On October 20, 2021 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported the first patient with metastatic sigmoid adenocarcinoma has been dosed in Perth, Australia in a phase Ib/II trial of GFH018 in combination with toripalimab (anti-PD-1 monoclonal antibody) as part of global multi-center clinical research (Press release, GenFleet Therapeutics, OCT 20, 2021, View Source;r1-inhibitor-in-combination-with-pd-1-inhibitor-in-global-multi-center-research-301404765.html [SID1234591610]). GenFleet also received IND approval from the food and drug administrative authorities in China’s Taiwan to proceed with phase Ib/II trial of GFH018 in combination with toripalimab in patients with multiple solid tumors.

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Potential indications for molecules targeting TGF-β pathway span across multiple solid tumors, and no drugs have been approved for this pathway thus far. There are broad indications for GFH018 in treating solid tumors with lower response rates to PD-1 inhibitors.

The primary objective of this combination study is to evaluate the safety/tolerability of GFH018 with toripalimab. It will also characterize the pharmacokinetics of GFH018 and the efficacy of the combination therapy. GFH018 demonstrated excellent safety profile in phase I trial. Preclinical data also suggested antitumor effects of low-dose GFH018 in combination with PD-1 inhibitors.

"TGF-β signaling pathway has been validated in recent years as crucial to regulating immune-microenvironment in cancer therapeutics. Drug candidates targeting this pathway offers a critical solution for patients resistant to previous immunotherapies with poor prognosis. Compared to antibodies targeting the TGF-β pathway, GFH018 as a small molecule inhibitor specifically targets TGF-β R1 (receptor type 1). And based on preliminary data in phase I trial, we can see that GFH018 has the potential to inhibit the growth of fibroblasts, regulate tumor microenvironments, and improve the response rate to PD-1 inhibitors in combination therapies," said Yu Wang, M.D./Ph.D., Chief Medical Officer of GenFleet.

"This multi-center trial the first POC (proof of concept) study designed by GenFleet and it’s also the company’s third program involving global research sites. The development of GFH018 progresses smoothly and is one of the leading drug candidates targeting TGF-β pathway and will hopefully offer a differentiated alternative to therapies in combination with immune checkpoint inhibitors. In continuous exploration of novel targets, we look forward to benefiting global patients with more innovative therapies in future," said Jiong Lan, Ph.D., Chief Executive Officer of GenFleet.

About toripalimab

Toripalimab is an anti-PD-1 monoclonal antibody developed by Junshi Biosciences ( SH: 688180；HK: 1877). More than thirty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally, including in China and the United States. Ongoing or completed pivotal clinical trials are evaluating the safety and efficacy of toripalimab for a broad range of tumor types including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney and skin.

In China, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (TUOYI). On December 17, 2018, toripalimab was granted a conditional approval by the National Medical Products Administration (NMPA) for the second-line treatment of unresectable or metastatic melanoma. In December 2020, toripalimab was successfully included in the updated National Reimbursement Drug List. In February 2021, the NMPA granted a conditional approval to toripalimab for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) after failure of at least two lines of prior systemic therapy. In April 2021, NMPA granted a conditional approval to toripalimab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

In the United States, the first toripalimab BLA has been submitted to the FDA for the treatment of recurrent or metastatic NPC. The FDA has granted 2 Breakthrough Therapy designations, 1 fast Track designation and 3 orphan drug designations for toripalimab in the treatment of NPC, mucosal melanoma and soft tissue sarcoma.

About GFH018 and TGF-β R1

Developed by GenFleet Therapeutics, GFH018 is an orally administered TGF-β R1 inhibitor and entered into phase I clinical trial in 2019. Preclinical data showed evidence of GFH018’s good anti-tumor properties against cancer cells in vivo and in vitro. Besides, translational and mechanistic studies confirmed it effectively acts on TGF-β signaling pathway and synergizes with checkpoint inhibitors.

