On November 18, 2024 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of Antibody Radiation Conjugates (ARCs) and other targeted radiotherapies, reported recent regulatory and development updates for its Iomab-B, Actimab-A and Iomab-ACT ARC clinical programs as well as its financial results for the third quarter ended September 30, 2024 (Press release, Actinium Pharmaceuticals, NOV 18, 2024, View Source [SID1234648483]). Iomab-B is a first in class CD45 targeted conditioning agent to enable bone marrow transplant (BMT) and has been studied in over four hundred patients including the completed Phase 3 SIERRA trial for patients with relapsed or refractory acute myeloid leukemia (r/r AML). Actimab-A is a targeted radiotherapeutic that uses the Actinium-225 (Ac-225) isotope payload directed against CD33 with broad potential for development in AML and other myeloid indications including in collaboration with the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement (CRADA). Iomab-ACT is a next-generation CD45 targeted conditioning agent being developed for cell and gene therapies for both malignant and non-malignant hematologic indications. Actinium is executing cutting-edge R&D focused on ARCs and other targeted radiotherapies for blood cancer and solid tumor indications leveraging its strong intellectual property portfolio of 230 patents and patent applications including several patents related to the manufacture of the isotope Ac-225 in a cyclotron.

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Sandesh Seth, Actinium’s Chairman and CEO, stated, "During the third quarter and over the last several weeks, we have made significant progress with our three ARC clinical programs. Actinium is now positioned to advance exciting clinical trials for Actimab-A and Iomab-ACT in large indications with high unmet needs that can deliver impactful clinical data in 2025. Actimab-A’s backbone therapy potential is poised to be realized with the operationally seamless Phase 2/3 trial following alignment with the FDA, additional clinical trials being planned under the NCI CRADA including the myeloMATCH program and via our R&D efforts to further elucidate Actimab-A’s mutation agnostic mechanism of action. The clinical data anticipated from Iomab-ACT in 2025 from the commercial CAR-T and sickle cell transplant trials has the potential to establish Iomab-ACT as a best-in-class targeted conditioning agent for both malignant and non-malignant hematology indications. In addition, our recent meeting with the FDA regarding Iomab-B established a clear development pathway, which will be incredibly valuable in securing a U.S. strategic partner. Finally, I am delighted to welcome Dr. June Almenoff to our Board of Directors, who brings over 25 years of biopharma industry experience with a proven track record of leading drug development through approvals and executing value enhancing business development transactions."

Actimab-A Regulatory and Development Update

Actinium met with the FDA in the third quarter and aligned with the FDA on an operationally seamless randomized Phase 2/3 trial to study Actimab-A + CLAG-M
In the Phase 2 portion of the study, the Actimab-A dose will be optimized in combination with CLAG-M
The Phase 3 portion will study the optimized dose of Actimab-A + CLAG-M versus CLAG-M alone in patients with r/r AML
Operationally seamless trial design is expected to reduce the required time and resources compared to separate Phase 2 and Phase 3 trials
Actinium continues to evaluate and develop additional Actimab-A clinical trials under its CRADA with the NCI, investigator initiated, or Actinium sponsored studies
Actimab-A selected by NCI for recently opened myeloMATCH precision medicine program for patients with AML and myelodysplastic syndrome (MDS)
Iomab-ACT Program Update

In the third quarter, the FDA cleared the investigational new drug (IND) applications for both the commercial CAR-T study led by the University of Texas Southwestern (UTSW) and the sickle cell trial being led by Columbia University
The UTSW commercial CAR-T trial expected to initiate patient enrollment in 1Q 2025 with proof-of-concept clinical data expected by year end
Commercial CAR-T sales exceeded $3.5 billion in 2023 with multiple CAR-T therapies approved for patients with lymphomas, leukemias and multiple myeloma
Columbia University sickle cell transplant trial to study Iomab-ACT for targeted conditioning prior to BMT for the first time in a non-malignant hematology setting, which is a rapidly growing indication for BMT; patient enrollment expected to commence in the first half of 2025
Iomab-B Regulatory Status and Program Update

