Lilly’s antipsychotic axe will shift attention to Roche.
Lilly's antipsychotic axe will shift attention to Roche
Development of Lilly’s pipeline glutamate receptor agonist, pomaglumetad methionil, has been discontinued following a confirmed lack of efficacy. Disappointingly, this promising new mechanism fails to translate into a viable drug, although Roche’s commitment to its own novel schizophrenia candidate, RG1678, shows that drug developers are not yet ready to move away from psychiatry.
Eli Lilly has announced that a futility analysis of its second pivotal Phase III trial of pomaglumetad methionil in schizophrenia suggested that a positive outcome was unlikely, prompting the company to discontinue all development of the candidate. The company also revealed that a mid-stage study of the drug as an add-on to common atypical antipsychotics also failed.
The drug, also known as LY2140023, now leaves behind a less-than-impressive list of negative or inconclusive studies. Eli Lilly reported in July that pomaglumetad methionil’s first potential registration study missed its primary endpoint while an active comparator significantly beat placebo. Previously, a second large Phase II trial failed to demonstrate efficacy at four different doses. Indeed, the only positive result came from a short-term trial conducted in Russia in which pomaglumetad methionil significantly improved schizophrenia symptoms compared to placebo but was again outperformed by a comparator.
The decision to pursue pomaglumetad methionil, a drug with an untried mechanism (agonism of glutamate 2 and 3 receptors), was always likely to carry substantial risk. Currently successful antipsychotics are commonly targeted against dopamine and serotonin receptors, although they fail to adequately address the negative and cognitive symptom domains of schizophrenia patients, and are associated with a broad range of side effects. Lilly was hoping that pomaglumetad methionil could occupy the sizable niche left by such drugs, which include its own blockbuster Zyprexa (olanzapine; Eli Lilly) and competitor antipsychotics Seroquel (quetiapine; AstraZeneca) and Abilify (aripiprazole; Bristol-Myers Squibb/Otsuka). However, as is all too often the case in psychiatry, innovation was met with clinical failure.
The next company with hopes of redefining the way schizophrenia is treated is Roche, whose own candidate, RG1678 (bitopertin), acts through inhibition of glycine reuptake – another variation of the glutamate hypothesis for schizophrenia. RG1678 is currently in the midst of a large Phase III program, entailing six separate trials which involve a total of approximately 3,600 patients with either suboptimally controlled or predominantly negative symptoms of schizophrenia. Datamonitor forecasts potential sales in excess of $500m for RG1678 in the seven major markets (the US, Japan, France, Germany, Italy, Spain, and the UK). While many of Roche’s Big Pharma peers have visibly scaled back research into disorders such as depression, bipolar disorders, and schizophrenia, RG1678’s extensive development program is a welcome sign that not all companies are ready to move away from the lucrative psychiatry field.