Pipeline of Dyskinesia (continued)

Drug	mechanism	Clinical	Patients	Design	results
amantadine ER (Gocovri), previously known as ADS-5102	an uncompetitive antagonist at the N-methyl-D-aspartate receptor known to have benefit to relieve the symptoms of dyskinesia and currently the only available molecule for management of dyskinesia. The rationale of extended release is to provide a therapeutic level of amantadine in the blood for a longer period of time, in this case enabling once a day dosing. Two capsules are administered at bedtime to give a slow increase during sleep, peak levels in the morning and a sustained concentration during the day.	P3. EASE LID P3. EASE LID3	at least 2 on question 4.2 of the UPDRS); at least two episodes of half an hour of troublesome dyskinesia when ON; and at least 3 administrations of levodopa per day. Exclusion criteria included a history of dyskinesia that was exclusively diphasic, OFF state, myoclonic, dystonic, or akathetic without peak-dose dyskinesia	TABLE 1 – Summary of EASE LID and EASE LID 3 trial plans EASE LID EASE LID 3 Title ADS-5102 for the Treatment of Levodopa-Induced Dyskinesia (EASE LID Study) Efficacy and Safety Study of ADS-5102 in PD Participants with Levodopa-Induced Dyskinesia (EASE LID 3) Status Complete Complete clinicaltrials.gov ID NCT02136914 NCT02274766 Enrolment 121 75 Study design Randomized, double blind, placebo-controlled, multi-centre (44 sites). Randomized, double blind, placebo-controlled, multi-centre (32 sites). Primary outcome measures Change in UDysRS to week 12, measured at weeks 0, 2, 4, 8 and 12. Change in UDysRS to week 12, measured at weeks 0, 2, 4, 8 and 12. Key Secondary outcome measures Change from baseline in the UDysRS total score at 24 Weeks. ON time without troublesome dyskinesia (ON time without dyskinesia plus ON time with non-troublesome dyskinesia) at 12 and 24 weeks. OFF time (amount of time the PD medication is not controlling motor symptoms) at 12 and 24 weeks. Change from baseline at 12 and 24 weeks in the UPDRS score. ON time with troublesome dyskinesia. Change in the standardized PD home diary (ON time without dyskinesia, ON time with troublesome dyskinesia, OFF time) at 12 weeks. Restuls] TABLE 2 – Summary of EASE-LID and EASE-LID 3 results EASE LID; Gocovri vs placebo* EASE LID 3; Gocovri vs placebo* Change in UDysRS at week 12 -7.90 (2.30) -14.40 (3.0) Change in UDysRS at week 24 -9.30 (2.70) ND Change in ON time without troublesome dyskinesia at week 12 (hours) 2.74 (0.61) 1.90 (0.78) Change in ON time without troublesome dyskinesia at week 24 (hours) 2.22 (0.63) ND Change in ON time with troublesome dyskinesia at week 12 (hours) -1.54 (0.51) -1.13 (0.65) Change in ON time with troublesome dyskinesia at week 24 (hours) -1.45 (0.53) ND Change in OFF time at week 12 (hours) -0.9 (0.37) -1.10 (0.46) Change in OFF time at week 24 (hours) -0.81 (0.39) ND CGIC score (reported improvement) at week 12 51/63 vs 21/58 ND CGIC score (reported improvement) at week 24 43/63 vs 27/58 ND ND = not determined * Standard error values in parentheses (McFarthing, 2019 #1708)
Dipraglurant by Addex	mGluR5 negative allosteric modulator	Preclinical 2b/3	Js: there seems no preclinical studies, (amantadine is an old drug) 20220627: Addex Therapeutics announced that it has terminated the Phase 2b/3 study evaluating dipraglurant (an mGluR5 negative allosteric modulator) as a potential treatment for dyskinesia associated with PD (PD-LID) due to the slow recruitment of patients
		P2a	Addex completed a Phase 2a trial for PD LID in 2012. Conducted in the US and Europe, it enrolled 76 people with moderate to severe LID, who received dipraglurant for 28 days, taken at the same time as levodopa. The dose was titrated from 50 mg once daily to 100 mg three times daily over 21 days, and fixed at 100 mg for the last 7 days. The primary endpoint was safety. Clinical endpoints included severity of dyskinesia rated on the modified AIMS on days 1, 14, and 28, plus UPDRS, CGIC), and patient diaries. The trial met its primary endpoints of safety and tolerability. The treatment group had more severe adverse events than the placebo group; two participants discontinued due to adverse events at 100 mg. Most common were dizziness, nausea, fatigue, and worsening dyskinesia between doses. On clinical endpoints, the treated group saw a 30 percent improvement of dyskinesia compared to placebo. The difference was statistically significant on days one and 14, but not 28. No differences were observed on UPRDS or patient-reported outcomes. The CGIC was improved in 71.2 percent of the treated group compared to 49.9 percent in placebo. Results are published (Tison, 2016 #1711)
		P2b/3 (planned)	The study is expected to enroll 140 (70 vs 70) patients for three months of treatment at 50 sites in the United States, and includes a parallel, 12-month open label extension. The primary endpoint will be change in the Unified Dyskinesia Rating scale at 3m
		preclinica	NHP	{Bezard, 2014 #1709} MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8). MPTP (daily iv) → (once parkinsonism get stable) L-Dopa (oral, BID,, 4-5m , at individualy tailored dose to produce a full reversal of PD symptoms) → Dipraglurant (single dose, oral) Results presentation: levodopa only vs levodopa+Dipraglurant (chorea, dystonia각 domain별로 1-4h의 AUC를 비교하는 듯)
			mouse	(Sciamanna, 2014 #1710) Dipraglurant also reduced involuntary muscle contractions in a mouse model of dystonia (Sciamanna et al., 2014).
Others	ORGANISATION THERAPY MODE OF ACTION CLINICAL STAGE Addex Therapeutics Dipraglurant mGluR5 negative allosteric modulator Phase 2 (complete) Coeptis/Eto Pharma Eltoprazine 5HT 1A/1B partial agonist Phase 2 Hôpitaux de Paris Buspirone 5-HT1A agonist Phase 3 Contera/Bukwang JM-010 (buspirone and zolmitriptan) 5-HT1A agonist and 5-HT1B/5-HT1D agonist combination Phase 2 Oregon University Buspirone and amantadine 5-HT1A agonist and NMDA inhibitor combination Phase 2 Integrative Research Laboratories IRL-790 Dopamine D3 receptor antagonist Phase 2 Prilenia Pridopidine Sigma-1 receptor inhibitor Phase 2 Trevi Therapeutics Nalbuphine Opioid μ antagonist/ κ agonist Phase 1 (McFarthing, 2019 #1708)

