Ocular Therapeutix™ Announces First Patient Randomized in HELIOS-3 Phase 3 Registrational Program for AXPAXLI™ in NPDR

Rhea-AI Summary

Ocular Therapeutix (NASDAQ: OCUL) announced the first patient randomized in HELIOS-3, the second Phase 3 registrational trial for AXPAXLI (OTX-TKI) in non-proliferative diabetic retinopathy (NPDR) on Nov 24, 2025. HELIOS-2 and HELIOS-3 are complementary global superiority studies using a novel ordinal ≥2-step diabetic retinopathy severity score (DRSS) primary endpoint, with primary assessment at Week 52. HELIOS-2 compares AXPAXLI dosed every 12 months to ranibizumab 0.3 mg; HELIOS-3 compares 6- and 12-month AXPAXLI regimens to sham. Ocular secured an SPA alignment with the FDA on the novel DRSS endpoint for HELIOS-2 and is targeting a broad DR label by including patients with non-center-involved DME (non-CI-DME).

Positive

• First patient randomized in HELIOS-3 on Nov 24, 2025
• FDA SPA alignment on novel ordinal ≥2-step DRSS endpoint for HELIOS-2
• Primary endpoint set at Week 52 for both HELIOS studies
• Broad label intent by including non-CI-DME patients
• Durable dosing goal with AXPAXLI dosed every 12 months

Negative

• None.

Insights

Clinical Development Strategist

First patient randomized in HELIOS-3 begins a paired Phase 3 registrational program for AXPAXLI in NPDR with FDA-aligned endpoint.

HELIOS-2 and HELIOS-3 form a dual, superiority-focused registrational program evaluating AXPAXLI (OTX-TKI) in non-proliferative diabetic retinopathy, including patients with non-center-involved DME; each study uses a novel ordinal ≥2-step DRSS primary endpoint assessed at Week 52. One study compares annual AXPAXLI to ranibizumab, the other compares 6- and 12-month AXPAXLI regimens to sham, creating complementary evidence paths against both active and placebo controls.

The program benefits from an SPA alignment with the FDA on the ordinal DRSS for HELIOS-2, which reduces regulatory risk for that trial’s endpoint but does not guarantee approval; success depends strictly on the Week 52 DRSS results and execution across both trials. Key operational risks include enrollment speed, consistency of DRSS assessments, and maintaining data quality across global sites.

Watch for the Week 52 primary-readouts from each HELIOS study, enrollment milestones and any interim analyses or safety signals in 2026–2027; those items will materially affect regulatory momentum and label scope within a clinical registrational timeframe.

First patient randomized into HELIOS-3, which along with HELIOS-2 form the basis of AXPAXLI’s registrational program in non-proliferative diabetic retinopathy (NPDR)

HELIOS-2 and HELIOS-3 are global, complementary superiority trials using a novel ordinal diabetic retinopathy severity scale (DRSS) primary endpoint

Targeting a broad diabetic retinopathy (DR) label by including patients with non-center-involved diabetic macular edema (non-CI-DME)

BEDFORD, Mass., Nov. 24, 2025 (GLOBE NEWSWIRE) -- Ocular Therapeutix, Inc. (NASDAQ: OCUL, “Ocular”), an integrated biopharmaceutical company committed to redefining the retina experience, today announced that the first patient has been randomized in the HELIOS-3 Phase 3 registrational program for AXPAXLI (also known as OTX-TKI) for the treatment of non-proliferative diabetic retinopathy (NPDR).

“Initiating the HELIOS registrational program marks a pivotal step toward redefining treatment for diabetic retinal disease. While there are more than 6 million NPDR patients in the U.S., fewer than 1% receive therapy today, due mostly to the burden of frequent injections in this working age population. AXPAXLI’s potential to deliver efficacy with attractive durability could help hundreds of thousands, if not millions more patients preserve vision,” said Pravin U. Dugel, MD, Executive Chairman, President and Chief Executive Officer of Ocular Therapeutix. “HELIOS-2 and HELIOS-3 are complementary superiority studies targeting a comprehensive and broad DR label. The HELIOS study designs reflect our intentional and strategic clinical philosophy: combining scientific rigor, outstanding clinical execution, and a focus on de-risking, with regulatory alignment to optimize the potential for success and a label that readily translates into broad adoptability. By aiming for a superiority-based DR label that spans the full continuum of disease – including NPDR and DME – we believe AXPAXLI could deliver a market opportunity that is not merely incremental, but transformative for patients, physicians, and payors around the world.”

