The 2018 APA (American Psychiatric Association) Annual Meeting was held from May 5 to May 9, 2018 in New York City. At the meeting, a number of drug marketers and developers presented clinical data for their respective therapies in schizophrenia—one of the key psychiatric illnesses—potentially to command an edge in this highly competitive market.
In this analysis, we provide a snapshot of findings from noteworthy poster presentations that were displayed at the 2018 APA Annual Meeting for oral and depot antipsychotics (see Table 1), including current and emerging therapies in schizophrenia and the potential advantages offered by them in this market.
Table 1. Key Highlights for Therapies in Schizophrenia Presented at the 2018 APA Annual Meeting
Allergan’s Vraylar (cariprazine) is one of the newer-to-market agents in schizophrenia in the United States. At the 2018 APA Annual Meeting, Allergan presented findings on the long-term efficacy of cariprazine in patients with negative symptoms of schizophrenia, based on a post-hoc analysis of pooled data from two open-label studies (clinicaltrials.gov, NCT01104792, NCT00839852) in a subset of patients with predominant moderate-to-severe negative symptoms of schizophrenia (n = 112).1 A notable reduction in mean PANSS-FSNS (Positive and Negative Syndrome Scale-Factor Score for Negative Symptoms) score, a negative symptoms efficacy outcome, from baseline was observed early in the treatment (i.e., by week 8) and cariprazine’s efficacy was maintained up to one year of treatment; a mean change in PANSS-FSNS score from baseline of -11.1 and a response rate (defined as ≥ 20% reduction from baseline in PANSS-FSNS) of 84.8% at one year were demonstrated. Similar findings were presented from the post-hoc analysis of the 20-week open-label phase of a relapse prevention study (clinicaltrials.gov, NCT01412060).
Additionally, a post-hoc analysis from a Phase IIIb study (EudraCT 2012-005485-36) in patients with predominant negative symptoms of schizophrenia (n = 456) demonstrated a significantly greater reduction in PANSS FS-PSM (factor score from the pentagonal structural model) score, another efficacy measure of negative symptoms, from baseline in cariprazine-treated patients versus risperidone-treated patients at week 26 (-9.7 vs. -8.1, P = 0.002, effect size = 0.31).2 This finding parallels the results from this study reported earlier on the primary end point of mean change in PANSS-FSNS from baseline.11 In addition to the PANSS FS-PSM score, a statistically significant improvement in expressive deficits, as well as social amotivation, from baseline were noted in cariprazine-treated patients when compared with risperidone (P = 0.004) in the post-hoc analysis.2
Overall, these data strengthen the evidence of the clinical efficacy of cariprazine in the treatment of patients with negative symptoms of schizophrenia. However, it is currently unclear if Allergan will pursue with an sNDA filing of Vraylar in patients with negative symptoms of schizophrenia in the United States,12 for which it received a refusal-to-file letter from the FDA in September 2017.13 We expect that Allergan would need to evaluate cariprazine in a randomized, double-blind study in the United States in patients with predominant negative symptoms of schizophrenia to obtain FDA approval in this indication.
Sumitomo Dainippon Pharma/Sunovion’s Latuda (lurasidone) is among the few FDA-approved atypical antipsychotics for the treatment of adolescents with schizophrenia. At the 2018 APA Annual Meeting, Sunovion presented interim results from a two-year open-label extension study in adolescent schizophrenia patients (n = 271; clinicaltrials.gov, NCT01914393), in which lurasidone treatment resulted in continuous improvements in PANSS total and factor scores, as well as functional and quality-of-life outcomes over the study duration.3 The mean change in PANSS total score from the double-blind baseline ranged from -34.0 to -35.0 from week 52 to week 104 of the open-label study for patients who continued for this duration. Over the two-year treatment, the drug was found to be safe and well-tolerated, with limited side effects noted on metabolic parameters, weight gain, and prolactin levels. These results support the chronic use of this efficacious and metabolically safe agent in adolescents with schizophrenia.
