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 September 30, 2022
☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
Commission File Number 001-38174
Citius Pharmaceuticals, Inc.
(Exact name of Registrant as specified in its Charter)
11 Commerce Drive, First Floor, Cranford,
NJ07016
(Address of principal executive offices) (Zip Code)
(908)967-6677
(Registrant’s telephone number, including
area code)
Securities registered pursuant to Section 12(b)
of the Exchange Act:
Title of Each Class Trading Symbol(s) Name of Each Exchange on Which Registered
Common Stock, par value $0.001 per share CTXR The NASDAQ Capital Market
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 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 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 during the preceding
12 months (or for such shorter period that the registrant was required to submit such files). ☒Yes☐ No
Indicate by check mark whether the registrant
is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company.
See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,”
and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If an emerging growth company, indicate by check
mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting
standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant
has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial
reporting under Section 404(b) of the Sarbanes-Oxley Act by the registered public accounting firm that prepared or issued its audit report.
☐
Indicate by check mark whether the registrant
is a shell company (as defined in Rule 12b-2 of the Exchange Act). ☐
Yes ☒ No
The aggregate market value of the voting and non-voting
common equity held by non-affiliates computed by reference to the price at which the common equity was last sold, or the average bid and
asked price of such common equity, as of the last business day of the registrant’s most recently completed second fiscal quarter
(March 31, 2022) was approximately $240 million.
Affiliates for the purpose of this item refers
to the issuer’s executive officers and directors and/or any persons or firms (excluding those brokerage firms and/or clearing houses
and/or depository companies holding issuer’s securities as record holders only for their respective clients’ beneficial interest)
owning 10% or more of the issuer’s common stock, both of record and beneficially.
Indicate the number of shares outstanding of each
of the registrant’s classes of common stock, as of the latest practicable date:
146,211,130 shares as of December 15, 2022, all
of one class of common stock, $0.001 par value.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the Company’s Proxy Statement
for the Annual Meeting of Stockholders expected to be held on February 7, 2023 are incorporated by reference in Part III of this Report.
Citius Pharmaceuticals, Inc.
FORM 10-K
September 30, 2022
TABLE OF CONTENTS
Page
PART I
Item 1. Business 1
Item 1A. Risk Factors 24
Item 1B Unresolved Staff Comments 45
Item 2. Properties 45
Item 3. Legal Proceedings 45
Item 4. Mine Safety Disclosures 45
PART II
Item 6. [Reserved] 46
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 53
Item 8. Financial Statements and Supplementary Data F-1 to F-20
Item 9A. Controls and Procedures 54
Item 9B. Other Information 54
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 54
PART III
Item 10. Directors, Executive Officers and Corporate Governance 55
Item 11. Executive Compensation 55
Item 14. Principal Accountant Fees and Services 55
PART IV
Item 15. Exhibits and Financial Statement Schedules 56
Signatures 60
i
NOTES
In this annual report on Form 10-K, and unless
the context otherwise requires, the “Company,” “we,” “us” and “our” refer to Citius Pharmaceuticals,
Inc. and its wholly-owned subsidiaries Citius Pharmaceuticals, LLC, Leonard-Meron Biosciences,
Inc. and Citius Acquisition Corp., and its majority-owned subsidiary, NoveCite, Inc.,
taken as a whole.
Mino-Lok® is our registered trademark. All
other trade names, trademarks and service marks appearing in this prospectus are the property of their respective owners. We have assumed
that the reader understands that all such terms are source-indicating. Accordingly, such terms, when first mentioned in this report, appear
with the trade name, trademark or service mark notice and then throughout the remainder of this report without trade name, trademark or
service mark notices for convenience only and should not be construed as being used in a descriptive or generic sense.
FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K contains “forward-looking
statements.” Forward-looking statements include, but are not limited to, statements that express our intentions, beliefs, expectations,
strategies, predictions, or any other statements relating to our future activities or other future events or conditions. These statements
are based on current expectations, estimates and projections about our business based, in part, on assumptions made by management. These
statements are not guarantees of future performance and involve risks, uncertainties and assumptions that are difficult to predict. Therefore,
actual outcomes and results may, and are likely to, differ materially from what is expressed or forecasted in the forward-looking statements
due to numerous factors discussed from time to time in this report, including the risks described under Item 1A - “Risk Factors,”
and Item 7 - “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in this report
and in other documents which we file with the Securities and Exchange Commission (“SEC”). In addition, such statements could
be affected by risks and uncertainties related to:
● the cost, timing, and results of our pre-clinical and clinical trials;
Any forward-looking statements speak only as of
the date on which they are made, and, except as may be required under applicable securities laws, we do not undertake any obligation to
update any forward-looking statement to reflect events or circumstances after the filing date of this report.
SUMMARY OF RISK FACTORS
An investment in our securities involves a high
degree of risk. You should carefully consider the risks summarized in Item 1A, “Risk Factors” included in this report. These
risks include, but are not limited to, the following:
ii
iii
iv
PART I
Item 1. Business
Overview
Citius Pharmaceuticals, Inc. (the “Company,”
“Citius” or “we”), headquartered in Cranford, New Jersey, is a late-stage pharmaceutical company dedicated to
the development and commercialization of first-in-class critical care products with a focus on oncology, anti-infectives in adjunct cancer
care, unique prescription products and stem cell therapy. Our goal generally is to achieve leading market positions by providing therapeutic
products that address unmet medical needs yet have a lower development risk than usually is associated with new chemical entities. New
formulations of previously approved drugs with substantial existing safety and efficacy data are a core focus. We seek to reduce development
and clinical risks associated with drug development, yet still focus on innovative applications. Our strategy centers on products that
have intellectual property and regulatory exclusivity protection, while providing competitive advantages over other existing therapeutic
approaches.
