Innovation in Schizophrenia Treatment: Evenamide Research With Anthony Grace, PhD

Psychiatric Times: Can you discuss evenamide’s mechanism of action and how it impacts treatment-resistant schizophrenia (TRS)?

Anthony Grace, PhD: One of the longstanding issues in schizophrenia treatment has been our reliance on dopamine antagonists, or D2 blockers, because of the serendipitous discovery that D2 antagonists worked against schizophrenia. But more recent literature has suggested that the dopamine system is not the site of the deficit. The site of the deficit appears to be in the hippocampus, and hippocampal hyperactivity, because of a loss of inhibitory interneurons in the hippocampus. And it is that hippocampal hyperactivity that not only drives the dopamine psychosis but is probably also responsible for the negative symptoms and cognitive deficits that you see in schizophrenia.

So, the focus has shifted from blocking dopamine to trying to normalize hippocampal activity. And this is where evenamide comes into play. Because of what evenamide is—a voltage gated sodium channel blocker—it is selective just for hyperactive neurons. And because it’s selective for hyperactive neurons, it does not interfere with normal hippocampal functioning. And it seems to reverse the hyperactivity that we believe not only drives dopamine psychosis but also disrupts cognitive function and is related to the negative symptoms of schizophrenia.

PT: What makes evenamide different from other approaches in addressing schizophrenia, including its potential as add-on therapy and ability to treat positive/negative/and cognitive symptoms?

Dr Grace: Current antipsychotic treatments—with the exception of Cobenfy—work by blocking dopamine receptors. Our prior work showed that if you have a hyperactive dopaminergic system, when you give a D2 antagonist, it pushes the system into what we call the polarization block, where it stops the neurons from firing. And by stopping the neurons from firing, you are getting rid of the excess dopamine release. But the consequence is it also stops the neurons that are projecting to the affect-related part of the striatum, which is where you get the negative symptom induction caused by D2 antagonists.

Now, one thing that has been found by Oliver Howes and Philip McGuire in London is that in treatment-resistant schizophrenia, the dopamine system is not as hyperactive. This means that it cannot use a D2 antagonist to achieve the same kind of therapeutic action, because it cannot over activate the dopamine system. Evenamide comes into play because it is working at the site of deficit. It does not depend on working downstream and inducing an offsetting deficit in the dopamine system. Instead, it seems to be working at the site of dysfunction and in that way, impacting the positive symptoms of schizophrenia that are not treated in TRS patients with D2 antagonists.

And because evenamide is working at the site of the deficit, it can fix some other symptom categories. When the hippocampus is hyperactive, and is not showing its normal rhythmicity, it overdrives the dopamine system, and interferes with frontal cortex, leading to cognitive deficits. And it interferes with amygdala function, which is involved more in emotional and negative symptom regulation. So, by fixing the hippocampus, evenamide has the potential to improve all three major symptom groups—positive, negative, and cognitive—something standard dopamine-blocking drugs cannot do.

PT: How does this medication address unmet needs in schizophrenia treatment?

Dr Grace: There are a lot of patients who are treatment resistant. These are both patients who are treatment resistant originally, as well as patients who have been on antipsychotic drugs, withdrew from taking them, and then reintroduced drugs repeatedly, which can also lead to a type of treatment resistance or not a full type of response.

Evenamide seems to be effective even in patients that have been on more than one standard-of-care antipsychotic drug. So, this rather significant patient population, about 30% of the schizophrenia patients, will be able to be treated for the first time. And unlike with D2 antagonists, the dropout rate in the evenamide trials has been incredibly low. So, the patients actually like the drug, probably because it is effective, but also because it does not have the untoward side effects of the other antipsychotic drugs.

PT: What are the next steps in investigating evenamide, including the Phase 3 ENIGMA-TRS trial?

