UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

For the Fiscal Year Ended December 31, 2023

For the transition period from _____ to _____

Commission File No. 001-34079

Ocuphire Pharma, Inc.

(Exact name of registrant as specified in its charter)

Registrant’s telephone number, including area code: (248)

957-9024

Securities registered pursuant to Section 12(b) of the Act:

Title of each class Trading Symbol Name of each exchange on which registered

Common Stock, $0.0001 par value per share OCUP The Nasdaq Stock Market LLC

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐No☒

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐No☒

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act

of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days: Yes☒ No ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule

405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes☒ No ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting

company or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with

any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its

internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. Yes ☐

securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate

by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §

240.10D-1(b). ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒

The aggregate market value of the common equity held by non-affiliates of the registrant on June 30, 2023, based on the closing price on that date

of $4.34, was approximately $89,224,159. As of March 5, 2024, there were 24,813,370 shares of the registrant’s common stock outstanding.

Documents Incorporated by Reference

Portions of the registrant’s Definitive Proxy Statement to be filed with the Commission pursuant to Regulation 14A in connection with the registrant’s 2024 Annual

Meeting of Stockholders, to be filed subsequent to the date hereof, are incorporated by reference into Part III of this report. Such Definitive Proxy Statement will be filed with the Securities and Exchange Commission not later than 120 days after

the conclusion of the registrant’s fiscal year ended December 31, 2023.

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TABLE OF CONTENTS

PART I 7

ITEM 1. BUSINESS 7

ITEM 1A. RISK FACTORS 44

ITEM 1B. UNRESOLVED STAFF COMMENTS 83

ITEM 1C. CYBERSECURITY 83

ITEM 2. PROPERTIES 84

ITEM 3. LEGAL PROCEEDINGS 84

ITEM 4. MINE SAFETY DISCLOSURES 84

PART II

ITEM 6. [RESERVED] 85

ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 99

ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 100

ITEM 9A. CONTROLS AND PROCEDURES 100

ITEM 9B. OTHER INFORMATION 101

ITEM 9C. DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 101

PART III

ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 102

ITEM 11. EXECUTIVE COMPENSATION 102

ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 102

PART IV

ITEM 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES 103

SIGNATURES

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In this Annual Report on Form 10-K, unless otherwise specified, references to “we,” “us,” “our,” “Ocuphire” or “the Company” mean Ocuphire Pharma, Inc. Our financial statements are prepared in

accordance with accounting principles generally accepted in the United States (“U.S. GAAP”).

FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements within the meaning of the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”),

and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). These forward-looking statements relate to us, our business prospects and our results of operations and are subject to certain risks and uncertainties posed by

many factors and events that could cause our actual business, prospects and results of operations to differ materially from those anticipated by such forward-looking statements. Factors that could cause or contribute to such differences include, but

are not limited to, those described under the heading “Risk Factors” included in this Annual Report on Form 10-K. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this report.

In some cases, you can identify forward-looking statements by the following words: “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “ongoing,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” or

the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. We undertake no obligation to revise any forward-looking statements in order to reflect events or circumstances that might

subsequently arise. Readers are urged to carefully review and consider the various disclosures made by us in this report and in our other reports filed with the U.S. Securities and Exchange Commission (the “SEC”) that advise interested parties of the

risks and factors that may affect our business.

SUMMARY RISK FACTORS

Our business is subject to a number of risks, as fully described in “Item 1A. Risk Factors” in this Annual Report. The principal factors and uncertainties include, among others:

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• We do not anticipate paying any cash dividends in the foreseeable future.

• The market price of our common stock may fluctuate significantly.

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INDUSTRY AND MARKET DATA

In this Annual Report, we reference information, statistics and estimates regarding the medical devices and healthcare industries. We have obtained this information from various third-party sources,

including industry and general publications, reports by market research firms and other sources. This information involves a number of assumptions and limitations, and we have not independently verified the accuracy or completeness of this

information. Some data and other information are also based on the good faith estimates of management, which are derived from our research, review of internal surveys, general information discussed in the industry, and third-party sources. We believe

that these external sources and estimates are reliable but have not independently verified them. The industries in which we operate are subject to a high degree of uncertainty, change, and risk due to a variety of factors, including those described

in “Item 1A. Risk Factors.” These and other factors could cause results to differ materially from those expressed in this Annual Report and other publications.

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PART I

ITEM 1. BUSINESS

Overview

Ocuphire Pharma, Inc. is a clinical-stage biopharmaceutical company focused on developing novel therapies for the treatment of unmet needs of patients with retinal and refractive eye disorders.

The Company’s lead retinal product candidate, APX3330, is a small-molecule inhibitor of Ref-1 (reduction oxidation effector factor-1 protein). Ref-1 is a regulator of transcription factors such as

HIF-1α and NF-κB. Inhibiting Ref-1 reduces levels of vascular endothelial growth factor (“VEGF”) and inflammatory cytokines which are known to play key roles in ocular angiogenesis and inflammation. APX3330 is an oral tablet administered once or

twice per day in development for the treatment of diabetic retinopathy (“DR”). A Phase 2 study in subjects with DR or diabetic macular edema was completed and results were reported in January 2023. An End-of-Phase 2 (“EOP2”) meeting with the U.S.

Food and Drug Administration (the “FDA”) was held in October 2023 at which the Company obtained agreement on the registration endpoint supporting the advancement of APX3330 into future clinical trials. The Company submitted a special protocol

assessment (“SPA”) to the FDA in February 2024 to seek agreement on the clinical trial protocol and statistical analysis plan and will share specifics on the study design parameters and anticipated timing if and when a SPA agreement is reached with

the FDA.

DR affects approximately 10 million diabetics and is projected to impact over 14 million Americans by 2050. DR is classified as either Non-Proliferative Diabetic Retinopathy (“NPDR”), the early stage

of the disease in which symptoms may be mild or non-existent or Proliferative Diabetic Retinopathy (“PDR”) which is the more advanced stage of diabetic eye disease that can be highly symptomatic with loss of vision. Approximately 8 million DR

patients have NPDR that may progress to PDR, if left untreated. Despite the risk for visual loss associated with this disease, over 90% of NPDR patients currently receive no course of treatment apart from observation by their eye care specialist

until they develop sight-threatening complications. This is due to various factors, including the treatment burden of the frequent eye injections required with currently approved therapies for this disease. APX3330, as an oral tablet, has the

potential to be an early, non-invasive treatment for the approximately 8 million NPDR patients in the US.

The Company has also in-licensed APX2009 and APX2014, which are second-generation analogs of APX3330. The unique mechanism of action of this family of Ref-1 inhibitors of reducing angiogenesis and

inflammation could potentially be beneficial in treating other retinal diseases such as age-related macular degeneration, geographic atrophy, and non-ophthalmic diseases.

In November 2022, the Company entered into a license and collaboration agreement (the “Viatris License Agreement”) with FamyGen Life Sciences, Inc. (“Famy”) (acquired by and now known as Viatris,

Inc. (“Viatris”) in January 2023) pursuant to which it granted Viatris an exclusive license to develop, manufacture, import, export and commercialize its refractive product candidate Phentolamine Ophthalmic Solution 0.75% (initially known as Nyxol)

(“PS”). PS is a once-daily eye drop formulation of phentolamine mesylate designed to reduce pupil diameter and improve visual acuity. PS was approved by the FDA for the treatment for pharmacologically-induced mydriasis under the brand name RYZUMVITM

in September 2023. PS is currently in Phase 3 clinical trials for presbyopia (age-related blurry near vision). The VEGA-2 Phase 3 study in presbyopia achieved its primary endpoint and Viatris, our development and commercial partner, is expected to

continue Phase 3 development in the first half of 2024. PS is also in Phase 3 for decreased vision under dim (mesopic or low) light conditions following keratorefractive surgery. On December 5, 2023, the Company received FDA Agreement Under Special

Protocol Assessment for LYNX-2, a Phase 3 trial of PS for the treatment of decreased vision under dim (mesopic or low) light conditions following keratorefractive surgery and Viatris, our development and commercial partner, is expected to continue

Phase 3 development in this indication in the first half of 2024.