The Company was founded as Citius Pharmaceuticals,
LLC, a Massachusetts limited liability company, on January 23, 2007. On September 12, 2014, Citius Pharmaceuticals, LLC entered into a
Share Exchange and Reorganization Agreement, with Citius (formerly Trail One, Inc.), a publicly traded company incorporated under the
laws of the State of Nevada. Citius Pharmaceuticals, LLC became a wholly-owned subsidiary of Citius. On March 30, 2016, Citius acquired
Leonard-Meron Biosciences, Inc. (“LMB”) as a wholly-owned subsidiary. LMB was a pharmaceutical company focused on the development
and commercialization of critical care products with a concentration on anti-infectives. On September 11, 2020, we formed NoveCite, Inc.
(“NoveCite”), a Delaware corporation, of which we own 75% of the issued and outstanding capital stock. NoveCite is focused
on the development and commercialization of its proprietary mesenchymal stem cells for the treatment of acute respiratory disease syndrome
(“ARDS”). On August 23, 2021, we formed Citius Acquisition Corp. (“Citius Acq.”) as a wholly-owned subsidiary
in conjunction with the acquisition of I/ONTAK, which began operations in April 2022.
Since its inception, the Company has devoted substantially
all of its efforts to business planning, acquiring our proprietary technology, research and development, recruiting management and technical
staff, and raising capital. We are developing five proprietary products: I/ONTAK, in-licensed in September 2021, a engineered IL-2 diphtheria
toxin fusion protein, for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (“CTCL”); Mino-Lok,
an antibiotic lock solution used to treat patients with catheter-related bloodstream infections by salvaging the infected catheter; Halo-Lido,
a corticosteroid-lidocaine topical formulation that is intended to provide anti-inflammatory and anesthetic relief to persons suffering
from hemorrhoids; Mino-Wrap, a liquifying gel-based wrap for reduction of tissue expander infections following breast reconstructive surgeries;
and NoveCite, a mesenchymal stem cell therapy for the treatment of ARDS. We believe these unique markets for our products are large, growing,
and underserved by the current prescription products or procedures.
Citius is subject to a number of risks common
to companies in the pharmaceutical industry including, but not limited to, risks related to the development by Citius or its competitors
of research and development stage products, market acceptance of its products that receive regulatory approval, competition from larger
companies, dependence on key personnel, dependence on key suppliers and strategic partners, the Company’s ability to obtain additional
financing and the Company’s compliance with governmental and other regulations.
I/ONTAK
Overview
In September 2021, the Company announced that
it had entered into a definitive agreement with Dr. Reddy’s Laboratories SA, a subsidiary of Dr. Reddy’s Laboratories, Ltd. (collectively,
“Dr. Reddy’s”), to acquire its exclusive license of E7777 (denileukin diftitox), a late-stage oncology immunotherapy for the
treatment of CTCL, a rare form of non-Hodgkin lymphoma. E7777, an engineered IL-2-diphtheria toxin fusion protein, is an improved formulation
of oncology agent, ONTAK®, which was previously approved by the U.S. Food and Drug Administration (“FDA”) for the treatment
of patients with persistent or recurrent CTCL. We have renamed E7777 as I/ONTAK although we refer to it as E7777 at times in this report.
1
Phase 3 Trial
A global, multicenter, open label single arm pivotal
clinical trial for the treatment of patients with persistent or recurrent CTCL was initiated in 2013. Inclusion criteria for the study
were to evaluate patients in advanced stage CTCL (Mycosis Fungoides or Sézary Syndrome), who received at least one prior CTCL therapy.
The pivotal trial was divided into two phases,
a lead-in phase with 21 subjects that evaluated dose finding, pharmacokinetics and immunogenicity, as well as assessing the Objective
Response Rate (the “ORR”). An ORR is defined as a greater than 50% reduction in tumor burden.
The results of the lead-in study were:
● No new safety signals were identified compared to Ontak.
The second phase to the pivotal trial was a 70-patient
study administered at the 9 mcg/kg/dose rate for 5 consecutive days in 21-day cycles, The inclusion criteria was identical to the lead-in
study and the primary objective was to evaluate the ORR.
According to the trial protocol, the treatment
would be considered efficacious and demonstrate clinical benefit if the lower limit of the 2-sided 95% exact confidence interval (CI)
of the observed ORR exceeds 25.0%, as determined by the Independent Review Committee (IRC).
The results of the pivotal trial were:
2
Selected Preliminary Efficacy Data Table
Duration of Response (months)
Subjects with Objective Response (n) 25 30
Median observed DOR (months) 6.5 5.7
Time to Response (months)
Subjects with Objective Response (n) 25 30
Investigator Initiated Trials
We believe there is an opportunity in the field
of immune-oncology and have undertaken two investigator-initiated trials to evaluate the potential safety and efficacy of E7777 for potential
as an immune-oncology combination therapy.
