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Zuranolone as an oral adjunct to treatment of Parkinsonian tremor: A phase 2, open-label study

Open AccessPublished:December 20, 2020DOI:https://doi.org/10.1016/j.jns.2020.117277

      Highlights

      • Zuranolone (SAGE-217) is an investigational oral neuroactive steroid GABAA receptor positive allosteric modulator (PAM).
      • Zuranolone was administered for seven days in 14 patients with PD, and reduction of tremor symptoms was assessed.
      • The MDS-UPDRS Part II/III tremor score improved 40% (p < 0.0001) from baseline on Day 8.
      • The motor score and non-motor and motor EDL scores (MDS-UPDRS Parts I and II, respectively) also improved at Day 8.
      • No serious AEs were reported, and no patients discontinued treatment.

      Abstract

      Parkinson's disease (PD) is characterized by both motor and nonmotor deficits. Among cardinal symptoms of this disorder, tremor is the least responsive to dopamine replacement therapy and is often undertreated. Zuranolone (SAGE-217) is an investigational oral neuroactive steroid (NAS) gamma-aminobutyric acid A (GABAA) receptor–positive allosteric modulator (PAM) that has been investigated for its safety and efficacy in patients with PD. In the current open-label study, zuranolone capsules (20 to 30 mg) were administered for 7 days in 14 patients (mean age, 65.1 years; mean time since PD diagnosis, 9 years). The primary efficacy endpoint was reduction in tremor symptoms, as assessed by change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II/III Tremor Scores on Day 8. Additional endpoints included improvements in overall motor symptoms, and motor and nonmotor aspects of daily living. Adverse events (AEs) were also monitored. The MDS-UPDRS Part II/III Tremor Score improved by 40% (P < 0.0001) from baseline on Day 8. The motor score, and nonmotor experiences of daily living (nM-EDL), and motor experiences of daily living (m-EDL) scores (MDS-UPDRS Parts I and II, respectively), also improved on Day 8. No serious AEs were reported, and no patients discontinued treatment. The most common AEs were dizziness, sedation, and somnolence. Zuranolone was generally well tolerated and improved tremor symptoms in patients with PD who were on stable doses of concurrent dopaminergic agents. These data support the further investigation of NAS GABAA receptor PAMs as adjunctive treatments for tremor in patients with PD.

