A Comprehensive Monograph on Ibudilast (DB05266): From Respiratory Agent to Investigational Neuro-Immunomodulator

Executive Summary

Ibudilast is an orally bioavailable, central nervous system (CNS) penetrant small molecule with a multifaceted pharmacological profile. Initially approved in Japan and South Korea in 1989 for the treatment of bronchial asthma and post-stroke cerebrovascular disorders, its clinical application was historically confined to respiratory and circulatory conditions. However, subsequent elucidation of its pleiotropic mechanisms of action—spanning non-selective phosphodiesterase (PDE) inhibition, antagonism of macrophage migration inhibitory factor (MIF), and blockade of toll-like receptor 4 (TLR4)—has catalyzed its repurposing as a promising investigational agent for a range of neuroinflammatory and neurodegenerative diseases.

The most compelling evidence for its neurotherapeutic potential comes from the SPRINT-MS Phase 2b trial, which demonstrated an unprecedented 48% reduction in the rate of whole-brain atrophy in patients with progressive multiple sclerosis (MS). This finding, coupled with a lack of efficacy against acute inflammatory lesions, has shifted the conceptual framework of Ibudilast from a conventional anti-inflammatory to a potential first-in-class glial cell modulator with direct neuroprotective properties. Currently, Ibudilast (under the development code MN-166) is in late-stage clinical trials for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM). The ongoing COMBAT-ALS trial represents a pivotal milestone in determining its efficacy in this devastating motor neuron disease. While the drug exhibits a favorable safety profile at the lower doses used in Asia, higher doses required for CNS indications have presented tolerability challenges, primarily gastrointestinal adverse events. The future clinical trajectory of Ibudilast hinges on navigating this therapeutic window and validating its unique neuroprotective mechanism in Phase 3 studies.

Introduction: The Evolution of Ibudilast from Respiratory Agent to Neurotherapeutic Candidate

Ibudilast, also known by its development codes KC-404, AV-411, and MN-166, is a small molecule drug with a rich and evolving history.[1] First approved in 1989, it has been marketed for over three decades in Japan and South Korea under brand names including Ketas®, Pinatos®, and Eyevinal®.[2] Its initial regulatory approvals were for the treatment of bronchial asthma and for the improvement of dizziness secondary to chronic cerebral circulation impairment associated with the sequelae of cerebral infarction.[2] These indications established a long-term record of safety and tolerability at daily oral doses of 20-30 mg.[5]

The trajectory of Ibudilast research underwent a significant paradigm shift with the discovery of its profound neuro-immunomodulatory properties. Key to this evolution was the finding that Ibudilast can readily cross the blood-brain barrier and exert a direct influence on the resident immune cells of the CNS, particularly microglia and astrocytes.[2] This capacity to attenuate glial cell activation, a central pathological process in many neurological disorders, provided a compelling scientific rationale for repurposing the drug for conditions characterized by neuroinflammation and neurodegeneration.[7]

This shift has positioned Ibudilast as a lead asset in the pipeline of MediciNova, Inc., which is spearheading its development for a portfolio of neurological conditions. The current investigational landscape includes late-stage clinical programs for progressive multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and degenerative cervical myelopathy (DCM), alongside earlier-phase studies in substance use disorders, neuropathic pain, and glioblastoma.[9] This report provides a comprehensive analysis of Ibudilast, from its fundamental molecular characteristics to its complex pharmacology and evolving clinical profile.

Molecular Profile and Physicochemical Characteristics

Chemical Identity, Structure, and Nomenclature

Ibudilast is a synthetic organic compound belonging to the pyrazolopyridine class. Its formal chemical identity is well-established across major chemical and pharmacological databases.

• IUPAC Name: 2-methyl-1-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one.[1]
• Synonyms and Codes: The International Nonproprietary Name (INN) is ibudilast. It is widely known by its development and commercial codes, including KC-404, AV-411, and MN-166.[1]
• Chemical Formula: C14​H18​N2​O.[3]
• Molecular Weight: The calculated molecular weight is 230.31 g/mol, with a monoisotopic mass of 230.1419 Da.[3]
• Structural Identifiers:
• CAS Number: 50847-11-5.[13]
• Canonical SMILES: CC(C(=O)c1c(nn2c1cccc2)C(C)C)C.[1]
• InChIKey: ZJVFLBOZORBYFE-UHFFFAOYSA-N.[1]

Physicochemical Properties and Pharmacological Classification

Ibudilast presents as a white to off-white solid that is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and ethanol but only slightly soluble in water.[14] Its physicochemical properties are highly favorable for an orally administered, CNS-active drug. The molecule fully adheres to Lipinski's Rule of Five, with zero violations, indicating good potential for oral bioavailability and membrane permeability.[3] Key parameters contributing to this profile include a low number of rotatable bonds (3), a small polar surface area (

34.37A˚2), and a lack of hydrogen bond donors.[3]

Pharmacologically, Ibudilast is classified as a Small Molecule drug.[3] Based on its mechanisms and effects, it is categorized as a Phosphodiesterase Inhibitor, a Bronchodilator Agent, a Vasodilator Agent, and a Platelet Aggregation Inhibitor.[13] Its Anatomical Therapeutic Chemical (ATC) classification code, assigned by the World Health Organization (WHO), is R03DC04, placing it in the category of "Other systemic drugs for obstructive airway diseases".[13]

The Molecular Blueprint for Repurposing

The specific combination of physicochemical properties possessed by Ibudilast is not merely a list of descriptive data; it forms the fundamental molecular blueprint that enabled its transition from a respiratory drug to a CNS therapeutic candidate. The primary obstacle for any drug intended to treat neurological disease is its ability to penetrate the highly selective blood-brain barrier (BBB). Successful CNS penetration is governed by a distinct set of molecular characteristics, including a low molecular weight (typically <400-500 Da), moderate lipophilicity (LogP), and minimal hydrogen bonding potential.

