Table 1.
Study design, safety, and metabolic results for clinical trials of discussed emerging treatments [73, 75, 76, 88, 89, 95, 100, 103, 128, 130, 140, 152]
| Drug | Daily doses | Study type | Sample size | Treatment length | Patient population | Overall safety | Metabolic dataa | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Deaths | AEs, n (%) | SAEs, n (%) | AE-related discontinuations, n (%) | Weight | Glucose (mg/dL) | Insulin (µIU/mL) | HbA1C (%)b | LDL/HDL (mg/dL) | ||||||
| Olanzipine/ Samidorphan |
OLZ/SMDP 5 mg/5 mg 10 mg/10 mg 20 mg/20 mg or OLZ/PBO |
Randomized, PBO-controlled, ph 2, multicenter, safety, dose-ranging, open-label OLZ, double-blind SMD | N = 347 | 12 weeks | 18–50 years of age, clinically stable schizophrenia, BMI 17–30 kg/m2 | 0 | OLZ + SMDP: 127 (54.3) OLZ + PBO: 41 (54.7) |
OLZ + SMDP: 11 (4.7) OLZ + PBO: 2 (2.7) |
OLZ + SMDP: 21 (9.0) OLZ + PBO: 3 (4.0) |
− 37% versus OLZ monotherapy | OLZ + SMDP: 5.4 OLZ + PBO: 4.1 |
OLZ + SMDP: 5.0 OLZ + PBO: 10.8 |
NA |
OLZ + SMDP: 7.4/− 2.1 OLZ + PBO: − 11.5/− 3.2 |
|
OLZ/SMDP 10 mg/10 mg 20 mg/10 mg or OLZ 10 or 20 mg |
Randomized, ph 3, multicenter, double-blind (ENLIGHTEN-2) |
N = 550 | 24 weeks | 18–55 years of age, clinically stable schizophrenia, BMI 18–30 kg/m2 | 0 |
OLZ + SMDP: 203 (74.1) OLZ: 227 (82.2) |
OLZ+SMDP: 10 (3.6) OLZ: 7 (2.5) |
OLZ + SMDP: 33 (12.0) OLZ: 27 (9.8) |
OLZ/SMDP: 4.21% OLZ: 6.59% (LS mean diff − 2.38%) |
OLZ+SMDP: 4.5 OLZ: 2.3 |
OLZ + SMDP: 3.22 OLZ: 3.40 |
OLZ + SMDP: 0.06 OLZ: 0.07 |
OLZ + SMDP: 0.6/− 5.1 OLZ: 0.9/− 4.5 |
|
|
OLZ/SMDP 10 mg/10 mg 15 mg/10 mg 20 mg/10 mg |
Open-label, ph 3, multicenter, extension (ENLIGHTEN-2-EXT) |
N = 265 | 52 weeks |
Completers of ENLIGHTEN-2, 18–55 years of age, clinically stable schizophrenia, BMI 18–30 kg/m2 |
0 | 161 (60.8) | 5 (1.9%) | 15 (5.7) |
Mean (SD), kg − 0.03 (6.22) |
1.3 | 2.5 | 0.03 | − 1.5/− 1.3 | |
| Iclepertin |
Iclepertin 2, 5, 10, 25 mg PBO |
Randomized, ph 2, double-blind, parallel-group, multicenter, PBO-controlled | N = 509 | 12 weeks | 18–50 years of age, clinically stable schizophrenia ≥ 3 months before randomization, on stable treatment | 0 |
Iclepertin 2 mg: 50 (59) Iclepertin 5 mg: 44 (52) Iclepertin 10 mg: 35 (41) Iclepertin 25 mg: 36 (42) PBO: 74 (44) |
Iclepertin 2 mg: 2 (2) Iclepertin 5 mg: 4 (5) Iclepertin 10 mg: 2 (2) Iclepertin 25 mg: 4 (5) PBO: 4 (2) |
Iclepertin 2 mg: 5 (6) Iclepertin 5 mg: 4 (5) Iclepertin 10 mg: 0 (0) Iclepertin 25 mg: 2 (2) PBO: 4 (2) |
NA | NA | NA | NA | NA |
| Xanomeline |
Xanomeline 225 mg PBO |
Randomized, pilot study, double-blind, PBO-controlled | N = 20 | 4 weeks | 18–60 years of age, diagnosis of schizophrenia or schizoaffective disorder, acute exacerbation of schizophrenia | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Xanomeline-Trospium |
Xanomeline 125 mg + Trospium 30 mg bid PBO |
