10-K
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tm211114d1_10k.htm
FORM 10-K
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
For the Fiscal Year Ended: December 31, 2020
For the transition period from _________ to _________.
Commission File Number 333-119366
CELLECTAR
BIOSCIENCES, INC.
(Exact name of Registrant as specified
in its Charter)
(State or other jurisdiction (I.R.S. Employer Identification No.)
of incorporation or organization)
100 Campus Drive
Florham Park, New Jersey 07932
(Address of principal executive offices,
including zip code)
(608) 441-8120
(Registrant’s telephone number,
including area code)
Securities registered pursuant to Section
12(b) of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
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 x
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Exchange Act. Yes ̈
No x
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 x
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 x 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 x Smaller reporting company x
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. ̈
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. ̈
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ̈
No x
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 June 30, 2020 was $32,346,423.
As of March 1, 2021, there were 50,504,064
shares of the registrant’s $0.00001 par value common stock outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the registrant’s definitive proxy statement
for the Registrant’s 2021 Annual Meeting of Stockholders are incorporated by reference in Part III of this annual report
on Form 10-K. The definitive proxy statement will be filed with the U.S. Securities and Exchange Commission within 120 days after
the end of the fiscal year covered by this annual report on Form 10-K.
CELLECTAR BIOSCIENCES, INC.
FORM 10-K
TABLE OF CONTENTS
Forward-Looking Statements 2
PART I 3
Item 1. Business 3
Item 1A. Risk Factors 20
Item 2. Properties 34
Item 3. Legal Proceedings 34
Item 4. Mine Safety Disclosures 34
Item 6. Selected Financial Data 35
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 40
Item 8. Financial Statements 41
Item 9A. Controls and Procedures 63
Item 9B. Other Information 63
PART III 64
Item 10. Directors, Executive Officers, and Corporate Governance 64
Item 11. Executive Compensation 64
Item 14. Principal Accounting Fees and Services 64
Item 15. Exhibits, Financial Statement Schedules 65
Signatures 67
FORWARD-LOOKING STATEMENTS
This annual report on Form 10-K of Cellectar
Biosciences, Inc. (the “Company”, “Cellectar”, “we”, “us”, “our”) contains
forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, which we refer
to as the Exchange Act. Examples of our forward-looking statements include:
· our projected operating results, including research and development expenses;
· any disruptions at our sole supplier of CLR 131;
· our ability to pursue strategic alternatives;
· our ability to advance our technologies into product candidates;
· assumptions underlying any of the foregoing; and
In some cases, you can identify forward-looking
statements by terminology, such as “expects,” “anticipates,” “intends,” “estimates,”
“plans,” “believes,” “seeks,” “may,” “should,” “could”
or the negative of such terms or other similar expressions. Accordingly, these statements involve estimates, assumptions and uncertainties
that could cause actual results to differ materially from those expressed in them. Forward-looking statements also involve risks
and uncertainties, many of which are beyond our control. Any forward-looking statements are qualified in their entirety by reference
to the factors discussed throughout this annual report on Form 10-K.
You should read this report completely
and with the understanding that our actual future results may be materially different from what we expect. You should assume that
the information appearing in this report is accurate as of the date hereof only. Because the risk factors referred to herein could
cause actual results or outcomes to differ materially from those expressed in any forward-looking statements made by us or on our
behalf, you should not place undue reliance on any forward-looking statements. Further, any forward-looking statement speaks only
as of the date on which it is made, and we undertake no obligation to update any forward-looking statement to reflect events or
circumstances after the date on which the statement is made or to reflect the occurrence of unanticipated events. New factors emerge
from time to time, and it is not possible for us to predict which factors will arise. In addition, we cannot assess the impact
of each factor on our business or the extent to which any factor, or combination of factors, may cause actual results to differ
materially from those contained in any forward-looking statements.
This annual report on Form 10-K contains
trademarks and service marks of Cellectar Biosciences, Inc. Unless otherwise provided in this annual report on Form 10-K,
trademarks identified by TM are trademarks of Cellectar Biosciences, Inc. All other trademarks are the properties of their
respective owners.
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PART I
Item 1. Business.
Business Overview
We are a late-stage clinical biopharmaceutical
company focused on the discovery, development and commercialization of drugs for the treatment of cancer. Our core objective is
to leverage our proprietary phospholipid drug conjugateTM (PDCTM) delivery platform to develop PDCs that are designed
to specifically target cancer cells and deliver improved efficacy and better safety as a result of fewer off-target effects. Our
PDC platform possesses the potential for the discovery and development of the next generation of cancer-targeting treatments,
and we plan to develop PDCs both independently and through research and development collaborations.
The COVID-19 pandemic has created uncertainties
in the expected timelines for clinical stage biopharmaceutical companies such as us, and because of such uncertainties, it is difficult
for us to accurately predict expected outcomes. We have not yet experienced any significant impacts as a result of the pandemic.
However, COVID-19 may impact our future ability to recruit patients for clinical studies, obtain adequate supply of CLR 131 and
obtain additional financing.
Our lead PDC therapeutic, CLR 131 is a
small-molecule PDC designed to provide targeted delivery of iodine-131 directly to cancer cells, while limiting exposure to healthy
cells. We believe this profile differentiates CLR 131 from many traditional on-market treatments. CLR 131 is currently being evaluated
in the CLOVER-WaM Phase 2 pivotal study in patients with relapsed/refractory (r/r) Waldenstrom’s macroglobulinemia (WM),
a Phase 2B study in r/r multiple myeloma (MM) patients and the CLOVER-2 Phase 1 study for a variety of pediatric cancers.
The CLOVER-1 Phase 2 study met the primary
efficacy endpoints from the Part A dose-finding portion, conducted in r/r B-cell malignancies. The CLOVER-WaM Study is a pivotal
registration study currently evaluating CLR 131 in Bruton tyrosine kinase inhibitor (BTKi) failed or suboptimal response in WM.
