On December 13, 2023 Abbisko Therapeutics Co., Ltd. ("Abbisko Therapeutics") reported that its CSF-1R inhibitor pimicotinib (ABSK021) has been granted the fast track designation ("FTD") by the U.S. FDA for the treatment of tenosynovial giant cell tumor ("TGCT") patients that are not amenable to surgery (Press release, Abbisko Therapeutics, DEC 13, 2023, View Source [SID1234638541]). Previously, pimicotinib was granted the breakthrough therapy designation ("BTD") by the U.S. FDA for TGCT in January, 2023. The grant of FTD and BTD will accelerate the global development and commercialization of pimicotinib.

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Fast Track is a policy designed to facilitate the development and expedite the review of drugs in order to treat serious conditions and fulfill unmet medical needs. Its purpose is to get important new drugs to patients earlier. Moreover, the FTD enables companies to maintain more frequent communications and meetings with the U.S. FDA. The drug also becomes eligible for accelerated approval and priority review by the U.S. FDA.

In early December, Abbisko entered into an agreement with Merck KGaA, Darmstadt, Germany that grants it the exclusive license to commercialize pimicotinib for all indications in China mainland, Hong Kong, Macau, and Taiwan. Merck KGaA, Darmstadt, Germany also obtained an exclusive option for global commercial rights of pimicotinib, subject to the terms and conditions as agreed between the parties. Pursuant to the terms of the License Agreement, Abbisko will receive a one-time, non-refundable down payment of US$ 70 million. In the event that Merck KGaA, Darmstadt, Germany exercises the global commercialization option, Merck KGaA, Darmstadt, Germany will pay Abbisko an additional option exercising fee. The aggregate amounts of upfront payment, option exercising payment, and payment for development and commercialization milestones will total US$ 605.5 million. Abbisko will also obtain from Merck KGaA, Darmstadt, Germany double-digit percentage (%) royalties based on actual annual net sales.

Pimicotinib is a novel, orally available, highly selective, and potent small molecule CSF-1R inhibitor, independently developed by Abbisko Therapeutics. It has been granted the BTD and Priority Medicine (PRIME) designation by China NMPA, U.S. FDA, and EMA for the treatment of TGCT patients that are not amenable to surgery. The study is the first global Phase III clinical trial of TGCT conducted simultaneously in China, the U.S., Canada and Europe.

Upon 1-year follow-up in a Phase 1b trial for TGCT, pimicotinib demonstrated an ORR of 87.5% (28/32, including 3 CR) in the 50 mg QD cohort, which was presented at the 2023 CTOS. A Phase I dose-escalation trial for pimicotinib has been completed in the U.S. previously.

In addition to TGCT, Abbisko is actively exploring the potential of pimicotinib in treating other indications including many types of solid tumors in clinic, and it has obtained approval from NMPA to conduct a Phase II clinical study in chronic graft-versus-host disease and advanced pancreatic cancer. Up until today, no highly selective CSF-1R inhibitors have been approved in China.

About TGCT

TGCT is a locally aggressive neoplasm that usually affects synovial joints, mucous sacs, and tendon membranes, resulting in swelling, pain, stiffness, and decreased activity of the affected joints, which seriously affects the patient’s quality of life [1]. According to the 2013 World Health Organization classification, TGCTs were classified as localized TGCT and diffuse TGCT. Diffuse TGCT encompasses formerly known nodular tenosynovitis and pigmented villonodular synovitis ("PVNS"). Overexpression of CSF-1 occurs in most TGCTs. Surgical resection is the standard treatment for TGCT. However, not all patients are suitable for surgical treatment. It is difficult to remove tumors of diffuse TGCT patients by surgery, which may possibly lead to severe joint damage, total synovectomy, joint replacement, or even amputation, and the risk of surgical complications can be high. It has been reported that more than 50% of patients with diffuse TGCT would undergo recurrence after surgical resection [2]. For TGCT patients who are not amenable to surgery, there is currently no approved drug available in China.