      Keywords

      1. Introduction

      Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disorder that results from loss of dopaminergic neurons in the substantia nigra pars compacta. PD is characterized by the cardinal motor symptoms of tremor, bradykinesia, rigidity, and postural instability, as well as nonmotor symptoms, including depression, anxiety, sleep disturbances, and dementia, which can severely compromise quality of life [
      • Poewe W.
      • Seppi K.
      • Tanner C.M.
      • et al.
      Parkinson disease.
      ]. The primary treatment for the motor symptoms of PD includes a combination of levodopa, which increases brain dopamine levels, and the aromatic amino acid decarboxylase inhibitor carbidopa. In addition, dopamine agonists, monoamine oxidase type B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors, which increase or mimic brain dopamine activity, have been widely used for the treatment of PD motor symptoms [
      • Fox S.H.
      • Katzenschlager R.
      • Lim S.Y.
      Et al; Movement Disorder Society evidence-based medicine company. International Parkinson and Movement Disorder Society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease.
      ,
      • Reich S.G.
      • Savitt J.M.
      Parkinson’s disease.
      ].
      Resting tremor has a variable, unpredictable response to dopaminergic therapies and is postulated to be mediated by a different pathway than are bradykinesia and rigidity [
      • Helmich R.C.
      The cerebral basis of parkinsonian tremor: a network perspective.
      ]. Unlike bradykinesia, rigidity, and postural instability, which exhibit an inverse correlation with function and striatal dopamine transporter binding, resting and active tremor in patients with PD do not correlate with the degree of dopaminergic denervation [
      • Pirker W.
      Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it?.
      ]. Levodopa is the most effective treatment for Parkinsonian tremor; however, higher doses are generally needed to address tremor symptoms, and the dose-limiting side effects of nausea, vomiting, dyskinesias, or psychosis can lead to the undertreatment of tremor symptoms [
      • Nonnekes J.
      • Timmer M.H.M.
      • de Vries N.M.
      • Rascol O.
      • Helmich R.C.
      • Bloem B.R.
      Unmasking levodopa resistance in Parkinson’s disease.
      ]. Like levodopa, dopamine agonists are also effective at reducing tremor and have a similar dose-limiting side-effect profile. Although anticholinergics, such as benztropine and trihexyphenidyl HCl, are effective for the treatment of tremor and are approved for the adjunctive treatment of parkinsonism, their use can be limited by intolerable side effects, including confusion, sedation, hallucinations, blurred vision, constipation, and urinary retention. Other nondopaminergic treatments, including amantadine, clozapine, clonazepam, propranolol, and gabapentin, have been used clinically for the treatment of Parkinsonian tremor; however, the lack of evidence-based efficacy and their side-effect profiles limit their use [
      • Marjama-Lyons J.
      • Koller W.
      Tremor-predominant Parkinson’s disease. Approaches to treatment.
      ].
      Treatment-resistant tremor may respond to nonpharmacologic, neurosurgical procedures, including deep brain stimulation and focused ultrasound thalamotomy, both of which carry their own inherent risks [
      • Fox S.H.
      • Katzenschlager R.
      • Lim S.Y.
      Et al; Movement Disorder Society evidence-based medicine company. International Parkinson and Movement Disorder Society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease.
      ,
      • Marjama-Lyons J.
      • Koller W.
      Tremor-predominant Parkinson’s disease. Approaches to treatment.
      ]. Hence, the need exists for novel, nondopaminergic therapeutics that address undertreated symptoms of PD such as tremor.
      Parkinsonian tremor may result from increased interactions between the basal ganglia and the cerebello-thalamo-cortical (CTC) circuit [
      • Helmich R.C.
      The cerebral basis of parkinsonian tremor: a network perspective.
      ]. It has been proposed that cerebral activity associated with Parkinsonian tremor arises in the internal globus pallidus (GPi) and is then propagated to the CTC motor loop [
      • Dirkx M.F.
      • den Ouden H.
      • Aarts E.
      • et al.
      The cerebral network of Parkinson’s tremor: an effective connectivity fMRI study.
      ]. This is important, because the striatum and pallidum send GABAergic projections, leading to a net inhibitory connection from the motor cortex (MC) to the GPi via the striatum, from the MC to the external globus pallidus (GPe) via the striatum, from the cerebellum to the subthalamic nucleus (STN) via the striatum, and from the GPe to the STN and the GPi to the MC via the thalamus [
      • Albin R.L.
      • Young A.B.
      • Penney J.B.
      The functional anatomy of basal ganglia disorders.
      ,
      • Dirkx M.F.
      • den Ouden H.
      • Aarts E.
      • et al.
      The cerebral network of Parkinson’s tremor: an effective connectivity fMRI study.
      ,
      • Horne M.K.
      • Butler E.G.
      The role of the cerebello-thalamo-cortical pathway in skilled movement.
      ,
      • Shinoda Y.
      • Futami T.
      • Kano M.
      Synaptic organization of the cerebello-thalamo-cerebral pathway in the cat. II. Input-output organization of single thalamocortical neurons in the ventrolateral thalamus.
      ]. Thus, modulating GABAergic neurons pharmacologically may impact the CTC circuit and thereby decrease tremor.
      GABA also plays a predominant role in the modulation of striatal outputs and is a novel target for the treatment of PD in intermediate nuclei downstream from the dopamine input of the substantia nigra (SN) [
      • Brickley S.G.
      • Mody I.
      Extrasynaptic GABAA receptors: their function in the CNS and implications for disease.
      ,
      • Kleppner S.R.
      • Tobin A.J.
      GABA signalling: therapeutic targets for epilepsy, Parkinson’s disease and Huntington’s disease.
      ]. Via the use of magnetic resonance spectroscopy imaging, GABA levels were found to be lower in the basal ganglia of patients with the tremor-dominant (TD) and the postural instability gait difficulty (PIGD) subtypes of PD compared with healthy controls [
