UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
For the Fiscal Year Ended December 31, 2022
or
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)
681-9815
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 ☐
If
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, 2022, based on the closing price on that date
of $1.92, was approximately $37,236,094. As of March 27, 2023, there were 20,947,830 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 2023 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, 2022.
Ocuphire Pharma, Inc.
Form 10-K
TABLE OF CONTENTS
PART I 6
ITEM 1. BUSINESS 6
ITEM 1A. RISK FACTORS 61
ITEM 1B. UNRESOLVED STAFF COMMENTS 103
ITEM 2. PROPERTIES 103
ITEM 3. LEGAL PROCEEDINGS 103
ITEM 4. MINE SAFETY DISCLOSURES 103
ITEM 6. [RESERVED] 104
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 119
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 119
ITEM 9A. CONTROLS AND PROCEDURES 119
ITEM 9B. OTHER INFORMATION 120
ITEM 9C. DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 120
ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 121
ITEM 11. EXECUTIVE COMPENSATION 121
ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 121
ITEM 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES 122
ITEM 16. FORM 10-K SUMMARY
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Form 10-K
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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• The market price of our common stock may fluctuate significantly.
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 is a late clinical-stage ophthalmic biopharmaceutical company focused on developing and commercializing therapies for the treatment of refractive and retinal eye disorders. Ocuphire’s
pipeline currently includes two small molecule product candidates targeting several of such indications.
Nyxol
In November 2022, Ocuphire signed a license and collaboration agreement (the “Nyxol License Agreement”) with FamyGen Life Sciences, Inc.
(acquired by Viatris, Inc. (“Viatris”) in January 2023) pursuant to which Ocuphire has granted to Viatris an exclusive license to develop, manufacture, import, export and commercialize Ocuphire’s product candidate phentolamine ophthalmic
solution 0.75% (Nyxol® Eye Drops or “Nyxol”) in all three indications (RM, presbyopia and DLD) in key territories. Under the terms of the Nyxol License
Agreement, Ocuphire is conducting development of Nyxol in the United States with its partner Viatris, and Viatris is responsible for developing Nyxol in countries and jurisdictions outside of the United States. Viatris will reimburse
Ocuphire for budgeted costs related to the development of Nyxol through U.S. Food and Drug Administration (“FDA”) approval as long as Ocuphire continues to conduct such development activities. Viatris or its affiliates will commercialize Nyxol in the Territory for each
indication that receives regulatory approval.
Pursuant to the Nyxol License Agreement, Ocuphire received an
upfront cash payment of $35 million. In addition Ocuphire is eligible to receive potential additional payments of up to $130 million, in the aggregate, upon achieving certain specified regulatory or net sales milestones, with the first
potential payment of $10 million to be made following approval by the FDA of Nyxol for the reversal of pharmacologically-induced mydriasis (“RM”) (dilation of the pupil). Ocuphire will also receive tiered royalties, starting at low double-digit royalties up to low twenty percent royalties, based on the aggregate annual net sales of
Nyxol in the United States, and will receive low double-digit royalties based on all annual net sales outside of the United States. Nyxol is a once-daily eye drop formulation of phentolamine mesylate designed to reduce pupil diameter
and improve visual acuity. Nyxol can potentially be used across multiple indications such as treatment of RM, presbyopia (age-related blurry near vision) and dim light or night vision disturbances (“DLD”) (halos, glares and starbursts).
Ocuphire’s management believes these multiple indications potentially represent a significant market opportunity. Nyxol has been studied in a total of 12 clinical trials (3 Phase 1, 5 Phase 2 and 4 Phase 3) in a total of over 650 patients (with
over 400 Nyxol-treated) and has demonstrated promising clinical data across the three targeted refractive indications.
Ocuphire reported positive top-line data from Phase 3 trials in RM: MIRA-2 in March 2021, MIRA-3 in March 2022 and MIRA-4 in April 2022.
Ocuphire also reported positive top-line data from a Phase 2 trial of Nyxol for treatment of presbyopia, both alone and with low-dose pilocarpine (pilocarpine
hydrochloride ophthalmic solution 0.4%, “LDP”) as adjunctive therapy (VEGA-1). Ocuphire reported top-line data from a Phase 3 trial in DLD in May 2022 (LYNX-1). Ocuphire submitted a new drug application (“NDA”) to the U.S. Food and
Drug Administration (“FDA”) in November 2022 under the 505(b)(2) pathway for Nyxol for RM with a Prescription Drug User Fee Act (PDUFA) goal date of September 28, 2023. The first phase 3 registration trial of Nyxol for the treatment of
presbyopia (VEGA-2), both alone and with LDP as adjunctive therapy, was started in late December 2022, and topline results from this trial are expected in late 2023. Future trials are planned to start in 2023 including the second Phase 3
registration trials for presbyopia (VEGA-3) and DLD (LYNX-2), and supportive long-term safety trial for both chronic indications (LYRA-1).