EEG

Bands

Gamma greater than 30(Hz)
BETA (13-30Hz),	enhanced during drowsiness, seen in a precentral distribution, and felt to be related to the functions of the sensorimotor cortex
ALPHA (8-12 Hz),
THETA (4-8 Hz),
DELTA(less than 4 Hz).

EEG in PD

{Quynh Tran, 2016 #2603}	↑ beta	spectral	gait	4 PD, no control	Multiple lead, channel	power spectra density (PSD) and centroid frequency (CF)	GIF episodes were associated with significant increases in the high beta band (21-38Hz) across the central, frontal, occipital and parietal EEG sites The mean, maximum and minimum values of PSD and CF of the 4 frequency bands in each electrode"s location were taken as inputs of the classifier to	Quantification? Can't as there is no HC,
{Tard, 2016 #2604}		ERD/ERS		parkinsonian patients with freezing of gait (FoG, n = 12) or without freezing of gait (n = 13), and in aged-matched HC (n = 13)		event-related desynchronization/synchronization (ERD/ERS); Attention during step preparation was modulated by means of an auditory oddball discrimination task. EEG oscillations in different frequency bands were measured for the attentional stimulus and the motor stimulus.	Over the 500 ms following the sound, low-frequency power increased in all three groups. This was followed by a power decrease in mid-range frequencies after both target and standard sounds in the healthy controls and in the non-FoG group. In contrast, EEG oscillations in the beta band were impaired in the FoG group, who notably failed to display event-related desynchronization after perceiving the sound. Conclusions: An attentional stimulus was able to trigger event-related desynchronization before motor preparation in the non-FoG group but not in the FoG group. Significance: In the FoG group, stimulus discrimination was maintained but the coupling between attention and motor preparation was impaired. Parkinsonian patients with freezing of gait did not display beta desynchronization Beta oscillations have a role in active immobilization (defined as a "sta tus quo" condition) (Engel and Fries, 2010) and are involved in the pathogenesis of bradykinesia. Premotor beta ERD is observed before movement onset (i.e. during motor prepa ration or execution) and is correlated with greater	Can't: multiple lead, channel

Uncertain Spans

location	transcription	uncertainty
Pipeline of Dyskinesia / dipraglurant block / preclinical row label	left column reads preclinica (sic, no trailing l) on the page; preserved verbatim.	source typo or page-edge clip — the visible glyphs end at a.
EEG in PD / Tard 2016 row / Quantification	text reads Can't: multiple lead, channel; the colon vs period after Can't is small but consistent with Can't:.	minor punctuation, low impact.