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Item 1. Business

2024-03-18 compared with 2023-03-31 · 175 added, 240 removed, 817 unchanged (34% of the section changed)

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Information contained on, or that can be accessed through, our website is not incorporated by reference into this report, and you should not consider information on our website to be part of this report.

We are a pre-commercial ophthalmic technology company developing the Optejet® delivery system both for use in combination with our own drug-device therapeutics and for out-licensing for use in combination with therapeutics for additional indications.

Our aim is to improve the delivery of topical ophthalmic medication through the ergonomic design of the Optejet which facilitates ease-of-use and delivery of more physiologically appropriate medication volume, with the goal to reduce side effects and improve tolerability, and introduce digital health technology to improve therapy compliance and ultimately medical outcomes.

The ergonomic and functional design of the Optejet® allows for horizontal drug delivery and eliminates the need to tilt the head back or the manual dexterity to squeeze a bottle, in order to administer medications.

We are an ophthalmic technology company commercializing Mydcombi™ (tropicamide and phenylephrine HCL ophthalmic spray) for inducing mydriasis for routine diagnostic procedures and in conditions where short term pupil dilation is desired, preparing for the commercialization of clobetasol propionate ophthalmic suspension 0.05% (“clobetasol propionate”), for the treatment of post-operative inflammation and pain following ocular surgery, and developing the Optejet® delivery system both for use in combination with our own drug-device therapeutic programs and for out-licensing for use in combination with therapeutics for additional indications.

Our aim is to improve the delivery of topical ophthalmic medication through the ergonomic design of the Optejet which facilitates ease-of-use and delivery of a more physiologically appropriate medication volume, with the goal to reduce side effects and improve tolerability, and introduce digital health technology to improve therapy compliance and ultimately medical outcomes.

The ergonomic and functional design of the Optejet allows for horizontal drug delivery and eliminates the need to tilt the head back or the manual dexterity to squeeze a bottle to administer medications.

Drug is delivered in a microscopic array of droplets faster than the blink reflex to help ensure instillation success.

The precise delivery of a low-volume columnar spray by the Optejet® minimizes contamination with a non-protruding nozzle and self-closing shutter.

The precise delivery of a low-volume columnar spray by the Optejet device minimizes contamination risk with a non-protruding nozzle and self-closing shutter.

In clinical trials, the Optejet has demonstrated that its targeted delivery achieves a high rate of successful administration, with 98% of sprays being accurately delivered upon first attempt compared to the established rate reported with traditional eye drops of ~ 50%.

A more physiologically appropriate volume of medication in the range of seven to nine microliters is delivered by the Optejet, which is approximately one - fifth of the 35 to 50 microliter dose typically delivered in a single eye drop.

A lower volume of medication exposes the ocular surface to less active ingredient and preservatives, potentially reducing ocular stress and surface damage and improving tolerability.

The lower volume also minimizes the potential for drugs to enter systemic circulation, with the goal of avoiding some common side effects that are related to overdosing of the eye.

We are developing versions of the Optejet with on-board digital technology to provide reminders via Bluetooth to smart devices and date and time stamp device use.

Lower volume of medication exposes the ocular surface to less active ingredient and preservatives, potentially reducing ocular stress and surface damage and improving tolerability.

The lower volume also minimizes the potential for drug to enter systemic circulation, with the goal of avoiding some common side effects that are related to overdosing of the eye.

We are developing versions of the Optejet with on-board digital technology that records the date and time of each use.

These data may be used to provide reminders via Bluetooth to smart devices and to allow healthcare practioners to monitor usage.

This information can then be used by practitioners and health care systems to measure treatment compliance and improve medical decision making.

In this way, the Optejet could serve as an extension of the physician’s office by providing information that is not currently possible to collect except through the use of diaries.

Our drug-device therapeutic programs include MicroPine, MicroLine and Mydcombi TM .

MicroPine is our first-in-class topical therapy for the treatment of progressive myopia, a back-of-the-eye ocular disease associated with pathologic axial elongation and sclero-retinal stretching.

Our drug-device product line includes Mydcombi (tropicamide and phenylephrine HCL ophthalmic spray), clobetasol propionate, and therapeutic programs MicroPine (atropine ophthalmic spray) and MicroLine (pilocarpine ophthalmic spray).

MicroPine is our first-in-class topical therapy for the treatment of progressive myopia, a disease associated with pathologic axial elongation of the eye and sclero-retinal stretching.

In the United States, myopia is estimated to affect approximately 25 million children, with up to five million considered to be at high risk for progressive myopia.

In February 2019, the FDA accepted our investigational new drug application, or IND, to initiate a Phase III registration trial of MicroPine, or the CHAPERONE study, to reduce the progression of myopia in children.

In February 2019, the FDA accepted our Investigational New Drug application (“IND”) to initiate the CHAPERONE study to reduce the progression of myopia in children.

The first patient was enrolled in the CHAPERONE study in June 2019.

On October 9, 2020, we entered into a license agreement, or the Bausch License Agreement, with Bausch + Lomb, pursuant to which Bausch + Lomb may develop and commercialize MicroPine in the United States and Canada.

Under the terms of the Bausch License Agreement, we received an upfront payment of $10.0 million and we may receive up to a total of $35.0 million in additional payments, based on the achievement of certain regulatory and launch-based milestones.

Bausch + Lomb also will pay royalties to Eyenovia on a tiered basis (ranging from mid-single digit to mid-teen percentages) on gross profits from sales of MicroPine in the United States and Canada, subject to certain adjustments.

Under the terms of the Bausch License Agreement, Bausch + Lomb assumed sponsorship of the IND as well as ownership and the costs related to the ongoing CHAPERONE study.

On October 9, 2020, we entered into a license agreement (the “Bausch License Agreement”) with Bausch + Lomb (“B+L”), pursuant to which B+L had the rights to develop and commercialize MicroPine in the United States and Canada.

Under the terms of the Bausch License Agreement, we received an upfront payment of $10.0 million and we were eligible to receive up to a total of $35.0 million in additional payments, based on the achievement of certain regulatory and launch-based milestones.

B+L also agreed to pay royalties to Eyenovia on a tiered basis (ranging from mid-single digit to mid-teen percentages) on gross profits from sales of MicroPine

in the United States and Canada, subject to certain adjustments.

Under the terms of the Bausch License Agreement, B+L assumed sponsorship of the IND as well as ownership and the costs related to the ongoing CHAPERONE study.

On January 12, 2024, we entered into a subsequent agreement with B+L to repatriate our rights to MicroPine and take control of the CHAPERONE study.

