UNITED STATES
SECURITIES AND EXCHANGE
COMMISSION
Washington, D.C. 20549
FORM 10-K
☒ANNUAL
REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended
December 31, 2022
☐TRANSITION
REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the transition period
from ________ to _________
Commission file number 001-40582
UNICYCIVE THERAPEUTICS,
INC.
(Exact name of registrant
as specified in its charter)
(Address of principal executive offices) (Zip Code)
Registrant’s telephone
number, including area code: (650)351-4495
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, par value $0.001 per share UNCY The Nasdaq Stock Market, LLC
Securities registered pursuant to section 12(g) of the Act: None.
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐No☒
Indicate by check mark if the registrant is not
required to file reports pursuant to Section 13 or 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 filter ☐ Accelerated filter ☐
Non-accelerated filter ☒ 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 the correction of an error to previously issued financial statements. ☐
Indicate by check mark
whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by
any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark whether the registrant
is a shell company (as defined by Rule 12b-2 of the Act). Yes ☐No☒
The aggregate market value of the voting stock
and non-voting common equity held by non-affiliates of the registrant as of the last business day of the registrant’s most recently
completed second fiscal quarter ended June 30, 2022 was $12,486,933 based upon the closing price of the registrant’s common
stock of $0.83 on The Nasdaq Capital Market as of that date.
The number of shares of common stock outstanding
as of March 30, 2023 was 15,233,836.
DOCUMENTS INCORPORATED BY REFERENCE
Specified portions of the registrant’s
proxy statement, which will be filed with the Securities and Exchange Commission pursuant to Schedule 14A in connection with the registrant’s
2023 Annual Meeting of Stockholders (the “Proxy Statement”), are incorporated by reference into Part III of this Annual Report
on Form 10-K. Except with respect to information specifically incorporated by reference in this Annual Report, the Proxy Statement is
not deemed to be filed as part hereof.
Table of Contents
Page
Part I 1
Item 1. Business 1
Item 1A. Risk Factors 33
Item 1B. Unresolved Staff Comments 61
Item 2. Properties 61
Item 3. Legal Proceedings 61
Item 4. Mine Safety Disclosures 61
Item 6. [Reserved] 62
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 71
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 72
Item 9B. Other Information 73
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 73
Part III 74
Item 10. Directors, Executive Officers and Corporate Governance 74
Item 11. Executive Compensation 74
Item 14. Principal Accountant Fees and Services 74
Item 15. Exhibit and Financial Statement Schedules 75
Signatures 77
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CAUTIONARY NOTE ON FORWARD-LOOKING STATEMENTS
This Annual Report on
Form 10-K contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of the Securities
Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange
Act”). These statements may be identified by such forward-looking terminology as “may,” “should,” “expects,”
“intends,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,”
“potential,” “continue” or the negative of these terms or other comparable terminology. Our forward-looking statements
are based on a series of expectations, assumptions, estimates and projections about our company, are not guarantees of future results
or performance and involve substantial risks and uncertainty. We may not actually achieve the plans, intentions or expectations disclosed
in these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed
in these forward-looking statements. Our business and our forward-looking statements involve substantial known and unknown risks and
uncertainties, including the risks and uncertainties inherent in our statements regarding:
● our projected financial position and estimated cash burn rate;
● our estimates regarding expenses, future revenues and capital requirements;
● our ability to continue as a going concern;
● our need to raise substantial additional capital to fund our operation;
● the success, cost and timing of our clinical trials;
● our dependence on third parties in the conduct of our clinical trials;
● the results of market research conducted by us or others;
-ii-
● our reliance on third-party suppliers and manufacturers;
● the success of competing therapies and products that are or become available;
All of our forward-looking statements are as
of the date of this Annual Report on Form 10-K only. In each case, actual results may differ materially from such forward-looking information.
We can give no assurance that such expectations or forward-looking statements will prove to be correct. An occurrence of, or any material
adverse change in, one or more of the risk factors or risks and uncertainties referred to in this Annual Report on Form 10-K or included
in our other public disclosures or our other periodic reports or other documents or filings filed with or furnished to the U.S. Securities
and Exchange Commission (the “SEC”) could materially and adversely affect our business, prospects, financial condition and
results of operations. Except as required by law, we do not undertake or plan to update or revise any such forward-looking statements
to reflect actual results, changes in plans, assumptions, estimates or projections or other circumstances affecting such forward-looking
statements occurring after the date of this Annual Report on Form 10-K, even if such results, changes or circumstances make it clear
that any forward-looking information will not be realized. Any public statements or disclosures by us following this Annual Report on
Form 10-K that modify or impact any of the forward-looking statements contained in this Annual Report on Form 10-K will be deemed to
modify or supersede such statements in this Annual Report on Form 10-K.
This Annual Report on Form 10-K may include market
data and certain industry data and forecasts, which we may obtain from internal company surveys, market research, consultant surveys,
publicly available information, reports of governmental agencies and industry publications, articles and surveys. Industry surveys, publications,
consultant surveys and forecasts generally state that the information contained therein has been obtained from sources believed to be
reliable, but the accuracy and completeness of such information is not guaranteed. While we believe that such studies and publications
are reliable, we have not independently verified market and industry data from third-party sources.