A Phase 1 trial was initiated in June 2021 at
the University of Minnesota, Masonic Cancer Center. This study is a single-arm non-randomized trial which has an estimated enrollment
of 30 participants who will be administered E7777 prior to tisagenlecleucel Chimeric Antigen Receptor, (“CAR-T”) therapy.
The Phase 1 study consists of two components: dose finding to establish a maximum tolerated dose (“MTD”) of E7777 in combination
with CART-T Therapy, and a small extension component to provide an estimate of efficacy at that MTD.
A second Phase 1 Study was initiated in September
2022 at the University of Pittsburg Medical Center, Hillman Cancer Center. This study will be investigating the safety and efficacy of
a combined regimen of pembrolizumab with T-regulatory cell depletion and E7777 in patients diagnosed with recurrent or metastatic solid
tumors in the second line setting.
3
Regulatory Development
In the 1990’s, denileukin diftitox was developed
at Boston University and the National Cancer Institute (“NCI”) in collaboration with Seragen, Inc. In 1999, Ontak® (denileukin
diftitox) was granted accelerated approval by the FDA for the treatment of persistent or recurrent CTCL with Ligand Pharmaceuticals, Inc.
(“Ligand”) acquiring the marketing rights in that same year. In 2006, Eisai Co., Ltd. (“Eisai”) acquired the commercial
rights to Ontak from Ligand.
In 2008, the FDA granted full approval to Ontak
for CTCL.
In 2011, there was a commercial supply disruption
due to manufacturing issues and a new formulation of denileukin diftitox was developed under the code name E7777. The FDA considered this
a new product with a new IND being filed. In ensuing discussions, the FDA agreed to a development plan that included a single arm, open
label study to conclude safety and efficacy of E7777 and a CMC development plan that demonstrates the new process results in a comparable
drug product.
In 2011, the FDA Office of Orphan Products Development
granted E7777 orphan drug designation status for the treatment of Peripheral T-Cell Lymphoma (“PTCL”). In 2013, the FDA Office
of Orphan Products Development granted E7777 orphan drug designation status for the treatment of CTCL.
In 2013, the first patient was enrolled into the
lead-in phase of the pivotal study for the E7777 U.S. CTCL clinical trial.
In 2014, commercial sales of Ontak were discontinued
when the product was voluntarily withdrawn from the market due to manufacturing issues at the contract manufacturer.
In 2015, the last patient enrolled exited the
lead-in phase of the E7777 U.S. CTCL clinical trial.
In March 2016, Dr. Reddy’s Laboratories
(“DRL”) acquired the global rights to E7777 from Eisai, other than far east countries, with Eisai retaining the rights in
those countries.
In June 2016, the first patient was enrolled in
the Phase 3 pivotal study for E7777 CTCL in the U.S.
In March 2020, Eisai filed an NDA for E7777 in
Japan for both CTCL and PTCL and in March 2021 received approvals in both CTCL and PTCL.
Patient enrollment for
the Phase 3 Pivotal study of E7777 was completed in December 2021. In April 2022, we reported that the topline results from the Phase
3 trial were consistent with the prior formulation. Moreover, no new safety signals were identified.
In September 2022, we
filed a biologics license application (“BLA”) for E7777. In December 2022, we announced that the FDA had accepted the BLA.
Market Opportunity
CTCL’s are a heterogeneous subset of extranodal
non-Hodgkin lymphomas (“NHL”) of mature, skin-homing T-cells that are mainly localized to the skin. The most common types
of CTCL are mycosis fungoides (“MF”) and primary cutaneous CD30+ anaplastic large cell lymphoma (pcALCL), jointly representing
an estimated 80–85% of all CTCL. Sézary Syndrome (“SS”), a very rare subtype (~2–5% of CTCL) characterized
by diffuse inflammatory, often exfoliative, erythroderma and by leukemic and nodal involvement, displays a significant degree of clinical
and biological overlap with MF and has long been considered a clinical variant of MF, although recent evidence suggests that it may be
a separate entity. The rest is represented by extremely rare, generally more aggressive subtypes. In light of the overlap between MF and
SS, and considering that many of the systemic therapy options for the two neoplasms are the same, some consider the treatment approach
to MF and SS as if they were a single disease entity (MF/SS). However, some of the drugs currently in use, or in development, for MF/SS
appear to be more effective in clearing different anatomical compartments (skin versus blood, for example) and therefore have differential
efficacy in MF and SS.
4
Based on Surveillance Epidemiology and End Results
(SEER) data from 2001–2007, the estimated incidence rate of MF/SS in the U.S. is 0.5/100,000 or about 2,500–3,000 new cases
per year representing about 25% of all T-cell lymphomas.
The Company estimates that there are 30,000 –
40,000 patients living with CTCL in the U.S. with approximately 16,000 – 20,000 having mycosis fungoides. Of those, the Company
further estimates that there are 10,000 patients with relapsed or refractory CTCL that require systemic therapy.
The Company also estimates that the addressable
U.S. market is approximately $300,000,000 - $400,000,000 for patients with advanced stage relapsed or refractory CTCL.
Proposed Spinoff
In May 2022, we announced
that we intend to split the Company’s assets into two separate publicly traded entities. We plan to form a new company focused on
developing and commercializing I/ONTAK. Our other pipeline assets, including Mino-Lok, would remain at Citius. Citius would continue to
trade on the Nasdaq exchange under its current ticker CTXR. The strategic action is intended to optimize organizational resources and
investment capital to support the successful execution of each development program. The transactions are expected to be completed in calendar
year 2023, subject to the satisfaction of customary conditions, including final approval from the Citius Board of Directors, regulatory
approvals, and SEC filings. There can be no assurance regarding the ultimate timing of the proposed transaction or that the transaction
will be completed at all.
