Brilaroxazine/High Efficacy & Mild Side Effects

Introduction

In October 2023, the results of a Phase 3 study of brilaroxazine were announced. Brilaroxazine is an antipsychotic drug under development in the United States. It is an evolutionary version of the drugs abilify and rexulti.

Phase 3 trials showed that it is highly effective and has few side effects.

In this article, I will first write an “abstract” on brilaroxazine for beginners. For beginners, I would like them to see just the “abstract”.

After that, I will write “detailed information” of brilaroxazine for advanced readers. I will analyze a little about the data and other information from the Phase 3 study.

Abstract (for beginners)

Again, brilaroxazine is an evolved version of abilify and rexulti. All three drugs have one thing in common: they are dopamine partial agonists.

Dopamine partial agonists are drugs that modulate the activity of dopamine in the brain to moderate levels.

Brilaroxazine has many actions on serotonin receptors in addition to its actions on dopamine receptors. Therefore, brilaroxazine is also an atypical antipsychotic.

Side Effects

Especially in the case of abilify, “extrapyramidal symptoms” such as “akathisia” are common.

However, brilaroxazine has considerably fewer akathisia and extrapyramidal symptoms, with less than 1% of patients experiencing them in the Phase 3 trial.

Brilaroxazine also has less “weight gain” than abilify and rexulti.

But “somnolence” is more common than abilify and rexulti, and brilaroxazine may be a more sedating drug.

Brilaroxazine tends to have fewer side effects overall, and if they do occur, they tend to be mild.

Efficacy

The “efficacy” of brilaroxazine was found in the Phase 3 study to have an effect size of 0.6. It may be as effective as olanzapine or Risperdal.

The data also show that the efficacy for cognitive dysfunction is fair to high.

Indications

In addition to schizophrenia, brilaroxazine is also indicated for the treatment of bipolar disorder, depression, ADHD, psychosis and agitation associated with Alzheimer’s disease, and psychosis associated with Parkinson’s disease.

Other indications include inflammatory diseases.

Development Status

Brilaroxazine is expected to be launched in the United States in late 2025 or early 2026.

Detailed information (for advanced readers)

In this section, I will report as much as possible about the data from the Phase 3 study of brilaroxazine.

The Phase 3 study included 411 patients. They were divided into three groups: brilaroxazine 15 mg group, brilaroxazine 50 mg group, and placebo group, and were treated for four weeks.

Data for the brilaroxazine 15 mg group are omitted below.

Efficacy Data Table

First, the data we have focused on in this blog are summarized in the table below.

For more information on PANSS, please refer to this article.
Positive and Negative Syndrome Scale(PANSS, Scale used to measure efficacy)

4 weeks	Mean score reduction (Brilaroxazine)	Mean score reduction (Placebo)	Difference from Placebo	p-value	Effect size
PANSS Total	-23.9	-13.8	-10.1	<0.001	0.6
PANSS Positive	?	?	-2.8	<0.001	0.5
PANSS Negative	?	?	-2.0	0.003	0.4

In the table above, we can look at “Mean score reduction” and “effect size” as a measure of efficacy.

Although “effect size” is treated more highly as evidence of efficacy, this blog also focuses on “Mean score reduction.

Efficacy 1 (PANSS Total Score Mean Reduction)

First, it should be noted that the “Mean score reduction” in PANSS total score with brilaroxazine administration is -23.9, which is very large.

As far as I know, the “Mean score reduction” in PANSS total score for other drugs is as shown in the table below.

Study drug	Dosing period	Phase	Mean score reduction
Ulotaront	4weeks	Phase2	-17.2
Ulotaront	6weeks	Phase3①	-19.6
Ulotaront	6weeks	Phase3②	-18.1
Lumateperone	4weeks	Phase3	-14.5
Lurasidone	6weeks	Phase3①	-17.9
Lurasidone	6weeks	Phase3②	-19.3
Emraclidine	6weeks	Phase1b	-19.5
KarXT	5weeks	Phase3①	-21.2
KarXT	5weeks	Phase3②	-20.6

As shown in the table above, the “Mean score reduction” in PANSS total score of -23.9 with brilaroxazine administration is the largest we have seen.