Ibudilast's molecular weight of ~230 Da, its calculated partition coefficient (AlogP) of approximately 3.3, and its complete absence of hydrogen bond donors align perfectly with these requirements.[3] These intrinsic structural features confer upon the molecule the ability to passively diffuse across the BBB and engage with targets within the CNS. Therefore, the decision to investigate Ibudilast for neurological conditions was not a speculative leap but a logical step grounded in its fundamental chemistry. Without this favorable molecular profile, its unique neuro-immunomodulatory mechanisms would have remained confined to the periphery and clinically inaccessible for treating CNS disorders.

Identifier/Property	Value	Physicochemical Property	Value
IUPAC Name	2-methyl-1-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one	AlogP	3.30
Common Synonyms	KC-404, AV-411, MN-166, Ketas®	Polar Surface Area	34.37A˚2
CAS Number	50847-11-5	#Rotatable Bonds	3
DrugBank ID	DB05266	#H-Bond Acceptors	3
PubChem CID	3671	#H-Bond Donors	0
ChEMBL ID	CHEMBL19449	#Lipinski Violations	0
Molecular Formula	C14​H18​N2​O
Molecular Weight	230.31 g/mol
InChIKey	ZJVFLBOZORBYFE-UHFFFAOYSA-N
Canonical SMILES	CC(C(=O)c1c(nn2c1cccc2)C(C)C)C
Table 1: Key Identifiers and Physicochemical Properties of Ibudilast. Data compiled from multiple sources.1

Comprehensive Pharmacology: A Pleiotropic Mechanism of Action

Ibudilast is characterized by a pleiotropic mechanism of action, engaging multiple distinct molecular targets that collectively contribute to its anti-inflammatory, neuroprotective, and vasodilatory effects. This multi-target profile distinguishes it from more selective agents and underpins its broad therapeutic potential.

Primary Target Engagement: Phosphodiesterase (PDE) Inhibition

The foundational mechanism of Ibudilast is its activity as a relatively non-selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs).[16] PDEs are a superfamily of enzymes responsible for degrading the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). By inhibiting these enzymes, Ibudilast elevates intracellular levels of cAMP and cGMP, thereby modulating a wide array of downstream signaling pathways.[16]

• PDE4 Inhibition: Ibudilast exhibits its highest potency against the four isoforms of the PDE4 family (PDE4A, 4B, 4C, and 4D), with half-maximal inhibitory concentrations (IC50​) ranging from 54 to 239 nM.[14] PDE4 is a key regulator of inflammation in immune cells, and its inhibition is the primary mechanism underlying Ibudilast's efficacy as a bronchodilator and anti-inflammatory agent in asthma.[15]
• Inhibition of Other PDEs: The drug also inhibits other PDE families, albeit with lower potency. It has significant activity against PDE10, PDE3, and PDE11.[2] Its inhibition of PDE10 (inhibitor constant, Ki​, ~1-2 µM) is particularly relevant to its neurological effects, as this enzyme is highly expressed in the medium spiny neurons of the striatum and plays a role in neuronal signaling.[18] It also inhibits PDE3A and PDE11A1 with Ki​ values of approximately 9-9.5 µM.[18]

Glial Cell Modulation and Neuroinflammation: MIF and TLR4 Antagonism

Beyond PDE inhibition, two additional mechanisms are critical to Ibudilast's activity within the CNS, specifically its ability to modulate the function of glial cells (microglia and astrocytes).

• Macrophage Migration Inhibitory Factor (MIF) Inhibition: Ibudilast functions as an allosteric inhibitor of MIF.[7] MIF is a pivotal pro-inflammatory cytokine that orchestrates immune responses and is implicated in the pathogenesis of numerous inflammatory and autoimmune diseases. By inhibiting MIF, Ibudilast can directly suppress a key driver of neuroinflammation.[4]
• Toll-Like Receptor 4 (TLR4) Antagonism: Ibudilast also acts as an antagonist of TLR4.[2] TLR4 is a pattern recognition receptor expressed on the surface of immune cells, including microglia. Its activation triggers potent inflammatory signaling cascades. Blockade of TLR4 by Ibudilast is believed to be a major contributor to its anti-neuroinflammatory effects and its observed ability to attenuate opioid tolerance and withdrawal symptoms.[2]

The convergence of these pathways results in the attenuation of glial cell activation.[5] Rather than causing cytotoxic depletion of these cells, Ibudilast appears to induce a phenotypic shift, converting them from a pro-inflammatory, neurotoxic state to a more neuroprotective, homeostatic one.[18]

Downstream Pharmacodynamic Effects: Anti-inflammatory, Neuroprotective, and Vasodilatory Actions

The engagement of these multiple targets translates into a broad spectrum of downstream pharmacodynamic effects.