Mino-Lok®
Overview
Mino-Lok is a patented solution containing minocycline,
disodium ethylenediaminetetraacetic acid (edetate), and ethyl alcohol, all of which act synergistically to treat and salvage infected
central venous catheters (“CVCs”) in patients with catheter related bloodstream infections (“CRBSIs”). Mino-Lok
breaks down biofilm barriers formed by bacterial colonies, eradicates the bacteria, and provides anti-clotting properties to maintain
patency in CVCs.
The administration of Mino-Lok consists of filling
the lumen of the catheter with 0.8 ml to 2.0 ml of Mino-Lok solution. The catheter is then “locked”, meaning that the solution
remains in the catheter without flowing into the vein. The lock is maintained for a dwell-time of two hours while the catheter is not
in use. If the catheter has multiple lumens, all lumens may be locked with the Mino-Lok solution either simultaneously or sequentially.
If patients are receiving continuous infusion therapy, the catheters alternate between being locked with the Mino-Lok solution and delivering
therapy. The Mino-Lok therapy is two hours per day for at least five days, usually with two additional locks in the subsequent two weeks.
After locking the catheter for two hours, the Mino-Lok solution is aspirated, and the catheter is flushed with normal saline. At that
time, either the infusion will be continued, or will be locked with the standard-of-care lock solution until further use of the catheter
is required. In a clinical study conducted by MD Anderson Cancer Center (“MDACC”), there were no serum levels of either minocycline
or edetate detected in the sera of several patients who underwent daily catheter lock solution with minocycline and edetate (“M-EDTA”)
at the concentration level proposed in Mino-Lok treatment. Thus, it has been demonstrated that the amount of either minocycline or edetate
that leaks into the serum is very low or none at all.
Phase 2b Results
From April 2013 to July 2014, 30 patients with
CVC-related bloodstream infection were enrolled at MDACC in a prospective Phase 2b study. Patients received Mino-Lok therapy for two hours
once daily for a minimum of five days within the first week, followed by two additional locks within the next two weeks. Patients were
followed for one month post-lock therapy. Demographic information, clinical characteristics, laboratory data, therapy, as well as adverse
events and outcome were collected for each patient. Median age at diagnosis was 56 years (range: 21-73 years). In all patients, prior
to the use of lock therapy, systemic treatment with a culture-directed, first-line intravenous antibiotic was started. Microbiological
eradication was achieved at the end of therapy in all cases. None of the patients experienced any serious adverse event related to the
lock therapy.
5
The active arm, which is the Mino-Lok treated
group of patients, was then compared to 60 patients in a matched cohort that experienced removal and replacement of their CVCs within
the same contemporaneous timeframe. The patients were matched for cancer type, infecting organism, and level of neutropenia. All patients
were cancer patients and treated at MDACC. The efficacy of Mino-Lok therapy was 100% in salvaging CVCs, demonstrating equal effectiveness
to removing the infected CVC and replacing it with a new catheter.
The main purpose of the study was to show that
Mino-Lok therapy was at least as effective as the removal and replacement of CVCs when CRBSIs are present, and that the safety was better,
that is, the complications of removing an infected catheter and replacing with a new one could be avoided. In addition to having a 100%
efficacy rate with all CVCs being salvaged, Mino-Lok therapy had no significant adverse events (“SAEs”), compared to an 18%
SAE rate in the matched cohort where patients had the infected CVCs removed and replaced with a fresh catheter. There were no overall
complication rates in the Mino-Lok arm group compared to 11 patients with events (18%) in the control group. These events included bacterial
relapse (5%) at four weeks post-intervention, and a number of complications associated with mechanical manipulation in the removal or
replacement procedure for the catheter (10%) or development of deep-seated infections such as septic thrombophlebitis and osteomyelitis
(8%). As footnoted, six patients had more than one complication in the control arm group.
Mino-Lok® Arm Control Arm
Parameter N (%) N (%)%
Cancer type
ICU Admission 4 (13 ) 4 (7 )
Mech.Ventilator 3 (10 ) 0 (0 )
Bacteremia
- Relapse 0 (0 ) 3 (5 )
Complications 0 (0 ) 8 (13 )
SAEs related R&R 0 (0 ) 6 (10 )
Overall Complication Rate 0 (0 )% 11 ** (18 )%
* 1 Polymicrobial patient had a Gram+ and a Gram- organism cultured
** 6 Patients had > 1 complication
Source: Dr. Issam Raad, Antimicrobial Agents
and Chemotherapy, June 2016, Vol. 60 No. 6, Page 3429
Phase 3 Trial
In November 2016, the Company initiated site recruitment
for Phase 3 clinical trials. From initiation through the first quarter of 2017, the Company received input from several sites related
to the control arm as being less than standard-of-care for some of the respective institutions. The Company worked closely with the FDA
with respect to the design of the Phase 3 trial and received feedback on August 17, 2017. The FDA stated that they recognized that there
is an unmet medical need in salvaging infected catheters and agreed that an open label, superiority design would address the Company’s
concerns and would be acceptable to meet the requirements of a new drug application. The Company amended the Phase 3 study design to remove
the saline and heparin placebo control arm and to use an active control arm that conforms with today’s current standard-of-care.
