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Retinal Physician

Article

Oral Drug Pipeline for Retinal Disease

Systemic options could reduce patient burden.

By: Charles DeBoer, MD, PhD, Suzanne Michalak, MD, Ehsan Rahimy, MD
Retinal Physician July 1, 2022 Vol 19, Issue July/August 2022 Page(s): 27, 28, 30, 32

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Although oral drug therapy is one of the most convenient methods of drug administration, for retinal disease, intravitreal or periocular injections are more commonly used. The drug concentration can be directly targeted to the retina, retinal pigment epithelium, and surrounding choroid instead of administered systemically, which may require larger doses and be associated with more systemic side effects. However, there are disadvantages to using injections, including pain, risk of endophthalmitis, risk of retinal tear/detachment, frequent appointments, clinic burden, and loss to follow-up. The oral route of medication has several advantages, including no need for procedures, medication stability, and reduced office visits. Therefore, there is significant interest in developing standalone or adjunct orally administered pharmacotherapies to treat various retinal diseases. This article describes the pharmaceutical pipeline of oral medications for retinal disease, categorized by therapeutic approach, including promising pharmaceuticals, repurposed medications, and pharmaceuticals that have failed to meet efficacy goals to demonstrate the effort required for success. Table 1 has a list of pharmaceuticals discussed.

Table 1: Oral Pharmaceuticals for Retinal Disease
PHARMACEUTICAL DISEASE STAGE MECHANISM
Inflammatory Mediators
40 mg doxycycline (Oracea; Galderma Laboratories) Dry AMD (GA), nAMD Phase 2/3 Anti-inflammatory
Minocycline DME, dry AMD (GA) Phase 2 Anti-inflammatory
OCX-063; Occurx Proliferative vitreoretinopathy, nAMD, NPDR Phase 1 complete Anti-inflammatory, antifibrotic
AKST4290; Alkahest nAMD Phase 2b Inhibitor of the eosinophil/mast cell chemokine receptor 3 (CCR3)
Tonabersat (Xiflam; Ocunexus DME, AMD (GA) Planning phase 2 trial Blocks connexin43 (Cx43) hemichannels that are responsible for inflammasome mediated autoinflammation
Oral Tyrosine Kinase Inhibitor
X-82; Tyrogenex nAMD Phase 2 trial terminated early Oral tyrosine kinase inhibitor active against VEGF receptors and platelet derived growth factor receptors
Oral Complement Inhibition
Danicopan; Alexion/Astrazeneca Rare Disease AMD (GA) Phase 2 trial Complement factor D inhibitor that inhibits the complement alternative pathway
Visual Cycle Modulators
Emixustat; Kubota Pharmaceutical Stargardt disease, dry AMD (GA), DR Phase 3 Stargardt; phase 2b/3 for GA did not meet primary efficacy Nonretinoid that inhibits RPE65 and modulates the visual cycle
Fenretinide; Revision Dry AMD (GA), Stargardt Phase 2 did not show a significant difference in growth rate of GA relative to control Vitamin A derivative with binds retinol-binding protein to help with secretion and reduce circulating retinol
ALK-001; Alkeus Pharmaceuticals Dry AMD (GA) Startgart AMD with GA phase 2/3 (NCT03845582); Stargardt phase 2NCT02402660 Deuterated vitamin A at the C20 position slows dimerization and formation of A2E which is believed to lead to lipofuscin formation and disease pathogenesis
LBS-008; Belite Bio Startgart, dry AMD with GA Phase 1 safety complete (NCT03735810); Phase 3 Stargardt expected Antagonist of serum retinol binding protein (RBP4) that lowers levels of RBP4 and vitamin A, reducing toxic byproducts of vitamin A
Kallikrein Inhibitors
RZ402; Rezolute Bio DME Phase 1b complete; phase 2 planned 2022 Small molecule plasma kallikrein inhibitor
KV123833, KV998076; Kalvista DME Intravitreal KVD001 did not meet primary endpoint in phase 2 trial, but showed less reduction in vision compared with sham. Oral medications in preclinical stage. Kallikrein inhibitors
VE-4840, VE-3539; Verseon DR Preclinical Kallikrein inhibitors
Pharmaceutical Disease Stage Mechanism
Peroxisome Proliferator-activated Receptor Alpha (PPARα) Agonists
Fenofibrate; Abbott DR Completed phase 3 (FIELD/ACCORD studies) PPARα agonist. PPARα forms a heterodimer with retinoid X receptor and interacts with a peroxisome proliferator response element, which is located in the promoter of target genes, leading to the activation of target gene transcription.
Pemafibrate; Kowa Pharmaceutical DR Phase 3 PROMINENT-Eye Ancillary Study subgroup, was cancelled as recruitment for the substudy did not meet the goals Selective PPARα agonist, intended to reduce systemic side effects such as elevated liver enzymes and to have less effect on the kidney compared with other PPARα agonist
Saroglitazar (Lipaglyn; Zydus Cadila) DR Approved for used in diabetes, being investigated for diabetic retinopathy Dual PPARα agonist
Rosiglitazone (Avandia; GlaxoSmithKline DR Approved for use with diabetes, being investigated for diabetic retinopathy PPARα agonist
Glycation Inhibitor
GLY-230; Glycadia Pharmaceuticals DR Phase 2 clinical development First-in-class selective glycation inhibitor. Prevents modification of albumin by Amadori glucose adducts. Amadori-modified glycated albumin has been associated with microvascular complications of diabetes, including nephropathy and retinopathy
Removal of Toxic Byproducts
RT11; Retrotope AMD Preclinical Isotopically stabilized, synthetic docosahexaenoic acid (DHA), designed to reduce oxidative stress from lipid peroxidation
REF-1 Inhibition
APX3330; Ocuphire Pharma DME/DR Phase 2 (NCT04692688) Ref-1 inhibitor, reduces vascular and inflammatory ocular disease.
AMD, age-related macular degeneration; DME, diabetic macular edema; DR, diabetic retinopathy; GA, geographic atrophy; nAMD, neovascular age-related macular degeneration; PPARα, peroxisome proliferator-activated receptor alpha.