On December 13, 2023 Transcenta Holding Limited ("Transcenta") (HKEX: 06628), a clinical stage biopharmaceutical company with fully-integrated capabilities in discovery, research, development and manufacturing of antibody-based therapeutics, reported that the preclinical anti-tumor efficacy and safety results of [177Lu]Lu-TST001 have been published on European Journal of Nuclear Medicine and Molecular Imaging (EJNMMI) (Press release, Transcenta, DEC 13, 2023, View Source [SID1234638540]). In this preclinical studies, [177Lu]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including gastric cancer.

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This research was conducted in collaboration between Transcenta and the team of Professor Hua Zhu from Beijing Cancer Hospital. In this study, a [177Lu]Lu-TST001 radionuclide antibody conjugate was developed that targets CLDN18.2 using a DOTA-TST001 as a precursor and is labeled with 177Lu, a therapeutic radionuclide. The clear molecular imaging, favorable biodistribution, and pharmacokinetics of [177Lu]Lu-TST001 were validated in a mouse xenograft GC model. Moreover, this study explored the short-term therapeutic efficacy of [177Lu]Lu-TST001 radioimmunotherapy (RIT) against CLDN18.2-positive tumors and determined the optimal therapeutic dose in a GC tumor model. Safety under the treatment dose of the probe was also examined. Significant therapeutic effects with acceptable short-term toxicity were achieved in the mouse model.

"The study represents the first application of the therapeutic radionuclide [177Lu]Lu-labeled CLDN18.2-targeting antibody TST001. This radionuclide antibody conjugate demonstrates great potential as an RIT drug for clinical application, which may offer a promising new treatment option for CLDN18.2-overexpressing tumors, such as gastric cancer, pancreatic cancer, esophageal cancer, and lung cancer, leading to improved survival outcomes." said Prof. Hua Zhu from Beijing Cancer Hospital.

"Compared to localized gastric cancer, advanced metastatic gastric cancer often cannot be cured by chemotherapy or external radiation alone. In such cases, targeted RIT provides an opportunity to deliver radiation selectively to disease sites in patients with metastases, regardless of disease stage, offering a potential clinical treatment strategy for advanced tumor patients. We look forward to continuing our work with Prof Zhu and his team in an effort to bring [177Lu]Lu-TST001 radionuclide antibody conjugate to patients in the near future." said Dr. Xueming Qian, CEO of Transcenta.

About Osemitamab (TST001)
Osemitamab (TST001) is a high affinity humanized anti-CLDN18.2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity ("ADCC"). It has shown potent anti-tumor activities in tumor xenograft models. Osemitamab (TST001) is the second most advanced CLDN18.2 targeting antibody being developed globally. Osemitamab (TST001) was generated using Transcenta’s Immune Tolerance Breaking Technology (IMTB) platform. Osemitamab (TST001) kills CLDN18.2 expressing tumor cells by mechanisms of ADCC. Leveraging advanced bioprocessing technology, the fucose content of Osemitamab (TST001) was significantly reduced during the production, which further enhanced NK cells mediated ADCC activity of Osemitamab (TST001). Clinical trials for Osemitamab (TST001) are ongoing in the U.S. and China (NCT05190575, NCT04396821, NCT04495296, NCT05608785 / CTR20201281). Osemitamab (TST001) was granted Orphan Drug Designation in the U.S. by FDA for the treatment of patients with gastric or gastroesophageal junction (G/GEJ) and pancreatic cancer.

On December 13, 2023 Dizal reported that the results of a phase 2 pivotal study of sunvozertinib for the treatment of platinum-pretreated non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations (exon20ins) (WU-KONG6) were published in the peer-reviewed journal The Lancet Respiratory Medicine (IF: 76.2) (Press release, Dizal Pharma, DEC 13, 2023, View Source [SID1234638539]). The publication of these research results further reinforces sunvozertinib’s leading position as a potential best-in-class treatment option, following its selection for an oral presentation at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting.