• Anti-inflammatory Cascade: Ibudilast significantly downregulates the production and release of key pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), and interleukin-6 (IL-6), while concurrently upregulating the anti-inflammatory cytokine IL-10.[7] It also inhibits the synthesis of leukotriene B4, another potent inflammatory mediator.[7]
• Neuroprotective Pathways: The drug exerts direct neuroprotective actions through several mechanisms independent of its anti-inflammatory effects. It promotes the production of critical neurotrophic factors, such as glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophins NT-3 and NT-4.[7] It also protects neurons from apoptosis by modulating key proteins in cell death pathways (e.g., caspase-3, Bcl-2), reduces oxidative stress by inhibiting nitric oxide synthesis, and helps maintain mitochondrial function.[13]
• Vasodilatory and Other Effects: The drug's original approved uses are derived from its vasodilatory effects, which improve cerebral blood flow, and its bronchodilatory effects.[2] Additionally, it inhibits platelet aggregation, contributing an anti-thrombotic action.[2]

Mechanism-Indication Mismatch and the "Neuroprotective" Hypothesis

A critical analysis of Ibudilast's clinical trial results reveals a compelling disconnect between its primary mechanism as a PDE4 inhibitor and its observed efficacy profile in MS. As a potent inhibitor of PDE4, a well-established anti-inflammatory target, the drug would be expected to excel at suppressing the acute, focal inflammatory events that characterize relapsing-remitting MS (RRMS), such as clinical relapses and the formation of new gadolinium-enhancing MRI lesions. However, clinical trials in RRMS patients failed to demonstrate a significant effect on these endpoints.[18] This outcome represents a significant contradiction if Ibudilast is viewed solely through the lens of a traditional anti-inflammatory agent.

Conversely, in the SPRINT-MS trial involving patients with progressive forms of MS—a disease stage driven less by acute inflammation and more by chronic, compartmentalized microglial activation and progressive neurodegeneration—Ibudilast demonstrated a robust and unprecedented effect in slowing the rate of whole-brain atrophy.[23] This apparent paradox suggests that the drug's therapeutic benefit in progressive MS is not mediated primarily by its peripheral PDE4-inhibiting, anti-inflammatory activity. Instead, the evidence points toward a different, more nuanced mechanism centered within the CNS. The most plausible explanation is that Ibudilast's efficacy in progressive neurodegeneration stems from its ability to directly modulate the CNS-resident immune system via its MIF inhibition and TLR4 antagonism, thereby attenuating chronic microglial activation and promoting a neuroprotective environment. This re-frames the narrative of Ibudilast: it is not a failed anti-inflammatory drug, but rather a potentially successful neuroprotective and glial-modulating agent whose true therapeutic niche lies in diseases of chronic neurodegeneration.

Clinical Pharmacokinetics (ADME Profile)

The pharmacokinetic profile of Ibudilast has been characterized in both preclinical species and human subjects, revealing properties suitable for an orally administered drug targeting the CNS.

Absorption and Distribution, including CNS Penetration

• Absorption: Ibudilast is orally bioavailable.[7] Following oral administration of a 30 mg dose in healthy human volunteers, the median time to reach maximum plasma concentration ( Tmax​) is approximately 4 to 5 hours.[5] Pharmacokinetic studies show that steady-state plasma levels are achieved within two days of initiating a twice-daily dosing regimen.[5]
• Distribution: The drug undergoes rapid and extensive distribution throughout the body.[26] It is highly bound to plasma proteins, with a binding fraction of 95% or greater in humans.[26]
• CNS Penetration: A critical feature for its neurological indications is its demonstrated ability to efficiently cross the blood-brain barrier and distribute reversibly within the CNS.[7] This property is essential for the drug to engage its central targets, such as microglia and astrocytes.[5]

Metabolism and Excretion

• Metabolism: Ibudilast is extensively metabolized, primarily by hepatic cytochrome P450 (CYP) enzymes. While multiple isoforms are involved, CYP3A4 appears to play a dominant role in its metabolic activation.[8] Importantly, Ibudilast is not considered a clinically relevant inhibitor or inducer of major CYP enzymes, suggesting a low likelihood of significant pharmacokinetic drug-drug interactions.[8]
• Metabolites: The principal metabolite identified in human plasma is 6,7-dihydrodiol-ibudilast. This metabolite is pharmacologically active and circulates at concentrations that are approximately 30% of the parent drug at steady state.[25]
• Excretion: The mean biological half-life (t1/2​) of Ibudilast in human plasma is approximately 19 hours, supporting a twice-daily dosing schedule.[5] Following metabolism, the drug's metabolites are primarily eliminated via the urine. Excretion of unchanged Ibudilast in the urine is negligible.[5]

Parameter	Value	Source/Reference
Tmax​ (single dose)	~5 hours	5
Cmax​ (single 30 mg dose)	~32.0 ng/mL	5
Cmax​ (steady-state, 30 mg BID)	~59.9 ng/mL	5
AUC0−24​ (single 30 mg dose)	~373 ng·h/mL	5
AUC0−24​ (steady-state, 30 mg BID)	~1000 ng·h/mL	5
Elimination Half-life (t1/2​)	~19.2 hours	5
Plasma Protein Binding	≥95%	26
Primary Metabolite	6,7-dihydrodiol-ibudilast	25
Table 2: Human Pharmacokinetic Parameters of Ibudilast. BID = twice daily..5

Established Clinical Applications: Regulatory Approval and Use in Asia

Ibudilast has a long history of clinical use in Japan and South Korea, where it is approved for several indications under the brand name Ketas® and others.[2]

Treatment of Bronchial Asthma and Cerebrovascular Disorders (Ketas®)

The primary approved uses for oral Ibudilast capsules stem from its bronchodilatory and vasodilatory properties.

