A Comprehensive Pharmacological and Clinical Monograph on Ponesimod

I. Executive Summary

Ponesimod, marketed under the brand name Ponvory, is an orally administered, small molecule drug classified as a selective sphingosine 1-phosphate (S1P) receptor modulator.[1] It is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.[1] The development of ponesimod was driven by the need for a more selective agent than the first-in-class S1P modulator, fingolimod, whose off-target activity at the S1P3 receptor was associated with certain adverse effects.[1]

The primary mechanism of action of ponesimod involves high-affinity agonism at the S1P receptor subtype 1 (S1P1) on lymphocytes. This interaction leads to the internalization and functional antagonism of the receptor, effectively sequestering lymphocytes within secondary lymphoid organs.[2] By preventing the egress of these immune cells into the peripheral circulation, ponesimod reduces the infiltration of autoaggressive lymphocytes into the central nervous system (CNS), thereby mitigating the inflammatory processes that drive MS pathology.[6] Its high selectivity for S1P1 over other S1P receptor subtypes is a key pharmacological feature intended to optimize its benefit-risk profile.[2]

The clinical efficacy of ponesimod was definitively established in the Phase III OPTIMUM trial, a head-to-head superiority study against the established oral MS therapy, teriflunomide.[10] In this trial, ponesimod demonstrated a statistically significant and clinically meaningful superiority in reducing the annualized relapse rate (ARR) by 30.5% and decreasing the number of active inflammatory brain lesions on magnetic resonance imaging (MRI) by 56%.[12] While it also showed a benefit in reducing patient-reported fatigue, it was not superior to teriflunomide in delaying confirmed disability progression.[11]

The pharmacokinetic profile of ponesimod is characterized by rapid oral absorption, a terminal half-life of approximately 33 hours, and, importantly, a rapid reversal of its effects on lymphocyte counts within one to two weeks of discontinuation.[2] This rapid reversibility provides significant clinical flexibility for managing vaccinations, infections, or family planning compared to older agents in its class.[17]

The safety profile of ponesimod is consistent with that of the S1P modulator class, with the most common adverse reactions being upper respiratory tract infections, hepatic transaminase elevations, and hypertension.[12] A critical component of its clinical use is a mandatory 14-day dose up-titration regimen, which is designed to mitigate the initial cardiac effects of the drug, specifically a transient reduction in heart rate.[20] Ponesimod is contraindicated in patients with certain pre-existing cardiovascular conditions, active malignancies, or moderate to severe hepatic impairment.[10]

Ponesimod received regulatory approval from the U.S. Food and Drug Administration (FDA) in March 2021 and the European Medicines Agency (EMA) in May 2021.[12] The commercial rights, originally held by Janssen, have since been transferred to Vanda Pharmaceuticals for the U.S. and Canada and to Juvisé Pharmaceuticals for the rest of the world, reflecting the competitive dynamics of the contemporary MS therapeutic landscape.[22]

II. Chemical Identity and Physicochemical Properties

Systematic Identification

Ponesimod is a synthetic, small molecule drug belonging to the therapeutic class of sphingosine 1-phosphate (S1P) receptor modulators and the pharmacological class of immunomodulatory agents.[1] For the purposes of scientific research, regulatory filing, and clinical practice, it is unambiguously identified by a standardized set of names, codes, and registry numbers across multiple international databases.

• Generic Name: Ponesimod [2]
• DrugBank ID: DB12016 [1]
• CAS Number: The primary Chemical Abstracts Service (CAS) Registry Number is 854107-55-4.[1] A deprecated CAS number, 1352632-69-9, is also noted in some databases.[1]
• Synonyms and Development Codes: Ponesimod is marketed under the trade name Ponvory.[12] During its development, it was referred to by the code ACT-128800 (also styled as ACT 128800 or ACT128800).[2]
• Other Key Identifiers:
• UNII (Unique Ingredient Identifier): 5G7AKV2MKP [1]
• KEGG (Kyoto Encyclopedia of Genes and Genomes) ID: D11215 [1]
• ChEMBL ID: CHEMBL1096146 [12]
• PubChem Compound ID (CID): 11363176 [12]

Structural Information

The precise chemical structure of ponesimod is defined by its systematic nomenclature and standardized chemical notations, which are essential for its synthesis, characterization, and understanding its interaction with biological targets.

• IUPAC Name: The formal International Union of Pure and Applied Chemistry (IUPAC) name for the molecule is (2Z,5Z)-5--3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one.[4] The specific designation of the (2R) stereoisomer within the dihydroxypropoxy moiety is a critical component of its official International Nonproprietary Name (INN) record and is fundamental to its biological activity.[34] This stereospecificity is a hallmark of modern, targeted drug design. The three-dimensional arrangement of atoms in a drug molecule dictates its binding affinity and selectivity for its biological target. The explicit definition of the (2R) configuration implies that this specific spatial arrangement is optimal for interacting with the S1P1 receptor. The alternative enantiomer, the (2S) isomer, would likely exhibit lower binding affinity, a different selectivity profile across the S1P receptor family, or altered metabolic properties. The development of ponesimod as a single, pure enantiomer, rather than a racemic mixture of both, was a deliberate strategy to maximize therapeutic efficacy while minimizing potential off-target effects that could arise from the other isomer. This level of chemical precision requires more complex and costly manufacturing processes, such as stereospecific synthesis or chiral separation, but is essential for creating a highly selective and predictable therapeutic agent.
• SMILES (Simplified Molecular Input Line Entry System): CCC/N=C1\S/C(=C\c2ccc(OC[C@H](O)CO)c(Cl)c2)C(=O)N1c1ccccc1C [9]
• InChI (International Chemical Identifier) Key: LPAUOXUZGSBGDU-STDDISTJSA-N [12]

Physicochemical Characteristics

The physical and chemical properties of ponesimod dictate its behavior in biological systems and inform its formulation as a pharmaceutical product.

• Molecular Formula: C23​H25​ClN2​O4​S [2]
• Molecular Weight: The average molecular weight is 460.97 g·mol⁻¹ (also cited as 460.98 or 461 Da), and the monoisotopic mass is 460.1223562 Da.[2]
• Physical Form: Ponesimod exists as a crystalline solid.[9] It is described as a white to light yellowish powder.[36]
• Solubility: It is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and ethanol but is practically insoluble in aqueous media across a physiological pH range.[9] This lipophilic nature and low aqueous solubility are key factors necessitating its formulation into an immediate-release, film-coated tablet for oral administration.

Property	Value
Generic Name	Ponesimod
Brand Name	Ponvory
DrugBank ID	DB12016
CAS Number	854107-55-4
Molecular Formula	C23​H25​ClN2​O4​S
Molecular Weight	460.97 g·mol⁻¹
IUPAC Name	(2Z,5Z)-5--3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one
Physical Form	Crystalline Solid; White to light yellowish powder
Solubility	Soluble in DMSO, Ethanol; Insoluble in water

Table 1: Chemical and Physical Properties of Ponesimod.

