Faculty Bibliography

BACKGROUND:Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease. METHODS:LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete. FINDINGS/RESULTS:Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]). INTERPRETATION/CONCLUSIONS:Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments. FUNDING/BACKGROUND:Teva Pharmaceutical Industries.

INTRODUCTION/UNASSIGNED:Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Complementary and alternative therapies are increasingly utilized to address its complex multisystem symptomatology. Art therapy involves motoric action and visuospatial processing while promoting broad biopsychosocial wellness. The process involves hedonic absorption, which provides an escape from otherwise persistent and cumulative PD symptoms, refreshing internal resources. It involves the expression in nonverbal form of multilayered psychological and somatic phenomena; once these are externalized in a symbolic arts medium, they can be explored, understood, integrated, and reorganized through verbal dialogue, effecting relief and positive change. METHODS/UNASSIGNED:42 participants with mild to moderate PD were treated with 20 sessions of group art therapy. They were assessed before and after therapy with a novel arts-based instrument developed to match the treatment modality for maximum sensitivity. The House-Tree-Person PD Scale (HTP-PDS) assesses motoric and visuospatial processing-core PD symptoms-as well as cognition (thought and logic), affect/mood, motivation, self (including body-image, self-image, and self- efficacy), interpersonal functioning, creativity, and overall level of functioning. It was hypothesized that art therapy will ameliorate core PD symptoms and that this will correlate with improvements in all other variables. RESULTS/UNASSIGNED:HTP-PDS scores across all symptoms and variables improved significantly, though causality among variables was indeterminate. DISCUSSION/UNASSIGNED:Art therapy is a clinically efficacious complementary treatment for PD. Further research is warranted to disentangle causal pathways among the aforementioned variables, and additionally, to isolate and examine the multiple, discrete healing mechanisms believed to operate simultaneously in art therapy.

Background: Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons during Huntington's Disease (HD) and alzheimer's Disease (AD) progression and triggers astrocytes that express plexin-B1/B2 receptor to undergo reactive gliosis with concomitant loss of normal astrocyte functions1. Drivers of glial cell activation represent novel targets to modify progression of neurodegenerative pathology. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in the SIGNAL-HD (NCT02481674) Phase 2 trial2 as well as in preclinical models of HD and AD. These studies provided clinical rationale for the ongoing Phase 1/2 SIGNAL-AD study (NCT04381468).
Objective(s): Present the updated safety, efficacy, and biomarker data from the completed SIGNAL-HD trial2. In addition, describe how neuroimaging and subgroup analysis of the clinical HD results provide further rationale for investigation in AD, and present the trial design, enrollment status, and updated blinded safety data for the Phase 1b/2a double-blind, randomized, placebO'Controlled SIGNAL-AD trial.
Method(s): The SIGNAL-HD phase 2 study included 301 subjects with late prodromal (LP) and early manifest (EM) HD. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD-CAB). Imaging endpoints included structural MRI to assess brain atrophy and FDG-PET to assess brain metabolism. The SIGNAL-AD study is in progress and is planned to enroll up to 40 subjects with early AD treated for approximately 1 year. Objectives include safety, change in brain metabolism via FDG-PET, and clinical endpoints including the alzheimer's Disease Assessment Scale - cognition (ADAS-cog) and Clinical Dementia Rating Scale - sum of boxes (CDR-SB).
Result(s): In SIGNAL-HD, pepinemab was well-tolerated and was shown to cross the BBB at a concentration sufficient to engage its target. While co-primary efficacy outcome measures did not achieve statistical significance in this study, multiple exploratory and post-hoc measures indicated significant cognitive benefit and were supported by pre-specified FDG-PET imaging that indicated significant reversal of decline in metabolic activity (p>=0.05) in 15/26 brain regions of interest. Treatment effects were observed in EM but not LP subjects. In 179 EM subjects, a treatment benefit was observed in 6/6 components of the HD-CAB cognitive assessment battery, with a significant treatment effect on the HD-CAB composite index (p=0.007). Post-hoc analysis of the HD-CAB results showed pepinemab treatment preserved the ability of EM subjects to learn from experience during sequential administration of HD-CAB and that the cognitive treatment benefit was greater in subjects that were more cognitively impaired at baseline, as judged by Montreal Cognitive Assessment (MoCA) score <26 vs. >=26. The largest metabolic decline in HD is observed in caudate and putamen. It is, therefore, striking that a treatment effect on FDG-PET SUVR was not observed in caudate and putamen of either EM or LP subjects. Since degeneration of medium spiny neurons in striatum is an early event in prodromal HD that continues following motor diagnosis, this could account for reduced glucose utilization that is not SEMA4D-dependent and, therefore, not affected by pepinemab treatment. Our data support an important glial contribution to glucose utilization in other brain regions that is reduced by reactive gliosis and restored by pepinemab treatment. This suggests distinct early and late stages of pathology during disease progression. The ongoing blinded SIGNAL-AD trial has enrolled approximately half of the 40 planned subjects, and top line data for a full year of randomized, double-blind treatment is anticipated in Q1 2024. It will be of particular interest to determine whether metabolic changes in the entorhinal cortex, a region of early degeneration in AD, are less SEMA4D-dependent than for other cortical regions that degenerate somewhat later in disease progression.
Conclusion(s): SIGNAL-HD showed a favorable safety profile and positive trends in cognition and imaging endpoints that encourage continued development in both HD and AD. The Phase 1b/2a study in AD (SIGNAL-AD), is currently enrolling and initial blinded safety review has suggested pepinemab is well tolerated in AD as well

