ponesimod and Multiple-Sclerosis--Relapsing-Remitting

To describe the safety, efficacy, and potential role in therapy of ponesimod, which was recently approved by the Food and Drug Administration (FDA) as a therapeutic option for the treatment of multiple sclerosis (MS).. A PubMed literature search using the following terms: ponesimod and MS (January 1, 2012-October 31, 2022). FDA product labeling was also reviewed for pertinent data sources.. All relevant English-language articles examining efficacy and/or safety of ponesimod were considered for inclusion.. Ponesimod is an orally administered second-generation sphingosine 1-phospate (S1-P) receptor modulator classified as a disease modifying treatment (DMT) for MS. Clinical studies have shown that ponesimod prevents relapse in patients with relapsing-remitting MS (RRMS) and has superior efficacy compared with teriflunomide. Nasopharyngitis, upper respiratory tract infections, headache, high blood pressure, and liver dysfunction were some of the common adverse effects associated with ponesimod. Dyspnea, bradyarrhythmias, atrioventricular conduction delays, and macular edema were some of the rare but serious adverse effects associated with ponesimod.. Some advantages of ponesimod over other S1-P receptor modulators approved for RRMS include selectivity for the S1-P. Currently available data suggest that ponesimod is a useful addition to other high-efficacy DMTs available to treat patients with MS.

Topics: Humans; Immunologic Factors; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sphingosine; Sphingosine-1-Phosphate Receptors; Thiazoles

Ponesimod, a selective, rapidly reversible, and orally active, sphingosine-1 phosphate receptor (S1P) modulator, is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS). The clinical pharmacokinetics (PK) and pharmacodynamics (PD) of ponesimod was studied in 16 phase I, one phase II, and one phase III clinical studies. Ponesimod population PK was characterized by an open two-compartment disposition model with a terminal half-life of 33 h (accumulation factor of 2- to 2.6-fold), and fast and almost complete oral absorption (absolute oral bioavailability: 84%), reaching peak plasma and blood concentrations within 2-4 h. Ponesimod is highly metabolized, and the parent compound along with its two major (non-clinically active) metabolites are mainly excreted in the feces (recovery: 57.3-79.6%) and to a lesser extent in the urine (recovery: 10.3-18.4%). Additionally, the population PKPD model characterized the ponesimod effects on heart rate: a transient, dose-dependent decrease in heart rate in the first days of dosing, that is mitigated by administering the first doses of ponesimod treatment using a gradual up-titration schedule, before reaching the daily maintenance dose of 20 mg. This selected maintenance dose has been shown to be superior in reducing annualized relapse rate (ARR) when compared with teriflunomide in a pivotal phase III study. Furthermore, a dose-dependent reduction of peripheral lymphocyte counts that is sustained with continued daily oral dosing of ponesimod and is rapidly (4-7 days) reversible upon drug discontinuation has been characterized with an indirect response model.

Topics: Humans; Immunologic Factors; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Thiazoles

Ponesimod (PONVORY™) is an orally administered selective sphingosine-1-phosphate (S1P) receptor 1 (S1P

Topics: Animals; Clinical Trials, Phase III as Topic; Humans; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic; Sphingosine-1-Phosphate Receptors; Thiazoles

Multiple Sclerosis (MS) is an immune-mediated, complex, chronic inflammatory, and neurodegenerative disease of the central nervous system. Among the several therapeutic options developed over the last decade for relapsing MS (RMS), fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, was the first oral treatment. The adverse events associated with fingolimod have limited its use in certain populations, thus further stimulating the search for other S1PR modulators.. The authors reviewed the English-published literature on ponesimod using the PubMed database. The search terms used were 'ponesimod' or 'ACT-128,800' and 'multiple sclerosis.' Available data on the pharmacological profile of ponesimod and the information on clinical efficacy and safety drawn from clinical trials in comparison with other S1PR modulators are presented and discussed.. Published peer-reviewed data on long-term safety and efficacy are still lacking but have been collected and regulatory authorities expressed a favorable opinion to market access. At present, we believe that ponesimod has little chance of becoming a leading treatment for RMS due to the availability of many alternative options and the timing of market access. Given its favorable risk-benefit and convenience profile, however, ponesimod might become a leading option among S1P receptor modulators used for RMS.

