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, 2023
☐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, 2023 was $19,502,100 based upon the closing
price of the registrant’s common stock of $1.28 on The Nasdaq Capital Market as of that date.
The number of shares of common stock outstanding as of March 28, 2024
was 34,756,436.
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 2024 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 64
Item 1C. Cybersecurity 64
Item 2. Properties 64
Item 3. Legal Proceedings 64
Item 4. Mine Safety Disclosures 64
Item 6. [Reserved] 65
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 74
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 75
Item 9B. Other Information 76
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 76
Part III 77
Item 10. Directors, Executive Officers and Corporate Governance 77
Item 11. Executive Compensation 77
Item 14. Principal Accountant Fees and Services 77
Item 15. Exhibit and Financial Statement Schedules 78
Signatures 80
-i-
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 Related to our Business
-iv-
● Our reliance on third parties heightens the risks faced by our business.
Risks
Relating to our Intellectual Property
General
Risk Factors
-v-
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: Oxylanthanum Carbonate, for treatment of hyperphosphatemia
in patients with chronic kidney disease on dialysis, and UNI 494, for treatment of acute kidney injury (AKI). Oxylanthanum Carbonate and
UNI 494 were initially developed by and licensed to us from Spectrum Pharmaceuticals (“Spectrum”) and Sphaera Pharma, respectively.
Spectrum conducted a Phase 1 clinical trial with Oxylanthanum Carbonate 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, after completing IND
enabling preclinical studies, we have conducted a Phase I clinical study in healthy volunteers with UNI 494 in 2023.
Chronic kidney disease (CKD) is the gradual loss of kidney (renal)
function that can get worse over time leading to lasting damage and possibly Stage 5 or end-stage renal disease (ESRD). 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 (ESRD) are on dialysis and of those, approximately 450,000 patients (~80%) take phosphate binders to control hyperphosphatemia
hyperphosphatemia (too much phosphorus in their blood). 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 patients 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. More than 300,000 patients per year
in the U.S. die due to AKI that has many causes.
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.
-1-
Pipeline
Our
proprietary pipeline is comprised of our two product candidates – Oxylanthanum Carbonate and UNI 494 – which are described
below.
Figure 1 Unicycive Product Pipeline
Oxylanthanum
Carbonate
Oxylanthanum
Carbonate Purchase Agreement
On
September 20, 2018, we entered into an Assignment and Asset Purchase Agreement (the “Spectrum 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 Oxylanthanum Carbonate 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 Spectrum
Agreement, in consideration for the Compounds, we issued 313,663 shares of common stock to Spectrum.
Additionally,
the Spectrum 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 Spectrum 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 Spectrum 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 Spectrum
Agreement.
-2-
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 Chronic Kidney Disease Stages
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 elevated phosphorus levels in the blood
lead to cardiovascular complications and vascular calcification (hardening). 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, normal
serum phosphorus levels are maintained s by absorbing from food and excreting (removing from the body) it 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 deaths from all-causes
(all-cause mortality) 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 2023 United States Renal Data System (USRDS) Annual
Report, it is estimated that 14% of U.S. adults (approximately 31 million people) have CKD. Most patients with Stage 5 CKD (ESRD) either
undergo kidney transplants or go on dialysis. The 2023 USRDS annual report indicates that there were 541,326 prevalent dialysis patients
in 2021 (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 2020-21, the number of prevalent dialysis patients declined due to an increased death
rate of dialysis patients as a consequence of COVID-19.
-3-
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: dietary
intake restrictions, use of phosphate binders, and dialysis, as shown in Figure 2 below.
Figure 2 KDIGO Guidelines Recommend Three
Main Strategies
While KDIGO guidelines do not recommend one phosphate binder over another,
they do recommend restricting the dose of calcium-based binders and avoiding long-term us of aluminum-containing binders.. 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 (disease) and mortality (death).
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.
-4-
Unmet
Medical Need in the Management of Hyperphosphatemia
The brief descriptions of the mechanism of action and what we believe
to be the advantages and disadvantages of various phosphate binders are shown below in Table 2.
Table
2: Adapted from Covic and Rastogi, 2013.
-5-
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 levels established by the KDIGO guidelines.
Moreover, serum phosphorus outcomes are trending downward—underscoring the need for new and effective treatment options.
Figure 3 Serum Phosphorus Target Achievement from 2012 to
2021
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 Oxylanthanum Carbonate
Oxylanthanum
Carbonate (lanthanum dioxycarbonate) is an investigational phosphate binding agent utilizing proprietary nanoparticle technology for
the treatment of hyperphosphatemia in CKD patients on dialysis.