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APX3330
Ocuphire’s product candidate, APX3330, is a twice-a-day oral tablet designed to target multiple pathways relevant to retinal and choroidal (the vascular layer of the eye) diseases such as
diabetic retinopathy (“DR”) and diabetic macular edema (“DME”) which, if left untreated, can result in permanent visual acuity loss and eventual blindness. DR is a disease resulting from diabetes in which chronically elevated blood sugar levels
cause progressive damage to blood vessels in the retina. DME is a severe form of DR which involves leakage of protein and fluid into the macula, the central portion of the retina, causing swelling and vascular damage. Prior to Ocuphire’s
in-licensing this product candidate, APX3330 had been studied by other sponsors in a total of 11 clinical trials (6 Phase 1 and 5 Phase 2) in a total of over 420 healthy volunteers or patients (with over 340 APX3330-treated) for inflammatory
(hepatic) and oncology indications, and had demonstrated evidence of target engagement, pharmacokinetics, durability, and favorable safety and tolerability. Ocuphire has also in-licensed APX2009 and APX2014, which are second-generation product
candidates and analogs of APX3330. In January 2023, Ocuphire reported top-line efficacy and safety results from the ZETA-1 Phase 2 trial conducted in 103 subjects (51 treated with 600 mg daily dose of APX3330) in DR, including moderately severe
non-proliferative DR (“NPDR”) and mild proliferative DR (“PDR”), as well as patients with DME without loss of central vision. Although the ZETA-1 clinical trial did not meet the primary endpoint of % 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, statistical significance was achieved on a key pre-specified secondary endpoint of preventing clinically meaningful
progression of diabetic retinopathy (defined by binocular 3 or more steps worsening on the DRSS scale, calculated as the sum of changes in each eye) after 24 weeks of treatment. Given the oral systemic delivery of APX3330, an endpoint that
evaluates the effects on both eyes is the planned Phase 3 primary endpoint for future registration trials; this will be confirmed at an End-of-Phase 2 (EOP2) meeting with the FDA in second half of 2023. APX3330 demonstrated favorable safety and
tolerability in the ZETA-1 trial, consistent with the safety data from the prior 11 clinical trials. Treatment-related adverse events were uncommon, and most were mild in severity. There were no treatment-related serious adverse events. No
changes were observed in liver, kidney, or heart function as well as complete blood count and comprehensive metabolic panel.
As part of its strategy, Ocuphire will continue to explore opportunities to acquire additional ophthalmic assets and seek strategic partners for late-stage development, regulatory preparation,
and commercialization of drugs in key global markets.
Corporate History
In February 2018, Ocuphire Pharma, Inc. (“Private Ocuphire”) was founded and subsequently merged in April 2018 with Ocularis Pharma, LLC, (the
original innovator of phentolamine mesylate ophthalmic solution to treat DLD), and in January 2020 obtained from Apexian Pharmaceuticals, Inc. certain rights to its Ref-1inhibitor program, including APX3330 (see “Apexian Sublicense Agreement”).
Many of Ocuphire’s employees, directors, advisors and consultants have been involved in the development of Nyxol and other ophthalmic drugs including approved products such as LUMIFY®, Zirgan®, Durezol®, Upneeq®,Rhopressa®, Roclatan®, Vyzulta®, Xiidra®,
Cequa®, and Dextenza®. The management team, led by CEO and founder Mina Sooch, collectively has significant experience in operating pharmaceutical companies and discovering, developing, and commercializing treatments in
multiple therapeutic areas. Ocuphire also has a world-class medical advisory board of over 20 key opinion leaders including retina specialists, refractive surgeons, and optometrists.
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 Nyxol License Agreement, licensing its product Nyxol to Viatris.
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Strategy
Ocuphire’s goal is to build a leading ophthalmic 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:
Ocuphire is developing Nyxol with its partner Viatris for multiple indications, and Ocuphire is continuing to develop APX3330 for multiple indications with the goal to eventually seek a
commercial partner for APX3330. Ocuphire believes the two programs present similar potential advantages: (1) promising clinical data to date; (2) both small-molecule clinical candidates; (3) convenient dosing route and schedule; (4) potential for
first-line or adjunctive therapy; and (5) significant commercial potential. TABLE 1 below summarizes Ocuphire’s current development pipeline of product candidates and their target indications and
anticipated milestones:
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TABLE 1: Ocuphire Pipeline: Product Candidates and Indications Pipeline
Note: 0.75% POS (Phentolamine Ophthalmic Solution) is the same as 1% PMOS (Phentolamine Mesylate Ophthalmic Solution). References to Nyxol with both designations appear throughout this document,
there is no difference in formulation between the two designations.
Ocuphire submitted its first NDA to the FDA for Nyxol for RM in November 2022 utilizing the 505(b)(2) pathway of the U.S. Federal Food, Drug, and Cosmetic Act (“FDCA”). The FDA notified Ocuphire
in February 2023 that it accepted the application for filing and that it has set a PDUFA goal date of September 28, 2023 for approval. Ocuphire anticipates submitting supplemental NDAs for Nyxol for presbyopia and DLD and is advancing APX3330
towards an NDA in the future.
Overview of Eye Disease Market
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. Nyxol, which was out-licensed in 2022, is currently in late-stage clinical development for reversal of mydriasis (eye dilation), presbyopia and night vision disturbances, and has the potential to address an
unmet need for millions of patients in the U.S.
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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 7 million patients suffer from diabetic retinopathy (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 and DME
market with a novel, dual mechanism of action of inhibiting VEGF 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. Avastin® (bevacizumab), a monoclonal antibody marketed by Genentech, is also used off-label to treat these same indications as
it is more cost-effective than the other branded drugs. These three 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).
Summary of Nyxol and APX3330
Nyxol (phentolamine 0.75% ophthalmic solution)
Nyxol, 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 for Nyxol for RM. The submission was accepted for filing by FDA with a PDUFA goal date of September 28, 2023. Phentolamine mesylate, the drug substance and active
component of Nyxol, is the active pharmaceutical ingredient (API) in two FDA-approved drugs, Regitine® and OraVerse®. Regitine, an injectable approved in 1952, is used mainly to treat pre- or intra-operative hypertensive
episodes in patients with pheochromocytoma. OraVerse, approved in 2007, is an intraoral submucosal injection used to reverse anesthesia after oral surgery. The FDA has stated that it would be acceptable for the Nyxol application to reference
the FDA’s previous review of safety and efficacy for Regitine® (Phentolamine Mesylate Injection, NDA 008278) and Oraverse® (Phentolamine Mesylate Injection, NDA 22159), pursuant to section 505(b)(2) of the U.S. Federal
Food, Drug, and Cosmetic Act (“FDCA”). In multiple clinical trials, Nyxol has been shown to reduce pupil size, improve near and distance visual acuity in light and dark conditions, and improve low contrast visual acuity. Ocuphire and Viatris are pursuing multiple indications for Nyxol, including RM, presbyopia, and DLD. For treatment of presbyopia, Ocuphire is evaluating the efficacy of Nyxol both as a
single-agent eye drop and as adjunctive therapy with LDP.
