AR-14034 for Age-Related Macular Degeneration

(NOVA-1 Trial)

Recruiting at 31 trial locations

Overseen By Alcon Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Alcon Research

Must be taking: Ocular anti-VEGF

Must not be taking: Ocular anti-VEGF

Disqualifiers: Ocular disease, Glaucoma, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 104

140 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary purpose of this study is to evaluate the safety and durability of single- and repeat administration of AR-14034 Sustained Release (SR) in subjects with neovascular age-related macular degeneration (nAMD).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had treatment with an ocular anti-VEGF product within 28 days before the study starts.

What data supports the effectiveness of the drug AR-14034 for age-related macular degeneration?

Research shows that axitinib, a component of AR-14034, effectively inhibits vascular endothelial growth factor (VEGF) receptors, which are involved in the development of abnormal blood vessels in age-related macular degeneration. Studies in animal models and its use in other conditions suggest it may help reduce these abnormal blood vessels. ^{1 2 3 4 5}

What safety data exists for axitinib, which may be related to AR-14034, in humans?

Axitinib, used for treating certain cancers, has shown variability in how different people process the drug, which can affect safety. Some patients have experienced impaired retinal circulation (reduced blood flow in the eye) as a side effect during treatment. ^{1 6 7 8 9}

How is the AR-14034 SR implant treatment different from other treatments for age-related macular degeneration?

The AR-14034 SR implant is unique because it delivers axitinib, a drug that blocks specific proteins (VEGF and PDGF) involved in abnormal blood vessel growth, directly into the eye, potentially offering longer-lasting effects compared to standard treatments that require frequent injections. ^{1 2 4 10 11}

Research Team

Director of Clinical Development, Alcon

Principal Investigator

Aerie Pharmaceuticals

Eligibility Criteria

This trial is for people with neovascular age-related macular degeneration (nAMD) who have had 3 to 6 prior anti-VEGF treatments in the last 8 months or are newly diagnosed within 9 months. Participants must have a certain level of vision in both eyes and be able to follow study procedures.

Inclusion Criteria

Additional requirements may also need to be met as specified in the study guidelines.

Your eye is clear and your pupil can open wide enough for all the tests and procedures in the study.

I have a specific eye condition due to aging that affects my vision.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage 1: Dose Escalation

48-week, open-label evaluation of AR-14034 SR with dose escalation in two cohorts

48 weeks

Regular visits through Week 48

Stage 2: Randomized Parallel-Group

56-week double-masked, active comparator evaluation of AR-14034 SR compared with aflibercept

56 weeks

Regular visits through Week 56

Open-label Extension

16-week open-label extension phase for continued treatment

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aflibercept Injection
• AR-14034 SR implant higher dose
• AR-14034 SR implant lower dose
• Sham procedure

Trial Overview The study tests AR-14034 SR implant at two different doses against Aflibercept Injection and a sham procedure, aiming to assess safety and how long the treatment effects last in controlling nAMD.

Participant Groups

Group I: Cohort 2 (Stage 1) Experimental Treatment 2 Interventions

One IVT injection of aflibercept 2 mg at Week -1 and one IVT insertion of AR-14034 SR higher dose at Baseline. Up to one retreatment with AR-14034 SR will be administered between Weeks 4 and 36 according to protocol-specified disease activity criteria.

Group II: Cohort 1 (Stage 1) Experimental Treatment 2 Interventions

One intravitreal (IVT) injection of aflibercept 2 mg at Week -1 and one IVT insertion of AR-14034 SR lower dose at Baseline. Up to one retreatment with AR-14034 SR will be administered between Weeks 4 and 36 according to protocol-specified disease activity criteria.

Group III: AR-14034 SR lower dose (Stage 2) Experimental Treatment 3 Interventions

One IVT injection of aflibercept 2 mg at Baseline, Week 4, and Week 8, with one IVT insertion of AR-14034 SR lower dose at Week 6. Up to one retreatment of AR-14034 SR will be administered between Weeks 16 and 52 according to protocol-specified disease activity criteria. Sham procedures will be performed between Weeks 16 and 52 except when AR-14034 SR repeat treatment is administered.