III. Preclinical and Clinical Pharmacology

3.1. Mechanism of Action: Selective S1P1 Receptor Modulation

Ponesimod is an orally available agonist of the sphingosine-1-phosphate receptor 1 (S1PR1, also known as S1P1), a G-protein coupled receptor that plays a fundamental role in immune cell trafficking.[4] The therapeutic mechanism of ponesimod in multiple sclerosis is predicated on its ability to modulate the S1P/S1PR signaling pathway, which governs the movement of lymphocytes from secondary lymphoid organs (e.g., lymph nodes, Peyer's patches, spleen) into the peripheral circulation and lymphatic system.[5]

Under normal physiological conditions, lymphocytes express S1P1 on their surface and respond to a concentration gradient of the endogenous ligand, sphingosine-1-phosphate (S1P), which is higher in the blood and lymph than within lymphoid tissues.[1] This gradient acts as a crucial signal, prompting lymphocytes to egress from the lymph nodes.[2] In multiple sclerosis, this process allows autoaggressive T and B lymphocytes to enter the circulation, cross the blood-brain barrier, and infiltrate the central nervous system (CNS), where they initiate an inflammatory cascade that leads to demyelination and axonal damage.[7]

Ponesimod functions as a pharmacological modulator, or more precisely, a functional antagonist, of the S1P1 receptor.[4] Upon oral administration, ponesimod binds with high affinity to S1P1 on lymphocytes. This binding initially activates the receptor, but this is quickly followed by a process of receptor internalization and subsequent degradation within the cell.[2] This downregulation of surface S1P1 receptors renders the lymphocytes insensitive, or "blind," to the endogenous S1P gradient.[2] Consequently, the lymphocytes are unable to receive the signal to exit the lymphoid organs and are effectively trapped, or sequestered, within them.[4] The primary therapeutic effect in MS is therefore believed to be the reduction of circulating lymphocytes, which limits the number of pathogenic immune cells available to migrate into the CNS and cause neuroinflammation.[8]

Receptor Selectivity Profile

A defining characteristic of ponesimod is its high selectivity for the S1P1 receptor subtype over the other four known S1P receptors (S1P2-S1P5).[12] This feature represents a deliberate and significant advancement in the S1P modulator class. The first-generation agent, fingolimod, is a non-selective modulator that binds to S1P1, S1P3, S1P4, and S1P5.[32] Agonism at the S1P3 receptor, which is expressed on cardiac and vascular cells, was suspected to contribute to some of fingolimod's adverse effects, particularly bradycardia and other cardiac events.[1] The development of ponesimod was a clear example of rational drug design, aiming to engineer a molecule that would retain the desired immunomodulatory efficacy mediated by S1P1 while minimizing the potential for off-target effects by avoiding significant activity at S1P3.

Quantitative binding and functional assays confirm the successful achievement of this goal. Ponesimod demonstrates high potency for the human S1P1 receptor, with a half-maximal inhibitory concentration (IC50​) of 6 nM and a half-maximal effective concentration (EC50​) of 5.7 nM.[24] In contrast, its affinity for other subtypes is substantially lower:

• S1P2: IC50​>10,000 nM [25]
• S1P3: IC50​=2,068 nM [25]
• S1P4: IC50​=1,956 nM [25]
• S1P5: IC50​=142 nM [25]

This profile makes ponesimod approximately 650-fold more selective for S1P1 over S1P3 than the endogenous ligand, S1P, a key differentiator that underpins its therapeutic design.[2]

Direct Central Nervous System Effects

In addition to its well-established peripheral mechanism of action, preclinical evidence suggests that ponesimod may also exert direct effects within the CNS. Animal studies have shown that ponesimod can cross the blood-brain barrier.[43] As S1P1 receptors are also expressed on CNS cells, including astrocytes, this raises the possibility of a dual mechanism of action. Studies have indicated that ponesimod can inhibit astrocyte-mediated neuroinflammation and may offer protective effects against demyelination in specific brain pathways, such as the cingulum.[2] While the primary therapeutic benefit is attributed to peripheral lymphocyte sequestration, these potential direct CNS effects represent an area of ongoing research and could contribute to its overall efficacy.

3.2. Pharmacodynamics

The pharmacodynamic effects of ponesimod are the direct physiological consequences of its mechanism of action and are central to both its efficacy and its safety profile.

Effect on Lymphocytes

The principal and intended pharmacodynamic effect of ponesimod is a rapid, dose-dependent, and reversible reduction in the number of circulating peripheral blood lymphocytes.[24] Following oral administration, maximal reduction in lymphocyte count occurs after approximately 6 hours.[16] At the maintenance dose of 20 mg daily, the absolute lymphocyte count typically decreases to 20-40% of baseline values.[16]

This immunomodulation is not uniform across all lymphocyte subpopulations. Studies in healthy subjects have demonstrated that ponesimod induces a more profound reduction in T and B cells compared to other immune cell types.[5] Specifically, the treatment leads to a dramatic decrease in CD4+ T cells, including both T-central memory (

CD45RA−CCR7+) and T-effector memory (CD45RA−CCR7−) subsets, which are key orchestrators of the autoimmune response in MS.[5] In contrast, CD8+ T-effector memory cells and Natural Killer (NK) cells, which are crucial for immune surveillance against viral pathogens, are not significantly reduced.[5] This differential effect suggests a more nuanced modulation of the adaptive immune system rather than global immunosuppression. By preferentially targeting the cell types most implicated in MS pathology while relatively sparing those critical for antiviral defense, ponesimod may achieve its therapeutic effect with a potentially more favorable infection risk profile compared to less selective immunomodulatory agents.

Cardiovascular Effects

The agonism of S1P1 receptors on cardiac pacemaker cells and atrial myocytes leads to predictable cardiovascular effects upon treatment initiation. Ponesimod causes a transient, dose-dependent decrease in heart rate (bradycardia) and may induce atrioventricular (AV) conduction delays.[2] This effect is most pronounced after the first dose. On Day 1 of treatment (at a 2 mg dose), the heart rate decrease typically begins within one hour, reaches its lowest point (nadir) within 2-4 hours, and returns to baseline levels within 4-5 hours.[21] The mean decrease in heart rate on Day 1 is approximately 6 beats per minute (bpm).[21]

A critical pharmacodynamic property is the development of tolerance or desensitization to this cardiac effect with continued dosing.[54] This phenomenon is the rationale for the mandatory 14-day gradual dose up-titration regimen. By starting with a very low dose and slowly increasing it, the cardiac S1P1 receptors adapt, and the heart rate-lowering effect is significantly attenuated. After Day 3 of the titration, no further post-dose decrease in heart rate is observed.[21] This built-in risk mitigation strategy is fundamental to the safe administration of ponesimod and allows most patients to initiate therapy without the need for intensive first-dose cardiac monitoring.[39]

IV. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of a drug describes its movement into, through, and out of the body. The ADME properties of ponesimod are well-characterized and are key to its clinical utility, defining its dosing regimen, duration of action, and management upon discontinuation.