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Lung cancer is the leading type of cancer with the highest incidence and mortality rates in China. In NSCLC, EGFR represents the most common driver gene mutation, with exon20ins mutations being the most prevalent rare subtype, accounting for approximately 12% of all EGFR mutations. However, due to its unique spatial configuration and high heterogeneity, there has been a persistent lack of safe and effective targeted treatment options for this mutation, leading to limited survival benefits for patients.

Yun Fan, MD, PhD from the Department of Thoracic Oncology at the Cancer Hospital of the University of Chinese Academy of Sciences, and the first author of the paper, emphasized the significant challenge presented by EGFR exon20ins mutations in drug development. Despite various treatment modalities including chemotherapy, traditional EGFR-TKIs, immunotherapy and other targeted therapies, the objective response rate (ORR) in platinum-pretreated NSCLC patients with EGFR exon20ins mutations has not exceeded 50%.

Sunvozertinib is a selective EGFR TKI developed to target a wide spectrum of EGFR mutations. It is the first Chinese innovative drug approved for NSCLC patients with EGFR exon20ins mutations. The National Medical Products Administration (NMPA) granted approval based on the results from the WU-KONG6 study, a single-arm, multicenter phase 2 pivotal study, conducted to evaluate the antitumor efficacy of sunvozertinib in platinum-pretreated advanced stage NSCLC patients with EGFR exon20ins mutations. The study’s primary endpoint, the independent review committee (IRC) -assessed ORR reached 61%, indicating a significant improvement over existing treatment options. With more than 100 different subtypes of EGFR exon20ins reported in NSCLC so far, thus making the treatment with a single agent even more challenging due to the diversified protein structure of different subtypes. However, owing to its unique chemical design and flexible compound, sunvozertinib was able to bind to different subtype proteins, and showed potent anti-tumor activities in cell lines expressing a broad variety of subtypes. More importantly, its activity was translatable to human. The ORRs were higher than 50% among different subtypes enrolled into this study. Additionally, the overall safety is similar to other EGFR TKIs and clinically manageable, which can be well managed in the clinic.

Mengzhao Wang, MD, PhD of the Department of Pulmonary Medicine at the Lung Cancer Center at Peking Union Medical College Hospital, and the first and corresponding author of the paper said, "Sunvozertinib, the first Category-I Innovative Drug approved for the treatment of EGFR exon20ins NSCLC in China, has demonstrated a superior efficacy, safety and convenience profile. It overcomes the existing treatment challenges faced by advanced NSCLC patients with EGFR Exon20ins mutations, offering an effective treatment option for this patient population."

"Sunvozertinib marks the first approved innovative drug from Dizal. We are delighted to see the increasing recognition of sunvozertinib’s potential as the best-in-class therapy for NSCLC patients with EGFR exon20ins mutations," said Xiaolin Zhang, PhD, Chairman and CEO of Dizal, "Dizal is expediting the global clinical research of sunvozertinib and eagerly anticipates collaborating with experts to explore additional treatment possibilities. Our goal is to deliver life-changing treatment options for patients worldwide."

About sunvozertinib (DZD9008)

Sunvozertinib is an irreversible EGFR inhibitor discovered by Dizal scientists targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023, sunvozertinib received approval from NMPA for the treatment of advanced NSCLC with EGFR exon20ins mutations after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins mutations. The primary endpoint of the study, which was the confirmed overall response rate (cORR) as assessed by the Independent Review Committee (IRC) reached 60.8%. Anti-tumor efficacy was observed across a broad range of EGFR exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins mutations.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug related TEAEs (treatment emergent adverse event) were Grade 1/2 in nature and clinically manageable.

Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 PART B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR exon20ins mutations.

Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery (IF:39.397) and The Lancet Respiratory Medicine (IF: 76.2).

