Dose Of Fingolimod Research Articles

Effects of fingolimod on heart injury induced by renal ischemia-reperfusion

Background. Renal ischemia-reperfusion injury (IRI) is one of the inevitable complications of surgery. The evidence shows that fingolimod, with its anti-inflammatory effects, can play a protective role in renal IRI. The main aim of the present study was to investigate the role of fingolimod against renal IRI in the heart tissue. Methods. Twenty-four male Wistar rats (220±20g) were treated with a single dose of fingolimod (1mg/kg) by intraperitoneal injection before the induction of kidney IRI. At the end of the reperfusion period, the oxidative stress biomarker (malondialdehyde) and antioxidant biomarkers (catalase, superoxide dismutase, glutathione, glutathione peroxidase, and total antioxidant capacity) were evaluated in the heart tissue. Results. Fingolimod pretreatment could increase cardiac glutathione enzyme activity in the fingolimod+IR group compared to the IR group, which was not statistically significant (P>0.05). The level of total antioxidant capacity in the heart tissue was also significantly increased in the fingolimod+IR group in comparison to the IR group (P<0.05). Conclusion. Fingolimod was able to prevent oxidative stress damage in the heart caused by kidney IR induction by increasing the level of total antioxidant capacity of the heart tissue. It is suggested that future studies evaluate the effects of this drug in clinical trials. Practical Implications. The total antioxidant capacity of the heart, as a distant organ affected by kidney IRI, is increased following fingolimod pre-treatment.

The Effect of Fingolimod on Renal Ischemia/Reperfusion Injury in a Rat Model.

Ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) that induces inflammation and oxidative stress. The main goal of the current study was to assess the impact of fingolimod on kidney IRI in rats. For this purpose, 18 male Wistar rats (220-250g) were divided into three groups including (i) Sham, (ii) I/R, and (iii) fingolimod+I/R. The last group was pretreated with a single dose of fingolimod (1mg/kg) (intraperitoneal injection) before induction of the I/R injury. Kidney function, oxidative stress marker (malondialdehyde), and antioxidant markers (catalase, superoxide dismutase, glutathione, glutathione peroxidase, and total antioxidant capacity) were determined in the kidney tissue of the rats. Moreover, kidney samples were taken for histological analysis. Fingolimod pre-treatment could significantly improve the glutathione peroxidase (p<0.01) and glutathione (p<0.001) activities along with the total antioxidant capacity levels (p<0.001) when compared to the I/R group. Moreover, significant recovery of kidney function and histology was seen in the fingolimod+ I/R group compared to the I/R group (p<0.01). Fingolimod pretreatment could improve renal function, antioxidant capacity, and histological alterations after I/R injury. Hence, it might protect the kidney against IRI-related kidney damage including AKI and transplantation.

Alternate dosing of fingolimod in relapsing-remitting multiple sclerosis: A systematic review.

Background: Fingolimod is approved in relapsing-remitting multiple sclerosis (RRMS) with the recommended dose of 0.5 mg daily. To tackle possible adverse events, some clinicians may reduce the dose of fingolimod, mainly in the alternate-day form. We systematically reviewed the literature for efficacy measures of this method. Methods: PubMed (Medline®), Web of Science, Embase, Scopus, and the Cochrane Library databases were searched until April 9, 2021. Clinical studies (other than case reports and case series), in English, were included. Then, publications concerning alternate dose fingolimod (including every other day, every two or three days) were selected. Those studies concerning reduced daily dose (any daily dose less than 0.5 mg/day) were excluded to focus on alternate dosing. Results: Four observational studies were included. Data on Ohtani et al. study were limited. Three other studies were of good quality based on the Newcastle-Ottawa Scale. A total of 296 patients on the standard dose were compared to 276 patients on the alternate dosage. The most common reason for switching to the alternate dose was lymphopenia, followed by elevated liver enzymes. Two studies concluded that the alternate dosing could be a safe, yet effective strategy in patients with intolerable adverse effects of daily dose. However, Zecca et al. warned about the high possibility of disease reactivation. Due to the differences in outcome measures of the studies, meta-analysis was not applicable. Conclusion: This systematic review highlights the ambiguity of evidence on safety and efficacy of alternate dosing of fingolimod, encouraging further research on the subject.