Key attributes of Nyxol include the following:
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Ocuphire and Viatris are initially pursuing Nyxol for the following three indications under the Nyxol License Agreement as a first-line therapy (in the case of
presbyopia, both as a single agent and with low-dose pilocarpine as an adjunctive drop):
APX3330
APX3330 (E3330), originally developed by Eisai Co., Ltd. and Apexian Pharmaceuticals, Inc., is a small molecule that specifically targets Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1
(APE-1/Ref-1, referred to as 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-1a 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). Moreover, data from these preclinical studies
suggest that APX3330 is a promising candidate for clinical evaluation of the efficacy and safety of an oral systemic therapy to treat these important diseases.
Key attributes of Ocuphire’s product candidate APX3330 include the following:
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Ocuphire is initially pursuing APX3330 for the DR indication as first-line therapy and may explore opportunities for clinical benefit as adjunctive therapy for other retinal indications such as
DME, wAMD, and GA:
Nyxol’s Target Indications
RM (Nyxol)
Mydriasis Overview
Every year in the U.S., over 100 million eye exams or procedures are performed that require dilation of the pupil (mydriasis) to examine the back of the eye either for routine check-ups, disease
monitoring or surgical procedures. The 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) or a combination of both mydriatic agents. Typically, pharmacologically induced mydriasis dilates the pupil to 7 mm to 8 mm, a size suitable for ophthalmic examination of the retina and other structures of the interior of the
eye. Such pharmacologically induced mydriasis can last from a few hours (typically 6 hours) up to 24 hours, depending on the pigmentation of the iris, one’s age, and other factors. Side effects of mydriasis include sensitivity to light and
blurred vision, which make it difficult to read, work, or drive. Many dilating drops also cause cycloplegia, the temporary paralysis of the muscle which allows the eye to focus on near objects. For this reason, many patients may request to avoid
dilation, thus limiting the eye care provider’s ability to conduct a comprehensive annual eye exam.
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Limitations of Existing Treatments for Reversal of Mydriasis
There is no approved product presently on the market for reversal of mydriasis and Ocuphire is not aware of any others in development. In 1990, the
FDA approved the selective alpha-1 antagonist dapiprazole, marketed as Rev-Eyes®, to reverse mydriasis induced by adrenergic or anticholinergic agents. Rev-Eyes
was eventually withdrawn from the market for reasons unrelated to safety or efficacy, according to the FDA.
Nyxol Opportunity in RM
Nyxol has been shown in clinical studies to expedite the reversal of mydriasis compared to the eye’s natural process. According to GlobalData market research, over 65% of patients report a
moderate to severe negative impact of a dilated exam, underscoring the potential value of Nyxol’s role in improving comfort and daily function after pupil dilation. Additionally, an estimated 45% of patients responded that they would be very
likely to request a dilation reversal drop, and more than 40% of eye care providers would be likely to use a reversal drop if such a treatment were commercially available. Ocuphire believes that many people who undergo pupil dilation would
benefit from a reversal treatment that has the potential to get patients back to their normal routines faster and avoid the subjective discomfort of dilation. Ocuphire also believes that if providers can offer a reversal drop there could
potentially be more compliance with annual dilated eye exams.
Presbyopia (Nyxol)
Presbyopia Overview
Presbyopia is an age-related condition with onset most common in people over 40 years old. As the eye ages, the lens becomes stiffer, which limits the eye’s ability to adjust its focus for
reading or for other tasks that require clear vision at near distances. Presbyopia patients experience blurred near vision, difficulty seeing in dim light, and eye strain. In young healthy eyes, lenses are able to focus light from objects at
different distances by a process called accommodation. During accommodation, muscles surrounding the lens contract, causing the lens to change shape and increasing the focusing power of the eye. This allows dynamic, clear vision at both near and
far distances. With increasing age, the lens becomes stiffer as the structural crystallin proteins become misfolded. This increased lens stiffness limits the eye’s ability to adjust its focus for reading or for other tasks that require clear
vision at near distances. Because of the ubiquity of the condition, presbyopia represents a large market both in the United States and abroad totaling over 2 billion presbyopia patients. It is estimated that 120 million Americans have presbyopia,
and this number is expected to grow as the population above the age of 45 increases.
Existing Treatments for Presbyopia
The U.S FDA approved VuityTM (1.25% pilocarpine) eye drop for the treatment of presbyopia in October 2021. Vuity
was launched in December 2021 and is marketed by Allergan, an AbbVie company. Additional available treatments for presbyopia include reading glasses, bifocals, gradients, bifocal contact lenses, and multifocal intraocular lenses. Reading glasses
can be inconvenient and must be taken off and put on frequently throughout the day to see objects at far and near distances, respectively. Many patients express frustration with losing or forgetting their glasses. Additionally, some patients find
glasses unflattering. Contact lenses for presbyopia also have drawbacks. They can only be used monocularly, where one eye is fitted with a presbyopic lens while the other is used for distance vision, which often leads to eye strain. Cholinergic
agonist (pilocarpine, carbachol, aceclidine) eyedrops have potential negative side effects such as headache, brow ache and retinal detachment.
