#1Ocuphire PHARMA Restore Vision & Clarity Ocuphire KOL Event: APX3330 October 14, 2022#2Disclosures and Forward-Looking Statements Ocuphire PHARMA This presentation contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements concerning the success and timing of planned regulatory filings, including planned NDA filings, pre- commercial activities, commercialization strategy and timelines, business strategy, product labels, cash runway, scalability, future clinical trials in reversal of mydriasis (RM), presbyopia (P), dim light/night vision disturbance (NVD) and diabetic retinopathy (DR)/diabetic macular edema (DME), and the potential market opportunity in DR/DME. These forward-looking statements are based upon the Company's current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: (i) the success, costs, and timing of regulatory submissions and preclinical and clinical trials, including enrollment and data readouts; (ii) regulatory requirements or developments; (iii) changes to clinical trial designs and regulatory pathways; (iv) changes in capital resource requirements; (v) risks related to the inability of Ocuphire to obtain sufficient additional capital to continue to advance its product candidates and its preclinical programs; (vi) legislative, regulatory, political, and economic developments, (vii) changes in market opportunities, (viii) the effects of COVID-19 on clinical programs and business operations, (ix) the success and timing of commercialization of any of Ocuphire's product candidates, including the scalability of Ocuphire's product candidates, and (x) the maintenance of Ocuphire's intellectual property rights. The foregoing review of important factors that could cause actual events to differ from expectations should not be construed as exhaustive and should be read in conjunction with statements that are included herein and elsewhere, including the risk factors detailed in documents that have been and may be filed by the Company from time to time with the SEC. All forward-looking statements contained in this presentation speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. The Company makes no representation or warranty, express or implied, as to the accuracy or completeness of the information contained in or incorporated by reference into this presentation. Nothing contained in or incorporated by reference into this presentation is, or shall be relied upon as, a promise or representation by the Company as to the past or future. The Company assumes no responsibility for the accuracy or completeness of any such information. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market shares and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. 2#3Ocuphire APX3330 KOL Event: Agenda & Speakers Ocuphire Speakers Mina Sooch, MBA President & CEO and Founder Ocuphire Caroline Baumal, MD Tufts Medical Peter Kaiser, MD Cleveland Clinic Cole Eye Institute David Lally, MD NEW ENGLAND RETINA CONSULTANTS Caroline Baumal, MD Tufts Medical Agenda Introductions & Company Overview Disease of Diabetic Retinopathy Current DR/DME Treatment Landscape APX3330, Paradigm-Shifting Oral Treatment Option ZETA-1, Phase 2b Trial in Diabetic Retinopathy and Masked Safety Data Time (EDT) 11:00 am - 11:10 am 11:10 am - 11:20 am 11:20 am - 11:35 am 11:35 am - 11:50 am 11:50 am - 12:00 pm 3#4Ocuphire APX3330 KOL Event: Agenda & Speakers Peter Kaiser, MD Cleveland Clinic Cole Eye Institute Mina Sooch, MBA President, CEO, and Founder Ocuphire Peter Kaiser, MD Cleveland Clinic Cole Eye Institute Ocuphire Speakers Caroline Baumal, MD Medical Tufts Center Mitch Brigell, PhD Head, Clinical Strategy Ocuphire Caroline Baumal, MD Tufts Center Medical David Lally, MD NEW ENGLAND RETINA CONSULTANTS Mark Kelley, PhD APX Program Scientific Advisor Ocuphire PHARMA David Lally, MD NEW ENGLAND RETINA CONSULTANTS Agenda ZETA-1 Trial Design and Data Expectations Q&A Closing Remarks Q&A Moderator: Corey Davis, PhD LifeSci Time (EDT) 12:00 pm - 12:15 pm 12:15 pm 12:30 pm 4#5Ocuphire Company Overview Presenter: Mina Sooch, CEO and Founder of Ocuphire Pharma Ocuphire PHARMA Mina Sooch, MBA Harvard University ● ● ● Over 25 years of pharmaceutical and biotech experience as CEO, entrepreneur, venture capitalist, and strategy consultant Successful track record of hundreds of millions of capital raised for leading private/public biotech companies Experience across multiple diseases (cardiovascular, oncology, renal, NASH, CNS, etc.) prior to ophthalmology Recipient of numerous awards, including Deal Makers of the Year in 2016 and Alumni Commencement Speaker WSU College of Engineering in 2021 LO 5#6Ocuphire Pharma Nasdaq: OCUP Upcoming Catalysts in 4Q22: • Topline Results APX3330 ZETA-1 P2b trial for DR/DME NDA Filing for Nyxol for RM ● P = Presbyopia RM = Reversal of Mydriasis NVD = Night Vision Disturbances DR/DME = Diabetic Retinopathy/Diabetic Macular Edema Ocuphire PHARMA Founded in 2018, Acquired 2 Lead Assets for Front & Back of Eye Therapies with Novel MOAS & Patent Coverage to 2034+ Nyxol eyedrops ● ● ● ● ● APX3330 oral tablets Diabetic retinopathy ("DR") - diabetes-related retinal (eye) disease Reversal of Mydriasis ("RM") - eye dilation Presbyopia - age-related blurry near vision Night Vision Disturbance ("NVD") - halos, glares, starbursts Four Large Markets (~$20B US total) w/Unmet Needs and Limited to No Competition Successful Execution of 5 Trials in last 2 Years with 6 Positive Phase 3 & Phase 2 Data Read-outs for Nyxol in RM, Presbyopia, and NVD Potential 2023 commercialization opportunities in RM Near-term initiation planned for Presbyopia VEGA Phase 3 program with Nyxol alone and Nyxol with 0.4% Low Dose Pilocarpine as adjunctive therapy ● ● CO 6#7Ocuphire Overview Two Late-Stage Clinical Assets Addressing Unmet Needs in Multiple Large Markets Nyxol 12 Completed Phase 1, Phase 2, and Phase 3 Trials Ocuphire Refractive Novel a1/a2 Blocker 505(b)(2) >650 Subjects Dosed Reversal