-iii-
RISK FACTOR SUMMARY
Our business is subject to numerous risks and
uncertainties, including those highlighted in the section titled “Risk Factors,” that represent challenges that we face in
connection with the successful implementation of our strategy. The occurrence of one or more of the events or circumstances described
in the section titled “Risk Factors,” alone or in combination with other events or circumstances, may have an adverse effect
on our business, cash flows, financial condition and results of operations. Such risks include, but are not limited to:
Risks Relating to Our Financial Position and
Capital Needs
Risks Relating to the Development and Regulatory
Approval of Our Product Candidates
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Risks Relating to our Business and Operations
Risks Relating to our Intellectual Property
General Risk Factors
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PART I
Throughout this Annual Report on Form 10-K,
references to “we,” “our,” “us,” the “Company,” “Unicycive,” or “Unicycive
Therapeutics” refer to Unicycive Therapeutics, Inc.
ITEM 1. BUSINESS
Overview
We are a biotechnology company dedicated to developing
treatments for certain medical conditions. Currently, two of our programs are focused on kidney disease, an area we believe we have the
potential to offer medical benefit. As we grow the company and build our team, we intend to focus on identifying medical conditions within
and outside of kidney disease. Our current development programs are focused on two novel therapies: RenazorbTM, for treatment of
hyperphosphatemia in patients with chronic kidney disease on dialysis, and UNI 494, for treatment of acute kidney injury (AKI). Renazorb
and UNI 494 were initially developed by and licensed to us from Spectrum Pharmaceuticals (“Spectrum”) and Sphaera Pharmaceuticals,
respectively. Spectrum conducted a Phase 1 clinical trial with Renazorb in 2012, prior to the grant of our license in 2018. Sphaera conceived
and performed initial characterization of various potential pro-drug linkers, including the initial patent application, and performed
some initial physiochemical characterization and preliminary animal pharmacokinetic studies. As discussed herein, during 2021 and 2022
we have conducted preclinical studies with UNI 494.
Chronic kidney disease (CKD) is the gradual loss
of kidney function that can get worse over time leading to lasting damage. Our initial focus is on developing drugs and getting them
approved in the U.S., and then to partner with global biopharmaceutical companies in the rest of the world. According to the United States
Renal Data System (USRDS) 2022 Annual Data Report, 30 million (14%) of adults in the United States are estimated to have CKD and, of
these, approximately 13 million patients have advanced CKD (stage 3-5). Approximately 550,000 patients with end-stage renal disease (ESRD)
are on dialysis and of those, approximately 450,000 take phosphate binders to control hyperphosphatemia. The number of patients with
ESRD in the U.S. is increasing steadily and is projected to reach between 971,000 and 1,259,000 in 2030.
AKI is a sudden episode of kidney failure or
kidney damage (within the first 90 days of injury). After 90 days, the patient is considered to have progressed into CKD. AKI affects
more than 2 million U.S. patients and costs the healthcare system in excess of $9 billion per year. AKI kills more than 300,000 patients
per year in the U.S. and is caused by multiple etiologies.
Our business model is to license technologies
and drugs in order to pursue development, regulatory approval, and commercialization of those products in global markets. Many biotechnology
companies utilize similar strategies of in-licensing and then developing and commercializing drugs. We believe, however, that our management
team’s broad network, expertise in the biopharmaceutical industry, and successful track record gives us an advantage in identifying
and bringing these assets into our company.
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Pipeline
Our proprietary pipeline is comprised of our two product candidates
– Renazorb and UNI 494 – which are described below.
UNI-014 (Renazorb)
Renazorb Purchase Agreement
On September 20, 2018, we entered into an Assignment
and Asset Purchase Agreement (the “Renazorb Purchase Agreement”) with Spectrum Pharmaceuticals, Inc. (“Spectrum”),
pursuant to which we purchased certain assets from Spectrum, including Spectrum’s right, title, interest in and intellectual property
related to Renazorb RZB 012, also known as RENALANTM (“Renalan”) and RZB 014, also known as SPI 014 (“SPI”
and together with Renalan, the “Compounds”). Pursuant to the Renazorb Purchase Agreement, in consideration for the Compounds,
we issued 313,663 shares of common stock to Spectrum.
Additionally, the Renazorb Purchase Agreement
provides that until the earlier of (i) 36 months from the first date on which our stock trades on a public market, or (ii) the date upon
which we attain a public market capitalization of $50,000,000 or greater, we are required to issue additional shares of our common stock
as may be needed to ensure Spectrum maintains a 4% ownership of our issued and outstanding common stock on a fully-diluted basis. Fully-diluted
shares of common stock for purposes of the Renazorb Purchase Agreement assumes conversion of any security convertible into or exchangeable
or exercisable for common stock or any combination thereof, including any common stock reserved for issuance under a stock option plan,
restricted stock plan, or other equity incentive plan approved by the Board of Directors of the Company immediately following the issuance
of additional shares of our common stock (but prior to the issuance of any additional shares of common stock to Spectrum). We are also
required to pay Spectrum 40% of all of our sublicense income for any sublicense granted to certain sublicensees during the first 12 months
after the Closing Date (as that term is defined in the Renazorb Purchase Agreement) and 20% of all other sublicense income. Our payment
obligations to Spectrum will expire on the twentieth (20th) anniversary of the Closing Date of the Renazorb Purchase Agreement.
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Disease overview: Hyperphosphatemia
Chronic kidney disease (CKD) is the gradual loss
of kidney function that can get worse over time leading to lasting damage. The stages of chronic kidney disease are shown below in table
1.