In this agreement, we agreed to pay B+L $2 million in cash and an additional $3 million in common stock upon successful transfer of the regulatory documents and study elements to Eyenovia.

We also agreed to pay B+L a 2% royalty on net sales once MicroPine is commercialized in the United States, assuming receipt of regulatory approvals.

We believe that this new arrangement is in our and our shareholders’ best interests, as it may substantially increase the value of the asset significantly through potential improvements in the conduct of the study, including a planned interim analysis of the data in late 2024.

We have also successfully expanded our manufacturing capabilities through a partnership with Coastline International, Inc.

located in Tijuana, Mexico, and the construction of our own fill and finish facility in Redwood City, California.

As of the date of filing, we are up-to-date supplying clinical product for this study.

MicroLine is our investigational pharmacologic treatment for presbyopia.

Presbyopia is a non-preventable, age-related hardening of the lens, which causes the gradual loss of the eye’s ability to focus on near objects and impairs near visual acuity.

Allergan recently launched Vuity TM , a pilocarpine drug product for the treatment of presbyopia.

Our second Phase III study, VISION-2, used the same drug, delivered with the advantages of the Optejet®.

located in Tijuana, Mexico, as well as the construction of our new manufacturing facility in Reno, Nevada and the construction of our own fill and finish facility in Redwood City, California.

We have received FDA clearance for using both Coastline International and our Redwood City facility for the production of Mydcombi cartridges, and FDA clearance for using our Reno facility for the production of technical elements such as the base unit for the Optejet device.

MicroLine is our investigational pharmacologic treatment for presbyopia, a non-preventable, age-related hardening of the lens, which causes the gradual loss of the eye’s ability to focus on near objects and impairs near visual acuity.

There are two FDA-approved treatments for presbyopia which use pilocarpine, the same drug used in our investigational product.

We have completed two Phase III studies using our Optejet® device.

In these studies, patients reported high satisfaction with using the device, and a strong preference over using an eye dropper bottle.

We released positive top-line results from VISION-2 in the fourth quarter of 2022.

Mydcombi TM is our fixed combination formulation of tropicamide-phenylephrine for mydriasis and a novel approach for the over 100 million office-based comprehensive and diabetic eye exams estimated to be performed every year in the United States.

We completed two Phase III trials for Mydcombi and announced positive results from these studies, known as MIST-1 and MIST-2, and have submitted a New Drug Application, or NDA, to the FDA seeking approval to market the product in the U.S.

In October 2021, we received a complete response letter, or CRL, in response to our NDA, which in part informed us that pre-filled or co-packaged ophthalmic drug dispenser products like Mydcombi have been reclassified as drug-device combination products.

This reclassification was based upon the U.S.

Court of Appeals for the D.C.

Circuit’s decision in Genus Medical Technologies v.

FDA, not involving Eyenovia, which ordered that products meeting the statutory definition of a device, but were previously classified by the FDA as drugs must be regulated as devices.

Before this ruling, the FDA regulated pre-filled or co-packaged ophthalmic dispensers as part of the approved ophthalmic drug distributed and sold with the dispenser.

After the ruling, however, the dispenser must be considered as a distinct device constituent part of a drug-device combination product.

We resubmitted the NDA on November 8, 2022, and the FDA is currently reviewing our application with a Prescription Drug User Fee Act (PDUFA) target action date of May 8, 2023.

On August 10, 2020, we entered into a license agreement, or the Arctic Vision License Agreement, with Arctic Vision (Hong Kong) Limited, or Arctic Vision, which was amended on September 14, 2021, pursuant to which Arctic Vision may develop and commercialize MicroPine, MicroLine and Mydcombi in Greater China (mainland China, Hong Kong, Macau and Taiwan) and South Korea.

Under the terms of the Arctic Vision License Agreement, as amended, we received an upfront payment of $4.25 million before any payments to Senju Pharmaceutical Co., Ltd., or Senju.

We are now planning to meet with the FDA in mid-2024 to discuss a transition of the product to our new Gen-2 Optejet device, which has a significantly lower cost to manufacture than the first generation device.

Mydcombi is our fixed combination formulation of tropicamide-phenylephrine for inducing mydriasis for diagnostic procedures and in conditions where short term pupil dilation is desired.

Mydcombi is a novel approach for the over 106 million office-based comprehensive and diabetic eye exams and 7 million ocular surgeries performed every year in the United States.

As the only FDA-approved fixed combination of the two leading mydriatic agents in the United States and as an ophthalmic spray, Mydcombi may present a number of benefits for ophthalmic surgical centers, optometric and ophthalmic offices and patients.

Those benefits may include improved cost-effectiveness in centers that employ single-use bottles for mydriasis, more efficient use of office time and resources, and an overall improved doctor-patient experience.

We are currently commercializing the product starting with a targeted launch and continuing to expand during 2024, when we expect our ten sales representatives and internal manufacturing capabilities to come on-line.

On August 10, 2020, we entered into a license agreement with Arctic Vision (as amended on September 14, 2021, the “Arctic Vision License Agreement”) pursuant to which Arctic Vision may develop and commercialize MicroPine, MicroLine and Mydcombi in Greater China (mainland China, Hong Kong, Macau and Taiwan) and South Korea.

Under the terms of the Arctic Vision License Agreement, as amended, we received an upfront payment of $4.25 million before any payments to Senju Pharmaceutical Co., Ltd.

In addition, we may receive up to a total of $37.7 million in additional payments, based on various development and regulatory milestones, including the initiation of clinical research and approvals in Greater China and South Korea, and development costs.

Arctic Vision also will purchase its supply of MicroPine, MicroLine and Mydcombi from Eyenovia or, for such products not supplied by Eyenovia, pay a mid-single digit percentage royalty on net sales of such products, subject to certain adjustments.

We will pay between 30 and 40 percent of such payments, royalties, or net proceeds of such supply to Senju pursuant to an exclusive license agreement with Senju dated March 8, 2015, as amended.

We will pay between 30 and 40 percent of such payments, royalties, or net proceeds of such supply to Senju pursuant to an exclusive license agreement with Senju dated March 8, 2015, as amended (the “Senju License Agreement”).

In addition to our own development programs, on August 15, 2023, we entered into a license agreement (the “License”) with Formosa Pharmaceuticals Inc.

(“Formosa”), whereby we acquired the exclusive U.S.

rights to commercialize any product related to a novel formulation of clobetasol propionate, which was approved by the U.S.

Food and Drug Administration (“FDA”) on March 4, 2024.