A small portion of patients elect surgical intervention, including laser treatment to achieve monovision and insertion of KAMRA Inlays, a plastic implant into the cornea of the non-dominant eye
to increase its depth of field. The risks of such interventions are those associated with all ocular surgeries, such as a potential decrease in contrast sensitivity and the creation or worsening of dim light or night vision disturbances.
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Nyxol Opportunity in Presbyopia
Pupil diameter management is a promising strategy for the pharmacological treatment of presbyopia. Recent research suggests that an optimal pupil size of 2 mm to 3 mm diameter will lead to
significant improvement in presbyopia symptoms by increasing depth of focus without compromising distance vision in photopic or mesopic lighting conditions. Ocuphire has been evaluating Nyxol as both a single-agent eye drop and with LDP as an
adjunctive eye drop to achieve optimal pupil size and improve near vision. Nyxol has shown in several Phase 2 trials the ability to reduce pupil diameter size by 1-1.5 mm alone and by 2-2.5 mm when Nyxol is used with LDP. Nyxol alone provides
durable near vision efficacy gain of up to 18 hours, and the Nyxol + LDP combination allows additional efficacy gains of up to least 6 hours.
With respect to the treatment of presbyopia, Ocuphire believes that tolerability, convenience, and preservation of distance vision quality are of the utmost importance. Presbyopia is considered a
“benign” condition, in that there is no risk of death or complete vision loss. Thus, any therapies without robust tolerability will not be suitable alternatives to reading glasses or contact lenses. Nyxol is being developed to be applied once
daily before bed, with potential resolution of any mild transient hyperemia by morning. Nyxol’s unique mechanism of action on the iris dilator muscle has no to low risk of retinal detachment. According to GlobalData market research, 69% of
patients would consider an eye drop alternative. Ocuphire believes that many presbyopes who are unsatisfied with their reading glasses or monocular contact lenses, and who would prefer a less invasive alternative than surgical intervention, would
find Nyxol single-agent eye drop or the Nyxol + LDP drops a promising option, if approved.
DLD (Nyxol)
DLD Overview
Vision at night or in dim light conditions is different from daytime vision in several important ways. Most notably, at night, the pupils dilate to allow more light into the eye. Diminished night
vision is a natural part of aging as well as a common side effect of several conditions and procedures. DLD is caused by peripheral imperfections (aberrations) of the cornea which scatter light when the pupil dilates in dim light conditions.
These imperfections can be naturally occurring, especially with age, or surgically induced from refractive procedures such as LASIK. As the pupil dilates in response to mesopic conditions, light passes through the periphery of the cornea and
lens, unlike during photopic conditions. Any imperfections or aberrations present on the periphery cause light to reach the retina in a non-focused and scattered way, creating glare, halos, starbursts, ghosting, and a loss of contrast sensitivity
(“CS”). These visual disturbances can be debilitating to a variety of everyday activities, especially driving. The light emitted by traffic lights and other cars scatters and obscures most of the visual field, making driving in dim light
conditions hazardous. Glare, in particular, can be dangerous while driving. In one study of 297 drivers given vision tests that correlate with accidents, 45% of the drivers who reported difficulty driving at night were unable to perform any of
the tests with glare.
The effects of DLD can be reduced or eliminated by reducing the pupil size to a smaller diameter that prevents the scattering effect without impeding the ability to see at night. DLD can occur
naturally (night myopia) and is commonly caused by ocular surgery (“LASIK”). One significant cause of night myopia is keratoconus, an orphan disease that starts at a young age with progressive thinning of the cornea usually due to genetic and
environmental causes. Ocuphire estimates there are about 38 million individuals in the U.S. that suffer from DLD, with an estimated 16 million having moderate-to-severe DLD that may be directly addressable with a pupil management approach. Market
research conducted by GlobalData of patients who self-report DLD showed 25% completely avoid driving at night. Furthermore, 67% who report moderate or severe DLD would be willing to try an eye drop treatment option. These patients can be
segmented by the origins of their vision disturbance. Approximately 44% of DLD are the result of night myopia, followed by approximately 30% from cortical cataracts, 15% from post-intraocular lens (“IOL”) implants, and 10% following LASIK
surgery. These conditions span an age range of late teenagers to those 80 years and older.
Limitations of Existing Treatments for DLD
The biggest challenge for the treatment of DLD is the lack of safe, tolerable, convenient, and effective treatments. Despite a large number of addressable patients with moderate-to-severe DLD,
there is no FDA-approved treatment on the market for DLD. Some commonly used tools such as tinted glasses are not effective, and in fact, may worsen patients’ vision at night. Off-label use of approved miotic agents, such as regular-strength
pilocarpine, are unsuitable for the treatment of DLD because they reduce pupil size to a degree that may impede safe night vision and may cause loss of accommodation.
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Nyxol Opportunity in DLD
Ocuphire believes it may have a new DLD treatment option that could improve patients’ ability to see in dim lighting and significantly improve their quality of life. Nyxol is currently the only
product candidate in development for DLD and could become the first pharmacological treatment option if approved. In addition to a potential first-mover advantage, Nyxol is being developed to be administered via convenient, once-daily dosing
before bedtime and has been shown in multiple Phase 2 clinical trials to improve low contrast visual acuity in mesopic (dim) conditions on the standard visual chart. Nyxol has also been shown to be well-tolerated in these trials.
APX3330’s Target Indications
Diabetic Retinopathy (APX3330)
Diabetic Retinopathy Overview
Diabetic Retinopathy (“DR”) is an eye disease resulting from diabetes, affecting over 7 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 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.
Diabetic Macular Edema (APX3330)
Diabetic Macular Edema Overview
Diabetic Macular Edema (“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.
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Limitations of Existing Treatments for DR and DME
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 DME and 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 and
DME. 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).
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 and DME
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 and DME, 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 (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
first-in-class, 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.