The HELIOS program is comprised of two complementary superiority studies, HELIOS-2 and HELIOS-3, designed to evaluate whether early AXPAXLI treatment, as infrequent as every 12 months, can meaningfully alter the course of non-proliferative diabetic retinopathy (NPDR). Ocular is targeting a broad diabetic retinopathy (DR) label with the HELIOS program by including patients with non-center-involved diabetic macular edema (non-CI-DME). The studies utilize a novel ordinal ≥2-step diabetic retinopathy severity score (DRSS) primary endpoint. HELIOS-2 is a superiority study comparing AXPAXLI dosed every 12 months to ranibizumab (0.3 mg), while HELIOS-3 compares 6- and 12-month dosing regimens of AXPAXLI to sham. The primary endpoint for each study is assessed at Week 52. Ocular has aligned with the FDA on the novel ordinal DRSS endpoint in its SPA agreement for HELIOS-2.

“The HELIOS program has the potential to transform care for patients with diabetic retinal disease, and my patients are excited to participate in this study. Current DR treatments are burdensome and unsustainable – particularly for this working age population, unlike wet AMD – requiring numerous intravitreal injections every year. This limits treatment uptake, leaving many at risk for disease progression and irreversible vision loss,” commented Allen Hu, MD, Principal Investigator at Cumberland Valley Retina Consultants. “AXPAXLI shows significant promise to address the unmet need for an effective treatment with durable efficacy, based on the encouraging HELIOS-1 data. Given the rapid enrollment and outstanding execution of the SOL studies for AXPAXLI in wet AMD, I have full confidence that the Ocular clinical team will deliver another highly successful program in NPDR.”

“The new ordinal ≥2-step DRSS endpoint Ocular has developed is an important and creative advancement for the retina field. This approach reflects real-world treatment goals, and I expect it will become the gold standard for DR trials going forward,” said Dilsher S. Dhoot, MD, of California Retina Consultants. “Unlike binary endpoints, this ordinal measure captures changes across the full DRSS spectrum, including improvement, stability, and progression. By allowing every patient to contribute to the primary analysis, it enables more efficient trials while generating clinically meaningful data. If the HELIOS trials are successful, I expect AXPAXLI will be widely adopted across diabetic retinal disease due to its potential for durable efficacy and low treatment burden, making it highly attractive to patients, physicians, and payors alike.”

About AXPAXLI
AXPAXLI™ (also known as OTX-TKI) is an investigational, bioresorbable, intravitreal hydrogel incorporating axitinib, a small molecule, multi-target, tyrosine kinase inhibitor with anti-angiogenic properties, being evaluated for the treatment of wet AMD, diabetic retinopathy, and other retinal diseases.

About the HELIOS-2 Study
The registrational Phase 3 HELIOS-2 trial is designed to evaluate the safety and efficacy of AXPAXLI in a multi-center, double-masked, randomized (1:1), parallel group study.
This trial is a superiority study of AXPAXLI in approximately 432 subjects with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME). Eligible subjects are randomized to receive a single dose of AXPAXLI or a single dose of ranibizumab (0.3 mg) at Day 1. At Week 52, all subjects are re-dosed with their respective initial treatment of AXPAXLI or ranibizumab (0.3 mg). Subjects will be followed for safety until the end of Year 2. Throughout the study, subjects are assessed monthly. Trial subjects and designated study personnel will remain masked through the end of Year 2.

The primary endpoint of HELIOS-2 is the ordinal DRSS 2-step change status at Week 52 from baseline (≥2-step improvement, ≥2-step worsening, less than 2-step change in either direction). The study is being conducted under a Special Protocol Assessment (SPA) agreement with the FDA.

