The first symptomatic treatment drug for schizophrenia! Roluperidone suffered a regulatory setback: rejected by the US FDA!

BIOON, Oct.
25, 2022 /BioValley/ -- Minerva Neurosciences is a biopharmaceutical company
focused on developing therapies for central nervous system (CNS) diseases.
Recently, the company announced that it has received a refusal-to-file letter (RFL)
from the U.
S.
Food and Drug Administration (FDA).
The notification relates
to roluperidone's (MIN-101) New Drug Application (NDA).
The FDA said it could request a Type A meeting to discuss the RFL
.

In August 2022, Minerva submitted a New Drug Application (NDA) to the FDA for roluperidone (dose 64mg): an oral small molecule compound that is an antagonist of serotonin 2A (5-HT2A) receptors, σ2 (sigma-2) receptors, α1A (alpha-1A) adrenergic receptors for the treatment of negative symptoms
in patients with schizophrenia.

While positive symptoms of schizophrenia can usually be well controlled with antipsychotic medications, negative symptoms are often the main burden
of the disease.
In the United States, no therapies
for the treatment of negative symptoms of schizophrenia have been approved.
Roluperidone may represent a new treatment option
for negative symptoms of schizophrenia.

The roluperidone NDA is supported
by the results of two Phase 3 clinical studies (MIN-101C03, MIN-101C07).
Two studies used the same design: both global, multicenter, randomized, double-blind, placebo-controlled trials evaluating the efficacy and safety
of roluperidone (2 doses: 32 mg, 64 mg) in patients with moderate to severe negative symptoms and stable positive symptoms of schizophrenia.

The results of the MIN-101C03 study showed that after 12 weeks of treatment, roluperidone was superior to placebo
in reducing negative symptoms of schizophrenia.
In the primary efficacy analysis, treatment with roluperidone at a dose of 64 mg resulted in a statistically significant reduction in negative symptoms of schizophrenia (p≤0.
0036),
as measured by the Pentagonal Structural Model Negative Score (PSM) of the Positive and Negative Syndrome Scale (PANSS).
Post-hoc analysis of the change in the PANSS Marder-negative symptom factor score (NSFS) from baseline to week 12 also showed a statistically significant difference between the 64 mg roluperidone group and the placebo group (p≤0.
001).

After 12 weeks of double-blind (DB) phase, a statistically significant improvement
of 64 mg roluperidone compared to placebo was also observed in multiple secondary/exploratory efficacy analyses.
NSFS also improved further during
the 24-week open-label (OL) period.

The MIN-101C07 study also demonstrated that roluperidone was superior to placebo
.
Although the change in NSFS from baseline to week 12 was statistically significant (p≤0.
064) compared to placebo (p0.
064) in the primary analysis, 64 mg roluperidone was numerically superior
in the outcome 。 In addition, an analysis of the modified intention-to-treat (mITT) population (the mITT dataset excluded data from one clinical trial site with untrustworthy results for 17 patients recruited) showed a nominally statistically significant improvement in NSFS at 64 mg roluperidone compared to placebo (p≤0.
044).

In addition, in the ITT and mITT population, a statistically significant improvement (unadjusted)
in NSFS compared to baseline was observed as early as weeks 4 and 8 with 64 mg roluperidone compared to placebo.
The overall PSP score (a key secondary endpoint of occupational and social skills) was statistically significant
in both the ITT population (p≤0.
021) and the mITT population (p≤0.
017).
The NSFS and PSP overall scores also improved
further during the 40-week Open Label (OL) period.

Schizophrenia is a chronic, severe, debilitating mental illness characterized by distortions
in thinking, perception, emotion, language, self-awareness, and behavior.
According to the World Health Organization (WHO), schizophrenia affects 20 million people
worldwide.
It is estimated that 69% of patients diagnosed with schizophrenia have negative symptoms and at least 42% have significantly negative symptoms
.

Negative symptoms can cause people with schizophrenia to withdraw from society, become apathetic or unable to complete tasks or feel happy
.
Negative symptoms are characterized by 5 structures: emotional retardation, aphasia, depression, anhedonia, and social disturbance
.
Negative symptoms are the main reason for poor functional outcomes in people with schizophrenia and may also be one of
the main reasons why ultra-high-risk adolescents may develop full-blown schizophrenia.

While positive symptoms of schizophrenia can often be well controlled with antipsychotic medications, negative symptoms are often the primary burden of the disease and can affect the patient's quality of life
due to disability due to impaired occupational and social skills.
Currently, there are no approved drugs
in the United States to treat negative symptoms of schizophrenia.

Roluperidone, a small molecule compound with a novel and unique mechanism of action, has been shown to block serotonin (5-HT) receptors, sigma (σ) receptors, alpha (α) adrenergic receptors, all of which are involved in regulating important brain functions, including mood, cognition, sleep, and anxiety
.
Currently, Roluperidone is being developed to treat negative symptoms
in patients with schizophrenia.

Roluperidone is designed to avoid direct blockade of dopaminergic receptors (key pharmacological targets of first- and second-generation antipsychotics) while maintaining a specific subtype of serotonin receptor 5-HT2A receptor (an additional key target for second-generation antipsychotics) as well as other pharmacological targets (sigma-2(σ2) receptors and adrenergic alpha 1A).

Roluperidone is able to block 5-HT2A receptors
.
When the 5-HT2A receptor is blocked, certain symptoms of schizophrenia, such as hallucinations, delusions, agitation, thinking and movement disorders, and side effects associated with antipsychotic therapy can be minimized
.
In addition, blocking 5-HT2A promotes slow-wave sleep, a sleep phase
that is often seen in people with schizophrenia.

Roluperidone is also able to block a specific subtype of the sigma (σ) receptor, σ2, which is involved in motor control, psychotic symptom control, and learning and memory
.
Blocking sigma-2 receptors, as well as blocking alpha(α) adrenergic receptor subtype α1A and, to a lesser extent, alpha1B, also increases calcium levels in neurons in the brain, which improves memory
.
The results of preclinical studies provide evidence of the effects of roluperidone on brain-derived neurotrophic factor ("BDNF"), which is associated with
neurogenesis, neuroplasticity, neuroprotection, synaptic regulation, learning and memory.

Minerva believes that based on an innovative mechanism of action supported by science, roluperidone has the potential to address unmet medical needs in the population of people with schizophrenia, including negative symptoms and cognitive impairment, without the side effects
of existing treatments.
(Bio Valley Bioon.
com)

Minerva Neurosciences receives Refusal to File Letter from FDA for its New Drug Application for Roluperidone for the Treatment of Negative Symptoms in Schizophrenia