      • Gong T.
      • Xiang Y.
      • Saleh M.G.
      • et al.
      Inhibitory motor dysfunction in Parkinson’s disease subtypes.
      ]. In addition, GABAA receptor binding is decreased in post-mortem human brain preparations from the SN and the globus pallidus, as well as from the caudate-putamen from patients with PD [
      • Griffiths P.D.
      • Sambrook M.A.
      • Perry R.
      • Crossman A.R.
      Changes in benzodiazepine and acetylcholine receptors in the globus pallidus in Parkinson’s disease.
      ,
      • Nishino N.
      • Fujiwara H.
      • Noguchi-Kuno S.A.
      • Tanaka C.
      GABAA receptor but not muscarinic receptor density was decreased in the brain of patients with Parkinson’s disease.
      ].
      Preclinical evidence implicates synaptic and extrasynaptic GABA receptors in the pathophysiology of movement disorders. Synaptic GABAA receptors in the medium spiny neurons (MSNs) are responsible for fast, phasic inhibition, whereas the slow, sustained, tonic inhibition is mediated by extrasynaptic GABAA receptors. This GABA-mediated intrinsic excitability of MSNs via synaptic and extrasynaptic GABAA receptors is dependent on the subunit composition of these receptors [
      • Brickley S.G.
      • Mody I.
      Extrasynaptic GABAA receptors: their function in the CNS and implications for disease.
      ,
      • Luo R.
      • Partridge J.G.
      • Vicini S.
      Distinct roles of synaptic and extrasynaptic GABAA receptors in striatal inhibition dynamics.
      ].
      In mouse brain slice preparations, the caudate-putamen expressed a higher level of extrasynaptic GABAA receptors in D2 MSNs than in D1 MSNs [
      • Ade K.K.
      • Janssen M.J.
      • Ortinski P.I.
      • Vicini S.
      Differential tonic GABA conductances in striatal medium spiny neurons.
      ]. Modifying phasic and tonic conductance of GABAA receptors has the potential to regulate neuronal excitability and improve motor control in patients with PD. As such, individuals with PD who are treated with zolpidem—a selective α1 GABAA positive allosteric modulator (PAM)—for insomnia have reported improvement in the clinical symptoms of PD, including akinesia, rigidity, and resting tremor, as well a reduction in dyskinesia [
      • Daniele A.
      • Panza F.
      • Greco A.
      • Logroscino G.
      • Seripa D.
      Can a positive allosteric modulation of GABAergic receptors improve motor symptoms in patients with Parkinson’s disease? The potential role of zolpidem in the treatment of Parkinson’s disease.
      ]. Additionally, midazolam—a benzodiazepine that binds to the GABAA receptor complex—has been shown to abort resting tremor during deep brain stimulation surgery [
      • Chowdhury T.
      • Cappellani R.B.
      • Kowalski S.E.
      Role of midazolam in parkinsonian tremors: to use or not to use.
      ].
      Therefore, positive modulation of GABAA receptors is a potential therapeutic target for the treatment of tremor in patients with PD. Neuroactive steroid (NAS) GABAA receptor PAMs, which modulate both synaptic and extrasynaptic GABAA receptors, may provide therapeutic utility beyond that of benzodiazepines, which bind only to synaptic GABAA receptors [
      • Martinez Botella G.
      • Salituro F.G.
      • Harrison B.L.
      • et al.
      Neuroactive steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano 1H pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): a clinical next generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid)A receptor.
      ,
      • Reddy D.S.
      • Estes W.A.
      Clinical potential of neurosteroids for CNS disorders.
      ]. Zuranolone (SAGE-217) is an investigational oral NAS GABAA receptor PAM [
      • Hoffmann E.
      • Nomikos G.G.
      • Kaul I.
      • et al.
      SAGE-217, a novel GABAA receptor positive allosteric modulator: clinical pharmacology and tolerability in randomized phase I dose-finding studies.
      ,
      • Martinez Botella G.
      • Salituro F.G.
      • Harrison B.L.
      • et al.
      Neuroactive steroids. 1. Positive allosteric modulators of the (γ-aminobutyric acid)A receptor: structure–activity relationships of heterocyclic substitution at C-21.
      ,
      • Martinez Botella G.
      • Salituro F.G.
      • Harrison B.L.
      • et al.
      Neuroactive steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano 1H pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): a clinical next generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid)A receptor.
      ] that binds both synaptic and extrasynaptic GABAA receptors, enhancing phasic and tonic inhibitory currents, respectively [
      • Lee V.
      • Maguire J.
      The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type.
      ], in contrast to benzodiazepines, which impact only phasic inhibition. Zuranolone has been shown to exhibit no activity against a panel of 22 nuclear hormone receptors [
      • Martinez Botella G.
      • Salituro F.G.
      • Harrison B.L.
      • et al.
      Neuroactive steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano 1H pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): a clinical next generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid)A receptor.
      ]. In preclinical studies of rodent models of seizure, zuranolone demonstrated anticonvulsant, anxiolytic, and sedative effects [
      • Althaus A.L.
      • Ackley M.A.
      • Belfort G.M.
      • et al.
      Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator.
      ,
      • Bialer M.
      • Johannessen S.I.
      • Levy R.H.
      • Perucca E.
      • Tomson T.
      • White H.S.
      Progress report on new antiepileptic drugs: a summary of the twelfth EILAT conference (EILAT XII).
      ]. The plasma half-life of zuranolone was 16 to 23 h in single ascending dose and multiple ascending dose studies of healthy volunteers; this duration is long enough to facilitate once-daily dosing [
      • Hoffmann E.
      • Nomikos G.G.
      • Kaul I.
      • et al.
      SAGE-217, a novel GABAA receptor positive allosteric modulator: clinical pharmacology and tolerability in randomized phase I dose-finding studies.
      ]. The current study is the first to evaluate zuranolone for the treatment of tremor symptoms in patients with PD.