About the HELIOS-3 Study
The registrational Phase 3 HELIOS-3 trial is designed to evaluate the safety and efficacy of AXPAXLI in a multi-center, double-masked, randomized (1:1:1), three-arm study. This trial will be the second superiority study of AXPAXLI in approximately 930 subjects with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME).

Subjects in the first arm receive a single dose of AXPAXLI at Day 1 and are re-dosed at Week 24. Subjects in the second arm receive a single dose of AXPAXLI at Day 1 and sham at Week 24. Subjects in the third arm receive sham at Day 1 and at Week 24, aligned with the AXPAXLI treatment arms for adequate masking. Throughout the study, subjects are assessed every 12 weeks.

The primary endpoint of HELIOS-3 is the ordinal DRSS 2-step change status at Week 52 from baseline (≥2-step improvement, ≥2-step worsening, less than 2-step change in either direction).

About Diabetic Eye Disease
Diabetic eye disease is an increasingly prevalent global health concern, driven by the rapidly rising number of individuals diagnosed with diabetes each year.

Diabetic retinopathy (DR) is the most common category of retinal diseases, affecting over an estimated 103 million people worldwide. DR is a progressive condition in which retinal blood vessels are damaged following a cascade of events triggered by chronically elevated levels of blood glucose. As many as half of all diabetic patients are expected to develop some form of DR in their lifetime. DR can progress from the non-proliferative (NPDR) stages to the proliferative (PDR) stage characterized by the growth of abnormal new blood vessels. Fewer than 1% of the 6.4 million NPDR patients in the U.S. receive treatment today, despite the availability of anti-VEGF therapies approved for the indication, largely due to the burden of frequent injections. Diabetic macular edema (DME) is also a leading cause of vision loss in the working-age population. DME, the result of an accumulation of fluid in the macula that can afflict patients with diabetes, can occur at any stage of DR. In patients with DME, blood vessels in the eyes leak and start to swell, which can cause vision loss or blindness. Anti-VEGF drugs are approved to treat DME, but these treatments typically require frequent intravitreal injections, placing a significant burden on patients and physicians alike.

About Ocular Therapeutix, Inc.
Ocular Therapeutix, Inc. is an integrated biopharmaceutical company committed to redefining the retina experience. AXPAXLI™ (also known as OTX-TKI), Ocular’s investigational product candidate for retinal disease, is an axitinib intravitreal hydrogel based on its ELUTYX™ proprietary bioresorbable hydrogel-based formulation technology. AXPAXLI is currently in Phase 3 clinical trials for wet age-related macular degeneration (wet AMD) and non-proliferative diabetic retinopathy (NPDR).

Ocular’s pipeline also leverages the ELUTYX technology in its commercial product DEXTENZA^®, an FDA-approved corticosteroid for the treatment of ocular inflammation and pain following ophthalmic surgery in adults and pediatric patients and ocular itching associated with allergic conjunctivitis in adults and pediatric patients aged two years or older, and in its investigational product candidate OTX-TIC, which is a travoprost intracameral hydrogel that has completed a Phase 2 clinical trial for the treatment of open-angle glaucoma or ocular hypertension. Ocular is currently evaluating next steps for the OTX-TIC program. Explore the Company’s new corporate branding and follow the Company on its website, LinkedIn, or X.

DEXTENZA^® is a registered trademark of Ocular Therapeutix, Inc. The Ocular Therapeutix logo, AXPAXLI™, ELUTYX™, and Ocular Therapeutix™ are trademarks of Ocular Therapeutix, Inc.

