Schizophrenia treatments

The schizophrenia market is expected to change dramatically in the next few years. Historically, compounds offering even modest efficacy or tolerability advantages captured double-digit market shares. The market was expected to grow in 2010 and 2011, with sales projected of $16.5bn. Despite the launch of numerous developmental agents, the market is anticipated to fall to just $4.6bn in 2017. Now, companies must convince prescribers and payers that their drugs are fundamentally safer or significantly more effective than the myriad of currently available, and soon to be generic, options.

Existing antipsychotics used to treat schizophrenia are comparable in terms of efficacy. The main distinguishing features between them are their frequency of administration, cost and adversity profiles. First-generation antipsychotics (such as chlorpromazine) are relatively efficacious but have a high risk of parkinsonian extrapyramidal side effects, including rigidity, bradykinesia, tremor, akathisia (subjective and objective restlessness) and tardive dyskinesia.

Second-generation, or atypical, antipsychotics have a more favourable adversity profile. Although these second generation antipsychotics are more widely used than older generation products, they are still associated with adverse events such as obesity, type 2 diabetes, dyslipidemia and hypertension. 

The development of long-acting (depot) intramuscular formulations of existing antipsychotic agents has been pursued in order to minimise non-compliance, a major issue in schizophrenia, leading to relapse and hospitalisation. Available depot formulations include two older generation agents (fluphenazine decanoate and haloperidol decanoate) and three second generation antipsychotics (Risperdal Consta, InvegaSustenna and Relprevv/Zypadhera). However, these formulations have been poorly received by patients and physicians, and use of depots is not expected to increase significantly over the next several years, according to inThought analysts.

Newly available agents
Expectations of new entrants for the treatment of schizophrenia have been high, but the need for twice-daily dosing in a patient population where compliance is poor, coupled with high price tags in an increasingly generic market, have led to disappointing sales. 

Iloperidone, approved in the US in July 2009, is a serotonin receptor antagonist and dopamine D2 receptor antagonist dosed twice daily. Iloperidone has a comparatively benign side effect profile – low weight gain, no induction of diabetes, low extrapyramidal symptoms, no akathisia or hyperprolactinaemia, and a low negative effect on cognition compared with placebo. Yet, full-year 2010 sales, as reported by the company, totalled just $31.4. inThought analysts, however, project $325m in worldwide sales by 2018. 

Asenapine is a twice-daily, sublingual tablet approved in the US for the treatment of acute schizophrenia and bipolar disorder in August 2009. In September 2010, the US FDA approved label expansions to include treatment of schizophrenia in adults, as monotherapy for the acute treatment of bipolar I disorder in adults, and as adjunctive therapy with either lithium or valproate for the acute treatment of bipolar I disorders in adults. Sales figures have not yet been posted, although it is projected that worldwide sales will be $629m by 2018. 

Lurasidone, an antagonist of dopamine D2, serotonin 2A, serotonin 7, serotonin 2C and a partial agonist of serotonin 1A, is being marketed by Sunovion Pharmaceuticals. Approved in October 2010, the once-daily tablet was expected to hit the US shelves in March with an expected sales force of 336 reps, emphasising a safer cardiovascular risk profile. While dosing may be less of an issue than for asenapine and iloperidone, the high price of $14 per dose will hinder adoption. Worldwide sales are forecast to reach $650m by 2018.

Unique delivery system
An inhaled formulation of the D2 receptor antagonist loxapine is being developed by Alexza Pharmaceuticals for the treatment of acute agitation in patients with schizophrenia and bipolar disorder. The product uses the Alexza's Staccato hand-held, disposable inhaler technology which vaporises loxapine by heating a thin film of the agent. 

Results reported in May 2010 showed that administration of inhaled loxapine rapidly treated the five individual dimensions of agitation in patients with schizophrenia or bipolar I disorder in additional efficacy analyses of two phase III trials. 

Alexza submitted a New Drug Application (NDA) in December 2009. However, the US launch has been pushed back to September 2012 following an End-of-Review meeting with the FDA in January 2011. Alexza expects to resubmit the NDA for inhaled loxapine in July 2011. 

The majority of schizophrenia treatments are in the form of tablets or intramuscular injection. Alexza's unique delivery of loxapine via inhalation may prove useful to patients due to its reportedly rapid onset of therapeutic effect coupled with its non-threatening route of administration. These attributes are especially important in swiftly calming the symptoms of agitation in patients with schizophrenia.

Cognitive dysfunction
In addition to behavioural symptoms such as agitation, cognitive dysfunction (in areas such as attention, vigilance, memory and reasoning) is a significant field of research in schizophrenia. A current focus is the development of products that target receptors involved in cognition. 

