Cardiac Safety of Ozanimod, a Novel Sphingosine‐1‐Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study

Tran, Jonathan Q.; Hartung, Jeffrey; Olson, Allan; Mendzelevski, Boaz; Timony, Gregg; Boehm, Marcus F.; Peach, Robert; Gujrathi, Sheila; Frohna, Paul

doi:10.1002/cpdd.383

Cited by 48 publications

(35 citation statements)

References 30 publications

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“…A third S1P receptor modulator, ozanimod, binds selectively with high affinity to receptor subtypes 1 and 5 and is undergoing regulatory assessment for the treatment of MS. A Phase 1 cardiac safety study in 145 healthy adults showed that although ozanimod blunted the observed diurnal increase in HR, excursions below pre-dose HR were no greater than with placebo. Ozanimod did not prolong the QTc interval or cause clinically significant bradycardia, suggesting a favourable cardiac safety profile [72]. In the Phase 2 RADIANCE study (n = 258), the maximum reduction in mean HR by Holter monitoring during the first 6 h in ozanimod-treated participants was <2 bpm compared with baseline, with no patient having a minimum hourly HR < 45 bpm.…”

Section: Ozanimodmentioning

confidence: 94%

Cardiac Autonomic Dysfunction in Multiple Sclerosis: A Systematic Review of Current Knowledge and Impact of Immunotherapies

Findling

Hauer

Pezawas

et al. 2020

JCM

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Cardiac autonomic dysfunction (CAD) has been reported in patients with multiple sclerosis (MS). This systematic review summarizes the evidence for the types and prevalence of CAD in MS patients, as well as its association with MS type, disease characteristics, fatigue and immunotherapies used to treat MS. The analysis revealed that CAD is correlated with pathophysiological processes of MS, can trigger serious cardiovascular complications that may reduce life expectancy, and may have implications for treatment with immunotherapies, especially fingolimod. Numerous mainly small case-control or cohort studies have reported various measures of CAD (particularly heart rate variation) in MS patients, showing higher rates of abnormality versus controls. A smaller number of studies have reported on cardiac autonomic symptoms in MS, including orthostatic intolerance/dizziness in around 50% of patients. CAD also appears to be associated with disease duration and to be more common in progressive than relapsing-remitting MS. However, although a substantial evidence base suggests that assessing CAD in people with MS may be important, standardised methods to evaluate CAD in these patients have not yet been established. In addition, no studies have yet looked at whether treating CAD can reduce the burden of MS symptoms, disease activity or the rate of progression.

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Section: Ozanimodmentioning

confidence: 94%

Cardiac Autonomic Dysfunction in Multiple Sclerosis: A Systematic Review of Current Knowledge and Impact of Immunotherapies

Findling

Hauer

Pezawas

et al. 2020

JCM

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“…All Holter data were transmitted to the ECG core laboratory (Bioclinica Inc, Princeton, NJ, USA) over the internet through a secure transfer program. The 12-lead ECGs were extracted automatically in triplicates at the following nominal time points on days -1, 1, 5, 8, and 28 just before pharmacokinetic (PK) sample collections (except on day -1 with no PK samples): prior to dosing (0 hour) and at 1,2,4,6,8,10,12,14,16, and 24 hours after dosing. The subject was rested in the supine position for the first 5 minutes before extractions and then 10 minutes during extractions.…”

Section: Ecg and Pk Collectionsmentioning

confidence: 99%

“…The proarrhythmic risk of ozanimod was previously evaluated in a thorough QT (TQT) study. 8 Following a 14-day titration regimen of QD oral doses of ozanimod 0.23 mg for 4 days, 0.46 mg for 3 days, 0.92 mg for 3 days, and 1.84 mg for 4 days in healthy subjects, no evidence of clinically significant QTc prolongation was observed, as demonstrated by the upper boundary of the 90% confidence interval (CI; two-sided) for the time-matched, placebo-corrected, baselineadjusted mean QTc (ΔΔQTc) being below the 10 msec threshold for both ozanimod 0.92 and 1.84 mg. The TQT study was conducted early during the clinical development and before the human mass balance study, which identified the active metabolites CC112273 and CC1084037.…”

Section: Introductionmentioning

confidence: 99%

Concentration‐QTc Modeling of Ozanimod’s Major Active Metabolites in Adult Healthy Subjects

Briggs¹,

Chapel²,

Zhang

et al. 2021

CPT Pharmacom & Syst Pharma

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Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability. Common linear, power, and maximum effect (E max) functions were assessed for characterizing the relationship of QTc with concentrations. Model goodness-of-fit and performance were evaluated by standard diagnostic tools, including a visual predictive check. The placebo-corrected change from baseline in QTc (ΔΔQTc) was estimated based on the developed C-QTc model using a nonparametric bootstrapping approach. QTc was better derived using a study-specific population formula (QTcP). Among the investigated functions, an E max function most adequately described the relationship of QTcP with concentrations. Separate models for individual analytes characterized the C-QTcP relationship better than combined analytes models. Attributing QT prolongation independently to CC1084037 or CC112273, the upper bound of the 95% confidence interval of the predicted ΔΔQTcP was ~ 4 msec at the plateau of the E max curves. Therefore, ΔΔQTcP is predicted to remain below 10 msec at the supratherapeutic concentrations of the major active metabolites.

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“…Reviews published in 2005 by Strnadova and 2011 by Satin and colleagues capture respective “snapshots in time” in this field. References to examples of individual TQT studies and related considerations are provided …”

Section: Technical Challenges In Conducting a Tqt Studymentioning

confidence: 99%

“…References to examples of individual TQT studies and related considerations are provided. [35][36][37][38][39][40][41][42]…”

Section: Technical Challenges In Conducting a Tqt Studymentioning

confidence: 99%

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Turner

Rodríguez

Mantovani

et al. 2018

The Journal of Clinical Pharma

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Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.

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Cardiac Safety of Ozanimod, a Novel Sphingosine‐1‐Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study

Cited by 48 publications

References 30 publications

Cardiac Autonomic Dysfunction in Multiple Sclerosis: A Systematic Review of Current Knowledge and Impact of Immunotherapies

Cardiac Autonomic Dysfunction in Multiple Sclerosis: A Systematic Review of Current Knowledge and Impact of Immunotherapies

Concentration‐QTc Modeling of Ozanimod’s Major Active Metabolites in Adult Healthy Subjects

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

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