Moreover, a reduction of -23.9 points after only 4 weeks of administration is very significant.

Efficacy 2 (effect size)

Next, we will look at the effect size, which should be seen most as evidence of efficacy. The previous table is shown again below. The rightmost column shows the effect size.

4 weeks	Mean score reduction (Brilaroxazine)	Mean score reduction (Placebo)	Difference from Placebo	p-value	Effect size
PANSS Total	-23.9	-13.8	-10.1	<0.001	0.6
PANSS Positive	?	?	-2.8	<0.001	0.5
PANSS Negative	?	?	-2.0	0.003	0.4

The effect sizes for the Phase 3 study of brilaroxazine are only published to the first decimal place. Since the second decimal place is not known, we can only approximate the efficacy.

Overall Efficacy

First, we will look at the overall efficacy of brilaroxazine for positive symptoms, negative symptoms, and other symptoms.

When looking at overall efficacy, we should look at the effect size of the PANSS total score. The effect size of the PANSS total score for brilaroxazine is 0.6 in the table above. Is this number large?

The effect sizes for other antipsychotics have been calculated using a method called meta-analysis. The table below shows the effect sizes for the other antipsychotics.

PANSS Total	Effect size
Cloza pine	0.89	Sulpiride	0.48	Asena pine	0.39
Ami sulpride	0.73	Chlorpro mazine	0.44	Lurasi done	0.36
Olanza pine	0.56	Quetia pine	0.42	Caripra zine	0.34
Risperi done	0.55	Aripipra zole	0.41	Iloperi done	0.33
Paliperi done	0.49	Ziprasi done	0.41	Brexpipra zole	0.26
Haloperi dol	0.47	Sertin dole	0.40

Brilaroxazine’s effect size of 0.6 is slightly greater than olanzapine’s 0.56 and risperidone’s 0.55. It is smaller than Amisulpride’s 0.73.

It is much larger than the same dopamine partial agonists, abilify and rexulti. Abilify is 0.41 and rexulti is 0.26.

Effects on Positive Symptoms

Next, we will focus on brilaroxazine’s effect on positive symptoms. The effect sizes for PANSS positive scores for other antipsychotics are shown in the table below.

PANSS Positive	Effect size
Ami sulpride	0.69	Haloperi dol	0.49	Lurasi done	0.33
Cloza pine	0.64	Asena pine	0.47	Caripra zine	0.30
Risperi done	0.61	Ziprasi done	0.43	Iloperi done	0.30
Chlorpro mazine	0.57	Quetia pine	0.40	Brex piprazole	0.17
Olanza pine	0.53	Sertin dole	0.40
Paliperi done	0.53	Ari piprazole	0.38

Brilaroxazine’s effect on positive symptoms comes out to 0.5 in terms of effect size. This is smaller than Olanzapine’s 0.53 and Invega’s 0.53. It is slightly larger than haloperidol’s 0.49.

Effects on Negative Symptoms

Next, we will focus on the effect of brilaroxazine on negative symptoms. The effect sizes of the PANSS negative scores for other antipsychotics are shown in the table below.

PANSS Negative	Effect size
Cloza pine	0.62	Paliperi done	0.37	Haloperi dol	0.29
Ami sulpride	0.50	Chlorpro mazine	0.35	Lurasi done	0.29
Olanza pine	0.45	Ari piprazole	0.33	Brex piprazole	0.25
Asena pine	0.42	Ziprasi done	0.33	Iloperi done	0.22
Sertin dole	0.40	Cari prazine	0.32
Risperi done	0.37	Quetia pine	0.31

Brilaroxazine’s effect on negative symptoms comes out to an effect size of 0.4. This is lower than olanzapine’s 0.45 and asenapine’s 0.42, but higher than risperidone’s 0.37.

Efficacy Summary

The efficacy of brilaroxazine is still high. I think its high sedative effect leads to its high short-term efficacy.

As for the long-term efficacy, I would like to look closely at the results of the long-term dosing study that is now underway.

Side Effects

Next, we will look at the side effects of brilaroxazine.

The only side effects that occurred in more than 5% of patients in the Phase 3 study were somnolence (7.5%) and headache (6%). They were not severe and appeared to be generally temporary.