4.1. Absorption and Distribution

• Absorption: Following oral administration, ponesimod is rapidly and almost completely absorbed from the gastrointestinal tract. It exhibits high absolute oral bioavailability of approximately 84%.[2] Peak plasma concentrations ( Tmax​) are typically reached within 2 to 4 hours after a single dose.[1] Importantly, the absorption of ponesimod is not significantly affected by food, allowing it to be taken with or without meals, which enhances patient convenience and adherence.[21]
• Distribution: Ponesimod is extensively distributed throughout the body, as indicated by its large apparent volume of distribution at steady state (Vss​), which is approximately 160 L.[2] It is highly bound to plasma proteins, with a binding fraction greater than 99%.[2] This extensive protein binding limits its removal by dialysis.[60] Furthermore, preclinical studies have demonstrated that ponesimod readily crosses the blood-brain barrier, which is relevant for its potential direct effects within the central nervous system.[43]

4.2. Metabolism and Elimination

• Metabolism: Ponesimod undergoes extensive metabolism in the body, and the parent compound is the primary active moiety. Two major, but pharmacologically inactive, metabolites, designated M12 and M13, have been identified in human plasma.[1] The metabolic pathways are complex and involve multiple enzymes. The M12 metabolite is formed through oxidation, a process mediated by several cytochrome P450 (CYP) enzymes, including CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12.[2] Other metabolic transformations include sulfation (to M5), reduction (to M6), dealkylation (to M32), and hydrolysis (to M13).[2] The involvement of multiple metabolic pathways reduces the likelihood that the inhibition of a single enzyme would lead to a clinically significant drug interaction.
• Excretion: The primary route of elimination for ponesimod and its metabolites is via the feces. Following administration of a single radiolabeled oral dose, approximately 57% to 80% of the radioactivity is recovered in the feces. A significant portion of this is comprised of the unchanged parent drug (16-26%) and the M12 metabolite (22%).[1] A smaller fraction of the dose, between 10% and 18%, is eliminated in the urine.[2]
• Half-Life and Clearance: Ponesimod has a terminal elimination half-life (t1/2​) of approximately 33 hours.[1] This half-life supports a once-daily dosing regimen and results in a modest accumulation factor of 2- to 2.6-fold at steady state.[47] The total body clearance of ponesimod is approximately 3.8 L/h.[2]

The pharmacokinetic properties of ponesimod, particularly its relatively short half-life and lack of active metabolites, confer a significant clinical advantage: rapid reversibility of its pharmacodynamic effects. This stands in stark contrast to the first-generation S1P modulator, fingolimod, whose longer half-life necessitates a washout period of up to 6 weeks for lymphocyte counts to recover.[47] Upon discontinuation of ponesimod, lymphocyte counts return to the normal range in over 90% of patients within one to two weeks.[16] This rapid restoration of normal immune function provides crucial flexibility in clinical management. For instance, a patient may need to temporarily pause treatment for a required live vaccine, to manage a serious infection, or for family planning purposes. The short washout period of approximately one week for fetal risk considerations allows women who wish to become pregnant to do so much sooner after stopping therapy compared to older agents.[6] This "agility" is a key differentiator that enhances the safety and practicality of ponesimod in real-world clinical practice.

Parameter	Value
Absolute Bioavailability	~84%
Time to Peak Concentration (Tmax​)	2–4 hours
Volume of Distribution (Vss​)	160 L
Plasma Protein Binding	>99%
Elimination Half-life (t1/2​)	~33 hours
Clearance (CL)	3.8 L/h
Primary Route of Excretion	Feces (57–80%)

Table 2: Summary of Ponesimod Pharmacokinetic Parameters.

V. Clinical Efficacy in Relapsing Forms of Multiple Sclerosis

The clinical development program for ponesimod was designed to rigorously evaluate its efficacy, safety, and optimal dose for the treatment of relapsing forms of multiple sclerosis. The program culminated in a pivotal Phase III trial that directly compared ponesimod to an established oral therapy.

5.1. Phase II Clinical Program

The foundation for the Phase III program was a 24-week, randomized, double-blind, placebo-controlled, dose-finding Phase IIb study (NCT01006265).[64] This trial enrolled 464 patients with relapsing-remitting multiple sclerosis (RRMS) who were assigned to receive once-daily oral ponesimod at doses of 10 mg, 20 mg, or 40 mg, or placebo.[16]

The primary efficacy endpoint was the cumulative number of new T1 gadolinium-enhancing (Gd+) lesions on brain MRI, a key marker of active inflammation, recorded between weeks 12 and 24.[64] The study met its primary endpoint, demonstrating a significant and dose-dependent reduction in inflammatory activity. Compared to the placebo group, all ponesimod doses significantly reduced the number of new T1 Gd+ lesions:

• 10 mg: 43% reduction (rate ratio 0.57, p=0.0318) [16]
• 20 mg: 83% reduction (rate ratio 0.17, p<0.0001) [16]
• 40 mg: 77% reduction (rate ratio 0.23, p<0.0001) [16]

The study also showed a beneficial effect on clinical endpoints. The annualized relapse rate (ARR) was lowest in the 40 mg group, which showed a 52% reduction compared to placebo (0.25 vs 0.53, p=0.0363).[64] However, the 40 mg dose was associated with lower tolerability, particularly regarding respiratory adverse events like dyspnea.[49] Based on a comprehensive assessment of the benefit-risk profile across the doses, the 20 mg daily dose was selected as the optimal dose to carry forward into the Phase III program, as it provided robust efficacy with an acceptable safety and tolerability profile.[39]

5.2. The Phase III OPTIMUM Trial (NCT02425644)

The pivotal evidence for ponesimod's approval came from the OPTIMUM (Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis) trial. This was a large-scale, multicenter, randomized, double-blind, active-controlled, superiority study involving 1,133 adult patients with relapsing forms of MS.[10] The trial was designed to directly compare the efficacy and safety of ponesimod 20 mg once daily against teriflunomide 14 mg once daily, an approved and widely used first-line oral disease-modifying therapy, over a treatment period of 108 weeks.[13]

The choice to conduct a head-to-head superiority trial against an active comparator, rather than a placebo-controlled study, was a significant strategic decision. In the mature and competitive therapeutic landscape of MS, simply demonstrating efficacy against placebo is often insufficient to establish a new drug's clinical value. By designing the OPTIMUM trial to prove that ponesimod was superior to an existing standard of care, the developers aimed to provide clear, comparative evidence to guide clinical decision-making and secure a distinct position for ponesimod in the treatment paradigm. This high-risk, high-reward approach, if successful, offers a much more compelling case for adoption by clinicians and payers.

5.2.1. Primary Endpoint: Annualized Relapse Rate (ARR)

The study successfully met its primary endpoint. Treatment with ponesimod resulted in a statistically significant and clinically meaningful reduction in ARR compared to teriflunomide. The ARR was 0.202 for the ponesimod group versus 0.290 for the teriflunomide group, representing a relative rate reduction of 30.5% (p<0.001).[10] This superiority was further reflected in the proportion of patients who remained relapse-free throughout the 108-week study: 71% in the ponesimod group compared to 61% in the teriflunomide group.[18]

5.2.2. Key Secondary Endpoints

Ponesimod also demonstrated superiority over teriflunomide on several key secondary endpoints:

• MRI Activity: Ponesimod was significantly more effective at reducing measures of inflammatory disease activity on brain MRI. It reduced the cumulative number of combined unique active lesions (CUALs) per year by 56% compared to teriflunomide (1.405 vs 3.164; p<0.0001).[10] This included a 59% reduction in new gadolinium-enhancing (GdE) T1 lesions.[19]
• Fatigue: Fatigue is one of the most common and debilitating symptoms of MS. Ponesimod showed a statistically significant benefit in reducing fatigue-related symptoms as measured by the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS). At week 108, patients treated with ponesimod had a mean score change from baseline of -0.01, compared to a worsening of +3.56 in the teriflunomide group, resulting in a mean difference of -3.57 (p=0.0019).[10]
• Disability Progression: In contrast to its effects on relapses and MRI activity, ponesimod was not superior to teriflunomide in slowing the time to 12-week or 24-week confirmed disability accumulation (CDA).[11] The rates of 12-week CDA were 10.1% for ponesimod and 12.4% for teriflunomide, a difference that was not statistically significant (p=0.29).[11] This indicates that while ponesimod is more effective at controlling inflammatory disease activity, its effect on the underlying neurodegenerative processes that drive long-term disability may be comparable to that of teriflunomide.

