It would appear that 2024 is shaping up to be a big year for the development of new treatments for schizophrenia, with several clinical trials under way.
Recently, Boehringer Ingelheim and Sosei Group Corporation (Sosei Heptares) announced a global collaboration and exclusive option-to-license agreement. This is to develop and commercialize Sosei Heptares’ portfolio of first-in-class GPR52 agonists, a novel G protein-coupled receptor (GPCR) target. The goal is to improve patient outcomes by addressing the positive, negative, and cognitive symptoms of schizophrenia.
Clíona MacSweeney, Sosei Heptares’ GPR52 program leader, spoke with us about that partnership, as well as other developments in the field of schizophrenia treatments.
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What is schizophrenia?
Schizophrenia is a serious condition that affects about 1 in 100 people worldwide.
It is characterized by three clusters of symptoms: ‘positive’ symptoms – such as psychosis, delusions and hallucinations; ‘negative’ symptoms – such as social withdrawal and apathy; and cognitive symptoms – such as attention, planning and memory deficits.
The impact of these symptoms on people’s ability to cope with normal day-to-day life is significant and the related burden on carers and society at large is substantial, especially since the age of onset of the disease is typically in the 20s.
While ‘positive’ symptoms of schizophrenia can be stabilized with antipsychotics, some of which can have side effects, there are currently no approved treatments for ‘negative’ or cognitive symptoms.
“Often it can be the cognitive impairments that are the first symptom to present and these are often what the patients will come to the physician about,” MacSweeney said.
She added that early treatment of these symptoms can be very helpful in treating schizophrenia.
“It has a very high mortality risk as well, so it’s one of the highest across the psychiatric disorders and patients’ lives are shortened on average by about 15 to 20 years, so really it’s quite a complex disorder and very serious one.”
What are the standard treatments for schizophrenia and how effective are they?
MacSweeney said the current treatments for schizophrenia fall into kind of two categories.
First generation antipsychotics include haloperidol, chlorpromazine and second-generation antipsychotics include Abilify, Risperdal and Seroquel.
“Fundamentally these treatments all act through the same mechanism, which is modulation of the dopamine D2 receptor,” MacSweeney explained.
She added that the choice of treatment will typically be based on a discussion between the patient and the physician psychiatrist. Things that will be taken into account are the range of symptoms the patient is displaying, and the side effects that can occur with these treatments.
Why is schizophrenia so difficult to treat?
MacSweeney said that one of the first challenges is diagnosis. This is because of the range of symptoms, some of which are seen with other disorders.
Another reason for schizophrenia being so challenging to treat is the different clusters of symptoms, she added.
“If you’re not taking the medication then you’re not going to see the efficacy that you need.”
“The current medications can maybe effectively treat some of the positive symptoms, they actually really do not effectively treat either the negative or the cognitive symptoms. And even within, I would say, the positive symptoms, up to about 30% of patients do not respond well to the treatments.
“And then you have the side effects. These include things like motor symptoms, such as tremor or stiffness that can occur after a certain period of treatment. There’s hyperprolactinemia that can occur. And then there’s weight gain.
“The weight gain can be really quite significant and patients don’t like this. So, what happens is patients don’t want to take the medications, you see very poor compliance among the patients and of course if you’re not taking the medication then you’re not going to see the efficacy that you need.”
What are the new treatments for schizophrenia?
Serotonin and dopamine modulation
While 2024 is shaping up to be an important year for progress with schizophrenia treatments, there are several mechanisms companies are pursuing.
MacSweeney said the development of psychedelics is going to be a “game changer” in psychiatry.
The current treatments primarily directly target the D2 dopamine receptor and some of those treatments also acted some of the serotonin receptors like 5-HT2A, MacSweeney said.
“There have been some efforts around targeting maybe more specifically the 5-HT2A receptor, but those results are quite mixed at the moment,” she said.
Muscarinic modulators
Muscarinic modulators are emerging from companies including Karuna, Cerevel and MapLight Therapeutics.
“And of course, there’s Neurocrine Biosciences as well, who had a licensing agreement not so long ago with Heptares. They’ve taken in our portfolio of muscarinic M1 and M4 agonists.
“It actually works in a number of different ways. If you look at the M4 receptor for example, that is expressed postsynaptically on the direct pathway medium spiny neurons. By modulating that receptor you can get an endocannabinoid dependent inhibition of dopamine release.