Table 1: adapted from The Renal Association (https://renal.org/information-resources/the-uk-eckd-guide/ckd-stages/)
eGFR = estimated glomerular filtration rate (a measure of kidney function)
Complications of CKD include electrolyte imbalances,
fluid build-up, anemia, bone disease, and heart disease. Hyperphosphatemia is an electrolyte disorder in which untreated elevated phosphorus
levels in the blood lead to cardiovascular complications and vascular calcification. According to Kidney Disease Improving Global Outcomes
(KDIGO) guidelines, hyperphosphatemia is defined as an abnormally high serum phosphorus concentration >4.5 mg/dL In healthy people,
phosphorus levels are maintained as phosphate is absorbed from food and excreted in the urine and feces. In people with CKD, not enough
phosphate is excreted, leading to elevated levels of phosphorus in the blood. In CKD, hyperphosphatemia is caused by a chronic dysregulation
of serum phosphorus levels as a result of progressive kidney damage. According to a 2009 paper authored by Covic, hyperphosphatemia is
associated with increased risk of cardiovascular disease, metabolic bone disease, and all-cause mortality. According to a study completed
by Palmer in 2011, it is estimated that all-cause mortality is increased by 18% for every 1 mg/dL increase in serum phosphorus concentration.
Hyperphosphatemia is also a major cause of morbidity in CKD patients, which increases the economic and clinical burden on patients and
the health system and results in Medicare expenditures of $70 billion in the U.S.
According to the 2022 United States Renal Data
System (USRDS), it is estimated that 14% of U.S. adults (approximately 31 million people) have CKD. Most patients with stage 5 CKD either
undergo kidney transplant or go on dialysis. The 2022 USRDS annual report indicates that there were 557,838 prevalent dialysis patients
in 2020 (the latest reported year). The prevalent U.S. dialysis population has grown at an average yearly rate of 3.5% over the past
decade. Furthermore, in a paper published by McCullough in 2019, the number of patients in the U.S. with ESRD is increasing steadily
and is projected to reach between 971,000 and 1,259,000 in 2030. In 2020, the number of prevalent dialysis patients declined due to an
increased death rate of dialysis patients as a consequence of COVID-19.
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Current treatment of hyperphosphatemia
The treatment goal for patients with hyperphosphatemia
is focused on controlling the level of phosphate in the body. KDIGO guidelines recommend three main strategies for managing hyperphosphatemia:
diet restrictions, phosphate binders, and dialysis, as shown in figure 1 below.
Figure 1: KDIGO guidelines recommend 3 main strategies.
While KDIGO guidelines support the treatment
of hyperphosphatemia with phosphate binders in patients with CKD, with the exception of calcium-based binders, they do not recommend
one agent over another. This means that physicians prescribe their medication of choice, usually based on clinical and patient factors.
Utilization of calcium-based binders is discouraged by the most recent KDOQI/KDIGO guidelines due to mounting clinical evidence that
excess calcium load from calcium-based phosphate binder is associated with hypercalcemia and cardiovascular calcification which has been
associated with an increased risk of morbidity and mortality.
According to data from the Dialysis Outcomes
and Practice Patterns Study (DOPPS) in 2021, 82% of U.S. dialysis patients were prescribed phosphate binders, which equates to approximately
450,000 patients.
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Unmet Medical Need in the Management of Hyperphosphatemia
The mechanism of action and what we believe to
be the advantages and disadvantages of various phosphate binders are shown below.
Table 2: Adapted from Covic and Rastogi, 2013.
Despite the commercial availability of the six
phosphate binders in the table above, 75% of U.S. dialysis patients fail to achieve the serum phosphorus target established by the KDIGO
guidelines. Moreover, serum phosphorus outcomes are trending downward—underscoring the need for newer, more effective treatment
options.
-5-
In 2005, Unruh, ML published a paper that showed
poor adherence to treatment is common in patients with ESRD and has been associated with an increased risk of mortality. In addition,
poor adherence to phosphate binder therapy has been associated with failure to adequately control serum phosphorus concentrations as
shown in a publication by Arenas, MD and others in 2010. Results from a study of 233 patients on maintenance dialysis from three different
dialysis units in the U.S. showed that patients took a mean of 11 ± 4 medications with a median daily pill intake of 19 as shown
by Chiu, YW in 2009. Phosphate binders accounted for nearly 50% of the total pill burden, with a median daily pill count of nine. Only
38% of patients in this study reported that they were adherent to their prescribed phosphate binder therapy and adherence decreased significantly
with increased pill count.
Potential strategies to improve adherence to
phosphate binders in patients with ESRD include: (i) a reduction in pill size and number, (ii) improvement of palatability, and (iii)
a reduction in associated adverse effects as published in a study by Covic and Rastogi in 2013.
Therefore, we believe there is a current need
for better phosphate binders with high phosphate binding capacity, enabling a reduced pill burden for better medication compliance.
Development of Renazorb
Renazorb (lanthanum dioxycarbonate) is an investigational
phosphate binding agent utilizing proprietary nanoparticle technology for the treatment of hyperphosphatemia in CKD patients on dialysis.
Renazorb Mechanism of Action
Renazorb binds to phosphates and forms an insoluble
lanthanum phosphate complex which is then excreted via the feces. This results in reduction of serum phosphorus levels.