The CLOVER-1 Phase 2B study is ongoing where CLR 131 remains under further evaluation in highly refractory multiple myeloma (MM)
patients.
The CLOVER-2 Phase 1 pediatric study is
an open-label, sequential-group, dose-escalation study to evaluate the safety and tolerability of CLR 131 in children and adolescents
with relapsed or refractory cancers, including malignant brain tumors, neuroblastoma, sarcomas, and lymphomas (including Hodgkin’s
lymphoma). The study is being conducted internationally at seven leading pediatric cancer centers.
The U.S. Food and Drug Administration (“FDA”)
granted CLR 131 Fast Track Designation for WM patients having received two or more prior treatment regimens, as well as r/r MM
and r/r diffuse large B-cell lymphoma (DLBCL). Orphan Drug Designations (ODDs) have been granted for WM, MM, neuroblastoma, rhabdomyosarcoma,
Ewing’s sarcoma and osteosarcoma. CLR 131 was also granted Rare Pediatric Disease Designation (RPDD) for the treatment of
neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma. The European Commission granted an ODDs for r/r MM and
WM.
Our product pipeline also includes one
preclinical PDC chemotherapeutic program (CLR 1900) and several partnered PDC assets. The CLR 1900 Series is being targeted
for solid tumors with a payload that inhibits mitosis (cell division) a validated pathway for treating cancers.
We have leveraged our PDC platform to establish
three ongoing collaborations featuring four unique payloads and mechanisms of action. Through research and development collaborations,
our strategy is to generate near-term capital, supplement internal resources, gain access to novel molecules or payloads, accelerate
product candidate development and broaden our proprietary and partnered product pipelines.
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Our PDC platform provides selective delivery of a diverse range
of oncologic payloads to cancerous cells, whether a hematologic cancer or solid tumor, a primary tumor, or a metastatic tumor and
cancer stem cells. The PDC platform’s mechanism of entry does not rely upon specific cell surface epitopes or antigens as
are required by other targeted delivery platforms. Our PDC platform takes advantage of a metabolic pathway utilized by all tumor
cell types in all stages of the tumor cycle. Tumor cells modify specific regions on the cell surface as a result of the utilization
of this metabolic pathway. Our PDCs bind to these regions and directly enter the intracellular compartment. This mechanism allows
the PDC molecules to accumulate in tumor cells over time, which can enhance drug efficacy, and to avoid the specialized highly
acidic cellular compartment known as lysosomes, which allows a PDC to deliver molecules that previously could not be delivered.
Additionally, molecules targeting specific cell surface epitopes face challenges in completely eliminating a tumor because the
targeted antigens are limited in the total number on the cell surface, have longer cycling time from internalization to being present
on the cell surface again and available for binding and are not present on all of the tumor cells in any cancer. This means a subpopulation
of tumor cells always exist that cannot be targeted by therapies targeting specific surface epitopes. In addition to the benefits
provided by the mechanism of entry, PDCs offer the ability to conjugate payload molecules in numerous ways, thereby increasing
the types of molecules selectively delivered via the PDC.
The PDC platform features include the capacity
to link with almost any molecule, provide a significant increase in targeted oncologic payload delivery and the ability to target
all types of tumor cells. As a result, we believe that we can generate PDCs to treat a broad range of cancers with the potential
to improve the therapeutic index of oncologic drug payloads, enhance or maintain efficacy while also reducing adverse events by
minimizing drug delivery to healthy cells, and increasing delivery to cancerous cells and cancer stem cells.
We employ a drug discovery and development
approach that allows us to efficiently design, research and advance drug candidates. Our iterative process allows us to rapidly
and systematically produce multiple generations of incrementally improved targeted drug candidates.
In June 2020, the European Medicines
Agency (EMA) granted us Small and Medium-Sized Enterprise (SME) status by the EMA’s Micro, Small and Medium-sized Enterprise
office. SME status allows us to participate in significant financial incentives that include a 90% to 100% EMA fee reduction for
scientific advice, clinical study protocol design, endpoints and statistical considerations, quality inspections of facilities
and fee waivers for selective EMA pre and post-authorization regulatory filings, including orphan drug and PRIME designations.
We are also eligible to obtain EMA certification of quality and manufacturing data prior to review of clinical data. Other financial
incentives include EMA-provided translational services of all regulatory documents required for market authorization, further reducing
the financial burden of the market authorization process.
A description of our PDC product candidates
follows:
Clinical Pipeline
Our lead PDC therapeutic, CLR 131 is a
small-molecule PDC designed to provide targeted delivery of iodine-131 directly to cancer cells, while limiting exposure to healthy
cells. We believe this profile differentiates CLR 131 from many traditional on-market treatments and treatments in development.
CLR 131 is currently being evaluated in the CLOVER-WaM Phase 2 pivotal study in patients with r/r WM, a Phase 2B study in r/rMM
patients and the CLOVER-2 Phase 1 study for a variety of pediatric cancers.
CLR 131 is currently being evaluated in
a pivotal study, CLOVER-WaM, in WM patients that have failed or had a suboptimal response to a BTKi therapy after receiving first
line standard of care. The CLOVER-1 Phase 2 study met the primary efficacy endpoints from the Part A dose-finding portion,
conducted in r/r B-cell malignancies, and is now enrolling an MM expansion cohort (Phase 2B). The Phase 2B study will evaluate
highly refractory MM patients including triple, quad and penta class refractory patients. The initial Investigational New Drug
(IND) application was accepted by the FDA in March 2014 with multiple INDs submitted since that time. The Phase 1 study was
designed to assess the compound’s safety and tolerability in patients with r/r MM (to determine maximum tolerated dose (MTD)
and was initiated in April 2015. The study completed enrollment and the final clinical study report is expected in the first
half of 2021. Initiated in March 2017, the primary goal of the Phase 2A study was to assess the compound’s efficacy
in a broad range of hematologic cancers.
