Products

Date: 2018-07-30

Type of information: Granting of a Market Authorisation in the EU

Product name: Rexulti®/Rxulti®

Compound: brexpiprazole - 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one

Therapeutic area: CNS diseases - Mental diseases

Action mechanism:

• psychotropic. Brexpiprazole is a serotonin-dopamine activity modulator (SDAM) that acts as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors. Brexpiprazole was discovered by Otsuka and co-developed with Lundbeck.
• The mechanism of action of Rexulti® in the treatment of MDD or schizophrenia is unknown. However, the efficacy of Rexulti®  may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors. In addition, Rexulti®  exhibits high affinity (subnanomolar) for these receptors, as well as for noradrenaline alpha1B/2C receptors.

Company: Lundbeck (Denmark) Otsuka Pharmaceutical (Japan)

Disease: schizophrenia

Latest news:

• • On June 30, 2018, the European Commission has approved Rxulti® (brexpiprazole) for the treatment of schizophrenia in adults. Lundbeck and Otsuka will now work with local pricing and reimbursement bodies in countries throughout Europe to help ensure that eligible patients are able to access Rxulti®. The medicine is expected to be made available in the first EU markets during first half of 2019.
• • On May 31, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Rxulti®, intended for the treatment of schizophrenia. Rxulti® will be available as film-coated tablets (0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg).  The benefits with Rxulti® are its ability to improve psychotic symptoms. The most common side effects are akathisia and weight gain.• On September 24, 2016, Lundbeck and Otsuka Pharmaceutical announced that the FDA approved the labeling update of Rexulti®(brexpiprazole) to reflect clinical data for maintenance treatment of schizophrenia. The approval was based on results from a long-term randomized withdrawal trial in adults with schizophrenia aged 18 to 65 years. The safety and efficacy of Rexulti® as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in a long-term randomized withdrawal trial. After cross-titration from a prior antipsychotic to Rexulti® and a 12 to 36-week, single-blind Rexulti® stabilization phase, patients who had been symptomatically stable on Rexulti® for 12 consecutive weeks in the stabilization phase were randomized in a double-blind treatment phase to either Rexulti® (n=97) or placebo (n=105). Impending relapse during the double-blind phase was determined if patients met any of the following pre-specified criteria: worsening symptoms defined by changes in PANSS or CGI-I scores; hospitalization for worsening psychotic symptoms; suicidal behavior or; violent/aggressive behavior.
• A pre-specified interim analysis conducted after about 50% of the expected relapses (in order to minimize continued exposure to placebo) demonstrated a statistically significant longer time to relapse in patients randomized to Rexulti® compared to placebo. The trial was subsequently terminated early because maintenance of efficacy had been demonstrated. The final analysis demonstrated a statistically significant longer time to relapse (hazard ratio: 0.292, p < 0.0001) in patients randomized to Rexulti® (1 mg/day to 4 mg/day) compared to placebo. The key secondary endpoint, the proportion of subjects who met the criteria for impending relapse, was statistically significantly lower in Rexulti-treated patients compared with placebo group.
• Lundbeck and Otsuka anticipate submitting a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for the use of brexpiprazole in the treatment of adult patients with schizophrenia.
• • On July 11, 2015, Lundbeck and Otsuka Pharmaceutical announced that the FDA approved Rexulti® (brexpiprazole) as an adjunctive therapy for the treatment of adults with major depressive disorder (MDD) and as a treatment for adults with schizophrenia.  It will be co-marketed by Otsuka and Lundbeck. and is expected to become available to patients in the US in early August 2015. Rexulti® was studied in more than 4,300 subjects in phase II and III clinical trials, and the approval was supported by four completed placebo-controlled clinical phase III studies in the now-approved indications — two studies as adjunctive therapy to antidepressants in MDD and two studies in schizophrenia.
• The efficacy of Rexulti® was established in two, 6-week, phase III randomized, placebo-controlled clinical trials with fixed doses of Rexulti® vs. placebo. Clinical trial data showed: Rexulti®, at an adequate dose for 6 weeks, demonstrated statistically significant efficacy for the primary endpoint of PANSS (Positive and Negative Syndrome Scale). In one trial, change from baseline in PANSS total score for Rexulti at both 2 mg/day and 4 mg/day (-20.73 and -19.65) was superior to placebo (-12.01); in a second trial, the change from baseline in PANSS total score at a dose of 4 mg/day (-20.00 vs. -13.53, respectively) was superior to placebo (2 mg was not superior to placebo in this trial)