5.2.3. Exploratory Endpoints

In exploratory analyses, ponesimod was associated with significantly less brain volume loss (a marker of neurodegeneration) from baseline to week 108 compared to teriflunomide (-0.91% vs -1.25%; p<0.001).[11] Furthermore, a higher proportion of patients in the ponesimod group achieved "no evidence of disease activity" (NEDA-3) status (25.0% vs 16.4%; p<0.001).[11]

Endpoint	Ponesimod 20 mg	Teriflunomide 14 mg	Relative Reduction / Difference	p-value
Annualized Relapse Rate (ARR)	0.202	0.290	30.5% reduction	<0.001
CUALs per year	1.405	3.164	56% reduction	<0.0001
Change in FSIQ-RMS (Fatigue)	-0.01	+3.56	-3.57 difference	0.0019
12-Week Confirmed Disability Accumulation	10.1%	12.4%	Not significant	0.29

Table 3: Key Efficacy Outcomes from the Phase III OPTIMUM Trial (Ponesimod vs. Teriflunomide).

5.3. Investigational Uses

Beyond its approved indication in MS, ponesimod has shown therapeutic potential in other immune-mediated inflammatory diseases. A Phase II clinical program in patients with moderate-to-severe chronic plaque psoriasis demonstrated significant efficacy.[12] In these trials (NCT00852670, NCT01208090), 46-48% of patients treated with ponesimod achieved a 75% or greater reduction in the Psoriasis Area and Severity Index (PASI 75) score at 16 weeks, compared to 13% for placebo.[12] Ponesimod has also been investigated for the treatment of chronic graft-versus-host disease, further highlighting the broad potential of S1P1 receptor modulation in autoimmune and inflammatory conditions.[39]

VI. Safety and Tolerability Profile

The safety and tolerability of ponesimod have been extensively evaluated throughout its clinical development program, including in the pivotal Phase III OPTIMUM trial. The overall safety profile is well-characterized and is largely consistent with the known class effects of S1P receptor modulators.[13]

6.1. Adverse Events

In the OPTIMUM trial, the overall incidence of treatment-emergent adverse events (TEAEs) was comparable between the ponesimod group (88.8%) and the active comparator teriflunomide group (88.2%).[11] The majority of adverse events were mild to moderate in severity.[13] Treatment discontinuations due to adverse events were slightly more common in the ponesimod group (8.7%) compared to the teriflunomide group (6.0%).[11]

• Most Common Adverse Reactions: The most frequently reported adverse reactions (with an incidence of at least 10%) in patients treated with ponesimod are upper respiratory tract infections (including nasopharyngitis), hepatic transaminase elevation, and hypertension.[12]
• Other Common Adverse Reactions: Other adverse reactions reported with an incidence of 2% to <10% and at a higher rate than the comparator include urinary tract infection, bronchitis, influenza, herpes zoster, lymphopenia, depression, insomnia, anxiety, dizziness, somnolence, dyspnea (shortness of breath), cough, back pain, arthralgia, pain in extremity, peripheral edema, and macular edema.[6]
• Serious Adverse Events: While rare, serious adverse events are known risks associated with the S1P modulator class and are included as warnings for ponesimod. These include serious and opportunistic infections, bradyarrhythmia, macular edema, posterior reversible encephalopathy syndrome (PRES), and an increased risk of cutaneous malignancies (e.g., basal cell carcinoma, squamous cell carcinoma, melanoma).[3] Progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection, has been reported with other S1P modulators, and although not observed in ponesimod clinical trials, it remains a potential risk.[15]

6.2. Warnings, Precautions, and Contraindications

The prescribing information for ponesimod includes several important warnings, precautions, and contraindications to ensure its safe use.

• Infections: Due to its mechanism of action involving lymphocyte sequestration, ponesimod increases the susceptibility to infections.[3] A complete blood count (CBC) with lymphocyte count must be obtained before initiating treatment. Initiation should be delayed in patients with a severe active infection until it is resolved. Patients should be monitored for signs and symptoms of infection during treatment and for one to two weeks after discontinuation.[3]
• Bradyarrhythmia and Atrioventricular Conduction Delays: The initiation of ponesimod treatment causes a transient decrease in heart rate and may cause AV conduction delays. A baseline electrocardiogram (ECG) is required for all patients to assess for pre-existing conduction abnormalities.[3] The mandatory 14-day dose up-titration regimen is a critical risk mitigation strategy designed to allow for cardiac adaptation and minimize these effects. This built-in safety feature is a direct result of understanding the drug's pharmacodynamics. Early clinical studies identified first-dose bradycardia as a predictable, on-target effect of S1P1 agonism. Subsequent pharmacodynamic studies confirmed that this effect is subject to desensitization with continued exposure.[54] Therefore, the titration schedule was developed not merely as a dosing guideline, but as an integral part of the drug's risk management plan. By gradually "acclimatizing" the heart to the drug, the regimen allows the effective 20 mg maintenance dose to be reached safely, enabling most patients to start therapy at home without the need for intensive cardiac monitoring that was a hallmark of earlier therapies in the class.[19]
• Liver Injury: Ponesimod can cause elevations in hepatic transaminases. Liver function tests (ALT, AST, and bilirubin) must be obtained before initiation.[1] The medication should be discontinued if the patient develops jaundice or other symptoms suggestive of significant liver injury.[3]
• Fetal Risk: Based on animal studies that showed embryofetal lethality and malformations, ponesimod may cause fetal harm.[42] It is therefore contraindicated during pregnancy. Women of childbearing potential must have a negative pregnancy test before starting treatment and must use effective contraception during therapy and for one week after the final dose to allow for drug elimination.[3]
• Contraindications: Ponesimod is strictly contraindicated in patients with certain conditions due to an unacceptable risk of serious adverse events. These include:
• Patients who have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), or decompensated heart failure requiring hospitalization within the last 6 months.[7]
• Patients with a history of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless they have a functioning pacemaker.[7]
• Patients with severe active infections or active chronic infections.[7]
• Patients with active malignancies.[7]
• Patients with moderate or severe hepatic impairment (Child-Pugh class B or C).[57]

6.3. Drug-Drug Interactions

The potential for drug-drug interactions must be carefully considered when prescribing ponesimod.

• Immunosuppressive or Immune-Modulating Therapies: Concomitant use with antineoplastic agents, other S1P modulators, or non-corticosteroid immunosuppressive therapies is not recommended due to the potential for additive immunosuppressive effects, which can increase the risk of serious infections.[8]
• Heart Rate-Lowering Medications: Co-administration with drugs that decrease heart rate (e.g., beta-blockers, certain calcium channel blockers like diltiazem and verapamil) or AV conduction can have additive effects and increase the risk of bradycardia. Consultation with a cardiologist should be considered before initiating ponesimod in patients taking these medications.[2]
• CYP3A4 and UGT1A1 Inducers: Ponesimod is metabolized by multiple pathways, including CYP and UGT enzymes. Co-administration with strong inducers of both CYP3A4 and UGT1A1 (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) may significantly decrease ponesimod plasma concentrations, potentially reducing its efficacy. Therefore, concurrent use is not recommended.[10]
• Vaccines: Treatment with ponesimod may reduce the efficacy of vaccinations. Live attenuated vaccines are contraindicated during treatment and for one to two weeks after discontinuation due to the risk of inducing an infection in an immunomodulated host. It is recommended that patients complete any necessary vaccinations with live attenuated vaccines at least one month prior to initiating ponesimod therapy.[17]

VII. Dosing, Administration, and Clinical Management

The clinical use of ponesimod requires strict adherence to a specific dosing regimen and a comprehensive monitoring plan to ensure both efficacy and patient safety.