Preclinical Evaluation of Fingolimod in Rodent Models of Stroke With Age or Atherosclerosis as Comorbidities.

Preclinical data indicate that fingolimod improves outcome post-ischaemia. This study used a rigorous study design in normal male C57BL/6JOlaHsd mice and in mice with common stroke comorbidities to further evaluate the translational potential of fingolimod. Stroke was induced via middle cerebral artery electrocoagulation in 8–9-week old mice (young mice), 18 month old mice (aged mice), and in high-fat diet-fed 22-week old ApoE−/− mice (hyperlipidaemic mice). Recovery was evaluated using motor behavioural tests 3 and 7 days after stroke. Tissue damage was evaluated at 7 days. A lower dose of fingolimod, 0.5 mg/kg, but not 1 mg/kg, increased lesion size but decreased ipsilateral brain atrophy in younger mice, without an effect on behavioural outcomes. Fingolimod-treated aged mice showed a significant improvement over saline-treated mice in the foot fault test at 7 days. Fingolimod-treated hyperlipidaemic mice showed a decreased infarct size but no difference in behavioural performance. Increasing fingolimod treatment time to 10 days showed no benefit in young mice. Pooled data showed that fingolimod improved performance in the foot fault test. Flow cytometry studies showed that fingolimod had marked effects on T cell frequencies in various tissues. The results show that the effects of fingolimod in stroke are less robust than the existing literature might indicate and may depend on the inflammatory status of the animals.

The effect of FTY720 at different doses and time-points on LPS-induced acute lung injury in rats

We sought to assess the protective effect of different doses of Fingolimod (FTY720) in a rat model of acute lung injury (ALI) induced by intratracheal instillation of lipopolysaccharide (LPS) and explored the underlying mechanisms. The ALI model was established in rats and different doses of FTY720 (0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, or 2 mg/kg) were injected intraperitoneally. Lung computed tomography and blood gas analyses were performed at 6 h, 24 h, and 48 h after intraperitoneal injection, and the lung tissues were extracted to prepare paraffin sections for histopathological examination. The levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) were detected by ELISA, and the expressions of inflammatory pathway proteins in each group were measured by Western blot analysis. A single intraperitoneal injection of FTY720 inhibited LPS-induced NF-κB activation, reduced the level of inflammatory cytokines, and decreased the infiltration of inflammatory cells. Moreover, it alleviated lung tissue injury, as shown by marked attenuation of pulmonary oedema and improved arterial partial pressure of oxygen (PaO2) and the general condition of ALI rats. In conclusion, our results demonstrate the protective effect of FTY720 against LPS-induced ALI. The underlying mechanism of the protective effect may involve inhibition of LPS-induced activation of NF-κB and regulation of the inflammatory pathway to alleviate barrier dysfunction of alveolar capillaries.

Different Doses of Fingolimod in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: The efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis (RRMS) had been well verified in several large randomized controlled trials (RCTs) during the past decade. However, there are fewer systematic comparisons of different doses of fingolimod and whether the dose of 0.5 mg/d is the optimal one still remains to be solved. Objective: The objective of this systematic review was to evaluate the efficacy and safety of the four existing doses of fingolimod in the treatment of RRMS, especially the dose of 0.5 mg/d. Methods: MEDLINE, EMBASE, Cochrane Library, and clinicaltrials.gov were searched for RCTs which were performed to evaluate different doses of fingolimod and the corresponding control (placebo or DMTs) up to October 2020. Review Manager 5.3 software was used to assess the data. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model. Results: We pooled 7184 patients from 11 RCTs. Fingolimod 0.5 mg/d was superior to control group in all eight efficacy outcomes including annualized relapse rate (ARR) (MD −0.22, 95%CI −0.29 to −0.14, p < 0.00001) but surprisingly showed a higher risk of basal-cell carcinoma (RR 4.40, 95%CI 1.58 to 12.24, p = 0.004). Although 1.25 mg/d is more than twice the dose of 0.5 mg/d, the effect size was almost similar between them. Dose of 5 mg/d obtained an unsatisfactory efficacy while showing a greater risk of adverse events than other three doses (RR 1.17, 95%CI 1.05 to 1.30, p = 0.003). Additionally, fingolimod 0.25 mg/d not only showed a better performance in delaying the disease progress of magnetic resonance imaging (MRI), but also achieved a certain degree of patient treatment satisfaction. Conclusion: At present, 0.5 mg/d remains to be the optimal dose of fingolimod for RRMS patients but trials of a lower dose are still of great clinical significance and should be paid more attentions.

