RNXT US Equity☆

UNITED

STATES

SECURITIES

AND EXCHANGE COMMISSION

Washington,

D.C. 20549

FORM

10-K

Commission

File Number: 001-40738

RENOVORX,

INC.

(Exact

name of registrant as specified in its charter)

4546

El Camino Real, Suite B1, Los Altos, CA94022

(Address

of principal executive offices, including zip code)

(650)284-4433

(Registrant’s

telephone number, including area code)

Securities

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

Title of each class Trading Symbol(s) Name of each exchange on which registered

Common Stock, $0.0001 par value RNXT The Nasdaq Capital Market

Securities

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

Indicate

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

Indicate

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

Indicate

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

Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)

has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

Indicate

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

405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant

was required to submit such files). Yes ☒ No ☐

Indicate

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

company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,”

“smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If

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

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

Indicate

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

of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered

public accounting firm that prepared or issued its audit report. ☐

If

securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant

included in the filing reflect correction of an error to previously issued financial statements. ☐

Indicate

by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation

received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate

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

The

aggregate market value of the voting and non-voting common equity held by non-affiliates on June 30, 2023, the last business

day of the registrant’s most recently completed second fiscal quarter, based upon the closing price of the registrant’s common

stock on such date as reported by The Nasdaq Capital Market, was approximately $15.5 million. Shares

of voting stock held by each officer and director have been excluded in that such persons may be deemed to be affiliates. This assumption

regarding affiliate status is not necessarily a conclusive determination for other purposes.

The

number of outstanding shares of the registrant’s common stock, $0.0001 par value per share,

as of March 25, 2024, was 16,865,975.

DOCUMENTS

INCORPORATED BY REFERENCE

None.

RENOVORX,

INC. FORM 10-K

TABLE

OF CONTENTS

Page

PART I

ITEM 1. BUSINESS 1

ITEM 1A. RISK FACTORS 43

ITEM 1B. UNRESOLVED STAFF COMMENTS 84

ITEM 1C. CYBERSECURITY 84

ITEM 2. PROPERTIES 85

ITEM 3. LEGAL PROCEEDINGS 85

ITEM 4. MINE SAFETY DISCLOSURES 85

PART II

ITEM 6. [RESERVED] 86

ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 97

ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 97

ITEM 9A. CONTROLS AND PROCEDURES 97

ITEM 9B. OTHER INFORMATION 99

ITEM 9C. DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 99

PART III

ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 99

ITEM 11. EXECUTIVE COMPENSATION 107

ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 120

PART IV

ITEM 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES 121

Solely

for convenience, trademarks and trade names referred to in this Report may appear without the ® or TM symbols.

i

CAUTIONARY

NOTE REGARDING FORWARD-LOOKING STATEMENTS

This

Annual Report on Form 10-K, or Form 10-K (this “Report”), particularly

in the sections captioned “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results

of Operations” and “Business,” contains forward-looking statements within the meaning of Section 27A of the Securities

Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange

Act”), that are based on our management’s beliefs and assumptions and on information currently available to our management.

Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. All statements

other than present and historical facts and conditions contained in this Report, including statements regarding our future results of

operations and financial position, business strategy, plans and our objectives for future operations, are forward-looking statements.

In some cases, you can identify forward-looking statements by terminology such as “anticipate,” “believe,” “can,”

“continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,”

“objective,” “ongoing,” “plan,” “potential,” “predict,” “project,”

“should,” “will,” or “would,” or the negative of these terms or other comparable terminology. Actual

events or results may differ from those expressed in these forward-looking statements, and these differences may be material and adverse.

Forward-looking statements include, but are not limited to, statements about:

● our financial performance;

● our anticipated use of our existing cash, cash equivalents, and investments;

ii

● the success of competing therapies that are or may become available;

We

have based the forward-looking statements contained in this Report primarily on our current expectations and projections about future

events and trends that we believe may affect our business, financial condition, results of operations, prospects, business strategy and

financial needs. The outcome of the events described in these forward-looking statements is subject to risks, uncertainties, assumptions

and other factors described in the section titled “Risk Factors” and elsewhere in this Report. These risks are not

exhaustive. Other sections of this Report include additional factors that could adversely affect our business and financial performance.

Moreover, we operate in a very competitive and rapidly changing environment. New risks and uncertainties emerge from time to time and

it is not possible for us to predict all risks and uncertainties that could have an impact on the forward-looking statements contained

in this Report. We cannot assure you that the results, events and circumstances reflected in the forward-looking statements will be achieved

or occur, and actual results, events or circumstances could differ materially from those described in the forward-looking statements.

In light of the significant uncertainties in these forward-looking statements, you should not regard these statements as a representation

or warranty by us or any other person that we will achieve our objectives and plans in any specified time frame or at all.

In

addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These

statements are based upon information available to us as of the date of this Report, and while we believe such information forms a reasonable

basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have

conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain

and investors are cautioned not to unduly rely upon these statements.

The

forward-looking statements made in this Report relate only to events as of the date on which such statements are made. We undertake no

obligation to update any forward-looking statements after the date of this Report or to conform such statements to actual results or

revised expectations, except as required by law. Unless the context otherwise indicates, “RenovoRx,” the “Company,”

“we,” “our,” and “us” refer to RenovoRx, Inc., a Delaware corporation. All information presented

herein is based on our fiscal calendar. Unless otherwise stated, references to particular years, quarters, months or periods refer to

the Company’s fiscal years ended in December and the associated quarters, months and periods of those fiscal years.