7.1. Recommended Dosing Regimen

The dosing of ponesimod is divided into two distinct phases: a mandatory initiation phase and a long-term maintenance phase.

• Treatment Initiation (Dose Titration): Treatment must be initiated using a 14-day starter pack. This regimen involves a gradual dose escalation, starting at 2 mg daily and increasing every one to two days until a dose of 10 mg daily is reached on Day 12. This titration is a critical safety measure designed to mitigate the first-dose effects on heart rate by allowing for cardiac desensitization.[7]
• Maintenance Dose: Following the completion of the 14-day titration, the recommended maintenance dosage is one 20 mg tablet taken orally once daily, beginning on Day 15.[20]
• Administration: Ponesimod tablets should be swallowed whole. They can be administered with or without food, as food does not have a clinically relevant effect on its pharmacokinetics.[21]

Titration Day	Daily Dose
Days 1–2	2 mg
Days 3–4	3 mg
Days 5–6	4 mg
Day 7	5 mg
Day 8	6 mg
Day 9	7 mg
Day 10	8 mg
Day 11	9 mg
Days 12–14	10 mg
Day 15 and thereafter	20 mg (Maintenance Dose)

Table 4: Ponesimod 14-Day Dose Titration Schedule.[16]

7.2. Patient Monitoring and Management

A thorough clinical management plan is essential for the safe and effective use of ponesimod.

• Pre-treatment Screening: Before a patient begins therapy, a comprehensive baseline assessment is required. This includes:
• Complete Blood Count (CBC): A recent CBC (within the last 6 months) with differential, including lymphocyte count, is necessary to establish a baseline.[10]
• Electrocardiogram (ECG): An ECG is mandatory to screen for pre-existing cardiac conduction abnormalities that could increase the risk of bradyarrhythmia.[10]
• Liver Function Tests (LFTs): Baseline levels of ALT, AST, and bilirubin should be obtained.[10]
• Ophthalmologic Evaluation: A baseline evaluation of the fundus, including the macula, is recommended to screen for pre-existing macular edema.[3]
• Varicella Zoster Virus (VZV) Serology: Patients should be tested for antibodies to VZV. VZV vaccination is recommended for antibody-negative patients at least one month prior to initiating ponesimod.[10]
• Skin Examination: A baseline skin examination is recommended to screen for cutaneous malignancies.[60]
• First-Dose Monitoring: While the titration regimen mitigates cardiac risks for the majority of patients, first-dose, 4-hour monitoring in a medical setting is recommended for individuals with certain pre-existing cardiac conditions. This includes patients with sinus bradycardia (heart rate <55 bpm), first- or second-degree (Mobitz type I) AV block, or a history of myocardial infarction or heart failure.[3] Monitoring should include at least hourly pulse and blood pressure measurements and an ECG at the end of the 4-hour period.[3]

7.3. Special Populations

• Hepatic Impairment: No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh class A). However, ponesimod has not been studied and is therefore not recommended (and is contraindicated in the EU) in patients with moderate or severe hepatic impairment (Child-Pugh class B and C).[52]
• Renal Impairment: Clinical pharmacology studies indicate that no dose adjustment is necessary for patients with any degree of renal impairment, from mild to severe, including those requiring hemodialysis.[21]
• Pediatric Population (age <18 years): The safety and efficacy of ponesimod have not been established in pediatric patients. Clinical trials in this population are ongoing.[12]
• Geriatric Population (age >65 years): Clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Ponesimod should be used with caution in this population due to a lack of data.[52]

7.4. Management of Treatment Interruption

The management of missed doses is critical due to the loss of cardiac tolerance. The procedure for restarting therapy depends on the duration of the interruption:

• If 1, 2, or 3 consecutive doses are missed: The patient should resume treatment by taking the first missed dose as soon as they remember. During titration, they then continue with the titration schedule as planned. During maintenance, they continue with the 20 mg dose.[16]
• If 4 or more consecutive doses are missed: The desensitization to the cardiac effects of ponesimod is lost. Treatment must be re-initiated with Day 1 of a new 14-day starter pack. Furthermore, first-dose cardiac monitoring must be performed again if the patient meets the criteria for such monitoring.[10]

VIII. Global Regulatory and Market Status

8.1. Regulatory Approvals

Ponesimod has successfully navigated the rigorous regulatory review processes in major global markets, securing approval for the treatment of relapsing forms of multiple sclerosis in adults.

• U.S. Food and Drug Administration (FDA): Ponesimod was granted approval in the United States on March 18, 2021. The approved indication is for the treatment of relapsing forms of MS, which includes clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease (aSPMS), in adults.[1]
• European Medicines Agency (EMA): Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in March 2021, the European Commission granted a centralized marketing authorization for ponesimod in May 2021 (some sources state June 2021).[7] The indication in the European Union is for the treatment of adult patients with relapsing forms of MS (RMS) with active disease defined by clinical or imaging features.[1]
• Other Jurisdictions: Ponesimod has also been approved by other major regulatory bodies, establishing its global presence. These include:
• Health Canada: Approved for the treatment of adult patients with RRMS.[12]
• Therapeutic Goods Administration (TGA) in Australia: Approved and listed as a prescription-only medicine (Schedule 4).[12]
• South Korea: Ponesimod has received approval, where it also holds an orphan drug designation for MS relapse, reflecting its role in treating a less prevalent condition in that region.[56]

8.2. Commercialization and Market Access

The commercial journey of ponesimod has been notable for its strategic shifts in ownership, reflecting the highly competitive nature of the MS therapeutic market.

• Brand Name: Ponesimod is marketed globally under the single brand name Ponvory.[2]
• Commercial Rights Holders: The commercial rights for Ponvory were originally held by Janssen Pharmaceutical Companies of Johnson & Johnson, which managed its initial global launch. However, the rights have since been strategically divested:
• United States and Canada: In December 2023, Vanda Pharmaceuticals acquired the U.S. and Canadian rights to Ponvory from Janssen's subsidiary, Actelion Pharmaceuticals Ltd..[17] The full transfer of the FDA marketing authorization was completed in May 2024, allowing Vanda to commence full commercialization and clinical development efforts in these territories.[98]
• Global (excluding U.S. and Canada): In March 2024, the French pharmaceutical company Juvisé Pharmaceuticals acquired the global commercial rights to Ponvory (excluding the U.S. and Canada) from Johnson & Johnson.[22]

This fragmentation of commercial rights for a recently launched drug by a major pharmaceutical company is a significant strategic development. It suggests a complex calculation of market dynamics and portfolio priorities. The MS therapeutic landscape is densely populated with numerous effective oral, injectable, and infused therapies, creating an intensely competitive environment.[100] For a large company like Johnson & Johnson, a new product must typically meet very high revenue projections to be considered a long-term strategic asset. It is plausible that while Ponvory demonstrated clear clinical superiority over an active comparator, its projected market share in this crowded field did not align with the "blockbuster" thresholds of a pharmaceutical giant. By divesting the asset, Johnson & Johnson could reallocate resources to other priority areas. Conversely, for smaller, more specialized companies like Vanda and Juvisé, Ponvory represents a flagship product. They can dedicate focused commercial and medical resources to maximize its value within their respective territories, tailoring their strategies to specific regional needs. This strategic shift thus tells a broader story about the high commercial bar and intense competition that characterize the modern specialty pharmaceutical market.