Actinium is seeking a U.S. strategic partner to advance clinical development of Iomab-B including the Phase 3 trial
Actinium met with the FDA in the fourth quarter and aligned on the patient population for the head-to-head Phase 3 trial to evaluate allogeneic BMT using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation (Flu/TBI) versus allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI
Head-to-head Phase 3 trial to enroll adult patients aged 18 and above with active AML with blasts counts greater than 5% and less than 20%, representing a broader patient population than that in the SIERRA trial
Dose optimization trial to be completed prior to initiating the head-to-head Phase 3 trial to determine the dose for Iomab-B based on radiation to the bone marrow rather than the maximum tolerable dose of 24 Gy of radiation to the liver as was done in the SIERRA trial based on several interactions with the FDA before starting the SIERRA trial
Mr. Seth added, "We are excited by our recent progress and committed to delivering on several milestones in the near-term and throughout 2025. Our current balance sheet provides strong runway into 2027, which enables us to deliver important clinical data and further realize our vision of being a leading fully integrated specialty radiopharmaceutical company."

Third Quarter 2024 Financial Results

Cash and cash equivalents of approximately $78.6 million as of September 30, 2024. Based on Actinium’s current operating plan, cash and cash equivalents are expected to fund operations into 2027.

Research and Development Expense, net of reimbursements

Research and development expenses of $9.8 million for the three months ended September 30, 2024 decreased $1.8 million from $11.6 million for the three months ended September 30, 2023. The decrease is primarily a result of a decline in Chemistry, manufacturing and controls, or CMC, expenses of $5.5 million and lower consulting expenses of $0.5 million, both due to lower activity in 2024 related to Iomab-B. These declines were partially offset by increased preclinical expenses of $3.9 million.

General and administrative expense

General and administrative expenses of $2.8 million for the three months ended September 30, 2024 increased by $0.1 million from $2.7 million for the three months ended September 30, 2023, primarily due to higher non-cash stock compensation expense of $0.5 million, partially offset by lower compensation expense of $0.3 million due to lower headcount.

In the third quarter of 2024, our overall headcount reduced by approximately twenty percent, with a majority of these former employees being from our clinical and CMC groups. As a result of these departures, we expect our personnel expenses to be reduced by approximately $3.7 million in 2025, which may be offset by additional hires or consultants. We do not expect these departures to have a material impact on our operations or ability to execute our operating plan and we are actively seeking a strategic partner for Iomab-B in the U.S. to advance the clinical development activity for Iomab-B including the planned Phase 3 trial.

Other income

Other income is comprised of net interest income in both reporting periods. The amount for the three months ended September 30, 2024 and 2023 of $1.0 million in each reporting period was virtually unchanged from the same time period in the prior year.

Net loss

Net loss of $11.6 million for the three months ended September 30, 2024 decreased by $1.7 million from $13.3 million for the three months ended September 30, 2023 due to lower research and development expenses partially offset by higher general and administrative expenses.

On November 18, 2024 Intensity Therapeutics, Inc. (Nasdaq: INTS), ("Intensity" or "the Company") a late-stage clinical biotechnology company focused on the discovery and development of proprietary, novel immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, reported that Christian F. Meyer M.D., Ph.D., Assistant Professor of Oncology and lead medical oncologist for adult sarcoma patients at Johns Hopkins University’s Sidney Kimmel Cancer Center, presented final safety and efficacy data from the Company’s Phase 1/2 clinical trial of INT230-6 that was used as a monotherapy in patients with relapsed, refractory, and metastatic sarcomas, along with an overview of the Company’s ongoing INVINCIBLE-3 Study design (NCT06263231) (Press release, Intensity Therapeutics, NOV 18, 2024, View Source [SID1234648482]). Dr. Meyer shared the information during an oral podium presentation in a late-breaking session at the 2024 Connective Tissue Oncology Society ("CTOS") on November 16, 2024, at 9 AM PST. The abstract’s lead author was Albiruni Razak, MB BCh, BM BCh, Clinician Investigator, Princess Margaret Cancer Centre at the University Hospital Network in Toronto, Ontario, Canada. Both Drs. Razak and Meyer, enrolled patients in the Phase 1/2 clinical trial. This year’s annual CTOS conference was held in San Diego from November 13 to 16, 2024 at the Grand Hyatt.

