Boehringer Ingelheim Refocuses PDE9 Inhibition Brain Research on Schizophrenia

Boehringer Ingelheim announced that their Phase II Alzheimer's disease trials with investigational compound BI 409306 had not met their efficacy endpoints and plans for further trials with BI 409306 in AD will therefore not be pursued. Instead, the company will refocus efforts on the ongoing schizophrenia trials with this compound.

These AD trials were part of an extensive clinical trial program exploring the efficacy of compounds which target malfunctioning of specific (glutamatergic) brain circuits as potential new treatments for specific symptoms and traits of mental illness. As such, the investigational compound BI 409306 was explored in patients with cognitive impairment and those with memory dysfunction in schizophrenia and in Alzheimer's disease. Future investigations will focus on two studies in schizophrenia, aimed at prevention of relapse and at prevention of occurrence of a first psychotic episode.

Boehringer Ingelheim's continued engagement in the dementia field is confirmed by the planned Phase II trials investigating another compound, BI 425809, a GlyT1 inhibitor, in a range of central nervous system (CNS) indications which also include Alzheimer's disease.

"We recognize the immense anticipation around any progress in brain research that brings us closer to finding solutions for the many millions of people living with dementia. However, this is what research is about: disappointments are a daily experience in science, but even these clinical trial results will add to the understanding of brain function and contribute to future progress in this area," said Jan Poth, Ph.D., therapeutic area head CNS Diseases at Boehringer Ingelheim.

Mental illness remains one of the greatest health, social and economic challenges of our time and despite intensive efforts over many years, there is still no cure for Alzheimer's and little in the way of treatments. As supporters of the European Federation of Pharmaceutical Industries and Associations (EFPIA) "We won't rest" initiative, Boehringer Ingelheim is determined to progress a deeper understanding of the brain pathways impacting mental illness. The recent Phase II trial results will add to the body of evidence and help refine CNS clinical trial programs in the future.

About BI 409306 and Phase II in Alzheimer's Disease Study Overview:

BI 409306 is a potent and selective phosphodiesterase E9A (PDE9A) inhibitor that targets the glutamatergic signaling pathways in the brain to increase synaptic strength and plasticity. These pathways are malfunctioning in schizophrenia and considered to be the pathophysiological basis of its positive, negative and cognitive symptoms. Dopaminergic pathways, which are also malfunctioning in schizophrenia, are understood to cause the psychotic exacerbations characteristic of relapse. Due to the functional interaction of the dopaminergic with the glutamatergic system in the pathophysiology of schizophrenia, it is conceivable that PDE9 inhibition might present an approach for prevention or reduction of symptomatic relapse.

• BI 409306 was investigated in two studies (NCT 02240693 and NCT 02337907), designed to show superiority of BI 409306 over placebo in cognition. Topline data were pooled for analysis.
• The studies were designed to show superiority of BI 409306 over placebo in cognition.
• Further analysis will be needed to fully understand the results and how best to shape future research in Alzheimer's disease
• The Phase II 12-week placebo controlled trials in Alzheimer's disease enrolled 457 participants in total.
• The aim of the trials was to investigate the efficacy, safety and tolerability of BI 409306 compared to placebo given for 12 weeks in patients with cognitive impairment due to Alzheimer's disease.
• BI 409306 blocks the action of a protein called phosphodiesterase 9A (PDE9A). Blocking the action of PDE9A improves signaling in certain parts of the brain/in the glutamatergic circuit of the brain. These pathways are thought to effect brain functions that are important to memory and learning.

Body of Evidence

• In 2017 the number of people believed to be living with some form of dementia is 50 million. This number will double almost every 20 years, reaching 75 million by 2030 and 131.5 million by 2050.
• Traditional research approaches for mental illness have not delivered sufficient solutions that truly improve people's lives.
• Cognitive impairment is one of a number of symptoms in mental illness that Boehringer Ingelheim is investigating by applying a systematic neurobiological approach to address these symptoms that goes beyond current disease classification.

About Relapse in Schizophrenia

Schizophrenia is a chronic, severe, and disabling brain disorder that may be caused by a combination of neurobiological and environmental factors. It affects about one percent of the world´s general population and occurs in men and women equally and at similar rates in all ethnic groups around the world. The onset of schizophrenia typically begins in early adulthood, but an individual may be diagnosed at any age.

The symptoms of schizophrenia fall into three broad categories: positive symptoms (e.g., delusions, hallucinations, disordered thoughts), negative symptoms (e.g., restricted mood and drive), and cognitive symptoms (e.g., poor executive functioning, trouble focusing or paying attention, and the impairment of working memory, verbal and visual learning, and visual spatial memory). All of these significantly impact daily living.

Existing treatment options for schizophrenia are primarily efficacious in treating positive symptoms and have limited, if any, efficacy for the prevention of relapse. Currently no specific therapy exists for the prevention of psychotic relapse in patients with schizophrenia, despite its high frequency. In subjects presenting with first-episode schizophrenia, relapse rates exceed 80% within five years, and relapse itself represents an important predictor of subsequent deterioration approximately tripling healthcare costs in the year following. Further, multiple relapses have been associated with poorer long-term outcomes.

About First Episode of Psychosis in Schizophrenia

'Psychosis' is a clinical term that refers to a loss of contact with reality, in which people have trouble distinguishing between what is real and what is not. Approximately three out of every 100 people will experience a psychotic episode in their lifetimes. Psychosis usually first appears in a person's late teens or early twenties. It occurs in men and women and across all cultures and socioeconomic groups. Psychosis is a symptom of several mental disorders, including schizophrenia.

A first episode of psychosis is often very frightening, confusing and distressing, particularly because it is an unfamiliar experience. Unfortunately, there are also many negative stereotypes and misconceptions associated with psychosis that can further add to a person's distress.

Research suggests that the earlier the first episode of psychosis is diagnosed and treated, the more effective treatment outcomes and recovery, will be. However, eight in ten patients receiving existing pharmacological therapy for schizophrenia do not achieve symptom remission in three months or more. Many of the currently available medications for psychosis also have severe side effects, which makes adherence challenging. There is a clear medical need to research and develop more effective treatments to help aid the recovery process and prevent further episodes of psychosis for people with schizophrenia.

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