Pursuant to the Viatris License Agreement, Ocuphire received an upfront cash payment of $35 million and a $10 million license agreement milestone payment for the NDA approval of RYZUMVI. In addition,

Ocuphire is eligible to receive potential additional payments of up to $120 million, in the aggregate, upon achieving certain specified regulatory or net sales milestones. Ocuphire will also receive tiered royalties based on annual net sales of PS in

and outside of the United States (with royalties ranging from percentages in the low double digits to the low twenties for annual net sales in the United States and percentages in the low double-digits for annual net sales outside of the United

States). The Viatris License Agreement does not expire until terminated under the terms of the agreement.

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Corporate History

In February 2018, Ocuphire Pharma, Inc. (prior to the Merger with Rexahn, “Private Ocuphire”) was founded and subsequently merged in April 2018 with Ocularis Pharma, LLC, (the original innovator of

phentolamine mesylate ophthalmic solution), and in January 2020 obtained from Apexian Pharmaceuticals, Inc. certain rights to its Ref-1inhibitor program, including APX3330 (see “Apexian Sublicense Agreement”).

In November 2020, Private Ocuphire completed a reverse merger (the “Merger”) into Rexahn Pharmaceuticals, Inc. (“Rexahn”), a publicly-traded company that had ceased its business of drug development

activities, and simultaneously raised $20 million through an offering of common shares and warrants to purchase common shares. In connection with the Merger, Rexahn changed its name to Ocuphire Pharma, Inc. and has since conducted, as a public

company, the business previously conducted by Private Ocuphire.

In November 2022, Ocuphire entered into the Viatris License Agreement, licensing its PS product to Viatris.

Many of Ocuphire’s employees, directors, advisors and consultants have been involved in the development of PS and other ophthalmic drugs including approved products such as LUMIFY® marketed by Bausch & Lomb Incorporated, Zirgan® marketed by marketed by Bausch &

Lomb Incorporated Durezol® marketed by Novartis, Upneeq® marketed by RVL Pharmaceuticals

plc, Rhopressa® marketed by Alcon, Rocklatan® marketed by Alcon, Vyzulta® marketed by Bausch & Lomb Incorporated, Xiidra® marketed by Bausch & Lomb

Incorporated, Cequa® marketed by Sun Pharmaceuticals Industries Limited, IyuzehTM marketed by Thea Pharma Inc., and Dextenza® marketed by Ocular Therapeutix, Inc. The management team, led by Chief Executive Officer (“CEO”) George Magrath, MS, MD, MBA, collectively has significant experience in operating pharmaceutical

companies and discovering, developing, and commercializing treatments in multiple therapeutic areas.

Strategy

Ocuphire’s goal is to build a leading biopharmaceutical company that discovers, develops, commercializes and/or out-licenses best-in-class therapies for patients and provides attractive solutions for

physicians and payers. The key elements of Ocuphire’s strategy to achieve its goal are the following:

• Advance the clinical development of our products.

For the APX3330 program, an End-of-Phase 2 (“EOP2”) meeting with the U.S. Food and Drug Administration (the “FDA”) was held in October 2023 at which the Company obtained

agreement on the registration endpoint supporting the advancement of APX3330 into future clinical trials. The Company submitted a SPA with the FDA in February 2024 and will provide further guidance on study design, cost and timelines if and when a

SPA agreement is reached with the FDA.

For PS, Ocuphire entered into the Viatris License Agreement in November 2022, pursuant to which Viatris has exclusive rights to develop and commercialize PS. Pursuant to the

Viatris License Agreement, Ocuphire continues to conduct development activities in the United States in partnership with Viatris, and is reimbursed by Viatris for such budgeted development activities. PS was approved by the FDA for the treatment for

pharmacologically-induced mydriasis under the brand name RYZUMVI in September 2023 and is advancing Phase 3 trials for presbyopia and decreased vision under dim (mesopic or low) light conditions after keratorefractive surgery. Viatris has exclusive

rights to pursue development and undertake commercialization efforts for PS outside of the United States.

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Ocuphire continues to explore additional opportunities to expand and extend this intellectual property protection, both in the U.S. and in other jurisdictions. Ocuphire owns an exclusive worldwide

sublicense for the Ref-1 Inhibitor program, including its product candidate APX3330, for all its ophthalmic and diabetic indications, and compositions and methods of use for Ref-1 pipeline candidates, including APX2009 and APX2014. Ocuphire continues

to explore additional opportunities to expand and extend this intellectual property protection, both in the U.S. and in other jurisdictions.

RYZUMVI, now FDA approved and PS, if approved for presbyopia and decreased vision under dim (mesopic or low) light conditions after keratorefractive surgery, will be commercialized by the Viatris Eye

Care Division in the U.S. and major non-U.S. markets pursuant to the Viatris License Agreement.

Ocuphire is continuing to develop APX3330 for multiple indications and may develop and commercialize on our own or seek a development and commercial partner for APX3330. Ocuphire is continuing the

development PS with its partner Viatris for multiple indications. Ocuphire believes the two programs present similar potential advantages, including: (1) promising clinical data to date; (2) both small-molecule late-stage clinical candidates; (3)

convenient dosing route and schedule; (4) potential for first-line or adjunctive therapy; and (5) significant commercial potential. FIGURE 1 below summarizes Ocuphire’s current development pipeline of product candidates and their target indications

and anticipated milestones:

FIGURE 1: Ocuphire Pipeline: Product Candidates and Indications Pipeline

Note: RYMZUMVI and 0.75% PS (Phentolamine Ophthalmic Solution) is the same as 1% PMOS (Phentolamine Mesylate Ophthalmic Solution). References to PS with both designations appear throughout this document, there is no

difference in formulation between the two designations.

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PS was approved by the FDA for the treatment for pharmacologically-induced mydriasis under the brand name RYZUMVI in September 2023 and is advancing in Phase 3 trials for treatment of presbyopia and

decreased vision under dim (mesopic or low) light conditions after keratorefractive surgery. Ocuphire anticipates submitting supplemental NDAs for PS for treatment of presbyopia and decreased vision under dim (mesopic or low) light conditions after

keratorefractive surgery and is advancing APX3330 towards an NDA in the future.

Overview of Eye Disease Market

Retinal (Back of the Eye) Disease Market

Retinal damage is one of the leading causes of blindness and continues to grow with aging and larger diabetic populations around the world. Diabetes is the leading cause of blindness among adults

aged 20 – 74. According to the National Eye Institute, in the United States alone, over 10 million patients suffer from DR, a complication of diabetes in which chronically elevated blood sugar levels cause damage to blood vessels in the retina. An

additional 750,000 patients suffer from diabetic macular edema (“DME”), one of the most common complications of diabetic retinopathy where the macula swells from fluid leaked from damaged blood vessels. The disease progression of both DR and DME

involves abnormal vessel proliferation via VEGF signaling and inflammation. Ocuphire’s APX3330 oral tablet recently completed a Phase 2 clinical trial for DR and has the potential to address this large DR market with a novel, dual mechanism of action

of inhibiting VEGF, a modulator of angiogenesis, and inflammation. In addition, over 1 million patients in the United States suffer from wAMD. These retinal and choroidal vascular diseases, which cause damage to the macula, are leading causes of

severe, permanent vision loss. Currently, there are several drugs on the market indicated for anti-VEGF therapy, including Lucentis® (ranibizumab), a monoclonal antibody

marketed by Genentech, and EYLEA® (aflibercept), a recombinant fusion protein marketed by Regeneron Pharmaceuticals, Inc., that have become the standard of care for

treating severe forms of DME and wAMD amongst other retinal conditions. These injectable drugs are biologics with treatment administered in an ophthalmologist’s office. Annual worldwide sales of Lucentis and EYLEA for all indications totaled over $13

billion in 2020 ($3.5 billion for Lucentis and over $10 billion for EYLEA).