      1.1 Objective

      The goal of this open-label, exploratory study was to evaluate zuranolone as an adjunctive treatment for tremor symptoms in 14 patients with PD who already were receiving stable doses of dopaminergic agents.

      2. Methods

      2.1 Trial design

      This was an open-label, exploratory study designed to evaluate the potential role of zuranolone as an adjunctive treatment for 7 days in patients with PD who already were receiving stable doses of ≥1 of the following agents: carbidopa/levodopa, dopamine agonists, MAO-B inhibitors, or COMT inhibitors.

      2.2 Participants

      A total of 14 patients with PD (Hoehn and Yahr Stages 1 to 4) and a tremor of moderate severity—defined as the sum of Movement Disorder Society-Unified Parkinson's disease Rating Scale (MDS-UPDRS) Parts II/III Tremor Scores—were enrolled in the study. The sum of items was calculated as follows: Part II: motor experiences of daily living [M-EDL], item 2.10 [Tremor] and Part III: Motor Examination [ME] items 3.15 [Postural Tremor of the Hands], 3.16 [Kinetic Tremor of the Hands], 3.17 [Rest Tremor Amplitude {upper and lower extremities and lip/jaw}], and 3.18 [Constancy of Rest Tremor] of ≥8 and an MDS-UPDRS item score of ≥3 for 1 limb [from items 3.15, 3.16, or 3.17]. All patients were evaluated for tremor symptoms using the MDS-UPDRS during the “ON” period and within 2 h of dosing with antiparkinsonian medications.
      The presence of levodopa-resistant tremor was not a criterion for study entry and was not defined in the protocol. Those patients taking anticholinergics and/or amantadine discontinued these drugs by Day −6 and Day −10, respectively. Participants were admitted on Day −1 and remained as inpatients during the first 8 days of the study period. All patients received zuranolone capsules, at a dose of 20 mg, at approximately 8 PM on Days 1 and 2 with food. On Day 3, patients who had tolerated the initial dose received zuranolone 30 mg for the remainder of the dosing period (ending on Day 7). Dose reductions for lack of tolerability to zuranolone were allowed. The participants received zuranolone for 7 days and were followed for an additional 7 days after administration of the last dose. Patients were evaluated 12 h and 23 h after each dose, and 7 days following discontinuation of dosing.