Other Indications:
wAMD
Age-Related Macular Degeneration (“AMD”) is a common eye condition affecting 11 million individuals in the U.S. and 196 million 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).
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GA
Geographic atrophy (GA) is an advanced form of age-related macular degeneration (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 people have GA in the United States, and 5 million people 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® is the only FDA approved treatment for GA and requires monthly or every other month
intravitreal injections. Based on APX3330 targeting Ref-1 with a MOA of anti-VEGF and anti-inflammatory MOA, it has potential use in GA.
Product Candidates-Nyxol
Nyxol Mechanism of Action
Nyxol 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 Nyxol, 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 cilliary muscle such as headaches, brow aches and retinal
detachments and have limited use in patients with high myopia. Nyxol 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 (FIGURE 1).
FIGURE 1: Nyxol Product Candidate Profile
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Phentolamine is a nonselective alpha-1 & alpha-2 adrenergic antagonist. Dilation of the pupil is controlled by the radial iris dilator muscles surrounding the pupil which are activated by the
alpha-1 receptors of the adrenergic nervous system. Alpha-1 antagonists bind to the receptors to inhibit the pupillary response and reduce dilation (FIGURE 2). Phentolamine mesylate is the active
ingredient in two injectable FDA-approved drugs, Regitine and OraVerse, as described previously.
For the RM indication, pharmacologically induced 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). Nyxol, 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 Nyxol 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 DLD indication, it is proposed that a moderate miotic effect by application of Nyxol 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.
FIGURE 2: Nyxol’s Mechanism of Action
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Nyxol Clinical Experience Summary
Nyxol has been assessed in twelve investigator-initiated and company-sponsored Phase 1, Phase 2 and Phase 3 clinical trials. Across all trials,
over 400 adult patients have been exposed to at least one dose of phentolamine ophthalmic solution. Phase 2 and Phase 3 trials have been accepted for poster or oral presentation 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.
Ocuphire believes that results from Nyxol’s Phase 1, Phase 2 and Phase 3 trials support its current development plan focused on RM, presbyopia and DLD patients. Specifically, patients treated
with Nyxol were observed to have statistically significant decreases in pupil diameter and improved visual acuity. Nyxol has shown consistent ability to decrease pupil diameter at the selected dose of 0.75% Phentolamine Ophthalmic Solution (POS)
by approximately 20-25% (~1 – 1.5 mm) in both mesopic and photopic conditions.
A summary of Ocuphire’s completed clinical trials is shown below (TABLE 2). Note that Nyxol in its current proprietary formulation of phentolamine mesylate ophthalmic solution was first introduced in the NYX-01a2 trial, and prior to that, a formulation of phentolamine mesylate in
artificial tears solution was used. In subsequent sections, completed Phase 3 trials for RM (MIRA-2, MIRA-3, and MIRA-4), a Phase 2 trial for Presbyopia (VEGA-1) and a Phase 3 trial for DLD (LYNX-1) will be highlighted. Additionally, an ongoing
Phase 3 trial for Presbyopia (VEGA-2) and preclinical animal studies will also be presented.
TABLE 2: Summary of Completed Clinical Trials with Nyxol
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Note: Nyxol = phentolamine mesylate in proprietary formulation, Nyxol* = phentolamine mesylate in commercial artificial
tears solution. ^ Total patient numbers will not equal to the sum of the subgroups in crossover studies (NYX-002, NYX-004, and NYXRM-201). 0.75% POS (Phentolamine
Ophthalmic Solution) is the same as 1% PMOS (Phentolamine Mesylate Ophthalmic Solution). References to Nyxol with both designations appear throughout this document, and there is no difference in formulation between the two designations.
CS, contrast sensitivity; DCNVA, distance-corrected near visual acuity; DLD, dim light vision disturbances; IND, Investigational New Drug application; IOP, intraocular pressure; LCVA, low-contrast visual acuity; LDP, low-dose pilocarpine; OHT,
ocular hypertension; PD, pupil diameter; POS, Phentolamine Ophthalmic Solution or Nyxol; PMOS, Phentolamine Mesylate Ophthalmic Solution or Nyxol; * represents phentolamine mesylate in commercial artificial tears solution; RM, reversal of
mydriasis; VA, visual acuity; WA, wavefront aberrometry.
Total subject numbers will not equal the sum of the subgroups in crossover studies (NYX-002, NYX-004, and NYXRM-201).
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MIRA PROGRAM – Reversal of Mydriasis Indication for Nyxol
Nyxol RM: MIRA-3 and MIRA-2 Phase 3 Registration Trials (Completed)
MIRA-2 and MIRA-3 were double-masked, randomized, placebo-controlled, multi-center trials of Nyxol compared with vehicle (placebo) in normal healthy subjects. In MIRA-2, a total of 185 subjects (including 14
pediatric subjects aged 12–17 years) were randomized 1:1 to receive Nyxol or placebo treatment 1 hour following dilation with 1 of 3 mydriatic agents (2.5% phenylephrine, 1% tropicamide, or Paremyd 3:1:1, respectively). Stratification by light or
dark irides was 1:1. Measurements were taken at 0 minutes, 30 minutes, 1 hour, 90 minutes, 2 hours, 3 hours, 4 hours, and 6 hours following administration of study medication. In MIRA-3, treatment randomization was 2:1 (Nyxol or vehicle
[placebo], respectively) and stratification by light or dark irides was 1:1. As in MIRA-2, the mydriatic agent randomization was 3:1:1 (2.5% phenylephrine, 1% tropicamide, or Paremyd), respectively, and the randomized subjects received 1 drop of
mydriatic agent 1 hour before treatment. In MIRA-3, a total of 368 subjects (including 31 pediatric subjects aged 12–17 years) were randomized to treatment.
