limited pathophysiologic understanding and the complexity of the conditions currently called schizophrenia, further problems in patient selection, psychiatric ratings and clinical trial conduct challenge the success of developing new medications for schizophrenia and its subdomains [46,135]. As the outcome in clinical trials is mainly measured using clinical interviews, personal impressions and expectation can bias the result increasing placebo response. Standardized rater training that includes not only passive rating of one or two unrepresentative interviews but also includes the active conduct of interviews, quality control and/or centralized ratings could help enhance objectivity and increased signal detection. Furthermore, the design of trials and its limitations (e.g., patient selection bias,

improved outcomes through trial participation, failed trials due to lack of separation of standard agents, etc.) can seriously hamper the identification of potential new agents. These general problems are accentuated when focusing on negative and cognitive symptoms that are even more difficult to assess than positive and general psychopathology. Challenges include the differentiation of primary from secondary negative or cognitive symptoms (e.g., depression, EPS, sedation, environmental deprivation), with secondary symptoms being likely more vulnerable to placebo effects. Moreover, the real-world impact of improvement in specific cognitive domains, measured with a cognitive test battery, on functional outcomes of patients remains unclear. A further complication arises from the possibility that relevant functional benefits are only achievable when psychosocial treatments are added to medications targeting negative and cognitive symptoms. However, such augmentation with active psychosocial interventions may also diminish the difference to placebo. Distinguishing whether substantial improvements in ‘persistent’ negative symptoms during placebo treatment in recent trials were due to a non-specific psychosocial effect of trial participation or more the result of expectation bias on the side of patients or raters, would help determine if psychosocial augmentation studies are a potential vehicle to enhance the signal of agents that reduce primary negative and/or cognitive symptoms. Since the enlarged placebo effect has become such an impediment for successful trials and signal detection, alternative trial designs may need to be explored. These include triple blind designs that use staggered randomization or delayed randomization only of patients without substantial early improvement, or a sequential parallel comparison design, in which placebo non-responders are re-randomized to drug or placebo, with patients and raters being blinded for when this occurs. Another possible design takes the alternative route and re-randomizes early drug responders to drug or placebo [121]. 7.

Conclusion

This article highlights the urgent need to develop novel medications that treat the entire spectrum of schizophrenia. Despite multiple approaches to rationally develop antischizophrenia medications and improved safety of newer antipsychotics, unfortunately there has been only limited progress in innovating mechanisms of action and developing novel therapeutic agents beyond the D2 receptor blockade. In addition to new agents targeting the dopaminergic system, there are several compounds in advanced clinical testing with non D2 receptor-based mechanisms of action that could lead to novel treatments for schizophrenia. Further innovative clinical research strategies that aim to minimize placebo response and increase signal to noise detection are needed, so that potentially useful medications are not dismissed too early and that likely ineffective agents are not pursued for too long. As monotherapy with non-D2 receptor-based mechanism failed to show efficacy in the past, add-on therapy of novel targets


15


to existing antipsychotics may be a promising approach. Clearly, the future identification of pathophysiologic mechanisms and biomarkers that correlate with specific symptoms dimensions and/or mechanisms of action/drug targets in patients with schizophrenia could improve drug development and personalized medicine by better identifying individuals who are likely to present a more homogenous subgroup and/or respond to specific agents/mechanisms of action.


8.

Expert opinion

Despite decades of massive pharmacologic development efforts, schizophrenia remains one of the most severe disorders, and dopamine blockade is currently the only known mechanism of action that has led to approved medications for schizophrenia. While modifications and variations of antidopaminergic mechanisms are expected to be successful, the added benefits will likely remain small, at least in the areas of broader symptomatic reach and enhanced efficacy. Greater innovation will come from further and deeper exploration of extra-dopaminergic mechanisms and from targeting the so far unmet needs of negative symptoms [136] cognitive dysfunction [137] as well as symptoms refractory to antidopaminergic therapies. However, actively pursued novel mechanisms of action for compounds targeting schizophrenia seem to be diminishing. Nevertheless, agents targeting neuro-inflammation, oxidative stress, apoptosis, neuroregeneration and neuroprotection may be important future leads [43]. To move the field forward, additional investment of resources and expertise is needed. Areas that would fertilize and accelerate the discovery of novel compounds include the development of clinically meaningful animal models, discovery of new and efficient in vivo screening mechanisms for potentially successful drug targets, such as ‘fast-fail’ proofof-clinical-mechanism and proof-of-concept trials [138] and parsing of the heterogeneous groups of schizophrenias into biologically more homogeneous subgroups. Finally, technological and neurobiological advances need to be matched by Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Acknowledgement We thank the following people who we contacted and who confirmed the correctness of publically available information and/or who provided us with additional information relevant for this article: E Ehrich, MD (Alkermes); Y Lavrovsky, PhD (Avineuro Pharmaceuticals, Inc.); I Lombardo, MD and N Ortiz, PhD (Forum Pharmaceuticals); M Rogerson (GW Pharmaceuticals); C O’Gorman, MD, MBA, N Schrameijer, MD, D Bugarski-Kirola, MD, T Haigh, DPhil, CMPP (Hoffmann-La Roche Ltd./Genentech); K Vanover, PhD (Intracellular Therapies); P Hertel, PhD (Lundbeck); R Sanchez, MD (Otsuka Pharmaceutical); Dean Mastrojohn (Pfizer); L Bhat, PhD (Reviva Pharmaceuticals, Inc.); L Rovati, MD (Rottapharm Madaus). We also thank R Goodwin for comments on an earlier draft of this paper.

Declaration of interest M Carbon has the same disclosure information as CU Correll due to family relationship. CU Correll and M Garbon have been a consultant and/or advisor to or have received honoraria from: Actelion, Alexza; American Academy of Child and Adolescent Psychiatry, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, National Institute of Mental Health, Janssen/J&J, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda. They have received grant support from Bristol-Myers Squibb, Feinstein Institute for Medical Research, Janssen/J&J, National Institute of Mental Health, Novo Nordisk A/S and Otsuka. L-S K€oster has nothing to disclose.

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Affiliation Luisa-Sophie K€oster1,2 MD, Maren Carbon2 MD & Christoph U Correll†3,4,5,6 MD † Author for correspondence 1 Technische Universita¨t Mu¨nchen, Klinik fu¨r Psychiatrie und Psychotherapie, Klinikum rechts der Isar, Mu¨nchen, Germany 2 The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, NY, USA 3 Hofstra North Shore LIJ School of Medicine, Hempstead, New York, NY, USA 4 The Feinstein Institute for Medical Research, Manhasset, New York, NY, USA 5 Albert Einstein College of Medicine, Bronx, New York, NY, USA 6 The Zucker Hillside Hospital, Psychiatry Research, Glen Oaks, New York, NY 11004, USA Tel: +1 718 470 4812; Fax: +1 718 343 1659; E-mail: [email protected]

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