On December 13, 2023 Imagion Biosystems Limited (ASX: IBX) reported positive results following completion of the IBI10103 phase I clinical trial evaluating the safety and clinical feasibility of MagSense HER2 Imaging Agent (MSH2IA) as an adjunct to MRI for the assessment of axillary lymph node metastasis in patients diagnosed with HER2+ primary breast cancer (Press release, Imagion Biosystems, DEC 13, 2023, View Source [SID1234638538]). The trial met its endpoint of safety and tolerability, and showed that blinded radiologists may be able to distinguish suspicious lymph nodes that are infiltrated with metastatic HER2+ cancer from those involved in a healthy immune response or otherwise normally reactive. Thirteen women definitively diagnosed with HER2+ breast cancer were enrolled and treated with the drug without any safety issues, toxicity or drug-related adverse events reported.

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Imagion Biosystems’ Managing Director & CEO, Dr. Isaac Bright, shares a scientific presentation, providing intricate insights into the Phase I Study conducted with MagSense HER2 Imaging Agent.
Imagion Biosystems’ Managing Director & CEO, Dr. Isaac Bright, shares a scientific presentation, providing intricate insights into the Phase I Study conducted with MagSense HER2 Imaging Agent.
Dr. Isaac Bright, Managing Director and CEO of Imagion, presented the data at the international San Antonio Breast Cancer Symposium last week and said, "Patients with HER2 positive breast cancer need better staging options that are safe, reliable, comprehensive, and less invasive than today’s standard of care – axillary ultrasound and serial biopsy procedures. Too many of these women endure unnecessary interventions that provide incomplete information and impose unnecessary costs on global healthcare systems. We are encouraged by MSH2IA’s potential to increase the accuracy of disease staging, and thus improve treatment decisions."

IBI10103 Phase I Study Results

The IBI10103 clinical trial was closed in October 2023 and evaluated the potential of the world’s first molecularly targeted MRI contrast agent, MSH2IA (MagSense HER2 Imaging Agent), to enhance clinicians’ ability to non-invasively and more accurately determine the stage of HER2+ breast cancer. This trial, which was a multi-center open-label study, demonstrated the drug is safe and well-tolerated.

An international panel of blinded radiologists assessed pre-dose versus post-dose MRI scans of treated patients. 5 patients’ scans were not interpretable due to image artifacts or tumor invasion that precluded lymphatic drainage of MSH2IA to axillary lymph nodes. In a comprehensive assessment of the other 8 patients’ scans, the radiologists recognized MSH2IA uptake in both normal and malignant lymph nodes. Normal lymph nodes were recognized by a uniformly dark contrast distributed throughout the entire node. Tumor-metastasized lymph nodes were observed to have heterogeneous scattered darkening. Importantly, MRI assessment of post-MSH2IA imaging achieved parity or outperformed standard-of-care axillary ultrasound imaging in all 8 of these patients. Molecular MRI with MSH2IA achieved nearly perfect patient-level concordance, as 7 of these 8 patients identified with tumor-metastasized lymph nodes post-MSH2IA MRI imaging were confirmed by post-surgical pathology analysis to have metastatic disease. The Company continues to work towards its Investigational New Drug application for submission to the US FDA, which was initially planned for Q1:2024, but now likely to be delayed as Imagion works to ensure sufficient resources are in place to pursue clinical development of the MagSense imaging technology. As the global first-mover enabling molecular MRI, these results are very promising for Imagion and for improved precision oncology care. The Company is encouraged by the feedback IBI10103 results are attracting from prospective partners.

San Antonio Breast Cancer Symposium Poster

Dr. Bright announced these findings last week in a premiere Spotlight poster presentation titled, ‘Noninvasive Detection of Lymph Node Involvement in Subjects with Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Cancer using the MagSense HER2 Test Reagent – A First-In-Human Phase I Study’ at the international San Antonio Breast Cancer Conference.

You can download a copy of the poster HERE >> View Source

About HER2+ Breast Cancer

More than 2 million women worldwide are diagnosed with breast cancer annually, and approximately 20% of them are diagnosed with HER2+ breast cancer. Accurate disease staging is crucial, as treatment strategies vary based on primary tumor characteristics, lymph node status, and more distant metastatic disease. The current clinical standard of care for breast cancer staging relies on clinical assessment and diagnostic imaging. Axillary ultrasound for staging breast cancer is highly subjective and operator-dependent – as many as 50% of breast cancer patients may have their disease inaccurately staged. Inaccuracies at the outset of disease management leave a number of patients inadequately treated and subject others to wasteful and potentially harmful treatments and interventions. Molecular MRI with MSH2IA may emerge as the new standard of care for accurately staging the disease in patients diagnosed with HER2+ breast cancer.