Efficacy and Safety of 2 Fingolimod Doses vs Glatiramer Acetate for the Treatment of Patients With Relapsing-Remitting Multiple Sclerosis

Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown. To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis. Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day. The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018. The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed. Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group). Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis. ClinicalTrials.gov Identifier: NCT01633112.

A Comprehensive Monitoring Study on Electrocardiographic Assessments and Cardiac Events After Fingolimod First Dose-Possible Predictors of Cardiac Outcomes.

Background: First dose observation for cardiac effects is required for fingolimod. Previous results in patients with relapsing remitting multiple sclerosis (RRMS) suggest that transient bradycardia and conduction abnormalities during the observation phase are rare, benign and reversible. Prior analyses corroborate these findings. The present large scale dataset allows subgroup analyses for differences in the incidence of cardiac findings depending on patient characteristics.Methods: START was an open-label, multi-center study that enrolled 6,998 RRMS patients. Primary endpoints were incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree atrioventricular (AV) block during treatment initiation. Subgroup analyses were performed according to age, gender, body mass index (BMI), baseline expanded disability status scale (EDSS), and concomitant medication to determine the impact of these variables on cardiac outcomes parameters.Results: 63 patients (0.9%) developed bradycardia (<45 bpm), 120 patients (1.7%) had a second-degree Mobitz I (Wenkebach) block and/or 2:1 AV block. One case of an asymptomatic third-degree AV block occurred. No Mobitz II AV block was observed. After 1 week, no second-/third-degree AV block was observed. The incidence of second- or third-degree AV blocks was significantly higher in older patients (≥50 years; p = 0.014 vs. patients 35–49 years). Second- or third-degree AV blocks were more frequent in females (87.5% of all patients with a second- or third-degree AV block; p < 0.001), while bradycardia occurred more often in males (58.7% of all bradycardia events; p < 0.001). Furthermore, patients with a BMI below 25 had a higher incidence of second- or third-degree AV block.Conclusions: In summary, transient bradycardia and AV conduction abnormalities after the first dose of fingolimod were rare and asymptomatic. When compared to females, male patients might have a higher risk for bradycardia during treatment initiation, presumably due to a lower resting heart rate. Furthermore, a low heart rate before treatment initiation, low body weight, or low BMI possibly increases the risk for bradycardia. Second- or third-degree AV blocks were more frequent in females, older patients and patients with a low BMI. Nevertheless, these cardiac events remained rare and benign, confirming the favorable cardiac safety profile of fingolimod upon treatment initiation in MS patients without cardiovascular comorbidities.

Clinical effectiveness of reduced fingolimod dose in relapsing remitting multiple sclerosis-a Portuguese cohort.

Fingolimod is an oral daily treatment for relapsing remitting multiple sclerosis (RRMS). A decrease in lymphocytes count is a common side effect, whereby clinicians occasionally propose a reduced dose rather than its discontinuation. However, current data on the effectiveness of these regimens are scarce and contradictory. Our objective was to investigate if the fingolimod effectiveness is maintained with reduction in dosing frequency. Retrospective and observational study of RRMS patients taking fingolimod-nondaily (FTY-ND) for at least 6months. Propensity score-based matching was performed to select patients taking daily dose (FTY-ED) with comparable baseline characteristics: age, sex, disease duration, annualized relapse rate (ARR), and expanded disability status scale (EDSS). Afterwards, clinical and laboratorial assessment was evaluated in both groups. Thirty-six patients were included in each group (FTY-ED vs. FTY-ND). Decrease in lymphocytes count was the main reason for switching to FTY-ND (88.9%). Previous treatment with natalizumab was inversely associated with risk of reducing dose (OR 0.253, 95%CI = 0.08-0.807, p = 0.016). There were no significant differences in clinical disease activity between patients FTY-ED vs. FTY-ND: mean ARR 0.4 vs. 0.3 (p = 0.247), median EDSS 2.0 vs. 2.0 (p = 0.687), and proportion of patients with EDSS increase 8.3% vs. 13.9% (p = 0.453). FTY-ND was overall well tolerated and was associated with an increase in the mean lymphocytes count (362 ± 103 cells/mm3 to 541 ± 183 cells/mm3, p < 0.001). These data suggest that the effectiveness of FTY is maintained despite the reduction of the dose, minimizing the most common adverse events. These findings warrant further confirmation, ideally with randomized clinical trials.

