The preferences of people with amyotrophic lateral sclerosis on riluzole treatment in Europe.

The Patient Preference Survey aims to understand unmet needs related to riluzole management in people with Amyotrophic Lateral Sclerosis (ALS) and to identify which characteristics of a new formulation could better match their preferences. The survey involved 117 people with ALS (PALS) treated with riluzole in four European countries. The dysphagic PALS were least satisfied with the riluzole tablet and oral suspension and with ease in self-administration; up to 68% of respondents postponed or missed the treatment due to swallowing difficulties and need of caregiver assistance. Overall, 51% of tablet and 53% of oral suspension users regularly crushed or mixed riluzole with beverages, respectively; PALS who always manipulated riluzole showed low satisfaction with the formulation and considered the risk of choking and pneumonia the most worrisome event. The survey evaluated the driving factors in choosing/switching the therapy: 67% of PALS declared a low risk of choking. The research finally evaluated which attributes of a new formulation would be preferred: the most relevant were ease of use (4.3/5), convenient/portable packaging (4.0/5) and oral-dissolving properties without tongue motility (3.9/5). The Patient Preference Survey suggests that patients have several unmet needs and preferences that could be addressed by a different formulation, e.g. using oral film technologies.

The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid ß Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer's Disease.

Soluble amyloid ß (Aß) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer's disease (AD). That makes soluble Aß oligomers a promising drug target. In addition to eliminating these toxic species from the patients' brain with antibody-based drugs, a new class of drugs is emerging, namely Aß aggregation inhibitors or modulators, which aim to stop the formation of toxic Aß oligomers at the source. Here, pharmacological data of the novel Aß aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aß1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aß oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aß1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aß oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aß1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.

Visual Field Endpoints Based on Subgroups of Points May Be Useful in Glaucoma Clinical Trials: A Study With the Humphrey Field Analyzer and Compass Perimeter.

PRECIS: Visual field (VF) endpoints based on average deviation of specific subsets of points rather than all points may offer a more homogeneous data set without necessarily worsening test-retest variability and so may be useful in clinical trials. PURPOSE: The purpose of this study was to characterize the outcome measures encompassing particular subsets of VF points and compare them as obtained with Humphrey [Humphrey visual field analyser (HVF)] and Compass perimeters. METHODS: Thirty patients with imaging-based glaucomatous neuropathy performed a pair of 24-2 tests with each of 2 perimeters. Nonweighted mean deviation (MD) was calculated for the whole field and separate vertical hemifields, and again after censoring of points with low sensitivity (MDc) and subsequently including only "abnormal" points with a total deviation probability of <5% (MDc5%) or <2% (MDc2%). Test-retest variability was assessed using Bland-Altman 95% limits of agreement (95%LoA). RESULTS: For the whole field, using HVF, MD was -7.5±6.9 dB, MDc -3.6±2.8 dB, MDc5% -6.4±1.7 dB, and MDc2% -7.3±1.5 dB. With Compass the MD was -7.5±6.6, MDc -2.9±1.7 dB, MDc5% -6.3±1.5, and MDC2% -7.9±1.6. The respective 95%LoA were 5.5, 5.3, 4.6, and 5.6 with HVF, and 4.8, 3.7, 7.1, and 7.1 with Compass. The respective number of eligible points were 52, 42±12, 20±11, and 15±9 with HVF, and 52, 41.2±12.6, 10±7, and 7±5 with Compass. With both machines, SD and 95%LoA increased in hemifields compared with the total field, but this increase was mitigated after censoring. CONCLUSION: Restricting analysis to particular subsets of points of interest in the VF after censoring points with low sensitivity, as compared with using the familiar total field MD, can provide outcome measures with a broader range of MD, a markedly reduced SD and therefore more homogeneous data set, without necessarily worsening test-retest variability.

Improved sensitivity of microperimetric outcomes for clinical studies in age-related macular degeneration.