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In rat studies, Renazorb exhibited comparable
reduction in the urine phosphorus excretion following administration of a lower dose of drug product (0.40g) vs a higher dose (0.57g)
of Fosrenol® (lanthanum carbonate tetrahydrate). While differing in the mass of drug product, each dose contained comparable amounts
of the active moiety (elemental lanthanum). In the same study, at equivalent doses, Renazorb was superior to sevelamer (the most commonly
used phosphate binder) in reducing urine phosphorus excretion (see Fig 2).
Figure 2: Urine phosphate levels in rats following comparable dosing
of Renazorb, Fosrenol, or Sevelamer
In animal toxicology studies no unexpected toxicity
was found and systemic absorption was extremely low, which is consistent with similar studies conducted with Fosrenol.
The chemical design of Renazorb allows for smaller
tablet size and fewer pills compared with currently available phosphate binder alternatives, specifically with a dosing regimen of only
one tablet per meal. The Renazorb tablet is designed to disintegrate in the stomach after swallowing and disperse the product in a short
period of time at a pH ≥3.0.
Clinical Trial Experience
In September 2012 a Phase 1 single-center clinical
trial evaluating Renazorb in 32 healthy volunteers was completed in the United States. Four sequential dose cohorts of 8 subjects each
(6 actives and 2 placebos) received Renazorb at 1500, 3000, 4500, or 6000 mg/day, taken orally in 3 divided doses within 15 minutes after
meals, for five consecutive days. The primary endpoint of the study was the evaluation of safety, and the secondary endpoint was the
phosphate binding capacity of Renazorb as judged by the level of phosphorus in feces and urine. We believe the study indicated
that Renazorb was minimally absorbed to the systemic circulation and was well-tolerated at doses up to 6000 mg/day. Renazorb significantly
reduced urine phosphate excretion and significantly increased fecal phosphate excretion at doses at and above 3000 mg/day. The
mean overall change in phosphorus from baseline in both urine and feces, across all treatment groups, showed a dose-response trend that
was statistically significant (p<0.0001 and p=0.0004, respectively). The mean reduction in urine phosphorus excretion was not significant
at 1500 mg/day (p=0.3676), but was significant at 3000 (p=0.0004), 4500 (p<0.0001), and 6000 (p=0.0001) mg/day, as shown in the figure
below.
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Figure 3: Daily urine phosphate reduction
Regulatory Strategy for Renazorb
Feedback from the FDA
We received additional guidance on the regulatory
pathway for Renazorb from the U.S. Food and Drug Administration (FDA) following a Type C meeting in March 2022, in which the FDA confirmed
that a single clinical bioequivalence study in healthy volunteers, together with the previously agreed-upon 6-month mouse toxicology
study can support the New Drug Application (NDA) filing of Renazorb through a 505(b)(2) pathway.
We reached an agreement with the FDA on the clinical
study design including the doses of Renazorb and Fosrenol, sample size and the primary endpoints of the bioequivalence study. The FDA
confirmed that no additional clinical studies would be required for the NDA application.
BE Study Description
We conducted a randomized, open label, two-way
crossover BE study to establish pharmacodynamic (PD) bioequivalence between Renazorb and Fosrenol. The primary objective of the study
was to demonstrate PD equivalence of orally administered Renazorb 1000 mg three-times daily (TID) to orally administered Fosrenol 1000
mg TID in healthy subjects, and the secondary objective was to compare the safety and tolerability of UNI-014 versus Fosrenol in healthy
subjects. The study design, including the dose, primary endpoint and the sample size was reviewed by the Agency prior to the initiation
of the study. The primary outcome measure was least squares (LS) mean change in urinary phosphorous excretion (in mg/day) from baseline
to the evaluation period. The evaluation period was defined as the approximately 72-hour urine collection period starting on Day 1 and
ending on Day 4. Baseline was defined as the approximately 48-hour urine collection period starting on Day -2 and ending on Day 1. PD
equivalence was to be claimed if the 90% confidence interval (CI) of the primary PD variable for UNI-014 was completely contained within
the reference interval, which was defined as ±20% of the LS mean of the primary PD variable for lanthanum carbonate. The LS mean
change from Baseline for UNI-014 (-320.4 mg/day) was similar to the LS mean change from Baseline for Fosrenol (-324.0 mg/day). The
90% CI for the LS mean was (-45.88, 53.16), which is well within the acceptance range of (-64.80, 64,80) (Table 3). It was concluded
that UNI-014 was bioequivalent to Fosrenol. Primary outcome data is presented
in the table below.
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Table 3 Summary of Mean
Change in Urinary Phosphorus Excretion (mg/day)
Phosphorus Excretion (mg/day)
Visit Statistics Renazorb (N=75) Fosrenol (N=75)
Change from Baseline LS Mean Change -320.4 -324.0
90% Confidence Interval for the LS mean (Test-Reference) (-45.88, 53.16)
Manufacturing
We do not own or operate manufacturing facilities
for the production of clinical or commercial quantities of our product candidates. We currently have no plans to build our own clinical
or commercial scale manufacturing capabilities. If and when any of our product candidates are approved, we plan to obtain manufacturing
capacity through contract manufacturing organizations (CMOs) to meet projected needs for commercial sale quantities and serve patient
needs.