Patient enrollment commenced in February 2018.
6
The Mino-Lok Phase 3 Trial was originally planned
to enroll 700 patients in 50 participating institutions, all located in the U.S. There were interim analyses at both the 50% and 75% points
of the trial as measured by the number of patients treated. As of November 30, 2022, there are 18 active sites in the United States currently
enrolling patients including such academic centers as MDACC, Henry Ford Health Center, Georgetown University Medical Center, and others.
In May 2022, the Company selected Biorasi, LLC
(“Biorasi”), a global clinical research organization (CRO), to help expand the Company’s Phase 3 Mino-Lok trial by implementing
additional sites outside the United States. There currently are 17 sites selected in India, making a total of 35 participating Mino-Lok
institutions globally.
In September 2019, the Company announced that
the FDA agreed to a new primary efficacy endpoint of “time to catheter failure” in comparing Mino-Lok to the antibiotic lock
control arm. This change in the trial design reduced the required patient sample size of the trial from 700 subjects to approximately
144 available subjects to achieve the pre-specified 92 catheter failure events needed to conclude the trial. Additionally, the Company
submitted a response to the FDA that it would implement this change in the primary endpoint and expected it to result in less than 150
subjects needed in its Phase 3 trial. The new primary endpoints require that the time to catheter failure be at least 38 days for Mino-Lok
versus 21 days for the standard of care antibiotic locks.
In October 2019, the FDA agreed that the patient
sample size of approximately 144 patients was acceptable.
In October 2019, the Company announced that the
Phase 3 trial had reached the 40% completion triggering an interim futility analysis by the data monitoring committee (the “DMC”).
The DMC is an independent panel of experts that review progress regarding the safety and efficacy of drugs in clinical trials, and to
determine if the trial may be futile in achieving its endpoints or if the trial should be modified in any way.
In December 2019, the DMC convened and recommended
that the trial continue with no changes because the analysis showed a positive outcome, as it met the prespecified interim futility analysis
criteria.
In May 2020, we announced that we are providing
free access to Mino-Lok for healthcare providers under an Expanded Access protocol to ease the burden associated with the COVID-19 pandemic.
Through the Expanded Access protocol, an infected central venous catheter can now be treated with Mino-Lok, potentially avoiding the need
for the removal and replacement procedure.
In June 2020, we announced that we had received
positive feedback from the FDA on our proposed catheter compatibility studies for Mino-Lok. The studies, if and when successfully completed,
should allow Mino-Lok to be labeled for use with all commercially available CVCs and peripherally inserted central catheters (PICCs) on
the U.S. market. We further assume that these studies will meet European and world standards. The ability to be labeled without restrictions
with respect to catheter type would allow Mino-Lok unrestricted access to the full U.S. and world markets for an effective antibiotic
lock therapy for central line associated blood stream infections (“CLABSIs”).
In September 2020, we announced that another DMC
meeting was held to review the data being generated and analyzed in the Mino-Lok Phase 3 trial based on progress to date, and to make
recommendations to us as to any action that may be necessary regarding the study. After reviewing these data, the DMC members stated that
they did not find any safety signals; and they also recommended continuing the trial without any modifications. The DMC further conducted
an ad hoc meeting and agreed with the Company that a 75% interim analysis be conducted as planned in which superior efficacy is
evaluated. The 75% interim analysis was subsequently changed to a 65% interim analysis by the Company.
In September 2020, the Company announced that
the three registration batches for all components of Mino Lok were manufactured and that clinical sites were resupplied with registration
product.
In November 2020, the Company announced that the
three components of Mino-Lok, minocycline, disodium edetate (“EDTA”), and ethanol, were superior to EDTA and ethanol in their
ability to eradicate resistant staphylococcal biofilms.
The 65% interim analysis was completed in June
2021. In July 2021, the Company announced that following an unblinded data review of safety and efficacy, the independent DMC for the
trial recommended proceeding with the trial as planned. The DMC did not identify any safety concerns and no modifications were recommended
to the protocol-defined sample size or power to achieve the primary endpoint.
7
As of December 21, 2022, the Mino-Lok Phase 3
trial has resulted in:
● 169 patients enrolled to date vs. a planned 144 patients;
● 72 failure events to date vs. a planned 92 failure events; and
Completion of enrollment is expected in 2023.
Fast Track Designation
In October 2017, the Company received official
notice from the FDA that the investigational program for Mino-Lok was granted “Fast Track” status. Fast Track is a designation
that expedites FDA review to facilitate development of drugs which treat a serious or life-threatening condition and fill an unmet medical
need. A drug that receives Fast Track designation is eligible for the following:
Mino-Lok International Study
In October 2017, data from an international study
on Mino-Lok was presented at the Infectious Disease Conference, (“ID Week”), in San Diego, California. The 44-patient study
was conducted in Brazil, Lebanon and Japan and showed Mino-Lok therapy was an effective intervention to salvage long-term, infected CVCs
in CRBSIs in patients who had cancer with limited vascular access. This study showed 95% effectiveness for Mino-Lok therapy in achieving
microbiological eradication of the CVCs as compared to 83% for the control. The single failure in the Mino-Lok arm was due to a patient
with Burkholderia cepacia that was resistant to all antibiotics tested.
Stability Patent Application for Mino-Lok
In October 2018, the U.S. Patent and Trademark
Office (“USPTO”) issued U.S. Patent No. 10,086,114, entitled “Antimicrobial Solutions with Enhanced Stability.”