To investigate sensitive outcome measures based exclusively on abnormal points in microperimetry testing of eyes with intermediate age-related macular degeneration (iAMD). 25 eyes of 25 subjects with iAMD had undergone 2 successive tests of mesopic microperimetry with the Macular Integrity Assessment Microperimeter (MAIA), using a custom grid of 33 points spanning the central 14 degrees of the macula. Each point was defined as abnormal if its threshold sensitivity was lower than 1.65 standard deviations (SD) (5%) or 2 SD (2.5%) than the expected threshold in healthy eyes according to the MAIA internal database. Among the 25 eyes there were 11.8 ± 9 and 8.4 ± 8.2 abnormal points at < 5% and < 2.5%, with mean deviation of thresholds from normal - 4.9 ± 1.2 dB and - 5.8 ± 1.5 dB, respectively. These deviations were greater, and their SD smaller, compared with the complete microperimetry grid, - 2.3 ± 2.0 dB. The 95% limits of agreement for average threshold between the 2 successive tests were smaller when only abnormal points were included. Analyzing only abnormal grid points yields an outcome parameter with a greater deviation from normal, a more homogenous dataset, and better test-retest variability, compared with analysis of all grid points. This parameter may thus be more sensitive to change, while moderately limiting the number of potential recruits. The proposed outcome measures should be further investigated as potential endpoints in clinical trials in iAMD.

MRZ-99030 - A novel modulator of Aß aggregation: I - Mechanism of action (MoA) underlying the potential neuroprotective treatment of Alzheimer's disease, glaucoma and age-related macular degeneration (AMD).

Therapeutic approaches addressing ß-amyloid1-42 (Aß1-42) aggregation represent a promising neuroprotective strategy for the treatment of Alzheimer's disease, dry age-related macular degeneration (AMD) and glaucoma. MRZ-99030 is a dipeptide containing d-tryptophan and 2-amino-2-methylpropionic acid in clinical development for the topical treatment of glaucoma and AMD. MRZ-99030 is an Aß aggregation modulator, previously reported to prevent the formation of soluble toxic oligomeric Aß species. The present study confirmed that MRZ-99030 prevents the formation of oligomeric Aß species using similar SDS-PAGE experiments. However, additional data from TR-FRET, DLS and AFM experiments revealed that MRZ-99030 does not directly prevent early protein/protein interactions between monomeric Aß, but rather promotes the formation of large, non-amyloidogenic, amorphous Aß aggregates and thereby reduces the amount of intermediate toxic soluble oligomeric Aß species. The affinity of MRZ-99030 to Aß1-42 determined by SPR was 28.4 nM but the ratio of compound to Aß is also important: a 10-20 fold excess of MRZ-99030 over Aß is probably required for effective modulation of protein/protein interactions. For example, in glaucoma, assuming a maximal Aß concentration of 1-15 nM in the retina, up to 150 nM MRZ-99030 could be required at the protein target. In line with this consideration, MRZ-99030 was able to prevent Aß-induced toxicity on PC12 cells, retinal ganglion cells and retinal pigment epithelium cells when present at a 10-20 fold stoichiometric excess over Aß. Moreover, in vivo studies demonstrate the neuroprotective potential of MRZ-99030 after systemic and topical administration in animal models of Alzheimer's disease and glaucoma/AMD respectively.

A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus.

BACKGROUND: Neramexane is a new substance that exhibits antagonistic properties at α9α10 cholinergic nicotinic receptors and N-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus. METHODS: A total of 431 outpatients with moderate to severe subjective tinnitus (onset 3-18 months before screening) were assigned randomly to receive either placebo or neramexane mesylate (25 mg/day, 50 mg/day and 75 mg/day) for 16 weeks, with assessment at 4-week intervals. The primary (intention-to-treat) efficacy analysis was based on the change from baseline in Week 16 in the total score of the adapted German short version of the validated Tinnitus Handicap Inventory questionnaire (THI-12). RESULTS: Compared with placebo, the largest improvement was achieved in the 50 mg/d neramexane group, followed by the 75 mg/d neramexane group. This treatment difference did not reach statistical significance at the pre-defined endpoint in Week 16 (p = 0.098 for 50 mg/d; p = 0.289 for 75 mg/d neramexane), but consistent numerical superiority of both neramexane groups compared with placebo was observed. Four weeks after the end of treatment, THI-12 scores in the 50 mg/d group were significantly better than those of the controls. Secondary efficacy variables supported this trend, with p values of < 0.05 for the 50 mg/d neramexane group associated with the functional-communicational subscores of the THI-12 and the assessments of tinnitus annoyance and tinnitus impact on life as measured on an 11-point Likert-like scale. No relevant changes were observed for puretone threshold, for tinnitus pitch and loudness match, or for minimum masking levels. The 25 mg/d neramexane group did not differ from placebo. Neramexane was generally well tolerated and had no relevant influence on laboratory values, electrocardiography and vital signs. Dizziness was the most common adverse event and showed a clear dose-dependence. CONCLUSIONS: This study demonstrated the safety and tolerability of neramexane treatment in patients with moderate to severe tinnitus. The primary efficacy variable showed a trend towards improvement of tinnitus suffering in the medium- and high-dose neramexane groups. This finding is in line with consistent beneficial effects observed in secondary assessment variables. These results allow appropriate dose selection for further studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00405886.

