01
Inflammation Control
Blocks master inflammatory transcription factors NF-κB, STAT3, HIF-1α, and AP-1 — reducing proinflammatory cytokines (TNF-α, IL-6, IL-1β) and ROS overproduction that sustain chronic mucosal inflammation.
Science
Upstream modulation.
Upstream modulation.
One target. Many diseases.
APX3330 is a first-in-class oral inhibitor of APE1/Ref-1 — the master regulator of transcription factors central to IBD disease progression. The mechanism fills gaps in current standard of care with future opportunities in cancer, diabetic retinopathy, rheumatoid arthritis, and neurodegenerative disease.
Mechanism of Action
A novel upstream point of intervention.
APX3330's upstream mechanism enables combination with every approved IBD class — including JAK, TNF-α, IL-23, TL1A, and α4β7 — without mechanistic redundancy or additive immunosuppression risk. NF-κB, for example, is a master "key" transcription factor modulating inflammation, immune response, and cell survival simultaneously.
APX3330 · APE1/Ref-1 inhibitor
NF-κB
Master inflammation
HIF-1α
Hypoxia / vascular
STAT3
Cytokine signaling
AP-1
Proliferation / stress
converges on validated downstream IBD biology
TNF-α / NF-κB
Anti-TNF class
IL-23 / Th17
Anti-IL-23 class
TL1A / remodeling
Anti-TL1A class
α4β7 / trafficking
Integrin class
JAK / STAT
JAK inhibitor class
Five Domains of Disease Impact
Addressing what current therapies leave unresolved.
Current IBD therapies primarily suppress downstream inflammation. They ignore key pathological processes including epithelial stress, oxidative injury, neuronal dysfunction, and systemic immune amplification. APX3330 is designed to address all five.
02
Barrier Integrity
Restores epithelial resilience and antimicrobial defense, stabilizing the gut mucosa and reducing permeability.
03
Neural Protection
Preserves enteric neurons and glial cells — addressing persistent dysmotility, urgency, and pain that existing therapies don't touch.
04
Oral Dosing
Daily 1–2× oral dosing with an established safety profile across ~400 patients in prior clinical studies. No injectable-related adherence burden.
05
CHIP & Hematopoiesis Correction
Dials down disease-driven Ref-1 signaling to restore hematopoietic stem cell function, correct myeloid bias, and limit IBD-driven CHIP expansion and myeloid infiltration in the colon.
↗ Forward
Future Indications
Beyond IBD: cancer, diabetic retinopathy, rheumatoid arthritis, Alzheimer's, Parkinson's, and neonatal necrotizing enterocolitis. One target, many diseases.
Human Safety & Tolerability
~400 subjects · 11 trials · chronic dosing supported.
~400
Subjects Dosed
Across 11 Phase 1/2 trials
600 mg
RP2D Established
Oral daily dosing
0
Treatment-Related SAEs
In Phase 1 oncology trial
<5%
Overall AE Rate
vs placebo in Phase 2
| Program | N | Dose | Duration | Key Safety Findings |
|---|---|---|---|---|
| Phase 1 Oncology NCT03375086 |
19 | 240–720 mg/d | 21-day cycles (to 421d) | No SAEs; G1 fatigue most common; 1 DLT at 720 mg (G3 rash, reversible). RP2D = 600 mg/d. |
| Phase 1 Healthy Volunteer (Eisai) |
~100 | 10–600 mg/d | Single & multi-dose | <10% mild diarrhea vs 0% placebo; 2 reversible rashes at 600 mg (MTD). Supports chronic dosing. |
| Phase 2 Hepatitis (Eisai, 422 patients) |
~200 | Up to 600 mg | Multi-month | AEs in <5% of patients, similar to placebo; favorable hepatic and renal safety. Largest chronic dataset. |
| ZETA-1 Phase 2b — Diabetic Retinopathy NCT04692688 |
~50 | 600 mg/d | 24 weeks | No drug-related AEs except 2 diarrhea episodes (same patient); 5 SAEs all unrelated. Placebo-level AE profile. |
Summary for IBD development: No significant organ toxicity (liver, heart, kidney, brain, lung).
No vital sign abnormalities. No treatment-related SAEs in oncology trial. AE rates comparable to placebo in
ZETA-1. Established 600 mg/day RP2D supports proposed IBD doses (300 mg & 600 mg for Phase 2a). Clean
profile is a critical differentiator versus JAK inhibitors (black-box warnings for VTE, MACE, malignancy) and
TNF-α inhibitors (serious infection risk).