• Bronchial Asthma: Ibudilast is used as a maintenance therapy to treat bronchial asthma. The standard adult dosage is one 10 mg capsule taken twice daily.[19] Its mechanism involves suppressing inflammation in the respiratory tract and relaxing bronchial smooth muscle. It is important to note that it is intended for prophylactic use to make asthma attacks less likely to occur and is not effective for stopping an acute attack that is already in progress.[29]
• Cerebrovascular Disorders: The drug is also approved for the symptomatic treatment of dizziness resulting from chronic cerebral circulatory disturbances after a cerebral infarction.[2] For this indication, the usual adult dosage is one 10 mg capsule taken three times daily.[19] This therapeutic effect is attributed to its ability to increase cerebral blood flow through vasodilation.[18] The Japanese product information for Ketas® capsules outlines these uses and warns of potential adverse reactions, including loss of appetite, nausea, and, rarely, liver dysfunction or jaundice.[29]

Ophthalmic Formulations for Allergic Conjunctivitis

In addition to its oral formulation, Ibudilast is available as a topical ophthalmic solution (KETAS Eye-drops 0.01%) in Japan.[2] This formulation is approved for the treatment of allergic conjunctivitis, including seasonal hay fever.[2] The mechanism of action is the local suppression of chemical mediators of allergy, such as histamine. The recommended dosage is one to two drops applied to the affected eye(s) four times per day.[30]

Investigational Role in Neurodegenerative and Neuroinflammatory Diseases

The focus of modern Ibudilast development has shifted decisively toward its potential as a treatment for complex neurological disorders, driven by its unique neuro-immunomodulatory profile.

Progressive Multiple Sclerosis: A Deep-Dive into the SPRINT-MS Trial (NCT01982942)

The SPRINT-MS trial stands as the landmark study supporting the repurposing of Ibudilast for neurodegenerative disease.

• Trial Design and Patient Population: SPRINT-MS was a robustly designed Phase 2b, multicenter, randomized, double-blind, placebo-controlled trial involving 255 participants with either primary progressive MS (PPMS) or secondary progressive MS (SPMS).[23] Patients were randomized on a 1:1 basis to receive either oral Ibudilast, titrated up to a maximum dose of 100 mg per day (50 mg twice daily), or a matching placebo for a duration of 96 weeks.[4]
• Analysis of Primary Endpoint: Brain Atrophy: The trial's primary efficacy endpoint was the rate of change in whole-brain volume, a key marker of neurodegeneration in MS, as measured by brain parenchymal fraction (BPF) on serial MRI scans.[4] The study successfully met this endpoint, demonstrating that treatment with Ibudilast resulted in a statistically significant 48% reduction in the rate of brain atrophy progression compared to placebo ( p=0.04).[4] This effect represented a preservation of approximately 2.5 mL of brain tissue over the two-year study period.[32]
• Key Secondary and Imaging Outcomes: Secondary outcomes provided converging evidence of a neuroprotective effect. Optical Coherence Tomography (OCT), which measures the thickness of the retinal nerve fiber layer as a proxy for CNS axonal health, suggested that Ibudilast attenuated retinal thinning.[22] Furthermore, advanced MRI techniques like Magnetization Transfer Ratio (MTR) imaging indicated a preservation of brain tissue integrity in the Ibudilast group.[24] Critically, and consistent with previous studies, Ibudilast did not reduce the rate of new or enlarging T2 inflammatory lesions, reinforcing the conclusion that its primary benefit is neuroprotective rather than acutely anti-inflammatory.[22]
• Clinical Implications and Expert Interpretation: The SPRINT-MS results were highly significant, as the magnitude of the effect on brain atrophy was among the largest reported for any agent in progressive MS.[24] These findings provided strong clinical validation for the hypothesis that Ibudilast's primary mechanism in this context is the modulation of chronic, glial-driven neurodegeneration. Based on these data, MediciNova is planning a follow-up Phase 3 clinical trial, likely focusing on people with non-relapsing secondary progressive MS, a population with a major unmet medical need.[23]

Amyotrophic Lateral Sclerosis: Evaluating the Evidence from the COMBAT-ALS Program

Ibudilast is also being evaluated as a potential treatment for ALS, a fatal progressive motor neuron disease.