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The CLOVER-2 Phase 1 pediatric study
is being conducted internationally at seven leading pediatric cancer centers. The study is an open-label, sequential-group,
dose-escalation study to evaluate the safety and tolerability of CLR 131 in children and adolescents with relapsed or
refractory cancers, including malignant brain tumors, neuroblastoma, sarcomas, and lymphomas (including Hodgkin’s
lymphoma). The FDA previously accepted our IND application for a Phase 1 open-label, dose escalating study to evaluate the
safety and tolerability of a single intravenous administration of CLR 131 in up to 30 children and adolescents with cancers
including neuroblastoma, sarcomas, lymphomas (including Hodgkin’s lymphoma) and malignant brain tumors. This study was
initiated during the first quarter of 2019. These cancer types were selected for clinical, regulatory and commercial
rationales, including the radiosensitive nature and continued unmet medical need in the r/r setting, and the rare disease
determinations made by the FDA based upon the current definition within the Orphan Drug Act.
In December 2014, the FDA granted
ODD for CLR 131 for the treatment of MM. In 2018, the FDA granted ODD and RPDD for CLR 131 for the treatment of neuroblastoma,
rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma. In May 2019, the FDA granted Fast Track designation for CLR 131
for the treatment of MM and in July 2019 for the treatment of DLBCL, in September 2019 CLR 131 received Orphan Drug Designation
from the European Union for Multiple Myeloma, in January 2020, the FDA granted Orphan Drug Designation for CLR 131 Waldenstrom’s
macroglobulinemia and the European Union granted Orphan Drug Designation for CLR 131 Waldenstrom’s macroglobulinemia. The
FDA granted Fast Track designation for CLR 131 for the treatment of WM in May 2020.
The FDA may award priority review vouchers
(PRV) to sponsors of a RPDD that meet its specified criteria. The key criteria to receiving a PRV is that the disease being treated
is life-threatening and that it primarily effects individuals under the age of 18. Under this program, a sponsor who receives an
approval for a drug or biologic for a rare pediatric disease can receive a PRV that can be redeemed to receive a priority review
of a subsequent marketing application for a different product. Additionally, the PRV’s can be exchanged or sold to other
companies so that the receiving company may use the voucher.
CLOVER-WaM: Phase 2 Study Pivotal Study in: Patients with
r/r Waldenstrom’s Macroglobulinemia
In
January 2021, we announced that a Type C guidance meeting with the FDA was conducted in September of 2020. The results
of that guidance meeting provided Cellectar with an agreed upon path for conducting the CLOVER-WaM study; a single arm, pivotal
study in WM patients that have received standard of care first line therapy and either failed or had a suboptimal response to BTKi
therapy. The FDA agreed with the dose to be tested, our proposal for a safety and futility assessment to be conducted on the first
10 patients, the endpoint to be assessed, the statistical analysis plan and study size of 50 patients. Based upon this agreement
the pivotal study was initiated. WM is a rare, indolent and incurable form of non-Hodgkin’s lymphoma (NHL) that is
composed of a patient population in need of new and better treatment options.
Phase 2A Study: Patients with r/r
Waldenstrom’s Macroglobulinemia Cohort
Current data from
our Phase 2A CLOVER-1 clinical study show that six WM patients demonstrated 100% overall response rate (ORR) and an 83.3% major
response rate with one patient achieving a complete response (CR), which continues at nearly 27 months post- last treatment. While
median treatment free survival (TRS) also known as treatment free remission (TFR)) and duration of response (DOR) has not been
reached, the average treatment TFS/TFR is currently at 330 days. This may represent an important improvement in the treatment of
r/r WM as we believe no approved or late-stage development treatments for second- and third-line patients have reported a CR to
date.
Phase 2A Study: Patients with r/r
Multiple Myeloma Cohort
In September 2020,
we announced that a 40% ORR was observed in the subset of refractory multiple myeloma patients deemed triple class refractory who
received 60 mCi or greater total body dose (TBD). Triple class refractory is defined as patients that are refractory to immunomodulatory,
proteasome inhibitors and anti-CD38 antibody drug classes. The 40% ORR (6/15 patients) represents triple class refractory patients
enrolled in Part A of Cellectar’s CLOVER-1 study and additional patients enrolled in Part B from March through
May 2020 and received >60mCi TBD. All MM patients enrolled in the expansion cohort are required to be triple class
refractory. The additional six patients enrolled in 2020 were heavily pre-treated with an average of nine prior multi-drug regimens.
Three patients received a TBD of > 60 mCi and three received less than 60 mCi. Consistent with the data released in February 2020,
patients receiving > 60 mCi typically exhibit greater responses. Based on study results to date, patients continue to
tolerate CLR 131 well, with the most common and almost exclusive treatment emergent adverse events being cytopenias.
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Phase 2A: Patients with r/r non-Hodgkin’s
lymphoma Cohort
In February 2020,
we announced positive data from our Phase 2a CLOVER-1 study in patients with relapsed/refractory non-Hodgkin lymphoma (NHL)
patients were treated with three different doses (<50mCi, ~50mCi and >60mCi TBD. Patients with r/r NHL who received
<60mCi TBD and the >60mCi TBD had a 42% and 43% ORR, respectively and a combined rate of 42%. These patients were
also heavily pre-treated, having a median of three prior lines of treatment (range, 1 to 9) with the majority of patients
being refractory to rituximab and/or ibrutinib. The patients had a median age of 70 with a range of 51 to 86. All patients had
bone marrow involvement with an average of 23%. In addition to these findings, subtype assessments were completed in the r/r B-cell
NHL patients. Patients with DLBCL demonstrated a 30% ORR with one patient achieving a (CR), which continues at nearly 24 months
post-treatment. The ORR for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and
marginal zone lymphoma (MZL) patients was 33%.