With regards to manufacturing, testing and potential
commercial supply of Renazorb, we have entered into an agreement with Shilpa Medicare Ltd based in India. According to the terms of the
agreement, following Renazorb approval by the FDA, Unicycive will pay the vendor $2 million in the first calendar year when the net revenue
reaches $10 million from sales of Renazorb and commercial supply of the product by the vendor (First Payment). Thereafter, we will pay
$2 million per year for four consecutive years, after the first year’s payment, for the total payments of $10 million, provided
all commercial supplies are continued to be manufactured and supplied by the vendor. Unicycive is not obligated to make any payments
to the vendor until FDA approval of the product is obtained and commercial revenue is generated.
Commercial Strategy for Renazorb
The worldwide market for hyperphosphatemia agents
is estimated at ~$2.5 billion and is growing at a 5.3% CAGR (Fortune Business Insights, Hyperphosphatemia Treatment Market, 2021-2028).
According to a study conducted by Syneos Health for the Company, the U.S. market makes up over $1 billion of that total. We own commercial
rights to Renazorb globally. For the U.S. market, we intend to maintain optionality by pursuing 3 potential go-to-market models in parallel.
We believe that this is the best strategy to maximize both the clinical value of the Renazorb asset for patients and the economic value
of the asset to our investors.
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Collaboration Partners
In July of 2022, we entered into an agreement
granting exclusive rights to develop, market and commercialize Renazorb (lanthanum dioxycarbonate) to Lee’s Pharmaceutical (HK)
in Mainland China, Hong Kong, and certain other Asian markets. Under the terms
of the agreement, Lee’s Pharm will be responsible for development, registration filing and approval for Renazorb in the licensed
territories. In addition, Lee’s Pharm will have sole responsibility for the importation of the drug product from Unicycive and
for the costs of commercialization of Renazorb in the licensed territories. We received an upfront payment of $1.0 million upon signature
and may receive up to $1.0 million in milestone payments upon product launch in China and will be eligible for tiered royalties upon
achievement of prespecified regulatory and commercial achievements.
In February of 2023, we entered into an exclusive
license agreement with Lotus Pharmaceutical for the development and commercialization of Renazorb in the Republic of Korea. Under the
terms of the agreement, Lotus will be responsible for development, registration filing and approval of Renazorb in the Republic of Korea.
In addition, Lotus will have sole responsibility for the importation of the drug product from Unicycive and for the costs of commercialization
of Renazorb in the Republic of Korea. We received an upfront payment of $750,000 and may receive up to $4.45 million in milestone payments
and tiered royalties upon achievement of prespecified regulatory and commercial achievements.
We will continue to seek licensing partners for
Renazorb in other territories outside the U.S. (i.e., Europe, Japan, Canada, South America, and the Middle East.)
U.S. opportunity for Renazorb
Renazorb is a phosphate binder for the treatment
of hyperphosphatemia in patients with CKD on dialysis and is intended to be administered as a tablet that will be swallowed whole at
mealtimes. CKD patients typically have co-morbidities, which often require them to be on strict pill schedules. Current phosphate binder
products such as Renvela®, Calcium Acetate, Auryxia®, Velphoro®, and Fosrenol involve patients
needing to take large numbers and/or large sized, chewable pills each day, which often results in poor adherence to the prescribed drug
therapy (Figure 4 below). By virtue of its novel nanoparticle technology, Renazorb leverages the high phosphate binding potency of lanthanum
in a palatable dose form that has the potential to substantially reduce the pill burden volume for patients. In this regard, we believe
that the combined effect of smaller pill size, lower number of pills, and improved palatability with Renazorb compared with currently
available phosphate binders is likely to lead to improved patient compliance/adherence and more effective disease management.
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Figure 4: Average daily dose of phosphate binder
therapies from www.dailymed.nlm.nih.gov. Product images are proportionally sized.
Tenapanor (Ardelyx): A Potential New Hyperphosphatemia
Market Player
Tenapanor is a new oral treatment for hyperphosphatemia
that utilizes a novel mechanism of action that inhibits paracellular transport of phosphorus into the bloodstream. Ardelyx filed an NDA
for tenapanor with the FDA in June of 2020. In July of 2021, Ardelyx received a Complete Response Letter (“CRL”) from the
FDA’s Division of Cardiology and Nephrology. According to the CRL, the Division characterized the treatment effect of tenapanor
as “small and of unclear clinical significance.” Ardelyx appealed FDA’s decision and ultimately was granted an Advisory
Committee meeting in November of 2022, where committee members voted in favor of approving tenapanor (9 to 4 in favor of approving tenapanor
as monotherapy and 10 to 2 in favor of its approval in combination with phosphate binders). Ardelyx is in discussions with FDA about
the nature of a potential approval of tenapanor and expects that approval in the second half of 2023.
While we can’t predict the outcome of these
negotiations, we believe that given the modest treatment effect of tenapanor that, regardless of the scope of the indication, the clinical
utilization of tenapanor will be predominantly in combination with phosphate binders. In FDA Advisory Committee briefing documents, the
efficacy of tenapanor in lowering serum phosphorus levels in dialysis patients in an intent-to-treat (ITT) analysis was 0.70mg/dL. By
comparison, in the same document FDA summarized the efficacy of lanthanum carbonate as resulting in a reduction in serum phosphorus of
2.0mg/dL in a comparable ITT analysis of clinical data. Based on this FDA commentary, we would expect Renazorb to be substantially more
effective than tenapanor when used as monotherapy. Similar to Renazorb, one of the key features of tenapanor’s value proposition
is its low pill burden. For this reason, we believe that Renazorb may be the most logical phosphate binder to combine with tenapanor
making the two potential new medicines more complimentary than competitive as it would leverage two distinct mechanisms of action to
control phosphorus with a much lower pill burden than the current standard of care.