of Mydriasis Presbyopia Night Vision Disturbances Exposure in Humans 28 Days Prevalence (US) ~100 M ~128 M NDA-Filing Ready ~36 M Patent Coverage 2034+ Development Milestone 2 Phase 3 Positive Data & Ped P3 Phase 2 Positive Data Single & Combo 1st Phase 3 Positive Data APX3330 11 Completed Phase 1 and Phase 2 Trials Source: Eisai and Apexian Data; GlobalData Market Research Report, 2020; Company Estimates for US Market Size; Ocuphire internal estimates Retina Oral REF-1 Inhibitor New Chemical Entity >340 Subjects Dosed Diabetic Retinopathy Diabetic Macular Edema Exposure in Humans 365 Days Prevalence (US) ~8 M Phase 2b Data 4Q22 ~2.4 M Patent Coverage 2034+ Development Milestone Phase 2b Last Patient Last Visit Completed Aug 22 7#8Track Record of Achieving Milestones Multiple Positive Data Readouts with Multiple Catalysts Ahead Positive Nyxol Phase 3 Data for RM (MIRA-2) 20211H 2022 Ocuphire PHARMA Positive Nyxol+LDP Phase 2 Data for Presbyopia (VEGA-1) Positive Nyxol Alone P2 Data for Presbyopia (VEGA-1) Positive Nyxol 2nd Phase 3 Data for RM (MIRA-3) Positive Nyxol Phase 3 Data for NVD (LYNX-1) Positive Nyxol Pediatric Data for RM (MIRA-4) 2H 2022 – 2023 Submit Nyxol NDA for RM Report APX3330 Phase 2b Data for DR/DME (ZETA-1) Initiate VEGA Phase 3 Presbyopia Program Potential Nyxol Approval and Commercialization Ongoing Partnering Discussions with Leading Ophthalmic Companies (including Europe and Asia) 8#9Ocuphire Disease of Diabetic Retinopathy Presented by: Caroline Baumal, MD Medical Tufts Center PHARMA Caroline Baumal, MD University of Toronto ● ● ● ● Professor of Ophthalmology at Tufts Medical Center Co-Director of the Retina Service and Medical Retina Fellowship at New England Eye Center Authored over 170 publications, 33 book chapters on retinal diseases, and edited the book Treatment of Diabetic Retinopathy Recognized by the American Society of Retinal Surgeons, The Retinal Hall of Fame and received such honors as the Donald J. Gass Beacon of Sight Award from the Florida Ophthalmologic Society and the ASRS Crystal Apple award from the Vit-Buckle Society. 9#10Diabetic Eye Disease is Common Cause of Blindness Diabetes and Diabetic Retinopathy (DR) Diabetes Mellitus is a group of diseases characterized by high blood glucose levels. Diabetes results from defects in the body's ability to produce and/or use insulin Ho Ocuphire PHARMA Type 1 diabetes (T1D): The body produces very little or no insulin, which means that patients need daily insulin injections to maintain blood glucose levels Type 2 diabetes (T2D): The most common form of diabetes either the body does not produce enough insulin, or resists insulin https://webeye.ophth.uiowa.edu/eyeforum/tutorials/diabetic-retinopathy-med-students/Classification.htm https://www.mayoclinic.org/diseases-conditions/type-1-diabetes/symptoms-causes/syc-20353011 https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/symptoms-causes/syc-20351193 Diabetic retinopathy (DR) occurs when fluctuations or instability in blood glucose levels damages blood vessels in the retina Normal Retina Diabetic Retina Two Types of DR Non-Proliferative Diabetic Retinopathy (NPDR) - most common form of DR - early stages of edema and exudates, blurred central vision Proliferative Diabetic Retinopathy (PDR) - later stage of DR, marked by abnormal blood vessels and scar tissue on retina Diabetic Macular Edema (DME) can occur at any stage of DR 10#11North America & Caribbean (NAC) 2045 63 million 2030 57 million 51 million 2021 South & Central America (SACA) 2045 49 million 2030 40 million 32 million 2021 Diabetes is a Growing Global Health Epidemic Diabetes Cost Burden Over $900 Billion Dollars in Worldwide Health Expenditure Africa (AFR) 2045 2030 2021 55 million 33 million 24 million ↑ 24% increase 50% increase ↑ 134% increase World 2045 783 million 2030 643 million 537 million 2021 Ocuphire Source: International Diabetes Federation, Diabetes Atlas 10th Edition, 2021, https://diabetesatlas.org/atlas PHARMA 个 46% increase Europe (EUR) 2045 2030 2021 Western Pacific (WP) 260 million 2045 2030 238 million 2021 206 million South-East Asia (SEA) 2045 69 million 67 million 61 million 2030 2021 152 million 113 million 90 million 2021 2045 136 million 2030 95 million 73 million 个 个 Middle East & North Africa (MENA) 个 13% increase 27% increase 68% increase ↑ 87% increase 11#12Diabetic Patients Usually Present with Complex Co-Morbidities Diabetic Patients are Young and Face Life-long Systemic and Ocular Complications DR is the most common cause of vision loss or blindness in working- age adults, usually affecting both eyes DME is a vision threatening complication caused by DR where excess fluid leaks near fovea and triggers swelling of the macula Treating DR leads to control of DME Ocuphire PHARMA Diabetic retinopathy¹ Dyslipidemia² Diabetic neuropathy¹ Patients with DME have an even greater risk of complications than diabetes patients without DME5,6 Stroke¹ K Cardiovascular disease² Diabetic nephropathy¹,2 Oral options have the potential to reach other vascular beds to treat kidney and neuropathic co-morbidities 1. Petrella RJ, et al. J Ophthalmol 2012;159167; 2. International Diabetes Federation, Diabetes Atlas 6th Edition, http://www.idf.org/diabetesatlas; 3. National Diabetes Fact Sheet, 2011 http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf; 4. Rodbard HW, et al. Endocr Pract 2007;13:4-69; 5. Wong TY, et al. JAMA 2002;288:67-74; 6. Nguyen-Khoa B, et al. BMC Ophthalmol 2012;12:11 12#13Global Prevalence of Diabetes-Associated Retinal Disease DR Affects 1 in 3 People with Diabetes; DME Affects 1 in 13 People with Diabetes 1 Ocuphire PHARMA North America & Caribbean DR: 16M* DME: 6M* USA DR: 8M² DME: 0.75M² DR: 4M* DME: 4M* DR: 18M* DME: 8M* DR: 7M* DME: 4M* DR: 15M* DME: 5M* *Global estimates are provided by the National Eye Institute, FactSheet, Global Data, Research and Markets, American Academy of Ophthalmology, and PLOS One 1. Holekamp N. M. (2016). Overview of diabetic macular edema. The American journal of managed care, 22(10 Suppl), s284-s291. 