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Item 1. Business

2026-03-04 compared with 2025-03-13 · 319 added, 170 removed, 710 unchanged (41% of the section changed)

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Our three lead programs are:

iopofosine I 131 (iopofosine), a beta-emitting iodine-131 based program which has been studied extensively, as described below;

CLR 121225, an actinium-225 based program;

and CLR 121125, an iodine-125 Auger-emitting program, both prepared to enter clinical trials in 2025.

● Iopofosine, the beta-emitting PRC, utilizes iodine-131 and was studied in our CLOVER-WaM Phase 2 study of iopofosine in patients with relapsed/refractory (r/r) Waldenstrom’s macroglobulinemia (WM), and our Phase 2b studies in r/r multiple myeloma (MM) patients and r/r central nervous system lymphoma (CNSL) are ongoing.

The CLOVER-2 Phase 1a study for a variety of pediatric cancers has concluded and a Phase 1b study in pediatric patients with high grade glioma is enrolling.

Additionally, a Phase 1 Investigator-initiated study conducted by the University of Wisconsin Madison of iopofosine in combination with external beam radiation in patients with recurrent head and neck cancer has also been completed.

As with all clinical trials, adverse events, serious adverse events or fatalities may arise during a clinical trial resulting from medical problems that may not be related to clinical trial treatments.

Furthermore, due to recent communications with the FDA regarding a confirmatory study to support accelerated approval and the regulatory submission for iopofosine, the Company is, in addition to determining the availability of funding for such a study, pursuing strategic options for the further development and commercialization of this product candidate.

● CLR 121225, the alpha-emitting, actinium-225 based PRC has demonstrated activity in multiple solid tumor animal models, including pancreatic, colorectal, and breast cancer.

CLR 121225 has been shown to be well tolerated in these models with the animals showing no adverse events at the highest doses tested.

It was also shown that the compound has excellent biodistribution and uptake by the tumor.

Furthermore, in multiple models of pancreatic adenocarcinoma, including highly refractory pancreatic cancer, we have observed the compound’s proportional dose response with a single dose providing either tumor stasis at the lowest dose tested or tumor volume reduction at the higher doses.

The Company is currently projected to be the subject of a Phase 1 imaging and dose escalation safety study in the first half of 2025.

● CLR 121125, the Auger-emitting PRC, utilizes iodine-125 and has demonstrated excellent tolerability with no toxicities in animal models.

Additionally, CLR 121125 has been shown to have good activity in multiple solid tumor models, especially in triple negative breast cancer.

CLR 121125 (CLR 125), an iodine-125 Auger-emitting program, prepared to enter a clinical trial in 2025;

CLR 121225 (CLR 225), an actinium-225 based program;

and iopofosine I 131 (iopofosine I 131, or simply iopofosine), a beta-emitting iodine-131 based program which has been studied extensively, as described below.

On June 4, 2025, the Company announced that the U.S Food and Drug Administration (the “FDA”) granted Breakthrough Therapy Designation for iopofosine I 131, as a radioconjugate monotherapy for the treatment of relapsed/refractory Waldenstrom macroglobulinemia (r/r WM).

On October 6, 2025, the Company announced that after a scientific advice procedure, the Scientific Advice Working Party (SAWP) of the European Medicines Agency (EMA) advised that filing for a Conditional Marketing Authorization (CMA) for iopofosine I 131 as a treatment for post - Bruton Tyrosine Kinase inhibitor (BTKi) refractory patients with Waldenstrom macroglobulinemia (WM) could be acceptable for a CMA.

● CLR 125, an Auger-emitting PRC, utilizes iodine-125 as its radiation source and has been observed to show tolerability with minimal toxicities in animal models.

Additionally, the Company observed CLR 125 to have good activity in multiple solid tumor models, especially in triple negative breast cancer.

Auger emitters provide the greatest precision in targeted radiotherapy as the emission can only travel a few nanometers.

This means that to cause the necessary breakage of the tumor cell DNA, the isotope most get inside the cell and near the cell nucleus to be effective.

CLR 121125 achieves this due to the Company’s novel phospholipid ether drug conjugate platform.

CLR 121125 is prepared to be the subject of a Phase 1b dose finding study in the first half of 2025.