With this in mind, Targacept is developing TC 5619, an orally administered small molecule that is highly selective for the α7 nicotinic acetylcholine receptor (α7 nAChR). Theα7 nAChR is associated with sensory gating and cognition, and compounds that modulate this target could play a role in protection of neuronal cells from deterioration and death. Therefore, such α7 nAChR agonists offer a treatment strategy for cognition disorders and schizophrenia. 

This agent is in phase II development for the treatment of cognitive dysfunction in schizophrenia and adult attention-deficit hyperactivity disorder, and phase I development in Alzheimer's disease. Results from a phase II, proof-of-concept trial showed that TC 5619, as augmentation therapy to quetiapine or risperidone, was effective in 185 patients with cognitive dysfunction in schizophrenia. TC 5619 met the pre-defined success criteria on the Groton Maze Learning Task at two of the trial's three measurement dates. 

US approval is anticipated in March 2015 and worldwide sales of $290m by 2018. There is presently no product approved in the US or Europe for the treatment of cognitive dysfunction in schizophrenia, and therefore Targacept's TC 5619 may provide a novel treatment in this arena.  

Dopamine receptor
There is an assortment of products that act on the principal neurotransmitter systems associated with psychosis, namely dopamine and serotonin. Gedeon Richter is developing cariprazine, a potent, orally administered dopamine D3 and dopamine D2 receptor antagonist for the treatment of schizophrenia, bipolar disorders and other psychiatric conditions. 

In preclinical studies, cariprazine has been shown to act as a dopamine system stabiliser through preferential D2 receptor binding. It has low potency at other receptor sites, such as serotonin 2C, histamine H1 and adrenergic receptor sites, which have been associated with adverse events. 

In a phase II trial, 732 patients with schizophrenia were randomised to receive cariprazine, risperidone or placebo for six weeks. Significant improvements in the Positive and Negative Syndrome Scale (PANSS) and in the Clinical Global Impression-Severity Score were observed after six weeks for all cariprazine doses, compared with placebo. 

Forest Laboratories and Gedeon Richter have started phase III trials of cariprazine in patients with schizophrenia and bipolar I disorders. An NDA submission is anticipated in 2012. However, new antipsychotics such as cariprazine will face competition from launches of generics over the next few years, and may gain only limited uptake. Worldwide revenue projections for inhaled loxapine, cariprazine and TC 5619 are represented in figure 1.  

Figure 1. Worldwide revenue projections for developmental schizophrenia agents
(click image to enlarge)

Glutamate focus
The interaction of glutamatergic and dopaminergic systems in the pathophysiology of schizophrenia has been widely documented, and studies suggest that high glutamate levels precede the onset of schizophrenia. While most antipsychotics act on the dopamine receptors, Eli Lilly is developing pomaglumetad methionil, an agonist of the metabotropic glutamate receptor types 2 (mGluR2) and 3 (mGluR3) for the treatment of schizophrenia. 

The compound is an oral prodrug of LY 404039, which is thought to reduce the presynaptic release of glutamate, an amino acid that functions as an excitatory neurotransmitter in regions of the brain where mGluR2 and mGluR3 receptors are expressed. A proof-of-concept phase II trial and a larger phase II trial of pomaglumetad methionil have been completed. However, results were inconclusive. In the larger phase II trial, comparing pomaglumetad methionil with placebo and olanzapine in 393 patients with acute schizophrenia, neither pomaglumetad methionil nor olanzapine (known to be more effective than placebo) were significantly different from placebo with respect to improvements in PANSS total score. 

The higher-than-expected placebo response (14.6-point improvement) was approximately double that historically seen in schizophrenia clinical trials. The proof-of-concept trial in 196 patients with schizophrenia, however, showed pomaglumetad methionil was superior to placebo at controlling the positive and negative symptoms of schizophrenia. Eli Lilly has initiated a phase III trial to determine whether at least one dose level of pomaglumetad methionil given to 950 acutely ill patients with schizophrenia will demonstrate efficacy. Phase III trials are expected to be completed in 2013. 

Roche and Chugai Pharmaceutical are partnering on small molecule compound RG 1678; an orally administered inhibitor of the glycine transporter GlyT1, which may act to restore appropriate levels of the neurotransmitter glutamate. Once-daily oral RG 1678 significantly improved negative symptoms in patients with schizophrenia in a phase II, double-blind, parallel, multicentre trial conducted in 323 patients. The change from baseline in the PANNS negative symptom factor score was significantly more favourable with RG 1678 than with placebo. 

RG 1678 is undergoing phase III clinical development in the US and in several countries globally. A submission for regulatory approval is planned for 2013. Glutamate appears to be an important area of research and development in schizophrenia, and further investigation in this field may warrant important findings.

The Author
Pipeline was written by Julia Watson of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought^TM. For Further information on Adis services, please contact Kuljeet Sohanpal on +44 (0) 207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com