2. American Diabetes Association; American Journal of Managed Care, International Diabetes Federation; Healthline; Ocuphire internal analysis and assumptions DR: 11M* DME: 7M* DR: 32M* DME: 14M* 13#14Measuring the Severity of Diabetic Retinopathy DRSS is Regularly Used For FDA Approvals; Not As Widely Used in Everyday Practice Ocuphire PHARMA Diabetic Retinopathy Severity Scale (DRSS) was developed to differentiate proliferative DR (PDR) from non-proliferative DR (NPDR) 10, 12 DR Absent 60, 61 Mild PDR 1 7 14, 15, 20 DR Questionable 65 Moderate PDR 2 8 35 Mild NPDR 71 High-risk PDR 3 43 Moderate NPDR 75 High-risk PDR 10 47 Moderately Severe NPDR 81 Advanced PDR 5 11 53 Severe NPDR 85 Advanced PDR Arcadu, F., Benmansour, F., Maunz, A. et al. Deep learning algorithm predicts diabetic retinopathy progression in individual patients. npj Digit. Med. 2, 92 (2019). https://doi.org/10.1038/s41746-019-0172-3. 12 14#15DRSS Predicts Vision-Threatening Complications (PDR/DME) Percent of Eyes Progress to PDR at 1-Year, 3-Year, and 5-Year Visits by Baseline DR Severity Ocuphire PHARMA Percentage of Eyes that Worsen to PDR 100% 80% 60% 40% 20% 0% Early screening and treatment for DR can reduce vision loss by up to 94% 5% Mild NPDR (35) 14% 25% 12% 30% Moderate NPDR (43) 66% 71% +41 48% 52% 40% 26% 1. Early treatment diabetic retinopathy study research group. ophthalmology. 1991;98(5 suppl):823-33. 2. Diabetes control and complications trial research group. N Engl J Med. 1993;329(14):997-86. 3. Moderately Severe NPDR (47) Regardless of severity, all eyes worsen over time Severe NPDR (53) 80% 5 Year Follow-up 3 Year Follow-up 1 Year Follow-up Fathy C, Patel S, Sternberg P Jr, Kohanim S. Disparities in adherence to screening guidelines for diabetic retinopathy in the United States: a comprehensive review and guide for future directions. Semin Ophthalmol. 2016;31(4):364-377. doi: 10.3109/08820538.2016.1154170 15#16Vision Loss is #1 Concern of Diabetic Patients Diabetic Retinopathy is a Progressive Vision-Threatening Disease Ocuphire PHARMA What are the top concerns for diabetic patients? Vision Loss Amputation, Losing a Leg Cardiovascular/Heart Problems Other Eye Problems Foot Problems Kidney Problems 0% 5% 10% 15% 25% 20% 25% Percent Responders Source: Patient survey adapted from Lions International Foundation and International Diabetes Foundation-Europe; Meltzer 2000 30% 30% 35% 35% 35% 38% 40% N=2702 40% 45% 16#17Early Management of Diabetic Retinopathy Poor Adherence to Medical Management and Lifestyle Options Worsen DR Control of Blood Sugar 8.8.8 Medical and lifestyle management is first line of treatment Ocuphire Source: Zhang X et al. Cell Biosci. 2014;14:4:27 PHARMA Control of Blood Pressure 13 20 27 Smoking Cessation 14 21 28 QUIT! 22 29 16 23 Control of Lipids 17#18Majority of Physicians Use a "Wait and Monitor" Approach for DR Patients Over 90% of DR Patients Are Not Treated Proactively and Anti-VEGF Use is Limited Ocuphire PHARMA How do physicians treat patients with severe NPDR without DME? Closely monitor retinopathy and encourage systemic glycemic control Consider anti-VEGF in some patients with poor glycemic control and/or other risks Consider anti-VEGF in some patients with good glycemic control and compliance Consider anti-VEGF therapy in all or most patients Source: ASRS 2021 Preferences and Trends (PAT) Survey Other 4.9% 3.1% 7.7% 7.8% 10.9% 3.7% 17.0% 24.9% 0.00% 10.00% 20.00% 30.00% 40.00% 50.00% International US 59.5% 60.5% 60.00% 70.00% 18#19Diabetic Retinopathy At a Glance Current Treatment Landscape Demonstrates Need for Less Invasive Therapies 4.HO 111 MAMMA There are ~8M adults in the U.S. with DR¹ The number of people with DR expected to increase more than 14M by 2050 Ocuphire PHARMA DR/DME affects about 1 in 4 people with type 1 and type 2 diabetes O 56% of patients reported anxiety related to anti-VEGF treatment DR is the leading cause of blindness among working-age adults $13B (2020) Global Intravitreal Injection Revenues in AMD, DME and BRVO4 If untreated, DR can rob people of their vision prematurely2,3 Majority of moderate to severe patients with DR are not treated with anti-VEGF due to injection fear and burden Source: 1. American Diabetes Association; International Diabetes Federation; Healthline; *Ocuphire internal analysis and assumptions; 2. Das UN. DME, retinopathy and age-related macular degeneration as inflammatory conditions. Arch Med Sci. 2016;12(5):1142-1157. doi:10.5114/aoms.2016.61918 3. Patient survey adapted from Lions International Foundation and International Diabetes Foundation-Europe; Meltzer 2000 4. Guidehouse Triangulation of Global Data, Market Scope and Investor Forecasts (2020) AMD = Age-Related Macular Degeneration; DME = Diabetic Macular Edema; BRVO = Branch Retinal Vein Occlusion 19#20W Ocuphire Current DR/DME Treatment Landscape Presented by: Peter Kaiser, MD Cleveland Clinic Cole Eye Institute Peter Kaiser, MD Harvard Medical School ● ● Chaney Family Endowed Chair in Ophthalmology Research, Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine and Cole Eye Institute Clinical research expert, serving as a Study Chairman of 5 major, multi-center, international trials, and principal investigator for numerous studies for AMD, DR, and other retinal disorders. Major contributions to medical literature having authored 7 textbooks, more than 250 peer-reviewed papers Recognized by American Academy of Ophthalmology and American Society of Retina Specialist with Senior Achievement Awards. 