On March 13, 2024, the NDA for the product was transferred from Formosa to Eyenovia.

The License will remain in effect for ten years from the date of the first commercial sale of clobetasol propionate, unless earlier terminated.

We paid Formosa an upfront payment in an aggregate amount of $2,000,000 which consisted of (a) cash in the amount of $1,000,000 and (b) 487,805 shares of common stock valued at $1,000,000.

We also capitalized $122,945 of transaction costs in connection with the License.

In addition, we must pay Formosa up to $4 million upon the achievement of certain development milestones and up to $80 million upon the achievement of certain sales milestones.

We are in active discussions with manufacturers of existing and late-stage ophthalmic medications to explore whether development with the Optejet technology can solve unmet medical and business needs.

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The following summarizes our product pipeline and anticipated milestones:

Product or Product

Next Expected Milestones

Pharmaceutical Mydriasis (Pupil Dilation)

Commercial Launch Underway

Clobetasol Propionate

Post Ocular Surgery Pain and Inflammation

Commercial Launch Pending

Improvement in Near Vision (Presbyopia)

Pre-NDA meeting April 2023

Pre-NDA Meeting Mid-2024

Pediatric Myopia Progression (Near-Sightedness)

Phase III CHAPERONE IND transferred to Bausch + Lomb

Pharmaceutical Mydriasis (Pupil Dilation)

Potential FDA approval date May 8, 2023

Phase III CHAPERONE Ongoing;

Planned Phase III Interim Analysis Q4 2024

Our goal is to become a leading developer and provider of advanced ophthalmic therapies based upon our microdose array print (MAP) platform technology and digital health platform for interactive patient care.

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We believe that the 505(b)(2) registration pathway, which reduces development risk compared to new molecular entity programs by working with known compounds with well-established safety and efficacy profiles, will be available for our development pipeline.

We believe our pipeline of patented micro-therapeutic product

candidates is highly differentiated by our improved tolerability and enhanced compliance profile and that our late-stage development programs could lead to additional NDA submissions in novel indications where the products can have unique dosing and therapeutic profiles.

We believe our pipeline of patented micro-therapeutic product candidates is highly differentiated by our improved tolerability and enhanced compliance profile and that our late-stage development programs could lead to additional NDA submissions in novel indications where the products can have unique dosing and therapeutic profiles.

We believe that this could lead to favorable pricing and a reduced risk of generic competition.

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We believe the Optejet will allow for high precision targeted microdosing for multiple eye treatments, while eliminating ophthalmic over-dosing and reducing ocular exposure to toxic preservatives and pharmacologic ingredients compared to conventional eye drop delivery mechanisms.

Our clinical trials have demonstrated similar efficacy to eye drops, improved side effect profile and enhanced patient experience with the Optejet as compared to conventional eye drops.

Leverage our electronic, smartphone-enabled “e-health” technology to introduce and develop patient-specific compliance monitoring program.

Our clinical trials have demonstrated similar efficacy to eye drops, as well as improved side effect profile and enhanced patient experience with the Optejet as compared to conventional eye drops.

Leverage our Optecare ™ technology to introduce and develop patient-specific compliance and treatment adherence enhancement programs.

The Optejet’s mobile e-health technology is designed to track when a patient administers treatments, allowing physicians to monitor patient compliance more accurately.

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For some topical medications, there also can be cardiovascular side effects such as changes in heart rate and arrhythmia that are caused when medications are absorbed into the circulation system from overdosing both through conjunctiva absorption and when drugs flow into the nose through the naso-lacrimal duct and are absorbed into the systemic circulation or swallowed.

For example, phenylephrine can cause cardiovascular adverse reactions including an increase in blood pressure, syncope, myocardial infarction, tachycardia,

arrhythmia and subarachnoid hemorrhage.

For example, phenylephrine can cause cardiovascular adverse reactions including an increase in blood pressure, syncope, myocardial infarction, tachycardia, arrhythmia and subarachnoid hemorrhage.

Severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate.

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Thus, physicians can make decisions regarding therapeutic regimens with knowledge of patient compliance.

The FDA has determined that our products will be treated as combination drug/device products, with CDER as the lead reviewing center.

The FDA has determined that our Optejet products are treated as combination drug/device products, with CDER as the lead reviewing center.

As such, we do not anticipate needing separate FDA approval for the Optejet dispenser alone.

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Unlike a simple aerosolized mechanism, the Optejet is designed with ejection control that creates a fast and targeted micro-jet delivery.

Solution is dispensed to the

ocular surface in less than 100 milliseconds between the time the first droplet hits the corneal surface to the completion of dose delivery, which is faster than the average involuntary blink response time.

Solution is dispensed to the ocular surface in less time than the average involuntary blink reflex from the time the first droplet hits the corneal surface to the completion of dose delivery.

Smart electronics:

A key feature of the Optejet is the embedded electronic, Bluetooth enabled “e-health” system, which we believe is the first intelligent electronic delivery system for ophthalmic therapies.

A key feature of the Optejet is the embedded electronic, Bluetooth enabled Optecare system, which we believe is the first intelligent electronic delivery system for ophthalmic therapies.

Our electronic functions are designed to enable patients and physicians to track when doses are administered.

We believe this technology will improve compliance and chronic disease management by empowering patients and physicians with access to dynamic, real time monitoring and compliance data for a more intelligent and personalized therapeutic paradigm.

Recent changes in payment codes now provide a way for healthcare providers to bill for this important service.

Recent changes in payment codes may now provide a way for healthcare providers to bill for this important service.

Clinical Trial Results

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Based on the results of these studies further validating microdose delivery of ophthalmic medication, we initiated Phase III programs in mydriasis in late 2018, progressive myopia in 2019, and presbyopia in 2020.

Our Product Candidates

Eyenovia is currently focused on three programs:

MicroLine (for presbyopia), MicroPine (for progressive myopia) and Mydcombi (for mydriasis).

Our Product and Product Candidates

Eyenovia currently has two FDA-approved products, Mydcombi and clobetasol propionate, and two research programs:

MicroLine (for presbyopia) and MicroPine (for progressive myopia).

Mydcombi is the only FDA-approved fixed combination of the two leading pupil dilation drugs, tropicamide and phenylephrine, delivered with our Optejet technology.

The product is indicted to induce mydriasis (pupil dilation) for routine diagnostic procedures and in conditions where short term pupil dilation is desired.

There are approximately 106 million estimated office-based comprehensive and diabetic eye exams and seven million ophthalmic surgical dilations performed every year in the United States.