Anterior (Front of the Eye) Segment Disease Market

There are approximately 100 million eye dilations in the United States and this number is expected to go up with the increasing aging and diabetic population that requires more frequent eye exams and

procedures. Millions of Americans also suffer from various refractive errors.

Presbyopia, one such refractive error, is common in patients over the age of 40 years, which results in decreased ability to see objects at a near distance. This condition affects over 120 million

Americans and usually requires reading glasses and/or contact lenses for focusing on near objects.

Further, according to GlobalData, approximately 38 million patients in the U.S. suffer from dim light or night vision disturbances caused by LASIK, night myopia, keratoconus, eye surgery, or the

natural aging process. There is also a global trend in vision disturbances in younger individuals due to the overuse of smartphone screens.

Summary of APX3330 and PS

APX3330

APX3330 is a small molecule that specifically targets Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 (APE-1/Ref-1, referred to as Ref-1),Ref-1, a dual function protein involved in the regulation

of transcription factors critical to cell signaling. Ref-1 regulates inflammation, angiogenesis (blood vessel formation), and reduction-oxidation (redox) signaling, as well as DNA repair that is critical to normal function of neurons. By inhibiting

redox activity and not DNA repair, APX3330 has been shown in preclinical studies to reduce angiogenesis and inflammation via modulation of several important proangiogenic and proinflammatory transcription factors such as NF-κB and HIF-1α and its

downstream target, VEGF (Vascular Endothelial Growth Factor). These transcription factors are implicated in multiple pathways relevant to the pathophysiology of retinal and choroidal vascular diseases, including diabetic retinopathy (DR), diabetic

macular edema (DME), wet age-related macular degeneration (wAMD) and geographic atrophy (GA).

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Key attributes of Ocuphire’s product candidate APX3330 include the following:

Ocuphire is initially pursuing APX3330 for the DR indication as first-line therapy and may explore opportunities for clinical benefit as monotherapy or adjunctive therapy for other retinal

indications such as DME, wAMD, and GA:

PS (phentolamine 0.75% ophthalmic solution)

PS, out-licensed to Viatris in 2022, is a once-daily, sterile, preservative-free eye drop formulation containing phentolamine mesylate, a reversible, non-selective alpha-1 and alpha-2 adrenergic

antagonist that acts on the adrenergic nervous system and inhibits contraction of smooth muscle. Ocuphire submitted an NDA to the FDA in November 2022 under the 505(b)(2) pathway and PS was approved by the FDA for the treatment for

pharmacologically-induced mydriasis under the brand name RYZUMVI in September 2023. RYZUMVI reverses the pharmacologically induced dilation of the pupils, where dilation leads to increased sensitivity to light and an inability to focus, making it

difficult to read, work, and drive.

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Viatris will continue to commercialize RYZUMVI for the treatment of pharmacologically-induced mydriasis. Ocuphire and Viatris are pursuing PS for the following additional indications under the

Viatris License Agreement:

APX3330’s Target Indications

Diabetic Retinopathy

Diabetic Retinopathy Overview

DR is an eye disease resulting from diabetes, affecting over 10 million patients in the U.S., in which chronically elevated blood sugar levels cause damage to blood vessels in the retina. It is the

leading cause of vision loss in adults aged 20–74 years. There are two major types of DR:

Therapies for NPDR and PDR are distinct. For NPDR, treatment is usually directed at observation, lifestyle changes, and control of elevated blood sugars that led to progression of NPDR in the first

place. Additionally, the current treatment paradigm is for physicians to wait and monitor early-stage DR/NPDR patients, with anti-VEGF or steroid injectable therapy or laser treatment reserved for patients who advance to proliferative DR or DME. In

the Protocol S trial by the Diabetic Retinopathy Clinical Research Network, Lucentis was found to be noninferior to laser therapy in patients with PDR. Moreover, in 2018, from Regeneron’s PANORAMA trial, EYLEA® reversed disease progression in patients with moderately severe to severe NPDR.

Limitations of Existing Treatments for DR

In DR (especially NPDR), despite the approvals of anti-VEGF therapeutics in recent years, the use of injectables is not adopted in practice as preferred treatment as the disease is asymptomatic and

patients are reluctant to undergo injections or laser therapy.

In late-stage DR, intravitreal VEGF inhibitors are approved globally; however, these therapies rarely provide a complete solution to the underlying vascular problem associated with DR. Although these

therapeutic agents have been successful for some patients, significant proportions of patients are resistant and refractory. Moreover, serious side effects including hemorrhage and intraocular infections are possible with intravitreal injections.

Both Lucentis and EYLEA are also associated with increased risks of blood clots in the arteries. In addition, intravitreal injections require frequent visits to the ophthalmologist, usually on the order of every 4 weeks with a few anti-VEGF therapies

in development that are working on increasing the time between injections (8 – 12 weeks).

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Furthermore, retinal diseases are initially or over time bilateral, and thus treatments that only treat one eye, leave the other eye to remain untreated.

APX3330 Opportunity in DR

In addition to being characterized by abnormal increases in VEGF levels, recent scientific literature reports indicate that diabetic eye disease has an inflammatory component, unrelated to VEGF.

Because inflammation and hypoxic signaling (VEGF production) play crucial roles in both vascular leakage and neovascularization of DR, treatments that impinge upon both pro-inflammatory and hypoxic signaling offer a promising therapeutic strategy.

APX3330’s target of Ref-1 (a protein associated with inflammation and immune response) may leverage this dual mechanism of action (or “MOA”) to reduce the production and hence the quantity of VEGF while also preventing inflammatory damage. The MOA of

APX3330 is differentiated from traditional anti-VEGF treatments in that it does not neutralize the elevated levels of VEGF, but rather brings VEGF levels to normal homeostatic levels, thereby making it an ideal treatment option to prevent progression

or worsening in earlier stages of diabetic eye disease.

This potentially allows for improved response to DR treatment and may extend the duration between invasive treatments for late-stage retinal diseases (DME, wAMD). Moreover, as a potential orally

administered product candidate twice a day, it has the potential to be a more convenient option at an earlier stage of disease especially for DR than intravitreal anti-VEGF injections, which are burdensome to patients and have a significant side

effect profile including cataract formation, increased intraocular pressure, intraocular infections, and retinal detachments. Furthermore, as a systemic therapy, APX3330 offers the potential to treat both eyes while maintaining a favorable safety

profile.

Potential Other Indications:

Diabetic Macular Edema

Diabetic Macular Edema Overview

DME is a common complication of DR where the macula swells with fluid leaked from damaged blood vessels as a result of worsening diabetic retinopathy. It is one of the most common reasons for

blindness in diabetics, affecting approximately 750,000 patients. DME may cause blurriness in the center of vision, the appearance of straight lines as wavy, colors that look dull or washed out, or blind spots. The pathogenesis of DME involves

vascular leakage, retinal ischemia, and release of vaso-proliferative growth factors and inflammatory mediators.

In DME, corticosteroids and anti-VEGF agents are used to treat vascular leakage, inflammation and hypoxia/angiogenesis. In patients whose disease has progressed to DR with DME, anti-VEGF agents are

first line therapy followed by corticosteroids. Lucentis was approved for treatment of DME with a dosing regimen of a 0.3 mg injection approximately every four weeks. Similarly, EYLEA® was approved with a dosing regimen of a 2.0 mg injection approximately every four weeks.

In DME, intravitreal VEGF inhibitors are approved globally; however, these therapies rarely provide a complete solution to the underlying vascular problem associated with DME. Although these

in development that are working on increasing the time between injections (8 – 12 weeks).