20#21IVT Anti-VEGF Therapies are Standard of Care for AMD/DME Anti-VEGF Therapies Over the Decades; Limited Use in DR Patients Ocuphire PHARMA 2004 Pegaptanib nAMD MÄCUGENⓇ PEGAPTANIB SODIUM INJECTION 2006 Source: Company websites Ranibizumab nAMD LUCENTISⓇ RANIBIZUMAB INJECTION 2011 Aflibercept nAMD EYLEAⓇ (aflibercept) Injection For Intravitreal Injection 2012 Ranibizumab DME LUCENTIS® RANIBIZUMAB INJECTION MOA focused on VEGF and local delivery have demonstrated efficacy for approved treatments, are the current standard of care, and have been highly effective for wAMD/DME. However, these therapies have limited use in DR 2014 Aflibercept DME EYLEA (aflibercept) Injection For Intravitreal Injection 2019 Brolucizumab- dbll AMD Beovu. (brolucizumab-dbll) Injection EYLEA (aflibercept) Injection For Intravitreal Injection LUCENTIS® RANIBIZUMAB INJECTION 2022 Faricimab- svoa nAMD/DME VABYSMO faricimab-svoa injection 6 mg $9b+ 2021 Revenue $2b+ 2021 Revenue 21#22Panorama Study Further Emphasizes Need for Proactive Treatment of NPDR Eyes Treated with Aflibercept Showed a >2-step Improvement in DRSS Level at 24 and 52 Weeks Population: Adults with severe NPDR w/o DME 225 Male; 177 Female Mean Age: 56 years (10.5) Setting: Global, Multi-Center Study Intervention: 402 Eyes randomized to 3 arms (1 eye per participant) ● IVT Aflibercept 2q16 Ocuphire PHARMA ● 2 mg monthly x 3 doses then every 8 weeks x 1 dose, followed by every 16 weeks through week 100 IVT Aflibercept 2q8 as needed 2 mg monthly x 5 doses then every 8 weeks through week 52 then as needed through week 100 Observation with sham IV injections Primary Endpoint: IVT Sham Proportion of participants with ≥2 step improvement in the DRSS scale at 24 and 52 weeks Proportion of Eyes Proportion of Eyes With ≥ 2-Step Improvement in DRSS Score From Baseline Through Week 100 (n = 133) 100% 80% 60% 40% 20% 0% 6% Sham n = 133 15% 13% 24 52 10 0 Aflibercept 2q16 n = 135 61% 65% 62% 24 52 10 Weeks 0 Aflibercept 2q8/PRN n = 134 55% 80% 50% 24 52 10 0 Brown DM, Wykoff CC, Boyer D, Heier JS, Clark WL, Emanuelli A, Higgins PM, Singer M, Weinreich DM, Yancopoulos GD, Berliner AJ, Chu K, Reed K, Cheng Y, Vitti R. Evaluation of Intravitreal Aflibercept for the Treatment of Severe Nonproliferative Diabetic Retinopathy: Results From the PANORAMA Randomized Clinical Trial. JAMA Ophthalmol. 2021 Sep 1;139(9):946-955. doi: 10.1001/jamaophthalmol.2021.2809. PMID: 34351414; PMCID: PMC8343518. 22#23AAO-Preferred Practice Pattern Reveals High Unmet Need in Mild, Moderate, and Severe NPDR Patients Unmet Need Remains High in Mild, Moderate and Severe NPDR Patients Severity of Retinopathy Normal or minimal NPDR Mild NPDR Moderate NPDR Severe NPDR Non-high-risk PDR High-risk PDR Management Recommendations for Patients with Diabetes Presence of Macular Panretinal Photocoagulation (Scatter) Laser Focal and/or Grid Laser* Edema No No NCI-DME CI-DME+ No NCI-DME CI-DME+ No NCI-DME CI-DME+ No NCI-DME CI-DME+ No NCI-DME CI-DME+ Follow-up (Months) 12 12 3-6 1* 6-12+ 3-6 1* 3-4 2-4 7 1* 3-4 2-4 1* 2-4 2-4 1* No No No No No No No Sometimes Sometimes Sometimes Sometimes Sometimes Sometimes Recommended Recommended Recommended No No Sometimes Rarely No Sometimes Rarely No Sometimes Rarely No Sometimes Sometimes No Sometimes Sometimes Intravitreal Anti- VEGF Therapy No No No Usually No Rarely Usually Sometimes Sometimes Usually Sometimes Sometimes Usually Sometimes ¹,2 Sometimes Usually Ocuphire Source: Diabetic Retinopathy Preferred Practice Pattern - AAO 2019; LTFU: Lost To Follow-up; IVT: Intravitreal Injections; PRP: Panretinal Photocoagulation PHARMA An oral option for DR strengthens treatment options across all stages Physicians have limited non-invasive treatment options 23#24Current Conventional Treatment is Challenging for Patients Access and Time Burden are Further Barriers for DR Patient Compliance Patient-Reported Barriers to Follow-Up Treatment (N = 209) Adjusted Odds Ratio (95% CI)* 1.22 (0.63-2.00) 1.91 (1.02-3.57) 4.35 (2.14-8.86) 1.15 (0.41-3.22) 1.81 (0.59-5.51) 2.14 (0.60-7.58) 0.92 (0.27-3.12) 0.70 (0.20-2.41) Reported Barriers Long waiting times Other medical or physical condition Forgot to come Unable to leave work responsibilities Other incidental obligations Lack of an escort Unhappy with previous care Financial cost * adjusted for age, gender, insurance type, severity of DR Lu AJ, et al. Analysis of patient-reported barriers to diabetic retinopathy follow-up. Ophthalmic Surg Lasers Imaging Retina. 2019;50(2):99-105. Ocuphire Prenner J et al. Am J Ophthalmol, 2015;160(4):725-731.e1. PHARMA Office Visit Time Commitments Mean: 90 min Range: 13-261 min DR patients are generally asymptomatic which contributes to poor adherence and compliance 24#25Multiple Targets in DME/DR Treatment Landscape Anti-VEGF Therapy is Mainstay, but Under/Non-Responders Remain, and Early Treatment is Limited Available Commercialized Therapies: Anti-VEGF IVT: Aflibercept (Eylea®) Ranibizumab (Lucentis®) Bevacizumab (Avastin®) Faricimab (VabysmoⓇ) Emerging therapies that could shape industry: Longer Duration IVTs Oral Therapies Extended Release Topical Combination Therapies Gene Therapies Ocuphire PHARMA IVT Steroids: Dexamethasone (OzurdexⓇ) https://www.reviewofophthalmology.com/article/a-peek-into-the-diabetic-retinopathy-pipeline I aflibercept brolucizumab Port Delivery System with ranibizumab VEGF-R1 V VEGF-R2 100001 ☐☐OPT-302 GB-102 VEGF-R3 0008 Tyrosine kinase faricimab HA-1077 Rho-kinase KVD001 THR-149 THR-687 TIE2 Receptor RGX-314 ADVM-022 Integrin Receptor lasma kallikrein 000 7 Gene Therapy 25#26Intravitreal Injections Landscape (DR patients) Eylea/Lucentis Approved, But Not Used in Patients with Mild NPDR and Mild PDR Company REGENERON Roche KODIAK EYEPOINT PHARMACEUTICALS Boehringer Ingelheim Therapeutix REGENXBIO Drug Eylea (aflibercept) Ocuphire Company websites; www.clinicaltrials.gov PHARMA Lucentis (ranibizumab) VEGF-A KSI-301 (Tarcocimab) EYP-1901 BI 764524 OTX-TKI Target/MOA RGX-314 VEGF-A/B; PIGF VEGF Voloronib (TKI) Anti-Sema3A Ischemia modulator Axitinib (TKI) AAV8-VEGF Route of Administration Intravitreal Intravitreal Intravitreal Intravitreal Intravitreal Intravitreal Suprachoroidal (Gene Therapy) ✓ Completed Phase 1 Phase 2 Phase 3 Commercial ✓ ✓ ✓ Ongoing N/A ✓*1 ✓*2 *Trials to Support Approval 1 Panorama Clinical Trial 2 Protocol I & T and Rise & Ride X Discontinued or Failed study 26#27Topical Eyedrops in Clinical Development for DR/DME Inflammation MOAS in Phase 2 with Novel Eyedrops Company Drug Oculis OCS-01 OCUTERRA THERAPEUTICS OTT 166 Ocuphire Company websites; www.clinicaltrials.gov PHARMA Target/MOA Steroid Integrin inhibitor Indication DME DR Route of Administration Eyedrop Eyedrop ✓ Completed Phase 1 Phase 2 Phase 3 Commercial ✓ ✓ Ongoing X Discontinued or Failed study 27#28Oral Treatments in Clinical Development (DR) Most Drugs Target Only Inflammation Company Lilly Ocuphire PHARMA B BAYER R OALKAHESTⓇ Roche Boehringer Ingelheim InflammX Valo REZOLUTE Drug LY333531 APX3330 BAY1101042 AKST4290 RG7774 BI 1467335 HCB 1019 (Xiflam) OPL-0401 RZ402 Company websites; www.clinicaltrials.gov Ocuphire Most Drugs Target Only Inflammation PHARMA Target/MOA Protein Kinase C inhibitor Ref-1 inhibitor (Anti-VEGF and Anti- inflammatory) Guanylate Cyclase activator CCR3 Eotaxin inhibitor CB2 receptor (cannabinoid) AOC3 Connexin 43 (inflammasome) ROCK 1/2 inhibitor Plasma Kallikrein Indication DR DR DR DR DR DR DR DR DME Route of Administration Oral ✓ Completed Oral Oral Oral Oral Oral Oral Oral Oral Phase 1 Phase 2 Phase 3 X 2006 ✓ O X 2021 ⒸOngoing X Discontinued or Failed study 28#29APX3330 is Different Than Past Oral Failures in Retina APX3330 Targets Dual, Validated Retinal Disease Pathways with Favorable Human Safety Data Phase 1 TKIs ● Phase 2 VEGF MOA Oral failed due to dose limiting organ toxicity (e.g., hepatic) Plasma Kallikrein MOA targets inflammation Oral failed due to systemic toxicity (liver, cardiovascular monitoring²) ● Iptacopan Oral Complement inhibitor for GA Safety in Ph2 PNH study: headache (31% of patients) abdominal discomfort (15%) blood alkaline phosphatase increase (15%) cough (15%), oropharyngeal pain (15%) pyrexia (raised body temperature; 15%), and upper respiratory infection (15%) Bhatwadekar 2020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265898/pdf/nihms-1594067.pdf Bryant 2009 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905712/pdf/nihms786745.pdf Ocuphire Eylea® and Lucentis label ARED & AREDS2 study PHARMA X Protein Kinase C VEGF MOA ● Phase 3 ● Phase 3 endpoint was visual acuity FDA requested more data for approval. Eli Lily did not pursue additional clinical trials Approved OTC Oral Successes Nutritional Supplements: Ocuvite®, PreserVision, EyePromise, Oral Vit C & E, Zn, Cu, Lutein, Zeaxanthin5 29#30Opportunities for New Therapies in Retina Unmet Needs in Retina Especially in NPDR New MOAs/therapies are needed to: Provide non-invasive options for early disease management Decrease in Diabetic Retinopathy Severity Score (DRSS) Ocuphire ● PHARMA ● ● ● ● ● ● ● APX3330 offers: ● Decrease in macular edema Reduce vision threatening complications (VTC) ● Improve in macular ischemia Improve compliance by longer acting drugs Manage inflammation Address non-responders A novel, dual MOA A novel and non-invasive route, where oral medication allows for early intervention 30#31Ocuphire APX3330: Paradigm Shift Oral Treatment Option Presented by: David Lally, MD NEW ENGLAND RETINA CONSULTANTS David Lally, MD Jefferson Medical College ● ● ● ● Director of the Retina Research Institute at New England Retina Consultants Retina Surgeon at Baystate Medical Center Assistant Professor of Ophthalmology at the University of Massachusetts Medical School-Baystate Published in over 25 peer-reviewed ophthalmic journals and delivered over 25 presentations at national meetings Active member of the American Society of Retina Specialists with the Fellow of the American Society of Retina Specialist (FASRS) award designation 31#32APX3330 - Novel and Dual-Acting MOA in an Oral Pill Ref-1 Involved in Multiple Key Pathways that Contribute to Diabetic Retinopathy and DME LucentisⓇ EYLEAⓇ Mechanism of Action - Ref-1 Inhibition PHARMA Hypoxia ↓ Ref-1 HIF-1a VEGF (Signaling Cascade) Anti-VEGF APX3330 Neovascularization Inflammation ↓ Ref-1 ↓ NF-kB ↓ TNF-a Chemokines Other Growth Factors (Signaling Cascade) Steroids ● • APX3330 is a small molecule oral drug candidate and a first-in-class inhibitor of Ref-1 ● Ref-1 (reduction-oxidation effector factor-1) is a novel target discovered by Dr. Mark R. Kelley at Indiana University School of Medicine ● APX3330 previously developed by Eisai for multiple hepatic inflammatory indications and later by Apexian for advanced solid tumors Similar oncology origin as approved anti-VEGFs MOA uniquely decreases both abnormal angiogenesis and inflammation by blocking pathways downstream of Ref-1 - Logsdon et al (2018), Li et al (2014). Ocuphire Rangasamy S, McGuire PG, Das A. Middle East Afr J Ophthalmol 2012;19:52-59; Sohn HJ et al. Am J Ophthalmol 2011;152:686-694. 32#33In Vitro Validation of APX3330 Mechanism of Action APX3330 Reduces VEGF levels and Inflammatory Cytokines; Provides Neuronal Protection APX3330 reduces VEGF protein expression in preclinical stroke model VEGF Control VEGF % Positive area (+SE) 2.6 1.3 0.0 Ocuphire PHARMA 0.1mm VEGF APX3330 * p<0.05 n=7/group T1DM-MCAO +APX3330 APX3330 reduces pro-inflammatory cytokines in LPS stimulated macrophages TNF-α µg/mL 14000 12000 10000 8000 6000 4000 2000 0 APX3330 LPS (1 µg/mL) 14000 12000 10000 8000 5000 4000 2000 0 Hg/mL 0 ug/mL APX3330 0 ug/mL LPS (1 µg/mL) 0 ug/mL + 25 ug/mL + Increasing APX3330 dose 6.3 ug/mL 12.5 ug/mL 25 ug/mL + + + IL-6 0 ug/mL + 6.3 ug/mL 12.5 ug/mL + APX3330 increases DNA oxidative repair and neuronal protection Percentage increase in APE1 repair activity 120 115 110 105 100 95 90 N = 4 ... 12.5 25 APX3330 (μM) 0 50 APX3330 enhances Ref-1 endonuclease activity in dorsal root ganglion neurons Tao Yan et al. APX3330 Promotes Neurorestorative effects after stroke in type one diabetic rats. Aging and Disease. Vol 9, Oct 2018 Apurinic/Apyrimidinic endonuclease 1 regulates inflammatory response in macrophages. Jedinak A, Dudhgaonkar S, Kelley MR, Sliva D. Anticancer Res. 2011 Feb;31(2):379-85. PMID: 21378315 Fehrenbacher, J. C., Guo, C., Kelley, M. R. & Vasko, M. R. DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1. Neuroscience 366, 23-35, doi:10.1016/j.neuroscience.2017.09.039 (2017). 