ANTI-INFLAMMATORY AGENTS

Multiple anti-inflammatory drugs are under evaluation to treat both forms of macular degeneration and diabetic retinopathy (DR). Tetracycline derivatives have been shown to have anti-inflammatory properties, including matrix metalloproteinase inhibition and neuroprotective properties. Forty mg doxycycline (Oracea; Galderma Laboratories) is being investigated for geographic atrophy (GA) in dry age-related macular degeneration (AMD) in a 24-month, 286 participant phase 2b/3 study.1-3 For neovascular AMD (nAMD) it has been shown to reduce angiographic leakage and choroidal neovascularization (CNV) in a laser induced mouse model of CNV.4 Minocycline has been evaluated for diabetic macular edema (DME)5 and is currently in a 36 month phase 2 (n=37) trial for its efficacy for GA in dry AMD.6

OCX063 (Occurx) is an oral anti-inflammatory antifibrotic agent for proliferative vitreoretinopathy, nAMD, and nonproliferative diabetic retinopathy (NPDR).7 It has been shown to reduce fibrosis in Norway rats with laser induced CNV, indicating its potential use in conjunction with anti-VEGF therapies8 and to reduce inflammatory markers in a diabetic rat model.9 To date, it has completed a phase 1 safety and pharmacokinetic study.7,10

AKST4290 (Alkahest) is an oral inhibitor of the eosinophil/mast cell chemokine receptor 3 (CCR3) being investigated for use in nAMD. CCR3 has been shown to be specifically expressed in human choroidal neovascular endothelial cells in the setting of nAMD.11 Preclinical studies demonstrated that blockage of CCR3 in mice and nonhuman primates cause direct inhibition of endothelial cell proliferation and reduction in CNV11-13 and that there may be an additive effect with CCR3 and VEGFR2 blockade.13-15 Patients in the phase 2a clinical trial (n=30) for nAMD had a mean increase in best-corrected visual acuity (BCVA) of 7.0 letters.16 AKST4290 started its 36-week phase 2b clinical trial (n=107) in 2020. Patients will receive oral AKST4290 400 mg or 800 mg twice daily vs control with an initial loading dose of intravitreal aflibercept. Primary endpoint is BCVA, with secondary endpoints of time to first rescue therapy, number of aflibercept injections provided, proportion of subjects with BCVA change >15 letters, mean change in central subfield thickness, and adverse events.17