On October 9, 2019, the European Patent Office (“EPO”) granted European Patent No. 3370794, entitled “Antimicrobial
Solutions with Enhanced Stability.” The grant of this European patent strengthens the intellectual property protection for Mino-Lok
through November of 2036. This invention overcomes limitations in mixing antimicrobial solutions in which components have precipitated
because of physical and/or chemical factors, thus limiting the stability of the post-mix solutions. The scientists and technologists at
MDACC have been able to improve the stability of the post-mixed solutions through adjustments of the post-mixed pH of the solution. This
may allow for longer storage time of the ready-to-use solution. Citius holds the exclusive worldwide license which provides access to
this patented technology for development and commercialization of Mino-Lok.
8
Market Opportunity
In spite of best clinical practice, catheters
contribute to approximately 70% of blood stream infections that occur in the intensive care unit or are associated with hemodialysis or
cancer patients (approximately 470,000 per year). Bacteria enter the catheter either from the skin or intraluminally through the catheter
hub. Once in the catheter, bacteria tend to form a protective biofilm on the interior surface of the catheter that is resistant to most
antimicrobial solutions. The most frequently used maintenance flush, heparin, actually stimulates biofilm formation. Heparin is widely
used as a prophylactic lock solution, in spite of the evidence that it contributes to the promotion of biofilm formation. The formation
of bacterial biofilm usually precedes CRBSIs.
The standard of care in the management of CRBSI
patients consists of removing the infected CVC and replacing it with a new catheter at a different vascular access site. However, in cancer
and hemodialysis patients with long-term surgically implantable silicone catheters, removal of the CVC and reinsertion of a new one at
a different site might be difficult, or even impossible, because of the unavailability of other accessible vascular sites and the need
to maintain infusion therapy. Furthermore, critically ill patients with short-term catheters often have underlying coagulopathy, which
makes reinsertion of a new CVC at a different site, in the setting of CRBSIs, risky in terms of mechanical complications, such as pneumothorax,
misplacement, or arterial puncture. Studies have also revealed that CRBSI patients may be associated with serious complications, including
septic thrombosis, endocarditis and disseminated infection, particularly if caused by Staphylococcus aureus or Candida species.
Furthermore, catheter retention in patients with CRBSIs is associated with a higher risk of relapse and poor response to antimicrobial
therapy.
According to Maki et al., published in the Mayo
Clinic Proceedings in 2006, there are approximately 250,000 CRBSIs annually in the U.S. Subsequent to this study, our estimates have
ranged upwards to over 450,000 CLABSIs annually (see analysis in the table below). CRBSIs are associated with a 12% to 35% mortality rate
and an attributable cost of $35,000 to $56,000 per episode.
We estimate that the potential market for Mino-Lok
in the U.S. to be approximately $500 million to $1 billion as shown in the table below based on a target price of up to $300 per dose
of each salvage flush treatment.
Short-Term CVC Long-Term CVC Total
No. of Catheters 3 million 4 million 7 million
Avg. Duration (Days) 12 100 N/A
Catheter Days 36 million 400 million 436 million
Flushes/Catheter 5 7 6.7
Sources: Ann Intern Med 2000; 132:391-402,
Clev Clin J Med 2011; 78(1):10-17, JAVA 2007; 12(1):17-27, J Inf Nurs 2004;27(4):245-250, Joint Commission website Monograph, CLABSI and
Internal Estimates.
Under various plausible pricing scenarios, we
believe that Mino-Lok would be cost-saving to the healthcare system given that the removal of an infected CVC and replacement of a new
catheter in a different venous access site is estimated by us to cost between $8,000 and $10,000. Furthermore, there are potential additional
medical benefits, a reduction in patient discomfort and avoidance of serious adverse events with the Mino-Lok approach since the catheter
remains in place and is not subject to manipulation. We believe there will be an economic argument to enhance the adoption of Mino-Lok
by infection control committees at acute care institutions.
In January of 2017, we commissioned a primary
market research study with MEDACore, a subsidiary of Leerink, a healthcare focused network with more than 35,000 healthcare professionals,
including key opinion leaders, experienced practitioners and other healthcare professionals throughout North America, Europe, Asia and
other locations around the world. This network includes approximately 55 clinical specialties, 21 basic sciences and 20 business specialties.
As part of this market research project, we commissioned a third-party survey of 31 physicians to qualify the need for catheter salvage
in patients with infected, indwelling central venous lines, especially when the catheter is a tunneled or an implanted port. There were
19 infectious disease experts and 12 intensivists surveyed who all agreed that salvage would be preferable to catheter exchange to avoid
catheter misplacements, blood clots, or vessel punctures that can potentially occur during reinsertion. Most were also concerned that
viable venous access may not be available in patients who were vitally dependent on a central line.
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Halo-Lido
Overview
Halo-Lido is a topical formulation of halobetasol
propionate, a corticosteroid, and lidocaine that is intended for the treatment of hemorrhoids. To our knowledge, there are currently no
FDA-approved prescription drug products for the treatment of hemorrhoids. Some physicians are known to prescribe topical steroids for
the treatment of hemorrhoids. In addition, there are various topical combination prescription products containing halobetasol propionate
along with lidocaine or pramoxine, each a topical anesthetic, that are prescribed by physicians for the treatment of hemorrhoids. These
products contain drugs that were in use prior to the start of the Drug Efficacy Study Implementation (“DESI”) program and
are commonly referred to as DESI drugs. However, none of these single-agent or combination prescription products have been clinically
evaluated for safety and efficacy and approved by the FDA for the treatment of hemorrhoids. Further, many hemorrhoid patients use over
the counter (“OTC”) products as their first line therapy. OTC products contain any one of several active ingredients including
glycerin, phenylephrine, pramoxine, white petrolatum, shark liver oil and/or witch hazel, for symptomatic relief.
