Schizophrenia is a major disorder of brain function, prevalent in 1% of the population worldwide and estimated by the World Health Organisation to be the fifth leading worldwide cause of disease. Symptoms of schizophrenia can be categorized as positive and negative; positive symptoms can include hallucinations, delusions and disordered thoughts and speech, while negative symptoms include apathy, poverty of speech, anhedonia (inability to experience pleasure) and social withdrawal. In general, positive symptoms are treated fairly well by antipsychotics but there is an unmet need for drugs that are able to treat the negative symptoms and these largely untreated symptoms remain a huge barrier to the resumption of a fully functional, “normal” life for affected individuals. Being unable to do so results in a huge emotional and societal burden, from the costs of the diseases management to the impact on caregivers and resources with an annual estimated cost in the UK alone of around £12 billion. Additionally, an inability to function and contribute to society often leads to withdrawal and depression, leading to a suicide rate of 4-5% in the schizophrenic population.
In January of this year, Roche announced that two Phase III clinical trials of bitopertin (RG1678, see here), a glycine transporter 1 (GlyT1) inhibitor, failed to achieve their primary end-point in the treatment of the negative symptoms of schizophrenia – severely reducing hopes that this might be the first drug to target currently untreatable negative symptoms (see here). At that time, four additional Phase 3 studies were continuing. However, in their quarterly report last month, the company stated that an additional Phase 3 study looking at sub-optimally controlled symptoms, such as hallucinations and delusions, also failed its primary endpoint (see here)In the light of these results, the company terminated two of the remaining three studies leaving just one study in sub-optimally controlled symptoms active.
And so once more a much-touted, potential breakthrough CNS therapeutic has essentially failed, prompting the obvious question of why? Well, the Phase III studies were triggered by a Phase II 8-week study of bitopertin in 2010, which demonstrated a significant improvement in negative symptoms compared to placebo, as measured by the PANSS negative symptom factor score (see Figure), although in retrospect, the narrow therapeutic window, with efficacy at 10, 30 but not 60 mg doses, might have been a cause for concern. However, this is not the first time (and unfortunately it will probably not be the last time) that Phase 2 efficacy does not translate into Phase 3 efficacy for a novel CNS therapeutic (with Merck’s NK1 antagonist being perhaps the most spectacular recent example). And at least Roche had positive Phase 2 data rather than the “Intriguing preliminary data” in a negative Phase 2 study that was the basis for Lilly to commence Phase 3 studies with their mGlu2/3 agonist pomaglumetad methionil (see here).
This once positive outlook of bitopertin can have only intensified the disappointment not only of Roche but also a neuroscience community in general. From a mechanistic point of view, the Roche data also calls into question the efficacy of therapeutically modulating glutamatergic pathomechanisms, thought to underpin schizophrenia and complement the dopaminergic hypothesis the underlies the positive symptoms. Roche’s rationale was to target the glycine transporter, GlyT1, and inhibit it with bitopertin in an effort to raise the synaptic levels of glycine and thereby increase the activity of NMDA receptors, for which glycine is a co-agonist along with glutamate. This is based on increasing evidence that implicates dysfunction in glutamatergic signaling pathways, specifically a hypofunction in NMDA receptor signaling, in the pathogenesis of schizophrenia and the appearance of negative symptoms and is also the basis of several other therapeutic approaches, including modulation of the mGluR2 and mGluR5 receptors. While it would be unwise to attempt to directly activate NMDA receptors, indirectly modulating NMDA receptor activity by blocking the reuptake transporter of glycine, has been an attractive and less risky alternative. An alternative approach to treating the negative symptoms of schizophrenia is being pursued by AbbVie and EnVivo who are both targeting nicotinic acetylcholine receptors and it is to be hoped that one or both of these drugs makes it to market to reenergize the beleaguered neuroscience therapeutic area.
Figure taken from Roche’s December 2010 pipeline update (see here).