The benefits of Mydcombi include effective, reliable dilation with low risk of cross-contamination as compared with eye dropper bottles, ease of use for technicians and doctors, and good tolerability for patients.

We believe the market for Mydcombi exceeds $250 million in the United States alone.

Background of Mydriasis and Market Opportunity

There are an estimated 106 million topical mydriatic applications performed every year as a required part of the comprehensive dilated eye exam and standard retina fundoscopy for diabetic retinopathy screening, macular degeneration evaluation, glaucoma optic disc evaluation and many other back-of-the-eye conditions.

There are an additional estimated four million applications for ocular surgery.

Most optometrist and ophthalmologist offices maintain bottles of both phenylephrine and tropicamide eyedrops and use the drops in combination.

Each bottle is used on multiple patients, which carries a risk of contamination and ocular infection.

The bottles are purchased directly from suppliers and are not subject to insurance reimbursement.

Our combination therapy allows the purchase of one product for eye dilation.

Additionally, the Optejet does not come in direct contact with the eye, thus minimizing the risk of infection.

Most dilated eye exams require the sequential administration of two separate topical pharmacologic agents/drops (tropicamide, followed by phenylephrine).

All current mydriatic formulations use conventional macrodose drop delivery (30–50 µL), which can significantly overdose the ocular surface whose physiologic capacity is only 6–8 µL.

Studies demonstrate that standard macrodosed pharmacologic dilation is associated with significant ocular discomfort and mild-moderate eye pain.

On the standard visual analogue scale for pain, such discomfort can exceed the levels of pain associated with a flu vaccine subcutaneous injection.

Additionally, there are systemic safety concerns with mydriatic macrodosing for retinopathy of prematurity retinal screening and pediatric dilated eye exams.

Studies comparing microdosed phenylephrine and cyclopentolate to traditional eye drops (30–50 µL drop size) in premature babies and in full-term infants have shown equivalent pupil dilation with drop sizes ranging from 5–8 µL while reducing systemic levels by more than 50%.

Pharmacologic mydriasis:

dilated pupil after application

Efficacy and Safety

The above diagram represents the pooled data (MIST-1 and MIST-2) from the approved labeling for Mydcombi.

The graph summarizes pupil diameter over time.

Vertical bars show 95% confidence interval for the mean at each point.

Smooth curves are based on 8 degrees of freedom (df) generalized additive model (GAM) smooth through time, adjusting for baseline pupil diameter.

Confidence intervals are not adjusted for correlation.

Mydcombi (TR-PH) was statistically and clinically superior to its components (TR – tropicamide, PH – phenylephrine) as well as placebo at all timepoints post-dosing.

By twenty minutes post-dosing, the mean pupil dilation was above 6mm, more than sufficient for a thorough clinical examination.

All adverse events were transient and mild and occurred in fewer than 2% of patients.

Commercial Plans

We plan to hire a ten-person sales team, managed by two experienced sales directors, to promote Mydcombi directly to institutions and key ophthalmic and optometric offices.

We have obtained wholesale licenses nation-wide and will be handling distribution internally to maintain control over the product and help ensure a good experience for this novel technology.

Ordering and reordering will be managed on-line at EyenoviaRx.com.

Clobetasol Propionate

We have licensed this topical ocular steroid from Formosa Pharmaceuticals and will have commercial rights to this product within the United States.

The product was approved by the FDA on March 4, 2024.

This unique post-ocular surgery steroid is the first product developed using Formosa’s proprietary APNT nanoparticle formulation platform, which reduces an active pharmaceutical ingredient’s particle size with high uniformity and purity, thereby allowing penetration to relevant compartments in the eye, and ultimately enhancing bioavailability.

Clobetasol propionate will be the first new steroid in this market in over 15 years, and one of the few that is dosed twice-daily (instead of up to 4 times daily) without the need to taper dosing over a 14 day course of therapy.

With 7 million ocular surgeries conducted annually in the United States, we estimate the market opportunity for this product to be over $200 million.

In clinical studies, clobetasol propionate was very effective, with approximately 90% of patients experiencing zero pain towards the end of therapy.

Adverse events were few and mild, including 1% of patients experiencing elevated intraocular pressure, which may have been related to the surgery itself.

We plan to leverage our Mydcombi sales team to also cover promotion of this new, differentiated eye drop, with an anticipated launch in the second half of 2024.

MicroLine is our proprietary microdosed version of pilocarpine, a well-understood ophthalmic medication that can dose-dependently induce miosis, or a contraction of the pupil.

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Reducing pupil size with pilocarpine has been shown to improve near visual acuity in individuals who have presbyopia.

In Benozzi et al, 2012, subjects aged 45‒50 years who bilaterally self-administered both pilocarpine 1% and diclofenac 0.1% eyedrops every six hours during the day for up to five years reported good improvement in near vision without compromising distance vision.

In one clinical study, subjects aged 45‒50 years who bilaterally self-administered both pilocarpine 1% and diclofenac 0.1% eyedrops every six hours during the day for up to five years reported good improvement in near vision without compromising distance vision.

Thus, pilocarpine’s miotic effect may be useful in treating the increasingly compromised near vision that parallels the development of presbyopia.

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Our second Phase III study, VISION-2 evaluated the safety, tolerability, and efficacy of Optejet-administered microdosing of pilocarpine 2% as an ophthalmic spray versus placebo.

The results of VISION-1 and VISION-2 are being presented to the FDA in a pre-NDA meeting scheduled for April 2023.

A key therapeutic program for Eyenovia is our first-in-class topical treatment for progressive myopia, a back-of-the-eye disease.

A key therapeutic program for Eyenovia is our first-in-class topical treatment for pediatric progressive myopia, a disease reaching epidemic proportions according to the American Academy of Ophthlmology.

Background of Progressive Myopia and Market Opportunity

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It is estimated that over 25 million children in the United States suffer from progressive myopia, with approximately 5 million children being at high risk.

Examples of Retinal Changes Due to Myopia

Progressive Myopia with Retinal Atrophy Changes

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Our MicroPine program involves the development of a micro-formulation (dilute and low volume) of atropine ophthalmic solution for reduction of myopia progression in children.

Delivered with the Optejet dispenser, the product is also intended to make use of the Optejet’s Optecare system to assist with compliance and adherence.

The potential market opportunity for MicroPine in the United States alone may be $1.2 billion, according to third party analysts.

Phase III Clinical Development Program

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The primary assessment of efficacy is based on reduction in myopia progression after 3 years of medication use.

The IND and responsibility for the CHAPERONE study have been transferred to Bausch + Lomb, who is responsible for the FDA filing strategy.

