New treatments being developed for schizophrenia

This year seems to be shaping up for therapeutic research and development (R&D) for schizophrenia as clinical trials testing different kinds of treatments are underway. One treatment to look out for is KarXT, which is anticipated to hit the market very soon.

Schizophrenia and current treatment challenges

This news is rather optimistic as schizophrenia has a very high mortality risk. “It’s one of the highest across 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,” said Cliona MacSweeney, Neuroscience Program Leader at Nxera Pharma.

To add to that, schizophrenia has been rather challenging to treat due to a number of reasons. One of them being that they are expressed through a cluster of symptoms. While current medicines can effectively treat some of the positive symptoms, MacSweeney, pointed out that “they 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,” said MacSweeney.

Side effects are another cause for concern. These include motor function problems like tremors and stiffness that can occur after a certain period of treatment. Hyperprolactinemia can also occur, a condition in which levels of the hormone prolactin are higher than normal. This can lead to milky discharge from the nipples when not pregnant or breastfeeding as well as irregular periods.

“And then there’s weight gain,” said MacSweeney. “The weight gain can be really quite significant and patients don’t like this. So, what happens is that 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.” 

KarXT: muscarinic agonist offers promising advances in the long-term management of schizophrenia

KarXT is hoped to improve this outlook. Owned by pharma giant Bristol Myers Squibb following its $14 billion buyout of Karuna Therapeutics, KarXT, belongs to a class of drugs called muscarinic agonists. These are drugs that activate a type of G protein-coupled receptors (GPCRs) called muscarinic acetylcholine receptors, which regulate the nervous system. They are of five subtypes: M1, M2, M3, M4, and M5 – each of which are encoded by different genes. 

These receptors are attractive drug targets and the agonist drugs work by binding to the receptor and mimicking the neurotransmitter acetylcholine, which is responsible for healthy brain and muscle function. A muscarinic agonist like KarXT is a breakthrough in schizophrenia that would offer the first new drug mechanism for millions of people in over 70 years.

Phase 3 trial results published last year showed that KarXT met its primary endpoint and there was an 8.4-point reduction in Positive and Negative Syndrome Scale (PANSS) total score – a scale that assesses the severity of symptoms in patients with schizophrenia – compared to placebo after five weeks. More recent long-term interim results showed that 75% of trial participants achieved at least 30% improvement in symptoms. The drug, which targets the M1 and M4 receptors, is a fixed dose combination of xanomeline and trospium and is dosed twice daily.

“These interim data from EMERGENT-4 continue to validate the potential of KarXT in the long-term management of schizophrenia, with continued benefit across 52 weeks of treatment,” said Elan Cohen, principal investigator, CenExel Hassman Research Institute and investigator in the EMERGENT program, in a press release. “The consistency of efficacy results across all EMERGENT clinical trial programs is encouraging and suggests KarXT could provide a differentiated treatment approach for people living with schizophrenia.”

KarXT is different from existing drugs in the market, in that it targets the M1 and M4 acetylcholine receptors and does not directly block dopamine receptors – which are how most currently-available antipsychotic medicines work.

Neurocrine, Cerevel, and MapLight: Leading the charge in muscarinic modulators for schizophrenia

Muscarinic modulator drugs are emerging to be a turning point in treating schizophrenia, a condition that currently affects 24 million people worldwide, according to the World Health Organization (WHO). 

“Currently, the most exciting class of drugs for schizophrenia is undoubtedly the muscarinic modulators. There hasn’t been a truly novel mechanism for antipsychotics in over 50 years, and so these muscarinics are a welcome new addition to the treatment paradigm for this difficult disease,” said Sam Clark, chief executive officer (CEO) of Terran Biosciences. “On the tail of KarXT’s success, other muscarinic compounds are now being developed at different companies attempting to achieve similar outcomes.”

California-based Neurocrine Biosciences’ M4 agonist NBI-1117568 is touted as KarXT’s rival – although it isn’t on par. The investigational drug met the primary endpoint in a phase 2 trial but while it was efficacious in the lowest dosage, the higher doses didn’t reap the same encouraging results. However, the drug had fewer side effects with 5% of patients on 20 mg experiencing constipation compared to 21% in the KarXT study. The drug is now being developed along with Japanese multinational Nxera Pharma, formerly known as Sosei Heptares.

Also in phase 2 are AbbVie-owned Cerevel’s emraclidine and American biotech MapLight Therapeutics’ ML-007. Cerevel’s drug is an M4 agonist whereas MapLight’s ML-007 is like KarXT, as it targets M1 and M4. Moreover, Terran’s preclinical candidate TerXT is also quite similar to KarXT as it contains the same active ingredients – xanomeline and trospium.