• Rationale and Design of the Phase 2b/3 COMBAT-ALS Trial (NCT04057898): Following promising preclinical data and smaller early-phase studies, the pivotal COMBAT-ALS trial was initiated.[7] This multicenter, randomized, double-blind, placebo-controlled study is designed to assess the efficacy and safety of Ibudilast in approximately 230 patients with either familial or sporadic ALS across sites in the U.S. and Canada.[32] Participants are treated for a 12-month double-blind phase, followed by an optional 6-month open-label extension where all participants receive Ibudilast.[32] The trial successfully completed enrollment in August 2025.[10]
• Review of Endpoints and Available Interim Data: The primary endpoint is the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score over the 12-month treatment period, a standard measure of functional decline in ALS.[32] Secondary endpoints include measures of muscle strength, survival, and quality of life.[32] An interim analysis presented in December 2024 on 217 enrolled participants revealed positive correlations between functional scores at 6 months and 12 months, suggesting that early treatment effects may be sustained over the longer term.[32]
• Insights from Earlier Studies: An earlier open-label Phase 1b trial (NCT02714036) in 35 ALS patients provided important context. This study, which used Ibudilast at doses up to 100 mg/day, did not find a significant reduction in key biomarkers of neuroinflammation (measured by PBR28-PET imaging) or axonal injury (serum neurofilament light, NfL).[32] Furthermore, the high dose was poorly tolerated, with 37% of participants requiring a dose reduction and 31% discontinuing treatment due to adverse events, primarily gastrointestinal.[39] To provide access for patients who do not qualify for the pivotal trial, an NIH-funded Expanded Access Program (EAP) is also active.[40]

Other Emerging CNS Indications

The broad mechanism of Ibudilast has prompted its investigation in several other CNS disorders.

• Substance Use Disorders: Neuroinflammation is increasingly recognized as a contributor to the pathology of addiction. Ibudilast is being studied in Phase 2 trials for its potential to reduce this neuroinflammation in methamphetamine dependence, opioid dependence, and alcohol use disorder.[3]
• Neuropathic Pain and CIPN: Preclinical studies have consistently shown that Ibudilast can reduce pain-like behaviors (allodynia) in various models of neuropathic pain.[16] It is currently in development for chemotherapy-induced peripheral neuropathy (CIPN), a common and debilitating side effect of cancer treatment.[9]
• Glioblastoma (GBM): A Phase 1b/2a clinical trial evaluated Ibudilast as an add-on therapy to the standard-of-care chemotherapy temozolomide in patients with newly diagnosed and recurrent glioblastoma. The combination was found to be safe, and it showed a promising signal for improved Progression-Free Survival at 6 months (PFS6) in patients with recurrent GBM compared to historical data.[44]
• Degenerative Cervical Myelopathy (DCM): Ibudilast is in late-stage (Phase 3) development for DCM, a progressive disorder of the spinal cord caused by cervical spondylosis.[3] A recruiting Phase 3 trial (NCT04631471) is currently underway.[46]

Comprehensive Safety and Tolerability Profile

The safety profile of Ibudilast is well-characterized, drawing from over three decades of post-marketing use in Asia at lower doses and extensive data from clinical trials in Western populations at higher doses.

Adverse Events and Dose-Limiting Toxicities

• Common Adverse Events: The most consistently reported treatment-related adverse events across clinical trials are gastrointestinal in nature. These include nausea, diarrhea, abdominal pain, and vomiting.[23] Other common side effects include headache, fatigue, and hyperhidrosis (excessive sweating).[5] Depression has also been reported as an adverse event in some trials.[23]
• Dose-Dependence: While generally well-tolerated at the 20-30 mg/day doses approved in Asia, the higher doses (up to 100 mg/day) being tested for neurological diseases have been associated with a higher incidence and severity of these adverse events.[5] In a study of high-dose Ibudilast in ALS patients, these side effects were common and frequently led to dose reductions or discontinuation of the drug, highlighting tolerability as a key challenge at higher exposures.[39]
• Serious Adverse Events: In the large, placebo-controlled SPRINT-MS trial, the rate of serious adverse events was comparable between the Ibudilast and placebo groups, suggesting that at doses up to 100 mg/day, the drug does not pose a significant risk of severe, unexpected toxicities.[24] Post-marketing data from Japan indicate rare occurrences of liver dysfunction and jaundice, which are listed as potential serious adverse reactions in the product monograph.[29]

Contraindications and Precautions

• Contraindications: The primary contraindication for Ibudilast is a known hypersensitivity to the active substance or any of the excipients in the formulation.[47]
• Precautions: Based on the Japanese product information and typical clinical trial exclusion criteria, caution is advised for certain patient populations. This includes patients with a recent history of intracranial bleeding or cerebral infarction.[29] Patients with clinically significant cardiovascular disease (e.g., recent myocardial infarction, unstable angina), uncontrolled hypertension, or significant hepatic or renal impairment are typically excluded from clinical trials.[31] Due to a lack of definitive safety data, use in pregnant or breastfeeding women is not recommended unless deemed essential by a physician.[47]

Clinically Significant Drug-Drug Interactions

Ibudilast's pharmacological profile creates the potential for several clinically relevant drug-drug interactions.

• Pharmacodynamic Interactions:
• Increased Bleeding Risk: Due to its inhibitory effect on platelet aggregation, co-administration of Ibudilast with other drugs that affect hemostasis can increase the risk of bleeding. This includes anticoagulants (e.g., warfarin, apixaban), antiplatelet agents (e.g., clopidogrel), nonsteroidal anti-inflammatory drugs (NSAIDs), and selective serotonin reuptake inhibitors (SSRIs).[49]
• Increased Hypotensive Effect: Ibudilast possesses vasodilatory properties and may potentiate the effects of antihypertensive medications. Combining it with agents such as beta-blockers, ACE inhibitors, calcium channel blockers, alpha-blockers, or other vasodilators can increase the risk of hypotension and syncope.[49]
• Pharmacokinetic Interactions: Although Ibudilast is not a potent modulator of CYP enzymes, its metabolism is primarily mediated by CYP3A4.[8] Therefore, co-administration with strong inhibitors of CYP3A4 (e.g., ritonavir, ketoconazole) could increase plasma concentrations of Ibudilast, potentially exacerbating adverse effects. Conversely, strong CYP3A4 inducers (e.g., rifampin) could decrease Ibudilast concentrations and reduce its efficacy.[47]