33#34APX3330 VEGF Effects in Normal Cells APX3330 Restores Normal Levels Unlike Biologic Anti-VEGFs that Reduce VEGF Below Normal Normal Conditions: Physiological level of VEGF activity Abnormal Conditions (e.g., hypoxic): Increased level of VEGF activity Biologic anti-VEGF agents inactivate VEGF directly and reduce VEGF levels below normal levels Biologic Anti-VEGF Treatment APX3330 Anti-Ref-1 Treatment Inhibition of Ref-1 by APX3330 returns VEGF levels to normal levels APX3330 prevents VEGF overproduction in ARPE-19 cells VEGF Concentrations (% of Control) Ocuphire Kamba 2007; Girardi 2010; Li 2014; APX3330 Investigator Brochure PHARMA 500 450 400 350 300 250 200 150 100 50 0 oxLDL APX3330 ARPE-19 cell line + * p<0.05 + 150µg/mL + 30μM VEGF is a growth factor that is necessary for normal function of multiple cell types including vascular endothelium and neurons → By returning VEGF levels to normal, APX3330 can reduce neovascularization, vascular leakage and the inflammatory response without adverse systemic effects The safety profile of APX3330 to date in over 300 subjects has not shown any of the adverse effects that has been seen with systemic administration of anti-VEGF biologics such as cardiovascular pathology, hypertension, arteriothrombotic events, or renal dysfunction 34#35APX3330 Preclinical & IND-Enabling Studies Completed Over 20 Preclinical Studies with Favorable Efficacy and Safety Toxicology Studies 11 PK, Absorption, Distribution, & Excretion Studies 3 Safety Pharmacology Studies Ocuphire Extensively Evaluated in Over 20 Studies by Large Japanese Pharma Eisai PHARMA 1 Geno Tox, Repro Tox & Antigenicity Studies 6 Pharmacology Models of Retinal Disease Studies Extensively Studied in Over 20 In-Vitro and Animal Studies with Favorable Efficacy and Safety 4 35#36Preclinical Data: Oral APX3330 Blocks Neovascularization Lesion Volume Decrease with Oral APX3330 in Murine Laser CNV Model Similar to EYLEAⓇ Data L-CNV Mouse Retina Model Lesion Size and Corresponding Fluorescent Stains in L-CNV Models Treated with APX3330 at 25 mg/kg oral gavage Silva et al, 2021 Vehicle Ocuphire PHARMA APX3330 25 mg/kg 50 mg/kg Lesion Volume (µm³) APX3330 Gavage OCT Lesion Volume 8x106 6x106 4x106- 2x106- 0 **** *** -55%. Vehicle 25 50 [APX3330] (mg/kg) (a) Silva et al. ARVO 2021 Annual Meeting *Published data on EYLEA. This study was performed independently from APX3330 study and is a cross-study comparison. **Li 2014; *** Pasha 2018; **** *Jiang 2011 (Vldlr -/- Very Low-Density Lipoprotein receptor knock-out mice) Day 7 (c) Day 14 ONL RPE L-CNV Mouse Retina Model Vehicle *EYLEA Anti-VEGF164 CNV lesion volume (um³) 1.2x107- 9.0x106- -44% ✓ Efficacy was also seen after single intravitreal injection of 20 µM APX3330 in mouse L-CNV model** ✓ Efficacy was also seen after dosing intraperitoneal injection of 50 mg/kg twice daily, 5 days on/2 days off, for 2 weeks in mouse L-CNV model** *** ✓ Efficacy was also seen after single intravitreal injection of 20 µM APX3330 in Vldlr / mice model* 6.0x106- 3.0x106- 0.0 Vehicle Anti-VEGF164 36#37Summary of APX3330 Prior Clinical Trials Completed 11 Clinical Trials Across Healthy, Hepatic and Cancer Patients Ocuphire PHARMA Extensively Studied in 11 Clinical Trials across Phase 1 and Phase 2 by Eisai and Apexian Study ID APX_CLN_0001 APX_CLN_0002 APX_CLN_0003 APX_CLN_0004 APX_CLN_0008 Phase 1 Studies Phase 1 Patient Population Healthy Subjects Healthy Subjects Healthy Subjects Healthy Subjects Healthy Subjects 5 Treatment Groups APX3330, Placebo APX3330, Placebo APX3330 APX3330 APX3330, Placebo Study ID APX_CLN_0005 APX_CLN_0006 APX_CLN_0007 APX_CLN_0009 APX_CLN_0010 APX_CLN_0011 Phase 2 Studies Phase 2 Patient Population Chronic Hep Chronic Hep C Chronic Hep C Acute severe hepatitis Alcoholic hepatitis Cancer (solid tumors) 6 Treatment Groups APX3330 APX3330 APX3330, Placebo APX3330 APX3330 APX3330 37#38Plasma concentration of APX3330² 70 60 50 40 30 20 10 Phase 1 Clinical Trials: PK Data Supporting the ZETA-1 Trial APX3330 has Oral Bioavailability and a Sustained PK Profile 1 2 3 Ocuphire PHARMA MEAN+SEM O120 mg Apexian preclinical data (unpublished) APX3330 Investigator Brochure Eisai PK clinical data APX_CLN_0002 240 mg ~40 µg/ml (240 mg/day) in human plasma ~20 µg/ml (120 mg/day) in human O plasma 2 µg/ml in mouse plasma at 2hrs; 25 mg/kg oral single dose 10 11 12 13 14 15 Time[day] Favorable Oral Bioavailability Sustained Pharmacokinetic Profile Tmax 3-4 hours Linear dose-proportional PK Dose-proportional increase in Cmax/AUC exposure Half-life elimination of 45 hours (steady state [SS] 5-6 days) Meals have no clinically meaningful impact on the PK of orally administered APX3330 Sufficient APX3330 Exposure Plasma levels observed after 120 and 240 mg/day dosing is multiple times higher than what was required for efficacy in preclinical studies planned clinical dose is 600 mg/day 38#39Safety Summary From Phase 1 and Phase 2 Trials Low AES Across 11 Trials, <5% Mild Drug Related AES, Discontinuations Similar Across Arms Any event Mild or Moderate adverse Events Serious adverse events Adverse events leading to discontinuation Diarrhea/Soft Stool (mild) Integrated Overall Summary of Adverse Events in Eisai Phase 2 Studies (Hepatitis) APX3330 20-240 mg (N=236) Rash/Pruritis (mild) n (%) 40 (16.9%) 39 (16.5%) PHARMA 1 (0.4%) 10 (4.3%) Totals Across ALL Phase 1 and Phase 2 Studies (Among Healthy Subjects, Hepatitis Patients, and Oncology Patients) APX3330 Placebo 14/346 (4%) # events 52 50 14/346 (4%) Ocuphire Phase 1 and Phase 2 Clinical Trials performed by Eisai and Apexian 2 16 % = proportion of subjects relative to N, where n = number of subjects