Pharmacodynamic synergism contributes to the antiseizure action of cannabidiol and clobazam.

The management of refractory epilepsy involves treatment with more than one antiseizure medication (ASM). Combination of ASMs with distinct mechanisms of action are hypothesized to improve overall treatment effectiveness. In clinical trials, concomitant use of cannabidiol (CBD) and clobazam (CLB) was associated with increased seizure reduction and bidirectional elevation in levels of their active metabolites, 7-hydroxy-cannabidiol (7-OH-CBD) and nor-clobazam (n-CLB). Using isobolographic analysis, we investigated whether CBD and CLB interacted pharmacodynamically. In the mouse maximal electroshock seizure (MES) test, brain tissue levels of CBD and CLB corresponding to seizure prevention in 50% of animals (brain Effective Exposure, bEE50) were 7.9 µM and 1.6 µM, respectively. In the 6 Hz psychomotor seizure model, 7-OH-CBD displayed a 5-fold greater potency than CBD (b-EE50, 8.7 µM vs 47.3 µM). Isobolographic analysis performed on combination of CBD/CLB at 1:1, 3:1, and 1:3 ratios based on equi-effective bEE50 values revealed synergism at all doses with combination indices (CI) of 0.43, 0.62 and 0.75 respectively. These outcomes were independent of pharmacokinetic interaction between CBD and CLB. These findings identify pharmacodynamic synergism as an important factor underlying enhanced antiseizure effect during concomitant CBD and CLB use.

CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis.

BACKGROUND: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). OBJECTIVE: Evaluate laquinimod's efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months (n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. RESULTS: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67-1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo (p < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both, p = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg. CONCLUSION: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01707992).

Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials.

OBJECTIVE: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. SIGNIFICANCE: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.

Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial.

Importance: Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). Objective: To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. Interventions: Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. Main Outcomes and Measures: The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. Results: Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. Conclusions and Relevance: Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. Trial Registration: ClinicalTrials.gov Identifier: NCT02544763.

Cannabidiol and Abnormal Liver Chemistries in Healthy Adults: Results of a Phase I Clinical Trial.

Liver safety concerns were raised in randomized controlled trials of cannabidiol (CBD) in patients with Lennox-Gastaut and Dravet syndromes, but the relevance of these concerns to healthy adults consuming CBD is unclear. The objective of this manuscript is to report on liver safety findings from healthy adults who received therapeutic daily doses of CBD for ~ 3.5 weeks and to investigate any correlation between transaminase elevations and baseline characteristics, pharmacogenetic, and pharmacokinetic data. Sixteen healthy adults were enrolled in a phase I, open-label, fixed single-sequence drug-drug interaction trial to investigate the effect of repeated dose administration of CBD (1,500 mg/day) on cytochrome P450 (CYP) 1A2 activity. Seven (44%) participants experienced peak serum alanine aminotransferase (ALT) values greater than the upper limit of normal (ULN). For five (31%) participants, the value exceeded 5 × ULN, therefore meeting the international consensus criteria for drug-induced liver injury. There was no correlation between transaminase elevations and baseline characteristics, CYP2C19 genotype, or CBD plasma concentrations. All ALT elevations above the ULN began within 2-4 weeks of initial exposure to CBD. Among the six participants with ALT elevations who were discontinued from the protocol, some had symptoms consistent with hepatitis or hypersensitivity. We conclude that healthy adults consuming CBD may experience elevations in serum ALT consistent with drug-induced liver injury. Given the demonstrated interindividual variation in susceptibility, clinicians should be alert to this potential effect from CBD, which is increasingly available in various nonprescription forms and doses to consumers.

A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis.

OBJECTIVE: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS). METHODS: In the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events. RESULTS: A total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%). CONCLUSIONS: Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48. CLINICALTRIALSGOV IDENTIFIER: NCT02284568. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS.

Cannabidiol efficacy independent of clobazam: Meta-analysis of four randomized controlled trials.

OBJECTIVE: The efficacy of cannabidiol (CBD) with and without concomitant clobazam (CLB) was evaluated in stratified analyses of four large randomized controlled trials, two in Lennox-Gastaut syndrome, and two in Dravet syndrome. METHODS: Each trial of CBD (Epidiolex® in the US; Epidyolex® in the EU; 10 and 20 mg/kg/day) was evaluated by CLB use. The treatment ratio was analyzed using negative binomial regression for changes in seizure frequency and logistic regression for the 50% responder rate, where the principle analysis combined both indications and CBD doses in a stratified meta-analysis. Pharmacokinetic data were examined for an exposure/response relationship based on CLB presence/absence. Safety data were analyzed using descriptive statistics. RESULTS: The meta-analysis favored CBD vs. placebo regardless of CLB use. The treatment ratio (95% CI) of CBD over placebo for the average reduction in seizure frequency was 0.59 (0.52, 0.68; P < .0001) with CLB and 0.85 (0.73, 0.98; P = .0226) without CLB, and the 50% responder rate odds ratio (95% CI) was 2.51 (1.69, 3.71; P < .0001) with CLB and 2.40 (1.38, 4.16; P = .0020) without CLB. Adverse events (AEs) related to somnolence, rash, pneumonia, or aggression were more common in patients with concomitant CLB. There was a significant exposure/response relationship for CBD and its active metabolite. CONCLUSIONS: These results indicate CBD is efficacious with and without CLB, but do not exclude the possibility of a synergistic effect associated with the combination of agents. The safety and tolerability profile of CBD without CLB show a lower rate of certain AEs than with CLB.

Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial.

Importance: Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. Objective: To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. Interventions: Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. Main Outcomes and Measures: The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. Results: Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. Conclusions and Relevance: Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02224703.

Validating the use of brain volume cutoffs to identify clinically relevant atrophy in RRMS.

BACKGROUND: Baseline brain volume (BV) is predictive at a group level but is difficult to interpret at the single patient level. OBJECTIVE: To validate BV cutoffs able to identify clinically relevant atrophy in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: The expected normalized brain volume (NBV) for each patient was calculated using RRMS patients from two phase III clinical trials, applying a linear formula developed on the baseline variable of an independent data set. The difference between these expected NBV values and those actually observed was calculated and used to categorize the patients in the low-NBV, medium-NBV, and high-NBV groups. RESULTS: The 2-year probability of 3-month confirmed disability worsening was significantly associated with the NBV categorization ( p = 0.006), after adjusting for treatment effect. Taking the high-NBV group as a reference, the hazard ratios for the medium-NBV and low-NBV groups were 1.22 (95% confidence interval (CI): 0.85-1.76, p = 0.27) and 1.69 (95% CI: 1.11-2.57, p = 0.01), respectively. CONCLUSION: This study validates the use of BV cutoffs to identify clinically relevant atrophy in RRMS study by showing that the three groups classified according to the baseline NBV adjusted for the other prognostic variables have a significant prognostic impact on the risk of disability progression.

Once-daily glatiramer acetate decreases magnetic resonance imaging disease activity in Japanese patients with relapsing-remitting multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) prevalence, clinical patterns, and treatment responses vary between races and geographical latitudes. Glatiramer acetate (GA; Copaxone) has provided a safe, effective treatment option for relapsing-remitting MS patients in the USA, European nations, and other countries for decades. The objective of the present study was to assess the safety and efficacy of GA in reducing magnetic resonance imaging disease activity in Japanese patients with active relapsing-remitting MS. METHODS: This phase 2, multicenter, open-label, single-arm, 52-week study measured the effect of GA 20 mg once-daily on magnetic resonance imaging disease activity. GA efficacy was evaluated through week 36, and safety through week 52. The primary end-point was change in the mean number of T1-weighted gadolinium-enhancing (GdE) lesions from pretreatment (weeks -8, -4 and baseline) to weeks 28, 32 and 36. Secondary end-points included a change in mean number of new T2-weighted lesions, GdE lesion and T2 lesion volumes, annualized relapse rate, and Expanded Disability Status Scale scores. RESULTS: GA therapy reduced the number of new GdE lesions by 65.66% (95% CI 33.19-82.35%). The number of new T2 lesions and GdE lesion volume were also reduced from pretreatment. The annualized relapse rate was reduced by 42% compared with the 1 year before treatment. Changes in T2 lesion volume and Expanded Disability Status Scale scores were favorable, but less pronounced. Most common adverse events were injection-site reactions. CONCLUSIONS: The present study confirmed the well-established safety, tolerability and efficacy profile of GA in Japanese MS patients.

Comparative utility of disability progression measures in PPMS: Analysis of the PROMiSe data set.

OBJECTIVE: To assess the comparative utility of disability progression measures in primary progressive MS (PPMS) using the PROMiSe trial data set. METHODS: Data for patients randomized to placebo (n = 316) in the PROMiSe trial were included in this analysis. Disability was assessed using change in single (Expanded Disability Status Scale [EDSS], timed 25-foot walk [T25FW], and 9-hole peg test [9HPT]) and composite disability measures (EDSS/T25FW, EDSS/9HPT, and EDSS/T25FW/9HPT). Cumulative and cross-sectional unconfirmed disability progression (UDP) and confirmed disability progression (CDP; sustained for 3 months) rates were assessed at 12 and 24 months. RESULTS: CDP rates defined by a ≥20% increase in T25FW were higher than those defined by EDSS score at 12 and 24 months. CDP rates defined by T25FW or EDSS score were higher than those defined by 9HPT score. The 3-part composite measure was associated with more CDP events (41.4% and 63.9% of patients at 12 and 24 months, respectively) than the 2-part measure (EDSS/T25FW [38.5% and 59.5%, respectively]) and any single measure. Cumulative UDP and CDP rates were higher than cross-sectional rates. CONCLUSIONS: The T25FW or composite measures of disability may be more sensitive to disability progression in patients with PPMS and should be considered as the primary endpoint for future studies of new therapies. CDP may be the preferred measure in classic randomized controlled trials in which cumulative disability progression rates are evaluated; UDP may be feasible for cross-sectional studies.