Changing Access and Reimbursement Environment
According to the most recent ESRD PPS “Final
Rule” published for 2023, drugs for the treatment of hyperphosphatemia for Medicare beneficiaries, which are currently provided
by Medicare Part D insurers are scheduled to be included into the dialysis bundle in 2025 and will be paid for separately by CMS through
a Transitional Drug Add-On Payment Adjustment (TDAPA) program for a minimum of 2 years. In the 2023 Final Rule, CMS stated, “We
have seen that incorporating Medicare Part D drugs into the ESRD PPS has had a significant positive effect of expanding access to such
drugs for beneficiaries who do not have Medicare Part D coverage.” (federalregister.gov/d/2022-13449). We believe that the
timing of this change coincides with our anticipated launch timing of Renazorb and could provide for a more rapid launch uptake and competitive
pricing advantages.
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UNI-494
Disease overview: acute kidney injury (AKI)
Acute kidney injury (AKI) is defined as a sudden
loss of kidney function that is diagnosed by increased serum creatinine levels and decreased urine output and is limited to a duration
of 7 days, whereas chronic kidney disease (CKD) is a defined as persistent decrease in kidney function beyond 90 days. Thus, AKI and
CKD can form a continuum whereby initial kidney injury can lead to persistent renal injury, eventually leading to CKD.
Acute kidney injury (AKI) is estimated to occur
in approximately 20–200 per million population in the community, 7–18% of patients in hospital, and approximately 50% of
patients admitted to the intensive care unit (ICU). Importantly, AKI is associated with morbidity and mortality; AKI affects 13 million
people worldwide, and an estimated 2 million people die of AKI every year, whereas AKI survivors are at increased risk of developing
chronic kidney disease (CKD) and end-stage renal disease (ESRD) — conditions that carry a high economic, societal and personal
burden (Chawla et al., Nature Reviews-Nephrology, 2017).
Current treatment of acute kidney injury
Currently there are no FDA approved medicines
to treat AKI. Treatment options for AKI include continuous renal replacement therapy, renal transplant, and dialysis. In most cases the
damage to the kidney is irreversible, and the patient needs to have a renal transplant or be on dialysis for life. Therefore, there is
a high unmet medical need. If approved, UNI-494 has the potential to be a first-in-class drug for the treatment of AKI.
Role of Mitochondria in kidney diseases
The kidney has one of the highest mitochondrial
densities in the body. Both acute and chronic kidney disease is associated with mitochondrial loss and impaired repair mechanisms, which
subsequently result in increased oxidative damage, cellular injury and cell death. AKI and CKD not only form a continuum but are a bidirectional
process, wherein maladaptive repair of AKI leads to CKD and patients with underlying CKD conditions are predisposed to the development
of AKI. Mitochondrial dysfunction plays a crucial role in both AKI and CKD, as shown in the diagram below. Since mitochondrial dysfunction
is an important factor in the pathogenesis of AKI and CKD, mitochondria have emerged as a therapeutic target for treatment of these diseases.
Figure 5
Adapted from Bhatia et al, Kidney Research
and Practice 2020 39(3):244-258.
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Background on nicorandil
Nicorandil, marketed in such products as Ikorel
and Dancor, is indicated for the treatment of chronic stable angina pectoris. It is currently not approved in the United States
but has been approved for use in Australia, the United Kingdom and most of Europe, and in India, Japan, South Korea, and Taiwan. Nicorandil
is a dual-action mitochondrial potassium (mitochondrial KATP) channel activator and nitrate-like vasodilator. Activation of
mitochondrial KATP channel leads to restoration of mitochondrial function and cytoprotection. Nicorandil has extensive safety
and efficacy data from multiple clinical trials, including a 5,000-patient randomized controlled trial (IONA Study, Lancet 2002) and
there is a consensus in the literature that the activation of mitochondrial KATP channel is the biological basis for
the observed cardio-protection and reno-protection in multiple clinical trials.
Nicorandil efficacy in acute kidney injury
Nicorandil has been reported to have a potential
protective effect in the kidneys in preclinical studies (Shiraishi 2014, Tamura 2012, Tanabe 2012). In animal studies, nicorandil has
demonstrated efficacy in multiple standard models of kidney disease such as ischemic reperfusion injury, 5/6 nephrectomy models of chronic
kidney disease, diabetic nephropathy and hypertensive models (see Table 4). Notably, these effects occur in a blood pressure-independent
manner, indicating that these beneficial effects are not simply a result of decreasing pressure-mediated kidney damage, but a direct
beneficial effect on the kidney. A brief summary from these preclinical studies is provided in the Table below.
Table 4: Efficacy of nicorandil in standard
models of kidney disease
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More importantly, several randomized clinical
studies have indicated improved renal outcomes with nicorandil in patients with chronic kidney disease, poor renal function, and those
undergoing coronary angiography/percutaneous coronary intervention (CAG/PCI). A brief summary from a couple of randomized clinical trials
in contrast induced nephropathy (AKI) is described in the table below.