This

Report contains market data and industry forecasts that were obtained from industry publications. These data and forecasts involve a

number of assumptions and limitations, and you are cautioned not to give undue weight to such information. We have not independently

verified any third-party information. While we believe the market position, market opportunity and market size information included in

this Report is generally reliable, such information is inherently imprecise.

iii

PART

I

ITEM

1. BUSINESS

Overview

We

are a clinical-stage biopharmaceutical company developing proprietary targeted combination therapies for high unmet medical needs with

a goal to improve therapeutic outcomes for cancer patients undergoing treatment. Our proprietary Trans-Arterial Micro-Perfusion (TAMPTM)

therapy platform is designed to ensure precise therapeutic delivery to directly target the tumor while potentially minimizing a therapy’s

toxicities versus systemic (intravenous (known as “IV”) therapy).

Our

novel and patented approach to targeted treatment offers the potential for increased safety, tolerance, and improved efficacy. Our Phase

III lead product candidate, RenovoGemTM, an oncology drug-device combination product, is being investigated under a

U.S. Investigational New Drug Application (“IND”) that is regulated by the U.S. Food and Drug Application (“FDA”)

21 CFR 312 pathway. RenovoGem is currently being evaluated for the treatment of locally advanced pancreatic cancer (“LAPC”)

by the Center for Drug Evaluation and Research (the drug division of FDA). We also plan to evaluate RenovoGem as a potential therapy

in bile duct cancer with other potential pipeline indication opportunities to follow including non-small cell lung cancer, uterine tumors,

glioblastoma, and sarcoma.

RenovoGem

received FDA Orphan Drug Designation for pancreatic cancer and bile duct cancer, which provides 7 years of market exclusivity upon approval

by the FDA of our New Drug Application (“NDA”) for RenovoGem Should such approval be obtained.

We

have completed our RR1 Phase I/II and RR2 observational registry studies of RenovoGem, with 20 and 25 patients respectively, in LAPC. These

studies demonstrated a median Overall Survival (known as “OS”) of 27.9 months in LAPC patients pre-treated with

radiation followed by treatment with RenovoGem. Based on previous large randomized clinical trials, the expected survival of LAPC

patients is 12 to 15 months in patients receiving only IV systemic chemotherapy or IV chemotherapy plus radiation (which are both

considered standard of care). Unlike the randomized trials that established these standard of care results, our RR1 and RR2 clinical

trials did not prospectively control the standard of care therapy received prior to administration of RenovoGem. Based on an FDA

safety review of our Phase I/II study, FDA allowed us to proceed to evaluate RenovoGem within our Phase III registrational clinical

trial, which is ongoing as described below.

Our

Phase III registrational trial of RenovoGem for the treatment of LAPC is called TIGeR-PaC. This clinical trial is an ongoing

randomized multi-center study using TAMP to evaluate RenovoGem. The study is evaluating trans-arterial delivery, a form of

intra-arterial (“IA”) administration, of an FDA-approved chemotherapy, gemcitabine, to treat LAPC following stereotactic

body radiation therapy (“SBRT”). The study is comparing treatment of an FDA-approved cancer drug, gemcitabine, with TAMP

versus systemic IV administration of gemcitabine and nab-paclitaxel.

Our

protocol for TIGeR-PaC involves systemic chemotherapy and only SBRT during the induction phase of the study (prior to randomization).

Patients receiving SBRT during the induction phase are required to complete 5 treatments, over 5 consecutive days, and do not receive

oral chemotherapy vs. previously utilized intensity-modulated radiation therapy (IMRT) where patients must complete 25 radiation treatments

in combination with oral chemotherapy during the induction phase of the study, which takes between 35 and 56 days to complete. In December

2021, we amended our protocol and statistical analysis plan for TIGeR-PaC (the “Modified SAP”) to (i) analyze only patients

receiving SBRT during the induction phase, (ii) include a second interim analysis, (iii) change the total number of patients randomized

in the study to 114 with a total of 86 deaths from SBRT patients, and (iv) repower the study from 90% to 80%, which is commonly used

in clinical trials. We believe this design will shorten the timeframe needed to complete the study and also significantly decrease our

costs. We have not discussed the protocol amendment or the Modified SAP with the FDA, and we cannot provide any assurance that the FDA

will agree with these modifications, but these modifications have been submitted to the FDA.

The

first interim analysis in the TIGeR-PaC study at the 26th event of the specified events (deaths), was completed in March 2023, with the

Data Monitoring Committee recommending a continuation of the study. The TIGeR-PaC study’s primary endpoint is a 6-month OS benefit

with secondary endpoints including reduced side effects versus standard of care. The data was first presented at the 2023 American Association

for Cancer Research Annual Meeting in April 2023 and then as a Late Breaker Oral Presentation with additional secondary endpoint data

at the 2023 European Society of Medical Oncology World Congress on Gastrointestinal Cancer in June 2023. The second interim analysis

for this study will be triggered by the 52nd event (death of patient), which is estimated to occur in late 2024. The second interim data

read out would follow thereafter, with the timing for such read out depending on customary factors such as time needed for analysis.