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

INTRODUCTION:Huntington's disease is a neurodegenerative disease that is characterized by motor dysfunction, behavioral/psychiatric symptoms, and cognitive impairment. Because of the lack of availability of curative or disease modifying treatments, much of clinical practice in HD care to date has focused on symptomatic treatment. Recent work has created optimism surrounding possible emerging disease modifying therapeutics. HD is a developing therapeutic field with diverse and promising emerging therapies. AREAS COVERED:A PubMed literature review was completed to discover pertinent reviews and analyses. ClinicalTrials.gov was referenced to find updated information about ongoing and planned trials. Lastly, because of the rapidly evolving nature of HD treatments, drug manufacturer websites and press releases were reviewed to provide current information surrounding recently reported trial results. EXPERT OPINION:Recent setbacks involving antisense oligonucleotide research should not diminish enthusiasm and hope for the many other novel therapies currently being pursued. We remain optimistic about the many promising emerging therapies for HD, and we expect that growing knowledge about the pathophysiology of the underlying disease and constant advances in biotechnology will lead to therapies that have a meaningful impact in the lives of patients, their families, and those who care for them.

Background Pridopidine is a safe, well-tolerated oral drug candidate, that potently activates the Sigma-1 Receptor (S1R). The S1R regulates many cellular processes. Human brain PET studies show that pridopidine 45 mg bid, the dose evaluated in PROOF, selectively and robustly occupies the S1R. Total Functional Capacity (TFC) is a validated, regulatory-accepted measure of disease stage and functional decline. To date, no therapeutic agent has shown benefit on the rate of decline in TFC. Analysis of the pre-specified endpoint TFC in the PRIDE-HD trial shows a beneficial effect of pri-dopidine 45 mg bid vs. placebo on maintenance of TFC at wk52 (D 0.87, p=0.0032). Post-hoc analysis revealed that this effect is driven by early HD patients (TFC 7-13) (D 1.16, p=0.0003). The effect remains significant using a more conservative analysis (nominal p=0.016). Responder analysis shows that 45 mg bid reduces the probability of worsening in TFC by 80% (p=0.002,). Exploratory analysis also shows improvements in total motor score, TFC, and the symbol digit modality test vs. placebo (D0.6, p=0.04) when assessed in combination. Q-motor, a quantitative motor test, demonstrated improvement in the finger inter-tap interval vs. placebo at wk26 (D-0.034 sec, p=0.035) and 52 (D-0.044, p=0.03). P-values are nominal. Aim Evaluate the efficacy and safety of pridopidine 45 mg bid on TFC in early HD. Design PROOF-HD is a 65-week, double-blind, placebo-controlled, global Ph 3 trial. PROOF assesses the effect of pridopidine 45 mg bid vs placebo on TFC in early HD patients. Primary endpoint is mean DTFC from baseline to Wk 65. Secondary endpoints are the proportion of patients with no TFC decline (TFC> 0) at Wk65 and changes from baseline to Wk65 in Q-motor, Total Motor Score (TMS) and cUHDRS. Status As of July 4, 2021, 58/60 (97%) of sites have been activated and 235 patients have been randomized (48% of the total). There have been no dropouts from the trial, supporting the tolerability and safety of the drug