Table 5: Efficacy of nicorandil in clinical
trials in Acute Kidney Injury
In 2020, to bring together the growing evidence
of the effectiveness of nicorandil for the prevention of Contrast Induced Nephropathy (CIN). Pranata published the results of a systematic
literature review and meta-analysis of clinical studies investigating the use of nicorandil in patients undergoing CAG or PCI. Across
the seven trials (sample size N=1,532), nicorandil was shown to decrease the incidence of CIN by 69% (OR: 0.31; 95% CI: 0.20, 0.46; independent
of other factors in the respective studies. In addition, a subgroup analysis showed that nicorandil also provided protection against
CIN in patients with renal dysfunction (OR: 0.37; 95% CI 0.22, 0.61), which was defined as an eGFR £60 mL/min/1.73 m2.
When analyzed by the mode of administration, oral nicorandil was shown to have greater efficacy compared with nicorandil infusions (OR:
0.29 vs 0.40). Overall, Pranata et al. concluded that nicorandil was associated with a lower risk of CIN in patients undergoing
CAG/PCI with a moderate level of certainty (Pranata et al 2020).
Limitations of Nicorandil
Despite these promising results, development
of nicorandil for use in acute kidney injury has not been successfully pursued to date. Nicorandil possesses at least two features that
may limit its use in this clinical setting. First, nicorandil has a short half-life in humans of approximately 1 hour, which results
in the need to dose nicorandil multiple times per day to achieve sustained blood levels. Second, nicorandil has been associated with
rare but serious ulcerations in the gastrointestinal tract. The chance of this rare, but potentially severe, side effect increases with
higher doses and long-term use of this drug and heals after drug withdrawal. A recent population-based study of this drug’s association
with GI ulceration or perforation has been reported (Lee et al., Scientific Reports, 2015). This study, based on more than 600,000 randomly
selected patients, found a 43% increase in the risk of GI ulceration and a 60% increase in the risk of GI perforation. This effect appears
dose-dependent and limits the maximum labeled dose of nicorandil in Europe.
UNI-494: a Pro-drug of Nicorandil
UNI-494 was rationally designed to be absorbed
into the systemic circulation, and once absorbed, to release nicorandil into the bloodstream. By avoiding direct exposure to the gastrointestinal
tract of nicorandil, it is believed that UNI-494 may be able to minimize or avoid the gastrointestinal side effects of nicorandil. Also,
based on the rate of conversion of UNI-494 to nicorandil in the systemic circulation, UNI-494 may offer greater and/or more prolonged
exposure to nicorandil for the treatment of patients with acute kidney injury. Our technology for UNI-494 is licensed from Sphaera Pharmaceutical
Private Limited, a Singapore-based company (“Sphaera”), with offices in India and the U.S. We have the global, exclusive
license to UNI-494. Sphaera conceived of and performed initial characterization of various potential pro-drug linkers, including the
initial patent application, and performed some initial physiochemical characterization and preliminary animal pharmacokinetic studies.
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We conducted preclinical studies in rats and
dogs demonstrating systemic exposure to nicorandil following oral dosing of UNI-494. In dogs, oral dosing of UNI-494 produced up to four
times greater systemic exposure to nicorandil compared with literature data on equimolar doses of nicorandil itself.
Fig 6
Mechanism of Action of UNI-494
UNI-494 is a novel proprietary drug that selectively
binds to the SUR2B subunit of the mitochondrial KATP channel and activates it to restore mitochondrial function and reduce
oxidative stress. UNI-494 is cleaved by esterase enzymes to form nicorandil, the active metabolite.
The proposed mechanism of action of UNI-494 is shown in the diagram below:
Fig 7
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Clinical trials for UNI-494 in AKI
It is challenging to conduct clinical trials
in AKI trials due to the multiple etiologies of AKI. We believe that UNI-494 should be evaluated in clinical trials focusing on a few
select etiologies in which UNI-494 has a very strong mechanistic rationale based on nicorandil clinical experience in terms of protection
of kidney function and secondary benefits.
Based on our understanding of the mechanism of
action of the drug, we are in discussions with key opinion leaders (KOLs) to identify the AKI subsets where UNI-494 can be most active
and subsets of AKI patients who are most likely to benefit from UNI-494. We are planning to conduct preclinical studies in animal models
to further explore the efficacy and development path in the AKI indication. We have also identified patient populations where we would
not likely evaluate UNI-494 in clinical trials, including patients with prior history of gastrointestinal ulcerations. This will become
exclusion criteria in future clinical trials for UNI-494.
UNI-494 Development Status
We have completed all
non-clinical safety assessment studies required for regulatory filing and submitted a Clinical Trial Application (CTA) to the Medicines
and Healthcare Products Regulatory Agency (MHRA) to initiate a Phase 1 study in healthy volunteers in the United Kingdom in December
2022. The MHRA has completed review of our CTA and issued a notice of acceptance for UNI-494 first-in-human Phase 1 study in healthy
volunteers. We also plan to file a corresponding Investigational New Drug (IND) application with the FDA in 2024 for a Phase 2 proof-of-concept
trial in acute kidney injury (AKI) patients.