As a multifunctional cytokine, transforming growth factor-β (TGF-β) is secreted into tumor microenvironment or peripheral circulation mainly by regulatory T cells, fibroblasts and endothelial cells. TGF-β binds to type 2 receptor (TGF-β R2) on cell membrane, and then recruits and phosphorylates type 1 receptor (TGF-β R1). The receptor dimer activates downstream SMAD-dependent & SMAD-independent signaling pathways to perform various biological functions.

In the microenvironment of advanced solid tumors, TGF-β signaling pathway can promote epithelial mesenchymal transition (EMT) & metastasis, induce the formation of cancer stem cells and their functional maintenance, inhibit anti-tumor immunity, enhance vasculature and fibrosis, and ultimately result in tumor progression. Among patients of hepatocellular carcinoma, glioma, colorectal cancer, lung cancer, pancreatic cancer, urothelial cancer and other solid tumors, high expression of genes related to TGF-β signaling pathway is frequently discovered in their blood and tumor tissues. The expression level is positively correlated to the malignancy & poor differentiation of tumor and unfavorable prognosis in patients.

On October 20, 2021 NANOBIOTIX (Euronext: NANO – NASDAQ: NBTX – the ‘‘Company’’), a late-clinical stage biotechnology company pioneering physics-based approaches to expand treatment possibilities for patients with cancer, reported operational progress and cash position (unaudited) for the third quarter of 2021 (Press release, Nanobiotix, OCT 20, 2021, View Source [SID1234591609]).

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Third Quarter Financial Updates

Nanobiotix reported cash, cash equivalents, and short-term investments totaling €89.8 million as of September 30, 2021, compared to €119.2M as of December 31, 20201.

Third Quarter Operational Highlights and Upcoming Milestones

Published preclinical findings with The University of Texas MD Anderson Cancer Center (MD Anderson) in the International Journal of Radiation Oncology, Biology, Physics (Red Journal) supporting continued exploration of NBTXR3 as a potential therapeutic option to induce significant tumor cell death, prime immune response, and overcome resistance to anti-PD-1.
Study hypothesized that NBTXR3 in combination with radiotherapy and anti-PD-1 could transform irradiated tumors into "self-vaccines" in anti-PD-1-sensitive and anti-PD-1-resistant mouse models
Data supported the hypothesis that the triple combination could effectively control primary and metastatic tumors, evoke abscopal effect, and reduce the possibility of developing distant lung metastases
Presenting two oral presentations and three poster presentations at the 2021 ASTRO Annual Meeting being held October 24-27, 2021, including:
First analysis of progression free survival (PFS) and overall survival (OS) from 41 evaluable patients from Study 102 Expansion, a phase I dose expansion study evaluating NBTXR3 as a single agent activated by radiotherapy in LA-HNSCC
Updated data including approximately 16 evaluable patients from Study 1100, a phase I basket study evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in locoregional recurrent or recurrent metastatic HNSCC, lung metastasis from any primary tumor and/or liver metastasis from any primary tumor
Long-term safety data from the phase II/III Act.In.Sarc Trial of NBTXR3 in locally advanced soft tissue sarcoma
Preclinical data on NBTXR3 plus anti-PD-1 in lung cancer model
Preparing to activate first clinical trial sites for NANORAY-312, a pivotal phase III global registration study evaluating NBTXR3 as a single-agent activated by radiotherapy for patients with LA-HNSCC
First site activations in Europe expected in the coming weeks with first patient randomized by early 2022.
US site activation and enrollment planned for 2022
About NBTXR3

NBTXR3 is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide nanoparticles that is administered via one-time intratumoral injection and activated by radiotherapy. The product candidate’s physical mechanism of action (MoA) is designed to induce significant tumor cell death in the injected tumor when activated by radiotherapy, subsequently triggering adaptive immune response and long-term anticancer memory. Given the physical MoA, Nanobiotix believes that NBTXR3 could be scalable across any solid tumor that can be treated with radiotherapy and across any therapeutic combination, particularly immune checkpoint inhibitors.