-6-
Oxylanthanum
Carbonate Mechanism of Action
Oxylanthanum Carbonate binds to phosphates and forms an insoluble lanthanum
phosphate complex which is then excreted via the feces. This results in reduced absorption of phosphate leading to a reduction of serum
phosphorus levels.
In rat studies, Oxylanthanum Carbonate 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) which is a currently approved lanthanum-based phosphate binder. 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, Oxylanthanum
Carbonate was superior to Sevelamer (the most commonly used phosphate binder) in reducing urine phosphorus excretion (see Fig 3).
Figure 4 Urine Phosphate Levels in Rats Following Comparable
Dosing of Oxylanthanum Carbonate, Fosrenol, or Sevelamer
In animal toxicology studies with oxylanthanum carbonate no unexpected
toxicity was found and systemic absorption of lanthanum was extremely low, which is consistent with similar studies conducted with Fosrenol.
The chemical design of Oxylanthanum Carbonate was designed to allow
for a smaller tablet size and require fewer pills compared with currently available phosphate binder alternatives, specifically with a
dosing regimen of only one tablet per meal. The Oxylanthanum Carbonate tablet is designed to disintegrate rapidly in the stomach after
swallowing and does not need to be chewed.
Clinical
Trial Experience
First-in-Human Phase 1 Study
In
September 2012 a Phase 1 single-center clinical trial evaluating Oxylanthanum Carbonate in 32 healthy volunteers was completed in the
United States. Four sequential dose cohorts of 8 subjects each (6 actives and 2 placebos) received Oxylanthanum Carbonate 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 Oxylanthanum Carbonate as
judged by the level of phosphorus in feces and urine. We believe the study indicated that Oxylanthanum Carbonate was minimally
absorbed to the systemic circulation and was well-tolerated at doses up to 6000 mg/day. Oxylanthanum Carbonate 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.
The mean reduction in urine phosphorus excretion was significant (p<0.001)
at all four doses of Oxylanthanum Carbonate (Figure 4).
-7-
Figure 5 Daily Urine Phosphate Reduction in Healthy
Volunteers
Oxylanthanum
Carbonate Bioequivalence Study in Healthy Volunteers
We conducted a randomized, open label, two-way crossover bioequivalence
BE study to establish the bioequivalence of the phosphate binding capacity of Oxylanthanum Carbonate and Fosrenol. The primary objective
of the study was to demonstrate PD equivalence of orally administered Oxylanthanum Carbonate 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 Oxylanthanum Carbonate
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 Oxylanthanum Carbonate (-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.
Table
3: Summary of Mean Change in Urinary Phosphorus Excretion (mg/day)
Phosphorus Excretion (mg/day)
Visit Statistics Oxylanthanum Carbonate (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)
Regulatory
Guidance
Unicycive is seeking approval for Oxylanthanum
Carbonate from the U.S. Food and Drug Administration (FDA) through the 505(b)(2) regulatory pathway. The 505(b)(2) pathway allows for
full approval of a drug using data from an approved drug with the same active moiety. The approved drug is called the Reference Listed
Drug (RLD). The RLD for the Oxylanthanum Carbonate submission is Fosrenol (lanthanum carbonate). The FDA recommended conducting a BE study
in healthy volunteers and a 6-month toxicity study in mice with both Oxylanthanum Carbonate and Fosrenol to be able to rely on the efficacy
and safety of Fosrenol. We completed both studies and submitted the data for the FDA’s review during the pre-NDA (New Drug Application)
meeting request. A summary of the human BE study is provided above. After reviewing the data, the Agency recommend that we conduct a tolerability
study of Oxylanthanum Carbonate in chronic kidney disease patients on dialysis before filing the NDA. We gained alignment with the FDA
on the study design, sample size, and endpoints of the proposed pivotal clinical study during a Type-C meeting in September 2023. This
study was initiated in December 2023 and the topline data is expected at the end of Q2, 2024. We plan to submit the NDA soon after the
completion of the clinical study.
-8-
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 Oxylanthanum Carbonate, we have entered into an agreement with Shilpa
Medicare Ltd based in India. According to the terms of the agreement, following Oxylanthanum Carbonate 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 Oxylanthanum Carbonate
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 Oxylanthanum Carbonate
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 Oxylanthanum Carbonate globally. For the U.S. market, we are preparing
to launch Oxylanthanum Carbonate on our own by building out a specialty commercial operation to address the highly concentrated nephrology
prescription market. Executive management of the company has considerable product launch experience in the nephrology space with specific
working knowledge of the hyperphosphatemia market. While there are ~10,000 prescribers of phosphate binders, ~2,500 prescribers are responsible
for over half of the ~2.5 million prescriptions written annually. We believe that we can efficiently create demand for Oxylanthanum Carbonate
within the most productive segments of the market with a relatively small salesforce, while addressing the broader segments of prescribers
through non-personal and digital promotion tactics.