Furthermore, retinal diseases are initially or over time bilateral, and thus treatments that only treat one eye, leave the other eye to remain untreated.

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Wet AMD

Age-Related Macular Degeneration (“AMD”) is a common eye condition affecting 11 million individuals in the U.S. and 196 million individuals globally, mostly over the age of 55 years. It is a progressive disease

affecting the central portion of the retina, known as the macula, which is the region of the eye responsible for sharpness, central vision and color perception. wAMD is an advanced form of AMD characterized by neovascularization and fluid leakage

under the retina. It is the leading cause of severe vision loss in patients over the age of 50 in the United States and EU. While wAMD represents only 10% of the number of cases of AMD overall, it is responsible for 90% of AMD-related severe

vision loss. Untreated or undertreated wAMD results in further blood vessel leakage, fluid in the macula, and ultimately scar tissue formation, which can lead to permanent vision loss or even blindness as a result of the scarring and retinal

deformation that occur during periods of non-treatment or undertreatment. Similar to severe DR and DME, current therapy for wAMD consists of intravitreal injections, mainly of Lucentis and EYLEA. The limitations of these therapies are described

in the section above titled, “Limitations of Existing Treatment for DR and DME”. Based on APX3330 targeting Ref-1 with a MOA of reducing overexpression of VEGF and inflammation, it has potential use in wAMD. Further, to enter the wAMD injectable

market, Ocuphire is considering the utility of an intravitreal or sustained delivery formulation of APX3330 and its second-generation analogs, APX2009 and APX2014. APX2009 and APX2014 data suggest improved efficacy against the Ref-1 target

compared to APX3330 (as published in the Journal of Pharmacology and Experimental Therapeutics).

Geographic atrophy (“GA”) is an advanced form of AMD that leads to progressive and irreversible vision loss. AMD is the leading cause of permanent vision loss in people over the age of 65 in

developed countries, and the risk of developing AMD increases with age. Based on published studies, approximately 1 million individuals have GA in the United States, and 5 million individuals have GA globally. In people with GA, photoreceptors, which

are light sensitive cells, deteriorate in the macula, a central portion of the retina responsible for central vision and color perception. This damage starts as small spots that grow into larger patches. As the cells in the macula die, the person

starts to lose vision. A person with early AMD may notice problems with reading or night vision. Eventually, if the disease progresses to advanced stages, permanent blind spots (scotomas) in the center of the visual field will develop. The cause of

GA is thought to be multifactorial including inflammation, with numerous environmental and genetic risk factors. The dysregulation of the complement cascade, an important part of the body’s immune system, plays a pivotal role. Excessive activation of

the complement cascade results in destruction of healthy cells, which can lead to the onset or progression of many diseases including GA. SYFOVRE® and IZERVAY® are the only FDA approved treatments for GA and requires monthly or every other month intravitreal injections.

Product Candidates

APX3330

APX3330 (E3330) is an oral formulation administered twice a day and is designed to target multiple pathways relevant to retinal and choroidal vascular diseases, such as DR and DME, which, if left

untreated, may progress to permanent visual acuity loss and eventual blindness. Mechanistic studies and prior clinical experience suggest that APX3330 is a promising candidate for clinical evaluation of its efficacy and safety in the treatment of

these diseases, beginning with DR and DME.

In preclinical pharmacology studies in animal models or in vitro, APX3330 has demonstrated the ability to decrease angiogenesis and inflammation in the retina whether delivered orally, systemically,

or directly into the eye via intravitreal injections. In humans, APX3330 was shown to be clinically well-tolerated in multiple Phase 1 and 2 trials with fewer than 10% of the patients experiencing mild, self-limiting side effects, such as nausea or

diarrhea. In addition, it was shown that significant amounts of oral APX3330 reach the bloodstream concentrations in humans and higher than the levels in mice which showed effects in the retina.

Ocuphire is initially pursuing a moderate-to-severe NPDR indication. Additionally, Ocuphire may explore opportunities for clinical benefit as monotherapy or adjunctive therapy for other retinal

indications such as DME, wAMD, and GA or other non-ophthalmic indications. Second-generation candidates, APX2009 and APX2014, may also be considered for intravitreal, oral or other injection routes of delivery for ophthalmic and non-ophthalmic

indications.

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Form 10-K

APX3330 Mechanism of Action

APX3330 is a selective small molecule that acts on the dual-functioning Apurinic/Apyrimidinic Endonuclease 1/Redox Effector Factor-1 (APE1/Ref-1) protein, referred to as Ref-1. This protein is

implicated in both redox signaling and DNA repair. Because APX3330 selectively inhibits the redox function without affecting the molecule’s ability to carry out DNA repair, normal cell function is left intact. Moreover, interference of Ref-1 activity

with APX3330 blocks angiogenesis and inflammation by simultaneously decreasing the activity of several important transcription factors such as HIF-1α and NF-κB (see FIGURE 2 below for a visual description).

HIF-1α regulates the expression of VEGF, a protein that is paramount for angiogenesis, and NF-κB is an upstream regulator of proteins involved in inflammatory processes such as TNFα and chemokines.

The development of DR/DME involves leakage from retinal vessels, lack of blood flow to the retina, and release of angiogenic growth factors and inflammatory mediators. The downstream targets of

HIF-1α and NF-κB serve as key mediators of these disease features and are targets of current therapy for diabetic eye disease and wAMD. Rather than inhibiting the action of VEGF protein, APX3330 has been shown in preclinical models to inhibit its

formation; this is a key potential distinction of APX3330 from the drugs currently approved or under development for DR such as Lucentis and EYLEA. APX3330’s potential ability to inhibit the activity of these two transcription factors may mitigate

the need for frequent intravitreal anti-VEGF or steroid injections.

APX3330 has a dual mechanism that decreases both abnormal angiogenesis and inflammation. APX3330 blocks pathways downstream of Ref-1. Blocking HIF-1α reduces VEGF signaling, and blocking NF-κB

modulates VEGF, TNF-α and other inflammatory cytokine production. In contrast, anti-VEGF agents solely inhibit the actions of VEGF (see FIGURE 2 below for a visual description).

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FIGURE 2: APX3330 Dual Mechanism of Action in Validated Disease Pathways

Note: Eylea® is registered trademark of Regeneron and Lucentis®

is registered trademark of Roche/Genentech, VABYSMOTM is a registered trademark of the Roche Group, OZURDEX® is registered trademark of Allergan, XIPERE® is registered trademark of Clearside Biomedical, Inc., ILUVIEN® is registered trademark

of Alimera Sciences Inc.

APX3330 Clinical Experience Summary

APX3330 has been studied in over 375 healthy volunteers or patients with hepatitis or cancer or diabetic retinopathy, over 270 of whom were given the product candidate for an average of 75 days or

more at up to 720mg per day dose. In these 12 Phase 1 and 2 non-ocular and ocular clinical trials, clinical data on safety and efficacy, effect upon the Ref-1 molecular target, and pharmacodynamic characteristics were collected. APX3330 showed

favorable safety tolerability and biological efficacy.

Across these 10 trials, it was found that APX3330 exhibited predictable PK that were consistent with the PK data obtained in nonclinical studies. In two studies it was found that meals have no impact

on the PK of APX3330. APX3330 has been demonstrated to be well tolerated at doses up to 600 mg/day.

In the 75 patients receiving either placebo or APX3330 treatment in the five Phase 1 trials (CLN_0001, 2, 3, 4, and 8), five patients in the treatment arms experienced AEs (mild diarrhea at doses of

120 mg, 180 mg, or 240 mg/day). In the five Phase 2 trials of the 279 patients given APX3330, 40 (14%) had AEs, the majority of which were mild. In a Phase 1 trial for patients with adult solid tumors, APX_CLN_0011, patients received doses of APX3330

up to 720 mg/day. Two of six patients receiving 720 mg/day had a diffuse rash that was spontaneously reversible. Patients receiving doses up to 600 mg/day did not have any signs of acute toxicity. Of the 19 patients in the APX_CLN_0011 Phase 1

oncology trial, four patients had over 6 months of exposure, and three patients (at a dose of 600 mg/day) had over 300 days of exposure without any significant drug-related AEs.