About MagSense HER2 Imaging Agent

The MagSense HER2 Imaging Agent features a superparamagnetic iron oxide nanoparticle core synthesized at Imagion’s GMP-compliant facility in San Diego, CA. It is coated with biocompatible polymers and functionalized with the monoclonal antibody trastuzumab or Herceptin. MSH2IA is designed to be a single dose injected near the primary tumor and has been proven to drain through lymphatics, specifically targeting and binding to HER2+ breast cancer cells.

On December 13, 2023 Inhibitor Therapeutics, Inc. ("Inhibitor") (OTCQB: INTI) has entered into an exclusive, worldwide licensing agreement (the "License") with Johns Hopkins University (JHU) for their U.S Patent 8,980,930 (Canada Patent 2,572,223) "New Angiogenesis Inhibitors" (Press release, Inhibitor Therapeutics, DEC 13, 2023, View Source [SID1234638537]). Angiogenesis Inhibitors, as described by the National Cancer Institute, are unique cancer fighting agents as they block the growth of blood vessels that support tumor growth rather than blocking the growth of the tumor cells themselves. Inventors affiliated with JHU developed this patent, listing Itraconazole as an Active Pharmaceutical Ingredient (API) that has anti-angiogenic properties.

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The License notes field of use is for use in Prostate Cancer, Basal Cell Carcinoma including Basal Cell Carcinoma Nevus Syndrome (an orphan oncology disease), and Lung Cancer, all of which emphasize a significant unmet need. Inhibitor believes the License is a mutually beneficial agreement, yielding a modest annual royalty rate with milestone payments typical to such a license.

Within the literature Head et al1 explains the long-term recognition that angiogenesis is a requirement for tumor growth and metastasis and that growing tumors can promote angiogenesis by secreting proangiogenic factors such as VEGF, basic FGF, EGF and others. These proangiogenic factors stimulate the proliferation, migration, and differentiation of the endothelial cells that make up the inner layer of all blood vessels, causing them to form new vessels that grow towards the source of these factors, this process termed "tumor angiogenesis". It is identified that the major target of itraconazole in endothelial cells is VDAC1. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in HUVEC revealing a previously unknown connection. Inhibition of VDAC1 by itraconazole leads to an increase in cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In their testing it was found that by using a phenotypical approach starting with the effect of itraconazole the G1-S cell cycle transition of the endothelial cells, itraconazole specifically inhibited the mTOR signaling pathway by downregulating the kinase activity of mTORC1.

Chow Et Al2 completed a study utilizing RNA sequencing to decipher the biological pathway propelling BCC growth. From the assay results, it was observed that BCCs exhibited a considerable amplification in the expression of the mTOR pathway. This pathway plays an essential role in regulating angiogenesis, the growth of new blood vessels from pre-existing ones. Thus, this indicates that it is the heightened activity of the mTOR pathway, and the consequent enhancement of angiogenesis, that stimulates the growth.

Data from Inhibitor’s completed Phase 2b SCORING Trial complements the literature with reference to the Lesion Response of the study which shows that across the 477 target lesions the investigators reported reductions of any size from baseline for 399 (83.65%) lesions, 64 (13.42%) had no change and 14 increased in size. A pre-determined reduction of 30% or greater was seen in 275 of the 477 (57.7%) target lesions, including 130 lesions which resolved completely (27.3%). A total of 13 new ‘surgically eligible’ lesions across 8 of the 38 patients developed over the duration of the study.

For more information about Inhibitor and our mission please visit us on our website (www.inhibitortx.com) and for any further or specific queries you may have please visit our contact us page, submit your details/query, and a representative will be happy to get in touch.