An
alternative commercial strategy would be to out-license and/or co-promote Oxylanthanum Carbonate with and established biopharmaceutical
company that has an existing commercial infrastructure in the renal disease space and/or enter into distribution agreement(s) with dialysis
organizations for the commercialization of Oxylanthanum Carbonate.
Collaboration
Partners
In
July of 2022, we entered into an agreement granting exclusive rights to develop, market and commercialize Oxylanthanum Carbonate (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 Oxylanthanum Carbonate 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 Oxylanthanum Carbonate 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 Oxylanthanum Carbonate in the Republic of Korea. Under the terms
of the agreement, Lotus will be responsible for development, registration filing and approval of Oxylanthanum Carbonate 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 Oxylanthanum Carbonate in the Republic of Korea. We received an upfront payment of $750,000 and may receive up to
$3.7 million in milestone payments and tiered royalties upon achievement of prespecified regulatory and commercial achievements.
We
will continue to seek licensing partners for Oxylanthanum Carbonate in other territories outside the U.S. (i.e., Europe, Japan, Canada,
South America, and the Middle East.)
-9-
U.S.
opportunity for Oxylanthanum Carbonate
Oxylanthanum
Carbonate 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, Oxylanthanum
Carbonate 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 Oxylanthanum Carbonate compared with currently available phosphate binders is likely to lead to
improved patient compliance/adherence and more effective disease management.
Figure 6 Phosphate Binders
Tenapanor
(Ardelyx): A 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 which received a Complete Response Letter (“CRL”)
from the FDA’s Division of Cardiology and Nephrology in July of 2021, 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 resubmitted
their application and was granted approval in October of 2023. The labelled indication for Xphozah (tenapanor) is “...as add-on
therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.”
The limited indication as add-on therapy is presumably due to the drug’s relatively modest treatment effect when used as monotherapy
in clinical trials (intent-to-treat (ITT) analysis of treatment effect of 0.70 mg/dL on serum phosphorus levels). Additionally, the product
label lists diarrhea as the most common adverse event occurring in 43-53% of patients.
We
believe that due to its novel mechanism of action, Xphozah represents an important new addition to the nephrologist’s hyperphosphatemia
treatment armamentarium. We believe that the relative competitive profile of Oxylanthanum Carbonate (OLC) has several advantages over
Xphozah: 1) Based on our demonstration of pharmacodynamic equivalence of OLC to the reference-listed drug, Fosrenol, our label for OLC
is expected to describe its treatment effect as a change of 1.91 mg/dL in serum phosphorus levels in an ITT analysis of patients treated
with OLC as monotherapy. This represents more than a 2.7 times greater treatment effect compared to Xphozah. 2) The labelled indication
for OLC is expected to be identical to that of Fosrenol which will support its use as monotherapy and will be not limited to add-on therapy,
3) The demonstrated adverse event profile of lanthanum-based phosphate binders (subject to validation of OLC’s GI tolerability
profile currently being evaluated in a clinical trial) will compare favorably to high rate of reported GI adverse events of Xphozah.
One
of the key features of Xphozah’s value proposition as an add-on therapy is its low pill burden. Given its substantially lower pill
burden than other phosphate binder options, we believe that OLC may be the most logical phosphate binder to combine with tenapanor making
these two new medicines more complimentary than competitive as the combination would leverage two distinct mechanisms of action to control
phosphorus with a much lower total pill burden than the current standard of care.
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Changing
Access and Reimbursement Environment
By
current federal regulation, phosphate lowering drugs (PLTs), which are currently provided to patients 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 ESRD PPS 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
favorably with our anticipated launch timing of Oxylanthanum Carbonate (OLC) and could provide for a more rapid launch uptake and competitive
pricing advantages. A key factor affecting initial launch uptake of OLC is the expanded access to our product to Medicare beneficiaries
which make up over two-thirds of patients on dialysis. Currently under Part D, patients often face high co-pays for branded drugs which
tends to restrict access to these drugs. Under the current TDAPA rules, CMS reimburses dialysis organizations for 100% of the average
selling cost (ASP) of all phosphate lowering drugs—eliminating the access restrictions patients face from Part D plans.
We
also see a pricing benefit to OLC under TDAPA. In the current reimbursement environment, manufacturers often pay significant rebates
to Part D plans for formulary access. Current branded PLTs have diluted their ASP as a result of these rebate agreements and under the
Inflation Reduction Act (IRA) are limited in their ability to raise prices above the rate of inflation. Due to the expected launch timing
of OLC, we expect to enjoy a pricing advantage over other branded competitors in the market.
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).
Delayed
Graft Function (DGF)
Our
initial target indication for UNI-494 is delayed graft function (DGF). DGF is a form of acute kidney injury (AKI) caused by the ischemia
reperfusion injury (IRI) phenomenon in kidney transplantation surgery. DGF is a serious complication of kidney transplantation with no
approved therapies. Patients who experience DGF have an increased risk of mortality that’s 59% higher than those without DGF. Patients
with DGF are also more than 2 times more likely to be readmitted to the hospital within 30-days post-transplantation and are at 41% increased
risk of long-term graft loss. Given the average cost of a kidney transplant of nearly $500,000, the economic implications of graft failure
due to DGF are staggering.
The
potential commercial opportunity for UNI-494 in DGF is substantial. In the US, 46,630 kidney transplants were performed in 2023. This
number would undoubtedly be higher were more donor organs available. Currently, there are over 80,000 Americans on the waitlist for a
donor kidney. 15% of transplanted kidneys come from living donors meaning that the remaining 85% of donor organs come from deceased donors.
While the incidence of DGF is relatively small (1.6 -3.6%) for living donor organs, the risk is considerably higher for deceased donor
organs. The rate of DGF is 20 - 30.4% for DBD (donor brain death) organs and 45 – 55.1% for DCD (donor circulatory death) organs.
Due to the shortage of donor kidneys and the size of the kidney transplant waitlist, the incidence of DGF is expected to increase as
lower quality organs are transplanted.
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Current
treatment of delayed graft function and acute kidney injury
Currently
there are no FDA approved medicines to treat DGF and/or 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
Mitochondria are where most of the energy in a cell is produced. 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 7 Mitochondrial Damage from Acute Kidney Injury and
Chronic Kidney Disease
Adapted
from Bhatia et al, Kidney Research and Practice 2020 39(3):244-258.
UNI-494:
a Novel Pro-drug of 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. Although nicorandil is known to be safe, gastrointestinal
ulceration is a rare but severe side effect and it is dose-dependent.
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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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:
Figure 8 Mechanism of Action of UNI-494
Figure
6
Ischemia/reperfusion
injury (IRI) is one of the main reasons for causing acute kidney injury (AKI) that results in DGF during kidney transplantation. Ischemic
preconditioning, that works by activating KATP channels in mitochondria, is a natural endogenous mechanism which protects
cells from IRI in the heart, kidney, liver, and other organs. UNI-494 is a pharmacological approach that emulates and enhances this natural
phenomenon of ischemic preconditioning.
Efficacy
of UNI-494 in Animal Models: We recently conducted pre-clinical pharmacology studies to evaluate the efficacy of UNI-494 in animal
models. The ischemia reperfusion injury (IRI) model of DGF in rats was used to study the efficacy of UNI-494 in preventive mode on kidney
injury with a special focus on kidney functional markers (serum creatinine [sCr], blood urea nitrogen [BUN], and urinary albumin/creatinine
ratio [ACR]), tubular injury markers (urinary neutrophil gelatinase-associated lipocalin [NGAL] and proximal tubular damage (proximal
tubular injury scores via histology. UNI-494 was administered 30 minutes prior to the induction of ischemia, IR induced significant increases
of sCr, BUN, ACR, NGAL, β2-MG, and proximal tubular injury damage scores in the vehicle treated DGF group when compared to No DGF
sham group (p<0.0001 – as per one-way ANOVA multiple comparison test). Following treatment with UNI-494, there was a statistically
significant reduction of biomarkers and improvement in tubular injury as shown in the figure below.
Figure 9 Effect of UNI-494 on Ischemia-Reperfusion Injury in
Rats
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UNI-494
Clinical Development Status
We
have completed 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. 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 initiated the Phase I study in healthy volunteers to evaluate the safety and tolerability of UNI-494. We expect
to complete the study during the 2H of 2024.
Clinical
trials for UNI-494 in Acute Kidney Injury
Phase
I study in Healthy volunteers: This is a single-center, double-blind, placebo-controlled, randomized single ascending dose (SAD)
(Part 1) and multiple ascending dose (MAD) (Part 2) study in healthy male and female subjects of non-childbearing potential. Part 1 will
enroll up to approximately 40 subjects in 5 cohorts of 8 subjects each (randomized to a ratio of 6 active and 2 placebo per cohort).