The Company believes that to cause the necessary breakage of the tumor cell DNA, the isotope must get inside the cell and near the cell nucleus to be effective.

The Company believes that CLR 125 achieves this condition because of the Company’s novel phospholipid ether drug conjugate platform.

CLR 125 is the subject of a Phase 1b dose finding study as described below.

● CLR 225, an alpha-emitting, actinium-225 based PRC has shown activity in multiple solid tumor animal models including pancreatic, colorectal and breast cancers.

CLR 121225 was well tolerated in these models with the animals showing no adverse events at the highest doses tested.

The compound demonstrated excellent biodistribution and uptake by tumors.

Furthermore, in multiple models of pancreatic adenocarcinoma, including highly refractory pancreatic cancer, we have observed proportional dose response with a single dose of CLR 225 providing either tumor stasis at the lowest dose tested or tumor volume reduction at the higher doses.

The Company is currently prepared to initiate a Phase 1 imaging and dose escalation safety study subject to our ability to obtain additional financing.

● Iopofosine, a beta-emitting iodine-131 PRC, was studied in our CLOVER WaM Phase 2 study of iopofosine in patients with r/r WM where it was observed to result in statistically significant outcomes on both primary and secondary endpoints, and our Phase 2b studies in r/r multiple myeloma (MM) patients and r/r central nervous system lymphoma (CNSL).

The CLOVER-2 Phase 1a study for a variety of pediatric cancers has concluded and a Phase 1b study in pediatric patients with high grade glioma is in follow-up.

Additionally, a Phase 1 investigator-initiated study conducted by the University of Wisconsin-Madison of iopofosine in combination with external beam radiation in patients with recurrent head and neck cancer has also been completed.

● To further develop iopofosine I 131, the Company will likely require either a strategic partner with the necessary resources or sufficient additional funding to initiate and at least partially enroll a confirmatory study, which has been identified as a required predicate to the submission of a New Drug Application (NDA) to the U.S.

Food and Drug Administration (FDA) for the accelerated approval of iopofosine I 131 as a treatment for WM.

The CLOVER-1 Phase 2 study of iopofosine, conducted in r/r B-cell malignancies, met the primary efficacy endpoints from the Part A dose-finding portion.

The CLOVER-1 Phase 2b study, where iopofosine remains under further evaluation in highly refractory MM and CNSL patients, is ongoing.

The CLOVER-WaM study was a pivotal registration study evaluating iopofosine in WM patients that were r/r to at least two prior lines of therapy including having failed or had a suboptimal response to a Bruton tyrosine kinase inhibitor (BTKi).

The CLOVER-1 Phase 2b study, where iopofosine remains under further evaluation in highly refractory MM and CNSL patients, is closed to enrollment but ongoing with patients in follow-up.

Fatalities have occurred in patients post-treatment with iopofosine.

The CLOVER WaM study was designed as a pivotal registration study evaluating iopofosine in WM patients that were r/r to at least two prior lines of therapy including having failed or had a suboptimal response to a BTKi.

The study completed enrollment in the fourth quarter of 2023, and initial top line data from the study was reported in January 2024.

WaM was a single-arm study with a target enrollment of 50 patients.

Topline safety data was reported on 45 patients meeting criteria for the modified Intent to Treat (mITT) population with a data cut-off date of January 3, 2024.

Topline efficacy evaluable population (41) is defined as patients who are in the mITT and had follow up of at least 60 days post last dose.

The CLOVER-WaM study met its primary endpoint with a major response rate (MRR) of 61% (95% confidence interval [44.50%, 75.80%, two-sided p value < 0.0001]) exceeding the FDA agreed-upon statistical hurdle of 20%.

CLOVER-WaM was a single-arm study with a target enrollment of 50 patients.

Based upon the data from September 2024, the CLOVER WaM study enrolled a total of 55 patients in the modified Intent to Treat (mITT) population and met its primary endpoint with a major response rate (MRR) of 58.2% (95% confidence interval [44.50%, 75.80%, two-sided p value < 0.0001]) exceeding the FDA agreed-upon statistical hurdle of 20%.

The overall response rate (ORR) in evaluable patients was 83.6%, and 98.2% of patients experienced disease control.

