On September 13, 2022 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat ESR1-mutated metastatic breast and gynecological cancers, reported results of its signal-seeking Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE 1) Phase 2 study (Press release, Sermonix Pharmaceuticals, SEP 13, 2022, View Source [SID1234619554]). The results were initially shared Sept. 10 during a late-breaking oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris.

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The open-label ELAINE 1 (NCT03781063) study began U.S. enrollment in September 2019, assessing the efficacy and safety of oral lasofoxifene versus intramuscular fulvestrant, a selective estrogen receptor degrader (SERD), in 103 patients. All participants were post-CDK4/6 inhibitor/aromatase inhibitor therapy and had an ESR1 mutation. Progression-free survival was the primary endpoint.

Top-line data included:

Median progression-free survival (PFS) was 6.04 mos. (95% CI, 2.82–8.04) for lasofoxifene vs. 4.04 mos. (95% CI, 2.93–6.04) for fulvestrant, P=0.138 (HR, 0.699 [95% CI, 0.445–1.125])
Clinical benefit rate (CBR) was 36.5% for lasofoxifene vs. 21.6% for fulvestrant, P=0.12. CBR is defined as the percentage of all subjects with a complete or partial response; or stable disease for >/= 24 weeks
Objective response rate was 13.2% for lasofoxifene vs. 2.9% for fulvestrant, P=0.12, with 1 confirmed complete response (CR) (72-week duration) and 4 confirmed partial responses (PR) in the lasofoxifene arm vs. 1 PR in the fulvestrant arm
PFS was numerically and consistently greater with lasofoxifene vs. fulvestrant when visceral metastasis and/or Y537S ESR1 mutation subgroups were analyzed
While not reaching statistical significance in this 103-patient study, all endpoints numerically favored lasofoxifene
Exploratory endpoints included:

PFS at 6 mos. for lasofoxifene was 53.4% vs. 37.9% for fulvestrant; PFS at 12 mos. was 30.7% for lasofoxifene vs. 14.1% for fulvestrant
Clearance of ctDNA also favored lasofoxifene over fulvestrant
Most common adverse events were fatigue, nausea, arthralgias and hot flashes; most were Grade 1/2. No thrombotic events occurred
ELAINE 1 is the first clinical trial comparing lasofoxifene with fulvestrant in ESR1-mutated metastatic breast cancer patients with progression on an aromatase inhibitor (Al) in combination with a CDK4/6 inhibitor, and the first to demonstrate anti-tumor activity and target engagement of a novel selective estrogen receptor modulator (SERM) in this setting. ELAINE 2, a Phase 2 single-arm trial of lasofoxifene in combination with the CDK4/6 inhibitor abemaciclib, showed efficacy in heavily pretreated patients with ESR1-mutated mBC post-CDK4/6i (ASCO 2022).

"Sermonix is pleased with the outcomes reported in our ELAINE 1 trial comparing lasofoxifene with fulvestrant, suggesting lasofoxifene’s anti-tumor activity and potential to play a critical role in the targeted precision medicine treatment of ESR1-mutated advanced ER+ breast cancer," said Dr. David Portman, Sermonix founder and chief executive officer. "Lasofoxifene following endocrine/CDK4/6 inhibitor therapies continues to be studied and we anticipate efficacy will be confirmed in a larger clinical study. Sermonix is planning a Phase 3 registrational combination study based on these results as well as encouraging efficacy and safety demonstrated in the ELAINE 2 study of lasofoxifene and abemaciclib reported at this year’s ASCO (Free ASCO Whitepaper) annual meeting."

"ELAINE 1 suggested lasofoxifene’s activity in patients with metastatic breast cancer post-CDK4/6i and an ESR1 mutation," said Dr. Paul Plourde, Sermonix vice president for clinical oncology development. "While not reaching statistical significance in our modestly powered study, all efficacy parameters numerically favored lasofoxifene over fulvestrant. Moreover, the safety profile indicates lasofoxifene was well tolerated with few Grades 3 and 4 adverse events and a differentiated profile from injectable and oral SERDs. Lasofoxifene trials may offer new hope for patients with mutated ESR1 metastatic breast cancer."

About Lasofoxifene

Lasofoxifene is an investigational, nonsteroidal selective estrogen receptor modulator (SERM), which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ: LGND) and has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a potent, oral SERM could, if approved, play a critical role in the targeted precision medicine treatment of advanced ER+ breast cancer.

On September 13, 2022 The Swedish scale-up company Genagon Therapeutics, together with Mosaique Diagnostics, reported that it receive 7 MSEK in funding from Eurostars for the continued development of biological treatment for triple negative breast cancer (Press release, Genagon Therapeutics, SEP 13, 2022, View Source;utm_medium=rss&utm_campaign=genagon-receive-eurostars-grant-funding [SID1234619530]).