Based upon the
dose response observed in the Phase 2A for patients receiving TBDs of 60mCi or greater, we determined that patient dosing of CLR
131 would be >60mCi TBD. Therefore, patients are now grouped as receiving <60mCi or >60mCi TBD.
The
most frequently reported adverse events in all patients were cytopenias, which followed a predictable course and timeline. The
frequency of adverse events have not increased as doses were increased and the profile of cytopenias remains consistent. Importantly,
these cytopenias have had a predictable pattern to initiation, nadir and recovery and are treatable. The most common grade ≥3
events at the highest dose (75mCi TBD) were hematologic toxicities including thrombocytopenia (65%), neutropenia (41%), leukopenia
(30%), anemia (24%) and lymphopenia (35%). No patients experienced cardiotoxicities, neurological toxicities, infusion site reactions,
peripheral neuropathy, allergic reactions, cytokine release syndrome, keratopathy, renal toxicities, or changes in liver enzymes.
The safety and tolerability profile in patients with r/r NHL was similar to r/r MM patients except for fewer cytopenias of any
grade. Based upon CLR 131 being well tolerated across all dose groups and the observed response rate, especially in difficult to
treat patients such as high risk and triple class refractory or penta-refractory, and corroborating data showing the potential
to further improve upon current ORRs and durability of those responses, the study has been expanded to test a two-cycle dosing
optimization regimen with a target TBD >60 mCi/m2 of CLR 131.
In July 2016, we were awarded a $2,000,000 National Cancer
Institute (NCI) Fast-Track Small Business Innovation Research grant to further advance the clinical development of CLR 131. The
funds supported the Phase 2 study initiated in March 2017 to define the clinical benefits of CLR 131 in r/r MM and other niche
hematologic malignancies with unmet clinical need. These niche hematologic malignancies include Chronic Lymphocytic Leukemia, Small
Lymphocytic Lymphoma, Marginal Zone Lymphoma, Lymphoplasmacytic Lymphoma/WM and DLBCL. The study is being conducted in approximately
10 U.S. cancer centers in patients with orphan-designated relapse or refractory hematologic cancers. The study’s primary
endpoint is clinical benefit response (CBR), with secondary endpoints of ORR, progression free survival (PFS,) median Overall Survival
(mOS) and other markers of efficacy following patients receiving one of three TBDs of CLR 131 (<50mCi, ~50mCi and >60mCi),
with the option for a second cycle approximately 75-180 days later. Dosages were provided either as a single bolus or fractionated
(the assigned dose level split into two doses) given day 1 and day 15.
In May 2020, we announced that the
FDA granted Fast Track Designation for CLR 131 in WM in patients having received two prior treatment regimens or more.
Phase 1 Study in Patients with r/r Multiple Myeloma
In February 2020, we announced the
successful completion of our Phase 1 dose escalation study. Data from the study demonstrated that CLR 131 was safe and tolerated
up to a TBD of approximately 95mCi in r/r MM. The Phase 1 multicenter, open-label, dose-escalation study was designed to evaluate
the safety and tolerability of CLR 131 administered in an up to 30-minute I.V. infusion, either as a single bolus dose or as fractionated
doses. The r/r multiple myeloma patients in this study received single cycle doses ranging from approximately 20mCi to 95mCi TBD.
An independent Data Monitoring Committee determined that all doses used were safe and well-tolerated by patients.
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CLR 131 in combination with dexamethasone
was under investigation in adult patients with r/r MM. Patients had to be refractory to or relapsed from at least one proteasome
inhibitor and at least one immunomodulatory agent. The clinical study was a standard three-plus-three dose escalation safety study
to determine the maximum tolerable dose. Multiple myeloma is an incurable cancer of the plasma cells and is the second most common
form of hematologic cancers. Secondary objectives included the evaluation of therapeutic activity by assessing surrogate efficacy
markers, which include M protein, free light chain (FLC), PFS and OS. All patients were heavily pretreated with an average of five
prior lines of therapy. CLR 131 was deemed by an Independent Data Monitoring Committee (IDMC) to be safe and tolerable up to its
planned maximum single, bolus dose of 31.25 mCi/m2 or a TBD of ~63 mCi. The four single dose cohorts examined were:
12.5 mCi/m2 (~25mCi TBD), 18.75 mCi/m2 (~37.5mCi TBD), 25 mCi/m2(~50mCi TBD), and 31.25 mCi/m2(~62.5mCi
TBD), all in combination with low dose dexamethasone (40 mg weekly). Of the five patients in the first cohort, four achieved stable
disease and one patient progressed at Day 15 after administration and was taken off the study. Of the five patients admitted to
the second cohort, all five achieved stable disease however one patient progressed at Day 41 after administration and was taken
off the study. Four patients were enrolled to the third cohort and all achieved stable disease. In September 2017, we announced
results for cohort 4, showing that a single infusion up to 30-minutes of 31.25mCi/m2 of CLR 131 was safe and tolerated
by the three patients in the cohort. Additionally, all three patients experienced CBR with one patient achieving a partial response
(PR). We use the International Myeloma Working Group (IMWG) definitions of response, which involve monitoring the surrogate markers
of efficacy, M protein and FLC. The IMWG defines a PR as a greater than or equal to 50% decrease in FLC levels (for patients in
whom M protein is unmeasurable) or 50% or greater decrease in M protein. The patient experiencing a PR had an 82% reduction in
FLC. This patient did not produce M protein, had received seven prior lines of treatment including radiation, stem cell transplantation
and multiple triple combination treatments including one with daratumumab that was not tolerated. One patient experiencing stable
disease attained a 44% reduction in M protein. In January 2019, we announced that the pooled mOS data from the first four
cohorts was 22.0 months. In late 2018, we modified this study to evaluate a fractionated dosing strategy to potentially increase
efficacy and decrease adverse events.