      2.3 Outcomes

      The primary outcome was improvement in severity of Parkinsonian tremor, as assessed by changes in the MDS-UPDRS Part II/III Tremor Score. Additional outcomes included improvement in PD motor symptoms, as assessed by changes in the MDS-UPDRS Part III total score, and improvement in MDS-UPDRS Part I (nonmotor experiences of daily living [nM-EDL]) and Part II (motor experiences of daily living [M-EDL]) scores. Improvement in overall PD symptoms was assessed by changes in the MDS-UPDRS Part I to IV total score. Frequency and severity of adverse events (AEs) were also monitored.

      2.4 Analysis

      The primary outcome and key secondary outcomes of observed values and change from baseline were assessed by the participants overall using summary statistics. In addition, the mean change from baseline in the MDS-UPDRS Part II/III Tremor Total Score was evaluated by a mixed model for repeated measures, with change from baseline in the MDS-UPDRS Part II/III Tremor Total Score as the dependent variable; treatment, study visit, as fixed effects; and baseline value as a covariate. A compound symmetry covariance matrix was used to model the within-patient correlation. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. No official statistics were calculated for the individual points or secondary endpoints.

      3. Results

      A total of 14 patients with PD with moderate tremor (as defined in the Methods section) during their “ON” periods were enrolled in the study and completed the 7-day treatment period. The baseline characteristics of these participants are summarized in Table 1. The patient population included 9 males and 5 females; the mean age of the participants was 65.1 ± 7.8 years (range, 45 to 74 years). The mean time since PD diagnosis was 9 ± 6.8 years (range, 1.6 to 25.5 years). Mean baseline values for the MDS-UPDRS scale, Parts I to IV, are shown in Fig. 1. All patients were receiving stable doses of carbidopa/levodopa, dopamine agonists, MAO-B inhibitors, and COMT inhibitors. Overall, 85.7% (12 of 14) of the patients were white, 7.1% (1 of 14) of the patients were black, and 7.1% (1 of 14) of the patients identified as multiracial. Further, 6 of the 12 white patients and 1 of the 2 nonwhite patients identified as Hispanic/Latino.
      Table 1Summary of demographics and baseline characteristics of the patient population (N = 14).
      Baseline CharacteristicPatients