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The consortium partners aim to jointly undertake major steps towards the transition from the preclinical to clinical development of GEN209 – a drug candidate for triple-negative breast cancer (TNBC). This will be a first-in-class monoclonal antibody-drug conjugate (ADC) targeting Clptm1, a novel molecular target expressed in solid tumors.

"This is very positive, and we are happy for this. This will help us secure in vivo efficacy data, identify biomarkers for patient selection and treatment outcome follow-up. We will also design regulatory and toxicology programs allowing for a successful transition to clinical trials", says Moa Fransson, CEO at Genagon Therapeutics.

On September 13, 2022 GENFIT (Nasdaq and Euronext: GNFT), a late-stage biopharmaceutical company dedicated to improving the lives of patients with severe chronic liver diseases, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to GNS5611 (ezurpimtrostat), a novel clinical-stage autophagy/PPT1 inhibitor, for the treatment of cholangiocarcinoma (Press release, Genfit, SEP 13, 2022, https://ir.genfit.com/news-releases/news-release-details/fda-grants-genfits-gns561-orphan-drug-designation-treatment [SID1234619526]).

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Cholangiocarcinoma is a rare liver malignancy with high mortality and limited treatment options. It occurs mostly in people over the age of 50.

GNS561 (ezurpimtrostat) is a PPT-1 (Palmitoyl Protein Thioesterase-1) inhibitor that blocks autophagy. Autophagy is activated in tumor cells in response to certain conditions, due to a tumor cell growth in advanced cancers. GNS561 has completed pre-clinical studies and a Phase 1b trial confirming the rationale for targeting cholangiocarcinoma. A Phase 2 trial is expected to start in the fourth quarter 2022, with a first patient visit expected in the first quarter 2023.

Dr Mark Yarchoan, Associate Professor of Oncology at John Hopkins Medicine (Baltimore, MD) commented: "Cholangiocarcinoma is a rare cancer with a high mortality rate. Patients have limited treatment options, particularly following first line therapy. This is why new therapies are urgently needed and is one of the reasons that GNS561 was granted Orphan Drug Designation by the FDA. There is a real path forward for new options for second line treatment in cholangiocarcinoma, and GNS561 represents a strong second-line therapy candidate and hope to patients."

ABOUT GNS561

GNS561 is a PPT-1 (Palmitoyl Protein Thioesterase-1) inhibitor that blocks autophagy. Autophagy is activated in tumor cells in response to certain conditions, due to a tumor cell growth in advanced cancers. One of the key cellular organs implicated in the autophagy process is the lysosome. By entering the lysosomes and binding to its target, GNS561 has an important inhibiting activity on late-stage autophagy, which leads to tumor cell death.

ABOUT CHOLANGIOCARCINOMA

Cholangiocarcinoma is a type of cancer that forms in the slender tubes (bile ducts) that carry the digestive fluid bile. Cholangiocarcinoma occurs mostly in people over the age of 50. Cholangiocarcinoma is divided into intrahepatic and extrahepatic types based on where the disease occurs in the bile ducts. Cholangiocarcinoma is often diagnosed when it is advanced, making successful treatment difficult to achieve. Several risk factors of chronic inflammatory damage and increased cellular turnover have been established, such as primary sclerosing cholangitis (a cholestatic liver disease), liver flukes, biliary tract cysts, hepatolithiasis and toxins. Treatment options for cholangiocarcinoma are limited and associated with high rates of tumor recurrence, and short survival times.

On September 13, 2022 Akeso, Inc. (9926.HK) ("Akeso"), a China-based biopharmaceutical company focusing on the development and commercialization of innovative therapeutic antibodies for Oncology & Immunology, reported that encouraging preclinical results in poster featuring its Fc-mutant anti-TIGIT antibody fused with TGF-βRII protein (AK130) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 (Press release, Akeso Biopharma, SEP 13, 2022, View Source;dual-targeting-antibody-fusion-protein-of-akeso-demonstrated-promise-in-preclinical-results-published-at-esmo-301622658.html [SID1234619522]).

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AK130 is the first and only TIGIT/TGF-β dual-targeting antibody fusion protein and the first novel dual-targeting antibody fusion protein developed in-house by Akeso. The clinical trial application for AK130 was just accepted by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) not long ago, demonstrating Akeso’s ability to develop breakthrough drugs with complete independence and autonomy.