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis.

BACKGROUND: Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials. METHODS: Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials. RESULTS: A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA). CONCLUSIONS: This study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone's MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone.

Laquinimod Safety Profile: Pooled Analyses from the ALLEGRO and BRAVO Trials.

BACKGROUND: Laquinimod 0.6 mg is a once-daily, oral, disease-modifying therapy in development for the treatment of multiple sclerosis (MS) that was investigated in two double-blind, placebo-controlled, phase 3 trials: ALLEGRO and BRAVO. METHODS: Data from these studies were pooled to assess the safety profile of laquinimod versus placebo. Adverse events (AEs), laboratory value changes, and potential risks identified in preclinical studies were evaluated in participants in ALLEGRO and BRAVO treated with at least one dose of laquinimod or matching placebo (1:1 random assignment). RESULTS: In total, 1988 patients received at least one dose of study drug (laquinimod: n = 983 [mean ± SD duration, 639 ± 190 days]; placebo: n = 1005 [mean ± SD duration, 627 ± 198 days]). Early terminations due to AEs were infrequent (laquinimod: 6.4%; placebo: 4.7%). Death was reported in four patients (laquinimod: n = 1; placebo: n = 3). Rates of serious AEs (including malignancies, infections, and cardiovascular AEs) were similar between groups. The most common AEs identified with laquinimod use were back and neck pain and appendicitis. Laquinimod was also associated with asymptomatic changes in liver enzyme levels, fibrinogen levels, and hematologic parameters that followed a consistent temporal pattern: mild, nonprogressive, and occurring within 90 days of treatment initiation, then stabilizing or reverting to baseline levels during continued treatment. CONCLUSIONS: Data from these pivotal laquinimod studies demonstrate a safety profile comprising benign or manageable AEs and asymptomatic laboratory findings with a clear temporal pattern. Potential risks noted in preclinical studies were not observed.

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

Time course of glatiramer acetate efficacy in patients with RRMS in the GALA study.

OBJECTIVE: To determine the time to efficacy onset of glatiramer acetate (GA) 40 mg/mL 3-times-weekly formulation (GA40). METHODS: This post hoc analysis of data from the 1-year, double-blind, placebo-controlled phase of the Glatiramer Acetate Low-Frequency Administration study (NCT01067521) of GA40 in patients with relapsing-remitting MS (RRMS) sought to determine the timing of efficacy onset using a novel data-censoring approach. RESULTS: Compared with placebo-treated patients, those receiving GA40 exhibited a >30% reduction in the accumulated annualized relapse rate (ARR) within 2 months of initiating treatment and generally sustained this treatment difference during the 1-year study. Similarly, the proportion of GA40-treated patients who remained relapse-free was distinctly greater by month 2 and continued to increase up to a 10.8% difference at the end of the study. In addition, GA40 treatment was associated with a significant reduction in the number of gadolinium-enhancing T1 lesions and new/enlarging T2 lesions by month 6, with full treatment effect observed after 1 year. CONCLUSIONS: GA40 contributes to efficacy within 2 months of the start of treatment in patients with RRMS. These results are consistent with the observed time to efficacy onset for patients treated with GA 20 mg/mL daily in previous randomized, placebo-controlled clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, a 3-times-weekly formulation of GA 40 mg/mL leads to a >30% reduction in the ARR within 2 months.

Pharmacogenomics strategies to optimize treatments for multiple sclerosis: Insights from clinical research.

Multiple sclerosis (MS) is a chronic, progressive, disabling disorder characterized by immune-mediated demyelination, inflammation, and neurodegenerative tissue damage in the central nervous system (CNS), associated with frequent exacerbations and remissions of neurologic symptoms and eventual permanent neurologic disability. While there are several MS therapies that are successful in reducing MS relapses, none have been effective in treating all patients. The specific response of an individual patient to any one of the MS therapies remains largely unpredictable, and physicians and patients are forced to use a trial and error approach when deciding on treatment regimens. A priori markers to predict the optimal benefit-to-risk profile of an individual MS patient would greatly facilitate the decision-making process, thereby helping the patient receive the most optimal treatment early on in the disease process. Pharmacogenomic methods evaluate how a person's genetic and genomic makeup affects their response to therapeutics. This review focuses on how pharmacogenomics studies are being used to identify biologically relevant differences in MS treatments and provide characterization of the predictive clinical response patterns. As pharmacogenomics research is dependent on the availability of longitudinal clinical research, studies concerning glatiramer acetate and the interferon beta products which have the majority of published long term data to date are described in detail. These studies have provided considerable insight in the prognostic markers associated with MS disease and potential predictive markers of safety and beneficial response.