Topics: Administration, Oral; Clinical Trials as Topic; Humans; Multiple Sclerosis, Relapsing-Remitting; Recurrence; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Thiazoles; Treatment Outcome

Diroximel fumarate (DRF), ponesimod (PON), and teriflunomide (TERI) are oral disease-modifying therapies approved for the treatment of relapsing multiple sclerosis. No randomized trials have compared DRF versus PON or TERI.. The objectives of this analysis were to compare DRF versus PON and DRF versus TERI for clinical and radiological outcomes.. We used individual patient data from EVOLVE-MS-1, a 2-year, open-label, single-arm, phase III trial of DRF (n = 1057), and aggregated data from OPTIMUM, a 2-year, double-blind, phase III trial comparing PON (n = 567) and TERI (n = 566). To account for cross-trial differences, EVOLVE-MS-1 data were weighted to match OPTIMUM's average baseline characteristics using an unanchored matching-adjusted indirect comparison. We examined the outcomes of annualized relapse rate (ARR), 12-week confirmed disability progression (CDP), 24-week CDP, absence of gadolinium-enhancing (Gd+) T1 lesions, and absence of new/newly enlarging T2 lesions.. After weighting, we did not observe strong evidence of differences between DRF and PON for ARR [DRF versus PON incidence rate difference (IRD) -0.02; 95% confidence interval (CI) -0.08, 0.04; incidence rate ratio (IRR) 0.92; 95% CI 0.61, 1.2], 12-week CDP [risk difference (RD) -2.5%; 95% CI -6.3, 1.2; risk ratio (RR) 0.76; 95% CI 0.38, 1.1], 24-week CDP (RD -2.7%; 95% CI -6.0, 0.63; RR 0.68; 95% CI 0.28, 1.0), and absence of new/newly enlarging T2 lesions (RD -2.5%; 95% CI -13, 7.4; RR 0.94; 95% CI 0.70, 1.2). However, a higher proportion of DRF-treated patients were free of Gd+ T1 lesions than PON-treated patients (RD 11%; 95% CI 6.0, 16; RR 1.1; 95% CI 1.06, 1.2). Compared with TERI, DRF showed improved ARR (IRD -0.08; 95% CI -0.15, -0.01; IRR 0.74; 95% CI 0.50, 0.94), 12-week CDP (RD -4.2%; 95% CI -7.9, -0.48; RR 0.67; 95% CI 0.38, 0.90), 24-week CDP (RD -4.3%; 95% CI -7.7, -1.1; RR 0.57; 95% CI 0.26, 0.81), and absence of Gd+ T1 lesions (RD 25%; 95% CI 19, 30; RR 1.4; 95% CI 1.3, 1.5). However, DRF and TERI did not appear to differ significantly with respect to absence of new/newly enlarging T2 lesions when based on comparisons using the overall EVOLVE-MS-1 sample (RD 8.5%; 95% CI -0.93, 18; RR 1.3; 95% CI 0.94, 1.6), or in a sensitivity analysis restricted to newly enrolled EVOLVE-MS-1 patients (RD 2.7%; 95% CI -9.1, 14; RR 1.1; 95% CI 0.68, 1.5).. We did not observe differences between DRF and PON for ARR, CDP, and absence of new/newly enlarging T2 lesions, but there was a higher proportion of patients free of Gd+ T1 lesions among DRF-treated patients than PON-treated patients. DRF had improved efficacy versus TERI for all clinical and radiological outcomes, except for absence of new/newly enlarging T2 lesions.. EVOLVE-MS-1 (ClinicalTrials.gov identifier: NCT02634307); OPTIMUM (ClinicalTrials.gov identifier: NCT02425644).

Topics: Dimethyl Fumarate; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence

To evaluate the dose-response relationship of 10, 20, and 40 mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in patients with relapsing-remitting multiple sclerosis (RRMS).. In the Core study, 464 patients were randomized (1:1:1:1): placebo (n = 121), 10 mg (n = 108), 20 mg (n = 116), or 40 mg ponesimod (n = 119) once daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks) and TP2 and TP3 (up to 432 weeks). The 40 mg dose was discontinued due to low tolerability at the end of TP1, and the 10 mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated.. A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg = 139, 20 mg = 145, and 40 mg = 151) at any time during the Core and/or the Extension study. As of March 31, 2019, 214 patients were still on ponesimod treatment. The median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod 20 mg, from Core up to the end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9%, and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%), and upper respiratory tract infection (21%).. The effects on multiple sclerosis disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified.. This study provides Class IV evidence that in individuals with RRMS, long-term treatment with ponesimod 20 mg was associated with a sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free.. EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study).

