Phase II study with first-in-class investigational drug demonstrates improvement in negative symptoms in patients with schizophrenia

Glycine reuptake inhibitor RG1678 with novel mode of action first compound to show meaningful impact on negative symptoms of disease

Roche (SIX: RO, ROG; OTCQX: RHHBY) today presented eight-week results from a phase II study of RG16781, its investigational first-in-class glycine reuptake inhibitor (GRI) for the treatment of schizophrenia. The data showed a clinically meaningful reduction in the negative symptoms of schizophrenia, accompanied by beneficial changes in patients’ personal and social functioning. The study measured improvements in patients with predominantly negative symptoms of schizophrenia who received RG1678 in combination with second-generation antipsychotics.

Schizophrenia affects approximately 24 million people worldwide and is usually diagnosed in young adults aged between 15 and 35 years. People living with schizophrenia often lose motivation and interest in social activities, become socially isolated and find it difficult to experience pleasure in everyday life. These are the so-called negative symptoms of the disease. Current schizophrenia treatments primarily address the positive symptoms of the disease, which include hallucinations and delusions, often leaving patients with continuing, uncontrolled negative symptoms.

“This new compound could be the first treatment to address the negative symptoms associated with schizophrenia, potentially enabling patients to carry out everyday tasks more effectively,” said Hal Barron, M.D., Head of Global Development and Chief Medical Officer at Roche. “The ultimate goal in treating patients with schizophrenia is getting them back as close as possible to a normal life. Discussions with health authorities have taken place and a phase III program is underway to confirm efficacy of RG1678.”

The glycine reuptake inhibitor RG1678 normalises glutamate neurotransmission by increasing synaptic levels of glycine, thereby targeting an important pathway in the treatment of psychiatric disorders. By normalising glutamate neurotransmission in the brain, RG1678’s unique mode of action could potentially have valuable therapeutic applications in other psychiatric disorders beyond schizophrenia.
About the study

In the study, the efficacy and safety profile of three dose regimens of RG1678 (10mg, 30mg and 60mg) were assessed. The primary efficacy endpoint was the change from baseline at week eight in the negative symptom factor score as assessed by the Positive and Negative Syndrome Scale (PANSS). Secondary endpoints were measured using the Clinical Global Impression (CGI)-Improvement in negative symptoms and Personal and Social Performance (PSP) scale. For the analysis, the patient population treated according to protocol was scientifically relevant for this proof-of-concept study.

* Changes in PANSS negative symptom factor score demonstrated a statistically significant improvement in negative symptoms in patients taking RG1678 10mg and 30mg compared to placebo2 (per-protocol (PP) population).
* Differences in CGI improvement in negative symptoms were statistically significant between RG1678 10mg and placebo3 (PP population).
* There was also a trend towards functional improvement as assessed by the PSP scale in the RG1678 10mg group4 compared to placebo (PP population).
* In line with pre-clinical data, the 60mg dose did not show statistically significant improvements in any endpoints.

RG1678 was generally well tolerated and the safety profile was favorable. The percentage of patients who experienced at least one adverse event was similar in the placebo, RG1678 10mg and 30mg groups. The percentage of patients withdrawn from the study due to adverse events was 1% in the placebo and RG1678 10mg groups, 9% in the RG1678 30mg group and 10% in the RG1678 60mg group. The percentage of withdrawals for any reason was similar in all treatment groups (13% - 20%).
About the study design

* A phase II multicentre, randomised, double-blind, parallel group, 323-patient study investigating RG1678 compared to placebo in patients with predominantly negative symptoms of schizophrenia.
* Patients were treated for eight weeks followed by a four-week follow-up period and received RG1678 or placebo given orally once a day in combination with second-generation antipsychotics.
* Primary endpoint was efficacy measured by change from baseline at week eight in PANSS negative symptom factor score.
* Secondary endpoints included treatment effects at week eight using percentage of PANSS negative symptom factor score responders (defined as ≥20% improvement from baseline), CGI-Improvement ratings in negative symptoms and mean change from baseline in the PSP scale total score.

Study protocol

* The patient population treated according to the protocol (i.e. per-protocol analysis population) was scientifically relevant for this proof-of-concept study, and the key efficacy results in this population were statistically significant. The intent-to-treat (ITT) population analysis results also showed a statistical trend, while including protocol non-compliant patients and sites.

Safety

* In the study, RG1678 was generally well tolerated and the safety profile was favorable.
* Three cases of serious adverse events for which the treatment relation could not be excluded by the investigator occurred during the study and follow up: one in the 10mg group (anxiety), one in the 30mg group (suicide attempt) and one in the 60 mg group (panic attack). Serious adverse events of this kind are not uncommon in this disease and patient population and are rigorously monitored in all clinical studies.
* A dose-dependent decrease in hemoglobin was observed in the study and was not considered clinically relevant.

About the scales used in the study

Positive and Negative Syndrome Scale (PANSS)

* PANSS is assessed using a 30-item scale designed to capture the degree of severity for many symptoms in schizophrenia. The patient is rated from one to seven on 30 different symptoms based on an interview as well as reports of family members or primary care hospital workers.

Clinical Global Impression (CGI)-Improvement scale

* CGI improvement is assessed each time the patient is seen after medication has been initiated. The physician compares the patient’s overall clinical condition to the baseline visit using a seven-point scale, ranging from very much improved (1) to very much worse (7).

Personal and Social Performance (PSP) scale

* PSP is assessed by a clinical interview combined with clinical observation looking at the patient’s functioning in four main areas: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviours. The scoring range is 0 to 100 on a scale subdivided into ten equal intervals, enabling the determination of small changes in levels of functioning.

About schizophrenia

Schizophrenia is a severe mental disorder, characterised by profound disruptions in thinking and behavior, affecting the ability to lead a normal life. According to World Health Organisation (WHO) estimates, the disorder affects approximately 24 million people worldwide and is usually diagnosed in adults aged between 15 and 35 years. The symptoms of schizophrenia are broadly categorised as positive and negative, and cognitive deficits. Positive symptoms are psychotic symptoms such as hallucinations and delusions. Negative symptoms are associated with disruption to normal behaviour and emotion, such as apathy, social withdrawal, lack of drive and reduced ability to feel pleasure in everyday life. Cognitive deficits include difficulty concentrating and/or following instructions, difficulty completing tasks, memory problems, and disorganized thinking.
About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2009, Roche had over 80’000 employees worldwide and invested almost 10 billion Swiss francs in R&D. The Group posted sales of 49.1 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.

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References:
1] ‘Glycine Transporter Type 1 (GLYT1) Inhibitor RG1678: Positive Results Of The Proof-Of-Concept Study For The Treatment Of Negative Symptoms In Schizophrenia’, Umbricht D. et al., ACNP 2010
2] P-value 0.049 and 0.034, per-protocol population.
3] P-value 0.025, per-protocol population.
4] P-value 0.072, per-protocol population.