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"The data in the Phase 1/2 study has shown that INT230-6 causes cell death leading to tumor necrosis, improved cancer recognition by immune cells, and an ignition of a systemic anti-cancer immune response that results in T-cells entering the tumor microenvironment and has shown a favorable safety profile in soft tissue sarcomas," said Dr. Razak. "Systemically delivered chemotherapies have severe side effects, including cardiotoxicity, and most sarcoma subtypes have only a minimal response to immunotherapies. In addition, most sarcoma patients remain on current therapies for only a few months prior to progression, death or excessive toxicity. Demonstrating statistically significant improvement in median overall survival for the INT230-6 treatment arm compared to the standard of care arm in the INVINCIBLE-3 Study would be a major step forward in treating patients with these deadly soft tissue sarcomas."

Phase 1/2 Study (Sarcoma Subset Data: 15 Patients):

Demographics:

Median (min, max) lines for prior drug therapies: 3 (1.00, 7.00)
Mean (SD) age: 62.8 (8.1) years and ranged from 41.9 to 76.1 years
ECOG performance status at screening was 0, 1 and 2 for 2 (13.3%), 12 (80.0%), and 1 (6.7%) subjects respectively
The sarcoma diagnoses of the Phase 2 patients included liposarcoma, pleomorphic sarcoma, leiomyosarcoma, chondrosarcoma, osteosarcoma (chondroid syringoma), myofibroblastic, osteosarcoma, Kaposi sarcoma and chordoma
Efficacy:

The mOS in the mixed sarcoma population: 21.3 months for INT230-6
The mOS had not been reached with 21.4 months of median follow-up for patients who received a cumulative INT230-6 dose volume that was greater than 40% of their total tumor burden
INT230-6 extended overall survival in refractory sarcoma subjects by nearly 15 months as monotherapy when compared to a synthetic control group based on the Royal Marsden Hospital scoring method
Sarcoma population’s overall disease control rate (DCR): 93.3% (95% CI: 68.1, 99.8) at 2 months
Median duration of response (DOR): 4.0 months (95% CI: 1.7, NA) and 11.3 months (95% CI: 2.8, NA) for subjects who received a cumulative dose of ≥ 40% of the total incoming total tumor burden
INT230-6 demonstrated an increase in T-cells within the tumors
27% of patients had uninjected tumors shrink (abscopal effects), though tumors less than 1 cm were uninjected, untracked and unreported by investigators, so the true abscopal percentage is unknown; further radiomics work is on-going
Safety

INT230-6 demonstrated a favorable safety profile and was well-tolerated
3 subjects (20%) had one or more drug regimen-related Grade ≥ 3 Treatment Emergent Adverse Events (TEAE); all were grade 3 (there were no grade 4 or 5 TEAEs)
INVINCIBLE-3 Study Overview
The INVINCIBLE-3 Study is designed to evaluate INT230-6 administered intratumorally by an interventional radiologist or an equivalently trained physician using image guidance compared to systemically dosed standard of care ("SOC") chemotherapy. The study endpoints are overall survival and safety, along with an exploratory quality of life (QoL) assessment using the EORTC-30 survey. This is a global randomized Phase 3 study comparing the efficacy and safety of INT230-6 intratumoral (IT) injection with any of three standard of care therapies (pazopanib, trabectedin, or eribulin) in approximately 333 adult participants with locally recurrent, inoperable, or metastatic soft tissue sarcoma ("STS") patients who had disease progression prior to study enrollment following standard therapies, which must have included an anthracycline-based regimen unless contraindicated. Participants may also have received a maximum of one additional regimen. Randomization will occur after screening and eligibility confirmation. As this is a survival study, there is no crossover allowed between SOC and INT230-6. Disease progression will be determined by the World Health Organization (WHO) criteria. Participants will be prospectively stratified into 1 of 3 histologically defined STS strata:

leiomyosarcoma
liposarcoma (dedifferentiated, myxoid, round cell and pleomorphic)
undifferentiated pleomorphic sarcoma
The comparator agents used are all U.S., Europe, Canadian and Australian-approved agents for sarcomas: pazopanib tablets, trabectedin, and eribulin mesylate. Authorizations for the INVINCIBLE-3 Study have been obtained from the U.S. FDA, Health Canada, the European Medicines Agency, and Australia’s Therapeutic Goods Administration. Sites will be opened in 8 countries and the study is presently recruiting participants in the U.S., Canada, and Europe.