Long-term safety and tolerability of glatiramer acetate 20 mg/ml in the treatment of relapsing forms of multiple sclerosis.

​Introduction: Glatiramer acetate (GA) is a first-line therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). It has a well-characterized long-term safety profile and established efficacy, with over 2 million patient-years of exposure. Areas covered: To present long-term safety and tolerability findings for GA 20 mg/mL daily in the management of patients with multiple sclerosis (MS). A database analysis of all patients with MS who have ever been exposed to GA 20 mg/mL daily in clinical trials, including patients with up to 20 years of continuous treatment.Total exposure to GA in the clinical trials analyzed was 10,017 patient-years, and treatment duration ranged from 0 to 23.1 years (median 1.8 years). No unexpected adverse events (AEs) were recorded. The most common AEs were injection-site related (ISR), affecting 49% of patients receiving GA in clinical trials. Development of erythema at the injection site was the most common ISR, affecting 29.2% of study patients. Immediate post-injection reactions (IPIRs) were experienced by 24.0% of study patients; dyspnea was the most common IPIR, affecting 12.1% of patients. Expert opinion: The results of this analysis are consistent with long-term studies showing GA to be safe and generally well tolerated.

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor.

Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR-/- mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.

Laquinimod efficacy in relapsing-remitting multiple sclerosis: how to understand why and if studies disagree.

BACKGROUND: The results of two randomized phase 3 trials that investigated the use of laquinimod in patients with relapsing-remitting multiple sclerosis were analyzed using a propensity score model. METHODS: The propensity score in each study was defined as the probability of an individual patient being assigned to either the laquinimod or placebo study arm. The analysis included two main stages: (1) calculation of a propensity score for each patient, given a broad set of baseline covariates that included second-degree interactions, and (2) incorporation of the propensity score as another covariate into the predefined primary analysis model to test the treatment effect of laquinimod (0.6 mg/d) vs placebo on the annualized relapse rate (ARR). RESULTS: The BRAVO study showed baseline imbalances for T2 volume and the proportion of patients with gadolinium (Gd)-enhancing lesions, both parameters known to correlate with risk of relapse. Adjustment using the propensity score as a categorical variable showed that the estimated difference in ARR between laquinimod and placebo was 0.078, in favor of laquinimod. In ALLEGRO, the baseline Gd-enhancing lesion mean score was higher for placebo vs laquinimod. When the primary analysis model was adjusted for the propensity score as a categorical variable, the covariate adjusted difference in mean ARR between laquinimod and placebo was 0.084, in favor of laquinimod. CONCLUSIONS: Propensity scores addressing differences in baseline characteristics may be helpful to better understand whether observed treatment effect differences in randomized controlled trials are accurate results or result from inherent differences between patients with multiple sclerosis.

Incidence and course of depression in multiple sclerosis in the multinational BEYOND trial.

Early experience in MS generated concerns that interferon beta treatment might provoke onset or worsening of depression. The objective of the study was to compare depression incidence in relapsing-remitting MS patients receiving interferon beta-1b (IFNB-1b) or glatiramer acetate (GA) in the BEYOND trial. 891/897 (99 %) of English, French, Spanish and Italian speakers among 2244 patients randomized (2:2:1) to receive either IFNB-1b 500 µg, 250 µg, or GA 20 mg QD for 2-3.5 years submitted Beck Depression Inventory Second Edition (BDI-II) scores at screening and serially thereafter, in which scores ≥14 indicated depression. Baseline BDI-II scores ≥14 were reported in 232/891 patients (26.3 %), with no meaningful difference among the three treatment arms noted at this or at any other time during the study including trial end. Percentages of patients depressed by BDI-II scores deviated little in any arm at any time (IFNB-1b 500 µg: 24.7 %, IFNB-1b 250 µg: 24.4 %, GA: 32.4 %). Antidepressant usage was likewise similar among the three treatment arms (IFNB-1b 500 µg: 33.7 %, IFNB-1b 250 µg: 31.8 %, GA: 28.8 %) as was depression severity and the frequency with which non-blinded treating physicians recorded depression as an adverse event (IFNB-1b 500 µg: 17.2 %, IFNB-1b 250 µg: 17.0 %, GA: 14.4 %). Treating physicians attributed depression to IFNB-1b 250 µg therapy in 53.6 % and to GA in 21.9 % of instances. This large, prospective, randomized-controlled MS dataset showed no increased risk of depression above baseline values with standard or double-dose IFNB-1b or GA QD treatment.