Tonabersat (Xiflam; Ocunexus) is a connexin hemichannel blocker18 which regulates activation signaling of the inflammasome, and is used for DME and dry AMD. Tonabersat has been shown to preserve retinal photoreceptor function in light-damaged retina animal model of dry AMD, and reduce incidence of microaneurysms in a diabetic rat model.19,20 It has been evaluated in human RPE cells21 and human retinal explants.22 A pilot study evaluating short-term efficacy of XiFlam for DME is being developed for the DRCR Retina Network.23

TYROSINE KINASE INHIBITORS

X-82 (Tyrogenex) is an oral tyrosine kinase inhibitor active against VEGF receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR) which was developed to treat patients with certain solid tumors, von Hippel-Lindau disease, and nAMD. The phase 2 trial consisted of 157 subjects with nAMD and at least 2 prior anti-VEGF intravitreal injections separated into a treated with placebo, 50 mg, 100 mg, or 200 mg daily of X-82 for 52 weeks. There was a dose dependent trend in reduction of anti-VEGF required for subjects while maintaining noninferiority BCVA. However, the trial was ended early due to insufficient benefit-to-risk ratio, given concerns of elevated liver enzymes and the number of patients stopping the trial due to adverse events.24

VISUAL CYCLE MODULATORS

Several pharmaceuticals are aimed at modulating the visual cycle to lower toxic byproducts of the visual cycle that are thought to contribute to the pathophysiology of Stargardt disease and AMD.25 Emixustat (Kubota Pharmaceutical) is an oral inhibitor of the RPE65 protein that slows the visual cycle.26 In phase 1/2 studies subjects reported transient visual phenomena related to the modulation of the rod visual cycle.26,27 It did not meet its primary endpoint for GA in the 24-month phase 2b/3 trial (n=508).28 Emixustat is currently undergoing a phase 3 trial for Stargardt disease29 and is in clinical trials for DR.30

Fenretinide (Revision) is a synthetic derivative of vitamin A which can bind to retinol-binding protein and be excreted in urine, thereby reducing circulating retinol. This reduced production of A2E in an animal Stargardt model.31 When evaluated in a phase 2 trial for GA in AMD, there was a trend for reduced growth rate of GA relative to control, but it did not meet statistical significance.32

Dimerization of vitamin A causes lipofuscin at the RPE level contributing to Stargardt disease and dry AMD. ALK-001 (Alkeus Pharmaceuticals) is a deuterated vitamin A that slows this dimerization while preserving the visual cycle.33 It has currently received FDA breakthrough therapy designation for Stargardt disease and is completing a 2-year phase 2 trial, the TEASE trial.34–36 The SAGA trial is a 24-month, multicentered placebo-controlled phase 2/3 clinical trial for GA planned to complete in 2023.37

LBS-008 (Belite Bio) is an antagonist of serum retinol binding protein (RBP4) that lowers levels of RBP4 and vitamin A, leading to reduced delivery of vitamin A to the eye, reducing toxic byproducts of vitamin A.38 It is being investigated for use in Stargardt disease and AMD. Phase 3 trials in Stargardt disease started in 2021.39

KALLIKREIN INHIBITORS

Several drugs in development for DME target inhibition of the kallikrein-kinin system, which causes activation of bradykinin, increased vascular permeability and inflammation, and induction of the intrinsic pathway of coagulation. Kalvista initially developed an intravitreal treatment, KVD001, which did not meet its primary (BCVA) or secondary endpoints in the phase 2 trial, although there was a decreased proportion of subjects with reduced vision in the treatment group.40 Kalvista is working on an oral plasma kallikrein therapy for DME, which has shown efficacy in a mouse model.41,42 RZ402 (Rezolute Bio) is an oral plasma kallikrein inhibitor that demonstrated safety in animal models,43 and it has completed phase 1b trials. Phase 2 trials are planned for 2022.44 Verseon uses physics and artificial intelligence to drive drug delivery and generates multiple chemically distinct drugs for targeted diseases. It has 2 oral plasma kallikrein inhibitors in a preclinical study, oral VE-4840, and oral VE-3539.45-47