Group IV: AR-14034 SR higher dose (Stage 2) Experimental Treatment 3 Interventions

One IVT injection of aflibercept 2 mg at Baseline, Week 4, and Week 8, with one IVT insertion of AR-14034 SR higher dose at Week 6. Up to one retreatment of AR-14034 SR will be administered between Weeks 16 and 52 according to protocol-specified disease activity criteria. Sham procedures will be performed between Weeks 16 and 52 except when AR-14034 SR repeat treatment is administered.

Group V: Aflibercept (Stage 2) Active Control 2 Interventions

One IVT injection of aflibercept 2 mg at Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48. Sham procedures will be performed between Weeks 16 and 52.

Who Is Running the Clinical Trial?

Alcon Research

Lead Sponsor

Trials

739

Recruited

128,000+

Raquel C. Bono

Alcon Research

Chief Medical Officer since 2022

MD from Harvard Medical School

David Endicott

Alcon Research

Chief Executive Officer since 2018

MBA from University of Southern California

Aerie Pharmaceuticals

Lead Sponsor

Trials

39

Recruited

8,300+

Findings from Research

Axitinib significantly inhibited choroidal neovascularization (CNV) growth by 70.1% in a mouse model of neovascular age-related macular degeneration (AMD), demonstrating its potential efficacy as a treatment.

The drug also caused a substantial regression of established CNV lesions, reducing their area by 71.1%, indicating that axitinib could be a promising therapeutic option for patients with neovascular AMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiangiogenic effects of axitinib, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, on laser-induced choroidal neovascularization in mice. Kang, S., Roh, CR., Cho, WK., et al.[2018]

A single suprachoroidal (SC) injection of axitinib resulted in significantly higher drug exposure in the posterior eye cup compared to intravitreal injection, suggesting better targeting of the affected areas in the eye.

Axitinib maintained sustained levels in the retinal pigment epithelium-choroid-sclera and retina for up to 91 days, indicating its potential as a long-acting treatment for neovascular age-related macular degeneration, which could reduce the frequency of treatments compared to current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Long-Lasting Potential of Suprachoroidal Axitinib Suspension Via Ocular and Systemic Disposition in Rabbits. Kansara, VS., Muya, LW., Ciulla, TA.[2021]

Axitinib is an effective treatment for advanced renal cell carcinoma, functioning as a selective inhibitor of vascular endothelial growth factor receptors, with a recommended starting dose of 5 mg twice daily that can be adjusted based on patient tolerance.

The drug is rapidly absorbed and has a short plasma half-life, with pharmacokinetics showing dose-proportionality within the clinical range, and it is primarily metabolized in the liver, indicating a well-defined safety profile with minimal drug interactions at therapeutic doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacology of axitinib. Chen, Y., Tortorici, MA., Garrett, M., et al.[2021]

In a 6-week study involving 30 treatment-naive patients with neovascular age-related macular degeneration, AKST4290 (400 mg orally twice daily) led to a significant improvement in best-corrected visual acuity (BCVA), with an average gain of +7.0 letters and 82.8% of patients showing stable or improved vision.

The treatment was well-tolerated, with no severe or serious adverse events reported, indicating that AKST4290 is safe for use and supports the need for further research in larger, randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SAFETY AND THERAPEUTIC EFFECTS OF ORALLY ADMINISTERED AKST4290 IN NEWLY DIAGNOSED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. Stewart, MW., Garg, S., Newman, EM., et al.[2022]

In a study of 253 patients with neovascular age-related macular degeneration (NV-AMD) treated with pegaptanib sodium, over 90% of patients experienced less than 15 letters of vision loss after 24 and 54 weeks, which is significantly better than the 70% reported in the VISION trial.

Pegaptanib was well tolerated among patients, with no serious adverse effects such as endophthalmitis or retinal detachment reported, indicating a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravitreal pegaptanib sodium for choroidal neovascularisation secondary to age-related macular degeneration: Pan-European experience. Sivaprasad, S., Hykin, P., Saeed, A., et al.[2016]

Axitinib is an effective second-line treatment for metastatic renal cell carcinoma, but patients show significant variability in how they respond to the standard 5 mg twice-daily dose.

