3 results
427 - HARMONY study: pimavanserin significantly reduces risk of relapse of dementia-related psychosis
- Erin P Foff, Jeffrey L Cummings, Maria-Eugenia Soto-Martin, Pierre Tariot, Bradley McEvoy, Srdjan Stankovic
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- Journal:
- International Psychogeriatrics / Volume 32 / Issue S1 / October 2020
- Published online by Cambridge University Press:
- 04 November 2020, p. 143
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Dementia-related psychosis (DRP) is common among patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD) and is associated with poor outcomes. HARMONY (NCT03325556) was a Phase 3, placebo-controlled, randomized, relapse-prevention study evaluating the efficacy and safety of pimavanserin for treating hallucinations and delusions associated with DRP. Patients with dementia and moderate-severe psychosis received open-label (OL) pimavanserin for 12 weeks. Patients with a sustained response (≥30% reduction in Scale for the Assessment of Positive Symptoms hallucinations+delusions Total Score AND Clinical Global Impression-Improvement score of much/very much improved) at Weeks 8 and 12 were randomized 1:1 to continue pimavanserin or receive placebo for up to 26 weeks in the double-blind (DB) period. The primary endpoint was time from randomization to relapse of DRP. 392 patients enrolled. 217 (61.8%) eligible patients experienced sustained response and were randomized. OL response was similar regardless of dementia subtype (randomization rates: 59.8% AD, 71.2% PDD, 71.4% VaD, 45.5% DLB, 50.0% FTD), baseline disease characteristics, age, dementia severity, or previous drug therapy. The study stopped early for superior efficacy when a prespecified interim analysis revealed >2.8-fold reduction in risk of relapse with pimavanserin (hazard ratio: 0.353; 95% CI: 0.172, 0.727; 1-sided p=0.0023). Adverse event rates were low and balanced (OL: 36.2%; DB: 41.0% pimavanserin, 36.6% placebo). No negative trends for worsening in cognition (as assessed by the Mini-Mental State Examination) or motor function were observed. The HARMONY study demonstrated a robust decrease in hallucinations and delusions and significant maintenance of efficacy with pimavanserin treatment in DRP.
Study Sponsored By: ACADIA Pharmaceuticals Inc.
DisclosuresThis study was funded by ACADIA Pharmaceuticals Inc.
Drs. Foff, McEvoy, and Stankovic are all employees of ACADIA Pharmaceuticals Inc. (San Diego, CA, USA).
Dr Cummings has provided consultation to ACADIA, Accera, Actinogen, AgeneBio, Alkahest, Allergan, Alzheon, Avanir, Axsome, Binomics, BiOasis Technologies, Biogen, Bracket, Cassava, Denali, Diadem, EIP Pharma, Eisai, Genentech, Green Valley, Grifols, Hisun, Idorsia, Lundbeck, Merck, Otsuka, Pain Therapeutics, Probiodrug, Proclara, QR, Resverlogix, Roche, Samumed, Shinkei Therapeutics, Sunovion, Suven, Takeda, and United Neuroscience pharmaceutical and assessment companies. He owns stock in ADAMAS, BioAsis, MedAvante, and QR Pharma. Dr. Cummings owns the copyright of the Neuropsychiatric Inventory (NPI). Dr. Cummings is supported by a COBRE grant from NIH/NIGMS #P20GM109025 and Keep Memory Alive.
Dr. Soto has provided consultation to ACADIA, Avanir, Eisai, Lundbeck, and Otsuka.
180 Improvement of Sexual Function Observed During Treatment of Major Depressive Disorder with Adjunctive Pimavanserin
- Marlene P. Freeman, Maurizio Fava, Bryan Dirks, Manish K. Jha, Richard C. Shelton, Michael E. Thase, Madhukar H. Trivedi, George I. Papakostas, Keith Liu, Troy Whitworth, Srdjan Stankovic
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 313-314
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Study Objectives:
Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepinephrine reuptake inhibitor (SSRI/SNRI) treatment. No new safety observations were reported in this study. This post-hoc analysis examines the potential impact of PIM treatment on sexual function.
Method:Study methodology has been presented previously (APA 2019). Adult male and female patients with moderate-to-severe MDD were randomized to PIM 34 mg/day (n=51) or placebo (PBO, n=152) added to ongoing SSRI/SNRI treatment. Massachusetts General Hospital–Sexual Functioning Inventory (MGH-SFI) and Hamilton Depression Rating Scale, 17-item version (HAMD-17) item 14 (sexual interest) scores were examined by analysis of covariance.