NBTXR3 is being evaluated in locally advanced head and neck squamous cell carcinoma (HNSCC) as the primary development pathway. The company-sponsored phase I dose escalation and dose expansion study has produced favorable safety data and early signs of efficacy; and a phase III global registrational study is planned to launch in 2021. In February 2020, the United States Food and Drug Administration granted regulatory Fast Track designation for the investigation of NBTXR3 activated by radiation therapy, with or without cetuximab, for the treatment of patients with locally advanced HNSCC who are not eligible for platinum-based chemotherapy—the same population being evaluated in the planned phase III study.

Nanobiotix has also prioritized an Immuno-Oncology development program – beginning with a Company- sponsored phase I clinical study evaluating NBTXR3 activated by radiotherapy in combination with anti-PD-1 checkpoint inhibitors for patients with locoregional recurrent or recurrent/metastatic HNSCC and lung or liver metastases from any primary cancer eligible for anti-PD-1 therapy.

Given the Company’s focus areas, and balanced against the scalable potential of NBTXR3, Nanobiotix has engaged in a strategic collaboration strategy with world class partners to expand development of the product candidate in parallel with its priority development pathways. Pursuant to this strategy, in 2019 Nanobiotix entered into a broad, comprehensive clinical research collaboration with The University of Texas MD Anderson Cancer Center to sponsor several phase I and phase II studies to evaluate NBTXR3 across tumor types and therapeutic combinations.

On October 20, 2021 Oncoinvent AS, a clinical stage company advancing a pipeline of radiopharmaceutical products across a variety of solid cancers, reported that it will present new preclinical data supporting the future clinical development of Radspherin, a novel alpha-emitting radioactive microsphere suspension designed for treatment of metastatic cancers in body cavities, in four digital presentations at the 34th Annual Congress of the European Association of Nuclear Medicine (EANM) (Press release, Oncoinvent, OCT 20, 2021, View Source [SID1234591608]).

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"We are thrilled to present these data at EANM, furthering our confidence in the potential of alpha-emitting radioactive particles for the treatment of metastatic cancers in body cavities," said Jan A. Alfheim, Chief Executive Officer of Oncoinvent. "These data demonstrate that Radspherin has potentially robust and retained biodistribution in body cavities, and give us important insights into the safety of clinical doses. We look forward to the continued clinical development of Radspherin in colorectal and ovarian cancer patients suffering from peritoneal carcinomatosis."

Synergy of 224Ra-labeled microparticles and chemotherapy in a murine ovarian cancer model
Presenting Author: Roxanne Wouters
Abstract Number: OP-0108

This preclinical study aimed to evaluate the effects of combining 224Ra-CaCO3-MP, radium-224-labeled calcium carbonate microparticles, with either first line chemotherapy for ovarian cancer, carboplatin-paclitaxel, or second line chemotherapy, carboplatin-pegylated liposomal doxorubicin (PLD), in an ovarian cancer model. Ovarian cancer mouse models were treated with 224Ra-CaCO3-MP (5 mg, 14-22 kBq/animal) one day following tumor cell inoculation. Additionally, 224Ra-CaCO3-MP treatment was combined with either carboplatin (100 mg/kg)-paclitaxel (10 mg/kg) on day 14, 21 or 28, or carboplatin (80 mg/kg)-PLD (1.6 mg/kg) on day 14.

Key results:

As a single treatment, 224Ra-CaCO3-MP delayed the onset of malignant ascites development compared to control.
When 224Ra-CaCO3-MP was administered in combination with carboplatin-PLD, survival was significantly prolonged compared to mice that received carboplatin-PLD alone.
Synergy when treating ovarian cancer cell lines with Radium-224 and PARP inhibitors
Presenting Author: Marion Masitsa Malenge
Abstract Number: EPS-064

This study evaluated the potential of combining radium-224 (224Ra), an alpha-emitter with 3.6 days half-life with the PARP inhibitors olaparib and niraparib to inhibit growth of ovarian cancer cell-lines. The effect of 224Ra in combination with olaparib and in combination with niraparib were evaluated in two human non-BRCA-mutated ovarian cancer cell-lines, ES-2 and SKOV-3. Cells were simultaneously treated with 224Ra and PARP inhibitors at escalating concentrations, and cell proliferation was measured 72, 96 and 120 hours after initiation of treatment.

