On April 12, 2021 Iovance Biotherapeutics, Inc. Presented the Corporate Presentation (Presentation, Iovance Biotherapeutics, APR 12, 2021, View Source [SID1234577907]).

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On April 12, 2021 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported initiation of its Phase 1/2 FORGE-1 study of TPX-0131, a potent inhibitor of the anaplastic lymphoma kinase (ALK) and multiple resistant mutations of ALK (Press release, Turning Point Therapeutics, APR 12, 2021, View Source [SID1234577924]).

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The investigational new drug (IND) application for TPX-0131 is Turning Point’s third IND to be cleared by the FDA in less than 2 years, and FORGE-1 is the company’s fourth clinical study to initiate during the same period of time.

The study was initiated in Australia, with U.S. site activations now planned.

"With a lack of available therapies to address a broad spectrum of ALK resistant mutations, we are encouraged by the preclinical potency for TPX-0131, particularly against the G1202R solvent front mutation which is reported to occur in more than 40% of biopsies with resistance mutations," said Ben Solomon, M.D., principal investigator for the FORGE-1 study, a medical oncologist and group leader of the Molecular Therapeutics and Biomarkers Laboratory at the Peter MacCallum Cancer Centre in Melbourne, Australia. "In addition, TPX-0131 has been shown preclinically to penetrate the central nervous system, which is important in the treatment of patients with ALK-positive non-small cell lung cancer as the disease often progresses in the brain."

ALK alterations are estimated to be responsible for 3% to 5% of non-small cell lung cancer (NSCLC) cases annually in the U.S. and EU5 countries. In preclinical studies, TPX-0131 potently inhibits wildtype ALK and is more potent in comparison to approved ALK inhibitors against many clinically observed resistance mutations, including the G1202R solvent front mutation, L1196M gatekeeper mutation, and multiple compound mutations. In addition, TPX-0131 has shown brain tissue penetration after repeat oral dosing.

"Our clinical study of TPX-0131 will begin with a Phase 1 dose finding portion in patients previously treated with up to 2 prior ALK tyrosine kinase inhibitors, a population we believe is underserved today by available therapies that are less potent against known resistant mutations of ALK," said Mohammad Hirmand, M.D., chief medical officer of Turning Point Therapeutics.

The Phase 1 dose finding portion of the FORGE-1 study will enroll patients with locally advanced or metastatic TKI-pretreated ALK-positive NSCLC. Patients with up to 2 prior ALK TKIs and 1 prior platinum-based chemotherapy will be enrolled. The study endpoints include safety and tolerability, determination of the maximum tolerated dose and/or the recommended Phase 2 dose, and objective response rate by RECIST 1.1.

On April 12, 2021 PharmAbcine Inc. (KOSDAQ: 208340ks), a clinical-stage biotech company focusing on the development of antibody therapeutics, reported that the company presented an e-poster featuring the non-clinical data of PMC-309 at American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting taking place virtually (Press release, PharmAbcine, APR 12, 2021, View Source [SID1234577940]).

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PMC-309, one of the company’s first immuno-oncology drug candidates, is a monoclonal IgG (Immunoglobulin G) that targets human VISTA (V-domain Ig Suppressor of T cell Activation), an immune checkpoint regulator. VISTA is found overexpressed on MDSC (Myeloid-Derived Suppressor Cells) and M2 macrophages both of which are immunosuppressive cells found abundantly around TME (Tumor Microenvironment).

The presentation highlighted that PMC-309 inhibits VISTA pathway on immunosuppressive cells and increases T cell activities in in vitro settings and shows potent anti-tumor effects in in vivo studies.

The in vitro studies confirmed that PMC-309 inhibits VISTA interaction and promotes T cell activation. PMC-309 blocked the VISTA pathway with its partner molecules such as VSIG3 (V-Set and Immunoglobulin domain containing 3), PSGL1 (P-selectin glycoprotein ligand-1) and other VISTA. In addition, there was a rise in the level of IFN-y, a pro-inflammatory cytokine, which indicates that PMC-309 enhanced T cell activities.

In in vivo studies, the test subjects administered with PMC-309 in both hPBMC (human Peripheral Blood Mononuclear Cell) engrafted mouse model and human VISTA Knock-In mouse model showed notable tumor growth inhibition. PMC-309 also showed a possible synergistic effect when used in combo with an anti-PD1 antibody because the combination of two antibodies demonstrated significantly improved tumor growth inhibition.

"Our non-clinical studies revealed PMC-309’s unique binding mechanism and its anti-tumor effect," said Dr. Jin-San Yoo, CEO of PharmAbcine. "The study results add to our confidence that PMC-309 can be a promising immunotherapeutic strategy in both mono and combo therapies for patients who do not respond to other immuno-oncology drugs."

Dr. Yoo also added, "We plan to initiate the IND (Investigational New Drug)-enabling studies and evaluate the potential toxicity risk this year. We expect PMC-309 to enter a clinical stage in 2022."

The e-poster presentation is currently available on the AACR (Free AACR Whitepaper) website. The details of the presentation are as follows:

Title: PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC)
Session category/title: Immunology/Immune Checkpoints
Abstract number: 1116
Poster number: 1626
Presentation Type: E-poster with audio presentation

On April 12, 2021 Junshi Biosciences (HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development and commercialization of novel therapies, reported that the National Medical Products Administration (NMPA) of China has 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 (Press release, Shanghai Junshi Bioscience, APR 12, 2021, View Source [SID1234578061]). This is the third approved indication for toripalimab in China. In December 2018, the NMPA granted a conditional approval to toripalimab for the second-line treatment of unresectable or metastatic melanoma. 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.