Mydcombi is a unique fixed combination micro-formulation product candidate for mydriasis (eye dilation) intended to facilitate the over 100 million estimated office-based comprehensive and diabetic eye exams and four million ophthalmic surgical dilations performed every year in the United States.

Our fixed combination product candidate has been developed to facilitate efficient pupil dilation with the potential to reduce unintended effects of conventionally administered mydriatic agents.

We believe the market for Mydcombi exceeds $250 million in the United States alone.

Background of Mydriasis and Market Opportunity

There are over an estimated one hundred million topical mydriatic applications performed every year as a required part of the comprehensive dilated eye exam and standard retina fundoscopy for diabetic retinopathy screening, macular degeneration evaluation, glaucoma optic disc evaluation and many other back-of-the-eye conditions.

There are an additional estimated four million applications for ocular surgery.

Most optometrist and ophthalmologist offices maintain bottles of both phenylephrine and tropicamide eyedrops and use the drops in combination.

Each bottle is used on multiple patients, which carries a risk of contamination and ocular infection.

The bottles are purchased directly from suppliers and are not subject to insurance reimbursement.

Our combination therapy, if approved, will allow the purchase of one product for eye dilation.

Additionally, the Optejet does not come in direct contact with the eye, thus minimizing the risk of infection.

Most dilated eye exams require two separate topical pharmacologic agents/drops be administered sequentially (tropicamide, followed by phenylephrine).

All current mydriatic formulations use conventional macrodose drop delivery (30–50 µL), which can significantly overdose the ocular surface whose physiologic capacity is only 6–8 µL.

Studies demonstrate that standard macrodosed pharmacologic dilation is associated with significant ocular discomfort and mild-moderate eye pain.

On the standard visual analogue scale for pain, such discomfort can exceed the levels of pain associated with a flu vaccine subcutaneous injection.

Additionally, there are systemic safety concerns with mydriatic macrodosing for retinopathy of prematurity retinal screening and pediatric dilated eye exams.

With millions of patients exposed to mydriatic pharmacologic agents every year, we are developing a microdose alternative whereby the Optejet can be deployed to reduce ocular and systemic exposure by more than 75%.

This potential improvement stems from lowering the dose from the 30–50 µL in standard drops to just 8 µL with MicroStat combined with targeted delivery to the ocular surface.

We expect to achieve similar mydriatic activity as drops without the high incidence of unwanted side effects.

Pharmacologic mydriasis:

dilated pupil after application

Phase III Clinical Development Program

We completed the Phase III clinical trials of fixed-combination tropicamide 1% and phenylephrine 2.5% administered using the Optejet for mydriasis in November 2019.

The MicroStat program consisted of two Phase III randomized, controlled, cross-over clinical studies evaluating pupil dilation with our fixed combination product (MicroStat) in comparison with the individual drug components (phenylephrine 2.5% and tropicamide 1%, respectively) (the MIST-1 study), and with a placebo (the MIST-2 study).

The primary endpoint for each study was the mean change in pupil diameter at 35 minutes post-drug administration.

The MIST-1 study was a double-masked, active-controlled, three-period cross-over superiority study evaluating MicroStat ophthalmic solution versus the two individual drug components contained in MicroStat (phenylephrine 2.5% and tropicamide 1% ophthalmic solutions).

All study drugs were administered using the Optejet.

Volunteer participants were evaluated for study eligibility during a screening visit and enrolled after providing study consent.

Subjects meeting all inclusion/exclusion criteria were scheduled for three treatment visits, which occurred at least two days, but no more than seven days apart.

At each treatment visit, baseline measurements were taken, then one of the three study drugs was administered to both eyes in two separate instances, approximately five minutes apart.

Afterwards, efficacy and safety assessments were performed at specific time intervals, including pupil diameter measured by digital pupillometry in highly photopic conditions established by using a fully-charged transilluminator at the brightest setting.

Subjects were equally randomized to receive all three treatments according to one of the six possible sequences of study drug administration.

The MIST-1 study was double-masked so that there were no differences in drug presentation.

Study drug administration was performed by seven different trained personnel during the trial.

To maintain masking, personnel who administered study drug were not allowed to perform post-drug administration ophthalmic assessments.

A total of 64 subjects were randomized to receive the study drug.

Two subjects withdrew after the first treatment visit;

therefore, the resulting per-protocol analysis population consisted of 62 subjects (124 eyes).

Mean pupil diameter for each eye at baseline and at 35 minutes post-drug administration is shown graphically below.

At 35 minutes, the treatment group difference between MicroStat and

tropicamide 1% was 0.440 mm (SE 0.1839), which was statistically significant (p = 0.0183).

The treatment group difference between MicroStat and phenylephrine 2.5% at the same timepoint was 3.638 mm (SE 0.1817), which was also statistically significant (p <0.0001).

Since the null hypothesis was rejected for both sets of comparisons, the primary endpoint was met.

Pupil Diameter by Treatment at Baseline and 35 Minutes

(PP Population)

Mean ± Standard Deviation

Tx A = phenylephrine 2.5%-tropicamide 1%;

Tx B = tropicamide 1%;

Tx C = phenylephrine 2.5%.

As shown below, at 35 minutes post-drug administration, Mydcombi achieved a clinically meaningful pupil diameter ≥ 6.0 mm in 95.2% of right eyes and 93.5% of left eyes compared to a lower proportion for tropicamide 1% (79.0% and 77.4% of right and left eyes, respectively) and for phenylephrine 2.5% (1.6% for both right and left eyes).

Mydcombi also achieved a pupil diameter ≥ 7.0 mm in 67.7% of right and left eyes compared to a lower proportion for tropicamide 1% (43.5% and 41.9% or right and left eyes, respectively) and for phenylephrine 2.5% (0% for right and left eyes).

Proportion of Eyes Achieving Pupil Diameter ≥ 6.0 mm and ≥ 7.0 mm at 35 Minutes

(PP Population)

35 Min Post Dose

Tropicamide 1%

Phenylephrine 2.5%

Combined Visits

Pupil diameter ≥ 6.0 mm

Pupil diameter < 6.0 mm

Pupil diameter ≥ 7.0 mm

Pupil diameter < 7.0 mm

The rate of treatment emergent adverse events, or TEAEs, was low, and consistent with those observed with commercially available dilating eye drops (e.g.

blurry vision and stinging).

Two TEAEs were reported in the MicroStat eyes, while four TEAEs were reported in each of the other two treatment groups.

All events were mild in nature.