• Market Status and Exclusivity: Ponvory is a prescription-only medicine in all jurisdictions where it is approved.[12] There is currently no generic version of ponesimod available. In the United States, it benefits from New Chemical Entity (NCE) exclusivity until March 18, 2026. Furthermore, it is protected by multiple patents, with the latest-expiring patents extending into the 2030s and even 2040s, ensuring a long period of market exclusivity.[23] Upon its launch, the pricing of Ponvory was positioned to be comparable to other leading oral MS therapies on the market.[100]

IX. Conclusion

Ponesimod (Ponvory) represents a significant and refined therapeutic option within the class of sphingosine 1-phosphate (S1P) receptor modulators for the treatment of relapsing forms of multiple sclerosis. Its development embodies the principles of second-generation rational drug design, successfully engineering high selectivity for the S1P1 receptor to retain the established immunomodulatory efficacy of the class while aiming to mitigate the off-target effects associated with less selective agents like fingolimod.

The pivotal Phase III OPTIMUM trial provided robust, high-level evidence of its clinical value, demonstrating superiority over an active oral comparator, teriflunomide, in reducing both clinical relapses and inflammatory brain lesion activity. This head-to-head trial design was a strategic success, providing clinicians with clear comparative data that positions ponesimod as a highly effective option for controlling the inflammatory aspects of MS. The additional finding of a statistically significant benefit in reducing patient-reported fatigue addresses a critical and often debilitating symptom of the disease.

From a clinical management perspective, ponesimod's pharmacokinetic profile is a key differentiator. Its relatively short elimination half-life allows for a rapid reversal of its effects on the immune system upon discontinuation. This "agility" provides crucial flexibility for patients and physicians when navigating events such as pregnancy planning, the need for live vaccinations, or the management of serious infections, representing a substantial practical advantage over first-generation S1P modulators.

The safety profile of ponesimod is well-defined and consistent with its class, with known risks that can be effectively managed through a comprehensive protocol of pre-treatment screening and ongoing monitoring. The mandatory 14-day dose up-titration regimen stands out as a well-conceived, built-in risk mitigation strategy that successfully minimizes the primary on-target cardiac effect of first-dose bradycardia, enabling safe treatment initiation for most patients in an outpatient setting.

In conclusion, ponesimod is a potent, selective, and clinically effective oral therapy for relapsing MS. Its demonstrated superiority in controlling inflammatory disease activity, favorable pharmacokinetic profile allowing for rapid reversibility, and a manageable safety profile supported by a structured risk mitigation plan establish it as a valuable and versatile treatment choice in the comprehensive management of multiple sclerosis.