“[TerXT] is designed to enable once-daily oral dosing and a long acting injectable (LAI) with multi-month duration. The prodrug approach has been utilized by some of the most effective antipsychotics to date including Invega and Aristida. We hope to be able to leverage the U.S. Food and Drug Administration’s (FDA’s) FDA’s accelerated 505(b)(2) regulatory pathway to reference the data already created by the KarXT studies, which could potentially reduce the amount of studies needed and thus shorten the TerXT approval timeline significantly,” said Clark. 

Compounds like xanomeline and trospium have limitations such as poor colonic absorption and high aqueous solubility. These factors affect these kinds of drugs when taken up by the body. Prodrugs are compounds that are inactive but they can be metabolized and activated once inside the body, thereby improving drug delivery and target specificity.

“We at Terran have been working on this promising mechanism for a couple years now with our TerXT program, and are glad to see the recent success stories across the industry,” said Clark.

GPR52 agonists, nicotinic modulators, and an ion channel program move up in schizophrenia R&D 

Like muscarinic agonists in the therapeutic field, GPR52 agonists are another class of drugs making headway. GPR52 is a G-protein-coupled receptor that is highly expressed in the brain and the drug binds to it and activates it, setting off a cascade of pathways. This aids in the release of neurotransmitters that influence brain function. 

Boehringer Ingelheim and Nxera Pharma are developing a GPR52 agonist that works like this. The collaboration, which is worth €25 million ($27.54 million) will see the drug move up from phase 1 in the clinic soon. The candidate HTL0048149 is an oral drug that aims to treat what are known as positive symptoms such as psychosis, delusions, and hallucinations, negative symptoms like social withdrawal and apathy, and cognitive impairment linked to schizophrenia.

Another type of drug in the clinic is a nicotinic modulator. German biopharma Atai Life Sciences’ RL-0071 is an example of it. The phase 2 candidate is being tested to treat cognitive impairment-associated with schizophrenia (CIAS). It is an oral drug that modulates cholinergic, glutamatergic, and GABA-B receptors,  thereby altering the excitatory and inhibitory balance in the brain to produce pro-cognitive effects. 

RL-0071 is now the main focus of Atai’s pipeline after it bid adieu to its depression drug that failed in the clinic last year. As there are currently no FDA-approved medications for CIAS, which is a major cause of disability in 80% of patients with schizophrenia, a nicotinic modulator like RL-0071 could change things for the better. 

Besides, add-on treatments are becoming more common to treat mental health conditions like schizophrenia. One major name in the game is investigational drug evenamide, developed by neurological diseases-focused Newron Pharmaceuticals. The Italian biotech’s drug targets sodium channels, which are key proteins that allow sodium to pass through a cell. Evenamide modulates a function of the nervous system called sustained repetitive firing – a case of a cell continuing to fire even after the stimulus that triggered it has stopped. The phase 3 drug does so while not impairing regular nerve cell activity. 

A phase 2/3 study found that the drug showed significant improvement on the PANSS scale. Patients on evenamide saw a 10.2-point reduction after 29 days compared to 7.6 for the placebo group. A drug like this could fill the gap of there barely being any treatment options for people who don’t respond well to current standards of care. It could be combined with drugs like antipsychotic medicine clozapine, which was FDA-stamped more than three decades ago.

Yet, muscarinic inhibitors seem most likely to come out on top this year with KarXT’s much-awaited approval, which has shown “robust efficacy and safety in patients with schizophrenia,” according to Clark.

Terran’s TerXT and KarXT: similar but different

But could it address the unmet needs that people with schizophrenia face? Clark explained that despite several therapeutic options, none are entirely effective or without side effects, and there remains a huge unmet need to further control the positive and negative symptoms of the disease, as well as deliver therapeutics in a patient-friendly dosing form.

“Patients with schizophrenia often have difficulty with medication adherence, and so, the ideal dosing forms for drugs are either once-daily oral or long-acting injectables that can last many months and are administered in a doctors office,” said Clark.

That’s where TerXT is determined to create a shift. Unlike BMS’ KarXT, which must be dosed twice a day, a dosing frequency that Clark notes “may be quite difficult for some schizophrenia patients,” Terran’s prodrug approach with TerXT could be easier for patients. 

“[TerXT] is designed specifically to address this unmet need through a prodrug strategy to enable a longer-acting treatment approach (once-daily oral and multi-month injectable), which we expect could be much preferred by patients and their families,” said Clark.

However, if KarXT wins FDA clearance – a decision that will be made on September 26th – it would mean that other drugs, especially muscarinic agonists, would have to fare better than KarXT in the clinic. And so, the race to develop the best schizophrenia drug continues.