The incidence of somnolence was 3.1% for abilify and 2.0% for rexulti, so the 7.5% rate for brilaroxazine is higher than those.

So, brilaroxazine may have a higher sedative effect among dopamine partial agonists.

Brilaroxazine has fewer side effects of weight gain. In the Phase 3 study, the percentage of patients who gained weight was 5.9%. For abilify, the rate was 9.2%, and for rexulti, the rate was 10.4%.

In the Phase 3 study, the percentage of patients who gained weight was about half that of abilify and rexulti.

Brilaroxazine also caused fewer extrapyramidal symptoms and akathisia, occurring in only 0.7%. The incidence of akathisia was 5.1% for rexulti and 11.7% for abilify.

The incidence of extrapyramidal symptoms and akathisia with brilaroxazine is much less frequent.

Brilaroxazine also has a low incidence of hyperprolactinemia. Sexual dysfunction and menstrual irregularities may be less common.

Summary of Side Effects

When compared to abilify and rexulti, we can say the following about the side effects of brilaroxazine.

• More drowsy and sedating.
• Less weight gain.
• Much less extrapyramidal symptoms and akathisia.

Tolerability and safety

Overall, brilaroxazine is well tolerated and safe with mild side effects.

In the Phase 3 study, the incidence of adverse events with brilaroxazine administration was 35.5%. The adverse event rates for other antipsychotics, to the best of my knowledge, are shown in the table below.

Investigational Drug	Treatment-emergent adverse events (TEAEs)
Lumateperone(Phase3)	64.7%
Ulotaront(Phase2)	45.8%
KarXT(EMERGENT-1)	54%
KarXT(EMERGENT-2)	75%
KarXT(EMERGENT-3)	70%

Looking at the table above, the adverse event rate of 35.5% with brilaroxazine is quite low.

Next, let’s look at the percentage of patients who discontinued brilaroxazine due to side effects.

The percentage of patients who discontinued brilaroxazine due to side effects was 0%. The percentage of patients who discontinued other antipsychotics due to side effects is shown in the table below.

Investigational Drug	Discontinuation Rate due to adverse events
Lumateperone(Phase3)	1.3%
Ulotaront(Phase2)	8.3%
KarXT(EMERGENT-1)	2%
KarXT(EMERGENT-2)	7%
KarXT(EMERGENT-2)	6%
Emraclidine(Phase1b)	7%

As expected, the 0% discontinuation rate of brilaroxazine due to side effects is low. For some other drugs, the discontinuation rate due to side effects are as high as 7%.

Next, we will look at the percentage of people who discontinued brilaroxazine for any reason, including side effects.

In general, the most common reasons for discontinuation are “serious side effects” as well as “lack of efficacy” and “discontinuation of the patient’s own free will.

The discontinuation rate for brilaroxazine was 16%. Dose discontinuation rates for other drugs, to the best of my knowledge, are shown in the table below.

Investigational Drug	Discontinuation Rate
Lumateperone(Phase3)	14.7%
Ulotaront(Phase2)	21.7%
KarXT(EMERGENT-1)	20%
KarXT(EMERGENT-2)	25%
KarXT(EMERGENT-3)	37%

Looking at the table above, the 16% discontinuation rate for brilaroxazine is low.

Development Status

As noted above, brilaroxazine is expected to be launched in the United States in late 2025 or early 2026.

Currently, a 52-week long-term dosing study is underway.

A 6-week Phase 3 trial (RECOVER-2) will be conducted in addition to the Phase 3 trial (RECOVER).

It is anticipated that the FDA will receive the application for approval in early 2025.

Comment

Brilaroxazine may have high efficacy and mild side effects.

In addition, the degree of improvement in “PANSS Social Cognition” and “Personal and Social Performance (PSP)” is fair to good. (both with an effect size of 0.5)

It might not be as novel as KarXT or Ulotaront, but some people may find it quite a good drug to use. I would like to keep an eye on it.

References

• https://pubmed.ncbi.nlm.nih.gov/31303314/
• https://en.wikipedia.org/wiki/Brilaroxazine
• https://revivapharma.com/reviva-announces-positive-topline-results-from-global-pivotal-phase-3-recover-trial-of-brilaroxazine-in-schizophrenia/