Depression occurs in ~50% of Parkinson’s disease (PD) patients, increases in severity and duration as the disease progresses, and is associated with increased morbidity. Improvement of depression in PD patients is correlated with reduced physical disability and improved quality of life. We are assessing use of pimavanserin (PIM) for treatment of depression in adults with PD.

A Phase-2, 8-week, open-label, single-arm study is being conducted to evaluate the safety and efficacy of PIM as an adjunct to SSRI/SNRI or as monotherapy in adults with both PD and symptoms of depression (baseline Hamilton Depression Scale [17-items] total score [HAMD-17] ≥15). The primary endpoint of the study is change from Baseline to Week 8 in the HAMD-17. Secondary measures included the Clinical Global Impression (CGI) scales (improvement and severity) and Scales of Outcomes in PD-Sleep (SCOPA).

Interim results based on the first 34 of 40 planned patients have been evaluated: 55.9% of patients were male, and average age was 68.1 years, with 19 patients on adjunctive therapy and 15 on monotherapy. At baseline, patients had a mean (SE) HAMD-17 of 19.8(0.6). Change from Baseline to Week 8 (least squares mean [LSM] [SE]) in the HAMD-17 was –10.7(1.0) (95% CI; –12.7,–8.7; P<0.001), with significant improvement seen as early as Week 2 (–8.4[1.0]; 95% CI; –10.5,–6.4; P<0.001). Significant improvement was seen for both adjunctive treatment and monotherapy: 45.2% of patients responded to treatment (≥50% improvement on the HAMD-17) at Week 8, and 35.5% reached remission (HAMD-17 ≤7). On the Clinical Global Impressions–Improvement scale, 54.8% were much/very much improved at Week 8. Significant improvement was seen in change from Baseline to Week 8 SCOPA–Global Sleep Quality, –Nighttime Sleep, and –Daytime Sleepiness: –1.0(0.4) (95% CI; –1.7,–0.3; P=0.010), –2.1(0.7) (95% CI; –3.6,–0.6; P=0.008), –2.1(0.4) (95% CI; –3.0,–1.2; P<0.001) respectively. Twenty-one of the 34 enrolled patients have completed the study to date, and another 7 are still continuing. Thirteen patients reported adverse events, the most common being falls, UTI, diarrhea, and nausea.

These interim data suggest that PIM as adjunctive treatment or monotherapy is associated with early improvement of depressive symptoms in patients with PD and is well tolerated. This is consistent with recently reported data of PIM in major depressive disorder. Final data will be shared at the time of this presentation. However, additional placebo-controlled data will be needed to determine fully the efficacy of PIM in patients with comorbid PD and depression.

ACADIA Pharmaceuticals Inc.

A planned subgroup analysis of a phase 3 study was performed to evaluate the efficacy and safety of pimavanserin (PIM) in Parkinson’s disease psychosis (PDP) patients withglobal cognitive impairment.

PDP is frequent, distressing, a leading cause of institutionalization, complicates PD management and is linked to increased morbidity, incident dementia and mortality. PIM, a selective serotonin receptor (5-HT2A) inverse agonist/antagonist, is newly FDA-approved for the treatment of hallucinations and delusions associated with PDP.

In Study 020, a 6-week FDA registration study, 199 patients with baseline Mini-Mental State Examination (MMSE) score ≥21, moderate-severe psychosis, and on stable PD meds, were randomized to PIM (34 mg/day) or placebo (PBO) for 6 weeks. This subgroup analysis evaluates efficacy and safety between two groups: those with MMSE total score ≥21 but <25 (cognitively impaired; equivalent to Montreal Cognitive Assessment [MoCA] score 15-19) and those with score ≥25 (cognitively normal; equivalent to MoCA score 20-30). Safety assessments were performed on the full safety dataset (i.e., three 6-week placebo-controlled studies) including 614 subjects (PIM=382, PBO=231).

Overall, patients in the PIM group experienced a statistically significant improvement in SAPS-PD scores from baseline to Day 43 compared with PBO (-5.79 vs. -2.73; p=0.001). In the subgroup analysis stratifying by baseline MMSE score, the change from baseline to Day 43 compared with PBO in the cognitively-impaired group (N=50) was numerically larger (-7.11 vs. -0.47; p=0.002). In the full safety dataset examining cognitively impaired patients, there were no between-group (PIM vs. PBO) differences in any treatment-emergent adverse event (TEAE) (57.6% vs. 56.1%) or serious TEAE (6.8% vs. 5.3%). The most common TEAEs occurring at ≥5% in either group were fall (7.4% vs.10.5%), confusional state (6.5% vs.1.8%), and orthostatic hypotension (0.0% vs. 8.8%).