Results:Adjunctive PIM resulted in significantly greater 5-week reduction (improvement) relative to SSRI/SNRI treatment plus placebo on mean MGH-SFI scores (difference –0.634, SE 0.167; P<0.001; effect size [ES], Cohen’s d 0.614). Similarly, PIM resulted in greater improvement compared with placebo on individual MGH-SFI items that applied to both males and females: Interest in Sex (P=0.006; ES=0.483), Ability to Get Sexually Aroused/Excited (P=0.001; ES=0.560), Ability to Achieve Orgasm (P<0.001; ES=0.609), Overall Sexual Satisfaction (P=0.003; ES=0.524). HAMD-17 item 14 scores were also significantly more reduced (improved) with PIM (P<0.001; ES=0.574).
Conclusions:These results underscore the potential of adjunctive PIM for improving sexual function in patients with MDD and inadequate response to SSRIs/SNRIs. Potential benefits should be confirmed in further studies.
Funding Acknowledgements:ACADIA Pharmaceuticals Inc.
181 A Phase-2 Sequential Parallel Comparison Design Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Major Depressive Disorder
- Maurizio Fava, Bryan Dirks, Marlene P. Freeman, Richard C. Shelton, Michael E. Thase, Madhukar H. Trivedi, George I. Papakostas, Keith Liu, Troy Whitworth, Srdjan Stankovic
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- Journal:
- CNS Spectrums / Volume 25 / Issue 2 / April 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 314-315
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Study Objectives:
Depression is the leading cause of disability worldwide, with fewer than 50% of treated patients achieving full remission. This study (“CLARITY,” ACP-103-042: NCT03018340) examined the 5-HT2A inverse agonist pimavanserin (PIM) as a potential adjunctive treatment for major depressive disorder (MDD).
Method:Adult female and male subjects with a DSM-5 primary diagnosis of a major depressive episode as part of MDD, inadequate response to ongoing SSRIs or SNRIs of adequate dose and duration as confirmed by the Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and a MADRS total score >20 were randomized to PIM 34 mg/day or placebo (PBO) added to their SSRI/SNRI treatment. A sequential parallel comparison design was used, consisting of two 5-week stages. PBO nonresponders in Stage-1 who met prespecified criteria were re-randomized to PIM or PBO for the second period (Stage-2). The primary efficacy measure was the weighted average of Stage-1 and Stage-2 total scores of the HAMD-17.
Results:Of the 207 patients enrolled, 52 received PIM, and 155 received PBO in Stage 1. Mean age was 46.2 years, and 72.9% of patients were female. Baseline MADRS total (mean [SD]: 31.5 [0.4]) and HAMD-17 total scores (22.2 [0.3]) indicated a moderate overall severity of illness. PIM met the primary endpoint, reducing the weighted Stage-1/Stage-2 HAMD-17 total score relative to PBO (least-square means [LSM] difference, –1.7; standard error [SE], 0.9; P=0.04). Stage-1 PIM patients demonstrated highly significant 5-week improvement on the HAMD-17 (LSM difference=–4.0, SE=1.1; P<0.001; effect size, Cohen’s d: 0.626), separating from placebo by the end of Week 1 (LSM difference=–1.7, SE=0.8; P=0.04). Stage-2 results showed no significant separation among Stage-1 placebo nonresponders (P=0.69). In Stage 2, a substantively smaller number of subjects (n=58) were rerandomized than planned, likely due to restrictive criteria for re-randomization. Greater overall improvement was seen with PIM relative to PBO on the key secondary endpoint, the Sheehan Disability Scale (LSM difference=–0.8, SE=0.3; P=0.004), and positive results were also seen on 7 of the 11 other secondary endpoints, including responder rate (≥50% reduction in HAMD-17 total; P=0.007), Massachusetts General Hospital Sexual Functioning Index (P<0.001), and Karolinska Sleepiness Scale for daytime sleepiness (P=0.02). Discontinuations due to adverse events were low (PIM 1.2%, PBO 3.2%). One serious adverse event was reported in each treatment group, deemed unrelated to treatment. No deaths were reported. Laboratory assessments, electrocardiography, and changes in vital signs were unremarkable, and no new safety signals were reported.
Conclusions:Study data provide evidence of the efficacy, safety, and tolerability of adjunctive PIM in treating MDD inadequately responsive to SSRI or SNRI therapy. Efforts to confirm these results are ongoing in a Phase 3 program.
Funding Acknowledgements:ACADIA Pharmaceuticals Inc.