Key results:

The combination index (CI) between both evaluated cell-lines was heterogenous across the tested range depending on the PARP inhibitor used in the combination, the concentrations of the combined drugs and the timepoint of assessment.
Combination treatment with PARP inhibitors and 244Ra was seen to be synergistic.
Biodistribution and dosimetry after intraperitoneal injection of 224Ra-labeled microparticles in rats
Presenting Author: Sara Westrøm
Abstract Number: EP-118

The presentation highlights the ex vivo biodistribution 224Ra-CaCO3-MP in preclinical models. In addition, dosimetry was calculated and extrapolated to the absorbed doses to human. 224Ra-CaCO3-MP (89 kBq/animal, 30 mg CaCO3) or vehicle was administered to preclinical rat models intraperitoneal. Ex vivo biodistribution was assessed at time points ranging from 2 to 336 hours post injection. For dosimetry calculations, the cumulated activity was determined by linear interpolation between the measured values. The dosimetry results were extrapolated to humans and scaling with relative biologically effectiveness (RBE) factors was performed.

Key results:

The majority of 224Ra was retained after intraperitoneal administration of 224Ra-CaCO3-MP.
Analyses of clinical pathology showed no treatment-related adverse effects, apart from a transient depression of neutrophils.
Dosimetry demonstrated that based on the low absorbed doses for all tissues, administration of up to 7 MBq 224Ra-CaCO3-MP, the maximum activity in ongoing Phase 1 studies, is deemed safe.
Dose response of 212Pb-labeled calcium carbonate microparticles in mice with intraperitoneal ovarian cancer
Presenting Author: Ruth Gong Li
Abstract Number: OP-0111

This study evaluated the intraperitoneal retention and biodistribution of 212Pb-CaCO3 microparticles in mouse models of ovarian cancer. Mice received a single intraperitoneal injection of either 2-5mg with doses ranging from 57-390 kBq 212Pb-CaCO3 microparticles, or vehicle.

Key results:

Calcium carbonate microparticles can be labeled with 212Pb in an easy, fast and efficient process; no chelator or co-precipitants are necessary.
212Pb-CaCO3 microparticles were retained in the peritoneal cavity.
The increased survival of mice with tumors that were treated with 212Pb-CaCO3 was dose-dependent and significant for all evaluated doses.

On October 20, 2021 Biological Dynamics, Inc., a multiomics liquid biopsy company focused on detecting cancers at the earliest stages, reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Device Designation for its liquid biopsy assay, Exo-PDAC (Press release, Biological Dynamics, OCT 20, 2021, View Source [SID1234591607]). The test is designed to provide early detection for pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive and lethal forms of cancer worldwide.

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"Early detection of pancreatic cancer in elevated risk individuals may help save a lot of lives," said Scott Lippman, MD, Director of Moores Cancer Center at UC San Diego Health. "The promise of Biological Dynamics’ cutting-edge exosomal isolation technology is addressing a critical, unmet medical need in our multidisciplinary and multi-dimensional fight against pancreatic cancer."

PDAC is projected to become the second leading cause of cancer-related deaths by 2040, due primarily to the fact that the disease is asymptomatic in its early stages. Therefore, patients are typically diagnosed during advanced stages of disease progression when treatments are limited. Detecting early PDAC biomarkers could help identify vulnerable patients before the disease progresses or metastasizes. However, it requires a high degree of sensitivity and specificity that conventional laboratory testing methods lack.

The Exo-PDAC diagnostic assay identifies exosomal biomarkers related to an elevated risk of pancreatic cancer, such as individuals with new-onset diabetes, a family history of pancreatic cancer, certain germline mutations, and other relevant factors that might be determined by the United States Preventive Services Task Force (USPSTF). Exo-PDAC is the first assay to use Biological Dynamics’ Verita platform, a novel alternating current electrokinetic-based technology applied for early disease detection, including cancer, Alzheimer’s disease, and infectious diseases. The test requires a small amount of blood from patients, which is then analyzed with minimal sample preparation or processing.