Responses were durable, with median duration of response not reached with 11.4 months of follow-up and 76% of patients remaining progression free at a median follow-up of eight months.

These outcomes exceed real world data, which demonstrate a 4-12% MRR and a duration of response of approximately six months or less despite continuous treatment in a patient population that is less pretreated and not refractory to multiple classes of drugs.

Responses were durable, with median duration of response not reached at 11.4 months of follow-up and 76% of patients remaining progression free at a median follow-up of eight months.

These outcomes exceed historic real world data which demonstrate a 4-12% MRR and a duration of response of approximately six months or less despite continuous treatment in a patient population that is less pretreated and not refractory to multiple classes of drugs.

Notably, iopofosine I 131 monotherapy achieved a 7.3% complete remission (CR) rate in this highly refractory WM population.

Overall, 45 (69.2%) patients had prior exposure to at least 3 drug classes and 19 (29.2%) patients had prior exposure to at least 4 drug classes of anti-cancer therapies.

Forty-eight (73.8%) patients had prior exposure to a BTKi of which 37 (77.1%) were deemed to be refractory to BTKis.

Forty-three (66.2%) patients were exposed to BTKi and anti-CD20 antibody with 25 (58.1%) being refractory to both BTKi and anti-CD-20 antibodies.

Thirty-seven (56.9%) patients had prior exposure to BTKi, anti-CD20 antibody, and chemotherapy and 18 (48.6%) patients were refractory to all three classes of drugs, BTKi, anti-CD20 antibody, and chemotherapy.

Iopofosine I 131 was well tolerated and its toxicity profile was consistent with the Company’s previously reported safety data.

There were no treatment-related adverse events (TRAEs) leading to discontinuation.

The rates of Grade 3 or greater TRAEs observed in more than 10% of patients included thrombocytopenia (55%), neutropenia (37%), and anemia (26%).

The safety population was 65 patients which was composed of patients that received at least a single dose of iopofosine I 131 but did not receive enough drug to be assessed for efficacy.

There were 3 (4.6%) patients that experienced treatment-related adverse events (TRAEs) leading to discontinuation.

The rates of greater TRAEs observed in more than 10% of patients included thrombocytopenia (56 [86.2%] patients), neutropenia (52 [80.0%] patients), anemia (42 [64.6%] patients) and decreased white blood cell count (21 [32.3%] patients) among hematologic toxicities and fatigue (22 [33.8%] patients), nausea (19 [29.2%] patients and diarrhea (13 [20.0%] patients) among non-hematologic toxicities.

The rates of Grade 3 or greater TRAEs observed in more than 10% of patients included thrombocytopenia (53 [81.5%] patients), neutropenia (43 [66.2%] patients), anemia (31 [47.7%] patients), decreased white blood cell count (18 [27.7%]), decreased lymphocyte count 8 (12.3%).

All patients recovered from cytopenias with no reported aplastic sequalae.

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There were no treatment-related deaths in the study.

The CLOVER-2 Phase 1a pediatric study was an open-label, sequential-group, dose-escalation study to evaluate the safety and tolerability of iopofosine in children and adolescents with relapsed or refractory malignant solid tumors (neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma) and lymphoma or recurrent or refractory malignant brain tumors (high grade glioma, glioblastoma, etc.) for which there are no standard treatments.

The study was conducted internationally at seven leading pediatric cancer centers.

The CLOVER-2 Phase 1b pediatric study is an open-label, dose finding study evaluating the activity of two different doses and dosing regimens of iopofosine in children and adolescents with r/r malignant brain tumors (high grade gliomas).

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 Phase 2b study evaluated highly refractory MM patients in triple class, quad- and penta-drug refractory patients, including post-BCMA immunotherapy patients and r/r CNSL 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 and 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 2026.

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.

The CLOVER-2 Phase 1a pediatric study, an open-label, sequential-group, dose-escalation study, was conducted internationally at seven leading pediatric cancer centers.

The study was an open-label, sequential-group, dose-escalation study to evaluate the safety and tolerability of iopofosine in children and adolescents with relapsed or refractory cancers, including malignant brain tumors, neuroblastoma, sarcomas, and lymphomas (including Hodgkin’s lymphoma).