Development of Hemorrhoids Drugs
Hemorrhoids are a common gastrointestinal disorder,
characterized by anal itching, pain, swelling, tenderness, bleeding and difficulty defecating. In the U.S., hemorrhoids affect nearly
5% of the population, with approximately 10 million persons annually admitting to having symptoms of hemorrhoidal disease. Of these persons,
approximately one third visit a physician for evaluation and treatment of their hemorrhoids. The data also indicate that for both sexes
a peak of prevalence occurs from age 45 to 65 years with a subsequent decrease after age 65 years. Caucasian populations are affected
significantly more frequently than African Americans, and increased prevalence rates are associated with higher socioeconomic status in
men but not women. Development of hemorrhoids before age 20 is unusual. In addition, between 50% and 90% of the general U.S., Canadian
and European population will experience hemorrhoidal disease at least once in life. Although hemorrhoids and other anorectal diseases
are not life-threatening, individual patients can suffer from agonizing symptoms which can limit social activities and have a negative
impact on the quality of life.
Hemorrhoids are defined as internal or external
according to their position relative to the dentate line. Classification is important for selecting the optimal treatment for an individual
patient. Accordingly, physicians use the following grading system referred to as the Goligher’s classification of internal hemorrhoids:
Grade I Hemorrhoids not prolapsed but bleeding.
Grade II Hemorrhoids prolapse and reduce spontaneously with or without bleeding.
Grade III Prolapsed hemorrhoids that require reduction manually.
Development Activities to Date
In the fall of 2015, we completed dosing patients
in a double-blind dose ranging placebo-controlled Phase 2a study where six different formulations containing hydrocortisone and lidocaine
in various strengths were tested against the vehicle control. The objectives of this study were to: (1) demonstrate the safety and efficacy
of the formulations when applied twice daily for two weeks in subjects with Grade I or II hemorrhoids, and (2) assess the potential contribution
of lidocaine hydrochloride and hydrocortisone acetate, alone or in combination for the treatment of symptoms of Goligher’s Classification
Grade I or II hemorrhoids.
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Symptom improvement was observed based on a global
score of disease severity (“GSDS”) and based on some of the individual signs and symptoms of hemorrhoids, specifically itching
and overall pain and discomfort. Within the first few days of treatment, the combination products (containing both hydrocortisone and
lidocaine) were directionally favorable versus the placebo and their respective individual active treatment groups (e.g., hydrocortisone
or lidocaine alone) in achieving ‘almost symptom free’ or ‘symptom free’ status according to the GSDS scale. These
differences suggested the possibility of a benefit for the combination product formulation. As a result of this study, we determined that
the performance of the active arms of the study relative to the vehicle could be improved by re-formulating our topical preparation. Therefore,
we initiated work on vehicle formulation and evaluation of higher potency steroids.
Overall, results from adverse event reporting
support the safety profile of all test articles evaluated in this study and demonstrate similar safety profiles as compared to the vehicle.
The safety findings were unremarkable. There was a low occurrence of adverse events and a similar rate of treatment related adverse events
across all treatment groups. The majority of adverse events were mild and only one was severe. None of the adverse events were an SAE
and the majority of adverse events were recovered/resolved at the end of the study. There were only two subjects who were discontinued
from the study due to adverse events.
As part of this Phase 2 trial, information was
obtained relating to the use of the GSDS as an assessment tool for measuring the effectiveness of the test articles. Individual signs
and symptoms were also assessed but can vary from patient to patient. Therefore, the goal of the GSDS was to provide an assessment tool
that could be used for all patients regardless of which signs and symptoms they are experiencing. The GSDS proved to be a more effective
tool for assessing the severity of the disease and the effectiveness of the drug when compared to the assessment of the individual signs
and symptoms.
Citius developed this assessment tool as well
as other patient reported outcome endpoints for use in the recently begun Phase 2b trial and in subsequent trials. In June and July 2016,
we engaged the Dominion Group, a leading provider of healthcare and pharmaceutical marketing research services. The primary market research
was conducted to understand the symptoms that are most bothersome to patients better in order to develop meaningful endpoints for the
clinical trials. We also learned about the factors that drive patients to seek medical attention for hemorrhoids in an effort to understand
the disease impact on quality of life. The results of this survey, along with the information from the Phase 2b trial, allowed us to develop
our patient reported outcome evaluation tool, ePro. This tool can be used in clinical trials to evaluate the patients’ conditions
and to assess the performance of the test articles.
In March 2018, we announced that we had selected
a higher potency corticosteroid in our steroid/anesthetic topical formulation program for the treatment of hemorrhoids. The original topical
preparation, which we referred to as Hydro-Lido or CITI-001, which was used in the Phase 2a study, was a combination of hydrocortisone
acetate and lidocaine hydrochloride. The new formulation, CITI-002, which we refer to as Halo-Lido, combine lidocaine with the higher
potency corticosteroid halobetasol propionate for symptomatic relief of the pain and discomfort of hemorrhoids.
