Overview
We are a late-stage clinical biopharmaceutical company focused on the discovery and development of drugs for the treatment of cancer. Our core objective is to leverage our proprietary PDC 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, including variants thereof, 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. While we have commenced dosing in our CLOVER-WaM
pivotal clinical study of iopofosine in WM, we have experienced material delays
in patient recruitment and enrollment as a result of continued resourcing issues
related to COVID-19 at study sites and potentially due to concerns among
patients about participating in clinical studies during a public health
emergency. The COVID-19 pandemic is also affecting the operations of third
parties upon whom we rely. We are unable to predict how the COVID-19 pandemic
may affect our ability to successfully progress our CLOVER-WaM pivotal clinical
study or any other clinical programs in the future. Moreover, there remains
uncertainty relating to the trajectory of the pandemic and whether it may cause
further delays in patient study recruitment. The impact of related responses and
disruptions caused by the COVID-19 pandemic may result in difficulties or delays
in initiating, enrolling, conducting or completing our planned and ongoing
studies and the incurrence of unforeseen costs as a result of disruptions in
clinical supply of iopofosine or preclinical study or clinical study delays and
our ability to obtain additional financing. The continued impact of COVID-19 on
results will largely depend on future developments, which are highly uncertain
and cannot be predicted with confidence, such as the ultimate geographic spread
of the disease or variants thereof, the duration of the pandemic, vaccination
rates, travel restrictions and social distancing in
Our lead PDC therapeutic, iopofosine 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 iopofosine from many traditional on-market treatments. Iopofosine 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 iopofosine in Bruton tyrosine kinase inhibitor (BTKi) failed or suboptimal response in WM. The CLOVER-1 Phase 2B study is ongoing where iopofosine remains under further evaluation in highly refractory 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 iopofosine 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
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.
18
Table of Contents
We have leveraged our PDC platform to establish four 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 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
A description of our PDC product candidates follows:
Clinical Pipeline
Our lead PDC therapeutic, iopofosine, 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 iopofosine from many traditional on-market treatments and treatments in development. Iopofosine is currently being evaluated in the CLOVER-WaM Phase 2 pivotal study in patients with r/r WM, a Phase 2B study in r/r MM patients and the CLOVER-2 Phase 1 study for a variety of pediatric cancers.
Iopofosine is currently being evaluated in a pivotal study, CLOVER-WaM, in
Waldenstrom's macroglobulinemia (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 a 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
19
Table of Contents
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 iopofosine 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 iopofosine 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
As the result of iopofosine's RPDD designation, we may be eligible to receive a priority review voucher (PRV) if the product receives approval for any of the treatment of neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma or osteosarcoma. The FDA may award PRV to sponsors of a RPDD that meet its specified criteria. The key criteria to receiving a priority review voucher 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
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 relapsed/refractory 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
20
Table of Contents
Phase 2A: Patients with r/r non-Hodgkin's lymphoma Cohort
In
Based upon the dose response observed in the Phase 2A for patients receiving total body doses of 60mCi or greater, we determined that patient dosing of iopofosine 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 iopofosine 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 total body dose >60 mCi/m2 of iopofosine.
In
In
Phase 1 Study in Patients with r/r Multiple Myeloma
In
21 Table of Contents
Iopofosine 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. Iopofosine 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 total body dose 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
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
Phase 1 Study in r/r Pediatric Patients with select Solid tumors, Lymphomas and Malignant Brain Tumors
In
22
Table of Contents
Phase 1 Study in r/r Head and Neck Cancer
In
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:
CLR 1900 Series is an internally developed proprietary PDC program leveraging a
novel small molecule cytotoxic compound as the payload. The payload inhibits
mitosis (cell division) and targets a key pathway required to inhibit rapidly
? dividing cells that results in apoptosis. We believe that this program could
produce a product candidate targeted to select solid tumors. Currently, the
program is in early preclinical development and if we elect to progress any
molecules further, we will select preferred candidates.