APX3330 Phase 2b Trial in DR/DME Patients (ZETA-1) (Completed)

In August 2022 Ocuphire completed ZETA-1, a Phase 2b double-masked, randomized, placebo-controlled, multi-center trial in patients with DR and DME, which started in April 2021. 103 DR subjects were

enrolled with 90% having NPDR (baseline DRSS of 47 or 53); mean baseline CST was 270 μm. This study evaluated the effect of 600 mg daily dose of APX3330 in treating patients with DR, including moderately severe NPDR to mild PDR, as well as patients

with DME without loss of central vision. The primary endpoint was percent of patients with a ≥2 step improvement in Early Treatment of Diabetic Retinopathy Study (ETDRS) diabetic retinopathy severity scale (DRSS) at week 24 in the study eye. Key

secondary endpoints at multiple time points included change in monocular and binocular DRSS, CST, and BCVA. Patient safety was assessed by AE monitoring, clinical laboratory evaluations, IOP, and vital sign assessments. The ZETA-1 trial did not meet

the primary endpoint in the study eye; however, the trial demonstrated the potential for clinically meaningful prevention of progression of diabetic retinopathy when evaluating both eyes. In contrast to intravitreal injections which treat a single

eye, systemic drugs treat both eyes, and thus the response of both eyes needs to be considered. Patients treated with APX3330 were less likely to worsen in DR severity compared to placebo. In ZETA-1 trial, 13% patients in placebo group compared to 5%

in APX3330 group (p=0.18) worsened by ≥ 3 step on binocular person-level scale from baseline at week 24 with a baseline binocular DRSS level 47, 53, or 61 (FIGURE 3). Additional efficacy endpoints were directionally favorable to support the

biological effect of APX3330 in slowing the progression of DR and preserving vision. Visual acuity was stable with APX3330, and a trend was seen with fewer APX3330 treated patients losing 5 or more letters of distance vision compared to placebo

patients (13% vs 26%, p=0.17) (FIGURE 3).

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FIGURE 3: Percentage of Subjects with Progression of DR, PDR and Vision Loss at Week 24

APX3330 showed a favorable safety profile. Of the treatment-emergent serious AEs, 14 were considered unrelated to study medication, 11 in the placebo group and 3 in the APX3330 group. Two subjects in each group

withdrew due to an AE, where one placebo subject had OU DME worsening considered treatment related. Overall, there were 211 AEs (91 APX3330, 120 placebo) in 64 subjects (29 APX3330, 35 placebo). Only 31 of these AEs were considered drug-related

(14 APX3330, 17 placebo). All treatment related AEs were mild or moderate in severity. There were no adverse treatment effects on any other characteristics of the ophthalmic examination or on any assessments of systemic safety (FIGURE 4).

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FIGURE 4: ZETA-1 Safety Overview

APX3330 – Ten Phase 1 and 2 Trials - Eisai (APX CLN 0001-0010)

Under the sponsorship of Eisai Co., Ltd., 10 clinical trials were conducted involving healthy volunteers as well as patients with chronic hepatitis diseases (i.e., Type C, B, alcohol-induced) in

Japan with the intent of developing a TNF-α blocking agent. At the time of their clinical trials, the molecular target of APX3330 had not been confirmed and was not known to be the Ref-1 protein.

Across these 10 trials, it was found that APX3330 exhibits predictable pharmacokinetics that were consistent with the pharmacokinetic data obtained in non-clinical studies. In addition, there was a

lack of significant acute toxicity at doses up to 600 mg/day. APX3330 has been demonstrated to be well-tolerated. Moreover, in two studies it was found that meals have no impact on the product candidate’s pharmacokinetics. Safety tolerability

measures showed no changes in vital signs and no changes in clinical laboratory values. The only adverse events observed included diarrhea and rash, each of which occurred in less than 5% of patients and were mild.

APX3330 Clinical Development Plan

For APX3330, the IND application for APX3330 to pursue retinal choroidal vascular diseases was submitted to the FDA Division of Ophthalmology in December 2018 and is in effect (IND 142152). APX3330

also has an IND with the FDA Division of Oncology for the treatment of pancreatic cancer (IND 125360). APX3330 has completed 12 trials (6 Phase 1 and 6 Phase 2 trials), mostly related to patients with liver disease, patients with solid tumors and

diabetic retinopathy. Ocuphire conducted an EOP2 meeting with the FDA and shared the outcome of the meeting in October 2023 which stated the agreement on the registration program including confirmation of the primary endpoint for registration of a

systemic agent for DR. The company has submitted a SPA to the FDA.

Potential Clinical Plans for APX3330:

Potential clinical plans for APX3330 will be based on the Phase 2 safety, tolerability and efficacy results of APX3330 in patients with DR/DME reported in January 2023 and the outcome from the EOP2

meeting with the FDA in October 2023 to confirm registration endpoints to finalize the design of the future trials for APX3330 as first-line therapy in DR in addition to defining the chronic safety exposure trial and any further animal toxicology

studies necessary prior to an NDA submission. Ocuphire may explore opportunities for clinical benefit as monotherapy or adjunctive therapy for other retinal indications such as DME, wAMD, and GA.

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Form 10-K

PS Mechanism of Action

PS is a once-daily sterile eye drop formulation of phentolamine mesylate designed to reduce pupil diameter and improve visual acuity. The active pharmaceutical ingredient of PS, phentolamine

mesylate, is a non-selective alpha-1 and alpha-2 adrenergic antagonist that inhibits activation of the smooth muscle of the iris, reducing pupil diameter. Unlike phentolamine, cholinergic agonists (such as pilocarpine, carbachol and aceclidine) work

on the iris sphincter muscle to reduce the pupil diameter, and are associated with side effects given the engagement of the ciliary muscle such as headaches, brow aches and retinal detachments and have limited use in patients with high myopia. PS

shares many of the attributes of existing ophthalmic eye drops, including a convenient route of administration and cost-effective manufacturing process, with the potential advantage of once-daily dosing.

PS is a relatively non-selective alpha-1 and alpha-2 adrenergic antagonist. Dilation of the pupil is primarily controlled by the radial iris dilator muscles surrounding the pupil; these muscles are

activated by the alpha-1 adrenergic receptors. Phentolamine reversibly binds to these receptors on the iris dilator muscle, thereby reducing pupil diameter. Phentolamine directly antagonizes the mydriatic effect of an α-1 adrenergic agonist, and

indirectly reverses mydriasis induced by muscarinic antagonist effects on the iris sphincter muscle. Alpha-1 antagonists bind to the receptors to inhibit the pupillary response and reduce dilation (FIGURE 5).

Phentolamine mesylate is the active ingredient in two injectable FDA-approved drugs, Regitine and OraVerse, as described previously.

For the treatment of pharmacologically-induced mydriasis indication, mydriasis is achieved either by stimulating the iris dilator muscle with the use of alpha agonists (e.g., phenylephrine), or by

blocking the iris sphincter muscle with the use of muscarinic antagonists (e.g., tropicamide). PS, either by directly antagonizing the alpha-1 agonist or by indirectly antagonizing the pupil dilation effect of muscarinic blocking, may expedite the

reversal of mydriasis prior to natural reversal.

For presbyopic patients, to overcome the lens’ inability to change shape (accommodation) and focus light from near objects, pupil diameter reduction to a small size will allow light to come in the

eye only in a near straight direction and increase the depth of focus (the “pinhole effect”). Ocuphire believes that it is possible to reach a target 2 mm to 3 mm optimal pupil diameter by relaxing the dilator iris muscle with PS and contracting the

iris sphincter muscle with a muscarinic agonist such as a low dose pilocarpine. This could result in an optimal depth of focus and near vision clarity without the assistance of lenticular accommodation.