“But the M4 receptor is also on cholinergic interneurons as an auto receptor, where it can cause a reduce of acetylcholine release. And then the M4 receptor is also on the glutamatergic inputs as a heteroreceptor. You can target dopamine transmission, through a number of different ways.
“And then some of these drugs also act at the M1 muscarinic receptor, which is expressed in the prefrontal cortex and other brain regions where it really modulates cognition, has beneficial effects on cognition.”
MacSweeney pointed to Karuna’s KarXT molecule, a combination of xanomeline and trospium, which is a peripherally restricted muscarinic antagonist.
“This is a way to target the receptors in the brain to get those CNS effects, but avoiding some of the side effects which are peripherally mediated. This is the molecule that’s furthest ahead in development and will be launched later this year, so that’s really exciting.
“And then Cerevel’s molecule, emraclidine, is currently in phase 2 studies. This is an M4 positive allosteric modulator. Neurocrine’s M4 agonist is also in phase 2 trials currently.”
Excitatory and inhibitory tone
MacSweeney said the balance between excitation and inhibition is crucial for normal physiological function.
“We know that the NMDA receptors play a critical role there. A number of companies are looking at that NMDA receptor and targeting that more specifically. It’s thought that in schizophrenia, NMDA hypofunction occurs. And this preferentially affects the interneurons, which then leads to greater activity among pyramidal neurons.
“This causes an uncoordinated increase in activity, which causes disruptions to normal coordinated oscillatory activity, which is passed down to subcortical regions and basically acts as noise.”
She said Boehringer Ingelheim has Iclepertin, a GlyT1 inhibitor, in phase 2 for the treatment of schizophrenia. Iclepertin targets the brain biology linked with the cognitive symptoms of schizophrenia.
Digital therapeutic and epigenetic modulation
Digital therapeutics is a growing area, according to MacSweeney.
“One nice example is the collaboration between Boehringer Ingelheim and Click Therapeutics, where they’re looking at using a digital therapeutic alongside a pharmacotherapy for the treatment of the negative symptoms specifically in schizophrenia.
“And thinking about epigenetic modulation, there are different targets that companies are looking at here, but a good example is Oryzon’s molecule which is currently in phase 2.
“This is an LSD1 inhibitor. The lysine-specific demethylase is a histone-modifying enzyme which controls expression of various genes and specifically some of those involved in schizophrenia. It is in phase 2 trials for a number of disorders including the negative and cognitive symptoms in schizophrenia.
“This is where you see the precision medicine approaches coming in.”
GPR52 agonists
Boehringer Ingelheim and Sosei Heptares will be collaborating on the development of a new schizophrenia treatment targeting GPR52. It has the potential to address all three aspects of schizophrenia, providing a novel precision treatment.
The GPR52 agonism calms the striatum while boosting frontal cortical function, which achieves further precision in treatment.
GPR52 is an orphan G protein-coupled receptor (GPCR) highly expressed in the brain, especially in the striatum and the prefrontal cortex, and represents a potential emerging therapeutic target for a range of neurological and neuropsychiatric disorders.
Sosei Heptares has developed a portfolio of selective GPR52 agonists and modulators leveraging proprietary insights from its StaR technology SBDD platform, the most advanced of which, HTL0048149, entered in a first-in-human clinical trial in 2023.
HTL’149 has been designed to selectively target GPR52 as a once-daily, oral drug with an antipsychotic and pro-cognitive profile. HTL‘149 aims to treat positive symptoms (e.g. psychosis, delusions, hallucinations), negative symptoms (e.g. social withdrawal and apathy) and cognitive impairment (e.g. attention, planning and memory deficits) associated with schizophrenia and to minimize adverse effects associated with some of the available antipsychotic drugs.
From Sosei Heptares to Nxera Pharma
MacSweeney also noted the change of name from Sosei Heptares to Nxera Pharma in April 2024.
A recent board meeting resulted in the merger of Idorsia Pharmaceuticals Japan (IPJ) Ltd. and Sosei Co. Ltd. to form the new company. Sosei acquired IPJ in July, 2023. Nxera is derived from the words ‘next’ and ‘era’ to reflect the next era in science and healthcare. The company’s new head office will be in Tokyo, Japan.
To learn more about schizophrenia treatments
Here are some links to more articles on the subject of neuroscience and schizophrenia treatments.