Intra-Cellular Therapies’ lumateperone, a novel mixed neurotransmitter modulator, is in the preregistration phase for schizophrenia in the United States.14 At the 2018 APA Annual Meeting, the company presented results from a six-week open-label safety study, in which stable schizophrenia patients on current antipsychotics who switched to lumateperone (n = 302) experienced improvement in adverse events, such as body weight gain, cardiometabolic, and endocrine parameters.4 Moreover, no increase in motor side effects was noted during lumateperone treatment. Adverse events worsened when patients switched back to the previous antipsychotics after the six-week treatment with lumateperone. The drug’s efficacy was also reported in this open-label trial based on improvement in mean change in PANSS total score from baseline, as well as PANSS sub-scores and PSP (Personal and Social Performance) scale. We expect these results, along with results from controlled Phase II and III trials,5 will be sufficient to secure FDA approval of lumateperone for the acute treatment of schizophrenia, thus adding a new oral therapy that has demonstrated a clean safety and tolerability profile to the schizophrenia treatment armamentarium in the United States. However, as is typical in the schizophrenia market in the United States, results from a long-term study will be necessary to obtain approval for the maintenance treatment of schizophrenia, as well as to establish the long-term safety profile of the drug in this chronic condition.
Invega Sustenna/Invega Trinza (paliperidone palmitate depots)
Janssen’s once-every-month depot Invega Sustenna and the only once-every-three-month depot Invega Trinza had significantly higher adherence rates in schizophrenia patients when compared with oral atypical antipsychotics (P < 0.001), based on a real-world study among Medicaid patients presented at the 2018 APA Annual Meeting.6 In this study, a long-term data analysis from 2010 to 2016 revealed that adherence of patients on Invega Trinza (n = 105) was 79%, on Invega Sustenna (n = 3,794) was 55%, and on oral atypical antipsychotics (n = 9,754) was 42%. Similarly, patients treated with these depots had significantly lower nonpersistence at 30, 60, and 90 days following the exhaustion of the previous claim’s days’ supply versus oral atypical antipsychotics (P < 0.001). In another study, real-world hospital data from 2009 to 2016 in the United States indicated that schizophrenia patients, including young adults, treated with Invega Sustenna had lower rates of rehospitalization 30-90 days after discharge versus oral atypical antipsychotics.8 These data support the use of Invega Sustenna in early adulthood schizophrenia patients. Additionally, a post-hoc analysis from three relapse-prevention studies with these depots and oral paliperidone in schizophrenia patients (n = 922; clinicaltrials.gov, NCT00086320, NCT00111189, and NCT01529515) suggest that treatment with Invega Trinza results in a lower rate of relapse and delayed time to relapse than Invega Sustenna, followed by oral paliperidone.7 Overall, these data highlight the benefits of using Invega Sustenna and Invega Trinza in schizophrenia patients and could potentially help Janssen in maintaining its leadership in the increasingly competitive schizophrenia depot market in the United States.
Aristada (aripiprazole lauroxil)
Alkermes’s Aristada (aripiprazole lauroxil) is the only depot formulation in the United States that offers the flexibility of monthly, every-six-weeks, and every-two-months dosing for schizophrenia. In a bid to eliminate the need for the 21-day oral aripiprazole overlap requirement for Aristada, the company has developed Aristada Initio—an intramuscularly administered aripiprazole lauroxil nanocrystal dispersion, which offers a one-day initiation regimen with Aristada in schizophrenia patients; Aristada Initio received FDA approval in July 2018.15 At the 2018 APA Annual Meeting, the company presented results from a Phase I study comparing pharmacokinetics, safety, and tolerability of the one-day initiation regimen of Aristada Initio versus a 21-day oral aripiprazole regimen with Aristada 441 mg and 882 mg doses (n = 161).9 Both regimens had comparable aripiprazole exposure from Day 0 to Day 28 post-dosing. The therapeutic blood levels were achieved within 24 hours of the one-day initiation regimen and the regimen was found to be safe and well-tolerated. Aristada Initio offers an advantage of achieving the drug’s therapeutic levels rapidly, eliminating the need for oral aripiprazole supplementation for 21 days, and will be particularly beneficial for nonadherent schizophrenia patients.