COMPLEMENT INHIBITION

ALXN2040 (Danicopan; Alexion Pharmaceuticals) is an inhibitor of complement factor D, an integral part of the complement alternative pathway. Dysregulation of the complement system has been implicated in pathogenesis of AMD. Preclinical work has demonstrated Danicopan crosses the blood-retinal barrier with concentration in the choroid/RPE in rabbit models.48,49 It has been evaluated in phase 1 trials50 and is being investigated in phase 2 trials for GA in AMD.51,52

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA AGONISTS

Peroxisome proliferator-activated receptor alpha (PPARα) agonists have been used to reduce triglyceride levels and low-density lipoproteins and have been evaluated for DR.53 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study demonstrated that in patients with preexisting retinopathy, fewer patients with fenofibrate (Abbott) therapy had a 2-step progression of ETDRS retinopathy grade. There was no statistical difference in loss of 2 lines of visual acuity or in rates of occurrence of macular edema.54 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study group found a benefit of fenofibrate therapy on the progression of DR, with benefit coming from subjects with preexisting DR. Moderate vision loss was not statistically different between control and fenofibrate groups. A recent retrospective cohort study found fenofibrate to be associated with a decreased risk of developing vision-threatening DR, due to a decreased risk in developing proliferative DR.56

Pemafibrate (Kowa Pharmaceuticals) is a selective PPARα agonist57 that has been shown promising results for DR in animal models,58–60 although the phase 3 trial subgroup for DR, PROMINENT-Eye Ancillary Study subgroup, was cancelled because recruitment for the substudy did not meet the goals.61 Other PPARa agonists include saroglitazar (Lipaglyn; Zydus Cadila), which has been evaluated in preclinical models,62 and rosiglitazone (Avandia; GlaxoSmithKline), which has been evaluated for delaying onset of proliferative DR in a retrospective study.63

GLYCATION INHIBITOR

GLY-230 (Glycadia Pharmaceuticals) is a first-in-class selective glycation inhibitor that has finished phase 1b/2a clinical trials.64 It prevents modification of albumin by Amadori glucose adducts, which has been associated with microvascular complications of diabetes, including nephropathy and retinopathy. It has shown to be related to decreased VEGF and increased PEDF in the vitreous of a diabetic rat model.65 It is currently in phase 2 clinical development for diabetic nephropathy and DR.66

REMOVAL OF TOXIC BYPRODUCTS

RT11 (Retrotope) is an isotopically stabilized, synthetic docosahexaenoic acid (DHA). It is designed to reduce oxidative stress from lipid peroxidation, which is a component of macular degeneration. A 26-week toxicity study was completed, and it was tolerated at doses tested.67

REF1 INHIBITION

APX3330 (Ocuphire Pharma) is a small molecule that targets apurinic/apyrimidinic endonuclease 1/redox effector factor-1, Ref-1. It is being investigated for DR and DME as it decreases abnormal angiogenesis and inflammation. It has been evaluated in preclinical models of CNV.68 A phase 2 trial for moderately severe NPDR and mild proliferative DR and DME is planned.69

CONCLUSION

Oral delivery of medication for eye disease would significantly reduce side effects of intravitreal therapy and clinic burden for patients and providers. However, there are limitations, including difficulty of targeting the eye as well as systemic side effects. Several pharmaceuticals are in development that could act as an adjunct to current therapy or as standalone treatment for retinal disease. RP

Ehsan Rahimy, MD, is a vitreoretinal specialist at Palo Alto Medical Foundation and an adjunct clinical assistant professor at Stanford University School of Medicine in Palo Alto, California. Charles DeBoer, MD, PhD, and Suzanne Michalak, MD, are ophthalmology fellows in the department of ophthalmology at Byers Eye Institute at Stanford University School of Medicine in Palo Alto, California. The authors report no relevant disclosures. This current work was partially funded by Research to Prevent Blindness and NIH grant P30-EY026877.

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