We held a Type C meeting with the FDA in December
2017 to discuss the results of the Phase 2a study and to obtain the FDA’s view on development plans to support the potential formulation
change for the planned Phase 2b study. We also requested the FDA’s feedback on our Phase 2b study design, including target patient
population, inclusion/exclusion criteria, and efficacy endpoints. The pre-clinical and clinical development programs for CITI-002 are
planned to be similar to those conducted for the development of CITI-001 to support the design for a planned Phase 3 clinical trial.
In April 2022,
we initiated a.multi-center, randomized, dose-ranging, double-blind, parallel group comparison Phase 2b
clinical trial. Five cohorts of adults with a clinical diagnosis of symptomatic Goligher’s classification Grade II or Grade III hemorrhoids
are planned to be dosed. Approximately 60 patients per cohort are expected to be enrolled, for a total of 300 patients.
The key objective of the study is to evaluate
the ability of the formulations used in each cohort to provide relief for patients with acute flare ups. The study will evaluate reduction
in hemorrhoidal symptoms (including: pain, burning, itching, and swelling) following treatment and is expected to provide the foundation
for development of the Phase 3 study.
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A Patient Reported Outcome (ePRO) instrument, developed by Citius with
FDA guidance, will be used by patients to record and report important safety and efficacy data in real time. The instrument has been adapted
for use on an electronic platform and will be loaded on patients’ hand-held smart devices. The study will also be used to validate the
ePRO. Data readout of the trial is expected in the second half of 2023.
Market Opportunity
The current market for OTC and topical prescription
(“Rx”) products for the symptomatic treatment of hemorrhoids is highly fragmented and includes approximately 20 million units
of OTC and over 4 million prescriptions. None of the Rx products have received FDA approval and are only available due to the DESI program,
which started decades ago after enactment of the 1962 Kefauver-Harris Drug Amendments. These DESI products have no FDA reviewed evidence
of efficacy or safety and may be subject to withdrawal if an approved product were to be introduced. Several topical combination prescription
products for the treatment of hemorrhoids are available containing hydrocortisone in strengths ranging from 0.5% to 3.0%, combined with
lidocaine in strengths ranging from 1.0% to 3.0%. The various topical formulations include creams, ointments, gels, lotions, enemas, pads,
and suppositories. The most commonly prescribed topical combination gel is sold as a branded generic product and contains 2.5% hydrocortisone
and 3.0% lidocaine.
We believe there are currently no FDA-approved
prescription drug products for the treatment of hemorrhoids. Although there are numerous Rx and OTC products commonly used to treat hemorrhoids,
none possess proven safety and efficacy data generated from rigorously conducted clinical trials. We believe that a novel topical formulation
of halobetasol propionate and lidocaine designed to provide anti-inflammatory and anesthetic relief and which has an FDA-approved label
specifically claiming the treatment of hemorrhoids will become an important treatment option for physicians who want to provide their
patients with a therapy that has demonstrated safety and efficacy in treating this uncomfortable and often recurring disease. We believe
that our Halo-Lido product represents an attractive, low-risk product opportunity with meaningful upside potential.
Market Exclusivity
We believe that we will be the first company to
conduct rigorous clinical trials and receive FDA approval of a topical corticosteroid-lidocaine combination product for the treatment
of hemorrhoids. If we receive FDA approval, we will qualify for three years of market exclusivity for our dosage strength and formulation.
In addition, we will also be the only product on the market specifically proven to be safe and effective for the treatment of hemorrhoids.
Generally, if a company conducts clinical trials and receives FDA approval of a product for which there are similar, but non FDA-approved,
prescription products on the market, the manufacturers of the unapproved but marketed products are required to withdraw them from the
market. However, the FDA has significant latitude in determining how to enforce its regulatory powers in these circumstances. We have
not had any communication with the FDA regarding this matter and cannot predict what action, if any, the FDA will take with respect to
the unapproved products.
We believe that should Halo-Lido demonstrate,
proven safety and efficacy data and receive FDA approval, and if Halo-Lido obtains three years of market exclusivity based on our dosage
strength and formulation, we are likely to have a meaningful advantage in our pursuit of achieving a significant position in the market
for topical combination prescription products for the treatment of hemorrhoids.
Mino-Wrap
Overview
On January 2, 2019, we entered into a patent and
technology license agreement with the Board of Regents of the University of Texas System on behalf of MDACC, whereby we in-licensed exclusive
worldwide rights to the patented technology for any and all uses relating to breast implants, specifically the Mino-Wrap technology. This
includes rights to U.S. Patent No. 9,849,217, which was issued on December 16, 2017. We intend to develop Mino-Wrap as a liquefying, gel-based
wrap containing minocycline and rifampin for the reduction of infections associated with breast implants following breast reconstructive
surgeries. We are required to use commercially reasonable efforts to commercialize Mino-Wrap under several regulatory scenarios and achieve
milestones associated with these regulatory options leading to an approval from the FDA. Mino-Wrap will require pre-clinical development
prior to any regulatory pathway. In July 2019, we announced that we intend to pursue the FDA’s Investigational New Drug (“IND”)
regulatory pathway for the development of Mino-Wrap. On August 4, 2020, we announced that we had submitted a briefing package to the FDA
for a pre-IND consultation on Mino-Wrap.
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In December 2020, the Company announced the receipt