Indivior’s RBP-7000, an extended-release risperidone depot, potentially offers an advantage of a longer dosing interval (i.e., once-monthly dosing) over Janssen’s Risperdal Consta, which is dosed every two weeks. Treatment with RBP-7000 also does not require dosing with oral antipsychotics at initiation, as is necessary with some other depots. RBP-7000 is currently in the preregistration phase in the United States.16 At the 2018 APA Annual Meeting, Indivior presented results from a double-blind eight-week Phase III study and an open-label 52-week Phase III study for RBP-7000.10 In the double-blind study in patients with acute exacerbations of schizophrenia (n = 259), RBP-7000 (90 mg and 120 mg dosed once monthly) significantly reduced PANSS scores from baseline versus placebo at eight weeks (P < 0.05). Of note, more than half of drug-treated patients had ≥ 20% reduction in PANSS total score at the end of study period versus 35% patients on placebo. The treatment effect of RBP-7000 was maintained in the long-term open-label study, with a decreasing trend noted in PANSS total score throughout the one-year period. Although oral risperidone was not included as a comparator in these trials, the safety profile of RBP-7000 was reportedly similar to that of oral risperidone in the trials. These results indicate the short- and long-term efficacy and safety of RBP-7000 in schizophrenia. However, its lack of substantial differentiation from other longer-duration/more-tolerable atypical depots in schizophrenia (e.g., Invega Sustenna) and the expected genericization of Risperdal Consta in the United States in 2019 may limit RBP-7000’s uptake in this market.17
Recent advances in schizophrenia are mainly limited to the development of more-tolerable oral agents and longer-acting depot antipsychotics, as indicated from many of the poster presentations on schizophrenia at the 2018 APA Annual Meeting. Notably, Allergan’s cariprazine had compelling clinical data on patients with negative symptoms of schizophrenia—an area of high unmet need.18 However, a dearth of clinical findings at the meeting for therapies in development for cognitive impairment associated with schizophrenia or for treatment-refractory schizophrenia—other areas of high unmet need—means that psychiatrists must continue to wait for progress in the treatment of these patients.
- McEvoy J, et al. Long-term effects of cariprazine in patients with negative symptoms of schizophrenia: a post hoc analysis of two 48-week, open-label studies. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P6-151.
- Earley W, et al. Consistent efficacy of cariprazine across PANSS-based factor scores for negative symptoms of schizophrenia. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P8-164.
- Goldman R, et al. Efficacy and safety of lurasidone in adolescents with schizophrenia: results of a 2-year, open-label extension study. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P7-045.
- Correll CU, et al. Lumateperone (ITI-007): results from an open-label switching study from standard-of-care antipsychotic therapy in patients with schizophrenia. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P6-155.
- Vanover KE, et al. Lumateperone (ITI-007) for the treatment of schizophrenia: overview of placebo-controlled clinical trials and an open-label safety switching study. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P5-178.
- Gilligan AM, et al. Treatment patterns in schizophrenia patients initiated on paliperidone palmitate long-acting injectable in a Medicaid population. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P7-130.
- Mathews M, et al. Schizophrenia relapse comparison between 3 paliperidone formulations differing in duration of action: results from post-hoc analysis. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P6-150.
- Pilon D, et al. Rehospitalizations in young adults with schizophrenia treated with once-monthly paliperidone palmitate or oral atypical antipsychotics. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P6-144.
- Walling D, et al. Aripiprazole lauroxil nanocrystal dispersion: a potential 1-day initiation regimen for long-acting aripiprazole lauroxil. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P6-142.
- Graham J, et al. Monthly extended-release risperidone injections (RBP-7000) in the treatment of schizophrenia: results from two Phase III trials. Annual Meeting of the APA; May 5-9, 2018; New York, NY. P5-130.
- Németh G, et al. Cariprazine vs. risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389:1103-1113.
- Allergan, Q1 2018 earnings presentation, April 30, 2018.
- Allergan, press release, September 22, 2017.
- Intra-Cellular Therapies, press release, June 6, 2018.
- Alkermes, press release, July 2, 2018.
- Indivior, press release, December 12, 2017.
- DRG’s Schizophrenia | Disease Landscape and Forecast | G7 | June 2018.
- Schizophrenia | Unmet Need | Detailed, Expanded Analysis (Negative Symptoms) | US/EU | April 2018.
DRG’s Recent and Upcoming Product Offerings in Schizophrenia
- Schizophrenia | Current Treatment | Detailed, Expanded Analysis - Treatment Algorithms - Claims Data Analysis (US) (published in March 2018)
- Schizophrenia | Unmet Need | Detailed, Expanded Analysis (Negative Symptoms) | US/EU (published in April 2018)
- Schizophrenia | Disease Landscape and Forecast | G7 (publishing in Q4 2018)