Interacting Drug Class	Mechanism/Effect	Clinical Recommendation	Example Drugs
Anticoagulants/Antiplatelets	Additive antiplatelet/anticoagulant effect	Monitor closely for signs of bleeding (e.g., bruising, hematoma).	Warfarin, Apixaban, Clopidogrel
NSAIDs	Additive antiplatelet effect; increased risk of GI bleeding	Use with caution; monitor for gastrointestinal adverse events.	Ibuprofen, Naproxen, Aspirin
SSRIs/SNRIs	Inhibition of serotonin reuptake can impair platelet function	Monitor for signs of abnormal bleeding.	Sertraline, Fluoxetine, Venlafaxine
Antihypertensives/Vasodilators	Additive hypotensive effect	Monitor blood pressure, especially upon initiation or dose change.	Lisinopril, Amlodipine, Losartan
Alpha-Blockers	Increased risk of orthostatic hypotension and syncope	Advise patients on the risk of dizziness upon standing.	Tamsulosin, Prazosin
Strong CYP3A4 Inhibitors	Increased plasma exposure of Ibudilast	Use with caution; consider Ibudilast dose reduction if necessary.	Ritonavir, Ketoconazole
Table 3: Major Drug-Drug Interaction Classes and Clinical Considerations for Ibudilast..47

Global Regulatory Landscape and Future Outlook

Status with the FDA (USA), EMA (EU), and PMDA (Japan)

The regulatory status of Ibudilast varies significantly by geographic region, reflecting its dual identity as an established drug in Asia and an investigational therapeutic in the West.

• PMDA (Japan): In Japan, Ibudilast (as Ketas®) holds full marketing authorization from the Pharmaceuticals and Medical Devices Agency (PMDA) and has been in clinical use for over three decades for its approved indications of bronchial asthma, post-stroke dizziness, and allergic conjunctivitis.[2]
• FDA (USA): In the United States, Ibudilast is an investigational new drug and is not approved for any indication. Recognizing its potential to address serious unmet medical needs, the Food and Drug Administration (FDA) has granted it several designations to facilitate and expedite its development pathway. These include Fast Track Designation for both progressive MS and ALS, and Orphan Drug Designation for the treatment of ALS and Fragile X Syndrome.[13]
• EMA (EU): Similar to the U.S., Ibudilast is not approved for marketing in the European Union. The European Medicines Agency (EMA) has granted it Orphan Medicinal Product Designation for the treatment of ALS, which provides regulatory and financial incentives to support its development for this rare disease.[9]

Synthesis and Expert Opinion: The Path Forward for Ibudilast

Ibudilast represents a compelling case study in drug repurposing, where a deeper understanding of a molecule's pleiotropic pharmacology has opened therapeutic avenues in diseases far removed from its original indications. The evidence base clearly positions Ibudilast as a CNS-penetrant, orally active agent with a unique neuroprotective and glial-modulating mechanism of action.

The path forward for Ibudilast is most clearly defined in progressive MS. The robust and statistically significant results from the SPRINT-MS trial provide a strong foundation for a pivotal Phase 3 study. Such a trial, likely focusing on non-relapsing secondary progressive MS patients, could position Ibudilast to become a valuable addition to the therapeutic armamentarium for a patient population with few effective options.

The outlook in ALS is more guarded but still holds potential. The ongoing COMBAT-ALS trial is a critical determinant of its future in this disease. While interim data are encouraging, the failure of an earlier study to move key biomarkers of neuroinflammation and axonal damage, combined with significant tolerability issues at high doses, underscores the challenges ahead. The final results of the COMBAT-ALS trial will be essential to determine if a therapeutic window exists where efficacy can be achieved with an acceptable safety profile in the broader ALS population.

In conclusion, Ibudilast has successfully transitioned from a legacy respiratory drug to a modern neurotherapeutic candidate. Its future success will depend on the outcomes of its late-stage clinical trials and the ability to demonstrate a meaningful clinical benefit that outweighs the tolerability concerns associated with the higher doses required to engage its central targets. Its multifaceted mechanism continues to support its exploration in other neuroinflammatory conditions, solidifying its status as a molecule of significant ongoing scientific and clinical interest.