Topics: Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence; Thiazoles; Treatment Outcome

The efficacy of ponesimod and teriflunomide for the treatment of relapsing multiple sclerosis (MS) was compared in a randomized phase III trial. This study explores the exposure-response (E-R) relationships of efficacy end points (annualized relapse rate [ARR] and combined unique active lesions [CUALs]) of ponesimod observed in this trial. The E-R relationships were described using nonlinear mixed effects models for count data. The effect of baseline covariates (demography and prognostic factors) was also explored. Ponesimod 20 mg reduced ARR (primary end point) by 30.5% (95% confidence interval [CI]: 9.8% to 46.4%) and the number of CUALs by 56% (95% CI: 46% to 64%) between baseline and week 108 compared to teriflunomide 14 mg. The E-R analyses indicated a significant relationship between ARR and CUAL. In turn, CUAL was significantly related to ponesimod systemic exposure. Based on these relationships, the predicted reduction of ARR was relatively flat in the range of ponesimod systemic exposure achieved with the 20 mg clinical dose: the expected ARR decrease ranged from 28% (95% CI: 11% to 42%) at the 5th percentile of ponesimod exposure to 34% (95% CI: 19% to 47%) at the 95th percentile. No significant baseline covariates affected the ponesimod effects and, consequently, dosage adjustments are not warranted by these analyses. Although significant relationships were found between ARR and CUAL and between ponesimod exposure and CUAL, these analyses were supportive of the use of a flat 20 mg maintenance dose for ponesimod in adult patients with MS.

Topics: Adult; Crotonates; Humans; Hydroxybutyrates; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Recurrence; Thiazoles; Toluidines; Treatment Outcome

To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS).. To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with RMS.. This multicenter, double-blind, active-comparator, superiority randomized clinical trial enrolled patients from April 27, 2015, to May 16, 2019, who were aged 18 to 55 years and had been diagnosed with multiple sclerosis per 2010 McDonald criteria, with a relapsing course from the onset, Expanded Disability Status Scale (EDSS) scores of 0 to 5.5, and recent clinical or magnetic resonance imaging disease activity.. Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days.. The primary end point was the annualized relapse rate. The secondary end points were the changes in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, the number of combined unique active lesions per year on magnetic resonance imaging, and time to 12-week and 24-week confirmed disability accumulation. Safety and tolerability were assessed. Exploratory end points included the percentage change in brain volume and no evidence of disease activity (NEDA-3 and NEDA-4) status.. For 1133 patients (567 receiving ponesimod and 566 receiving teriflunomide; median [range], 37.0 [18-55] years; 735 women [64.9%]), the relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001); the mean difference in FSIQ-RMS, -3.57 (-0.01 vs 3.56; P < .001); the relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P < .001); and the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively. Brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001); the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).. In this study, ponesimod was superior to teriflunomide on annualized relapse rate reduction, fatigue, magnetic resonance imaging activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was in line with the previous safety observations with ponesimod and the known profile of other S1P receptor modulators.. ClinicalTrials.gov Identifier: NCT02425644.

Topics: Adolescent; Adult; Crotonates; Disease Progression; Female; Humans; Hydroxybutyrates; Immunologic Factors; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Neoplasm Recurrence, Local; Nitriles; Thiazoles; Toluidines; Young Adult