Regulatory Strategy for UNI-494
Nicorandil is already approved in Europe and
Asia for the treatment of heart disease. We believe there is a possibility these historical Nicorandil data, along with preclinical and
clinical data with UNI-494 itself, can be utilized for streamlined U.S. FDA review of UNI-494. While pre-clinical requirements to start
a clinical program for an IND would be similar for UNI-494 as for NCE (New Chemical Entity). We believe that the vast clinical data set
from Nicorandil will potentially help us to expedite the clinical development program with the FDA.
Market Potential
According to a 2017 article by Silver and Chertow,
the current cost of care for AKI in the U.S. is estimated to be between $5.4 billion to $24 billion per year. In England, inpatient costs
related to AKI are estimated to make up 1% of the total National Health Service budget. With no effective treatment for AKI, it is not
possible to definitively state a market figure. However, with the high cost and burden of caring for AKI patients, we believe a conservative
market estimate is approximately $3 billion in the U.S. alone. The lack of effective therapeutic interventions for AKI means that UNI-494
has the potential to be the first drug approved for the treatment of AKI. AKI is a heterogeneous disease. We plan to target a more homogeneous
AKI population for UNI-494 by focusing on kidney injury caused by complications from heart failure, surgeries, drugs, and contrast induced
nephropathy.
Sphaera License Agreement
On October 1, 2017, we entered into an exclusive
license agreement (the “Sphaera License Agreement”) with Sphaera Pharma Pte. Ltd., a Singaporean pharmaceutical corporation
(“Sphaera”). Pursuant to the Sphaera License Agreement, we acquired an exclusive royalty-bearing worldwide license to develop,
make, have made, use, practice, research, distribute, lease, sell, offer for sale, license, import or otherwise dispose of certain rights
owned or controlled by Sphaera and/or any of its affiliates, related to UNI-494 (the “UNI-494 Rights”). We also acquired
a non-exclusive license to certain know-how and technology related to the UNI-494 Rights. Sphaera conceived of and performed initial
characterization of various potential pro-drug linkers, including the initial patent application, and performed some initial physicochemical
characterization and preliminary animal pharmacokinetic studies.
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Under the terms of the Sphaera License Agreement,
we are obligated to pay to Sphaera, on a quarterly basis, a running royalty of 2% of our net sales (including our affiliates) in connection
with the global sales of UNI-494; provided, however, that if we are required to make royalty payments to one or more third parties whose
patent rights would be infringed by the exercise of the UNI-494 Rights, we may reduce such running royalty due to Sphaera by the amount
of such third-party royalty rate.
We are also required to pay to Sphaera certain
milestone payments, including, upon our initiation of a second clinical trial; $50,000 at the time the first patient in such trial is
dosed; an additional $50,000 within 30 days of completion of such trial; and at the time the FDA accepts a NDA for UNI494, $1.65 million.
In addition, we are responsible for the prosecution of patent rights, and any related costs and expenses for patent prosecution and maintenance.
We also have the right, but not the obligation,
to defend the UNI-494 rights during the term of the Sphaera License Agreement; provided, however, that if we determine not to prosecute
or maintain such rights in any country, we must provide ninety (90) days written notice to Sphaera. We may terminate the Sphaera License
Agreement at any time by providing thirty (30) days’ written notice to Sphaera. Additionally, in the event that either we or Sphaera
breach any of our respective material obligations, the non-breaching party may, in its sole discretion, have the right to terminate the
Sphaera License Agreement, provided that it give the breaching party written notice specifying the nature of the breach and amounts of
running royalty payments due, if any. In such an occurrence, the termination notice is effective ninety (90) days from receipt of the
notice if the breaching party has failed to cure the breach.
Competition
We operate in a highly competitive and regulated
industry that is subject to rapid and frequent changes. We face significant competition from organizations that are pursuing products
that would compete with the product candidates we are developing and the same or similar products that target the same conditions we
intend to treat. Due to our limited resources, we may not be able to compete successfully against these organizations, which include
many large, well-financed and experienced pharmaceutical and biotechnology companies, as well as academic and research institutions and
government agencies.
Intellectual Property
Our commercial success depends in part on our
ability to obtain and maintain proprietary protection for our product candidates, as well as novel discoveries, product development technologies,
and know-how.
Our commercial success also depends in part on
our ability to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary rights.
Our policy is to develop and maintain protection of our proprietary position by, among other methods, filing or in-licensing U.S. and
foreign patents and applications related to our technology, inventions, and improvements that are important to the development and implementation
of our business.
We also rely on trademarks, trade secrets, know-how,
continuing technological innovation, confidentiality agreements, and invention assignment agreements to develop and maintain our proprietary
position. The confidentiality agreements are designed to protect our proprietary information and the invention assignment agreements
are designed to grant us ownership of technologies that are developed for us by our employees, consultants, or other third parties. We
seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and
physical and electronic security of our information technology systems. While we have confidence in our agreements and security measures,
either may be breached, and we may not have adequate remedies. In addition, our trade secrets may otherwise become known or independently
discovered by competitors.
With respect to both licensed and company-owned
intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with
respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents that
may be granted to us in the future will be commercially useful in protecting our commercial products and methods of using and manufacturing
the same.
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Renazorb Patent Portfolio
Our Renazorb patent portfolio includes one family
of granted United States patents, with related applications pending, and an additional family of granted foreign patents, with related
applications also pending. Granted and pending claims offer various forms of protection for Renazorb including claims to compositions
of matter, pharmaceutical compositions, specific forms (such as polymorphs of lanthanum dioxycarbonate), methods of making the composition