Industry Trend Analysis - Reagila Is A New Option In A Crowded Market - SEPT 2017

BMI View: A s an atypical antipsychotic, Reagila join s a crowded market and sales growth will be slow but steady, mirroring the experience with Vraylar in the US. This is an effective drug with potential in other conditions and its development for the treatment of predominant negative symptoms of schizophrenia targets a serious unmet need.

Almost two years since the drug's FDA approval, the EC has granted marketing authorisation to Reagila (cariprazine), a novel antipsychotic for the treatment of schizophrenia in adult patients. This decision follows a positive opinion from the EMA's CHMP announced in May 2017 and is applicable for all Member States in the EU.

Cariprazine is an orally active and potent dopamine D 3/D 2 receptor partial agonist with preferential binding to D 3 receptors and partial agonist at 5-HT 1A receptors. It was discovered by Gedeon Richter scientists, and developed for the treatment of schizophrenia and bipolar mania jointly by Allergan (earlier Forest/ Actavis) and Richter, and is licensed to Allergan in the US and Canada. Following its FDA approval in September 2015, the product was launched in the US in March 2016 under the trademark of Vraylar for the treatment of both schizophrenia and bipolar mania. In August 2016, Richter and Recordati signed an exclusive licence agreement to commercialise cariprazine in Western Europe, Algeria, Tunisia and Turkey.

The European application for the treatment of schizophrenia includes results from three short-term, placebo and partly active controlled positive trials in over 1,800 patients and one long-term trial, using the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score and the time to relapse as primary efficacy endpoints, respectively. A clinical trial with positive results was also carried out in patients suffering from predominant negative symptoms of schizophrenia.

Lack Of Differentiation Will Slow Uptake

The atypical antipsychotic class has produced numerous blockbuster drugs, but this market is now crowded and heavily genericised, limiting the commercial potential of new drugs, which thus need to differentiate themselves in order to stand out and gain a foothold. Cariprazine is a new molecular entity and offers an additional treatment option, however the pharmacology of the drug follows traditional lines and thus it will struggle to differentiate itself from alternatives, limiting the overall potential.

Vraylar Off To A Steady Start
Allergan's Vraylar Net Revenues (USDmn)
Source: Allergan, BMI

Additional Indications May Offer Sales Boost

Ongoing clinical developments of cariprazine are being currently managed by Allergan (earlier Forest/Actavis) and Richter for bipolar depression and as adjunctive therapy for major depressive disorder (MDD) in the US. Additionally, Mitsubishi Tanabe Pharma is developing cariprazine for the treatment of schizophrenia in Japan and in other Asian countries. However, results from a trial in MDD, reported by Allergan and Richter in August 2016, failed to show separation from placebo.

The MD-72 trial was a prospective, randomised, double-blind, placebo-controlled, parallel-group study evaluating flexible doses of cariprazine (1.5-4.5mg) as an adjunctive treatment to antidepressant therapy in adults with MDD who failed to adequately respond to antidepressant monotherapy. The study was conducted at multiple centres, all within the US.

Top-line results from the MD-72 trial indicated that flexible doses of cariprazine did not separate significantly from placebo as an add-on treatment in this trial. In a previously conducted trial (MD-75), flexible doses of cariprazine (2-4mg) were significantly more effective than placebo as an adjunctive treatment to antidepressant therapy in adults with MDD who failed to adequately respond to antidepressant monotherapy. The companies noted that it is not uncommon that clinical trials in MDD fail to show a separation from placebo even with effective drugs, adding that they both remained committed to developing cariprazine as a potential treatment option for patients suffering from this illness and would continue to work on a subsequent Phase III trial.

Allergan and Richter also reported having started the patient enrolment in their Phase III trial programme investigating the use of cariprazine as a treatment for bipolar depression, with two parallel studies to be conducted at approximately 85 sites across the US and Europe. The companies have previously announced positive Phase IIb data for cariprazine for the treatment of bipolar depression.

In March 2017, Allergan announced that the FDA had accepted for filing the company's sNDA for Vraylar, seeking the addition of new clinical data evaluating Vraylar for the maintenance of efficacy in adults with schizophrenia to the current product label. The data included in the sNDA are from a Phase III multinational, randomised, double-blind, placebo-controlled, parallel-group study of cariprazine in adults with schizophrenia (RG-MD-06), which found cariprazine compared to placebo significantly delayed the time to relapse.

Despite a wide availability of drugs, the following unmet needs remain in schizophrenia: improved adherence to antipsychotic medication; treatment of negative symptoms associated with schizophrenia; treatment of cognitive symptoms of schizophrenia; drugs for treatment-resistant schizophrenia; and drugs with improved safety and tolerability.

In January 2015, Richter announced a positive Phase III study that evaluated cariprazine for the treatment of predominant negative symptoms of schizophrenia. It was reported in August 2016 that both Richter and Allergan were in active discussions with the FDA regarding the submission of an efficacy supplement to provide for the treatment of predominant negative symptoms. Based on their current regulatory interactions, the companies intended to file in H117.