No non-ocular adverse events were reported.

The MIST-2 Study was a multi-center, double-masked, placebo-controlled, three-period crossover superiority study evaluating MicroStat ophthalmic solution versus placebo.

Both study drugs were administered using the Optejet.

Volunteer participants were evaluated for study eligibility during a screening visit and enrolled after providing study consent.

Subjects meeting all inclusion/exclusion criteria were scheduled for three treatment visits, which occurred at least two days, but no more than seven days apart.

A two-sequence, three-period crossover design was used.

At each treatment visit, baseline measurements were taken, then either the investigational drug or the placebo was administered to both eyes in two separate instances, approximately five minutes apart.

Only one study drug was administered per treatment visit, and subjects were equally randomized to one of two sequences,

ABB and BAA, where A was the Eyenovia fixed combination and B was placebo.

Like MIST-1, this study was double-masked so that there were no differences in drug presentation.

Study drug administration was performed by five different trained personnel and, to maintain masking, personnel who administered study drug were not allowed to perform post-drug administration ophthalmic assessments.

A total of 70 subjects at two investigational sites were randomized to receive study drug.

One subject withdrew after the first treatment visit;

therefore, the resulting per-protocol analysis population consisted of 69 subjects (138 eyes).

Mean pupil diameter for each eye at baseline and at 35 minutes post-drug administration is shown graphically below.

At 35 minutes, the treatment group difference between Mydcombi and placebo was 4.63 mm (SE 0.0544), which was highly statistically significant (p < 0.0001);

consequently, the null hypothesis was rejected and the primary endpoint was met.

Pupil Diameter by Eye and Treatment at Baseline and 35 Minutes

(PP Population)

Mean ± Standard Deviation

As shown in the table below, at 35 minutes post-drug administration, Mydcombi achieved a clinically meaningful pupil diameter ≥ 6.0 mm in 92.8%% of right eyes and 94.2% of left eyes and pupil diameter ≥ 7.0 mm in 69.6% of right and 68.1% of left eyes.

None of the eyes in the placebo group achieved similar dilation.

Proportion of Eyes Achieving Pupil Diameter ≥ 6.0 mm and ≥ 7.0 mm at 35 Minutes

(PP Population)

35 Min Post Dose

Combined Visits (1, 2, 3)

Pupil diameter ≥ 6.0 mm

Pupil diameter < 6.0 mm

Pupil diameter ≥ 7.0 mm

Pupil diameter < 7.0 mm

Two TEAEs (one event of mild instillation site pain and one event of moderate photophobia) were reported in the Mydcombi group, while none were reported with the use of placebo.

No non-ocular adverse events were reported.

Essentially pain-free mydriasis was achieved without the use of a topical anesthetic, which is often the practice.

The outcomes of MIST-1 and MIST-2 are consistent.

As shown below, in both studies, Mydcombi achieved a mean change in pupil size between 4.6 mm and 4.8 mm at 35 minutes post-dose.

In both studies, between 93% and 95% of eyes treated with the fixed

combination mydriatic drug achieved a pupil diameter ≥ 6.0 mm at this same timepoint.

Additionally, in MIST-1, the median time to maximum post-baseline pupil diameter with ≥ 1.0 mm increase from baseline for fixed combination solution was 73.0 minutes, while in MIST-2, it was 71.0 minutes.

Efficacy of Mydcombi in MIST-1 and MIST-2 Studies (PP Populations)

Mean change in pupil diameter from baseline at 35 minutes

4.6 mm right eyes

4.7 mm left eyes

4.7 mm right eyes

4.8 mm left eyes

Proportion of eyes with pupil diameter ≥ 6.0 mm at 35 minutes

95.2% of right eyes

93.5% of left eyes

92.8% of right eyes

94.2% of left eyes

Median time to maximum post-baseline pupil diameter with ≥ 1.0 mm increase from baseline

The consistency of these results validates the robustness of the study designs and demonstrates the impressive treatment effect of Mydcombi.

More generally, these outcomes serve to further validate the bioavailability and efficacy of Optejet drug administration to the ocular surface.

With the primary objectives of our Phase III clinical program met, in December 2020, we submitted an NDA to the FDA for marketing approval in the United States.

In October 2021, we received a CRL in response to our NDA, which in part informed us that pre-filled or co-packaged ophthalmic drug dispenser products like Mydcombi have been reclassified as drug-device combination products.

This reclassification was based upon the U.S.

Court of Appeals for the D.C.

Circuit’s decision in Genus Medical Technologies v.

FDA, not involving Eyenovia, which ordered that products meeting the statutory definition of a device but were previously classified by the FDA as drugs must be regulated as devices.

Before this ruling, the FDA regulated pre-filled or co-packaged ophthalmic dispensers as part of the approved ophthalmic drug distributed and sold with the dispenser.

After the ruling, however, the dispenser must be considered as a distinct device constituent part of a drug-device combination product.

As a result, we resubmitted the NDA on November 8, 2022, and announced on December 13, 2022 that the FDA has accepted the resubmission.

The FDA has assigned the resubmitted NDA a standard review with a Prescription Drug User Fee Act (PDUFA) target action date of May 8, 2023.

We expect that over half of the intended enrollment of CHAPERONE will have reached the three-year efficacy endpoint in late 2024.

At that time, we plan to discuss an interim analysis with the FDA to determine if there is a more efficient pathway towards approval for the product.

Our Technology

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Doses are delivered by attaching the cartridge to the base, pressing an activation button which loads a single drug dose, then, holding it between one and two inches from the eye while looking directly into an illuminated circle, pressing a second button to emit the micro-droplet delivered medication.

The micro-droplets are emitted in a quickly repeating array, that in aggregate form a directed mist.

The micro-droplets are emitted in a

quickly repeating array, that in aggregate form a directed mist.

Solution is dispensed to the ocular surface in less than 100 milliseconds between the time the first droplet hits the corneal surface to the completion of dose delivery, which is faster than the average involuntary blink response time.

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Sales and Marketing

We are taking a staged approach to the commercialization of our products, retaining rights for Mydcombi to potentially optimize the introduction of the technology to the market, and establishing partnerships with licensees for products that require a larger investment in terms of sales force and distribution.

We are building a sales and distribution organization that will be staged to match with our planned product launches and size of the opportunities.

We have hired and plan to deploy ten sales representatives and two national sales directors who will focus on the promotion of Mydcombi as well as clobetasol propionate.

We have also built the infrastructure to act as a wholesaler for Mydcombi, and will be partnering with an online pharmacy for the launch of clobetasol propionate.