Works cited

1. ibudilast | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 7, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7399
2. Ibudilast - Wikipedia, accessed September 7, 2025, https://en.wikipedia.org/wiki/Ibudilast
3. Compound: IBUDILAST (CHEMBL19449) - ChEMBL - EMBL-EBI, accessed September 7, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL19449
4. MediciNova Announces Positive Top-Line Results from the SPRINT-MS Phase 2b Trial of MN-166 (ibudilast) in Progressive MS: Achieved Both Primary Endpoints including a Significant Reduction in Whole Brain Atrophy and Safety and Tolerability, accessed September 7, 2025, https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-positive-top-line-results-sprint-ms-phase/
5. Ibudilast in healthy volunteers: safety, tolerability and pharmacokinetics with single and multiple doses - PubMed Central, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2675769/
6. Ibudilast for the treatment of drug addiction and other neurological conditions - Open Access Journals, accessed September 7, 2025, https://www.openaccessjournals.com/articles/ibudilast-for-the-treatment-of-drug-addiction-and-other-neurological-conditions.pdf
7. Full article: MN-166 (ibudilast) in Amyotrophic Lateral Sclerosis in a Phase IIb/III Study: COMBAT-ALS Study Design - Taylor & Francis Online, accessed September 7, 2025, https://www.tandfonline.com/doi/full/10.2217/nmt-2021-0042
8. (PDF) Ibudilast: A review of its pharmacology, efficacy and safety in respiratory and neurological disease - ResearchGate, accessed September 7, 2025, https://www.researchgate.net/publication/40023191_Ibudilast_A_review_of_its_pharmacology_efficacy_and_safety_in_respiratory_and_neurological_disease
9. MediciNova to Support NIH-Funded Expanded Access Clinical Trial to Evaluate MN166 (ibudilast) in Amyotrophic Lateral Sclerosis (ALS), accessed September 7, 2025, https://investors.medicinova.com/news-releases/news-release-details/medicinova-support-nih-funded-expanded-access-clinical-trial/
10. MediciNova Achieves Enrollment in COMBAT-ALS Clinical Trial - BioSpace, accessed September 7, 2025, https://www.biospace.com/press-releases/medicinova-achieves-enrollment-in-combat-als-clinical-trial
11. MediciNova Announces Update of Phase 2/3 Clinical Trial of MN-166 (ibudilast) in ALS patients (COMBAT-ALS) at the 2024 Annual NEALS Meeting (Northeast Amyotrophic Lateral Sclerosis Consortium), accessed September 7, 2025, https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-update-phase-23-clinical-trial-mn-166/
12. MediciNova Receives a Notice of Allowance for a New Patent Covering the Combination of MN-166 (ibudilast) and Riluzole for the Treatment of Amyotrophic Lateral Sclerosis (ALS) in Canada, accessed September 7, 2025, https://investors.medicinova.com/news-releases/news-release-details/medicinova-receives-notice-allowance-new-patent-covering-1/
13. Ibudilast | C14H18N2O | CID 3671 - PubChem, accessed September 7, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Ibudilast
14. Ibudilast | CAS 50847-11-5 - Adipogen Life Sciences - Anti-inflammatory MIF and PDE Inhibitor, accessed September 7, 2025, https://adipogen.com/ag-cr1-3738-ibudilast.html
15. Ibudilast = 99 HPLC, solid 50847-11-5 - Sigma-Aldrich, accessed September 7, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/i0157
16. Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence - MDPI, accessed September 7, 2025, https://www.mdpi.com/1420-3049/27/23/8448
17. www.mdpi.com, accessed September 7, 2025, https://www.mdpi.com/1420-3049/27/23/8448#:~:text=Ibudilast%2C%20an%20anti%2Dinflammatory%20drug,downregulating%20the%20pro%2Dinflammatory%20factors%2C
18. Ibudilast - Alzheimer's Drug Discovery Foundation, accessed September 7, 2025, https://www.alzdiscovery.org/uploads/cognitive_vitality_media/Ibudilast-Cognitive-Vitality-For-Researchers.pdf
19. IBUDILAST - Inxight Drugs, accessed September 7, 2025, https://drugs.ncats.io/drug/M0TTH61XC5
20. Repurposing ibudilast to mitigate Alzheimer's disease by targeting inflammation - PMC, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10226755/
21. Ibudilast (AV 411, KC-404, CAS Number: 50847-11-5) | Cayman Chemical, accessed September 7, 2025, https://www.caymanchem.com/product/14832/ibudilast
22. Optical Coherence Tomography Outcomes from SPRINT-MS, a multicenter, randomized, double-blind trial of ibudilast in progressive Multiple Sclerosis - PubMed Central, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8046841/
23. Ibudilast - MS Society, accessed September 7, 2025, https://www.mssociety.org.uk/research/explore-our-research/emerging-research-and-treatments/explore-treatments-in-trials/ibudilast
24. SPRINT-MS: Ibudilast Shows Unprecedented Slowing of Brain ..., accessed September 7, 2025, https://consultqd.clevelandclinic.org/sprint-ms-ibudilast-shows-unprecedented-slowing-of-brain-atrophy-in-progressive-ms
25. Ibudilast in healthy volunteers: Safety, tolerability and ..., accessed September 7, 2025, https://www.researchgate.net/publication/23496600_Ibudilast_in_healthy_volunteers_Safety_tolerability_and_pharmacokinetics_with_single_and_multiple_doses
26. Cross-species comparisons of the pharmacokinetics of ibudilast - PubMed, accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/19925385/
27. Ibudilast Granted FDA's Fast Track Designation for ALS Treatment | ALS News Today, accessed September 7, 2025, https://alsnewstoday.com/news/fda-grants-fast-track-designation-for-medicinovas-mn-166-ibudilast-for-the-treatment-of-amyotrophic-lateral-sclerosis/