Our

TAMP therapy platform is focused on optimizing drug concentration in solid tumors using approved small molecule chemotherapeutics. Our

platform enables physicians to isolate segments of the vascular anatomy closest to tumors and force chemotherapy across the blood vessel

wall to bathe these difficult-to-reach solid tumors in chemotherapy. Specifically, our patented approach allows physicians to combine,

on the one hand, pre-treatment of the local blood vessels and tissue with standard-of-care radiation therapy to decrease chemotherapy

washout and, on the other hand, local delivery via our patented RenovoCath delivery system which utilizes pressure to force small

molecule chemotherapy into the tumor tissue. We believe there are many advantages to our TAMP therapy platform, including:

In

further validation of our TAMP platform, in July 2023, we announced a collaboration with Imugene (ASX:

IMU) to explore expansion of our TAMP product pipeline with Imugene’s CF33 oncolytic virus therapy for the treatment of

difficult-to-access tumors. We are constantly in discussions regarding similar collaborations and potentially out-licenses of RenovoGem

as we gear up for the RenovoGem NDA filing (assuming we meet our study endpoints) and commercialization of RenovoGem (if approved by

FDA) as well as other potential collaborations with our TAMP platform.

Figure

1: Graph showing first interim analysis in the TIGeR-PaC study

Research

and Development Pipeline

Our

portfolio of cancer therapies is based on our lead product candidate, RenovoGem (gemcitabine delivered via our patented delivery system),

regulated by the FDA as a novel oncology drug product. RenovoGem utilizes pressure-mediated delivery of gemcitabine across the arterial

wall to bathe tumor tissue in chemotherapy.

Funding

permitting, we plan on further evaluating RenovoGem in other cancer indications. Our current pipeline is summarized below:

Figure

2: RenovoGem Clinical Pipeline detailing our potential portfolio of cancer therapies based on our TAMP therapy platform.

Gemcitabine

has been considered a standard of care drug for several solid tumors, and the drug’s anti-cancer tumor effects are well profiled.

Our TAMP platform therapy utilizes pressure mediated delivery of gemcitabine across the arterial wall to bathe the pancreatic tumor tissue

in 120 mL of saline with 1,000 mg/m2 of the drug over a 20-minute delivery period (delivering 1,500-2,000 mg of drug depending

upon patient body surface area). Our delivery system, RenovoCath, is a double balloon catheter designed with the capability to isolate

sections of the blood vessel through the adjustment of the distance between the balloons, thereby excluding any branching blood vessel

offshoots in order to create the pressure head needed to push drug across the blood vessel wall.

We

intend to explore applications of our TAMP platform in additional indications, including bile duct cancer, locally advanced lung cancer,

locally advanced uterine cancer, and glioblastoma. We have completed and presented data on a lung cancer application in preclinical studies,

and additional preclinical experiments in lung cancer may be conducted.

We

are using gemcitabine in our initial anti-cancer product candidate, RenovoGem. However, multiple small molecule therapeutics are compatible

with our TAMP platform. We intend to opportunistically develop additional anti-cancer product candidates using small molecule therapeutics

in combination with our therapy platform.

While

the field of oncology has seen progress in treating a handful of deadly cancers over the last few decades, there is a common

objective in chemotherapy: enhanced dosing of the drug to impact the tumor while minimizing systemic toxicity. The characteristics

of the blood vessels, within and surrounding the tumor, can limit or thwart the achievement of this goal. For example, LAPC and bile

duct cancer, known as extrahepatic (or outside the liver) cholangiocarcinoma (“eCCA”) are more difficult to treat due to

the lack of blood vessels that feed these tumors, making it difficult to expose tumors to chemotherapy, which is typically delivered

intravenously. Trans-arterial chemoembolization (“TACE”) is an established first line therapy for solid tumors. A key

component of this approach is to identify and isolate vessels feeding the tumor, known as tumor feeder blood vessels. However, in

patients with pancreatic cancer, no tumor feeder blood vessels are visible despite attempts to image them using a variety of

modalities. In the absence of visible tumor feeder blood vessels, our therapy platform has the potential to introduce drugs directly

across the arterial wall into the surrounding tissue via pressurized diffusion.

RenovoGem

in Locally Advanced Pancreatic Cancer (LAPC)

Our

protocol for the TIGeR-PaC clinical trial involves systemic chemotherapy and only SBRT during the

induction phase of the study (prior to randomization). Patients receiving SBRT during the induction phase are required to complete 5

treatments, over 5 consecutive days, and do not receive oral chemotherapy vs. previously utilized intensity-modulated radiation therapy

(“IMRT”) where patients must complete 25 radiation treatments in combination with oral chemotherapy during the induction phase of the study,

which takes between 35 and 56 days to complete. In December 2021, we amended the protocol as follows: we plan to (i) analyze only patients

receiving SBRT during the induction phase, (ii) include a second interim analysis, (iii) change the total number of patients randomized

in the study to 114 with a total of 86 deaths from SBRT patients, and (iv) repower the study from 90% to 80%, which is commonly used

in clinical trials. We believe this design will shorten the timeframe needed to complete the study and also significantly decrease our

costs. We have not discussed the protocol amendment or the Modified SAP with the FDA, and we cannot provide any assurance that the FDA

will agree with these modifications, but these modifications have been submitted to the FDA.

The

first interim analysis in the TIGeR-PaC study at the 26th event of the specified events (deaths), was completed in March 2023, with the

Data Monitoring Committee recommending a continuation of the study. The TIGeR-PaC study’s primary endpoint is a 6-month OS benefit

with secondary endpoints including reduced side effects versus standard of care. The data was first presented at the 2023 American Association

for Cancer Research Annual Meeting in April 2023 and then as a Late Breaker Oral Presentation with additional secondary endpoint data

at the 2023 European Society of Medical Oncology World Congress on Gastrointestinal Cancer in June 2023. The second interim analysis

for this study is expected to occur at the 52nd event which is estimated to occur in late 2024.