Cohort 5 and 6 were fractionated cohorts
of 31.25 mCi/m2(~62.5mCi TBD) and 37.5 mCi/m2(~75mCi TBD), each administered on day 1 and on day 8. Following
the determination that all prior dosing cohorts were safe and tolerated, we initiated a cohort 7 utilizing a 40mCi/m2 (~95mCi TBD)
fractionated dose administered 20mCi/m2 (~40mCi TBD) on days 1 and day 8. Cohort 7 was the highest pre-planned dose cohort and
subjects have completed the evaluation period. The study completed enrollment and the final clinical study report is expected in
the first half of 2021.
In May 2019, we announced that the
FDA granted Fast Track Designation for CLR 131 in fourth line or later r/r MM. CLR 131 is our small molecule radiotherapeutic PDC
designed to deliver cytotoxic radiation directly and selectively to cancer cells and cancer stem cells. It is currently being evaluated
in our ongoing CLOVER-1 Phase 2 clinical study in patients with relapsed or refractory multiple myeloma and other select B-cell
lymphomas.
Phase 1 Study in r/r
Pediatric Patients with select Solid tumors, Lymphomas and Malignant Brain Tumors
In December 2017 the Division of Oncology
at the FDA accepted our IND and study design for the Phase 1 study of CLR 131 in children and adolescents with select rare and
orphan designated cancers. This study was initiated during the first quarter of 2019. In December 2017, we filed an IND application
for r/r pediatric patients with select solid tumors, lymphomas and malignant brain tumors. The Phase 1 clinical study of CLR 131
is an open-label, sequential-group, dose-escalation study evaluating the safety and tolerability of intravenous administration
of CLR 131 in children and adolescents with cancers including neuroblastoma, sarcomas, lymphomas (including Hodgkin’s lymphoma)
and malignant brain tumors. Secondary objectives of the study are to identify the recommended efficacious dose of CLR 131 and to
determine preliminary antitumor activity (treatment response) of CLR 131 in children and adolescents. In August 2020, it was
announced that four dose levels 15mCi/m2 up to 60mCi/m2 were deemed safe and tolerable by an independent
Data Monitoring Committee and evaluation of the next higher dose cohort, 75mCi/m2 was initiated. In November 2020, we
announced that CLR 131 had been measured in tumors, confirming that systemic administration of CLR
131 crosses the blood brain barrier and is delivered into tumors and that disease control has been exhibited in heavily pretreated
patients with ependymomas. In 2018, the FDA granted ODD and RPDD for CLR 131 for the treatment of neuroblastoma, rhabdomyosarcoma,
Ewing’s sarcoma and osteosarcoma. Should CLR 131 be approved for any of these pediatric indications, the first approved RPDD
would enable us to receive a priority review voucher. Priority review vouchers can be used by the sponsor to receive priority review
for a future New Drug Application (“NDA”) or Biologic License Application (“BLA”) submission, which would
reduce the FDA review time from 12 months to six months. Currently, these vouchers can also be transferred or sold to another entity.
In December 2020, the FDA extended the Priority Review Voucher Program through September 2026 for rare pediatric diseases.
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Phase 1 Study in r/r Head and Neck Cancer
In August 2016, the University of Wisconsin Carbone Cancer
Center (“UWCCC”) was awarded a five-year Specialized Programs of Research Excellence (“SPORE”) grant of
$12,000,000 from the National Cancer Institute and the National Institute of Dental and Craniofacial Research to improve treatments
and outcomes for head and neck cancer, HNC, patients. HNC is the sixth most common cancer across the world with approximately 56,000
new patients diagnosed every year in the U.S. As a key component of this grant, the UWCCC researchers completed testing of CLR
131 in various animal HNC models and initiated the first human clinical study enrolling up to 30 patients combining CLR 131 and
external beam radiation with recurrent HNC in Q4 2019. This clinical study was suspended due to the COVID-19 pandemic over the
first three quarters of 2020 but is now open and actively enrolling patients.
Preclinical Pipeline
We believe our PDC platform has potential
to provide targeted delivery of a diverse range of oncologic payloads, as exemplified by the product candidates listed below, that
may result in improvements upon current standard of care (“SOC”) for the treatment of a broad range of human cancers:
Technology Overview
Our product candidates are based on a cancer-targeting
delivery platform of optimized phospholipid ether (PLE) analogs (phospholipid ether proprietary delivery vehicle) that interact
with lipid rafts. Lipid rafts are specialized regions of a cell’s membrane phospholipid bilayer that contain high concentrations
of cholesterol and sphingolipids and serve to organize cell surface and intracellular signaling molecules. As a result of enrichment
and stabilization of lipid rafts in cancer cells, including cancer stem cells, our product candidates provide selective targeting
preferentially to cancer cells over normal healthy cells. The cancer-targeting PLE delivery vehicle was deliberately designed to
be combined with therapeutic, diagnostic and imaging molecules. For example, the cytotoxic radioisotope, iodine-131 can be attached
via a stable covalent bond to the PLE resulting in our lead PDC, CLR 131. Non-radioactive molecules, including many classes of
small molecule chemotherapeutic compounds, peptides and other molecules can also be attached to the delivery vehicle.