The maximum tolerated dose was determined to be greater than 60mCi/m2 administered as a fractionated dose.

CLOVER-2 Phase 1b study is an open-label, international dose-finding study evaluating two different doses and dosing regimens of iopofosine in r/r pediatric patients with high grade gliomas.

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.

This study is partially funded (~$2M) by a National Institutes of Health SBIR grant from the National Cancer Institute.

Food and Drug Administration (FDA) granted iopofosine Fast Track Designation for lymphoplasmacytic lymphoma (LPL) and 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).

Food and Drug Administration (FDA) granted iopofosine Break-through Designation for r/r Waldenstrom’s macroglobulinemia (WM), Fast Track Designation for lymphoplasmacytic lymphoma (LPL) and 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 LPL/WM, MM, neuroblastoma, soft tissue sarcomas including rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma.

Iopofosine was also granted Rare Pediatric Disease Designation (RPDD) for the treatment of neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma.

The European Commission granted ODD to iopofosine for treatment of r/r MM and WM, as well as PRIME designation for WM.

The European Commission granted PRIME designation and ODD to iopofosine for treatment of r/r MM and WM.

Additionally, 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.

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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.

We are also evaluating other alpha-emitting isotopes such as astatine-211 and lead-212 in preclinical studies.

Additionally, we have preclinical PDC programs focused on the delivery of conjugated small molecule chemotherapeutic compounds, oligonucleotides and peptides to solid tumors.

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.

Our PDC platform is designed to provide 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 is designed not to rely upon a specific cell surface epitope or antigen as are required by other targeted delivery platforms but rather a unique change in the tumor cell membrane.

Our PDC platform takes advantage of a metabolic pathway (beta oxidation) utilized by nearly all tumor cell types in all stages of the tumor cycle.

Tumor cells modify the cell membrane to create specific, highly organized microdomains by which to transport lipids and long chain fatty acids into the cytoplasm, as a result of the utilization of this metabolic pathway.

Our PDCs are designed to bind to these regions and directly enter the intracellular compartment.

This mechanism

allows the PDC molecules to accumulate in tumor cells over time, which we believe can enhance drug efficacy.

The direct intracellular delivery allows our molecules to avoid the specialized, highly acidic cellular compartment known as lysosomes, which allows a PDC to deliver payloads that previously could not be delivered in this targeted manner.

Additionally, molecules targeting specific cell surface epitopes face challenges in completely eliminating a tumor because the targeted antigens are limited in the total number presented on the cell surface, limiting total potential uptake and resulting in heterogenous uptake across the tumor, have longer cycling time from internalization to relocation on the cell surface, again diminishing their availability for binding, and are not present on all of the tumor cells because of the heterogenous nature of cancer cells, further increasing the unequal distribution of the drug across the tumor.

This means a subpopulation of tumor cells always exists that cannot be addressed by therapies targeting specific surface epitopes.

Additionally, the epitope utilized is also present on other normal tissue, resulting in off-target toxicities.

Beyond the benefits provided by the mechanism of entry, the PDC platform features include the capacity to link with almost any molecule, provide a significant increase in targeted oncologic payload delivery, a more uniform delivery, and the ability to target nearly all types of tumor cells.

As a result, we believe that we can create 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 without the expense of having to generate significant compound libraries.

Clinical Pipeline

Our lead clinical programs are:

iopofosine, an iodine-131 beta-emitting program;

CLR 121225, an actinium-225 based program;

and CLR 121125, an iodine-125 Auger-emitting program.

All three of these product candidates are designed to provide targeted delivery of the respective radioisotope directly to cancer cells, while limiting exposure to healthy cells.

We believe this profile differentiates our PRCs from many traditional on-market treatments and treatments in development.

Iopofosine was evaluated in the recently completed CLOVER-WaM Phase 2 pivotal study in patients with r/r WM, while evaluation is ongoing in a Phase 2b study in r/r MM and CNS lymphoma patients and the CLOVER-2 Phase 1b study for pediatric patients with high grade gliomas.

Adverse events across all studies have been largely restricted to fatigue (39%), and cytopenias;

specifically, thrombocytopenia (75%), anemia (61%), neutropenia (54%), leukopenia (56%), and lymphopenia (34%).

