Clinical effect of nemifitide, a novel pentapeptide antidepressant, in the treatment of severely depressed refractory patients.

Clinical data were evaluated from an open-label, single-center, pilot study in patients with chronic refractory depression. The primary efficacy criterion was the change from baseline using the Montgomery-Asberg Depression Rating Scale. The secondary efficacy criteria were the 17-item Hamilton Depression Rating Scale and the Clinical Global Impression-Improvement scale. Response to treatment (40-240 mg once per day by subcutaneous injection for 10-20 doses) was defined as more than 50% improvement in the Montgomery-Asberg Depression Rating Scale from baseline or Clinical Global Impression-Improvement < or =2 and lasting for at least two sequential weeks. Patients with a sustained response at the end point in the acute main treatment phase were enrolled for up to 2 years in a maintenance phase of the study to determine duration of response and to initiate retreatments upon relapse. Of the 25 patients with chronic refractory depression, 11 patients showed a response for Montgomery-Asberg Depression Rating Scale and one responded according to the secondary criterion Hamilton Depression Rating Scale. In seven of the 11 responders to Montgomery-Asberg Depression Rating Scale the effects were sustained for the remainder of the acute phase. Two additional sustained responders identified according to secondary criteria (Hamilton Depression Rating Scale or Clinical Global Impression-Improvement) were also enrolled in the maintenance phase. All nine sustained responders were retreated, as needed, in the maintenance phase of the study, ranging from 71 to 660 days. Mean duration of response following initial treatment and between retreatments was around 2 months. Pharmacokinetic data indicated dose-proportional systemic exposure to the drug.

Antidepressant-like effects of a novel pentapeptide, nemifitide, in an animal model of depression.

BACKGROUND: Nemifitide is a novel peptide analog of melanocyte-inhibiting factor (MIF) that has been reported to relieve depressive symptoms in a very short period. OBJECTIVES: The Flinders Sensitive Line (FSL) rat, a genetic animal model of depression with innate exaggerated immobility in the forced swim test, was used to obtain more detailed information about the antidepressant-like effects of nemifitide. METHODS: The FSL rats were treated chronically with various doses of nemifitide or reference antidepressants desipramine and fluoxetine for 5 or 14 days and the forced swim test was conducted 22-24 h after the last treatment. RESULTS: Nemifitide significantly increased swimming in the FSL rats at both low (0.025-0.3 mg/kg) and high (3.0-15.0 mg/kg) doses but not at intermediate (0.4-2.4 mg/kg) doses. Nemifitide (0.3 mg/kg) and desipramine (5.0 mg/ kg) significantly increased swimming in the FSL rats after just 5 days of treatment, but fluoxetine (5.0 mg/kg) did not. Nemifitide (0.3 mg/kg) and fluoxetine (5.0 mg/kg) had long-lasting effects, but desipramine (5.0 mg/kg) did not. CONCLUSIONS: These findings support the value of developing nemifitide and its analogs as potential antidepressants.

Efficacy and safety of 30 mg/d and 45 mg/d nemifitide compared to placebo in major depressive disorder.

Nemifitide is a novel pentapeptide antidepressant, which appears to be effective in the treatment of major depressive disorder (MDD). In the present study 81 patients with MDD, DSM-IV criteria were randomized following a 1-wk screening period to receive 30 mg/d nemifitide, 45 mg/d nemifitide or placebo in a 6-wk double-blind, multicentre, outpatient efficacy study. Nemifitide or placebo was delivered by subcutaneous injection for 2 wk daily for 5 days (Monday to Friday) in the first 2 wk and patients were followed up for a further 4 wk. The primary efficacy measure was the change from baseline on the Montgomery-Asberg Depression Rating Scale. Secondary measures included the 17-item Hamilton Psychiatric Rating Scale for Depression (HAMD), the CGI severity and improvement scale and the Carroll Self-Rating Scale for Depression. This proof-of-principle study demonstrated a statistically significant superiority of the 45-mg/d dose vs. placebo at the time-point of peak effect (1 wk after the end of treatment). There appeared to be a greater effect with the 45 mg/d nemifitide dose than with 30 mg/d. An additional exploratory analysis by stratification of all patients by severity above and below or equal to the median baseline HAMD score of 22 showed a higher percentage of responders for both doses of nemifitide with statistical separation from placebo for patients with baseline HAMD score of >22 (above the median). There was no significant difference among treatment groups for patients with baseline HAMD score of

Clinical effectiveness of nemifitide, a novel pentapeptide antidepressant, in depressed outpatients: comparison of follow-up re-treatment with initial treatment.

Data from two Phase 2 clinical studies with nemifitide, a novel pentapeptide antidepressant, were evaluated. The initial double-blind, placebo-controlled study was performed on outpatients with DSM-IV criteria for major depressive disorder. An open-label extension study enrolled subjects either completing or having been discontinued due to lack of efficacy during the follow-up period of the initial study. In the extension study, both the investigator and the subjects were blinded to the previous treatment in the initial study. No clinically significant side-effects were observed in either study. Twenty-seven subjects have been entered and evaluated in the extension study. Eighteen of these 27 subjects (66.7%) responded to re-treatment in the extension study. Mean duration of effect between re-treatments was 3.3 months. The results of the extension study support investigating a range of doses of nemifitide from 18 to 72 mg/d in future clinical trials. Further studies are planned to determine the most effective nemifitide clinical treatment regimen.

Clinical pharmacokinetic studies with INN 00835 (nemifitide), a novel pentapeptide antidepressant.

Nemifitide (4-fluoro-L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-arginylglycyl-L-tryptophanamide ditrifluoroacetate) is a novel antidepressant, currently in phase 2/3 clinical trials. The purpose of our phase 1 clinical trials (conducted over a three year period) was to provide safety and pharmacokinetic data to support its clinical development as an antidepressant drug. Single and multiple doses ranging from 18 to 320 mg were administered subcutaneously to healthy volunteers in five phase 1 studies. Plasma concentrations of unchanged parent drug were determined by a validated LC/MS/MS method in blood samples collected at timepoints between 10 min and 72 h after dosing. Nemifitide was rapidly absorbed (C(max) at 10 min) and eliminated (t(1/2) 15-30 min) in most subjects. Regression and power model analyses were used to evaluate the data. The results indicate that pharmacokinetic parameters: AUC(0-t), AUC (0-infinity) and C(max), were close to dose proportional in the dose range investigated. There was no evidence of systemic accumulation of drug following 5 daily doses. No serious adverse events or clinically significant systemic adverse events occurred at any of the doses investigated in the over 100 subjects dosed in these studies. Drug-related adverse events were limited to local and transient skin reactions (pain and/or erythema) at the injection site, especially at the high doses administered: 240 and 320 mg.