Sources: Kelley et al., medRxiv 2025; Su et al., IOVS 2022 (ZETA-1); Nagakawa et al., JPET 1993 (Eisai hepatitis); Kelley Lab, IU School of Medicine.
Preclinical Validation
Validated in multiple translatable IBD models.
Winnie Mouse Model — Chronic Colitis
APX3330 corrects inflammation, provides neuroprotection, and attenuates weight loss.
- Blocks inflammation and reduces clinical symptoms
- Corrects colonic contractile activity and GI transit
- Regeneration of nerve fibers and glial cells in colon
- Prevents oxidative stress and DNA damage in myenteric neurons
DSS Mouse Model — Acute Colitis
APX3330 corrects inflammation, increases colon length, and soothes intestines.
- Decreased body weight loss, rectal prolapse, edema, bleeding
- Corrects intestinal permeability
- Normalizes GI antibacterial defense
- Published in Inflamm. Bowel Dis. 2020 · PMID 32618996
APX3330 compares favorably to successful IBD MOAs across acute DSS, chronic Winnie, adoptive transfer, and T-cell transfer models. See full preclinical benchmarking in the data room.
Pipeline
Late-stage program · multiple indications.
| Program | Indication | Preclinical | IND-Ready | Phase 1 | Phase 2 | Phase 3 | Notes |
|---|---|---|---|---|---|---|---|
| APX3330 | Ulcerative Colitis | ✓ | ✓ | ✓ | FOCUS → P2a/P2b | — | Lead indication · 2027 topline P2a |
| APX3330 | Crohn's Disease | ✓ | ✓ | — | Label expansion | — | Follow-on · single study for label expansion |
| APX3330 | Diabetic Retinopathy | ✓ | ✓ | ✓ | Completed 2b | — | Proven safety, moderate efficacy at 6 mos |
| APX3330 | Necrotizing Enterocolitis (NEC) | ✓ | — | — | — | — | Orphan · grants & FDA SPA pathway |
| APX2009 / APX2014 | TBD (2nd gen) | ✓ | — | — | — | — | Second-generation composition of matter |
Clinical Development Plan
Phase 2a POC in Australia, then Phase 2b at FDA-approvable endpoints.
Phase 2a · POC
Open-label proof of concept
Inclusion
- Refractory UC patients
- Biologic-experienced
- Open to add-on design
Structure
- 10–20 open-label patients
- 300–600 mg/day oral
- 3-month endpoint (+3 extension)
- ~5 Australian sites
Endpoints
Clinical response · clinical remission · endoscopic improvement · inflammatory/blood/mechanistic biomarkers · weight loss · PROs
Budget: $1.5M AUD → $1M USD (60% AUS R&D saving)
6 months to FPI · 6 months to full data (2H 2027)
6 months to FPI · 6 months to full data (2H 2027)
Phase 2b · FDA-Approvable
Randomized double-blind placebo-controlled
Inclusion
- Refractory UC patients
- Biologic-experienced
- Add-on design possible
Structure
- 150–240 randomized, double-blind
- Placebo + active dose arm(s)
- 3-month endpoint
- ~5 AUS + 25+ AUS/US sites
Endpoints
Clinical response · clinical remission · endoscopic improvement · biomarkers · PROs · optional 6-month maintenance
Budget: ~$8.5M gross → $5–6M net
9 months to FPI · 18–24 months to data
9 months to FPI · 18–24 months to data
Intellectual Property
Protected through 2044+ before PTE.
Seven patent families covering composition of matter, methods of use, and formulation — providing extended global commercial runway.
| Family | Patent No. | Scope | Expiry |
|---|---|---|---|
| APE1/Ref-1 Combo Therapy | US20190160034A1 | Granted US · GI inflammation claims | 2034 |
| 2nd-Generation Compounds | US11,723,886 B2 | APX2009 / APX2014 · inflammation claims | 2036 |
| Inflammation / Pain / IBD | US11,351,130 B2 | IBD claims · DNA repair in gut/ENS | 2038 |
| Polymorphs & Salts | US12,312,308 B2 | Issued 05/27/25 · 9 countries | 2044 |
| Ca Salt Formulations | WO 2025/194083 | Published · national stage Sep 2026 | 2045 |
| NEC Method of Use | IU disclosure (2021) | APE1/Ref-1 inhibition in neonatal NEC | 2041 |
| IBD Method of Use | IU filings | UC/Crohn's treatment · exclusivity | ~2038+ |
Sources: Frontage 039567/039837; CRL-ASH 20488855/60; ¹⁴C-QWBA; IURTC Patent Portfolio; OPUS Vendor List.