Phase 3 Study in Patients with r/r Waldenstrom’s macroglobulinemia

On March 6, 2025, the Company conducted its End-of-Phase-2 (EOP2) meeting with the U.S.

Food and Drug Administration (FDA).

As a result of the meeting, and clarified by subsequent written correspondence, the Company believes that it understands a path forward for potential accelerated and full approval of iopofosine I 131 based upon the CLOVER WaM study and the initiation of a comparator controlled Phase 3 confirmatory trial assessing progression free survival as the primary endpoints in WM patients.

The submission for accelerated approval utilizing the CLOVER WaM study data can occur at the time of the initiation of Phase 3 randomized controlled confirmatory study and patient enrollment must be ongoing at the time of decision on the accelerated NDA.

The confirmatory study will be executed in an earlier line of therapy than was tested in the CLOVER WaM patients.

The initiation of this study is dependent on funding.

Clinical and Preclinical Pipeline

CLR 125 Study

In preclinical in vivo evaluations of CLR 125 utilizing triple-negative breast cancer (TNBC) models, the compound was observed to have tumor uptake at a substantially higher rate than that of healthy tissue.

Additionally, no signs of end-organ toxicity were observed including hematological toxicity.

The Company initiated a Phase 1b clinical study in TNBC with CLR 125.

The study is a randomized, open-label, multi-center study designed to compare the safety and efficacy of CLR 125 in patients with advanced TNBC who are relapsed/refractory (r/r) to at least one prior therapy.

Three dose levels will be assessed in parallel, with enrollment of patients in a 1:1:1 manner.

We expect that each arm will have a minimum of 15 evaluable patients.

CLR 125 will be administered as a fractionated dose on Day 1 and Day 3 for cycle 1 and repeat approximately every 8-weeks for subsequent cycles.

Depending on arm assignments, patients will receive between two and four cycles.

An expansion arm may consist of at least 15 patients following evaluation of the three dose levels by the data monitoring committee (DMC).

We anticipate a maximum of 75 patients to be enrolled in the trial.

Safety and tolerability of CLR 125 will be assessed by physical examination, Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, laboratory changes over time, ECGs and adverse events of special interest.

Efficacy of CLR 125 will be assessed by CT (or MRI if needed) examinations obtained at six-week intervals following the initial dose of CLR 125.

The study objective is to determine the Phase 2 dosing level with secondary endpoints including safety, tolerability, initial response assessment and distribution.

Preclinical Evaluations of CLR 225

In preclinical, in vivo evaluations of CLR 225, utilizing a pancreatic cancer model, the compound was observed to reduce tumor volume and improved survival benefit at four different dosing levels.

Observed biodistribution exhibited substantial uptake in the tumor while remaining low in healthy tissue.

Clinical Studies in Iopofosine

The CLOVER-1 Phase 2 study of iopofosine, conducted in r/r B-cell malignancies, met the primary efficacy endpoints from the Part A dose-finding portion.

The CLOVER-1 Phase 2b study, where iopofosine remains under further evaluation in highly refractory MM and CNSL patients, is closed to enrollment but ongoing with patients in follow-up.

Fatalities have occurred in patients’ post-treatment with iopofosine.

The CLOVER-WaM pivotal Phase 2b study completed enrollment of WM patients that have received at least two previous lines of therapy including those that failed or had a suboptimal response to a BTKi therapy in 4Q 2023.

Topline safety data was reported on 45 patients meeting the criteria for the mITT population with a data cut-off date of January 3, 2024.

Topline efficacy evaluable population (n=41) was defined as patients who were in the mITT and had follow up of at least 60 days post last dose.

The CLOVER-WaM study met its primary endpoint with a MRR of 61% (95% confidence interval [44.50%, 75.80%, two-sided p value < 0.0001]) exceeding the agreed-upon statistical hurdle of 20%.

The ORR in evaluable patients was 75.6%, and 100% of patients experienced disease control.

Responses were durable, with median duration of response not reached with 11.4 months of follow-up and 76% of patients remaining progression free at a median follow-up of eight months.

Notably, iopofosine monotherapy achieved a 7.3% complete remission (CR) rate in this highly refractory WM population.