CLR 2000 Series is a collaborative PDC program with Avicenna Oncology, or
Avicenna, that we entered into in
antibody drug conjugates ("ADCs"). The objective of the research collaboration
is to design and develop a series of PDCs utilizing Avicenna's proprietary
cytotoxic payload. Although Avicenna is a developer of ADCs, this collaboration
? was sought as a means to overcome many of the challenges associated with ADCs,
including those associated with the targeting of specific cell surface
epitopes. The CLR 2000 Series has demonstrated improved safety, efficacy and
tissue distribution with the cytotoxic payload in animal models. A candidate
molecule and a back-up have been selected for further advancement at a future
time.
CLR 12120 Series is a collaborative PDC program with Orano Med for the
? development of novel PDCs utilizing Orano Med's unique alpha emitter, lead 212
conjugated to our phospholipid ether; the companies intend to evaluate the new
PDCs in up to three oncology indications.
Expanded ongoing collaboration with biotechnology company
? combining their novel linker chemistry with our validated targeting platform to
create novel next generation phospholipid drug conjugate therapeutics.
Co-development and commercialization collaboration with LegoChemBio, a clinical
? stage biotechnology company to utilize their proprietary drug conjugate
linker-toxin platform to further enhance our portfolio of next generation PDC
therapeutics. 23 Table of Contents Results of Operations
Research and development expense. Research and development expense consist of costs incurred in identifying, developing and testing, and manufacturing product candidates, which primarily include salaries and related expenses for personnel, cost of manufacturing materials and contract manufacturing fees paid to contract manufacturers and contract research organizations, fees paid to medical institutions for clinical studies, and costs to secure intellectual property. The Company analyzes its research and development expenses based on four categories as follows: clinical project costs, preclinical project costs, manufacturing and related costs, and general research and development costs that are not allocated to the functional project costs, including personnel costs, facility costs, related overhead costs and patent costs.
General and administrative expense. General and administrative expense consists primarily of salaries and other related costs for personnel in executive, finance and administrative functions. Other costs include insurance, costs for public company activities, investor relations, directors' fees and professional fees for legal and accounting services.
Three Months Ended
Research and Development. Research and development expense for the three months
ended
The following table is an approximate comparison summary of research and development costs for the three months endedSeptember 30, 2021 andSeptember 30, 2020 : Three Months Ended September 30, 2021 2020 Variance Clinical project costs$ 2,242,000 $ 1,184,000 $ 1,058,000 Manufacturing and related costs 506,000 655,000 (149,000) Pre-clinical project costs 4,000 36,000 (32,000)
General research and development costs 1,185,000 809,000 376,000
$ 3,937,000 $ 2,684,000 $ 1,253,000
The overall increase in research and development expense of
General and administrative. General and administrative expense for the three
months ended
Nine Months Ended
Research and Development. Research and development expense for the nine months
ended
24
Table of Contents
The following table is an approximate comparison summary of research and development costs for the nine months endedSeptember 30, 2021 andSeptember 30, 2020 : Nine Months Ended September 30, 2021 2020 Variance Clinical project costs$ 8,237,000 $ 3,066,000 $ 5,171,000 Manufacturing and related costs 1,664,000 1,918,000 (254,000) Pre-clinical project costs 9,000 193,000 (184,000)
General research and development costs 3,288,000 2,589,000 699,000
$ 13,198,000 $ 7,766,000 $ 5,432,000
The overall increase in research and development expense of
General and administrative. General and administrative expense for the nine
months ended
Liquidity and Capital Resources
As of
Our cash requirements have historically been for our research and development
activities, finance and administrative costs, capital expenditures and overall
working capital. We have experienced negative operating cash flows since
inception and have funded our operations primarily from sales of common stock
and other securities. As of
We believe that the cash balance is adequate to fund our basic budgeted operations for at least 12 months from the filing of these financial statements. However, our future results of operations involve significant risks and uncertainties. Our ability to execute our operating plan beyond that time depends on our ability to obtain additional funding via the sale of equity and/or debt securities, a strategic transaction or otherwise. We plan to actively pursue all available financing alternatives; however, there can be no assurance that we will obtain the necessary funding. Other than the uncertainties regarding our ability to obtain additional funding, there are currently no known trends, demands, commitments, events or uncertainties that are likely to materially affect our liquidity.
© Edgar Online, source