Is Gender Associated to Extended Cardiac Monitoring after First Dose of Fingolimod and Level of Satisfaction with the Monitoring Experience in Relapsing-Remitting Multiple Sclerosis Patients? A Post-hoc Analysis of the BEAT Study

Objective: Fingolimod, a second-line therapy for relapsing-remitting multiple sclerosis, may cause transitory effects on heart rate and atrioventricular conduction that may result in bradycardia and atrioventricular blocks, mainly following first administration; an ECG monitoring for at least 6 hours is therefore recommended, to be extended in case of bradycardia. The BEAT study showed that the dominance of cardiac vagal modulation, though not representing a risk factor for rhythm complications, can help identifying patients with higher probability to require extended monitoring. Methods: This is a post-hoc analysis of the BEAT study, aimed at assessing the association between gender and need of extension of the ECG and gender differences in patients’ satisfaction with drug administration and monitoring experience. Results: Of the 625 patients evaluated in the BEAT study (67% were women), only 45 (7.2%; 95% CI: 5.3%; 9.5%) required an extended monitoring. Gender differences emerged in the assumption of drugs altering heart rate or atrioventricular conduction (6.4% of females vs. 0.5% of males, Chi-square test p-value=0.001) and in the sympathovagal balance status (median (interquartile range) RR LF/HF in women: 3.3 (1.3-7.4) respectively vs. 4.5 (2.1-10.2) in men, Wilcoxon test p-value=0.001). However, keeping constant the effect of these variables, no association emerged between sex and early ECG abnormalities requiring a prolongation of post-first dose monitoring. Our specifically developed satisfaction score showed a higher level of satisfaction with the overall care experience in women than in men (beta female vs. male=1.69 points) and women perceived a greater favorable impact of the drug on their daily living than man (median of ‘impact of treatment’ item in males and females 7.0 and 2.0, respectively, Wilcoxon test p-value=0.005). Conclusion: No association emerged between sex and early ECG response to fingolimod administration requiring extended cardiac monitoring. More women than men reported a higher level of satisfaction with drug administration and monitoring procedures.

P1453Safe multidisciplinary management of new therapies: the ritmo project (real time continuous web monitoring)

Abstract Background Fingolimod is an immunosuppressive drug that prevents the typical autoimmune responses of multiple sclerosis (MS). This drug can cause, even after the first dose, bradycardia and atrioventricular conduction block (AVB). According to a decree of the Committee for Medicinal Products for Human Use (CHMP), the first administration of a dose of fingolimod must meet the following conditions: a) 12-lead electrocardiogram (ECG) and blood pressure (BP) evaluations before first dose administration; b) continuous ECG and BP monitoring every hour during the first 6 hours of treatment. The aim of the study was to evaluate the efficacy of our virtual Intensive Care Unit connected to selected Departments of Neurology for cardiology monitoring via web, during the first dose administration of fingolimod in patients with MS. Methods Health Telematic Network, in collaboration with our Cardiology Department, has installed in several Neurology Departments in the country intensive care equipment with real time monitoring via the web of ECG, BP and oximetry. The telemonitoring system is composed of an IntelliVue MP2 monitor, for 12-lead ECG recording, and by an IntelliVue Philips M3150 Central, for continuous remote monitoring of ECG and the detection and storage of arrhythmias. The HTN Cardiologist thus can evaluate in real time ECG monitored and each alarm detected. Results From Jan 2014 to Dec 2018, 172 sites participated and 6041 patients were enrolled. The telemonitoring system recognized 5116 episodes of bradycardia, 297 first degree AVB, 213 second degree AVB Mobitz I, 48 second degree AVB Mobitz II, 618 pathological lengthening of the QTc interval, single monomorphic ventricular ectopic beats in 266 patients, bigeminy ventricular extrasystoles in 15 patients and polymorphic ventricular extrasystoles in 3 cases. 6 cases of nonsustained ventricular tachycardia occurred and were recognized. Conclusion This web-based real time telemonitoring project was an optimal solution for the administration of the first dose of fingolimod, according to current indications of the CHMP. The RITMO project could lead the way for the use of a multidisciplinary approach for the management of new therapies.

