Indications for APX3330

APX3330, a novel twice-daily oral tablet drug candidate, is currently being developed for diabetic retinopathy (DR) and diabetic macular edema (DME). These indications have approved intravitreal injection products that have established a precedent FDA approval pathway. APX3330 is an investigational drug candidate that is being tested in clinical trials and has not yet been approved by the FDA or other regulatory bodies for commercial sale.


Given the progressive nature of these diseases and the need for repeated therapy, only a fraction of patients can sustain the initial improvement in vision seen with current therapies, highlighting the unmet need for better pharmacologic interventions. Earlier treatment options to prevent or delay vision loss for patients with diabetic eye disease are also important.

Diabetic Retinopathy

Diabetes, a worldwide epidemic, is the leading cause of blindness among working-age adults. Diabetic retinopathy (DR) is a diabetes complication that affects eyes, caused by chronic elevated blood sugar levels, and other metabolic problems. The condition can develop in anyone who has type 1 or type 2 diabetes. The longer you have diabetes and the less controlled your blood sugar is, the more likely you are to develop this eye complication. Diabetes leads to damage to the blood vessels of the light-sensitive tissue at the back of the eye (retina), which at first might cause no symptoms or only mild vision problems, but eventually it can cause blindness.

When DR is in its early stages, blood vessels in the retina are damaged and can begin to leak fluid into the retina, a problem called diabetic macular edema (DME). In advanced stages, new and abnormal blood vessels form which may break and bleed. Fluid and hemorrhage interfere with vision and may further cause irreversible visual impairment due to retinal scarring and even retinal detachment. Even though biologic injection therapies have been approved for DR and treatment is possible, patients with DR are not widely treated in this early stage of the disease.

We believe that APX3330’s oral delivery could be preferred over current invasive methods, and it has the potential to be used as monotherapy (non-proliferative or early proliferative stages of diabetic retinopathy) or as an adjunct therapy (advanced stages).

Diabetic Macular Edema

Diabetic Macular Edema (DME) is the most common cause of vision loss in people with DR. The pathogenesis of DME involves abnormal vascular leakage, accumulation of fluid in the macula, retinal ischemia, and release of vasoproliferative growth factors and inflammatory mediators. In DME, the primary drug therapies today are intravitreal anti-VEGF antibodies and intravitreal corticosteroids, which are given as injections into the white (sclera) of the eye every one to three months.

Earlier treatment options to prevent or delay vision loss for patients with diabetic eye disease are important. APX3330’s safety profile, pharmacokinetic properties, and molecular target engagement data observed in clinical trials and its drug exposure in the retina seen in mouse models, combined with a unique oral tablet formulation, suggest its potential to reduce the frequency of anti-VEGF treatments and increase compliance for better outcomes.

Other Indications: Wet Age-Related Macular Degeneration and Retinal Vein Occlusion

Wet age-related macular degeneration (wAMD) is the most severe form of AMD, and the leading cause of irreversible vision loss in industrialized nations for those ages 65 and above. Patients with wAMD develop choroidal neovascularization, retinal pigment epithelial detachment, subretinal hemorrhages and fibrovascular scarring. Currently, three types of innovative treatments have been demonstrated to limit or delay loss of vision in patients with wAMD: laser photocoagulation, photodynamic therapy and anti-VEGF.

Retinal vein occlusion (RVO) is a vascular disorder of the retina and one of the most common causes of vision loss worldwide. It is classified according to the occlusion location; central retinal vein occlusion (CRVO) at the level of the optic nerve and branch retinal vein occlusion (BRVO) at the level of any central vein branch. Although the exact etiology of RVO remains unclear, it is likely to follow a thrombotic event. The vein blockage leads to ischemia, vascular leakage, macular edema, inflammation and neovascularization.

Given APX3330’s similar anti-angiogenesis MOA and novel oral administration, future clinical studies to explore wAMD and RVO with a partner of interest.

APX3330 Product Profile

APX3330 is a first-in-class orally administered inhibitor of Ref-1 (known also as APE-1/Ref-1 or APE1) targeting multiple retina (back-of-the-eye) disorders, initially diabetic retinopathy and diabetic macular edema; future indications may include wet age-related macular degeneration and retinal vascular occlusion. APX3330 has been dosed twice-a-day in over 400 subjects across 11 Phase 1 and Phase 2 trials, with few systemic adverse events reported and clinical data that supports chronic administration. Based on APX3330’s clinical and pre-clinical data, Ocuphire plans to begin a Phase 2 proof-of-concept study in non-proliferative DR and DME in 2020.

Mechanism of Action

Ref-1 keeps a diverse group of proteins called transcription factors in their active state so they can bind to DNA and activate the transcription of other protein coding genes related to multiple survival pathways, including hypoxia and neovascularization. APX3330 has a dual mechanism of action in validated pathways, uniquely decreasing both abnormal angiogenesis and inflammation by blocking pathways downstream of Ref-1. APX3330 specifically blocks Ref-1’s redox signaling function leading to simultaneous decreases in the activity of several important proangiogenic and proinflammatory transcription factors relevant to the pathophysiology of retinal and choroidal vascular diseases: HIF-1a to reduce VEGF signaling and NF-κB to modulate VEGF, TNF-α and other inflammatory cytokines.