Lastly, for the dim light vision disturbances, it is proposed that a moderate miotic effect by application of PS might mitigate night vision difficulties, a large portion of which are caused by

imperfections or aberrations present on the periphery of the cornea. Therefore, the effects of these imperfections can be reduced or eliminated by reducing the pupil size to a smaller diameter, knowing that a smaller pupil blocks what would be

unfocused, aberrant rays of light on the retina.

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FIGURE 5: PS’s Mechanism of Action

PS Clinical Experience Summary

PS has been assessed in twelve investigator-initiated and company-sponsored Phase 1, Phase 2, and Phase 3 clinical trials. Across all trials, over 700 adult patients have been exposed to at least one

dose of phentolamine ophthalmic solution. Clinical trial data from Phase 2 and Phase 3 trials were presented at the annual American Academy of Ophthalmology (AAO), Association for Research in Vision and Ophthalmology (ARVO), or American Society of

Cataract and Refractive Surgery (ASCRS) meetings. Results of VEGA-2 trial may be presented at future medical conferences.

VEGA PROGRAM Presbyopia Indication for PS

PS Presbyopia: Phase 3 VEGA-2 Trial (Completed)

VEGA-2 (NYXP-301) was a double-masked, randomized, placebo-controlled multi-center trial of PS, placebo and with adjunctive LDP compared with vehicle (placebo) in presbyopic patients. Three hundred

thirty-three subjects were randomized to one of 4 treatment groups in 2 stages.

The primary efficacy endpoint was met. The data from this study may be presented at future medical conferences.

Phase 2 VEGA-1 Trial (Completed)

VEGA-1 (NYXP-201) was a double-masked, randomized, placebo-controlled, multi-center trial of PS and LDP compared with vehicle (placebo) ophthalmic solution in presbyopic patients. A total of 150

patients were randomized 3:2:2:3 to one of four treatment groups. The primary efficacy endpoint for this study was met. The data from this study was presented at several medical conferences in 2021 and 2022.

LYNX PROGRAM – Decreased Vision Under Dim (Mesopic or Low) Light Conditions After Keratorefractive Surgery Indication for PS

PS: Phase 3 LYNX-1 Trial (Completed)

LYNX-1 (NYXDLD-301) was a Phase 3 double-masked, randomized, placebo-controlled, multi-center study of PS compared with placebo ophthalmic solution in patients with dim light vision disturbances at

multiple sites in the U.S. In this trial, 145 patients who experienced vision impairment under dim light conditions were randomized to receive either PS or placebo. Each subject was randomized 1:1 to treatment with PS or placebo ophthalmic solution

and stratified by iris color (light/dark irides). Treatment was self-administered in each eye QD at or near bedtime for 14 days.

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At Day 8 (primary endpoint), a statistically significantly greater percent of subjects treated with PS in the mITT Population had study eyes with ≥ 15 letters improvement from baseline in mLCVA

compared with placebo treatment (13% vs 3%, respectively; p=0.0459). A significantly greater percentage of subjects treated with PS also had study eyes with ≥ 15 letters improvement from baseline in mLCVA compared with placebo treatment at Day 15

(21% vs 3%, respectively; p=0.0042) PS demonstrated favorable safety and tolerability in this study.

PS Nonclinical Toxicology Studies

As part of a comprehensive nonclinical toxicity program, Ocuphire conducted single and repeated-dose toxicity studies of phentolamine mesylate drug substance in rabbits and beagle dogs. There were no

PS-related histopathologic ocular pathology findings.

Nonclinical information (pharmacological properties, general and reproductive toxicology) for phentolamine mesylate is described in the literature in connection with other approved phentolamine drug

products and formulations, and was reviewed by the FDA in the approval process of the market applications for RYZUMVI, Oraverse and Regitine.

PS Clinical Development Plan

Ocuphire is developing PS in partnership with Viatris. For PS, the investigational new drug (IND) application was submitted to the FDA Division of Ophthalmology in July 2011 and is in effect (IND

70499). In November 2022, Ocuphire submitted an NDA for PS for the treatment of pharmacologically induced-mydriasis and was approved in September 2023. PS has completed 12 trials (3 Phase 1 trials, 5 Phase 2 trials and 4 Phase 3 trials), mostly in

young and older healthy volunteers in reversal of pharmacologically induced mydriasis, presbyopia, dim light disturbance and glaucoma patients. In December 2023, Ocuphire received SPA agreement with the FDA for PS for decreased vision under dim

(mesopic or low) light conditions after keratorefractive surgery.

PS Potential Clinical Plans

Ocuphire and its partner, Viatris, VEGA-3 (NYXP-302) trial is planned as a double-masked, randomized, placebo-controlled, multicenter trial in approximately 545 patients with presbyopia. This second

registration trial will evaluate efficacy and safety of PS similar to VEGA-2 and include similar primary and key secondary endpoints and analysis, with assessment of tachyphylaxis and an optional extension for a total of 48 weeks. Viatris, our

development and commercial partner, is expected to continue Phase 3 development in the first half of 2024.

Based on the positive results of the first Phase 3 trial, LYNX-1, Ocuphire and its partner, Viatris, are planning a similar second registration trial for PS in up to 200 subjects for the treatment of

decreased vision under dim (mesopic or low) light conditions after keratorefractive surgery. Viatris, our development and commercial partner, is expected to continue Phase 3 development in the first half of 2024.

Future In-Licensing and Acquisition Opportunities

Ocuphire continually evaluates product candidates based on scientific merit, patent protection, regulatory pathways, and commercial opportunity.

Sales and Marketing

The company maintains discussions with a range of ophthalmic drug companies regarding development and commercialization of APX3330, including co-development, distribution, license, or mergers and

acquisitions. As part of the pre-commercialization planning, Ocuphire has started market development activities, which include engaging with key opinion leaders as well as increased visibility and presence at retina, ophthalmology and optometry

medical and industry conferences.

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In November 2022, Ocuphire entered into a licensing agreement with Viatris for the development and commercialization of all PS indications in the U.S. and ex-U.S. markets (excluding certain countries

in Asia).

Manufacturing

For APX3330, PS, and for other product candidates that will be developed in the future, Ocuphire’s contract manufacturers are currently producing, and will produce, its bulk drug substances and drug

products for use in Ocuphire’s preclinical studies and clinical trials, utilizing reliable and reproducible synthetic processes and common manufacturing techniques.

Pursuant to the Viatris License Agreement, Ocuphire intends to transfer commercial manufacturing responsibilities for PS to Viatris. Ocuphire does not have any long-term agreements but Ocuphire or

its development partners intend to secure such arrangements for drug substances or drug products as appropriate, and currently uses purchase orders with multiple manufacturers. Ocuphire is qualifying its selected manufacturers to provide bulk drug

substances and drug products in conjunction with the NDA regulatory submission to the FDA. Ocuphire plans to continue to rely upon contract manufacturers and, potentially, collaboration partners to manufacture commercial quantities of its drug

substances and drug products, if approved for marketing by the applicable regulatory authorities. Ocuphire does not own or operate, and currently has no plans to establish, any manufacturing facilities.

APX3330

APX3330 is an oral formulation of a small molecule drug substance that is synthesized from readily available raw materials and using conventional chemical processes. The APX3330 drug substance has

been optimized to a new form. Process and analytical development of APX3330 drug substance and drug product is being finalized, and their production scaled-up under cGMP regulatory requirements. Previously, the APX3330 drug product manufacturer has

performed pharmaceutical development to support the cGMP manufacturing campaign for tablets of 60 mg and 120 mg dose strengths, the latter being used in prior clinical trials. Ocuphire has reformulated the drug product and increased the dose strength

to 300 mg for convenient once or twice a day dosing. Ocuphire is also planning additional stability studies for future lots of both the drug substance and drug product of APX3330 in order to establish expiry of the new tablet strength, formulation,

and to support regulatory approval and commercial stage.

