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BackgroundCurrently available treatments for Parkinson’s disease (PD) do not slow clinical progression nor target alpha-synuclein, the main pathology associated with the disease.ObjectiveThe study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. The study rationale, design, and baseline characteristics of enrolled subjects are presented here.MethodsThe PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1500 mg or 4500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g. resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson’s Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.ResultsOf the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. The mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society – Unified Parkinson’s Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS Total score [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) also showed a similar severity in MDS-UPDRS scores (e.g. MDS-UPDRS Total score [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).ConclusionsThe PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial RegistrationNCT03100149

Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer’s disease (AD). Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. Methods: In this Phase II study ({"type":"clinical-trial","attrs":{"text":"NCT01677754","term_id":"NCT01677754"}}NCT01677754), 542 patients with moderate dementia (MMSE 13–20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. Results: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was – 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: – 2.80 (p = 0.014; 1 mg) and – 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). Conclusions: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

Adequate pediatric formulations are a must to ensure compliance to treatment, and safe delivery of the intended dose. Adult formulations may not be suitable for children, and new pediatric formulation(s) must be developed for the pediatric studies, and for market. As the development of pediatric formulations with optimized properties for market might be challenging, preliminary "enabling" formulations might be envisaged for early pediatric studies, prior to the introduction of more elegant market formulations in the confirmatory study. Supportive clinical studies, such as relative bioavailability (RBA) studies may be necessary to establish the bridge from adult and/or enabling formulations to the final pediatric formulation. Late changes to the pediatric formulation will necessitate establishment of bioequivalence (BE) between the two drug products. As failure to demonstrate BE can delay approval, it is strongly advised that the final pediatric formulation(s) be introduced no later than in the pivotal program. RBA studies assessing performance of pediatric formulations are typically performed in adult healthy volunteers, however a possible interplay between age/disease and formulation effects must be taken into account. Formulation bridging based on in vitro approaches might be envisaged under certain circumstances, such as minor formulation changes, development of new dosage strengths, or BCS class-supported biowaivers.

Purpose In Alzheimer’s disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. Methods This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [11C]-L-deprenyl-D2 radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6–15 days. Results At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an Emax of ∼80–90 % across brain regions of interest and in an EC50 of 1–2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. Conclusions This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD. Electronic supplementary material The online version of this article (doi:10.1007/s00259-016-3510-6) contains supplementary material, which is available to authorized users.