RenovoGem

in eCCA and Other Potential Clinical Indications

Funding

permitting, we also plan to evaluate RenovoGem as a potential therapy in bile duct cancer with other potential pipeline indication opportunities

to follow including non-small cell lung cancer, uterine tumors, glioblastoma, and sarcoma.

After

significant input from key opinion leaders across the spectrum of relevant medical specialties and feedback from the FDA, we submitted

the protocol for a Phase II/III eCCA clinical trial to FDA, and after receiving feedback, we are finalizing the protocol and also including

incorporating a recently approved drug, durvalumab into the study protocol with guidance from the Steering Committee. We anticipate launching

this study mid-2024. We have also secured FDA Orphan Drug Designation for RenovoGem for the treatment of cholangiocarcinoma, which would

provide us with seven years of orphan exclusivity to market RenovoGem for our eCCA indication upon NDA approval, provided that we are

the first sponsor to obtain FDA approval for IA gemcitabine for the eCCA indication.

Our

Team

Our

management team, Board of Directors, and Scientific Advisors provide us with expertise across multiple sectors to drive success through

clinical development and subsequent commercialization of our novel therapy platform. Our Chief Executive Officer, Shaun Bagai, gained

extensive experience running clinical trials and launching, creating, and developing new markets for novel therapies at TransVascular,

Medtronic, Ardian, and HeartFlow. Dr. Ramtin Agah, our Co-Founder and Chief Medical Officer, is a practicing cardiovascular specialist

who has 20 years of research experience in vascular biology and disease in both academia and industry. Leesa Gentry, our Chief Clinical Officer, with 29 years of experience focused

on improving clinical research programs in Contract Research Organization (CRO), pharmaceutical, and biotech industries. Past employers

include IQVIA (Quintiles), PPD, OmnicareCR and Otsuka. Prior to RenovoRx, she was Senior Vice President (SVP) of Clinical Operations at

Evotec. Our Board of Directors includes

a wide range of public and private company management, board and life sciences experience, including drug/device combination and oncology

experience. Clinical advisors include experts across many specialties who treat solid tumors. Dr. Margaret Tempero is Professor of Medicine,

Division of Hematology and Oncology, at UCSF. She also serves as Chair of the NCCN Guidelines Panel on Pancreatic Cancer (since 2000),

editor-in-chief of JNCCN, and on the ASCO Conquer Cancer Foundation Board. Previously, Dr. Tempero has served on the ASCO Board of Directors,

as ASCO President, and as a member of FDA’s Oncology Drug Advisory Committee. Dr. Michel Ducreux is the Head of the Gastrointestinal

Oncology Unit and Gastrointestinal Oncology Tumor Board at Gustave Roussy, Professor of Oncology at Paris-Saclay University in France,

and Vice-Chair of ESMO GI. Dr. Michael Pishvaian, a medical oncologist, has extensive experience running oncology studies and is an Associate

Professor, and Director of the Gastrointestinal, Developmental Therapeutics, and Clinical Research Programs at the NCR Kimmel Cancer

Center at Sibley Memorial Hospital Johns Hopkins University School of Medicine. Dr. Pishvaian is the Principal Investigator / Global

Study Chair of our TIGeR-PaC Phase III study. Dr. Karyn Goodman serves as the Radiation Monitor for our TIGeR-PaC Phase III study and

Professor and Vice Chair of Clinical Research, Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai, and Associate

Director of Clinical Research at the Tisch Cancer Institute at Mount Sinai.

Current

Treatments and Limitations of Approaches

Currently, solid tumors are typically treated using one or a combination

of treatment modalities: surgery, radiation, and pharmacological therapies (chemotherapy). For solid tumors, when possible, surgical resection

of the tumor is the most frequently employed treatment approach. If the tumor is detected at an early stage and is localized to the affected

organ, surgical removal of the entire tumor may be an effective and potentially curative treatment. In most cases, surgery is undertaken

and / or completed prior to commencing additional treatment approaches. However, multiple solid tumor types, including LAPC and eCCA are

diagnosed at advanced stages, which precludes surgery as a treatment approach. In many of these circumstances, the tumor has grown into

adjacent anatomical structures making surgery difficult or impossible.

IV,

also known as systemic, chemotherapy (gemcitabine and nab-paclitaxel), which has a seven-week survival benefit over IV gemcitabine alone,

is considered standard of care for most solid tumors, but limitations include less than acceptable efficacy, systemic toxicities, and

other side effects.

For

the treatment of some localized solid tumors, TACE is an established first line therapy. Many companies have developed therapeutic products

for use in this approach to treat tumors of the liver, uterus, and prostate. Many solid tumors have a dedicated blood supply: small blood

vessels, called tumor feeder blood vessels, that branch off of larger native arteries and terminate in the tumors to provide nutrition

to the tumors. A key aspect of TACE is to identify and isolate these tumor feeder blood vessels during x-ray angiography and then deliver

the desired therapy including chemotherapy and embolic agents. In patients with LAPC, no tumor feeder blood vessels are visible during

angiography due to the avascular (lack of blood vessels) nature of these tumors. This limitation has rendered TACE ineffective in the

treatment of patients with LAPC, eCCA, and a subset of other solid tumors. The limitations of TACE translate to low survival rates in

these tumor subtypes. The use of TACE with or without immuno-oncology treatment approaches, which harness the body’s immune system

to treat cancer, has not significantly improved survival rates in these subtypes. For example, due to the inability of immune cells to

penetrate the tumor tissue, early studies of targeted immunotherapies in pancreatic cancer have demonstrated limited success.