In MIRA-2 and MIRA-3, treatment (Nyxol or placebo) was administered OU, with the study eye defined as the right eye (OD) and the fellow eye defined as the left eye (OS). Subjects had 2 drops of treatment administered
5 minutes apart in the study eye (OD) and 1 drop of treatment administered in the fellow eye (OS) 1 hour after mydriatic drug administration. Pediatric subjects (aged 12–17 years) in MIRA-2 received only 1 drop of treatment OU.
In both of the 2 Phase 3 registration studies, Nyxol met the primary endpoint (FIGURE 3A). In the mITT Population, a statistically significant
and clinically meaningful greater percent of subjects treated with Nyxol had study eyes that showed reversal of mydriasis 90 minutes post-dose, using a PD threshold of ≤ 0.2 mm from baseline compared with the placebo treatment (49% vs 7%,
respectively, in MIRA-2 and 58% vs 6%, respectively, in MIRA-3; all p<0.0001). Importantly, similar statistically significant results were observed 60 minutes post-dose (28% vs 2%, respectively, in MIRA-2; p<0.0001 and 42% vs 2%,
respectively, in MIRA-3; p<0.0001). The statistically significant benefit was also seen at all other time points and persisted through 24 hours. In the 2 studies 80% and 79% of Nyxol-treated subjects had their pupils return to pre-dilation
pupil size within 3 hours compared with only 18% and 14% of subjects treated with placebo for the MIRA-2 and MIRA-3 studies, respectively.
In each of the studies, Nyxol effect on mean PD further supported the results of the primary endpoint analysis. A statistically significant reduction in mean PD from maximum PD (0 minutes) with Nyxol versus placebo
treatment was observed as early as 60 minutes post-dose, increasing in magnitude through 90 minutes. The significant reduction in PD compared to placebo persisted through 24 hours. Results were consistent between the 2 trials (FIGURE 3B). In both studies, the mean PD of Nyxol-treated study eyes returned from maximum PD to predilation baseline values (> 1.8 mm decrease) at 90 minutes post-dose. In contrast, in study eyes
treated with placebo, the mean PD decreased by < 0.5 mm at 90 minutes post-treatment and the mean PD remained greater than baseline through 6 hours (7 hours after dosing of the mydriatic) in both studies. Overall, Nyxol reduced PD from
baseline by 20 to 30% (1 to 1.5 mm)
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FIGURE 3: Study OPI-NYXRM-302 (MIRA-3) and OPI-NYXRM-301 (MIRA-2): Percent of patients returning to ≤0.2 mm of baseline pupil diameter in MIRA-3 (left panel) and MIRA-2 (right panel)
1.
B.
Note: POS = Nyxol
Similar efficacy results were observed regardless of whether eyes were treated with 1 drop or 2 drops. Efficacy was demonstrated across all 3 mydriatic agents and in light and dark irides.
Treatment with Nyxol was generally safe and well tolerated. The most common adverse reactions (> 5.0%) that have been reported are conjunctival hyperemia, instillation site discomfort, and dysgeusia; all were
transient and primarily mild. Most TEAEs were ocular, as expected, and the vast majority were mild in intensity and resolved within hours of study medication instillation. There were no deaths, serious AEs or other significant AEs. Results from
MIRA-2 and MIRA-3 studies were presented at several medical conferences in 2022.
Nyxol RM: MIRA-4 Pediatric Trial (Completed)
MIRA-4 was a 1-day, double-masked, randomized, placebo-controlled, single-dose, multi‐center study with 23 pediatric subjects aged 3 to 11 years, healthy or with ocular conditions. A total of 23 randomized pediatric subjects were evaluated for the safety and efficacy of Nyxol in reversal of pharmacologically induced mydriasis. Each subject was randomized to
unmasked mydriatic agent and masked treatment. Treatment randomization was 1:1 (Nyxol or placebo [vehicle], respectively) and stratification by subject age group was 1:1, 3 to 5 years of age or 6 to 11 years of age. The mydriatic agent
randomization was 3:1:1 (2.5% phenylephrine, 1% tropicamide, or Paremyd, respectively).
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In MIRA-4, study treated with Nyxol, 64% had PD returned to ≤ 0.2 mm from baseline PD at 90 minutes compared to 25% of study eyes treated with placebo eyes in the mITT
Population. This effect is similar to those seen in the adult registration studies (study eye: 49% vs 7%, respectively, in MIRA-2; p<0.0001 and 58% vs 6%, respectively, in MIRA-3; p<0.0001; fellow eye: 49% vs 6%, respectively, in MIRA-2;
p<0.0001 and 52% vs 6%, respectively, in MIRA-3; p<0.0001). Among subjects aged 3 to 5 years (n=11), Nyxol showed numerically greater reversal of mydriasis in the study eye compared with placebo at 90 minutes (60% vs 17%, respectively), 3
hours (80% vs 50%, respectively), and 24 hours (100% vs 50%, respectively). Among subjects aged 6 to 11 years (n=12), Nyxol showed numerically greater reversal of mydriasis in the study eye compared with placebo at 90 minutes (67% vs 33%,
respectively), 3 hours (83% vs 17%, respectively), and 24 hours (83% vs 50%, respectively).
The efficacy of Nyxol in pediatric subjects showed a similar magnitude of reversal of mydriasis to the efficacy of Nyxol in adults overall and across mydriatic agents. In a pooled analysis of 45
pediatric subjects (aged 12-17 years) in MIRA-2 and MIRA-3, 44% of Nyxol-treated study eyes (vs 6% placebo; p=0.0286) at 60 minutes and 63% (vs 0% placebo; p=0.0067) at 90 minutes returned to baseline PD. Results with the individual agents were
also similar to those observed in adults.
No overall differences in safety have been observed between pediatric subjects aged 3 to 17 years or the elderly when compared to adult subjects. Results from MIRA-4 study were presented at the annual American
Academy of Optometry 2022 meeting in San Diego.