Works cited

1. Ponesimod - PubChem, accessed September 1, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Ponesimod
2. Ponesimod: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 1, 2025, https://go.drugbank.com/drugs/DB12016
3. 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PONVORY safely and eff - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213498s005s006lbl.pdf
4. Definition of ponesimod - NCI Drug Dictionary, accessed September 1, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/ponesimod
5. Effects of multiple-dose ponesimod, a selective S1P1 receptor modulato | DDDT, accessed September 1, 2025, https://www.dovepress.com/effects-of-multiple-dose-ponesimod-a-selective-s1p1-receptor-modulator-peer-reviewed-fulltext-article-DDDT
6. Ponvory (ponesimod) - MS Trust, accessed September 1, 2025, https://mstrust.org.uk/a-z/ponvory-ponesimod
7. Ponvory | European Medicines Agency (EMA), accessed September 1, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/ponvory
8. Sphingosine 1-phosphate Receptor Modulators (Comprehensive) - Cleveland Clinic, accessed September 1, 2025, https://my.clevelandclinic.org/departments/neurological/depts/multiple-sclerosis/ms-approaches/sphingosine-1-phosphate-receptor-modulators
9. Ponesimod | CAS NO.:854107-55-4 - GlpBio, accessed September 1, 2025, https://www.glpbio.com/ponesimod.html
10. Ponesimod (Ponvory) - Multiple Sclerosis Centers of Excellence - VA.gov, accessed September 1, 2025, https://www.va.gov/MS/TREATING_MS/DMTs/Ponesimod_Ponvory.asp
11. (PDF) Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial - ResearchGate, accessed September 1, 2025, https://www.researchgate.net/publication/350477337_Ponesimod_Compared_With_Teriflunomide_in_Patients_With_Relapsing_Multiple_Sclerosis_in_the_Active-Comparator_Phase_3_OPTIMUM_Study_A_Randomized_Clinical_Trial
12. Ponesimod - Wikipedia, accessed September 1, 2025, https://en.wikipedia.org/wiki/Ponesimod
13. European Commission approves PONVORYTM (ponesimod), a Once Daily, Oral Therapy for the Treatment of Adults with Relapsing Forms of Multiple Sclerosis with Active Disease Defined by Clinical or Imaging Features, accessed September 1, 2025, https://www.jnj.com/media-center/press-releases/european-commission-approves-ponvorytm-ponesimod-a-once-daily-oral-therapy-for-the-treatment-of-adults-with-relapsing-forms-of-multiple-sclerosis-with-active-disease-defined-by-clinical-or-imaging-features
14. New Head-to-Head Phase 3 Study Data Show Ponesimod Superiority Versus Aubagio® (teriflunomide) 14 mg in Adults with Relapsing Multiple Sclerosis (MS), accessed September 1, 2025, https://www.jnj.com/media-center/press-releases/new-head-to-head-phase-3-study-data-show-ponesimod-superiority-versus-aubagio-teriflunomide-14-mg-in-adults-with-relapsing-multiple-sclerosis-ms
15. 213498Orig1s000 - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213498Orig1s000SumR.pdf
16. Ponesimod | Cleveland Clinic, accessed September 1, 2025, https://my.clevelandclinic.org/departments/neurological/depts/multiple-sclerosis/ms-approaches/ponesimod
17. PONVORY® (ponesimod) | Official Patient Website, accessed September 1, 2025, https://ponvoryus.com/
18. FDA Approves Ponvory™ for the Treatment of Relapsing Forms of MS | MSAA, accessed September 1, 2025, https://mymsaa.org/news/fda-approves-ponvory-for-the-treatment-of-relapsing-forms-of-ms/
19. FDA approves Ponvory an Oral Treatment for relapsing MS - Multiple Sclerosis Foundation, accessed September 1, 2025, https://msfocus.org/About-Us/MSF-News-Articles/2310.aspx?feed=39559079-8e06-4ce5-abca-427009089971&lang=es-mx
20. Ponesimod: uses, dosing, warnings, adverse events, interactions - MedCentral, accessed September 1, 2025, https://www.medcentral.com/drugs/monograph/181158-321026/ponesimod-oral
21. Ponvory, INN-ponesimod, accessed September 1, 2025, https://ec.europa.eu/health/documents/community-register/2023/20230315158588/anx_158588_en.pdf
22. Juvisé Pharmaceuticals Acquires Multiple Sclerosis Drug PONVORY® (ex-US/Canada) and Opens Its Capital to Bpifrance and Pemberton - BioSpace, accessed September 1, 2025, https://www.biospace.com/juvise-pharmaceuticals-acquires-multiple-sclerosis-drug-ponvory-ex-us-canada-and-opens-its-capital-to-bpifrance-and-pemberton
23. Vanda Pharmaceuticals Acquires U.S. and Canadian Rights to PONVORY® (ponesimod), a Selective S1P1R Modulator Approved for Patients with Relapsing Multiple Sclerosis - PR Newswire, accessed September 1, 2025, https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-acquires-us-and-canadian-rights-to-ponvory-ponesimod-a-selective-s1p1r-modulator-approved-for-patients-with-relapsing-multiple-sclerosis-302008402.html
24. Ponesimod (ACT-128800) | S1P1 Agonist - MedchemExpress.com, accessed September 1, 2025, https://www.medchemexpress.com/Ponesimod.html
25. Ponesimod, sphingosine-1-phophate receptor agonist (CAS 854107-55-4) (ab231509), accessed September 1, 2025, https://www.abcam.com/en-us/products/biochemicals/ponesimod-sphingosine-1-phophate-receptor-agonist-ab231509
26. Ponesimod | CAS 854107-55-4 | Cayman Chemical | Biomol.com, accessed September 1, 2025, https://www.biomol.com/products/chemicals/biochemicals/ponesimod-cay22053-1
27. Ponesimod | C23H25ClN2O4S | CID 11363176 - PubChem, accessed September 1, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/11363176
28. Ponesimod | ACT-128800 | CAS#854107-55-4 | S1P1 immunomodulator | MedKoo, accessed September 1, 2025, https://www.medkoo.com/products/6745
29. Ponesimod | CAS# 854107-55-4 - APExBIO, accessed September 1, 2025, https://www.apexbt.com/ponesimod.html
30. Ponesimod - KEGG DRUG, accessed September 1, 2025, https://www.kegg.jp/entry/D11215
31. Ponesimod | LPL Receptor - TargetMol, accessed September 1, 2025, https://www.targetmol.com/compound/ponesimod
32. Ponesimod - LiverTox - NCBI Bookshelf, accessed September 1, 2025, https://www.ncbi.nlm.nih.gov/books/NBK572852/
33. Compound: PONESIMOD (CHEMBL1096146) - ChEMBL - EMBL-EBI, accessed September 1, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL1096146
34. ponesimod | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 1, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=9320
35. Chemical structure of ponesimod, C23H25N2O4CIS (molecular weight 460.98). | Download Scientific Diagram - ResearchGate, accessed September 1, 2025, https://www.researchgate.net/figure/Chemical-structure-of-ponesimod-C23H25N2O4CIS-molecular-weight-46098_fig1_289494410
36. 213498Orig1s000 - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213498Orig1s000ChemR.pdf
37. Attachment-Product information for Ponvory - Therapeutic Goods Administration (TGA), accessed September 1, 2025, https://www.tga.gov.au/sites/default/files/2022-11/auspar-ponvory-221031-pi.pdf
38. Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway Modulators, from Current Insights to Future Perspectives - MDPI, accessed September 1, 2025, https://www.mdpi.com/2073-4409/11/13/2058
39. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases - PMC - PubMed Central, accessed September 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4707431/
40. Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study - PMC - PubMed Central, accessed September 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3845312/
41. Ponesimod (Ponvory) - MS Society, accessed September 1, 2025, https://www.mssociety.org.uk/living-with-ms/treatments-and-therapies/disease-modifying-therapies/ponesimod-ponvory
42. 213498Orig1s000 - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213498Orig1s000PharmR.pdf
43. 213498Orig1s000 - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213498Orig1s000OtherR.pdf
44. Ponvory - FEPBlue, accessed September 1, 2025, https://www2.fepblue.org/-/media/PDFs/Medical-Policies/2025/March/Pharmacy-Policies/Remove-and-Replace/560049-Ponvory-ponesimod.pdf
45. PONVORY® Mechanism of Action, accessed September 1, 2025, https://www.ponvorypro.com/mechanism-of-action
46. Ponesimod inhibits astrocyte‐mediated neuroinflammation and protects against cingulum demyelination via S1P1‐selective modulation - PubMed Central, accessed September 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8740777/
47. Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis | Request PDF - ResearchGate, accessed September 1, 2025, https://www.researchgate.net/publication/374339183_Clinical_Pharmacokinetics_of_Ponesimod_a_Selective_S1P1_Receptor_Modulator_in_the_Treatment_of_Multiple_Sclerosis
48. Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis - PubMed, accessed September 1, 2025, https://pubmed.ncbi.nlm.nih.gov/37776485/
49. Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis | Neurology, accessed September 1, 2025, https://www.neurology.org/doi/10.1212/WNL.0000000000200606
50. Ponvory 20 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (emc), accessed September 1, 2025, https://www.medicines.org.uk/emc/product/100485/smpc
51. HOW TO INITIATE ONCE-DAILY PONVORY® - Vanda Assets, accessed September 1, 2025, https://www.assets.vandapharma.com/Ponvory/dosing_flashcard.pdf
52. PONVORY® 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg film-coated tablets PRESCRIBING INFORMATION ACTIVE IN, accessed September 1, 2025, https://static.janssen-emea.com/sites/default/files/United%20Kingdom/SMPC/GB-PL-0021.pdf