Our

Platform: TAMP

TAMP

may work best with avascular tumors

Certain

tumor types are sufficiently vascularized (i.e., tumors with blood vessels associated with them) to enable use of systemic chemotherapy

and standard of care local therapy techniques. In Figure 3 below, for example, the panel on the left depicts visualization of an actual

tumor, hepatocellular carcinoma (“HCC”), or primary liver cancer, under x-ray angiography as dye injected through the arteries

reaches the tumor itself. Further, visible tumor feeder blood vessels can be reached by simple end-hole catheters to deliver targeted

therapy to these liver tumors. In contrast, the panel on the right illustrates the typical lack of tumor feeder blood vessels to a pancreatic

tumor. Given the lack of tumor feeder blood vessels, the dye does not reach the tumor, rendering the tumor “invisible” under

x-ray angiography.

Figure

3: Showing liver tumors that are highly vascularized, and pancreatic tumors that are avascular.

TAMP

has been under development for over 14 years

In

2009, our founder Dr. Ramtin Agah, an experienced interventional cardiologist with a degree in biomedical engineering, developed the

concept for TAMP as a way to deliver chemotherapy locally to treat poorly vascularized tumors. He joined forces with Kamran Najmabadi,

who brought significant medical device engineering experience, to found RenovoRx in 2009. Subsequently, we engaged a contract manufacturer

to prototype and manufacture our RenovoCath delivery devices. We received our first FDA 510(k) clearance for RenovoCath in 2014, a second

clearance to use the RenovoCath for infusion of chemotherapy agents in 2017, a further clearance to use RenovoCath with a power-injector

in 2019, and a fourth clearance in 2021 to expand vessel diameter range to 3-11mm, implement certain changes in the Instructions for

Use, change the recommended saline to contrast solution ratio, among other changes and improvements. RenovoCath is intended for the isolation

of blood flow and delivery of fluids, including diagnostic and/or therapeutic agents, to selected sites in the peripheral vascular system.

RenovoCath is also indicated for temporary vessel occlusion in applications including arteriography, preoperative occlusion, and chemotherapeutic

drug infusion. RenovoCath is intended for general intravascular use in the peripheral vasculature in arteries 3 mm and larger as well

as for use in arteries from 3 mm in diameter for vessel entry and to occlude vessels ranging between 3 mm to 11 mm in diameter. We are

evaluating our lead product candidate RenovoGem under an IND filed in 2018. FDA has determined that RenovoGem will be regulated as, and

if approved we expect will be reimbursed as, a new oncology drug product.

How

it works: we developed TAMP as an attempt to solve the problems of treating avascular tumors

To

overcome the limitations resulting from a lack of tumor feeder blood vessels, we explored a different approach to locally deliver anti-cancer

drugs. By isolating a section of the blood vessel and then increasing the intravascular pressure in the isolated segment, we can introduce

chemotherapy directly across the arterial wall into the surrounding tissue via pressurized diffusion, which we call Trans-Arterial Micro-Perfusion

(for the acronym TAMP). To isolate the vessel and create this pressure gradient, we developed RenovoCath, a patented adjustable double

balloon catheter to occlude the proximal and distal part of the vessel. Using the TAMP technique in explanted (dissected out of the animal

and used separately in a saline water bath) pig aorta and iliac arteries (peripheral arteries that carry blood to the legs, reproductive

organs and pelvis), we were able to validate our hypothesis by demonstrating >99% gemcitabine pressurized diffusion across the arterial

wall in the absence of feeder vessels. This mechanism of action was further supported by exploratory acute animal studies measuring the

pressure gradient within the artery during double balloon occlusion. Figure 4 demonstrates the change in IA pressure over

time from catheter introduction to balloon inflation, start of infusion, and pressure plateau when chemotherapy is forced out of vessel.

These changes in pressure are a result of pressure declining as the first balloon blocks blood inflow and then rising as the drug is

administered and fills up the space between the balloons.

Figure

4: Occluding the vessel with RenovoCath, while adjusting the balloon-to-balloon distance to exclude all blood vessel branches, established

an intravascular interstitial pressure in the isolated blood vessel segment of approximately 20 mmHg. With subsequent infusion of fluids

between the balloons at 6 mls/minute, the intravascular pressure increases to above 45 mmHg, trans-arterially forcing the small molecule

drug across the arterial wall via diffusion (this patented process of perfusing the vessel wall is Trans Arterial Micro Perfusion or

TAMP).

Our

TAMP platform therapy utilizes pressure mediated delivery of gemcitabine across the arterial wall to bathe the pancreatic tumor tissue

in 120 mL of saline with 1,000 mg/m2 of drug over a 20-minute delivery period (delivering 1,500 - 2,000 mg of drug depending

upon patient body surface area. This blanketing approach of large fluid volume delivery over time may enable the drug to approach these

difficult-to-reach tumors.