with an event and N = the number of subjects in the enrolled population. Note: This table was generated by Eisai which has slightly different event and sample size counts than the Ocuphire analysis. Ocuphire will be creating an integrated safety database. The overall conclusions between the Eisai and Ocuphire analyses are the same. 2/95 (2%) n (%) 11 (16.2%) 9 (13.2%) 1/95 (1%) 2 (2.9%) 5 (7.4%) Placebo (N=68) #events 15 13 2 7 This includes over 2078 subject-days of exposure at doses 2600mg and over 17,961 subject-days of exposure at doses <600mg. 39#40Ocuphire ZETA-1 Phase 2b Trial in Diabetic Retinopathy Presented by: David Lally, MD NEW ENGLAND RETINA CONSULTANTS David Lally, MD Jefferson Medical College 40#41ZETA-1 Phase 2b Design for DR/DME Ongoing, Randomized, Double-Masked, Placebo-Controlled 24-Week Trial (Similar To Eylea P3 DR Trial) 25 US sites 90-100 participants with moderately severe to severe NPDR or mild PDR Noncentral DME is permitted Eligibility Screening Ocuphire 1:1 PHARMA Randomization Week 0 APX3330 600 mg/day (BID) Primary Endpoint Week 4 Week 12 Enrollment of 103 DR Patients Completed (Apr 2021 to Mar 2022) Top Line Data Expected in Q4 2022 Placebo BID NPDR = non-proliferative diabetic retinopathy (which includes non centrally involved diabetic macular edema) PDR = proliferative diabetic retinopathy (which includes non centrally involved diabetic macular edema) ZETA-1 Clinical Trial is Sponsored by Ocuphire Pharma https://clinicaltrials.gov/ct2/show/NCT04692688?term=ZETA-1&draw=2&rank=1 Week 24 Endpoints Primary: % of subjects with a ≥2 step improvement on the DRSS (Diabetic Retinopathy Severity Scale) score at week 24 Secondary: Central subfield thickness (CST) BCDVA (ETDRS) ● ● ● ● ● DRSS change at week 12 Rescue subjects Safety and tolerability Exploratory: Labs / PK 41#42● ● Key Eligibility Criteria in ZETA-1 Oral Medication Provides Binocular Treatment; DME Allowed in Fellow Eye Inclusion Males or non-pregnant females ≥ 18 years of age At least one eye with DR graded at least moderately severe to severe NPDR or mild PDR (corresponding to DRSS 47, 53, or 61, confirmed by a central reading center) in which PRP and intravitreal injections of an anti-VEGF agent can be safely deferred for ≥ 6 months in the opinion of the Investigator BCVA assessed by ETDRS protocol letters score of ≥ 60 letters (Snellen equivalent 20/63 or better) in the study eye Body mass index (BMI) between 18 and 40 kg/m², inclusive Ocuphire Source: ZETA-1 trial PHARMA ● ● ● ● ● Exclusion Retinopathy from causes other than diabetes in study eye Presence of center involved diabetic macular edema (DME) defined as a central subfield thickness (CST) ≥ 320 μm on SD-OCT or the presence of intra- or subretinal fluid within the central subfield Center involved DME in the fellow eye is allowed Prior treatment in study eye with focal/grid laser photocoagulation within the past year, PRP at any time, systemic or intravitreal anti-VEGF agents within last 6 months in study eye Intraocular steroids including triamcinolone and dexamethasone implant within the last 6 months Fluocinolone implant within the last 3 years HbA1c ≥ 12.0% Clinically significant systemic disease (e.g., uncontrolled diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardio- vascular disorders) that might interfere as deemed by Investigator 42#43Why DRSS is an Important Endpoint? FDA Accepted Endpoint for EYLEAⓇ in PANORAMA Pivotal DR Trial - 2 Step Improvement on the DRSS Score Diabetic Retinopathy Severity Scale (DRSS) ► INCREASING RISK OF DEVELOPING VISION THREATENING COMPLICATIONS ► DRSS 35 Mild NPDR • Visual symptoms mostly absent • Small bulges in blood vessels and intraretinal hemorrhages ■ Ocuphire Eylea® Panorama study PHARMA DRSS 43 Moderate NPDR • May experience visual symptoms Spotted leaking of blood ● ¯¯¯¯¯¯¯¯¯¯¯ DRSS 47 Moderately Severe NPDR • May experience visual symptoms • Leaking of blood in retina, unevenly shaped veins Example of 2-step improvement DRSS 53 Severe NPDR • May experience visual symptoms Widespread leaking of blood, more unevenly shaped veins DRSS > 60 PDR • Visual symptoms are usually present • Growth of new fragile blood vessels, in some cases leading to bleeding in the retina and center of the eye ■ 43#44Ocuphire PHARMA ZETA-1 Trial: Demographics and Masked Safety Data Presented by: Caroline Baumal, MD Tufts Medical Caroline Baumal, MD University of Toronto 44#45Baseline Characteristics for ZETA-1 Trial Typical Demographics for Diabetic Population Ocuphire PHARMA Parameter Age (years): Sex: n (%) Race: n (%) BMI (kg/m²): Systolic BP (mmHg): mean (range) Heart rate (BPM): mean (range) Diastolic BP (mmHg): mean (range) Hemoglobin A1c: mean (range) Source: ZETA-1 Demographics and Baseline Characteristics mean (range) Total N = 103 56 (24-81) Male Female American Indian or Alaskan Native Asian Black or African American White Other 31 (21-40) 138 (100-180) 80 (53-109) 77 (51-96) 8.1 (5.3-12.3) 50 (49%) 53 (51%) 4 (4%) 4 (4%) 11 (11%) 81 (79%) 3 (3%) 45#46Baseline Characteristics for ZETA-1 Trial (Continued) DRSS Scores in Diabetic Study Population Ocuphire PHARMA Parameter Study Eye DRSS n(%) Fellow Eye DRSS n(%) Total N = 103 Source: ZETA-1 Demographics and Baseline Characteristics DRSS 47 (Moderately Severe NPDR) DRSS 53 (Severe NPDR) DRSS 61 (Mild PDR) DRSS 20-40 (Mild to Moderate NPDR) DRSS 47 (Moderately Severe NPDR) DRSS 53 (Severe NPDR) DRSS 61 (Mild PDR) DRSS 65-85 (Moderate to Severe PDR) Not Graded Note: 15 fellow eyes were CST>320 microns (center-involved DME eyes) 39 (38%) 53 (52%) 11 (11%) 29 (28%) 34 (33%) 22 (21%) 5 (5%) 11 (11%) 2 (2%) 46#47Baseline Characteristics for ZETA-1 Trial (Continued) Key Visual Metrics in Diabetic Study Population Ocuphire PHARMA Study Eye Screening CST (um): Parameter Fellow Eye Screening CST (um)*: Study Eye BCVA: Fellow Eye BCVA: IOP Study Eye and Fellow Eye (mmHg): Diabetic Status (Years): Study Eye with anti-VEGF injections