The review emphasizes a 'flexible dosing' strategy that helps doctors adjust doses based on individual patient safety and tolerability, aiming to optimize treatment outcomes while maintaining safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Individualized dosing with axitinib: rationale and practical guidance. Schmidinger, M., Danesi, R., Jones, R., et al.[2018]

A 57-year-old male with metastatic renal cell carcinoma developed impaired retinal circulation after 2 years of axitinib treatment, indicating a novel ocular adverse event associated with this medication.

After discontinuing axitinib and switching to temsirolimus, the patient's retinal symptoms improved, but his visual acuity declined, highlighting the need for clinicians to monitor for potential retinal complications in patients receiving axitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired Retinal Circulation during Axitinib Treatment for Metastatic Renal Cell Carcinoma. Kimura, M., Kusuhara, S., Tagami, M., et al.[2022]

In a phase II study involving 32 patients with metastatic melanoma, axitinib demonstrated an objective response rate of 18.8%, indicating it can provide clinical activity as a treatment option.

Axitinib was generally well tolerated, with common side effects including fatigue and hypertension, but it also posed risks such as a serious bowel perforation in one patient, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Fruehauf, J., Lutzky, J., McDermott, D., et al.[2020]

Axitinib, a drug for advanced renal cell carcinoma, was studied in 337 healthy volunteers, revealing a two-compartment model for its pharmacokinetics, with key parameters like systemic clearance and bioavailability established.

Body weight influenced the volume of distribution of axitinib, but this effect was not significant enough to require any dose adjustments, ensuring consistent plasma exposure across different body weights.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of axitinib in healthy volunteers. Garrett, M., Poland, B., Brennan, M., et al.[2022]

In a Phase 1 study involving 35 participants with neovascular age-related macular degeneration, the oral treatment X-82 showed promising results, with 71% of participants maintaining or improving their visual acuity after 24 weeks, and 60% requiring no anti-VEGF injections.

While X-82 was associated with some adverse events, such as diarrhea and nausea, these were generally mild and reversible, indicating that liver function monitoring is necessary but the treatment could be a viable alternative to more invasive injection therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Tyrosine Kinase Inhibitor for Neovascular Age-Related Macular Degeneration: A Phase 1 Dose-Escalation Study. Jackson, TL., Boyer, D., Brown, DM., et al.[2019]

Axitinib, a tyrosine kinase inhibitor, effectively inhibits the proliferation and migration of human endothelial cells and pericytes in a dose-dependent manner, suggesting its potential as a treatment for neovascular age-related macular degeneration (nAMD).

The study demonstrated that axitinib can reverse the formation of capillary structures induced by VEGF, indicating its ability to modulate angiogenesis through interference with both VEGF and PDGF signaling pathways, all while remaining non-toxic at effective concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined VEGF and PDGF inhibition for neovascular AMD: anti-angiogenic properties of axitinib on human endothelial cells and pericytes in vitro. Siedlecki, J., Wertheimer, C., Wolf, A., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Antiangiogenic effects of axitinib, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, on laser-induced choroidal neovascularization in mice. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Evaluation of Long-Lasting Potential of Suprachoroidal Axitinib Suspension Via Ocular and Systemic Disposition in Rabbits. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical pharmacology of axitinib. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

SAFETY AND THERAPEUTIC EFFECTS OF ORALLY ADMINISTERED AKST4290 IN NEWLY DIAGNOSED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Intravitreal pegaptanib sodium for choroidal neovascularisation secondary to age-related macular degeneration: Pan-European experience. [2016]

6. England pubmed.ncbi.nlm.nih.gov

Individualized dosing with axitinib: rationale and practical guidance. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Impaired Retinal Circulation during Axitinib Treatment for Metastatic Renal Cell Carcinoma. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of axitinib in healthy volunteers. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Oral Tyrosine Kinase Inhibitor for Neovascular Age-Related Macular Degeneration: A Phase 1 Dose-Escalation Study. [2019]

11. Germany pubmed.ncbi.nlm.nih.gov

Combined VEGF and PDGF inhibition for neovascular AMD: anti-angiogenic properties of axitinib on human endothelial cells and pericytes in vitro. [2021]