VEGA PROGRAM – Presbyopia Indication for Nyxol and Nyxol+LDP
Nyxol Presbyopia: Phase 2 VEGA-1 Trial (Completed)
VEGA-1 (NYXP-201) was a double-masked, randomized, placebo-controlled, multi-center trial of Nyxol and LDP compared with vehicle (placebo) ophthalmic solution in presbyopic patients. A total of 150 patients were
randomized 3:2:2:3 to receive Nyxol + LDP, Nyxol alone, LDP alone, or placebo, respectively. Nyxol or placebo was dosed for 3 or 4 consecutive evenings prior to binocular and monocular testing under photopic and mesopic lighting conditions.
Measurements were made between 0 and 6 hours following administration of Treatment 2 (LDP or No Treatment). The primary efficacy endpoint for this study was the percent of patients who improved by ≥ 15 letters in DCNVA at 90 minutes
post-treatment.The data from this study was presented at several medical conferences in 2021 and 2022.
Nyxol as a Single Agent
Following 3 to 4 days of treatment with Nyxol or placebo, 29% of Nyxol-treated subjects had ≥ 15 letters improvement in photopic binocular DCNVA compared with 12% of placebo-treated subjects 12 hours after the last
dose (p=0.02). This benefit was durable and remained stable over the next 6 hours (or 18 hours), with a mean of 37% of Nyxol-treated subjects improving by ≥ 15 letters DCNVA 18 hours post-dose. Using a clinically meaningful criterion of a
10-letter improvement in DCNVA, 53% of subjects responded to Nyxol at the 12-hour time point compared to 28% of placebo-treated subjects (p=0.0046) (FIGURE 4).
Nyxol + LDP as Adjunctive Therapy
A statistically significant greater number of subjects in the PP Population treated with Nyxol + LDP had ≥ 15 letters improvement in photopic binocular DCNVA at 1-hour post-LDP treatment (primary endpoint) compared
with placebo alone (61% vs 14%, respectively; p<0.0001). In addition, the Nyxol + LDP arm had significantly more subjects with ≥ 15 letters improvement in photopic binocular DCNVA compared with placebo alone at all time points from 30 minutes
through 4 hours post-LDP treatment (p≤0.0166). This benefit was retained for all time points between 30 minutes and 4 hours when requiring that subjects with ≥ 15 letters improvement in photopic binocular DCNVA also had to have < 5 letters
loss in photopic binocular BCDVA, the accepted registration endpoint. The percentage of Nyxol + LDP responders was also significantly better than placebo at 30 minutes (77% vs 51%, respectively; p=0.0146) and all subsequent timepoints through 3
hours (p≤0.0312) when using a clinically meaningful criterion of a 10-letter improvement in DCNVA (FIGURE 4).
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FIGURE 4: Study OPI-NYXP-201 (VEGA-1): Percent of Patients Gaining ≥ 15 Letters in Binocular Photopic DCNVA by Treatment Arm and Timepoints
Nyxol and Nyxol+LDP provided durable optimal pupil diameter of ~ 2 mm to 3 mm, offering improvement in near vision without the loss of distance vision (FIGURE 5). Nyxol
and Nyxol+LDP maintained a dynamic pupillary response when transitioning between photopic and mesopic lighting conditions.
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FIGURE 5: Study OPI-NYXP-201 (VEGA-1): Mean pupil diameter
Nyxol alone as well as Nyxol +LDP were both well-tolerated with a favorable safety profile. Instillation site discomfort and conjunctival hyperemia were the only adverse events (AEs) that occurred in ˃5% patients,
and 95% of the AEs were mild and none were severe. Visual acuity was not adversely affected. There were no deaths, no systemic AEs, no serious AEs or withdrawals due to AEs in patients receiving Nyxol only. No headaches, brow aches or blurry
vision AEs were observed.
Nyxol Presbyopia: Phase 3 VEGA-2 Trial (Ongoing)
VEGA-2 (NYXP-301) is a double-masked, randomized, placebo-controlled multi-center trial of Nyxol as a single agent compared to placebo and with adjunctive LDP compared with vehicle (placebo) in presbyopic patients.
Approximately 320 subjects are randomized to one of 4 treatment groups in 2 stages.
The first stage consists of 2 treatment groups (Nyxol or Placebo [i.e., Nyxol vehicle]), with approximately 160 subjects in each group. Stage 2 consists of 4 treatment groups (Nyxol + LDP, Nyxol + LDP vehicle,
placebo + LDP, and placebo + LDP vehicle), with approximately 80 subjects per treatment group. Randomization will be stratified by light/dark irides. The first subject was enrolled into the study in late December 2022. Patients are treated with
Nyxol or Placebo for 7 days followed by a washout period of 7 to 14 days. During the washout period, patients will return on Day 10 to assess the resolution of drug treatments effects on PD.
In the second stage, Nyxol + LDP will be evaluated following 1 day and 7 days of dosing with both treatment regimes. For both stages of the trial, Nyxol or Placebo is dosed once daily in each eye in the evening and
for stage 2, LDP or LDP vehicle is dosed once daily in each eye in the morning.
The primary efficacy endpoint is the percent of subjects with ≥ 15 letters of improvement in photopic binocular DCNVA and with < 5 letters of loss in photopic binocular BCDVA from Baseline comparing Nyxol-treated
subjects to placebo-treated subjects at 12 hours post-dose at Day 8 during stage 1. The key secondary endpoint to evaluate LDP adjunctive to Nyxol in stage 2 is the percent of subjects with ≥ 15 letters of improvement in photopic binocular DCNVA
and with < 5 letters of loss in photopic binocular BCDVA at 30 minutes post-LDP/vehicle comparing LDP as adjunctive therapy to Nyxol to placebo, Nyxol alone, and LDP alone following 8 days of dosing. This trial is ongoing with topline results
expected in late 2023.