Our management team and directors, which are leading the commercialization planning of our lead product candidates in the United States, have substantial experience in the commercialization of ophthalmic therapeutics.

Mydcombi is our first expected commercial product.

Mydcombi is a cash-pay pharmaceutical supply, administered and purchased by clinics and doctors for in-office use.

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Lastly, we believe that we can be successful with a limited in-person sales force as we are not aware of any active competition in this space.

MicroLine is our second expected product for commercialization.

Like Mydcombi, MicroLine would also be “cash-pay,” negating the need for infrastructure focused on managed care reimbursement.

We currently have licensed MicroLine as well as Mydcombi to Arctic Vision for development and commercialization in Greater China and South Korea.

Unless we establish additional partnerships for MicroLine, we plan to expand our sales force from approximately ten to fifty people in the United States and focus on promotion in the optometrist office.

Clobetasol propionate is our second product for commercialization.

Like Mydcombi, clobetasol will also be “cash-pay,” negating the need for infrastructure focused on managed care reimbursement.

Clobetasol will be sold in two ways:

(1) prescribed by ocular surgeons to patients through an online pharmacy, and (2) purchased directly from Eyenovia by offices who sell the medication directly to their patients as part of their overall fee.

MicroLine, if approved, would again be “cash-pay”.

If we decide to pursue approval, and receive approval, for this product, we would expand our sales force in the United States and focus on promotion in the optometrist office.

We also plan to leverage the experience that these offices have had with Mydcombi to speed acceptance and prescribing of MicroLine to appropriate patients.

MicroPine is our third expected product for commercialization.

MicroPine is a more standard therapeutic, likely reimbursed by payers after negotiating for formulary position.

We have licensed MicroPine to Arctic Vision in Greater China and Korea, and to Bausch Health in the United States and Canada.

In both cases, our licensee will be responsible for commercialization within their own sales and marketing structures.

MicroPine is our fourth expected product for commercialization.

MicroPine is planned to be launched as a reimbursed product, similar to glaucoma medications, where formulatory position is obtained through negotiations with payers.

We would make use of our planned sales force calling on optometrists, many who have a specialty in treating pediatric progressive myopia.

Manufacturing

For clinical supply, Eyenovia relies on internal manufacturing capabilities along with third-party contract manufacturing organizations (CMOs) to produce the Optejet® cartridges and bases.

In order to streamline our manufacturing process and reduce costs, Eyenovia has invested in commissioning a facility located in Redwood City, CA.

The facility is dedicated to the fill and finish for Eyenovia’s proprietary primary closure container, which is used in its different therapies, as well as assembly and final packaging of cartridges.

Redwood City came on-line with the production of clinical materials in mid-2022.

Base units are manufactured by Eyenovia at its Reno, NV engineering center.

In order to streamline our manufacturing process and reduce costs, Eyenovia has invested in two of its own facilities, one in Redwood City, CA that was recently FDA-approved for Mydcombi cartridge production, and one in Reno, NV that has recently been FDA-approved for ejector and base unit manufacturing.

We also use a CMO, Coastline International in Mexico, for production of certain subassemblies as well as a CMO for the production of our drug substances.

We are currently developing and manufacturing the second generation of our device, and we expect our strategy for moving from the first to the second generation device to be the subject of an FDA meeting this summer.

Assuming we come to an agreement with the FDA to demonstrate comparability between the two devices, this should provide a path for Eyenovia to introduce the second generation platform to the commercial market in 2026.

The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.

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There are competitive macrodose drop formulations of individual therapeutics for mydriasis such as tropicamide and phenylephrine marketed by companies such as Akorn, Alcon and others, as well as pharmacies that compound the combination on an individual basis for physicians.

For clobetasol propionate, there are several steroid options in this field, but we are not aware of any product with the combination of dosing, efficacy and safety attributes that our product will have.

Additionally, we believe our “value pricing” approach, where patients can expect to pay a fixed amount regardless of their insurance coverage or status, will further differentiate us in this market.

For MicroLine, Allergan has launched Vuity, a pilocarpine eye drop for the treatment of presbyopia.

Along with Allergan, there are other pharmaceutical companies developing therapies for presbyopia, none of which makes use of microdosing technology or deliver medication as a spray.

We expect that both Mydcombi and MicroLine would be “cash pay” products, as Mydcombi is purchased directly by offices and used routinely in eye exams, and MicroLine would be considered an “aesthetic” prescription product not generally covered by third party insurance.

For MicroPine, we are not aware of any FDA-approved drugs to slow the progression of myopia.

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and foreign patent applications for our future innovations.

The Company is currently engaged in three inter partes review, or IPR, proceedings challenging the validity of certain patents owned by Sydnexis, Inc.

The IPRs are as follows:

IPR2022-00384, filed on December 29, 2021, challenging U.S.

IPR2022-00414, filed on January 7, 2022, challenging U.S.

and IPR2022-00415, filed on January 7, 2022, challenging U.S.

All three IPRs were instituted by the Patent Trial and Appeal Board.

Final decisions in each of these proceedings are expected on or before July 15, 2023.

As of December 31, 2022, we owned eighteen U.S.

issued and allowed utility patents or design patents, and eight pending U.S.

We are currently engaged in an appeal taken from three inter partes review (“IPR”) proceedings successfully challenging the validity of certain patents owned by Sydnexis, Inc.

The Patent Trial and Appeal Board instituted IPR2022-00384, filed by Eyenovia on December 29, 2021 and challenging claims in U.S.

and IPR2022-00414 and IPR2022-00415, both filed by Eyenovia on January 7, 2022, and challenging claims in U.S.

10,940,145 and 10,888,557, respectively.

All three IPR proceedings were instituted and then consolidated for trial.

On July 13, 2023, the Board determined in a final written decision that all claims across the three challenged Sydnexis patents were unpatentable.

Sydnexis subsequently appealed to the U.S.

Court of Appeals for the Federal Circuit, and briefing is currently in progress, with a decision anticipated in 2025.

As of December 31, 2023, we owned seventeen U.S.

issued and allowed utility patents or design patents, and ten pending U.S.

patent applications, as well as 97 issued foreign patents, and 26 pending foreign patent applications, and one pending international PCT application.

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patent will be obtained and, if obtained, the duration of such extension.

Similar patent term extension/reduction provisions are available in the European Union and other jurisdictions.

Similar patent term

extension/reduction provisions are available in the European Union and other jurisdictions.

In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we will apply for patent term extensions on issued patents covering our products to the extent available under the applicable law, depending upon the length of any such clinical trials for any product and other factors.