Randomized, ph 2, double-blind, multicenter, PBO-controlled | N = 182 | 5 weeks | 18–60 years of age, primary diagnosis of schizophrenia, PANSS total score ≥ 80 (≥ 5 on one positive symptom or ≥ 4 on 2 positive symptoms) | 0 |
Xanomeline + trospium: 48 (54) PBO: 39 (43) |
Xanomeline + trospium: 1 (1) PBO: 0 (0) |
Xanomeline + trospium: 2 (2) PBO: 2 (2) |
Mean, kg Xanomeline + trospium: 1.5 ± 2.8 PBO: 1.1 ± 3.5 |
NA | NA | NA | NA |
| Emraclidine |
Emraclidine 5–40 mg PBO |
Part A: Sequential assignment, randomized, ph 1b, multiple ascending-dose | N = 49 | NA | 18–50 years of age, primary diagnosis of schizophrenia, PANSS total score ≤ 80 | 0 |
Emraclidine: 16 (41) PBO: NA |
NA | NA | NA | NA | NA | NA | NA |
|
Emraclidine 30 mg qd Emraclidine 20 mg bid PBO |
Part B: Randomized, ph 1b, PBO-controlled | N = 49 | 6 weeks | 18–55 years of age, primary diagnosis of schizophrenia, PANSS total score ≥ 80, CGI-S score ≥ 4, PANSS positive subscale score ≥ 4 for at least 2 positive subscale items | 0 |
Emraclidine 30 mg qd: 14 (52) Emraclidine 20 mg bid: 15 (56) PBO: 14 (52) |
Emraclidine 30 mg qd: 2 (7.0) Emraclidine 20 mg bid: 1 (4.0) PBO: 0 (0) |
Emraclidine 30 mg qd: 2 (7.0) Emraclidine 20 mg bid: 1 (4.0) PBO: 0 (0) |
Mean (SD), kg Emraclidine 30 mg qd: 1.4 (4.3) Emraclidine 20 mg bid: 1.7 (3.1) PBO: 1.6 (4.0) |
NA | NA | NA | NA | |
| Ulotaront |
Ulotaront 50 mg Ulotaront 75 mg PBO |
Randomized, ph 2, double-blind, multicenter | N = 245 | 4 weeks | 18–40 years of age, diagnosis of schizophrenia ≥ 6 months, acute exacerbation of psychotic symptoms for ≤ 2 months, PANSS total score ≥ 80 and CGI-S score ≥ 4 | 1 |
Ulotaront 50 or 75 mg: 55 (45.8) PBO: 63 (50.4) |
Ulotaront 50 or 75 mg: 2 (1.6) PBO: 4 (3.2) |
Ulotaront 50 or 75 mg: 10 (38.5) PBO: 8 (30.8) |
Mean, kg Ulotaront 50 or 75 mg: 0.3 ± 1.9 PBO: − 0.1 ± 2.3 |
Median change from baseline, mmol/L Ulotaront 50 or 75 mg: 0.0 PBO: 0.1 |
NA | NA |
LDL, mmol/L Ulotaront 50 or 75 mg: − 0.1 PBO: 0 |
|
Ulotaront 25 mg Ulotaront 50 mg Ulotaront 75 mg |
Open-label safety extension study | N = 157 | 26 weeks | 18–40 years of age, diagnosis of schizophrenia ≥ 6 months, acute exacerbation of psychotic symptoms for ≤ 2 months, PANSS total score ≥ 80 and CGI-S score ≥ 4, completion of 4 week lead in study | 0 | Ulotaront 25, 50, or 75 mg: 88 (56.4) | Ulotaront 25, 50, or 75 mg: 15 | Ulotaront 25, 50, or 75 mg: 18 (11.5) |
Mean (SD), kg Ulotaront 25, 50, or 75 mg: − 0.3 (3.7) |
Median Ulotaront 25, 50, or 75 mg: 2.0 |
NA |
Median Ulotaront 25, 50, or 75 mg: 0.0 |
Ulotaront 25, 50, or 75 mg: − 9.0/0.0 | |
AE adverse event, bid twice daily, BMI body mass index, CGI-S Clinical Global Impressions Scale, HbA1c hemoglobin A1c, HDL high-density lipoprotein, LDL low-density lipoprotein, LS least squares, NA not available, OLZ olanzapine, PANSS Positive and Negative Syndrome Scale, PBO placebo, ph phase, qd once daily, SAE serious adverse event, SD standard deviation, SMDP samidorphan
aChange from baseline to study end. bNonfasting.