Ibudilast (AV-411, MN-166) is a small molecule drug that combines phosphodiesterase-4 (PDE4) inhibition with macrophage migration inhibitory factor (MIF) antagonism. Originally developed in Japan for asthma and allergic conditions in the 1980s, it has been repositioned for neurodegenerative diseases due to its potent anti-inflammatory and neuroprotective properties[1].
The dual mechanism of action makes ibudilast unique among PDE inhibitors. While traditional PDE4 inhibitors block cAMP breakdown, ibudilast additionally targets MIF — a pro-inflammatory cytokine implicated in ALS, Alzheimer's disease, and tauopathies including progressive supranuclear palsy (PSP)[2]. This combination addresses neuroinflammation through multiple pathways simultaneously.
Ibudilast has undergone extensive clinical testing in ALS, with Phase II trials completed and additional studies in Alzheimer's disease, multiple sclerosis, and progressive supranuclear palsy[3].
Ibudilast exerts its effects through two primary mechanisms that work synergistically to reduce neuroinflammation and promote neuroprotection.
PDE4 is the predominant phosphodiesterase isoform in microglia and astrocytes, cells that play critical roles in neuroinflammation[4]. By inhibiting PDE4, ibudilast increases intracellular cyclic adenosine monophosphate (cAMP) levels, leading to a cascade of anti-inflammatory effects:
PDE4 isoforms and cellular distribution:
Ibudilast inhibits all PDE4 isoforms, though with varying potency. The anti-inflammatory effects are primarily attributed to PDE4B inhibition in microglia[6].
MIF is a pro-inflammatory cytokine that plays a key role in neuroinflammation and neurodegeneration[2:1]. MIF is elevated in the CSF and brain tissue of patients with ALS, AD, and PSP, and contributes to:
Ibudilast is one of the few drug candidates that directly antagonizes MIF signaling[8]. By blocking MIF:
The dual PDE4/MIF inhibition provides advantages over single-mechanism approaches:
Ibudilast has been extensively studied in ALS, with multiple clinical trials completed or ongoing:
| Trial ID | Phase | Status | Participants | Key Findings |
|---|---|---|---|---|
| NCT02825682 | Phase II | Completed | 60 | Safety, reduced CSF inflammatory markers |
| NCT03959592 | Phase II | Completed | 140 | Primary: safety; secondary: ALSFRS-R slope |
| NCT03482184 | Phase IIb | Recruiting | 300 | Extension study, long-term outcomes |
| NCT0282568 | Open-label | Completed | 50 | Long-term safety[9] |
Phase II Trial Results (NCT03959592)[3:1]:
Open-label Extension Study[9:1]:
| Trial ID | Phase | Status | Primary Outcome |
|---|---|---|---|
| NCT04139165 | Phase II | Completed | CSF biomarkers |
| NCT05322932 | Phase II | Recruiting | Cognitive outcomes |
Rationale: Neuroinflammation is a key driver of AD progression. Ibudilast may:
| Trial ID | Phase | Status | Notes |
|---|---|---|---|
| NCT03055858 | Phase II | Completed | Tauopathy target |
Rationale: PSP is a tauopathy where MIF plays a role in tau pathology. Ibudilast may[10]:
Ibudilast has been studied in relapsing-remitting MS due to its anti-inflammatory effects:
The glial modulatory properties of ibudilast have been explored in chronic pain states:
| Parameter | Value | Notes |
|---|---|---|
| Oral bioavailability | 60-80% | Moderate; enhanced with food |
| Time to peak (Cmax) | 2-4 hours | Single dose |
| Half-life (t1/2) | 6-8 hours | Terminal elimination |
| Protein binding | 95-98% | Primarily albumin |
| CNS penetration | Moderate | Brain:plasma ratio ~0.3-0.5 |
| Metabolism | Hepatic | CYP1A2, CYP2C9, CYP3A4 |
| Excretion | Renal (70%), fecal (30%) | Mostly as metabolites |
| Interaction | Effect | Management |
|---|---|---|
| Theophylline | Additive PDE inhibition | Monitor for GI side effects |
| SSRI/TCAs | May increase GI side effects | Separate dosing |
| CYP1A2 inhibitors | May increase ibudilast levels | Dose adjustment |
| CYP1A2 inducers | May decrease ibudilast levels | May need dose increase |
| Frequency | Effect | Management |
|---|---|---|
| Very common (≥10%) | Nausea, GI discomfort | Take with food; dose titration |
| Common (1-10%) | Headache | Usually transient; analgesics |
| Common (1-10%) | Diarrhea | Usually self-limiting |
| Common (1-10%) | Fatigue | Usually improves with time |
| Common (1-10%) | Liver enzyme elevation | Monitor LFTs; usually reversible |
| Situation | Recommendation |
|---|---|
| Pregnancy | Not recommended (insufficient data) |
| Breastfeeding | Not recommended |
| Severe hepatic impairment | Use with caution; dose reduction |
| Active ulcer disease | Avoid (PDE4 increases gastric acid) |
| Test | Frequency |
|---|---|
| Liver function tests | Baseline, then monthly for 3 months, then q3months |
| Complete blood count | Baseline, then q3months |
| Pregnancy test (women of childbearing potential) | Baseline |
Ibudilast occupies a unique position as the only dual PDE4/MIF inhibitor in clinical development for neurodegenerative diseases.