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LYNX PROGRAM – Dim Light Vision Disturbances Indication for Nyxol
Nyxol DLD: Phase 3 LYNX-1 Trial (Completed)
LYNX-1 (NYXDLD-301) was a Phase 3 double-masked, randomized, placebo-controlled, multi-center study of POS compared with placebo ophthalmic
solution in patients with dim light vision disturbances (DLD) 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 Nyxol or placebo. Each subject
was randomized 1:1 to treatment with Nyxol or placebo ophthalmic solution andstratified by iris color (light/dark irides). Treatment was self-administered in each eye QD at or
near bedtime for 14 days.Efficacy was measured by assessment of mLCVA, photopic LCVA (pLCVA), best-corrected distance visual acuity (BCDVA), mesopic high-contrast BCDVA
(mHCVA), distance-corrected near visual acuity (DCNVA), mesopic high-contrast DCNVA, mesopic PD, photopic PD, subject questionnaire, and wavefront aberrometry. Safety assessments included conjunctival hyperemia, slit lamp biomicroscopy,
ophthalmoscopy, IOP, physical exams, HR, and BP. Data from LYNX-1 may support the Nyxol-single agent differentiation in presbyopia.
At Day 8 (primary endpoint), a statistically significantly greater percent of subjects treated with Nyxol 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 Nyxol 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) (FIGURE 6).
FIGURE 6: Percent of Subjects With ≥ 15 Letters Improvement in Mesopic Low-Contrast Best-Corrected Distance Visual Acuity in the Study Eye by Visit (mITT Population)
Nyxol was safe and well tolerated in this study. Adverse events occurring in ≥ 5% of subjects were instillation site erythema, instillation site
pain, conjunctival hyperemia, and dysgeusia. No subjects in the Nyxol group experienced AEs of vitreous floaters, retinal tears, or retinal detachment. No subjects had any serious TEAEs or any TEAEs leading to withdrawal from the study, and no
subjects died during the study. One subject in each treatment group had TEAEs leading to study medication discontinuation (instillation site erythema and instillation site pain in the Nyxol group and instillation site irritation and lacrimation
increased in the placebo group. A total of 66 TEAEs were reported in 23 subjects (32%) treated with Nyxol and 22 TEAEs were reported in 12 subjects (16%) treated with placebo. All TEAEs were mild or moderate in intensity, except for 1 TEAE
experienced by a subject in the Nyxol group, which was severe in intensity (instillation site pain), which was considered definitely related per the Investigator).
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Nyxol Nonclinical Toxicology Studies
As part of a comprehensive nonclinical toxicity program, Ocuphire conducted 3 exploratory and 2 GLP single- and repeated-dose toxicity studies of phentolamine mesylate drug substance in rabbits and beagle dogs. There were no Nyxol-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 Oraverse and Regitine.
For chronic administration of Nyxol, a 6-month repeated-dose toxicity study with Phentolamine Ophthalmic Solution 0.75% in Dutch-belted rabbits showed that topical administration of the drug
product is safe and well tolerated. The study was reported to the FDA and no adverse comments were received. This 6-month toxicology study supports the long-term safety exposure trial which will be the basis of the marketing authorization for
long-term treatment and chronic indications of presbyopia and DLD for Nyxol.
In support of administration of Pilocarpine Hydrochloride Ophthalmic Solution 0.4% (LDP) as adjuctive therapy to Nyxol for long term treatment, Ocuphire has performed a 99-day nonclinical
toxicology study with Nyxol and LDP doses in Dutch belted rabbits. The study showed that the combination was well tolerated, with findings similar across all nonclinical studies performed with Nyxol by Ocuphire. The findings of this study support
any future chronic indication for such combination.
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 diabetic retinopathy (DR)
and diabetic macular edema (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. Ocuphire believes APX3330 shares desirable attributes for back of the eye therapies, including broad therapeutic applications, a convenient route
of administration and cost-effective manufacturing process, without the need for uncomfortable intravitreal injections (FIGURE 7).
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 non-proliferative retinopathy (NPDR) or mild proliferative retinopathy (PDR) indication, as well as patients with DME without loss of central
vision. Additionally, Ocuphire may explore opportunities for clinical benefit as adjunctive therapy for other retinal indications such as DME, wAMD, and GA. Second-generation candidate, APX2009, may also be considered for intravitreal or
sustained injections.
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FIGURE 7: APX3330 Product Candidate Profile
*1 subject had vision blur thought to be related by investigator in ZETA-1 trial
APX3330 Mechanism of Action
APX3330 is a highly 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 (FIGURE 8). 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/DME 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-kB
modulates VEGF, TNF-α and other inflammatory cytokine production. In contrast, anti-VEGF agents solely inhibit the actions of VEGF (FIGURE 8).
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FIGURE 8: APX3330 Dual Mechanism of Action in Validated Disease Pathways
Note: Eylea® is registered trademark of Regeneron and Lucentis® is registered trademark of Roche/Genentech
APX3330 Clinical Experience Summary
APX3330 has been studied in over 375 (of over 470 total) healthy volunteers or patients with hepatitis or cancer or diabetic retinopathy patients, over 270 of whom were given the product
candidate for an average of 75 days or more. 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.
A summary of the 12 completed trials including the Phase 2 ZETA-1 trial can be found below (TABLE 3). In subsequent sections, a Phase 2b trial for DR/DME (ZETA-1), a Phase 1 trial for oncology (APX CLN 0011),
Phase 1 and 2 trials for chronic hepatitis disease (APX CLN 0001-0010), and nonclinical studies will be highlighted.
TABLE 3: Summary of APX3330 Completed Clinical Trials
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