"The safety and efficacy data of our lead drug candidate, INT230-6, generated for sarcomas was quite encouraging. Many insights were gained from the over 200 patients treated before initiating the INVINCIBLE-3 study and applied to the ongoing study. Our approach uses sophisticated interventional radiology technologies to guide needles into tumors to inject our novel cytotoxic drug, which is highly absorbed by tumors, and showed a potential meaningful impact on lengthening metastatic sarcoma patient lives, reducing toxicities and improving quality of life compared to current treatments in our first clinical trial," said Lewis H. Bender, Intensity’s President and Chief Executive Officer. "Our unique chemistry enables water-based products to diffuse throughout tumors and into cancer cells, causing immunologic cell death."

About INT230-6
INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is comprised of two proven, potent anti-cancer agents, cisplatin and vinblastine sulfate, and a penetration enhancer molecule (SHAO) that helps disperse potent cytotoxic drugs throughout tumors for diffusion into cancer cells. These agents remain in the tumor, resulting in a favorable safety profile. In addition to local disease control and direct tumor killing, INT230-6 causes a release of a bolus of neoantigens specific to the malignancy, leading to immune system engagement and systemic anti-tumor effects. Importantly, these effects are mediated without immunosuppression, which often occurs with systemic chemotherapy.

On November 18, 2024 VelaVigo Cayman Limited (VelaVigo), a biotech company focusing on discovery and development of multi-specific antibodies and antibody-drug conjugates (ADC), reported it has entered into an agreement with Avenzo Therapeutics, Inc. (Avenzo) granting Avenzo an exclusive option to an exclusive license to develop, manufacture and commercialize a potential first-in-class Nectin4/TROP2 bispecific ADC globally (excluding Greater China) (Press release, Avenzo Therapeutics, NOV 18, 2024, View Source [SID1234648481]). VelaVigo will maintain rights for Greater China and plans to collaborate with Avenzo in global development.

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"The partnership with Avenzo is a validation of VelaVigo’s strong antibody and ADC discovery engine for First-in-Class/Best-in-Class (FIC/BIC) molecules. I’m proud of our team’s achievement in bringing multiple molecules to IND-enabling stage within 3 years and look forward to continued advancement of our pipeline", said Jing Li, founder, Chairman and CEO of VelaVigo. "Partnership is an integral part of VelaVigo’s strategy to bring our novel pipeline to patients in need and maximize value for our investors. We look forward to advancing the development of our Nectin4/TROP2 ADC program globally with Avenzo’s strong expertise", commented Tong Zhang, co-founder, CBO and CFO of VelaVigo.

Since its inception in 2021, VelaVigo has built an extensive pipeline of over ten FIC/BIC multi-specific antibodies and ADC molecules for oncology and autoimmune diseases. It has also set up VelaVigo Bio, Inc. in the US to drive clinical development and partnership globally.

Under the terms of the agreement, VelaVigo will receive an upfront fee and potential near-term milestones upon option exercise by Avenzo of up to $50 million. In addition, VelaVigo is eligible to receive future potential development, regulatory, and commercial milestone payments of up to approximately $750 million in total, as well as tiered royalties on sales in Avenzo’s territory.

An Investigational New Drug application is planned for submission to the U.S. Food and Drug Administration (FDA) and Chinese National Medical Products Administration (NMPA) in 2025.

On November 18, 2024 GRAIL, Inc. (Nasdaq: GRAL), a healthcare company whose mission is to detect cancer early when it can be cured, reported that the first patient has been tested for eligibility with the investigational GRAIL Non-Small Cell Lung Cancer (NSCLC) ctDNA Assay in the global TROPION-Lung12 Phase 3 study evaluating adjuvant treatment regimens in patients with Stage I adenocarcinoma NSCLC (Press release, Grail, NOV 18, 2024, View Source [SID1234648480]). The study is sponsored by AstraZeneca (LSE/STO/Nasdaq:AZN) in collaboration with Daiichi Sankyo (TSE: 4568).

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The study, which is being conducted under an FDA-approved Investigational Device Exemption application, held by GRAIL, leverages GRAIL’s targeted methylation platform to detect ctDNA. With GRAIL’s blood-only approach, tissue analysis and bespoke panel development are not required, enabling simple integration into pharmaceutical clinical trial workflows. In TROPION-Lung12, patients will be screened with the GRAIL assay prior to surgery to inform eligibility for post-surgery randomization to an adjuvant treatment regimen (NCT06564844). Assay performance was previously reported in the Journal of Thoracic Oncology and presented at the 2023 North America Conference on Lung Cancer.