We

believe some of the key advantages of TAMP include:

● High local concentration of drug into the tumor tissue

Developing

a therapeutic platform using an adjustable two-balloon catheter and IA gemcitabine

By

isolating the vessel adjacent to the tumor and creating a pressure gradient across the arterial wall between the isolated vessel segment

and the surrounding tissue or tumor, we are able to force the small molecule chemotherapy across the vessel directly into surrounding

tissue or tumor. To accomplish this, we needed a minimally invasive technique to isolate the blood vessel next to the tumor, exclude

any branches that can cause washout of chemotherapy away from the target, and then infuse the chemotherapy into the isolated segment

to achieve pressure mediated diffusion through the vessel wall and into the tumor tissue. We accomplished this with our patented RenovoCath

delivery system. RenovoCath is a double balloon catheter designed with the capability to isolate the proximal and distal sections of

the vessel through the adjustment of the distance between the balloons, thereby excluding any branching blood vessel offshoots. Using

standard interventional techniques, an interventional radiologist inserts the RenovoCath delivery system into the body through the femoral

artery and positions it in the artery closest to the tumor. Once the balloons are inflated and the position is confirmed, chemotherapy

is delivered through the handle, exiting the device between the balloons. It is forced through the vessel wall into the tissue over a

20-minute period. The RenovoCath delivery system is depicted below in Figure 5.

Figure

5: RenovoCath delivery system illustrating two balloon configuration to isolate the target vessel segment, and chemotherapy delivery

port and exit hole.

After

the procedure is complete, RenovoCath is discarded, and the patient is generally discharged the same day. On average, the entire procedure

takes approximately 90 minutes. According to the TIGeR-PaC study protocol, IA treatment is administered through RenovoCath

every other week for a maximum of 8 treatments for approximately 16 weeks. Interventional radiologists using the device are typically

proctored for their first 2-3 cases only. In addition, platform training for our primary indication should transfer to other indications.

RenovoGem

for LAPC

Disease

Overview

Pancreatic

cancer is one of the deadliest cancers in the U.S. with very poor outcomes. According to American Cancer Society’s Cancer Facts

& Figures 2023, pancreatic cancer has a 5-year combined overall survival rate of 12% (Stages I-IV) and is on track to be the second

leading cause of cancer-related deaths before 2030. LAPC is diagnosed when the disease has not spread far beyond pancreas, however, has

advanced to the point where it cannot be surgically removed. LAPC is typically associated with patients in stage 3 of the disease as

determined by the TNM (tumor, nodes and metastasis) grading system.

Current

Treatment Landscape and Limitations

Pancreatic

cancer has limited treatment options including one or a combination of surgery, radiation, chemotherapy, and/or some targeted therapies.

Only a small subset of pancreatic cancer patients is eligible for surgery (“Resectable” at the time of presentation (Stage

I-II: 15%); the rest are distributed between having tumors with unresectable LAPC (Stage III: 30%) and metastatic pancreatic cancer (Stage

IV: 50%).

Chemotherapy

is at the forefront of systemic therapy for cancer. It can be used in the neoadjuvant (before surgery) setting to attempt to decrease

tumor size in resectable or borderline resectable patients, in the adjuvant (after surgery) setting, or first line in the metastatic/advanced

setting. The backbone of our first product candidate, gemcitabine, is a nucleoside metabolic inhibitor that exhibits antitumor activity

by blocking the synthesis of new DNA, which results in cell death. Gemcitabine administered as an IV infusion has an established

role in the treatment of both unresectable LAPC and metastatic pancreatic cancer. Since its introduction in the US as Gemzar® (gemcitabine

for injection) in 1996 with an FDA approved indication as such, it remains in the guidelines as standard of care. It has been demonstrated

to provide clinical benefit for subjects (decreased pain and improved performance status) as well as to improve the time to tumor progression

and survival for subjects with metastatic pancreatic cancer and LAPC. However, major improvement in the survival curve of all pancreatic

cancer subjects has been a clinical challenge, with an average median survival time for LAPC stalled at 12-15 months from time of diagnosis.

A

key limitation of conventional chemotherapy in these tumors can be attributed to their avascular nature and desmoplasia (fibrosis or

the growth of scar tissue) that impedes drug delivery. Pancreatic tumor cells have a thick and poorly perfused stroma, or connective

tissue, and high interstitial pressure. This can potentially constrict blood vessels leading to an avascular or hypovascular environment

that impedes chemotherapy from reaching tumor cells in high enough volume, rendering them relatively resistant to chemotherapy.

In

patients with metastatic disease, two chemotherapy combination regimens have shown superiority to gemcitabine, albeit with increased

toxicity. First, the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) in a relatively young cohort of

metastatic pancreatic cancer patients appears superior to gemcitabine by improving survival from 6.8 to 11.1 months. Second, in the Metastatic

Pancreatic Adenocarcinoma Clinical Trial (MPACT) trial, the combination of gemcitabine plus nab-paclitaxel (Abraxane) demonstrated an

OS benefit of 9 weeks versus gemcitabine alone at the cost of increased toxicity.

A

major focus of clinicians is determining the optimal method to treat patients with LAPC, patients with localized disease who are not

surgical candidates, roughly 30% of all pancreatic cancer patients. IV, or systemic, administration of chemotherapy has yielded unsatisfactory

results in these patients. Various localized treatments have included high dose local radiation, direct attempts at local injection of

drugs, and use of adenoviral vectors to deliver toxic agents. These treatment options demonstrated limited success in the treatment of

LAPC. The lack of successful treatment options represents a recognized unmet medical need for these patients.