8
In parallel to advancing the clinical development
of our lead PDC, CLR 131 in both adult and pediatric orphan indications; we remain focused on exploring the creation of additional
PDCs ranging from newly discovered to well-characterized anti-cancer agent payloads. The objective is to develop PDC chemotherapeutics
through conjugation of our delivery vehicle and non-targeted anti-cancer agents to improve therapeutic indices and expand potential
indications through the targeted delivery of chemotherapeutic payloads. Initial PDC product candidates include our CLR 1900, 2000
and 12120 series of conjugated compounds currently being researched independently and through partnerships. Other than CLR 12120,
all are small-molecule, cancer-targeting chemotherapeutics in pre-clinical research. To date, multiple cancer-targeting product
profiles have been generated from a single chemical core structure that is the foundation of our technology platform. We also believe
that additional cytotoxic PDCs may be developed possessing enhanced therapeutic indices versus the original, non-targeted cytotoxic
payload as a monotherapy.
Malignant tumor targeting, including targeting
of cancer stem cells, has been demonstrated in vivo in animal models as well as in clinical studies. Mice without intact
immune systems and inoculated with Panc-1 (pancreatic carcinoma) cells, were injected with CLR 1502, 24 or 96 hours prior to imaging.
In vivo optical imaging showed pronounced accumulation of CLR 1502 in tumors versus non-target organs and tissues. Similarly,
positron emission tomography (PET) imaging of tumor-bearing animals (colon, glioma, triple negative breast and pancreatic tumor
xenograft models) administered the imaging agent CLR 124 clearly shows selective uptake and retention by both primary tumors and
metastases, including cancer stem cells. PET/CT analysis following co-injection of CLR 131 (for therapy) and CLR 124 (for imaging)
revealed time-dependent tumor responses and disappearance over nine days in a cancer xenograft model. We believe that the capability
of our technology to target and be selectively retained by cancer stem cells in vivo, was demonstrated by treating glioma
stem cell-derived orthotopic tumor-bearing mice with another fluorescent-labeled PDC (CLR 1501), and then removing the tumor and
isolating cancer stem cells, which continued to display CLR 1501 labeling even after three weeks in cell culture.
The basis for selective tumor targeting
of our compounds lies in differences between the plasma membranes of cancer cells as compared to those of most normal cells. Data
suggests that lipid rafts serve as portals of entry for PDCs such as CLR 131 and our multiple series of drug conjugates. The marked
selectivity of our compounds for cancer cells versus non-cancer cells likely results from cancer cells maintenance of an overabundance
of lipid rafts and the stabilization of these microdomains within the plasma membrane as compared to normal cells. Following cell
entry via lipid rafts, CLR 131 is transported into the cytoplasm, where it traffics along the Golgi apparatus and is distributed
to various peri-nuclear organelles (including mitochondria and the endoplasmic reticulum). The pivotal role played by lipid rafts
is underscored by the fact that disruption of lipid raft architecture significantly eliminates uptake of our PDC delivery vehicle
into cancer cells.
Products in Development
CLR 131
CLR 131 is a small-molecule PDC designed
to provide targeted delivery of iodine-131 (radioisotope) directly to cancer cells, while limiting exposure to healthy cells unlike
many traditional on-market treatment options. CLR 131 is comprised of our proprietary PLE, 18-(p-[I-131]iodophenyl) octadacyl phosphocholine,
acting as a cancer-targeting delivery and retention vehicle, covalently labeled with iodine-131, a cytotoxic (cell-killing) radioisotope
with a half-life of eight days that is already in common use to treat thyroid, pediatric tumors and other cancer types including
NHL. It is this “intracellular radiation” mechanism of cancer cell killing, coupled with delivery to a wide range of
malignant tumor types that we believe provides CLR 131 with anti-cancer activity and a unique product profile. Selective uptake
and retention have been demonstrated in cancer stem cells compared with normal cells, offering the prospect of longer lasting anti-cancer
activity.
9
The
primary objective of the multicenter Phase 1b dose-escalation study in patients with a range of advanced solid tumors was to define
the MTD of CLR 131. In addition to determining the MTD, the Phase 1b study was intended to evaluate overall tumor response (using
standard RESIST 1.1 criteria) and safety. In September 2012, we announced that we had successfully completed the second cohort
in this Phase 1b dose-escalation study. Dose escalation in four cohorts subsequently occurred with refractory cancer patients receiving
single doses of 25 mCi/m2, 31.25 mCi/m2 or 37.5 mCi/m2.
Tumor treatment with radioactive isotopes
has been used as a fundamental cancer therapeutic for decades. The goals of targeted cancer therapy — selective delivery
of effective doses of isotopes that destroy tumor tissue, sparing of surrounding normal tissue, and non-accumulation in vital organs
such as the liver and kidneys — remain goals of new therapies as well. We believe our targeted delivery technology has the
potential to achieve these goals. CLR 131 has been shown in animal models to reliably and near-universally accumulate in cancer
cells, including cancer stem cells.
10
In view of CLR 131’s selective uptake
and retention in a wide range of solid tumors and in cancer stem cells, its single-agent efficacy in animal models and its non-specific
mechanism of cancer-killing (radiation), along with an understanding of classical oncology drug development our initial plan was
to develop CLR 131 as a monotherapy for cancer indications with significant unmet medical need. CLR 131’s unique benefits
such as a novel mechanism of action, ease of administration, and positive benefit/risk profile offered potential treatment benefits
for a variety of high unmet cancer populations. While a number of cancer indications were evaluated as the initial target treatment,
multiple myeloma was selected principally because, like many hematologic malignancies, is known to be highly radiosensitive and
remained an incurable hematologic disease with significant unmet medical need in the relapse or refractory clinical setting. Additionally,
MM is designated as an orphan disease and drugs granted an orphan drug designation (ODD) are provided regulatory and marketing
exclusivity benefits. The IND application for MM was accepted by the FDA in September 2014. In December 2014, the FDA granted ODD
for CLR 131 for the treatment of MM. We initiated our Phase 1 Study of CLR 131 for the treatment of r/r MM in April 2015. The Phase
1 study was a multicenter, open-label, dose-escalation study designed to evaluate the safety and tolerability of CLR 131 administered
as a 15-20-minute IV infusion, either as a single bolus dose or as two fractionated doses, in patients with R/R MM. All cohorts
dosed were deemed safe and well tolerated by an independent Data Monitoring Committee (DMC). The study was successfully completed
in February 2020.