53. 1 - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213498s000lbl.pdf
54. Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects - PubMed, accessed September 1, 2025, https://pubmed.ncbi.nlm.nih.gov/25612299/
55. Ponesimod in the Treatment of Relapsing Forms of Multiple Sclerosis: An Update on the Emerging Clinical Data - PMC - PubMed Central, accessed September 1, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8958267/
56. In which countries is Ponesimod approved? - Patsnap Synapse, accessed September 1, 2025, https://synapse.patsnap.com/article/in-which-countries-is-ponesimod-approved
57. Ponvory, INN-ponesimod, accessed September 1, 2025, https://ec.europa.eu/health/documents/community-register/2021/20210519151522/anx_151522_en.pdf
58. Ponesimod tablets - [Product Monograph Template - Standard], accessed September 1, 2025, https://pdf.hres.ca/dpd_pm/00060843.PDF
59. PONVORY II-13 - European Medicines Agency, accessed September 1, 2025, https://www.ema.europa.eu/en/documents/product-information/ponvory-epar-product-information_en.pdf
60. Ponvory (ponesimod) dosing, indications, interactions, adverse effects, and more - Medscape Reference, accessed September 1, 2025, https://reference.medscape.com/drug/ponvory-ponesimod-4000139
61. Population pharmacokinetics of ponesimod and its primary metabolites in healthy and organ-impaired subjects - PubMed, accessed September 1, 2025, https://pubmed.ncbi.nlm.nih.gov/27108115/
62. Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator for autoimmune diseases: review of clinical pharmacokinetics and drug disposition - PubMed, accessed September 1, 2025, https://pubmed.ncbi.nlm.nih.gov/28489480/
63. Safety and side effects - PONVORY® (ponesimod), accessed September 1, 2025, https://ponvoryus.com/side-effects-of-ponvory
64. Oral ponesimod in relapsing–remitting multiple sclerosis: a randomised phase II trial, accessed September 1, 2025, https://jnnp.bmj.com/content/85/11/1198
65. Ponesimod Completed Phase 2 Trials for Multiple Sclerosis Treatment | DrugBank Online, accessed September 1, 2025, https://go.drugbank.com/drugs/DB12016/clinical_trials?conditions=DBCOND0027885&phase=2&purpose=treatment&status=completed
66. Ponesimod (PONVORY) National Drug Monograph August 2022 - VA.gov, accessed September 1, 2025, https://www.va.gov/formularyadvisor/DOC_PDF/MON_Ponesimod_PONVORY_Monograph_Aug_2022.pdf
67. Study Details | Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis, accessed September 1, 2025, https://www.clinicaltrials.gov/study/NCT02425644?term=PONESIMOD&viewType=Table&rank=6
68. Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis | Clinical Research Trial Listing - CenterWatch, accessed September 1, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT02425644/oral-ponesimod-versus-teriflunomide-in-relapsing-multiple-sclerosis
69. Europe approves Ponvory (ponesimod) for multiple sclerosis, accessed September 1, 2025, https://www.europeanpharmaceuticalreview.com/news/155150/europe-approves-ponvory-ponesimod-for-multiple-sclerosis/
70. Janssen Receives Positive CHMP Opinion for PONVORY™ (ponesimod) for the Treatment of Adults With Relapsing Forms of Multiple Sclerosis With Active Disease Defined by Clinical or Imaging Features, accessed September 1, 2025, https://www.jnj.com/media-center/press-releases/janssen-receives-positive-chmp-opinion-for-ponvory-ponesimod-for-the-treatment-of-adults-with-relapsing-forms-of-multiple-sclerosis-with-active-disease-defined-by-clinical-or-imaging-features
71. Janssen Announces U.S. FDA Approval of PONVORY™ (ponesimod), an Oral Treatment for Adults with Relapsing Multiple Sclerosis Proven Superior to Aubagio® (teriflunomide) in Reducing Annual Relapses and Brain Lesions - Johnson & Johnson, accessed September 1, 2025, https://www.jnj.com/media-center/press-releases/janssen-announces-u-s-fda-approval-of-ponvory-ponesimod-an-oral-treatment-for-adults-with-relapsing-multiple-sclerosis-proven-superior-to-aubagio-teriflunomide-in-reducing-annual-relapses-and-brain-lesions
72. FDA Approves Ponesimod for Relapsing Multiple Sclerosis - - PracticalNeurology, accessed September 1, 2025, https://practicalneurology.com/news/fda-approves-ponesimod-for-relapsing-multiple-sclerosis/2469532/
73. Patients With Multiple Sclerosis Show Willingness to Trade-Off Disease Progression for Improvements in Fatigue - NeurologyLive, accessed September 1, 2025, https://www.neurologylive.com/view/patients-with-multiple-sclerosis-show-willingness-trade-off-disease-progression-for-improvements-in-fatigue
74. Subject: Ponesimod (Ponvory™) Tablet - Medical Coverage Guideline - Florida Blue, accessed September 1, 2025, http://mcgs.bcbsfl.com/MCG?mcgId=09-J3000-98&pv=false
75. Ponesimod versus teriflunomide in relapsing multiple sclerosis: efficacy results from the OPTIMUM phase 3 randomised, double-blind superiority study | Cochrane Library, accessed September 1, 2025, https://www.cochranelibrary.com/content?templateType=related&urlTitle=/central/doi/10.1002/central/CN-02160829&doi=10.1002/central/CN-02160829&p_p_id=scolariscontentdisplay_WAR_scolariscontentdisplay&_scolariscontentdisplay_WAR_scolariscontentdisplay_action=related-content&p_p_lifecycle=0&p_p_mode=view&type=central&contentLanguage=
76. Ponesimod Completed Phase 2 Trials for Psoriasis Vulgaris (Plaque Psoriasis) Treatment | DrugBank Online, accessed September 1, 2025, https://go.drugbank.com/drugs/DB12016/clinical_trials?conditions=DBCOND0070073&phase=2&purpose=treatment&status=completed
77. Ponvory (ponesimod) FDA Approval History - Drugs.com, accessed September 1, 2025, https://www.drugs.com/history/ponvory.html
78. Ponvory for Multiple Sclerosis: 5 FAQs Answered - GoodRx, accessed September 1, 2025, https://www.goodrx.com/ponvory/ponvory-for-ms
79. Comparable overall rates of TEAEs and SAEs vs Aubagio ® (teriflunomide) 1 - PONVORY® (ponesimod) HCP, accessed September 1, 2025, https://www.ponvorypro.com/safety-and-adverse-events
80. Ponesimod Side Effects: Common, Severe, Long Term - Drugs.com, accessed September 1, 2025, https://www.drugs.com/sfx/ponesimod-side-effects.html
81. ponesimod tablet, film coated PONVORY - DailyMed, accessed September 1, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5be69660-738c-4db7-b0d4-517aa873dc41
82. PONVORY® (ponesimod) HCP: The Official HCP Website for PONVORY®, accessed September 1, 2025, https://www.ponvorypro.com/
83. Ponesimod (oral route) - Side effects & dosage - Mayo Clinic, accessed September 1, 2025, https://www.mayoclinic.org/drugs-supplements/ponesimod-oral-route/description/drg-20510810
84. Ponvory (ponesimod) tablets - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213498Orig1s001ltr.pdf
85. How To Take PONVORY, accessed September 1, 2025, https://ponvoryus.com/how-to-take-ponvory
86. Starting PONVORY® Treatment, accessed September 1, 2025, https://ponvoryus.com/starting-ponvory
87. 3 STEPS TO YOUR FIRST DOSE - Vanda Assets, accessed September 1, 2025, https://www.assets.vandapharma.com/Ponvory/welcome_kit_3_steps.pdf
88. PONVORY® Dosing & Dose Titration, accessed September 1, 2025, https://www.ponvorypro.com/dosing-and-dose-titration
89. Ponesimod Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed September 1, 2025, https://www.drugs.com/dosage/ponesimod.html
90. Ponesimod: MedlinePlus Drug Information, accessed September 1, 2025, https://medlineplus.gov/druginfo/meds/a621025.html
91. en.wikipedia.org, accessed September 1, 2025, https://en.wikipedia.org/wiki/Ponesimod#:~:text=It%20is%20a%20sphingosine%2D1%2Dphosphate%20receptor%20modulator.&text=The%20most%20common%20side%20effects,European%20Union%20in%20June%202021.
92. Ponesimod: First Approval - PubMed, accessed September 1, 2025, https://pubmed.ncbi.nlm.nih.gov/33939119/
93. Ponvory (ponesimod) tablets - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213498Orig1s000ltr.pdf
94. CENTER FOR DRUG EVALUATION AND RESEARCH - accessdata.fda.gov, accessed September 1, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/213498Orig1s000Approv.pdf
95. 1 Ponesimod Resolution of: 2 December 2021 valid until, accessed September 1, 2025, https://www.g-ba.de/downloads/91-1455-706/2021-12-02_Resolution_Ponesimod_D-702_EN.pdf
96. Vanda Pharmaceuticals Acquires U.S. and Canadian Rights to PONVORY® (ponesimod), a Selective S1P1R Modulator Approved for Patients with Relapsing Multiple Sclerosis - Investors, accessed September 1, 2025, https://vandapharmaceuticalsinc.gcs-web.com/node/15626/pdf
97. Vanda Pharmaceuticals Announces a U.S. Patent Allowance for PONVORY® (ponesimod) in the U.S. - Investors, accessed September 1, 2025, https://vandapharmaceuticalsinc.gcs-web.com/node/15696/pdf
98. Vanda Pharmaceuticals Announces Completion of Transfer of FDA Marketing Authorization for PONVORY® - PR Newswire, accessed September 1, 2025, https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-announces-completion-of-transfer-of-fda-marketing-authorization-for-ponvory-302160024.html
99. Generic Ponvory Availability - Drugs.com, accessed September 1, 2025, https://www.drugs.com/availability/generic-ponvory.html
100. FDA Approves Ponvory | Anton RX Report, accessed September 1, 2025, https://antonhealth.com/fda-approves-ponvory/