Ponesimod is a sphingosphine-1-phosphate receptor modulator being developed for the treatment of multiple sclerosis. The effects of disease-modifying treatments on magnetic resonance imaging (MRI) lesions in relapsing multiple sclerosis accurately predict effects on clinical relapses, therefore MRI lesion counts are generally accepted efficacy endpoints in phase II clinical studies of multiple sclerosis disease-modifying treatments. Here, we characterize the effect of ponesimod systemic exposure on the cumulative number of T1 gadolinium-enhancing (Gd+) lesions and the annualized relapse rate in a phase IIb study.. This study assessed the cumulative number of new Gd+ lesions on T1-weighted MRI scans (primary endpoint) at weeks 12, 16, 20, and 24 and the annualized relapse rate (secondary endpoint). The effect of the demographic and prognostic covariates of sex, age, weight, T1 Gd+ lesions at baseline, and Expanded Disability Status Scale score at baseline were explored. Analyses were performed using NONMEM, Version 7.3.0 (ICON plc).. An increase in ponesimod exposure led to a statistically significant decrease in the cumulative T1 Gd+ lesions on MRI from week 12 to 24 of treatment. Increasing the ponesimod daily dose beyond 20 mg did not provide significant additional  benefits. Sex, age, T1 Gd+ lesions at baseline, and Expanded Disability Status Scale score at baseline were associated with a higher number of new cumulative T1 Gd+ from week 12 to 24 of treatment.. This analysis shows a relationship between ponesimod exposure and the cumulative number of new T1 Gd+ lesions. Sex, age, T1 Gd+ lesions at baseline, and Expanded Disability Status Score at baseline were not found to be importantly associated with the magnitude of ponesimod effect, and consequently, there is no indication from these analyses that dosage adjustments based on the explored covariates are warranted.. ClinicalTrials.gov Identifier: NCT01006265, registration date 1 November, 2009.

Topics: Humans; Infant; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Thiazoles; Treatment Outcome

This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS).. 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated.. The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥ 1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema.. Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RRMS is under consideration.. NCT01006265.

Topics: Administration, Oral; Adolescent; Adult; Double-Blind Method; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Receptors, Lysosphingolipid; Severity of Illness Index; Thiazoles; Young Adult

Ozanimod and ponesimod are sphingosine 1-phosphate receptor modulators approved by the U.S. Food and Drug Administration for treatment of relapsing forms of multiple sclerosis (MS). Given that no head-to-head trials have assessed these two treatments, we performed a matching-adjusted indirect comparison (MAIC) to compare efficacy and safety outcomes between ozanimod and ponesimod for MS.. A MAIC compared efficacy and safety of ozanimod and ponesimod at 2 years. Outcomes included annualized relapse rate (ARR) and percentage change from baseline in brain volume loss (BVL) as well as rates of any treatment-emergent adverse events (TEAEs), serious adverse events (AEs), AEs leading to discontinuation, and other safety outcomes. Individual patient-level data were obtained for ozanimod from the RADIANCE-B trial, while aggregate-level patient data were obtained for ponesimod from the OPTIMUM trial. The MAIC was not anchored owing to lack of a common comparator across the two trials. The following characteristics were matched between the trials' populations: age, sex, time since MS symptom onset, relapses in prior year, Expanded Disability Status Scale score, disease-modifying therapies received in the prior 2 years, absence of gadolinium-enhancing T1 lesions, and percentage of patients from Eastern Europe.. After matching, key baseline characteristics were balanced between patients receiving ozanimod and ponesimod. Compared with ponesimod, ozanimod had a numerically lower ARR (rate ratio: 0.80 [95% CI: 0.57, 1.10]) and was associated with a significant reduction in BVL (% change difference: 0.20 [95% CI: 0.05, 0.36]). Additionally, ozanimod was associated with a significantly lower risk of TEAEs (risk difference: -11.9% [95% CI: -16.8%, -7.0%]), AEs leading to discontinuation (-6.1% [95% CI: -8.9%, -3.4%]), and lymphocyte count <0.2 K/μL (-2.3% [95% CI: -4.2%, -0.5%]). There were no statistically significant differences in the other safety outcomes.. The MAIC results suggest that, compared with ponesimod, ozanimod is more effective in preserving brain volume, is comparable in terms of reducing relapse rates, and has a favorable safety profile.

Topics: Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence

Topics: Administration, Oral; Crotonates; Dose-Response Relationship, Drug; Double-Blind Method; Drug Approval; Humans; Hydroxybutyrates; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Randomized Controlled Trials as Topic; Sphingosine 1 Phosphate Receptor Modulators; Thiazoles; Toluidines; United States; United States Food and Drug Administration

Topics: Female; Humans; Male; Multiple Sclerosis, Relapsing-Remitting; Receptors, Lysosphingolipid; Thiazoles