In February 2020, final results from a
multicenter, phase 1 clinical trial of CLR 131 in r/r MM were presented. The trial was designed to evaluate the safety and potential
initial efficacy of CLR 131 in heavily pretreated MM patients and enrolled a total of 26 evaluable patients at three trial sites.
For the trial, which used a modified 3 + 3 dose escalation design, 15 evaluable patients were dosed in single bolus doses from
12.5mCi/m2 up to 31.25mCi/m2 (TBD 20.35-59.17 mCi) and 11 evaluable patients were dosed in fractionated dosing cohorts of 31.25mCi/m2
to 40mCi/m2 (TBD 54.915-89.107 mCi). An independent data monitoring committee determined that no dose-limiting toxicities were
seen in any cohort. Of the 26 evaluable patients in the trial, a partial response was seen in 4 of 26 patients (15.4%) and stable
disease or minimal response in 22 of 26 patients (84.6%), for a disease control rate of 100%. A significant decrease in M-protein
and FLC was also observed, suggesting ample targeting of the tumor.
The Phase 2 A study (CLOVER-1) of CLR 131
was initiated in July 2017 and conducted in approximately 10 leading cancer centers in the United States for patients with relapsed
or refractory B-cell hematologic cancers. The hematologic cancers being studied in the trial included MM, lymphoplasmacytic lymphoma
(LPL) / Waldenstrom’s macroglobulinemia (WM), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal
zone lymphoma (MZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).
The planned study enrollment was up to
80 patients. Its primary endpoint was clinical benefit response (CBR), with additional endpoints of ORR, progression free survival
(PFS), median overall survival (OS) and other markers of efficacy. Over the course of the study the dosing regimen of CLR 131 advanced
from a single bolus dose to two cycles of fractionated administrations of 15 mCi/m2 per dose on days 1, 15 (cycle 1), and days
57, 71 (cycle 2).
In September 2020,
we announced that a 40% ORR was observed in the subset of r/r MM deemed triple class refractory who received 60 mCi or greater
TBD. Triple class refractory is defined as patients that are refractory to immunomodulatory, proteasome inhibitors and anti-CD38
antibody drug classes. The 40% ORR (6/15 patients) represents triple class refractory patients enrolled in Part A of our CLOVER-1
study and additional patients enrolled in Part B from March through May 2020 and received >60mCi TBD.
All MM patients enrolled in the expansion cohort are required to be triple class refractory. The six patients enrolled from March
through May 2020 were heavily pre-treated with an average of nine prior multi-drug regimens. Three patients received a TBD of >
60 mCi and three received less than 60 mCi. Consistent with the data released in February 2020, patients receiving >
60 mCi typically exhibit greater responses. Based on study results to date, patients continue to tolerate CLR 131 well, with the
most common and almost exclusive treatment emergent adverse events being cytopenias. This
cohort will continue to enroll and evaluate patients that are even more refractory (quad-class refractory (proteasome inhibitor,
immunomodulatory drug, anti-CD-38 antibodies, nuclear export inhibitors, or BCMA antibody drug conjugates) or hepta-drug refractory)
to determine if CLR 131 at the dose of >60mCi TBD can be effective in patients that likely have no alternative therapies.
Data from our
Phase 2 CLOVER-1 clinical study show that six WM patients demonstrated 100% ORR and an 83.3% major response rate with one patient
achieving a CR, which continues at nearly 27 months post- last treatment. While median treatment free survival (or treatment free
remission) and duration of response has not been reached, the average treatment free survival is currently at 330 days. This may
represent an important improvement in the treatment of r/r WM as we believe no approved or late-stage development treatments for
second- and third-line patients have reported a CR nor do any therapies provide any significant benefit after the therapy is stopped.
11
In January 2021, we announced the initiation
of the CLOVER-WaM pivotal study in WM. The study is designed as a global, non-comparator, single arm,
study of CLR 131. We believe this design is in alignment with the feedback received from the FDA during the guidance meeting held
in September 2020.
The study will enroll 50 WM patients who
have failed first-line therapy and have failed or had a suboptimal response to a BTK i (i.e. ibrutinib). Patients in the trial
will receive up to 4-doses of CLR 131 over two cycles (cycle one days 1, 15, and cycle two days 57, 71). The primary endpoint of
the trial is major response rate (MRR) as defined as a partial response (a minimum of a 50% reduction in IgM) or better in patients
that receive a minimum TBD of 60 mCi with secondary endpoints of treatment free survival (treatment free remission), duration of
response and progression free survival. An independent data monitoring committee (iDMC) will perform an interim safety and futility
evaluation on the first 10 patients enrolled. The assessment will occur patient by patient and will conclude after the tenth
patient is evaluated; there is no planned study stoppage. The trial has been initiated at select US cancer centers and will
roll out to additional US and international sites in early 2021.
In
July 2018, we announced that after a single 25mCi/m2 IV administration of CLR 131, patients with relapsed/refractory
aggressive DLBCL were assessed for response. These interim data show a 33% ORR and a 50% CBR. In addition, the observed responses
to date show overall tumor reduction ranged from 60% to greater than 90%. As a result of these favorable outcomes, we have expanded
this cohort to include up to 30 additional patients. We also announced that a patient in the lymphoplasmacytic lymphoma (LPL) arm
with advanced Waldenstrom macroglobulinema showed a 94% reduction in tumor burden and complete resolution in four of five targeted
masses after two doses of CLR 131 separated by 123 days.