• The most common adverse reactions (incidence of 4% or greater, and twice the incidence of placebo) from the pooled safety data associated with Rexulti® at 1, 2 and 4 mg vs. placebo, included weight gain (4% vs. 2%, respectively)
• The incidence of somnolence (also including sedation and hypersomnia) in all patients with schizophrenia who received Rexulti® (n=1,256) was 4.9% compared to 3.2% for patients receiving placebo (n=463).
• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
• Rexulti® will become available to patients in the US in early August 2015. It is given in a once-daily oral dose with a well-defined titration schedule that can be taken with or without food. Schizophrenia: Initiate treatment at 1 mg once daily for the first 4 days. Titrate to 2 mg once daily on Day 5 through Day 7, then to 4 mg on Day 8 based on the patient's clinical response and tolerability
• • On September 24, 2014, Lundbeck and Otsuka Pharmaceutical  announced that the FDA has determined that the New Drug Application (NDA) for brexpiprazole for monotherapy in adult patients with schizophrenia and for adjunctive treatment of major depressive disorder (MDD) in adult patients is sufficiently complete to allow for a substantive review and the NDA is considered filed as of 9 September 2014 (60 days after submission). The PDUFA date is July 11, 2015.
• The NDA is supported by seven completed placebo-controlled clinical phase II or III studies in proposed indications — three studies in schizophrenia and four studies with brexpiprazole as adjunct therapy in MDD. The dossier included data from more than 6,000 participants of whom more than 5,000 received brexpiprazole.
• Brexpiprazole in adult patients with schizophrenia: One clinical phase II and two clinical phase III placebo-controlled studies have been finalized using brexpiprazole in adult patients suffering from schizophrenia. Across the three studies more than 1,700 patients have been randomized. In the first pivotal phase III study randomizing approximately 625 patients, brexpiprazole 2 mg/day and 4 mg/day both demonstrated greater improvement of symptoms relative to placebo as measured by change from baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at week 6 (p<0.05). Results of the key secondary endpoint supported primary results. In the second pivotal phase III study randomizing approximately 650 patients, brexpiprazole 4 mg/day again demonstrated greater improvement of symptoms relative to placebo (p<0.05) in change from baseline in the PANSS Total Score at week 6. Brexpiprazole 2 mg/day showed numerical improvement (p>0.05) over placebo at week 6. The results from the clinical phase II study  were presented at the 24th Annual US Psychiatric and Mental Health Congress in November 2011. The study showed a clinically meaningful improvement from baseline measured by PANSS total score at week 6, although it did not achieve statistical separation from placebo. In the placebo-controlled phase II and III studies, the rates of discontinuation due to adverse events were 8.1% for patients receiving brexpiprazole compared to 12.7% of patients receiving placebo; the only adverse event that occurred in more than 5% of brexpiprazole patients and more frequently than placebo was akathisia (5.8% vs. 4.5%).
• Across the four placebo-controlled phase II and III studies, over 90% of patients completed the studies. The rates of discontinuation due to adverse events was 2.9% for patients receiving brexpiprazole compared to 0.8% of patients receiving placebo; the only adverse events that occurred in more than 5% of brexpiprazole patients and more frequently than placebo were akathisia (8.6% vs. 2.8%) and weight increased (7.3% vs. 1.9%).
• • On July 14, 2014, Otsuka Pharmaceutical and Lundbeck announced the submission of a New Drug Application (NDA) to the FDA for brexpiprazole for the treatment of schizophrenia and as adjunctive treatment of major depressive disorder (MDD). The clinical development program included data from more than 6,500 participants of whom more than 5,300 received brexpiprazole. Following the submission the FDA will determine if the NDA is sufficiently complete to allow for a substantive review of the data; a decision from the FDA on initiation of the substantive review is expected in September 2014.

Patents:

Submission of marketing authorization application USA : 2014-07-14

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2015-07-10

UE authorization: 2018-07-30

Favourable opinion UE: 2018-05-31

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes