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, 2024
☐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, 2024 was $18,679,544 based upon the closing price of the registrant’s common stock
of $0.50 on The Nasdaq Capital Market as of that date.
The number of shares of common stock outstanding as of March 28, 2025
was 119,705,026.
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 2025 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 36
Item 1B. Unresolved Staff Comments 67
Item 1C. Cybersecurity 67
Item 2. Properties 67
Item 3. Legal Proceedings 67
Item 4. Mine Safety Disclosures 67
Item 6. [Reserved] 68
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 76
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 77
Item 9B. Other Information 78
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 78
Part III 79
Item 10. Directors, Executive Officers and Corporate Governance 79
Item 11. Executive Compensation 79
Item 14. Principal Accountant Fees and Services 79
Item 15. Exhibit and Financial Statement Schedules 80
Signatures 82
-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
● Our reliance on third parties heightens the risks faced by our business.
Risks
Relating to our Intellectual Property
General
Risk Factors
-iv-
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 clinical-stage biotechnology company
focused on identifying, developing, and commercializing innovative therapies to address significant unmet medical needs, with an initial
focus on kidney disease. Founded in 2016, Unicycive was established to create a streamlined and efficient drug development platform capable
of accelerating the advancement of promising therapies from discovery to commercialization. Currently, our two programs are focused on
kidney disease, an area we believe we have the potential to offer medical benefit. 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. As we grow the company
and build our team, we intend to focus on identifying medical conditions within and outside of kidney disease. 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.
Our current development programs are focused on
two novel therapies: Oxylanthanum Carbonate, a next-generation phosphate binder for the treatment of hyperphosphatemia in chronic kidney
disease patients on dialysis, and UNI-494, a novel drug candidate in development for the treatment of acute kidney injury. 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. As discussed herein, after completing IND enabling preclinical studies, we have completed a Phase I clinical study in healthy
volunteers with UNI-494 in 2024.
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). CKD affects nearly
36 million Americans; approximately 550,000 of them have end stage renal disease and require dialysis. Hyperphosphatemia is common in
people with CKD and has been directly linked to increased morbidity and mortality for people on dialysis. For an estimated 75% of people
in the U.S. on dialysis, hyperphosphatemia remains uncontrolled due to challenges with the six currently available phosphate binders,
namely insufficient potency, pill burden and unpalatable formulations. To address this significant and growing challenge, Unicycive is
developing Oxylanthanum Carbonate, which leverages proprietary nanoparticle technology to address the shortcomings of current therapies
by delivering higher potency that enables fewer and smaller pills — all in a formulation that is more acceptable for patients because
it is swallowed, not chewed. With OLC, if approved, people on dialysis and their physicians may have a better option to control hyperphosphatemia.
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. 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.
We operate with a sense of urgency to bring new
treatments to patients faster, leveraging our team’s expertise, operational efficiency, and strategic focus on high-value opportunities
within the renal space. Through this approach, we aim to deliver innovative therapies that provide meaningful clinical and economic benefits
for patients, providers, and healthcare systems.
-1-
Pipeline
Our proprietary
pipeline is comprised of our two product candidates – Oxylanthanum Carbonate and UNI-494 – which are described below in Figure
1:
Figure
1: Unicycive Therapeutics’ Pipeline
Oxylanthanum
Carbonate
Oxylanthanum
Carbonate (lanthanum dioxycarbonate) is an investigational next-generation lanthanum-based phosphate binding agent being developed
for the treatment of hyperphosphatemia in CKD patients on dialysis.
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 involve patients needing to take a
large number of pills daily, some of which are large and/or must be chewed, often resulting in poor adherence to the prescribed drug therapy.
By virtue of its novel nanoparticle technology,
OLC 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 will compete favorably with currently available phosphate binders and may lead
to improved patient compliance/adherence and more effective disease management.
Unicycive
is seeking the U.S. Food and Drug Administration (FDA) approval of OLC via the 505(b)(2) regulatory pathway. The Company has submitted
a New Drug Application (NDA) and has an assigned Prescription Drug User Fee Act (PDUFA) date of June 28, 2025.
-2-
Disease
Overview: Hyperphosphatemia
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). The stages of chronic kidney disease are shown below in Figure 2.
eGFR =
estimated glomerular filtration rate (a measure of kidney function)
Image
Source: https://www.kidney.org/kidney-topics/stages-chronic-kidney-disease-ckd
Figure
2: Stages of Chronic Kidney Disease
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). Complications of CKD include electrolyte
imbalances, fluid build-up, anemia, bone disease, and heart disease. Most patients with Stage 5 CKD (ESRD) either undergo kidney transplantations
or go on dialysis. The 2023 USRDS annual report indicates that there were 541,326 prevalent dialysis patients in 2021 (the latest reported
year), and of those, approximately 450,000 patients (~80%) take phosphate binders to control hyperphosphatemia. The prevalent U.S. dialysis
population has grown at an average yearly rate of 3.5% over the past decade. 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.
Hyperphosphatemia
is a bone and mineral metabolism 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 CKD, hyperphosphatemia is caused by a chronic dysregulation of serum phosphorus
levels as a result of progressive kidney damage. In healthy people, normal serum phosphorus levels are maintained in the body by the
absorption from food and subsequent excretion from the body via urine and feces. In people with CKD, not enough phosphate is excreted,
leading to elevated levels of phosphorus in the blood.
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). 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.
-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 3 below.
Figure
3: KDIGO Guidelines Recommend Three Main Strategies for Managing Hyperphosphatemia
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 use of aluminum-containing binders. This means that physicians prescribe their medication of choice, usually
based on clinical factors and patient preferences. 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.
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 Figure 4.
Figure 4: Phosphate Binder Mechanisms of Action,
Adapted from Covic and Rastogi, 2013.
-4-
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, the
percentage of patients achieving these serum phosphorus guidelines is trending downward — underscoring the need for new and effective
treatment options (Figure 5).
KDOQI:
The Kidney Disease Outcomes Quality Initiative
Figure
5: 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.
By
virtue of its novel nanoparticle technology, OLC 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 may lead to improved patient compliance/adherence and more effective disease management.
-5-
Development
of Oxylanthanum Carbonate
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 Figure 6 below).
Figure
6: 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 structure 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
Unicycive
is seeking FDA approval of OLC via the 505(b)(2) regulatory pathway. The NDA submission package is based on data from three clinical
studies: a first in human Phase I study in healthy volunteers, a Bioequivalence (BE) study in healthy volunteers, and a pivotal Phase
2 tolerability study of OLC in CKD patients on dialysis, as well as multiple preclinical studies, and the chemistry, manufacturing and
controls (CMC) data.
Pivotal
Phase 2 Study
We
conducted a Phase 2, open-label, single-arm, multicenter trial in adult patients receiving maintenance hemodialysis with hyperphosphatemia.
The primary objective was to evaluate the tolerability of OLC at clinically effective doses with a goal serum phosphate concentration
(sP) ≤5.5 mg/dL. The trial included washout, titration, and maintenance periods. Eligible patients had sP ≥4.0 and ≤7.5 mg/dL
for at least 8 weeks prior to screening while receiving thrice weekly hemodialysis and a stable phosphate binder regimen. Patients started
titration when sP was >5.5 mg/dL and entered maintenance once sP was ≤5.5 mg/dL. The starting dose of OLC during titration was
1500 mg/day (500 mg thrice daily).
-6-
In
the study, 106 patients were enrolled, of which 86 patients entered titration and were followed as the Safety Population. Of the 86,
78 entered the maintenance period. Of the 78 patients that entered maintenance, 7 patients did not have phosphate control, leaving an
Evaluable Population of 71 patients, exceeding the planned enrollment number of 60. Of the 86 patients, the trial enrolled 47 males and
39 females with a mean age of 62. Renvela® was the most prescribed phosphate binder for patients entering the study.
Primary
Endpoint - Tolerability: The objective of the OLC-201 trial was to evaluate the tolerability of clinically effective doses of OLC
in CKD patients on dialysis. A clinically effective dose was established when a patient achieved a serum phosphate level ≤5.5 mg/dL.
Tolerability was assessed based on the incidence of treatment-related AEs leading to discontinuation from the study in the maintenance
period. In the OLC-201 trial, there was only 1 discontinuation due to a treatment-related AE in the Evaluable Population, a rate of 1.4%.
In the Safety Population of 86 patients there were only 3 treatment-related discontinuations, a rate of 3.5%. In total, 5 patients discontinued
due to AEs in the Safety Population, 3 were related to OLC and 2 were deemed unrelated to OLC.
Secondary
Endpoint - Safety: The secondary endpoint assessing safety was reported as the treatment-related AEs occurring in ≥5% of patients.
The safety analysis covered all 86 patients in the Safety Population. Consistent with the AEs observed with other phosphate binders,
the AEs were gastrointestinal related with diarrhea and vomiting being the most common at 9% and 6% respectively. There were no treatment-related
serious adverse events (SAEs). Six patients experienced SAEs but those were deemed not related to OLC treatment. Most treatment-related
AEs were mild to moderate in severity with only 2 AEs reported as severe. (Figure 7)
Figure
7: OLC Pivotal Phase 2 Trial Treatment-Related Adverse Events
Serum
Phosphate Control: While the UNI-OLC-201 study was not designed to evaluate efficacy, the trial enrolled patients on stable doses
of approved hyperphosphatemia medications. At baseline 59% of patients had phosphate levels ≤5.5 mg/dL, the level recommended by KDOQI
guidelines. After washout from the prior phosphate binders, 90% of patients were able to achieve phosphate levels ≤5.5ng/dL at the
end of titration with OLC. This includes the last serum phosphate levels from all patients including those that discontinued during titration:
77/86 (90%) (Figure 8). In addition, 69% of the 71 Evaluable Patients achieved a target serum phosphate level of ≤5.5 mg/dL
at OLC doses of 1500 mg/day or lower. (Figure 9)
Figure
8: 90% Of Patients Were Able to Achieve Phosphate Levels ≤5.5ng/dL with OLC.
-7-
Figure
9: 69% of the 71 Evaluable Patients Achieved a Target Serum Phosphate Level of ≤5.5 mg/dL at OLC Doses of 1500 mg/Day or Lower
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 10).
Figure 10: Daily Urine Phosphate Reduction in Healthy Volunteers
-8-
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 Oxylanthanum Carbonate 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 (-37.83, 45.12), which is well within the acceptance range of (-64.80, 64,80). It was concluded that Oxylanthanum
Carbonate was bioequivalent to Fosrenol. Primary outcome data is presented in the table below (Figure 11).
Figure
11: Summary of Mean Change in Urinary Phosphorus Excretion (mg/day)
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. After reviewing the data, the Agency recommended 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 reported positive results in June 2024. Unicycive announced the OLC NDA submission in September
2024 and received a PDUFA date of June 28, 2025. In March 2025, FDA conducted a general surveillance inspection
of Shilpa Medicare Ltd, where the company received one procedural observation in form 483.
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U.S.
Commercial 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 pills each day which in some cases must be chewed and which often results in poor adherence to the prescribed
drug therapy (Figure 12). 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 may lead to improved patient compliance/adherence and more effective disease management.
Figure
12: Recommended Daily Starting Dose for 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.We believe that due to its novel mechanism of action, Xphozah represents an
important new addition to the nephrologist’s hyperphosphatemia treatment armamentarium. 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 lowering
therapy options, we believe that OLC may be the most logical phosphate binder to combine with tenapanor making these two new medicines
complimentary rather 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.
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 and in some territories have licensed out commercial rights. 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 or complementary 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.
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Changing
Access and Reimbursement Environment
Historically, under the End-Stage Renal Disease
(ESRD) Prospective Payment System (PPS), referred to commonly as “the bundle”, dialysis-related drugs have been included
in the bundled payment system, with certain exceptions. Oral-only drugs, including phosphate lowering therapies (PLTs) like OLC, had
been exempted from inclusion in the ESRD PPS until January 1, 2025. Beginning in 2025, the Centers for Medicare & Medicaid Services
(CMS) has included these oral-only renal dialysis drugs into the PPS. Because PLT payments were not previously included in the bundle,
CMS has added these drugs through the Transitional Drug Add-on Payment Adjustment (TDAPA). The TDAPA is designed to provide separate
reimbursement for eligible new dialysis drugs for a period of two or more years, based on the drug’s Average Sales Price (ASP).
This adjustment is paid as an add-on to the base PPS rate for each dialysis treatment to facilitate the adoption of innovative therapies
in the dialysis space.
Upon FDA approval, we believe our product, OLC,
will be included in the ESRD PPS bundle and be eligible for TDAPA. We will be required to submit a TDAPA application for OLC, a process
that has historically taken from 3-6 months from time of submission to approval. If TDAPA designation is granted, OLC will become eligible
for separate TDAPA payment based on its average sales price (ASP), subject to quarterly updates by CMS. The payment rate will be at 100%
of OLC’s ASP for 2 years and at 65% of ASP for an additional 3 years under the post-TDAPA extension. After the end of the TDAPA
period for OLC, no further separate payments will be made and dialysis organizations will absorb the cost of OLC into the established
ESRD PPS bundled payment.
We believe that the timing of these reimbursement
changes coincides favorably with our anticipated launch timing of OLC and may provide for a more rapid launch uptake and for additional
market access and 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. Under prior Part D reimbursement, Medicare patients often faced prior
authorization and high co-pays for branded drugs which tended to restrict access to these drugs. In the new bundled reimbursement environment
with TDAPA, Medicare patients no longer face Part D program restrictions and are expected to enjoy greater access to phosphate lowering
therapies.
We also see a pricing benefit to OLC under TDAPA.
In the past reimbursement environment, manufacturers often paid 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 net price advantage over
other branded competitors in the market.
Most dialysis clinics operate within dialysis
organization networks, the largest of which are Fresenius, DaVita, and U.S. Renal Care, which together account for over 85% of US dialysis
patients. Treatment within these dialysis organizations is usually driven by medical protocols that dialysis organizations (DOs) implement
across their entire network of clinics. Upon approval of OLC, we intend to enter into mutually beneficial commercial supply contracts
with DOs to ensure access to OLC for appropriate patients by gaining favorable placement on treatment protocols and formularies.
There is no guarantee that CMS will ultimately designate OLC as eligible
for TDAPA, and should such eligibility be denied, it could substantially impact the commercialization and revenue potential of OLC. Even
if TDAPA is granted, downward pricing pressure in the post-TDAPA period could materially reduce our revenue from the drug and adversely
affect our profitability, financial results, and future prospects.
Transitional Drug Add-on Payment Adjustment
(TDAPA)
The Transitional Drug Add-on Payment Adjustment
(TDAPA) is part of the End-Stage Renal Disease (ESRD) Prospective Payment System (PPS), providing additional payments for certain new
renal dialysis drugs and biological products. Implemented by the Centers for Medicare & Medicaid Services (CMS), TDAPA helps integrate
innovative treatments into ESRD care by offering financial support to dialysis facilities during the adoption phase. This support enables
facilities to utilize new treatments that may otherwise face adoption barriers, such as high initial costs and the need for adjustments
to new therapies. The program also helps bridge the gap between product launch and integration into the ESRD PPS, fostering the introduction
of novel treatments and innovation in ESRD care.
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Applications
for the TDAPA under the ESRD PPS must be submitted through the electronic application intake system, Medicare Electronic Application
Request Information SystemTM (MEARIS). Under CMS regulations (42 C.F.R. § 413.234(a)), to be eligible for a TDAPA, the product must
be a “new renal dialysis drug or biological product,” meaning it:
● Is commercially available.
● Has been designated by CMS as a renal dialysis service under § 413.171.
HCPCS
codes (Healthcare Common Procedure Coding System) are a set of standardized codes used to identify medical procedures, services, supplies,
and equipment for billing and documentation purposes in healthcare settings. HCPCS codes are primarily used by healthcare providers,
Medicare, Medicaid, and private insurers for billing, claims processing, and reimbursement. These codes ensure that healthcare providers
are reimbursed accurately and consistently for services and products provided to patients.
A
company typically applies for a HCPCS (Healthcare Common Procedure Coding System) code when they introduce a new product, service, or
procedure that needs to be standardized for billing and reimbursement purposes. The review cycle for HCPCS codes generally occurs quarterly,
with specific deadlines for submission.
Because
applicants are required to provide a Healthcare Common Procedure Coding System (HCPCS) Application Confirmation Number when applying
for the TDAPA, the TDAPA application should be submitted after the application for a HCPCS code. The TDAPA and HCPCS application submissions
will be reviewed simultaneously on a quarterly basis, by following the CMS Level II HCPCS application deadlines for drugs and biological
products. The TDAPA submissions received after the Level II HCPCS quarterly submission deadline will be reviewed in the following quarter.
CMS
aims for an effective date for applying the TDAPA for a particular product that is one quarter after the effective date of the HCPCS
code for the product, or approximately 6 months after the quarterly submission deadline, however, a longer evaluation period may be necessary
due to a number of factors.
TDAPA
Payment Process
The TDAPA
is based on 100 percent of average sales price (ASP). If ASP is not available, then the TDAPA is based on 100 percent of wholesale acquisition
cost (WAC). If WAC is unavailable, then the payment is based on the drug manufacturer’s invoice.
The
TDAPA is paid for 2 years. The TDAPA payment period begins on the effective date of the CMS Change Request (CR). During the time a new
renal dialysis drug or biological product is eligible for the TDAPA, it is not an eligible ESRD outlier service as defined under 42 C.F.R.
§ 413.237(a)(1) and therefore is ineligible for outlier payment.
Post-TDAPA
Add-On Payment Adjustment
At the end
of the TDAPA payment period, the new renal dialysis drug or biological product is paid the post-TDAPA add-on payment adjustment and no
changes to the base rate are made. New drugs or biological products are eligible for the post-TDAPA add-on adjustment for 3 years.
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CMS
calculates the adjustment annually based on the most recent 12 months of claims data. For products without a full year of data, the adjustment
amount will be published in a Change Request (CR) once 12 months of data are available (89 FR 89135–98136). The adjustment is based
on the total expenditure for the drug divided by total ESRD PPS expenditures, reduced by a case-mix standardization factor and a 65%
risk-sharing factor, then inflated by the market basket price proxy for pharmaceuticals. All Part B drug manufacturers report Average
Sales Price (ASP) data for relevant products on the ASP Reporting website. If CMS doesn’t receive the latest ASP data, the adjustment
won’t be applied for the drug in the upcoming or future years. The adjustment may vary quarterly, depending on the number of drugs
and biological products included in the calculation. The adjustment paid on a claim is adjusted by patient-level case-mix factors.
Recent
TDAPA Approvals:
In October
2024, CMS approved a TDAPA application for Akebia’s VAFSEO® (vadadustat) under the ESRD PPS. The TDAPA payment period is January
1, 2025, through December 31, 2026.
Effective
January 1, 2025, the following oral-only phosphate binders are approved for the TDAPA under the ESRD PPS: sevelamer carbonate, sevelamer
hydrochloride, sucroferric oxyhydroxide, lanthanum carbonate, ferric citrate, and calcium acetate. Phosphate binders are not considered
included in the ESRD PPS base rate, and they will be paid for using the TDAPA under the ESRD PPS for at least 2 years. At the end of
the TDAPA payment period, CMS will go through rulemaking to modify the base rate, if appropriate, to account for these drugs in the ESRD
PPS bundled payment. Implementation instructions are included in the TDAPA Administrative Issuances section above.
Previous
TDAPA Approvals:
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, on October 31, 2020, the Company entered into an agreement with Shilpa Medicare Ltd (“Shilpa”)
based in India. Pursuant to the Agreement, Shilpa provides certain development, manufacturing, supply and other CMC-related services related