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"Following the approval of indications in melanoma and nasopharyngeal carcinoma, toripalimab has reached a new milestone in the treatment of urothelial carcinoma, under the joint efforts of patients, investigators, and our R&D personnel," said Dr. Patricia Keegan, Chief Medical Officer of Junshi Biosciences. "Junshi Biosciences has pioneered clinical exploration for unselected UC patients in China and achieved remarkable results, which makes us very excited and confident in the development potential of toripalimab as an anti-tumor drug with a broad therapeutic profile. We also look forward to providing Chinese UC patients with more treatment options that work better and cost less through the company’s collaboration with AstraZeneca."

The supplemental NDA is based on the POLARIS-03 study (NCT03113266) led jointly by Professor Guo Jun of the Peking University Cancer Hospital and Professor Huang Yiran of Renji Hospital affiliated to the Shanghai Jiao Tong University School of Medicine. Among the 136 patients with locally advanced or metastatic urothelial carcinoma after failure of platinum-based chemotherapy including neoadjuvant or adjuvant chemotherapy within 12 months, the evaluation results of the Independent Review Committee (IRC) indicated that the overall objective response rate (ORR) was 27.2%, the disease control rate (DCR) was 46.3% and the median overall survival (mOS) reached 14.6 months. The median duration of response (DOR) had not yet reached a mature stage, with 67.1% of patients with objective responses continuing after a 12-month period.

POLARIS-03 is the first pivotal clinical study on the treatment of advanced urothelial carcinoma with an unselected population after failure of first-line standard treatment in China. Data showed that toripalimab demonstrated explicit anti-tumor activity and continuous efficacy among all patients and within each subgroup. ORR of all patients was 27.2%. ORR of PD-L1 positive patients reached 42.2%. ORR of PD-L1 negative patients reached 18.8%. Therefore, advanced urothelial carcinoma patients benefit from toripalimab regardless of PD-L1 expression. In addition, the safety and tolerability of toripalimab were consistent with previous research results.

On April 12, 2021 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers, reported a clinical collaboration agreement with GlaxoSmithKline ("GSK") in which Zentalis will evaluate the combination of ZN-c3, Zentalis’ oral WEE1 inhibitor product candidate, and ZEJULA (niraparib), GSK’s poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with advanced epithelial ovarian cancer (Press release, Zentalis Pharmaceuticals, APR 12, 2021, View Source [SID1234643100]). Zentalis is currently conducting clinical studies with ZN-c3 both as a monotherapy and in combination with certain standard of care therapies.

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"This clinical collaboration and supply agreement with GSK allows us to investigate the broader potential of our WEE1 inhibitor when used as part of a combination treatment with niraparib, a PARP inhibitor," commented Dr. Anthony Sun, Chairman and Chief Executive Officer of Zentalis Pharmaceuticals. "As demonstrated in our preclinical studies, ZN-c3 is designed to have significant advantages over other investigational WEE1 inhibitor therapies. We believe this combination has the potential to meaningfully improve the outcomes for patients with ovarian cancer."

PARP inhibitors prevent DNA damage repair in cancer cells. Similar to PARP, WEE1 plays a role in cellular regulation and repair, allowing cells with DNA damage to repair and survive. Inhibition of WEE1 causes dysregulation of DNA replication and subsequently induces apoptosis. Based on these complementary mechanisms of action, the use of WEE1 and PARP inhibitors could potentially have synergistic anti-tumor activity.

More than 300,000 women worldwide are diagnosed with ovarian cancer each year, leading to over 180,000 fatalities1. While substantial progress has been made in the treatment of this disease, there is an urgency to address the remaining unmet need through the development of innovative combination treatments.

Under the terms of the non-exclusive collaboration, Zentalis is responsible for conducting the study with GSK providing all required doses of niraparib. Zentalis maintains full ownership of ZN-c3.

1www.cancerresearch.org

About ZN-c3

ZN-c3 is an oral inhibitor of WEE1 in development for the treatment of advanced solid tumors. The inhibition of WEE1, a DNA damage response protein, aims to generate sufficient DNA damage in cancer cells, causing cell death, thereby preventing tumor growth and potentially causing tumor regression. Zentalis is currently conducting a Phase 1/2 clinical trial in patients with advanced solid tumors and reported initial data from the Phase 1 portion at the AACR (Free AACR Whitepaper) Annual Meeting 2021. In addition, the Company is also conducting a Phase 1b trial evaluating ZN-c3 in combination with chemotherapy in patients with advanced ovarian cancer, with plans to initiate a Phase 1/2 trial in combination with GSK’s niraparib in patients with advanced ovarian cancer, a Phase 1/2 trial in combination with chemotherapy in osteosarcoma and a Phase 2 trial investigating ZN-c3 as a monotherapy in patients with uterine serous carcinoma in 2021.

About ZEJULA (niraparib)

GSK’s ZEJULA (niraparib) is an FDA and EMA-approved oral, once-daily poly (ADP-ribose) polymerase inhibitor that is currently being evaluated in multiple pivotal trials. GSK is building a robust niraparib clinical development programme by assessing activity across multiple tumour types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development programme for niraparib includes several combination studies, including Phase III studies in ovarian and non-ovarian indications.