OBJECTIVE:Recent studies on a rodent model of Parkinson's disease (PD) have raised the possibility of increased blood-brain barrier (BBB) permeability, demonstrated by histology, autoradiography, and positron emission tomography (PET). However, in human PD patients, in vivo evidence of increased BBB permeability is lacking. We examined the hypothesis that levodopa treatment increases BBB permeability in human subjects with PD, particularly in those with levodopa-induced dyskinesia (LID). METHODS:Rb concentration in brain tissue and blood, was estimated with good stability as a local measure of the volume of distribution. RESULTS:measured off- and on-levodopa infusion were also not significant for dyskinetic and non-dyskinetic subjects. CONCLUSION/CONCLUSIONS:Rb PET did not reveal significant changes in BBB permeability in PD patients.

OBJECTIVE:To explore the potential rehabilitative effect of art therapy and its underlying mechanisms in Parkinson's disease (PD). METHODS:Observational study of eighteen patients with PD, followed in a prospective, open-label, exploratory trial. Before and after twenty sessions of art therapy, PD patients were assessed with the UPDRS, Pegboard Test, Timed Up and Go Test (TUG), Beck Depression Inventory (BDI), Modified Fatigue Impact Scale and PROMIS-Self-Efficacy, Montreal Cognitive Assessment, Rey-Osterrieth Complex Figure Test (RCFT), Benton Visual Recognition Test (BVRT), Navon Test, Visual Search, and Stop Signal Task. Eye movements were recorded during the BVRT. Resting-state functional MRI (rs-fMRI) was also performed to assess functional connectivity (FC) changes within the dorsal attention (DAN), executive control (ECN), fronto-occipital (FOC), salience (SAL), primary and secondary visual (V1, V2) brain networks. We also tested fourteen age-matched healthy controls at baseline. RESULTS:At baseline, PD patients showed abnormal visual-cognitive functions and eye movements. Analyses of rs-fMRI showed increased functional connectivity within DAN and ECN in patients compared to controls. Following art therapy, performance improved on Navon test, eye tracking, and UPDRS scores. Rs-fMRI analysis revealed significantly increased FC levels in brain regions within V1 and V2 networks. INTERPRETATION/CONCLUSIONS:Art therapy improves overall visual-cognitive skills and visual exploration strategies as well as general motor function in patients with PD. The changes in brain connectivity highlight a functional reorganization of visual networks.

PURPOSE OF REVIEW/OBJECTIVE:This article describes and discusses new potential disease-modifying therapies for Huntington's disease that are currently in human clinical trials as well as promising new therapies in preclinical development. RECENT FINDINGS/RESULTS:Multiple potential disease-modifying therapeutics for HD are in active development, including direct DNA/gene therapies, RNA modulation, and therapies targeted at aberrant downstream pathways. The etiology of Huntington's disease (HD) is well-known as an abnormally expanded trinucleotide repeat within the huntingtin gene. However, the pathogenesis downstream of the mutant huntingtin gene is complex, involving multiple toxic pathways, including abnormal protein fragmentation and neuroinflammation. The current treatment of HD focuses largely on symptomatic management. This article discusses new, potential disease-modifying therapies that are currently in human clinical trials and preclinical development.