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In addition to patents, we may rely on trade secrets and proprietary know-how to protect our technology.

We endeavor to protect our proprietary technology and processes in the appropriate manner to maintain their secrecy including confidentiality

agreements when dealing with third parties.

We endeavor to protect our proprietary technology and processes in the appropriate manner to maintain their secrecy including confidentiality agreements when dealing with third parties.

We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

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Such authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved NDA.

In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.

of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.

In addition, the results of the nonclinical 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.

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When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with FDA certain regulatory requirements in order to use the study as support for an IND or application for marketing approval.

In particular, such studies must be conducted in accordance with GCP, including review and approval by an independent ethics committee, or IEC, and informed consent from subjects, and must meet other clinical trial

requirements, such as sufficient patient population size and statistical powering.

The FDA must be able to validate the data through an onsite inspection, if deemed necessary by the FDA.

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Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial.

Clinical trials are conducted in accordance with written study protocols detailing, among other things, study objectives, participant inclusion and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Clinical trials are conducted in accordance with

written study protocols detailing, among other things, study objectives, participant inclusion and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

A protocol for each phase of a clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.

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The FDA may grant a waiver for some or all of the requirements for a diversity action plan.

It is unknown at this time how the diversity action plan may affect Phase III trial planning and timing or what specific information FDA will expect in such

plans, but if FDA objects to a sponsor’s diversity action plan and requires the sponsor to amend the plan or take other actions, it may delay trial initiation.

It is unknown at this time how the diversity action plan may affect Phase III trial planning and timing or what specific information FDA will expect in such plans, but if FDA objects to a sponsor’s diversity action plan and requires the sponsor to amend the plan or take other actions, it may delay trial initiation.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

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The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA.

This type of application allows the applicant to rely, in part, on the FDA’s previous findings of safety and efficacy for a drug product previously approved under an NDA, published literature, or a combination of both.

This type of application allows the applicant to rely, in part, on the FDA’s previous findings of safety and efficacy for a drug product previously

approved under an NDA, published literature, or a combination of both.

Specifically, Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.

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The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the drug’s clinical benefit.

As a result, a drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase IV or post-approval clinical trials to confirm the effect on the clinical endpoint.

As a result, a drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase IV or post-approval clinical trials to

confirm the effect on the clinical endpoint.

Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the drug from the market on an expedited basis.

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Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If the FDA approves a product, it may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase IV clinical trials, be conducted to further assess the drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, which can

materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.

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There also are continuing, annual program fee requirements for any marketed products, as well as new application fees for supplemental applications with clinical data.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic announced or unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.

the FDA and these state agencies for compliance with cGMP requirements.

Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented.

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Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label.

Although physicians

may prescribe legally available products for off-label uses, manufacturers may not market or promote such uses.

Although physicians may prescribe legally available products for off-label uses, manufacturers may not market or promote such uses.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

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In 1984, with passage of the Drug Price Competition and Patent Term Restoration Act, informally known as the Hatch-Waxman Act, that established an abbreviated regulatory scheme authorizing the FDA to approve generic drugs based on an innovator or “reference” product, Congress also enacted Section 505(b)(2) of the FDCA, which provides a hybrid pathway combining features of a traditional NDA and a generic drug application.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the agency.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug

application, or ANDA, to the agency.

In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug, or RLD.

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With enactment of the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012, PREA was made permanent and sponsors are required to submit pediatric study plans to the FDA prior to the assessment data.

In particular, a sponsor that is planning to

submit a marketing application for a product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-Phase II meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase III or Phase II/III study.

In particular, a sponsor that is planning to submit a marketing application for a product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-Phase II meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase III or Phase II/III study.

The initial PSP must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

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If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months, including orphan drug exclusivity.

This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another application.

This is not a patent term extension,

but it effectively extends the regulatory period during which the FDA cannot approve another application.

The FDA’s issuance of a Written Request does not require the sponsor to undertake the described studies.

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● post-market surveillance regulations, which apply to certain Class II or III devices when necessary to protect the public health or to provide additional safety and effectiveness data for the device.

Under the FDA medical device reporting, or MDR, regulations, medical device manufacturers are required to report to the FDA information that a device has or may have caused or contributed to a death or serious injury or has malfunctioned in a way that would likely cause or contribute to death or serious injury if the malfunction of the device or a similar device of such manufacturer were to recur.

The decision to file an MDR involves a judgment by the manufacturer.

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Pharmaceutical Coverage, Pricing and Reimbursement

Our Mydcombi and MicroLine product candidates are intended as “cash pay” and therefore are not likely subject to the significant uncertainty that exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities.

Our Mydcombi, MicroLine and clobetasol propionate product candidates are intended as “cash pay” and therefore are not likely subject to the significant uncertainty that exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities.

The sales of MicroPine, however, would likely depend in part on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, such products.

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A decision by a third-party payor not to cover a product could reduce physician utilization once the product is approved and have a material adverse effect on sales, our operations and financial condition.

Additionally, a payor’s decision to provide coverage

for a drug product does not imply that an adequate reimbursement rate will be approved.

Additionally, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.

Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product.

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The False Claims Act also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the False Claims Act and to share in any monetary recovery;

a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or state governmental program;

● the anti-inducement law, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value (with limited exceptions), to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or state governmental program;

● the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal laws that prohibit, among other things, knowingly and willingly executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;

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The United States and some foreign jurisdictions are considering enacting or have enacted a number of additional legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our product candidates profitably, if approved.

may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations.

If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we otherwise may have obtained and we may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations.

In addition, the containment of healthcare costs has become a priority of federal and state governments and the prices of therapeutics have been a focus in this effort.

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Cost reduction initiatives and changes in coverage implemented through legislation or regulation could decrease utilization of and reimbursement for any approved products we may market in the future.

While Medicare regulations apply only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates.

While Medicare regulations apply only to drug benefits for Medicare beneficiaries, private payors

often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates.

Therefore, any reduction in reimbursement that results from federal legislation or regulation may result in a similar reduction in payments from private payors.

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There has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries, presidential executive orders and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for pharmaceutical products.

Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medical products and services, implementing reductions in Medicare and other healthcare funding and applying new payment methodologies.

applying new payment methodologies.

In addition to the sweeping reforms contained in the ACA, other legislative changes have been proposed and adopted in the United States that may affect healthcare expenditures.

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Chairman and Director of Eyenovia

Michael Geltzeiler

Director of Eyenovia

Rachel Jacobson

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business