In this subgroup analysis of PDP patients, the treatment effect of PIM on SAPS-PD was larger in the cognitively-impaired group, with similar TEAE and serious TEAE rates. These results hold promise for cognitively-impaired patients that will be further elucidated in future studies.

Clinical study was funded by ACADIA Pharmaceuticals Inc.

Psychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.

NNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.

NNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are <10, and as robust as 4, denoting that PIM is a potentially efficacious intervention. NNH values for tolerability outcomes for PIM 34 mg/d (as well as for doses that range from 8.5 mg/d to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.

Using the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.

Clinical study was funded by ACADIA Pharmaceuticals Inc.

Psychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated withincreased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved in the U.S. for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Depression affects up to 60% ofPD patients and is frequently treated with SSRIs/SNRIs. Data suggest the potential for a synergistic effect between 5 HT2A receptor inverse agonist/antagonists and SSRIs insubjects with neuropsychiatric disease. This post-hoc analysis evaluated a subgroup of subjects from the pimavanserin clinical program to determine if there was any difference in antipsychotic response between the subjects receiving pimavanserin in combination with an SSRI versus those without.

A pooled analysis of two 6-week randomized, double-blind, placebo-controlled Phase 3 studies was conducted to assess the overall treatment effect of pimavanserin34 mg. The outside-North America region in Study 012 was not included due to a difference in methodology in the assessment of the primary endpoint. Subjects in both the 020 and 012 studies received 42 days of treatment. The mITT population included 268 subjects; with 135 in the pimavanserin group. The full safety dataset included 433 subjects; with 202 in the pimavanserin group. Of the 268 subjects in the mITT population, a total of 77 received concomitant therapy with SSRIs. A subgroup analysis was conducted to determine if there was any difference in response among the subjects receiving concomitant SSRIs.

Overall, pimavanserin demonstrated a -6.21-point improvement in psychosis at Week 6 as measured by the PD-adapted Scale for Assessment of Positive Symptoms (primary change from baseline analysis [MMRM]). The treatment difference was 2.87 points over placebo (p<0.001) and was clinically meaningful. Both subgroups (pimavanserin +/- SSRI) demonstrated a statistically significant improvement over placebo. Among subjects taking concomitant SSRIs, the decrease in psychosis symptoms was more prominent for both pimavanserin and placebo-treated subjects (-8.33 points and -4.01 points, respectively) compared to the 189 subjects not taking SSRIs (-5.36 points and -3.01 points, respectively); the treatment difference was of greater magnitude in the concomitant SSRI treated group (-4.32 vs. -2.34). A total of 10% (4/40) and 7.4% (12/162) of pimavanserin treated subjects, with and without SSRIs, respectively, discontinued because of adverse reactions.

The results of this analysis further support findings that the combination of selective 5-HT2A agonist/antagonists and SSRIs may have additive beneficial effects, suggesting a possible enhancement of antipsychotic effect in subjects treated with concomitant SSRIs.

Clinical study was funded by ACADIA Pharmaceuticals Inc.

Our aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH).

Categorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event.

NNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are <10, and as robust as 4. NNH values for tolerability outcomes for pimavanserin 34 mg/d (as well as for doses that range from 8.5 to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson’s disease) versus discontinuation due to an adverse event.

Using the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

Red Bull Stratos was a commercial program that brought a test parachutist, protected by a full-pressure suit, in a stratospheric balloon with pressurized capsule to over 127,582 ft (38,969 m), from which he free fell and subsequently parachuted to the ground. Given that the major risks to the parachutist included ebullism, negative Gz (toe-to-head) acceleration exposure from an uncontrolled flat spin, and trauma, a comprehensive plan was developed to recover the parachutist under nominal conditions and to respond to any medical contingencies that might have arisen. In this report, the project medical team describes the experience of providing emergency medical support and crew recovery for the manned balloon flights of the program.

The phases of flight, associated risks, and available resources were systematically evaluated.

Six distinct phases of flight from an Emergency Medical Services (EMS) standpoint were identified. A Medical Support Plan was developed to address the risks associated with each phase, encompassing personnel, equipment, procedures, and communications.

Despite geographical, communications, and resource limitations, the medical team was able to implement the Medical Support Plan, enabling multiple successful manned balloon flights to 71,615 ft (21,828 m), 97,221 ft (29,610 m), and 127,582 ft (38,969 m). The experience allowed refinement of the EMS and crew recovery procedures for each successive flight and could be applied to other high altitude or commercial space ventures.

BlueRS, NortonSC, LawJ, PattariniJM, AntonsenEL, GarbinoA, ClarkJB, TurneyMW. Emergency Medical Support for a Manned Stratospheric Balloon Test Program. Prehosp Disaster Med. 2014;29(5):1-6.