The proprietary formulation of PS is a sterile, preservative-free, isotonic, buffered aqueous solution containing phentolamine mesylate, mannitol, and sodium acetate. The drug substance phentolamine

mesylate USP is a small molecule that can be manufactured by reliable and reproducible synthetic processes from readily available starting materials. Ocuphire currently obtains the active pharmaceutical ingredient for PS from a single supplier in

Italy and is presently taking steps to develop a second source, but is working with Viatris to determine the long-term commercial manufacturing strategy. All lots of drug substance phentolamine mesylate and PS drug product used in clinical trials are

manufactured under current good manufacturing practices (cGMP), a quality-system regulating manufacturing, with processes registered by the supplier with FDA in an active Drug Master File (DMF). PS was previously packaged in a single-use bottle with

cap served as the container closure system for Phase 1 and 2 clinical trials. Ocuphire transitioned the container closure system to an industry standard, single-use preservative-free blow-fill-seal (“BFS”) container for PS, which is being formulated

and filled by a leading U.S. manufacturer. PS eye drops in the BFS container are classified by FDA as a drug-device combination product. The current manufacturing process has been scaled to a commercial capacity. PS has demonstrated stability at 5°C

refrigerated for a minimum of two years. Ocuphire is performing additional stability studies on lots of both the drug substance phentolamine mesylate and the drug product of PS in order to establish expiry dating and to support regulatory submissions

and commercial manufacturing. To supply eventual global markets and to avoid reliance on a single facility, Ocuphire and its partner Viatris are evaluating the establishment of second-source manufacturing facilities for drug substance and drug

product.

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Apexian Sublicense Agreement

On January 21, 2020, Ocuphire entered into a sublicense agreement with Apexian pursuant to which it in-licensed patents and other intellectual property relating to the APX3330 product candidate and

second-generation product candidates owned by Apexian, and intellectual property that Apexian in-licensed from Eisai, including certain study reports, manufacturing and analytical records, data, know-how, technical and other proprietary information

relating to APX3330. This intellectual property constitutes a Ref-1 Inhibitor program focused on developing therapeutic applications to treat disorders related to ophthalmic and diabetes mellitus conditions. The lead compound in the Ref-1 Inhibitor

program is APX3330, which Ocuphire intends to develop as an oral tablet therapeutic to treat DR and DME, and potentially wAMD. See “Ocuphire Management’s Discussion and Analysis of Financial Condition and Results of

Operations—Contractual Obligations and Commitments—Apexian Sublicense Agreement” for more details regarding the Apexian Sublicense Agreement.

Intellectual Property

APX3330

As of December 31, 2023, the patent estate that Ocuphire has in-licensed for APX3330 and related compounds contains nine U.S. patents and two pending U.S. non-provisional patent applications, as well

as issued patents in Europe, Japan, Canada, China, and Australia, and pending patent applications in Europe, Japan, Canada, and South Korea. The license is for the use and commercialization of APX3330 and related composition of matter compounds

covered by the subject patents and patent applications in the field of human health uses for ophthalmic and diabetes mellitus indications.

In-licensed U.S. patent 9,040,505 has claims to methods of treating diabetic retinopathy and other diseases using, for example, APX3330 and is scheduled to expire in year 2030. Counterpart patents

have issued in Europe, Japan, Australia, and Canada, which are scheduled to expire in year 2028, and there is a related pending U.S. patent application with method of treatment claims that, if issued as a patent, would expire in year 2028. Pending

U.S. application 18/341,077 and pending applications in Europe, Japan, Canada, South Korea have claims to methods of treating wAMD and other diseases using, for example, APX3330, APX2009, or APX2014. Patents, if granted, based on these pending patent

applications would expire in year 2039. The U.S. and certain foreign countries permit extension of patent term for up to five years to compensate for patent term lost during the government regulatory review process for a new medicine. If U.S. patent

9,040,505 qualifies for the full five years of patent term extension, the expiration of U.S. patent 9,040,505 would be in year 2035. Whether U.S. patent 9,040,505 qualifies for the full five years of patent term extension depends in part on the date

of FDA approval for the new medicine.

Ocuphire in-licenses one U.S. patent directed to methods of treating certain retinal disease using APX2014, whereby this U.S. patent is scheduled to expire in year 2030. Ocuphire also in-licenses

patent applications in the U.S. and Canada directed to a combination therapy composition comprising an APE1/REF-1 inhibitor, such as APX3330, and a second therapeutic agent, and methods of using such combination therapy to treat retinal diseases

and/or treat other indications are pending in the U.S. and Canada. Patents, if granted, based on these applications would expire in year 2038. In-licensed patent applications directed to use of an APE1/REF-1 inhibitor, such as APX3330, in monotherapy

or combination therapy to reduce neuronal sensitivity and/or treat other indications are pending in Europe, Japan, and Canada, whereby patents, if granted based on these applications, would expire in year 2038. This same patent family includes one

in-licensed U.S. patent directed to methods using APX3330 to treat inflammation and pain as part of a combination therapy.

U.S. patents that Ocuphire has in-licensed to derivatives of APX3330 include U.S. patents 9,089,605; 9,193,700; 9,877,936; 10,154,973; 11,160,770; 11,648,226; and 11,723,886. These U.S. patents are

schedule to expire from 2029 to 2032. Foreign patents that Ocuphire has in-licensed to derivatives of APX3330 include patents in Europe, Japan, Australia, China, and Canada that are scheduled to expire between the years 2028 to 2039.

In addition to patents and patent applications that Ocuphire has in-licensed, as of December 31, 2023, Ocuphire owns a patent application that is pending in the U.S., Europe, Japan, Australia,

Canada and other countries and directed to methods of treating diabetic retinal diseases using APX3330. Patents, if granted, based on the foregoing patent applications would expire in year 2042. Additionally, Ocuphire owns one pending international

patent application with counterpart patent applications pending in the U.S., Taiwan, and Argentina directed to APX3330 salts and esters, compositions comprising an APX3330 salt or ester and therapeutic uses of APX3330 salts and esters. A patent

granted on the foregoing patent applications would expire in year 2043. Ocuphire also owns one pending U.S. provisional patent application directed to additional therapeutic methods using APX3330 in patients with diabetic retinal disease, and one

U.S. provisional patent application directed to additional therapeutic methods using new generation molecules APX2009 or APX2014, whereby any patents, if granted, from an application filed based on these provisional patent applications would expire

in year 2044.

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Ocuphire’s patent estate includes patents and patent applications to forms of phentolamine mesylate, formulations containing phentolamine mesylate, methods of using phentolamine mesylate, and methods

of manufacturing phentolamine mesylate. Ocuphire primarily protects its intellectual property through a combination of patents and patent applications on inventions, trademark protection on Ocuphire’s product name, and trade secret protection as

Ocuphire deems appropriate. Ocuphire owns all of the worldwide rights to PS for all indications, but has out-licensed certain rights to PS pursuant to the Viatris License Agreement.

As of December 31, 2023, Ocuphire’s patent estate relating to PS contains twelve U.S. patents, nine pending U.S. non-provisional patent applications, as well as issued patents in Australia, Canada,

Europe, Japan, and Mexico and pending patent applications in Australia, Canada, Europe, Japan, China, and other foreign countries.

Ocuphire’s U.S. Patents 9,795,560; 10,278,918; 10,772,829; 11,090,261 and 11,844,858 and counterpart Australian Canadian, European, and Japanese patents each contain composition of matter claims to

aqueous phentolamine mesylate formulations and are scheduled to expire in year 2034. In the same patent family, Ocuphire also has 1 pending U.S. patent application with additional claims to aqueous phentolamine mesylate formulations, whereby a

patent, if granted, would expire in year 2034. The patents and patent applications cover the current clinical formulation for the PS product.