      N = 14
      Age, mean years (SD)65.1 (7.76)
      Gender, n (%)
       Male9 (64.3)
       Female5 (35.7)
      Ethnicity, n (%)
       Hispanic or Latino7 (50.0)
       Not Hispanic or Latino7 (50.0)
      Race, n (%)
       White12 (85.7)
       Black or African American1 (7.1)
       More than one race1 (7.1)
      Concomitant antiparkinsonian medications, n (%)
       Carbidopa/levodopa13 (92.9)
       Dopamine agonists6 (42.9)
       COMT inhibitors1 (7.1)
       MAO-B inhibitors3 (21.4)
      Time since PD diagnosis, mean years (SD)9.04 (6.83)
      COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase type B; PD, Parkinson's disease; SD, standard deviation.
      Fig. 1
      Fig. 1Representation of the time course of improvement observed in tremor severity, as assessed by MDS-UPDRS Part II/III. Data represent mean total scores ±SEM at 12 and 23 h post Dose 1 through Dose 6.
      MDS-UPDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale;
      SEM, standard error of the mean.
      Adjunctive treatment with zuranolone for 7 days in 14 patients with PD improved tremor symptoms, as assessed by a reduction in the sum of the MDS-UPDRS Parts II/III Tremor Score over time. The mean change from baseline in MDS-UPDRS Part II/III Tremor Total Score on Day 8 (12 h post Dose 7) was −7.7 (40%; P < 0.0001; see Supplemental Table 1 and Fig. 1). The improvement in tremor symptoms was observed during the “ON” state as early as 12 h following the first dose of zuranolone (−5.4; 26%) and was sustained throughout the treatment period. In addition, a reduction from baseline in tremor during the “ON” state (−3.7; 19%) was observed 1 week after discontinuation of the study drug. Numerical decreases in tremor scores, approximating the percent improvement in the total score, were observed for both the MDS-UPDRS Part II (M-EDL) tremor item and all the Part III (ME) tremor items.
      Similar improvements were also noted in PD motor symptoms that were evaluated by changes in the MDS-UPDRS Part III total score. The mean change from baseline in MDS-UPDRS Part III total score on Day 8 (12 h post Dose 7) was −18.6 (36%; see Supplemental Table 1). Similar to the improvements noted in MDS-UPDRS Part II/III Tremor Score, the MDS-UPDRS Part III score decreased 12 h following the first dose (−8.4; 15%) and was still reduced relative to baseline 7 days after treatment discontinuation (−14.5; 27%).
      Improvements were also observed in overall experiences of daily living (EDL), as assessed by the MDS-UPDRS Part I (nM-EDL) and Part II (M-EDL) score. At the end of the 7-day treatment period (12 h post Dose 7), the mean change from baseline in MDS-UPDRS Part I total score was −4.7 (25%) and that in the MDS-UPDRS Part II (M-EDL) score was −3.9 (16%).
      The MDS-UPDRS Part IV (motor complications) subscale was scored as part of administration of the total MDS-UPDRS. Ad hoc analysis of total MDS-UPDRS Part IV score showed a mean change from baseline to the end of treatment (12 h post Dose 7) of −2.7 points (27.3%; see Supplemental Table 1). The MDS-UPDRS Part IV subscale is a measure of medication-related motor complications (ie, dyskinesia, dystonia, motor fluctuations [ON-OFF]) that are associated with long-term dopaminergic treatment. The greatest numerical decreases contributing to the change in Part IV total score were observed for items 4.1 (time spent with dyskinesias) and 4.2 (functional impact of dyskinesias).
      Oral administration of zuranolone was generally well tolerated, with no serious AEs (SAEs) and no AEs leading to treatment discontinuation reported. All patients received 7 days of treatment. Of the 14 participants, 12 tolerated the planned maximal dose of 30 mg administered in the evening, with 2 patients reducing their dose to 20 mg in the evening on Days 5 and 6, respectively, because of limb discomfort and salivary hypersecretion in 1 patient, and a confusional state in another. Treatment emergent adverse events (TEAEs) were reported in 57.1% (8 of 14) of the participants. All of the reported TEAEs were considered mild or moderate in severity. The most common TEAEs were dizziness (2 of 14 patients; 14.3%), somnolence (2 of 14 patients; 14.3%), and sedation (2 of 14 patients; 14.3%), all of which were considered mild (defined as “aware of sign or symptom, but easily tolerated”) in severity.