Details of the poster are as follows:

Poster: AK130, a first-in-class Fc-mutant anti-TIGIT antibody fused with TGF-βRII protein, elicits potent anti-tumor efficacy in preclinical studies.
Abstract: #486P
Presenters: Jing Min, Vice President of Akeso
Although TIGIT is considered a promising immune checkpoint molecule, the single-agent efficacy of anti-TIGIT therapy is limited. AK130, a novel anti-TIGIT antibody fused with TGF-βRII protein, was designed to inhibit TIGIT-mediated immunosuppression while decreasing the TGF-β levels in the tumor microenvironment (TME). Mutations were introduced in the Fc region of the antibody with IgG4 backbone to avoid antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) to minimize lymphocyte loss.

The encouraging observations from preclinical results of AK130 supports its clinical development for the treatment of human cancers:

AK130 could specifically bind to human TIGIT and TGF-β with high affinity.
In reporter gene assays, AK130 efficiently blocked the interaction between TIGIT and CD155, as well as TGF-β1/TGF-β3 and TGFβ-RII.
As expected, AK130 did not show ADCC or CDC activity compared to tiragolumab.
AK130 shows great anti-tumor efficacy in a mouse tumor model.
About AK130 (TIGIT/TGF-β dual-targeting antibody fusion protein)

AK130 is a bifunctional antibody-fusion protein entirely independently developed by Akeso. It consists of an anti-TIGIT monoclonal antibody fused to the extracellular domain of human transforming growth factor-β receptor II (TGFβ-RII). TIGIT is an emerging immune checkpoint that blocks TIGIT-CD155 interaction, relieves the inhibition of tumor-infiltrating CD8 + T cells and NK cells and promotes their anti-tumor function. TGF-β signaling can lead to immunosuppression, cancer immune escape, and immune checkpoint inhibitor resistance. Dual blockade of TIGIT and TGF-β activates T cell immune responses and reduces TGF-β-mediated immunosuppressive activity of Tregs, thereby achieving better antitumor effects.

On September 13, 2022 GeneCentric Therapeutics, a company making precision medicine more precise through RNA-based diagnostics, reported the poster presentation of further clinical validation data for PurISTSM, a novel RNA-expression test, in collaboration with Tempus (Press release, GeneCentric Therapeutics, SEP 13, 2022, View Source [SID1234619498]). PurIST identifies patients with the classical subtype of pancreatic ductal adenocarcinoma (PDAC) that are likely to experience longer overall survival (OS) with standard of care (SOC) FOLFIRINOX than patients with the basal subtype of PDAC. The presentation will be made at the 8th AACR (Free AACR Whitepaper) Special Conference on Pancreatic Cancer in Boston, Massachusetts, which runs from September 13-16, 2022.

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Title: Purity Independent Subtyping of Tumor (PurIST): Real-world data validation of a pancreatic ductal adenocarcinoma (PDAC) gene expression classifier and its prognostic implications

First Author: Stephane Wenric, PhD, Principal Scientist, Computational Systems Biology, Tempus, Chicago, Illinois

Presenting Author: James M. Davison, PhD, Senior Translational Genomics Scientist, GeneCentric Therapeutics, Durham, NC

PurIST is a laboratory developed test (LDT) validated by Tempus using a real-world dataset of advanced PDAC patients. Over 250 patients with advanced PDAC who were previously treated with SOC FOLFIRINOX or gemcitabine/nab-paclitaxel were identified in Tempus’ multimodal data library. RNA sequencing (RNAseq) was performed on either primary or metastatic tumor tissue using the CAP/CLIA-validated Tempus xT assay platform. Patients were identified as either basal or classical molecular subtype. For FOLFIRINOX-treated patients, those with a classical molecular subtype had extended survival compared to those with basal molecular subtype. Survival was similar for FOLFIRINOX and gemcitabine/nab-paclitaxel treatment regimens in basal patients, but classical patients had extended survival when treated with FOLFIRINOX.

Further details surrounding test development and validation will be presented as part of an upcoming publication.

About Pancreatic Cancer

Pancreatic cancer is one of the most common cancers worldwide, and the National Cancer Institute estimates there will be 62,210 new cases and 49,830 deaths in the U.S. in 2022. It is the third-leading cause of cancer-related deaths in the U.S. and has the highest mortality rate of all major cancers. More than 90% of pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC), and the 5-year overall survival for resectable/borderline-resectable and non-resectable PDAC is approximately 20-30% and 1-3%, respectively. The average patient diagnosed with Stage IV PDAC will live for about one year after diagnosis. The three main treatments for PDAC are surgical resection (if diagnosed early), radiation therapy and chemotherapy. For resectable tumors, surgical resection is provided with curative intent, however, for non-resectable tumors, chemotherapy such as FOLFIRINOX or gemcitabine with nab-paclitaxel is often used.