"For far too long, patients have needed innovative technologies with the potential to detect cancer at the earliest stages, and we look forward to working closely with the FDA, to do exactly that, with our pancreatic cancer test," said Biological Dynamics CEO Raj Krishnan, PhD. "And for us, this is an important milestone as we accelerate our vision of improving global health outcomes by advancing our unique multiomics platform for multiple cancers and other diseases."

According to the FDA, "The goal of the Breakthrough Devices Program is to provide patients and health care providers with timely access to these medical devices by speeding up their development, assessment, and review, while preserving the statutory standards for premarket approval, 510(k) clearance, and de novo marketing authorization, consistent with the Agency’s mission to protect and promote public health."

On October 20, 2021 Enzychem Lifesciences (KOSDAQ: 183490) reported that positive Phase 2 results from a U.S. clinical trial of its lead candidate EC-18 in chemoradiation-induced oral mucositis (CRIOM). EC-18, a novel, first-in-class, small molecule oral immunomodulator, reduced the duration and incidence of severe oral mucositis in patients with head and neck cancer undergoing concurrent chemoradiation therapy (Press release, Enzychem Lifesciences, OCT 20, 2021, View Source [SID1234591606]).

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CRIOM is a painful and debilitating side effect of chemoradiation in which patients experience severe mouth ulcerations that significantly impacts everyday activities, such as eating, swallowing, and talking. The pain from severe ulcerations can prevent a patient’s intake of solid food and fluids, leading to malnutrition and dehydration that requires hospitalization. Patients with the most severe form of oral mucositis often have to discontinue or modify their cancer treatment.

"Severe CRIOM affects almost 75% of patients being treated with concomitant chemoradiation for head and neck cancers with symptoms that are so severe that they challenge a patients’ ability to tolerate optimal treatment," said Dr. Stephen Sonis, Professor, Harvard School of Dental Medicine and Key Advisor for the U.S. Phase 2 CRIOM Study. "Despite its frequency and burden it places on patients and their caregivers, there is no approved pharmaceutical intervention. The results observed with EC-18 support its continued development and offer encouragement as an effective CRIOM therapy."

"We are delighted to announce these positive results from our Phase 2 U.S. study, which confirm that EC-18 is safe and well-tolerated," said Ki-Young Sohn, CEO & Chairman, Enzychem Lifesciences. "In addition, EC-18 may have a number of key advantages, including oral route of administration and convenience of use. We are excited to advance this novel candidate into a pivotal study and will also evaluate EC-18 for other radiation-induced inflammatory diseases."

The Phase 2 U.S. study evaluated EC-18 in oral mucositis in patients with concomitant chemo-irradiation (standard fractionated Intensity-Modulated Radiation Therapy with cisplatin) for cancers of the mouth, oropharynx, hypopharynx and nasopharynx. In Stage 1 of the study, 24 subjects were randomized to receive one of three doses of EC-18 (500 mg, 1000 mg, or 2000 mg; unit dose of 500 mg) or placebo. For Stage 2 of the study, 81 patients were randomized to receive either placebo or 2000 mg of EC-18 twice-daily over a period of approximately 7 weeks.

EC-18 successfully met both its primary and secondary endpoints in terms of efficacy and safety in the Phase 2 U.S. study. Patients on EC-18 reported a reduction in the duration of severe oral mucositis (SOM) through a short-term follow-up period from 13.5 days to 0 day (100% reduction) in comparison to the placebo arm. EC-18 also reduced the incidence of SOM through completion of radiation by 37.1% in comparison to the placebo arm (65% vs. 40.9%). The incidence of SOM through a short-term follow-up period was reduced by 35.1% in comparison to the placebo arm (70% vs. 45.5%). No serious adverse events (SAE) were reported between placebo and EC-18 groups and none of the SAEs were related to EC-18. Safety was also comparable across arms with all adverse events (AEs) attributable to expected chemoradiation-related toxicity. One-year long-term follow-up for tumor outcomes is ongoing.

Based on positive Phase 2 data, Enzychem plans to file for Breakthrough Therapy Designation to the FDA later this year, and advance EC-18 into a global Phase 3 clinical program.