"We’re excited to continue our strategic collaboration with AstraZeneca with the use of our novel assay in the TROPION-Lung12 study. We hope this study will further demonstrate the potential of GRAIL’s Methylation Platform to enhance patient selection for cancer treatment," said Harpal Kumar, President, International Business & Biopharma, at GRAIL. "GRAIL’s ctDNA detection approach, which does not require tumor tissue, has the potential to offer oncologists a rapid, accessible method to help refine patients’ diagnostic and prognostic profiles for better guided cancer therapy. This is among the first times a ctDNA assay has been used in a clinical trial of early-stage lung cancer patients to identify those most likely to benefit from further treatment. As such, we hope this approach could provide substantial additional benefit for patients diagnosed with Stage 1 lung cancer."

"In TROPION-Lung12, screening for ctDNA is intended to identify the patients at an increased risk of disease recurrence after surgery and thus most likely to benefit from adjuvant therapy," said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. "The novel strategy we are deploying in this trial illustrates our commitment to both detect cancer earlier and use those early insights to enable more personalized treatment decisions for the benefit of patients."

In 2022, GRAIL announced a broad strategic collaboration with AstraZeneca to develop and commercialize companion diagnostic (CDx) assays for use with AstraZeneca’s therapies. GRAIL is committed to leveraging its blood-based methylation testing for patient care by developing fit-for-purpose diagnostics to enable precision oncology strategies with biopharma partners.

On November 18, 2024 SK Biopharmaceuticals, a biotech company, reported that it has entered into an agreement with the Korea Institute of Radiological and Medical Sciences (KIRAMS), Korea’s premier research institution dedicated to the study and advancement of radiological and medical sciences, to collaborate on discovering and developing preclinical radiopharmaceutical drug candidates (Press release, SK biopharmaceuticals, NOV 18, 2024, View Source [SID1234648479]).

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This marks the first collaborative research agreement in which both sides will aim to discover radiopharmaceutical compounds and investigate novel oncological treatments, using actinium-225 (225Ac), an alpha-particle emitting radioisotope that selectively kills cancer cells. The research for radiopharmaceutical therapy (RPT) focuses on this application that has been gaining attention for its high potential in nuclear medicine.

SK Biopharmaceuticals has already initiated its 225Ac-based research as it secured a supply of the radioisotope from TerraPower Isotopes, a subsidiary of TerraPower, a nuclear innovation company whose investors include SK Biopharmaceuticals’ parent SK Inc. and Bill Gates.

SK Biopharmaceuticals and KIRAMS will seek to submit an Investigational New Drug application by 2027, as they leverage each other’s resources to optimize their drug discovery efforts. SK Biopharmaceuticals said it could significantly reduce the time and cost of new drug development, with KIRAMS’ researchers, facilities and equipment using the radioisotope, enabling the company to further accelerate in securing and expanding its RPT pipeline and capability.

The agreement is in line with SK Biopharmaceuticals’ so-called "RPT Roadmap" recently introduced to become a global leading RPT player by 2027, as the company will fortify its RPT business by discovering new drug compounds, extending supply and production capacities, and developing a tech platform, via strengthened internal assets and strategic partnerships.

In addition to the 225Ac supply agreement aligned with its roadmap, the company has in-licensed SKL35501 (FL-091) radiopharmaceutical compound targeting neurotensin receptor 1 (NTSR1) solid tumors.

Jinkyung Lee, President of KIRAMS, stated, "Through this joint research agreement, we aim to take a leading role in developing innovative radiopharmaceutical therapeutics, in alignment with the Ministry of Science and ICT’s strategic initiative to drive advancements in Radiation Biology. We look forward to contributing to the growth of the domestic radiopharmaceutical industry in close collaboration with SK Biopharmaceuticals."

Donghoon Lee, CEO and President of SK Biopharmaceuticals, said "This agreement is one of key steps in enhancing SK Biopharmaceuticals’ research capabilities. We will seek to spur SK Biopharmaceuticals to become a leading global RPT player through strengthened ties."