Ocuphire’s U.S. Patent Nos. 9,089,560; 9,789,088; 11,000,509 and 11,717,510 contain claims directed to methods of improving visual performance using, for example, phentolamine mesylate and are

scheduled to expire in year 2034. Counterpart patents have issued in Australia, Canada, Europe, and Japan, which are scheduled to expire in year 2034. In the same patent family, Ocuphire also has 1 pending U.S. patent application with additional

claims to methods of improving visual performance using, for example, phentolamine mesylate, whereby a patent, if granted, based on this pending application would expire in year 2034. The patents and patent applications cover uses of the current

clinical formulation for the PS product.

Ocuphire has patent applications pending in the U.S., Australia, Canada, China, Europe, and Japan directed to treating glaucoma and other medical disorders using phentolamine mesylate. Patents, if

granted, based on these pending applications would expire in year 2039.

Ocuphire’s U.S. Patent 10,993,932 contains claims directed to methods of treating presbyopia using phentolamine mesylate with adjunctive pilocarpine and is scheduled to expire in year 2039.

Ocuphire’s U.S. Patent 11,400,077 contains claims directed to methods of treating mydriasis using phentolamine mesylate and is scheduled to expire in year 2039. In the same patent family as U.S. Patent Nos. 10,993,932 and 11,400,077, Ocuphire has

four pending U.S. patent applications, two of which have claims to treating presbyopia and the other two U.S. applications have claims to treating mydriasis. Counterpart patent applications are pending in Australia, Canada, China, Europe, Japan, and

other foreign countries, whereby a patent, if granted, based on these pending U.S. and foreign patent applications would expire in year 2039.

Ocuphire’s U.S. Patent 11,566,005 contains claims directed to high-purity phentolamine mesylate as composition of matter, methods to make phentolamine mesylate from phentolamine and methods for

inhibiting contraction of smooth muscle of a subject’s iris, improving visual contrast sensitivity or visual acuity, treating a dim light or night vision disturbance, treating or reversing pharmacologically induced mydriasis, and treating

presbyopia, with phentolamine mesylate. Counterpart patent applications are pending in the U.S., Europe, Japan, and other foreign countries. This U.S. patent and other patents, if granted on the foregoing patent applications are projected to

expire in year 2042. Ocuphire also has one patent application that is pending in China and directed to methods for making high purity phentolamine mesylate and compositions comprising phentolamine mesylate. A patent granted on this Chinese

application would expire in year 2041, In addition, Ocuphire has a patent application that is pending in Europe directed to particular phentolamine mesylate crystal forms and their use. A patent granted on this European patent application would

expire in year 2043. Ocuphire also has a pending patent application in the U.S., Europe, Japan, and other foreign countries directed to additional methods for treating mydriasis and glaucoma, whereby any foreign patents, if granted, based on the

foregoing patent applications would expire in year 2042.

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Form 10-K

Ocuphire also owns an issued patent in Mexico that is scheduled to expire in year 2025 and has claims to ophthalmic formulations.

Ocuphire has registered trademark protection in the United States for the NYXOL® and a pending U.S. federal trademark

application for RYZUMVI.

Additional Patent Term Information

As background, the patent term is typically 20 years from the date of filing a non-provisional application. In the United States, a patent’s term may be lengthened several ways. First, patent term

adjustment (PTA) compensates a patentee for administrative delays by the USPTO in granting a patent. Second, in certain instances, a patent term extension (PTE) can be granted to recapture a portion of the term effectively lost as a result of the FDA

regulatory review period, as provided under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Act. This restoration period cannot be longer than 5 years for approval of a drug, and the total patent

term, including the restoration period, must not exceed 14 years following FDA approval. Only patent(s) applicable to an approved drug is (are) eligible for the PTE and the application for the extension must be submitted prior to the expiration of

the patent and within 60 days from market approval. Independent of patent protection, in the United States, the Hatch-Waxman Act provides a 5-year period of non-patent data exclusivity within the United States to the first applicant to gain approval

of an NDA for a new chemical entity (NCE). Under this provision, APX3330 may be eligible for up to 5 years of data and market exclusivity under the Hatch-Waxman Act, because it is considered an NCE as the FDA has not previously approved any other

drug containing the active ingredient of APX3330.

In Europe, under the Data Exclusivity Directive, pharmaceutical companies may receive up to 11 years to market their product without risk of competition. In Japan, under the Pharmaceuticals Act of

Japan, the market authorization holder, based on the length of a required study period reexamination, may have up to 10 years before a generic can enter the market. Further, the expiration date of certain patents may be extended for up to a maximum

of 5 additional years to accommodate for time spent seeking government approval to market a new medicine, in those countries that permit extension of patent term to accommodate for time spent seeking government approval to market a new medicine.

Ocuphire also protects its proprietary information through written agreements. Ocuphire’s employees, consultants, contractors, partners and other advisors are required to execute nondisclosure and

assignment of invention agreements upon commencement of employment or engagement. In addition, Ocuphire protects its proprietary information through written confidentiality agreements with outside parties who may come into possession of Ocuphire’s

confidential information.

Competition

There is intense competition within the pharmaceutical industry. While Ocuphire believes that RYZUMVI and its current product candidates, APX3330 and PS, are well-positioned for development in each

indication, Ocuphire or its development partners will face competition from both branded and generic pharmaceutical companies as well as products that are currently in development. Many of these companies have significantly greater financial and

human resources and experience in drug development, R&D, and commercialization. These competitors compete with Ocuphire in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient

enrollment for clinical trials as well as acquiring products, product candidates or other technologies complementary to Ocuphire program. Smaller and other early-stage companies may also prove to be significant competitors if they choose to partner

with large, established companies.

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Ocuphire Pharma, Inc.

Form 10-K

Government Regulation and Product Approvals

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union (EU), extensively regulate, among other

things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of

pharmaceutical products. The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities,

require the expenditure of substantial time and financial resources.

The EMA is a decentralized agency governed by an independent management board responsible for the evaluation, supervision, and safety monitoring of medicines in the EU. The Medicines and Healthcare

products Regulatory Agency (MHRA) regulates medicines, medical devices, and blood components in the United Kingdom (UK) and serves as a similar function to the EMA in the EU, following the exit of the UK from the EU in Brexit. The Japanese

Pharmaceuticals and Medical Devices Agency serves a similar function to the FDA in the United States and is an independent administrative institution. The National Medical Products Administration (NMPA) is the Chinese agency for regulating drugs and

medical devices (formerly the China Food and Drug Administration or CFDA).

Review and Approval of Drugs in the United States

In the United States, the FDA regulates drug products under the Federal Food, Drug, and Cosmetic Act, or FDCA, and implementing regulations. The failure to comply with applicable requirements under

the FDCA and other applicable laws at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to

approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions,

fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.

An applicant seeking approval to market and distribute a new drug product in the United States must typically undertake the following:

• preparation and submission to the FDA of an NDA;

Table of Contents

Ocuphire Pharma, Inc.

Form 10-K

Preclinical Studies

Preclinical studies include laboratory evaluation of the purity and stability of the manufactured drug substance or active pharmaceutical ingredient and the formulated drug or drug product, as well

as in vitro and in vivo animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use.

The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations. The results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or

literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. Some long-term preclinical testing, such as long-term repeat-dose toxicology studies, may continue after the IND is submitted.

Companies usually must complete some long-term preclinical testing, such as long-term repeat-dose toxicology studies, and must also develop additional information about the chemistry and physical

characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of

the candidate product and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final product. Additionally, appropriate packaging must be selected and tested, and stability studies

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IRD · 10-K · period ended 2023-12-31

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IRD · 10-K · period ended 2023-12-31

ITEM 1. BUSINESS

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