Cardiovascular autonomic individual profile of relapsing-remitting multiple sclerosis patients and risk of extending cardiac monitoring after first dose fingolimod

Fingolimod exerts its therapeutic effect in multiple sclerosis by modulating sphingosine-1P receptors which are expressed in the heart mediating fingolimod first dose effects. Understanding potential interactions of baseline characteristics and autonomic profile with fingolimod first dose effects may add novel safety information and help explain cases requiring extension of the 6-hour ECG monitoring period. We aimed at characterizing the patient population treated with the first dose of fingolimod in clinical practice in an observational, multicenter, prospective 6-hours (up to 24) study. ECG was recorded for 15 min before first fingolimod administration and for 6 h after. Heart rate (HR) and HR variability in the frequency domain were derived from ECG traces. Out of the 625 enrolled patients, 580 (92.8%) were discharged at the sixth hour after fingolimod first dose; 45 (7.2%) required monitoring extension. Data confirm the well characterized cardiovascular fingolimod profile upon treatment initiation. Ten (1.6%) patients showed an atrioventricular block, all asymptomatic and self-resolving. Normalized spectral power in the High Frequency band (marking vagal modulation) and previous annualized relapse rate were independently correlated with the probability of undergoing extended monitoring. Our results could provide useful information for the stratification and individualized monitoring of MS patients prescribed with fingolimod.

Acute Fingolimod Effects on Baroreflex and Cardiovascular Autonomic Control in Multiple Sclerosis.

Background:Fingolimod, an oral drug used in multiple sclerosis (MS) treatment, exerts its action through S1P-receptor engagement. These receptors are also expressed in heart and endothelial cells. The engagement of receptors on the atrial heart myocytes may cause a slowing effect on heart rate (HR). We aimed to explore the acute effect of fingolimod on the cardiac autonomic control, a side-effect of the drug that still needs to be clarified.Methods:In 10 MS patients, we investigated the influence of the first administration of fingolimod (0.5 mg) on sympathetic and parasympathetic indexes via the analysis of the HR variability, and on the baroreflex sensitivity via sequence and alpha coefficient techniques.Results:Fingolimod produced an average HR maximal drop of 12.7 (7.8) beats/min and the minimal HR occurred after 2.73 (0.38) hours from the dose administration. The pulse interval (PI) mean value and the pNN50 and RMSSD indexes of parasympathetic drive to the heart significantly increased. Interestingly, in 6 out of 10 patients also the power in the low-frequency band (LF) increased. The baroreflex sensitivity was not modified by the first dose of the drug.Conclusions:Our findings indicate that although the first dose of fingolimod invariably activates the parasympathetic system, in several subjects, it may induce also a surge in the sympathetic cardiac drive. This suggests that not only the vagal, as usually assumed, but also the sympathetic autonomic branch should be considered in the risk profile assessment of MS patients starting treatment with fingolimod.

On the road to new treatments for multiple sclerosis: targeting dendritic cell migration into the central nervous system.

On the road to new treatments for multiple sclerosis: targeting dendritic cell migration into the central nervous system.

Are there any clinical and electrocardiographic predictors of heart rate reduction in relapsing- remitting multiple sclerosis patients treated with fingolimod?