Placebo influences on dyskinesia in Parkinson's disease.

Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents.

The management approaches to dyskinesia vary from country to country.

Many Parkinson's disease (PD) patients treated with levodopa develop motor fluctuations and/or dyskinesia. This large, retrospective study was conducted to compare the prevalence and treatment of dyskinesia in PD patients in seven countries. A total of 380 physicians were interviewed and completed patient record forms retrospectively for their last 5 patients with dyskinesia (total 1,900). The overall prevalence of dyskinesia in PD patients was 34%, but the rate varied from 24 to 51% according to geographical location. This study showed that 51.0% of Japanese physicians and 50.6% of UK physicians were dissatisfied with current treatment strategies for dyskinesia. Regardless of geographical location, physicians were dissatisfied with the current treatment strategies for dyskinesia.

Sarizotan as a treatment for dyskinesias in Parkinson's disease: a double-blind placebo-controlled trial.

The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.

Patient evaluation of a home diary to assess duration and severity of dyskinesia in Parkinson disease.

OBJECTIVE: To evaluate patient perceptions of a new home diary designed to assess the duration and severity of dyskinesia in patients with Parkinson disease (PD) and to investigate whether the use of a training video and pictograms aids patient understanding of PD terminology. METHODS: Fifty advanced PD patients (Hoehn and Yahr stage 2.5-4.0; dyskinesia for >25% of the waking day) from the United States (n = 18), France (n = 12), and Germany (n = 20) were allocated alternately to 1 of 2 groups and shown a training video either with pictograms or without pictograms. The video explained the functional states "asleep," "OFF," "ON without dyskinesia," and "ON with dyskinesia," and how to complete the diary. Patients were given the corresponding version of the diary with or without pictograms to complete over a 24-hour period. Patients then participated in a second interview in which they were shown the alternate version of the video and diary for discussion only. RESULTS: Almost 95% of patients (47/50) reported that the video helped them to understand and clarify terms. Most patients [39/50 (78%)] preferred the diary with pictograms, but there was no evidence that pictograms improved the accuracy of diary completion. Overall, 80% of patients (40/50) completed the diaries correctly. Incorrect diary completion was usually because of confusion about the different functional states. CONCLUSIONS: Patients perceive diaries with pictograms as more helpful than those with words alone. Videos, in the patients' primary language, are considered valuable training aids that help patients complete daily diaries.

Levodopa, motor fluctuations and dyskinesia in Parkinson's disease.

Parkinson's disease (PD) is one of the most frequent, chronic, progressive degenerative disorders of the CNS, characterised by altered neurotransmission of dopamine in the basal ganglia. This may result in disturbances of movement, mobility and posture symptoms, all of which cause severe disability in PD patients. There is no cure for PD. Current treatment approaches aim at symptomatic improvement with a balance of the altered neurotransmission, particularly in striatal dopaminergic neurons. Levodopa, the metabolic precursor of active dopamine, is the most effective compound in the drug treatment of PD. However, chronic exposure to levodopa and related dopaminergic agents supports an onset of movement behaviour fluctuations and dyskinesia in the long term. Dyskinesia is unwanted, sometimes excessive and causes abnormal facial, body and limb movements that appear in many PD patients who are often dependent on the overall dosage of dopaminergic substitution. This complication of anti-Parkinsonian drug therapy supports disability and reduces quality of life in PD patients and their caregivers. This review focuses on the major clinical features and knowledge on the aetiology of these treatment-associated, long-term side effects of dopaminergic drug treatment in PD. It also gives an overview of existing and potential future treatment-strategies for the management of these troublesome treatment complications that affect motor behaviour in PD patients.