      4. Discussion

      Results from this open-label, exploratory study show that 7-day oral administration of zuranolone as an adjunct to dopaminergic therapy improved tremor in patients with PD, compared with baseline values, as measured by the MDS-UPDRS Part II/III Tremor Total Score. In addition, treatment with zuranolone was associated with improvements in overall PD motor symptoms, as well as motor and nonmotor experiences of daily living. Furthermore, these improvements were noted to persist 1 week following the last (Day 7) zuranolone dose, although the effects were less pronounced in the week after treatment had ended. Zuranolone was generally well tolerated, with no SAEs reported.
      Improvement in Parkinsonian tremor was observed 12 h after the first dose of zuranolone, with the magnitude of tremor improvement observed at 1 week comparable to treatment effects observed in studies after longer treatment durations. In a similar population of patients with PD with residual tremor symptoms, adjunctive treatment with the dopamine agonist pramipexole reduced tremor by approximately 49% (−5.8 points; 11.9 points at baseline), based on changes in the tremor items of the MDS-UPDRS Part III scale. In this study, maximal benefit was seen after a 7-week titration phase and was sustained during 4 weeks of maintenance therapy [
      • Pogarell O.
      • Gasser T.
      • van Hilten J.J.
      • et al.
      Pramipexole in patients with Parkinson’s disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study.
      ]. It is important to note that in the pramipexole trial, however, patients had refractory tremor, whereas in the current study, patients had moderate tremor. In a post-hoc analysis of the LARGO study, adjunctive treatment with the MAO-B inhibitor rasagiline was associated with a reduction in tremor, based on MDS-UPDRS Part III tremor items at 10 and 18 weeks, which ranged from 24% in all patients to 44% in those with a severe tremor at baseline [
      • Lew M.F.
      Rasagiline treatment effects on parkinsonian tremor.
      ]. Given the range of levodopa doses, as well as the number of patients on multiple different antiparkinsonian medications (8 of 14; 57%), the sample size in the current study is not large enough to support any conclusions regarding the efficacy of zuranolone relative to adjunctive dopaminergic treatment.
      Because of the open-label nature of the present study, its short duration, and the limited number of patients, it will be important to replicate these results in a lengthier study with a larger patient population. Since the TEAEs of somnolence and sedation were each observed in 14.3% of patients, it is possible that these events confounded the direct effects of zuranolone on tremor. Furthermore, as the PD population has demonstrated susceptibility to the placebo effect in trials of both pharmacologic and surgical interventions alike [
      • Quattrone A.
      • Barbagallo G.
      • Cerasa A.
      • Stoessl A.J.
      Neurobiology of placebo effect in Parkinson’s disease: what we have learned and where we are going.
      ], a placebo-controlled trial would be an important next step to confirm these results. In fact, the demonstration of an effect on all measured outcomes further underscores the need for placebo-controlled follow-up. The current open-label study is an important foundation for facilitating implementation of a double-blind trial. As zuranolone—a PAM of GABAA receptors—has a novel mechanism of action, was generally well tolerated, and demonstrates the potential for improving symptoms that are either untreated or undertreated with dopaminergic agents, these data warrant the further study of zuranolone as an adjunctive treatment for tremor in patients with PD.

      Author roles

      Note that some submission types limit the number of authors permitted. At the end of the manuscript, all authors must be listed, along with their specific roles in the project and manuscript preparation. These should include, but not be restricted to, the following:
      1. Research project: A. Conception, B. Organization, C. Execution;
      2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique;
      3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;
      A.B.: 1, 2, 3.
      I.K.: 1, 2, 3.
      S.L.: 1, 2, 3.
      C.S.: 1, 3.
      J.D.: 1, 3.
      S.J.K.: 1, 3.

      Disclosures

      • Funding Sources and Conflict of Interest:
        A.B., S.L., C.S., J.D., and S.J.K. are employees of Sage Therapeutics, Inc.
        I.K. received a consulting fee from Sage Therapeutics, Inc.
      • Financial Disclosures for the previous 12 months:
      A.B., S.L., C.S., J.D., and S.K. own Sage Therapeutics, Inc., stock/stock options.

      Compliance with journal ethical publication guidelines statement

      • All 11 sites used Copernicus Group Independent Review Board as their IRBs
      • Patient consent was a written declaration on an Informed Consent form with the patient's signature and date of consent. These Informed Consent forms are kept at the site

      Acknowledgments

      We would like to acknowledge the following investigators:
      • Martha Hernandez-Illas, MD; Principal Investigator, QPS Miami Research Associates
      • Jeff Groves, MD; Principal Investigator, Aspen Clinical Research
      • We thank members of the Sage Therapeutics, Inc., Clinical Operations team, including Amanda Moore, MSHS, and Brent Jones, BS, CCRA, for the planning, management, and execution of the clinical trials.
      • Hilary North Scheler, PhD, from Axon Communications for medical writing support.
      • Claire Sauvageot, PhD, and Michael Craig, MSc, from Sage Therapeutics, Inc., for editorial support.

      Appendix A. Supplementary data

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