BackgroundFingolimod, a sphingosine-1-phosphate receptor agonist, is used for treatment of relapsing-remitting multiple sclerosis (RRMS). S1P receptors that fingolimod acts upon have also been shown to be expressed on atrial myocytes. This expression pattern has been linked with the drug's cardiovascular effects, such as bradycardia. We aimed to evaluate the clinical and electrocardiographic predictors of heart rate (HR) reduction in patients receiving first-dose fingolimod. MethodsWe retrospectively analyzed subjects diagnosed with RRMS who were allocated to fingolimod treatment. HR, systolic and diastolic blood pressure values and electrocardiography during the first dose of fingolimod were accessed. ResultsA total of 114 RRMS patients (65.8% female, 33.58 ± 8.63 years) were included. After the initial dose of fingolimod, the heart rate decreased significantly at each hour (each p < 0.001). Nadir heart rate was reached at 4 h. The multivariate binary logistic regression analysis revealed that BMI (OR: 0.878, p = 0.045), optic nerve involvement (OR: 3.205, p = 0.018), baseline HR (OR: 1.079, p = 0.002) and T-peak-T-end interval (OR: 1.046, p = 0.030) were independent predictors of greater HR reduction. During 6-h monitorization, none of the patients had relevant adverse reactions. ConclusionOur findings provide an insight on clinical and electrocardiographic predictors of HR reduction that occurs in RRMS patients receiving first dose of fingolimod.

The First Dose of Fingolimod Affects Circulating Extracellular Vesicles in Multiple Sclerosis Patients.

Extracellular vesicles (EVs) are membrane-bound particles involved in intercellular communication. They carry proteins, lipids, and nucleotides such as microRNAs (miRNAs) from the secreting cell that can modulate target cells. We and others have previously described the presence of EVs in peripheral blood of multiple sclerosis (MS) patients and postulated them as novel biomarkers. However, their immune function in MS pathogenesis and the effect during the onset of new immunomodulatory therapies on EVs remain elusive. Here, we isolated plasma EVs from fingolimod-treated MS patients in order to assess whether EVs are affected by the first dose of the treatment. We quantified EVs, analyzed their miRNA cargo, and checked their immune regulatory function. Results showed an elevated EV concentration with a dramatic change in their miRNA cargo 5 h after the first dose of fingolimod. Besides, EVs obtained prior to fingolimod treatment showed an increased immune regulatory activity compared to EVs obtained 5 h post-treatment. This work suggests that EVs are implicated in the mechanism of action of immunomodulatory treatments from the initial hours and opens a new avenue to explore a potential use of EVs for early treatment monitoring.

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial

Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Novartis Pharma.

Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in Healthy Subjects.

This open‐label, single‐sequence study in healthy subjects investigated the effects of steady‐state carbamazepine on the pharmacokinetic (PK) profile of a single 2‐mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up‐titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady‐state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod Cmax was reduced by 18% and AUCinf by 40%, as was T1/2 (106 vs 163 hours). A similar trend was observed for fingolimod‐P. Models linking fingolimod‐P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution.

Effectiveness of alternative dose fingolimod for multiple sclerosis.

Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

Modulation of Cardiac Autonomic Function by Fingolimod Initiation and Predictors for Fingolimod Induced Bradycardia in Patients with Multiple Sclerosis.

Objective: It is well-known that initiation of fingolimod induces a transient decrease of heart rate. However, the underlying cardiac autonomic regulation is poorly understood. We aimed to investigate the changes of autonomic activity caused by the first dose of fingolimod using a long-term multiple trigonometric spectral analysis for the first time. In addition, we sought to use the continuous Holter ECG recording to find predictors for fingolimod induced bradycardia.Methods: Seventy-eight patients with relapsing-remitting multiple sclerosis (RRMS) were included. As a part of the START study (NCT01585298), continuous electrocardiogram was recorded before fingolimod initiation, and until no <6 h post medication. Time domain and frequency domain heart rate variability (HRV) parameters were computed hourly to assess cardiac autonomic regulation. A long-term multiple trigonometric regressive spectral (MTRS) analysis was applied on successive 1-h-length electrocardiogram recordings. Decision tree analysis was used to find predictors for bradycardia following fingolimod initiation.Results: Most of the HRV parameters representing parasympathetic activities began to increase since the second hour after fingolimod administration. These changes of autonomic regulations were in accordance with the decline of heart rate. Baseline heart rate was highly correlated with nadir heart rate, and was the only significant predicting factor for fingolimod induced bradycardia among various demographic, clinical and cardiovascular variables in the decision tree analysis.Conclusions: The first dose application of fingolimod enhances the cardiac parasympathetic activity during the first 6 h post medication, which might be the underlying autonomic mechanism of reduced heart rate. Baseline heart rate is a powerful predictor for bradycardia caused by fingolimod.