Standard

of care chemotherapy for the treatment of pancreatic cancer has historically shifted a couple of times with the addition of erlotinib

to gemcitabine 15 years ago resulting in a 14-day survival benefit. In 2013, the addition of Abraxane to gemcitabine was approved, with

immediate deep market penetration based on an 8-week survival benefit despite higher systemic drug toxicities.

Our

Solution

We

believe that our product candidate, RenovoGem, has the potential to address the recognized unmet medical need. Utilizing our patented

TAMP therapy platform, we believe RenovoGem can enhance local drug concentration, thereby increasing efficacy and decreasing systemic

exposure and toxicity to improve patient outcomes. RenovoGem is a drug/device combination product candidate consisting of IA

gemcitabine and our proprietary RenovoCath delivery system which forces the anti-cancer drug into the tumor. RenovoGem is regulated by

the FDA as a new oncology drug product. While we may explore commercial opportunities to sell RenovoCath as a standalone catheter, our

main focus currently is to sell RenovoCath in combination with IA gemcitabine (as RenovoGem) or potentially with other therapeutic

agents.

Based

on primary market research and analysis of the U.S. market sponsored by us and conducted by third parties, we believe that over 5,000

patients per year would be excellent candidates and undergo RenovoGem treatment if and once it is approved in the U.S. The independent

oncologists interviewed stated their dissatisfaction with current standard of care and the strong desire for a therapy like ours to extend

potential survival while maintaining quality of life. Further, the analysis suggests, based on analogous oncology drugs with only a modest

efficacy benefit, a novel drug can expect 50-80%+ penetration in a first line setting. The results of the Key Opinion Leader, or

KOL interviews revealed that a majority of oncologists would refer 90%+ of their LAPC patients who are eligible for the procedure for

TAMP if the current Phase III trial demonstrates at least a 4-month survival benefit over systemic chemotherapy. As of March 8, 2023,

we announced interim analysis results of the study suggesting a 6-month potential improvement in median overall survival with RenovoGem,

pending ongoing clinical investigation. We believe this first-of-two interim analyses indicates that the TIGeR-PaC study is on track

to demonstrate increased lifespan for patients being treated with RenovoGem for LAPC.

Figure

6: We invented a new therapy platform, TAMP, that uses pressure to force small molecule chemotherapeutics across the vessel wall into

the surrounding tissue using our patented RenovoCath delivery system. Our first product candidate, RenovoGem, is a drug/device combination

of IA gemcitabine and the RenovoCath delivery system, and is under development for LAPC and eCCA. We have secured Orphan

Drug Designations for RenovoGem for the treatment of both pancreatic cancer and cholangiocarcinoma.

Clinical

Development of RenovoGem in LAPC

Preclinical

Studies and Data

Once

RenovoCath is introduced via standard interventional technique to the arterial vessel segment next to the targeted tissue, both balloons

are inflated, and the vessel segment is isolated from the rest of the circulatory system. With inflation of balloons, the pressure is

observed to drop within the vessel. However, with infusion of fluids between the balloons, the intravascular pressure increases beyond

45 mmHg until plateauing, generating a gradient and trans-arterially forcing the infusate across the arterial wall via diffusion or Trans-Arterial

Micro-Perfusion (i.e., TAMP). A key aspect of this approach is to adjust the distance between the balloons to exclude any side blood

vessel branches in the isolated segment to allow the increase in pressure gradient, rather than drug washout via the side branches. Figure

7 shows a comparison, in an animal study, between proper balloon positioning with no side branches, allowing maximum drug to cross the

arterial wall, versus improper balloon positioning to include side branches, resulting in drug washing out via the side branches.

Figure

7: Top panel demonstrates proper balloon positioning with no side branch. Pressure increases with infusion and reaches a plateau of approximately

75 mmHg higher than initial pressure. Bottom panel demonstrates improper balloon positioning with side branch between the balloons. Pressure

increases with infusion and reaches a plateau of approximately only 15mmHg higher than initial pressure.

With

diffusion of fluids across the arterial wall in TAMP, we expected to be able to deliver small molecules into the surrounding tissue.

We performed the following studies to validate this hypothesis:

In

explanted (dissected out of the animal and used separately in a saline water bath) pig iliac and aortic artery, with the introduction

of RenovoCath and infusion of gemcitabine in the isolated vessel segment, we were able to measure (in a time dependent fashion) the amount

of gemcitabine crossing the arterial wall into the surrounding fluid. We isolated the arterial vessel segment using RenovoCath and then

delivered 60 mg/minute of gemcitabine into the isolated area over 20 minutes. By the end of the infusion, we measured 1,188 mg of gemcitabine

in the surrounding fluid around the vessel and 9 mg in the analyzed tissue of the vessel. This demonstrated that 99% of the drug crosses

the arterial wall and only 0.75% is retained in the arterial tissue (Figure 8).

Figure

8: TAMP: delivery of chemotherapy through the RenovoCath and into the tissue to bathe the tumor in chemotherapy. In a preclinical study

using gemcitabine, 99% of the drug crosses the arterial wall and less than 0.75% is retained in the vessel wall tissue.

Six

pigs were treated with gemcitabine via TAMP (6 mL/min for 20 minutes). Target vessels included selection of the superficial femoral artery

(SFA) and splenic arteries from each animal (either test or saline control). A total of 6 vessels (3 SFA and 3 splenic arteries) were

treated with an equal number of control vessels. All animals survived the 7-day in-life period although two of the animals with gemcitabine

treatment in the splenic artery experienced atypical pain during the post-operative phase and required additional pain management with

eventual complete recovery.