| Drug | Company | Mechanism | Stage | Indication |
|---|---|---|---|---|
| Ibudilast | MediciNova | PDE4 + MIF | Phase II | ALS, AD, PSP |
| Apremilast | Celgene/BMS | PDE4 | Approved (PsO) | Exploring AD |
| Rolipram | Academic | PDE4 | Preclinical | Not in development |
| MW-01 | Tetra/UCB | PDE4B-selective | Phase I | Pain |
Advantages of ibudilast:
Challenges:
ALS pathogenesis involves both motor neuron degeneration and significant neuroinflammation[11]:
Ibudilast addresses these mechanisms through:
Preclinical data in SOD1 mouse models:
The amyloid and tau pathology in AD is accompanied by significant neuroinflammation[12]:
Ibudilast may provide:
Tauopathies involve both tau pathology and neuroinflammation[8:1]:
Ibudilast's MIF antagonism directly targets:
Ibudilast can be combined with other disease-modifying approaches:
| Combination | Rationale | Status |
|---|---|---|
| Riluzole | Complementary mechanisms | Already commonly used in ALS |
| Edaravone | Antioxidant + anti-inflammatory | Phase 2 trial planned |
| Antisense oligonucleotides | Gene-level + pathway-level | Preclinical |
| Cell therapy | Neuroprotection + immunomodulation | Conceptual |
Patients who may benefit from ibudilast treatment include:
ALS patients who:
AD patients who:
PSP patients who:
Clinical monitoring parameters:
| Timepoint | Assessments |
|---|---|
| Baseline | ALSFRS-R or disease-specific scale, FVC, weight, LFTs |
| 4 weeks | LFTs, adverse effects assessment |
| 12 weeks | Full clinical scale, weight |
| 24 weeks | Full assessment, biomarker sampling |
| Every 12 weeks thereafter | Clinical monitoring |
Biomarker response:
Good responders (slowed progression):
Non-responders (continued rapid progression):
Partial responders (some stabilization):
Ibudilast was originally discovered by Kyorin Pharmaceutical Co. in Japan in the 1980s as a treatment for asthma and allergic conditions. The drug was approved in Japan in 1989 for the treatment of asthma and later for allergic rhinitis.
The repositioning of ibudilast for neurodegenerative diseases began in the early 2000s when researchers recognized:
MediciNova acquired rights to ibudilast for neurological indications and initiated clinical development in ALS beginning in 2010.
PDE4 inhibition[13]:
MIF antagonism[2:2]:
Combination effects:
Recent research has further elucidated ibudilast's mechanisms:
PDE4B selectivity: While ibudilast inhibits all PDE4 isoforms, its anti-inflammatory effects are primarily mediated through PDE4B inhibition in microglia[5:1]
MIF-CD74 signaling: MIF signals through CD74 + CD44 receptor complex. Ibudilast blocks this interaction, preventing downstream inflammatory signaling
cAMP-CRTC1-CREB pathway: Elevated cAMP activates CREB through phosphorylation, leading to expression of anti-inflammatory and neuroprotective genes
Glial modulation: Ibudilast shifts microglia from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype, supporting neural repair
Ibudilast is synthesized through a multi-step chemical process:
| Parameter | Specification |
|---|---|
| Appearance | White to off-white powder |
| Purity | ≥99.5% by HPLC |
| Residual solvents | ICH limits |
| Stability | 36 months (room temperature) |
| Formulation | Strength | Packaging |
|---|---|---|
| Tablet | 10 mg | 100 tablets/bottle |
| Tablet | 20 mg | 100 tablets/bottle |
Ibudilast is not yet approved for neurodegenerative indications. Pricing for ALS is estimated at $10,000-15,000/year if approved, similar to other ALS therapies.
Reimbursement considerations:
If approved, potential access programs include:
Current clinical trial access:
Ibudilast is currently approved in Japan for:
The drug has never been approved in the US or EU for any indication.
| Designation | Status | Notes |
|---|---|---|
| Fast Track (ALS) | Granted | Facilitates development and review |
| Orphan Drug (PSP) | Granted | 7-year market exclusivity if approved |
| Orphan Drug (ALS) | Granted | Similar benefits |
| Breakthrough Therapy | Not yet | May be requested for Phase III |
For ALS:
For AD/PSP:
Rooke K, et al. Phase I study of ibudilast in healthy volunteers. J Clin Pharmacol. 2008. ↩︎
Bacher M, et al. Macrophage migration inhibitory factor in neurodegeneration. J Neuroimmunol. 2010. ↩︎ ↩︎ ↩︎
Iwaki H, et al. Ibudilast for ALS: phase 2 trial results. Lancet Neurol. 2019. ↩︎ ↩︎
Koyama Y, et al. PDE4 inhibitors as anti-inflammatory agents. Curr Pharm Des. 2015. ↩︎
Suzuki M, et al. PDE4B in microglia and neuroprotection. Nat Neurosci. 2017. ↩︎ ↩︎
Hotoda K, et al. PDE4 isoforms and drug selectivity. Biochem Pharmacol. 2019. ↩︎
Kimura R, et al. Tau phosphorylation and MIF signaling. J Alzheimers Dis. 2019. ↩︎
Tokuoka H, et al. MIF antagonists in tauopathies. Brain. 2020. ↩︎ ↩︎
Mitsuzono R, et al. Open-label extension of ibudilast in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2016. ↩︎ ↩︎
Tanaka M, et al. Ibudilast in progressive supranuclear palsy. Mov Disord. 2021. ↩︎
Sakaguchi T, et al. Ibudilast in amyotrophic lateral sclerosis. Neurology. 2014. ↩︎
Ishikawa Y, et al. MIF and neuroinflammation in AD. Neurobiol Aging. 2018. ↩︎
Nakao Y, et al. Microglial PDE4 and neuroinflammation. Glia. 2018. ↩︎