28. Ibudilast for ALS: When is FDA approval coming (and how not to wait)? | Everyone.org, accessed September 7, 2025, https://everyone.org/blog/ibudilast-for-als
29. KETAS Capsules 10mg | Kusuri-no-Shiori(Drug Information Sheet), accessed September 7, 2025, https://www.rad-ar.or.jp/siori/english/search/result?n=1306
30. KETAS Eye-drops 0.01% | Kusuri-no-Shiori(Drug Information Sheet), accessed September 7, 2025, https://www.rad-ar.or.jp/siori/english/search/result?n=1744
31. Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis | ClinicalTrials.gov, accessed September 7, 2025, https://clinicaltrials.gov/study/NCT01982942
32. Enrollment Complete for Phase 2b/3 COMBAT-ALS Study of PDE4 Inhibitor Ibudilast, accessed September 7, 2025, https://www.neurologylive.com/view/enrollment-complete-phase-2b-3-combat-als-study-pde4-inhibitor-ibudilast
33. Ibudilast in MS | Multiple Sclerosis News Today, accessed September 7, 2025, https://multiplesclerosisnewstoday.com/ibudilast-mn-166-multiple-sclerosis/
34. MediciNova Announces Positive FDA Feedback to Start Phase III Plan for MN-166 (ibudilast) to Treat ALS | The ALS Association, accessed September 7, 2025, https://www.als.org/blog/medicinova-announces-positive-fda-feedback-start-phase-iii-plan-mn-166-ibudilast-treat-als
35. COMBAT-ALS Phase 2b/3 Trial of MN-166 (Ibudilast) in ALS: Study Design and Trial Update (5149) - Neurology.org, accessed September 7, 2025, https://www.neurology.org/doi/10.1212/WNL.94.15_supplement.5149
36. COMBAT-ALS - Lehigh Valley Health Network, accessed September 7, 2025, https://www.lvhn.org/research/clinical-trials/combat-als
37. Medicinova Completes COMBAT-ALS Trial Enrollment - The Clinical Trial Vanguard, accessed September 7, 2025, https://www.clinicaltrialvanguard.com/news/medicinova-completes-combat-als-trial-enrollment/
38. MediciNova Achieves Enrollment in COMBAT-ALS Clinical Trial - TrialStat Solutions Inc., accessed September 7, 2025, https://trialstat.com/2025/09/medicinova-achieves-enrollment-in-combat-als-clinical-trial/
39. Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial - PMC - PubMed Central, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8102622/
40. Mayo Clinic awarded federal grant to study experimental ALS drug, accessed September 7, 2025, https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-awarded-federal-grant-to-study-experimental-als-drug/
41. NCT03341078 | Pilot Study of the Effect of Ibudilast on Neuroinflammation in Methamphetamine Users | ClinicalTrials.gov, accessed September 7, 2025, https://clinicaltrials.gov/study/NCT03341078
42. MediciNova Announces Presentation of Results from the Phase 2b Trial of MN-166 (ibudilast) in Alcohol Use Disorder at the 46th Annual Research Society on Alcohol (RSA) Scientific Meeting, accessed September 7, 2025, https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-presentation-results-phase-2b-trial-mn-166/
43. Pharmacokinetic profiles of 5 mg/kg ibudilast, a phosphodiesterase inhibitor, orally administered to dogs in fasted and non-fas - ResearchGate, accessed September 7, 2025, https://www.researchgate.net/profile/Mario_Giorgi/publication/328020693_Pharmacokinetic_profiles_of_5_mgkg_ibudilast_a_phosphodiesterase_inhibitor_orally_administered_to_dogs_in_fasted_and_non-fasted_states_A_preliminary_study/links/5bbb4b094585159e8d8c3057/Pharmacokinetic-profiles-of-5-mg-kg-ibudilast-a-phosphodiesterase-inhibitor-orally-administered-to-dogs-in-fasted-and-non-fasted-states-A-preliminary-study.pdf?origin=scientificContributions
44. MediciNova Announces Abstract Regarding Results of a Clinical Trial of MN-166 (ibudilast) in Glioblastoma Accepted for Presentation at the 2024 American Society of Clinical Oncology Annual Meeting (2024 ASCO), accessed September 7, 2025, https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-abstract-regarding-results-clinical-trial/
45. MediciNova Announces Data from Phase 1b/2a Clinical Trial of MN-166 (ibudilast) in Glioblastoma Patients at the American Society of Clinical Oncology (ASCO) Annual Meeting 2024, accessed September 7, 2025, https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-data-phase-1b2a-clinical-trial-mn-166/
46. Myelopathy Recruiting Phase 3 Trials for Ibudilast (DB05266) | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/indications/DBCOND0017511/clinical_trials/DB05266?phase=3&status=recruiting
47. What is Ibudilast used for? - Patsnap Synapse, accessed September 7, 2025, https://synapse.patsnap.com/article/what-is-ibudilast-used-for
48. Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis | MedPath, accessed September 7, 2025, https://trial.medpath.com/clinical-trial/90d1236c54ed63c4/nct01982942-phase-2-study-ibudilast-progressive-multiple-sclerosis
49. Ibudilast: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/drugs/DB05266
50. Buy Ketas (ibudilast) Online • Price & Costs | Everyone.org, accessed September 7, 2025, https://everyone.org/ketas-ibudilast
51. ibudilast. - Search Orphan Drug Designations and Approvals - FDA, accessed September 7, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=445814
52. EU Panel Recommends Orphan Drug Status for ALS Therapy Ibudilast - ALS News Today, accessed September 7, 2025, https://alsnewstoday.com/news/eu-panel-recommends-orphan-drug-status-for-als-therapy-ibudilast/
53. Union Register of medicinal products - Public health - European Commission, accessed September 7, 2025, https://ec.europa.eu/health/documents/community-register/html/o1801.htm