Analysis

of the vessels demonstrated preserved vessel shape with intact endothelial cells (cells on the inside of the vessels). Minimal to no

inflammation was observed. The only vessel toxicity observed was a reduction of smooth muscles cells in the vessel wall, primarily close

to the inside of the vessel.

3) In preclinical studies, TAMP achieved targeted local drug (dye) delivery.

I.

Targeted small molecule delivery (dye) into pancreatic tissue

We

further validated our approach for tissue drug delivery using acute animal experiments. Using both dye and gemcitabine infusion via the

TAMP therapy, we were able to demonstrate that fully isolating a segment of a vessel (by blocking inflow and outflow in the target vessel

as well as side branches with the RenovoCath double balloons) can lead to dye penetration greater than 4.0 cm from the vessel wall and

drug tissue concentration (gemcitabine) up to 100-fold greater than systemic administration.

In

an acute pig experiment, RenovoCath was introduced into the gastro-duodenal artery (GDA), a side branch was excluded (using small implants

that block the artery, coils), and then dye was introduced at 6mls/minute over 2 minutes. Analysis demonstrated that the blue dye diffused

covered approximately 10.56 cm2 (2.2 cm x 4.8 cm) of the pancreas.

Figure

9: RenovoCath was introduced into the GDA and a side branch was excluded by coiling. This test was conducted in an acute porcine model

and demonstrated a dye coverage area of approximately 10.56 cm2 for a 2-minute dye infusion. All dimensions in above figure

are in cm.

The

study was repeated in 6 other vessel targets to validate the impact of vessel isolation on dye penetration into the surrounding tissue

with similar results.

II.

Small molecule delivery (dye and gemcitabine) locally into lung tissue

In

another set of acute animal experiments, the pulmonary artery was isolated via access through the internal jugular vein. Six ml of methylene

blue dye was injected over 1 min and gemcitabine was subsequently delivered locally at rate of 6 mls/minute for 20 minutes to the lung

tissue using the TAMP procedure.

Dense

dye staining localized to the area of the isolated vessel segment was observed. Again, analysis established penetration into surrounding

tissue (4 cm). Furthermore, TAMP achieved greater than 100-fold tissue concentration of gemcitabine versus the tissue level achieved

by IV (systemic) delivery of gemcitabine at the same infusion rate.

Figure

10: Dense dye staining localized to the area of the isolated pulmonary artery segment and penetrating 4 cm into surrounding tissue following

1 minute dye infusion. In addition, gemcitabine was delivered via TAMP for 20 minutes demonstrating 100-fold increase in tissue concentration

of gemcitabine compared to IV delivery of gemcitabine at the same infusion rate.

We

concluded that TAMP can achieve drug penetration into the surrounding tissue and can achieve high dose concentrations in local tissue.

The tissue concentration with IV and/or distant from TAMP site (likely after recirculation through systemic system)

were two orders of magnitude lower than tissue levels achieved with TAMP (p<0.02).

Figure

11: Local tissue concentration of gemcitabine. control (Blue): Intravenous infusion versus TAMP (Orange): TAMP: IA infusion.

The tissue concentration with intravenous infusion and/or distant from TAMP site (likely after recirculation through systemic system)

are 100-fold lower than tissue levels achieved with TAMP.

This

animal lung study successfully validated the ability of RenovoCath to deliver small molecules locally and effectively to lung tissue.

III.

Based on the results of preclinical studies, increase in local tissue delivery of gemcitabine in LAPC may enhance tumor reduction and

therapeutic response

In

relevant mouse models of pancreatic tumors, it has been demonstrated that targeted IA infusion of gemcitabine into the pancreas after

surgical isolation of arterial blood flow has a superior therapeutic effect with greater reduction in tumor volume compared to the same

concentration administered by conventional IV injection. To achieve a comparable reduction in tumor growth as seen with IA treatment,

gemcitabine had to be given intravenously at over 300 times the dose which was associated with increased toxicity.

TAMP

and Radiation

Traditionally

the goal of radiation includes debulking the tumor and/or acting as a chemo-sensitizer. In our RR1 dose escalation safety study and RR2

observational registry study, the benefit of TAMP appeared to be enhanced in patients with prior radiation. As we were observing this

effect months after radiation and although several randomized studies have not demonstrated a benefit of chemotherapy plus radiation

versus chemotherapy alone, we hypothesized that a direct effect of radiation on the vasculature may be enhancing the effect of TAMP.

One of the side effects of radiation is a decrease in the micro-vasculature in the irradiated tissue including the small blood vessels

that exist in the vessel walls themselves. Therefore, we postulated that by eliminating microvasculature in and around the vessel wall,

radiation may enhance drug penetration into the tissue via TAMP (Figure 12). As such, a possible enhancing effect of radiation on TAMP

may involve decreasing washout of the drug as it crosses the arterial wall by preventing draining into the surrounding microvasculature.

We

completed a pig study where we observed the impact of TAMP in recruiting the vasa vasorum (small blood vessels within the larger blood

vessel walls) around the vessel during drug/dye infusion. It was discovered that the dye drained into the vasa vasorum and other small

vessels in the adjacent tissue (Figure 12); as these vessels can directly connect to the adjacent venous system, the microvascular networks