within 6 months prior to Screening Fellow Eye with anti-VEGF injections within 6 months prior to Screening Source: ZETA-1 Demographics and Baseline Characteristics * N=102 due to a fellow eye not being graded. mean (range) mean (range) mean (range) mean (range) mean (range) mean (range) 270 (203-319) 289 (211-491) Letters Read: 80 (60-93) Letters Read: 77 (0-91) 15 (8-22) 16 (0-58) None 15 Total N = 103 Snellen Equivalent: 20/25 (20/63-20/15) Snellen Equivalent: 20/32 (20/1000-20/15) 47#48Comprehensive Laboratory Panels Collected in ZETA-1 Blood, Kidney, and Inflammatory Markers Evaluated High HbA1c Chemistry Albumin Creatinine Glucose (Random) Sodium Alanine aminotransferase (ALT) Alkaline Phosphatase Aspartate aminotransferase (AST) Blood Urea Nitrogen (BUN) Total bilirubin Total protein Ocuphire Red blood cell Glucose PHARMA Low HbA1c Test Panel Components Hematology (CBC without Differential) WBC RBC HGB (Hemoglobin) HCT (Hematocrit) Platelet Count Calcium Carbon Dioxide (Bicarbonate) Chloride IL-18- L-tra Sa Bacteria CD14 Macrophage Fibroblast SAA LIVER HDL-3 CAP PK and Biomarkers REF-1 ELISA 1 Pharmacokinetics Cell Bebris and Bacterial Lipids Bacteria. Heme-Haptoglobin Haptoglobin CRP R amichymotrypsin Cathepsin G Heme BLOCKS Cytokine Panel (Biomarker) Interleukin-1 ß (IL-1B) Interleukin-6 (IL-6) Interleukin-8 (IL-8) Tumor Necrosis Factor a (TNF-a) Kidney Function eGFR Creatinine 48#49Masked Safety Findings from Ongoing ZETA-1 Trial Favorable Safety Profile (as of 9/15/2022) Observed with 600 mg Oral Daily Doses in Diabetic Subjects 103 Subjects Enrolled 95 Subjects completed thru week 12 91 Subjects completed thru week 24 Ocuphire PHARMA 169 TEAES In 62/103 Subjects (60%) 30 Treatment-Related 18 Mild 12 Moderate¹ 0 Severe 3 withdrew due to an AE³ 6 lost to follow-up 149 Unrelated 92 Mild 48 Moderate 9 Severe 3 withdrew consent or site closure 0 Treatment- Related AEs involving liver, heart, kidney, brain, lung, or vital signs 16 SAES in 12/103 Subjects 0 Treatment Related 16 Unrelated² >7900 Subject-Days of Treatment at 600 mg/day APX3330 Exposure Oral APX3330 safety profile consistent with that seen in prior trials 1. 12 events in 8 subjects: diarrhea, worsening DME (OD and OS), pruritis, urticaria, blurry vision, decrease in hemoglobin level, ischemic diabetic maculopathy and central vision scotoma (in same subject), photophobia (OD and OS) and hypoaesthesia (in same subject) 2. Cellulitis (2 events in same subject), dyskinesia, transient ischemic event, COVID-19 and acute respiratory failure (same subject), progression of multivessel coronary artery disease, cholelithiasis, osteomyelitis, vertigo, chest pain, infection of toe and ulcer of toe and embolism (3 events in same subject), multi-system organ failure, worsening bradycardia 3. DME, Dyspnea, Pre-Syncope. Note: ZETA-1 Interim Data as of database 9/15/22 with monitoring to be completed before final database lock; assumes 50% subjects on APX3330 49#50APX3330 Product Candidate Profile for Multiple Retinal Indications Oral, First-In-Class Ref-1 Inhibitor with Favorable Human Safety Data APX3330: Well-tolerated Oral Dose up to 600 mg/day | Twice Daily Dosing Favorable Safety Profile ~10,000 Subject-exposure days* at ≥ 600 mg/day dose Expected Efficacy Data Novel MOA for treating retina ↓Inflammation ↓ Abnormal Angiogenesis Convenient Oral Dosing for Patient Compliance Allow Daily vs. Episodic Exposure Oral pill may reduce the burden of frequent anti-VEGF injections O Few Systemic Adverse Effects ~ 5% Mild Diarrhea ~ 5% Mild Skin Rash (reversible) No Treatment-Related Organ Toxicity (Liver, Cardiovascular {BP, HR}, Kidney, Neurologic, Pulmonary) No Ocular Effects No observed ocular AEs ● Ocuphire *11 completed Phase 1 and Phase 2 clinical trials by Eisai and Apexian; along with ongoing ZETA-1 trial by Ocuphire (*includes ~103 subject) PHARMA S 50#51Ocuphire PHARMA ZETA-1 Trial Design and Data Expectations 51#52APX3330 has the Potential to be First Line of Therapy for DR Patients Efficacy Signal Percent of patients on APX3330 with a ≥ 2 step improvement on the DRSS score at week 24 (and 52) compared to placebo in 2 well-controlled, multi-center clinical trials Safety Approval depends on a product's benefit outweighing its risks in the intended population - this benefit should be evaluated in multi-center, 2-year clinical trials Non-Invasive Treatment Option FDA does not require comparative arm of approved anti-VEGF injections such as Eylea for DR Ocuphire Eylea® label; APX3330 Investigator Brochure, ZETA-1 clinical trial PHARMA FDA Guidance Physician/ Patients Efficacy Signal Clinically meaningful decrease in diabetic retinopathy severity with APX3330 ● ● Safety ● Early intervention with oral may reduce progression to vision threatening DR into DME ● Non-Invasive Treatment Option Eylea, although approved, is currently not used as standard of care because of the treatment burden for asymptomatic DR patients Ability to be prescribed by all eye care doctors. Oral option increases global access, especially in underserved regions ● No major organ toxicities Well-tolerated (e.g., AEs acceptable if mild and infrequent for oral) 52#53APX3330 is Positioned to Fulfill a Significant Unmet Need in Diabetic Eye Disease Ocuphire PHARMA Favorable PK and safety data from clinical trials and overall masked safety data supports a potential oral treatment for diabetics with DR/DME Ý Dual mechanism of action may benefit inflammation from co-morbidities Oral therapeutic decreases burden of treatment (invasive intravitreal injections, time devoted to treatment, etc.) which may strengthen adherence and overall favorable outcomes mis DR/DME treatments are large attractive market opportunity Oral therapeutic can be prescribed as early treatment option for diabetic patients who may otherwise fall under the "wait and see" treatment approach Well-controlled, multi-center Phase 2b ZETA-1 for APX3330 topline results expected in 4Q22 53