In
December 2017, we filed an IND application with the Division of Oncology at the FDA for a proposed Phase 1 study of CLR 131 in
children and adolescents with select rare and orphan designated cancers. The
Phase 1 pediatric study is an open-label, sequential-group, dose-escalation study to evaluate the safety and tolerability of CLR
131 in children and adolescents with relapsed or refractory cancers, including malignant brain tumors, neuroblastoma, sarcomas,
and lymphomas (including Hodgkin’s lymphoma). The Phase 1 study was initiated in 2019 at 3 pediatric cancer
centers and is currently
being conducted internationally at seven leading pediatric cancer centers. Secondary objectives of the study are
to identify the recommended Phase 2 dose of CLR 131 and to determine preliminary antitumor activity (treatment response) of CLR
131 in children and adolescents.
In
November 2020, we announced that CLR 131 demonstrated preliminary activity in inoperable brain tumors as part of the Phase 1 study.
Similar to previous CLR 131 studies in adults, this study demonstrated that 20-40% of the infused CLR 131 is delivered to cancer
tumors. Additionally, the study demonstrated that systemic administration of CLR 131 results in a sufficient proportion of infused
drug crossing the blood brain barrier and is delivered to different types of malignant brain tumors. CLR 131 has achieved disease
control at multiple dose levels in rapidly progressing, heavily pretreated patients, including two patients at distinct dose levels
with rapidly growing ependymomas. Pediatric HGGs are a collection of aggressive brain and central nervous system tumor subtypes
(i.e. diffuse intrinsic pontine gliomas, glioblastomas, astrocytomas, ependymomas, etc.) with about 400 new pediatric cases diagnosed
annually in the United States. Children with these tumors have a poor prognosis and limited 5-year survival.
The FDA has granted ODD’s and RPDDs
for CLR 131 for the treatment of neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma. Should any of these indications
reach approval, the RPDD may enable us to receive a priority review voucher. Priority review vouchers can be used by the sponsor
to receive Priority Review for a future NDA or BLA submission, which would reduce the statutory FDA review time from 12 months
to six months. Currently, these vouchers can also be transferred or sold to another entity.
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Market Overview
Our target market is broad and represents
the market for the treatment of cancer. The American Cancer Society estimated that approximately 1.90 million new cancer cases
were expected to be diagnosed in the U.S. in 2019 and approximately 608,570 cancer deaths in the U.S.1 The global market for cancer
drugs reached $143 billion in annual sales (2019), and could reach $250 billion by 2024, according to a report dated September
2020 by McKinsey & Company.2 This growth will be driven by emerging targeted therapies, which are expected to change the cancer
treatment landscape (Cowen Report), and an increased use of cancer drug combination regimens.
Waldenstrom’s macroglobulinemia
Waldenstrom’s macroglobulinemia (WM)
is a rare and incurable disease defined by specific genotypic subtypes that defines patient responses and long-term outcomes. The
annual incidence is 6,500 with prevalence of approximately 60,000 patients globally. WM is a lymphoma, or cancer of the lymphatic
system. The disease occurs in a type of white blood cell called a B-lymphocyte or B-cell, which normally matures into a plasma
cell whose job is to manufacture immunoglobulins (antibodies) to help the body fight infection. In WM, there is a malignant change
to the B-cell in the late stages of maturing, and it continues to proliferate into a clone of identical cells, primarily in the
bone marrow but also in the lymph nodes and other tissues and organs of the lymphatic system. These clonal cells over-produce an
antibody of a specific class called IgM.
WM cells have characteristics of both cancerous
B-lymphocytes (NHL) and plasma cells (multiple myeloma), and they are called lymphoplasmacytic cells. For that reason, WM is classified
as a type of non-Hodgkin’s lymphoma called lymphoplasmacytic lymphoma (LPL). About 95% of LPL cases are WM; the remaining
5% do not secrete IgM and consequently are not classified as WM.
Several drugs have demonstrated activity
either alone or in combinations but only a single drug has received regulatory approval. Treatment is mainly focused on the control
of symptoms and the prevention of organ damage. Front-line treatments for WM include rituximab alone or in combination with other
agents. In the salvage therapy (second line or later) setting, ibrutinib, combinations of proteosome inhibitors and immunomodulatory
drugs and stem cell transplantation are considered. Ibrutinib is the only drug to receive regulatory approval (2015) as a salvage
therapy; in late 2019, it was approved for front-line treatment in combination with rituximab. Factors such as long-term cytopenias,
age, hyper viscosity, the need for quick disease control, lymphadenopathy, co-morbidities, and IgM-related end-organ damage are
key consideration in the choice of treatment.
Multiple Myeloma
According to the National Cancer Institute
SEER database, multiple myeloma is the second most common hematologic cancer with a U.S. incidence rate and a relapse or refractory
patient population of 10,000 to 15,000. In 2019, Global Data Research Group estimated the multiple myeloma dollar market size to
be over $20B in 2021 and is forecasted to increase to nearly $28B in 2027. The increase in drug sales over this period will be
mainly driven by the increasing incidence of multiple myeloma with the U.S. market remaining the largest potential market. It is
believed the largest growth will occur in patients receiving at least three lines of treatment due to the expanding elderly population,
increases in treatment population and increasing rates of survival from earlier lines of treatment. According to data obtained
from Decision Resource Group, over 40% of patients in later lines of therapy while eligible, refuse treatment due to higher treatment
failure, severity of adverse events and difficulty of treatment dosing regimen. The average response rates for patients receiving
their fourth- and fifth-line treatment are 15% and 8% response rates respectively. Additionally, the mOS for these patients also
decreases by line of therapy and is less than 9 months post third-line treatment.
Based on the CLR 131 Phase 1 and Phase
2 product profile demonstrated in fifth-line patients to date with a single dose, we believe CLR 131 may meet the unmet medical
need in the heavily pre-treated patient population described above.
13
B-Cell Lymphoma