Dr Grace: The new ENIGMA-TRS trial will be looking at patients on second-generation antipsychotics (SGAs), including clozapine. This trial will enroll at least 600 patients at study centers in Europe, Asia, Latin America, and Canada. And it is a trial that we hope will immediately cement evenamide as a treatment of choice when it comes to treatment resistant schizophrenia. Right now, the criteria we use to define treatment resistance is for patients who have been on two drugs that have failed to work, particularly a failure of clozapine to work, since clozapine is usually prescribed to treatment-resistant patients.

This trial should be able to show us that evenamide is going to be long-term effective. The initial studies have shown that evenamide’s efficacy actually increases over a rather long period of treatment—up to a year. This is unique because most drugs plateau after a month or 2, whereas with evenamide, we are seeing efficacy continue. Now one thing I would like to see is for this drug to be tried as a monotherapy as well, because if it is working at the site of action, as our preclinical studies suggest, it should be effective as a monotherapy.

PT: What can you tell us about the safety and tolerability profile compared to other agents?

Dr Grace: With evenamide, since it is working in the hippocampus, you are not going to see a lot of the other D2 side effects. You are not going to get anhedonia. You are not going to get interference with movement. You are not going to get the hyperprolactinemia. This drug does not seem to exhibit any of those effects. And it does not seem to exhibit those effects in our animal models.

And in Newron’s clinical trials, there have not been any noticeable side effects. In fact, the side effect profile was the same between evenamide and the placebo group. But importantly, there has to be more than just no side effects. It actually has to work, and it seems to be working quite well in the study group of patients.

PT: Can you discuss the data and results of your paper “Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model”

Dr Grace: The dopamine system is very multifaceted. There is a dopamine system that controls emotion. There is a dopamine system that controls things related to sensory processing like psychosis. And there is a dopamine system related to movement disorders. The first-generation antipsychotic drugs, of course, hit all of the dopamine systems, which is why you get movement disorders like Parkinsonism and tardive dyskinesia, as well as some of the negative symptoms like anhedonia.

The second generation D2 antagonists did not affect the movement related system. So, you did not get movement disorders. It treated psychosis, but it also induced negative symptoms because of its impact on the dopamine system that projects to the ventromedial striatum. This is more involved in affect or emotion and which we think is more related to the D2 antagonist-associated negative symptoms.

What we found with evenamide, was that it only impacted the dopaminergic neurons that projected to the associative striatum, which studies show are hyperactive and related to psychosis. So, it does not have the negative symptom effects that first and second generation antipsychotic drugs have. The other thing we found is that by normalizing the hippocampus, it also seems to normalize cognitive function. In this case, we looked at something called novel object recognition, where you expose an animal to 2 identical objects, you take them out of the arena, wait for an hour, then replace one of the objects normal animals explore the novel object. The schizophrenia developmental disruption animals cannot really tell which one is novel, and which one is not. Evenamide fixes that. So now they start to recognize what the novel object is.

We also looked at sociability. For this, we had a 3-chamber test area, where we put a rat in the central chamber, along with one chamber containing a toy animal and another chamber with a second rat. Most normal rats will tend to explore the other rat rather than the toy. The developmental disruption rats do not have a preference for the toy versus the rat. However, when you give them evenamide, they regain sociability and start interacting with the rat rather than with the toy. So, in our animal models, evenamide seems to hit the dopamine positive symptoms, the negative symptoms and the cognitive deficits.

PT: Any final thoughts for psychiatric clinicians?

Grace: I think evenamide will not only be effective but will be very well tolerated. And the patients seem to like it, which is unusual for antipsychotic drugs, as compliance is a really big issue. And the compliance rate in the evenamide studies was very high, suggesting that this is not going to be as much of a problem as it is with other drugs. And the lack of the side effect profile is going to be another big positive.

And importantly, we found that this drug was effective at normalizing the hippocampus. And we know it works in the hippocampus because when we inject it directly there, we see the same effect. This really is hitting at the site of deficit, which is one of the first drugs to do that.

PT: Thank you!