Forward-Looking Statements
Any statements in this press release about future expectations, plans, and prospects for the Company, the development and regulatory status of the Company’s product candidates, the timing, design, enrollment, randomization, conduct and retention of subjects in the Company’s clinical trials, including the Company’s SOL-1 and SOL-R Phase 3 clinical trials of AXPAXLI (also known as OTX-TKI) for the treatment of wet AMD, and the Company’s HELIOS-2 and HELIOS-3 Phase 3 clinical trials of AXPAXLI for the treatment of NPDR; the Company’s plans to advance AXPAXLI, OTX-TIC, and its other product candidates; the potential utility or adoption, if approved, of any of the Company’s product candidates; and other statements containing the words “anticipate”, “believe”, “estimate”, “expect”, “intend”, “designed”, “goal”, “may”, “might”, “plan”, “predict”, “project”, “target”, “potential”, “will”, “would”, “could”, “should”, “continue”, and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors. Such forward-looking statements involve substantial risks and uncertainties that could cause the Company’s development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the timing and costs involved in commercializing any product or product candidate that receives regulatory approval; the ability to retain regulatory approval of any product or product candidate that receives regulatory approval; the initiation, design, timing, conduct and outcomes of ongoing and planned clinical trials, including the SOL-1 trial, the SOL-R trial, the planned SOL-X trial, the HELIOS-2 trial, and the HELIOS-3 trial; the risk that the FDA will not agree with the Company’s interpretation of the written agreements under the Special Protocol Assessments for AXPAXLI, including for the SOL-1 and HELIOS-2 trials; the risk that even though the FDA has agreed with the overall design of the SOL-1 and HELIOS-2 trials, the FDA may not find that the data generated by the applicable trial supports potential marketing approval; the risk that the FDA might not agree to the Company’s design, protocol, and statistical analysis plan of the SOL-R trial or the HELIOS-3 trial; the risk that the Company and the FDA may not agree on the registrational pathway for any of its product candidates; uncertainty as to whether the data from earlier clinical trials will be predictive of the data of later clinical trials, particularly later clinical trials that have a different design or utilize a different formulation than the earlier trials, whether preliminary or interim data from a clinical trial (including masked safety or masked rescue data from the Company’s SOL-1 trial or SOL-R trial) will be predictive of final data from such trial, or whether data from a clinical trial assessing a product candidate for one indication will be predictive of results in other indications; uncertainty as to whether data from the Company’s SOL-X trial will demonstrate clinically meaningful, long-term benefits; uncertainties regarding the potential commercial advantages and/or position of the Company’s product candidates; availability of data from clinical trials and expectations for regulatory submissions and approvals; the Company’s scientific approach and general development progress; uncertainties inherent in estimating the Company’s cash runway, future expenses and other financial results, including its ability to fund future operations, including clinical trials; the Company’s existing indebtedness and the ability of the Company’s creditors to accelerate the maturity of such indebtedness upon the occurrence of certain events of default; and other factors discussed in the “Risk Factors” section contained in the Company’s quarterly and annual reports on file with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent the Company’s views as of the date of this press release. The Company anticipates that subsequent events and developments may cause the Company’s views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so, whether as a result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this press release.

Investors & Media
Ocular Therapeutix, Inc.
Bill Slattery
Vice President, Investor Relations
bslattery@ocutx.com

FAQ

What milestone did Ocular Therapeutix (OCUL) announce on November 24, 2025?

Ocular announced the first patient randomized in the HELIOS-3 Phase 3 registrational trial for AXPAXLI in NPDR.

What is the primary endpoint and timing for HELIOS-2 and HELIOS-3 (OCUL)?

Both HELIOS studies use a novel ordinal ≥2-step DRSS primary endpoint with assessment at Week 52.

How do HELIOS-2 and HELIOS-3 differ in comparators and dosing for OCUL's AXPAXLI?

HELIOS-2 compares AXPAXLI every 12 months to ranibizumab 0.3 mg; HELIOS-3 compares 6- and 12-month AXPAXLI regimens to sham.

Did Ocular Therapeutix receive regulatory alignment for the HELIOS program (OCUL)?

Yes, Ocular secured an SPA agreement with the FDA aligning on the novel DRSS endpoint for HELIOS-2.

What patient population are the HELIOS trials targeting for OCUL's AXPAXLI?

The trials target patients with non-proliferative diabetic retinopathy (NPDR) and include those with non-center-involved DME to pursue a broad DR label.

What is the intended dosing frequency highlighted for AXPAXLI in the HELIOS program (OCUL)?

Ocular is evaluating AXPAXLI with an intended durable dosing approach, including dosing as infrequent as every 12 months.