On January 13, 2022 BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported a non-exclusive clinical collaboration with Amgen Inc (Press release, BridgeBio, JAN 13, 2022, View Source [SID1234598653]). (Amgen) to evaluate the combination of BBP-398, a potentially best-in-class SHP2 inhibitor, with LUMAKRAS (sotorasib), a KRASG12C inhibitor, in patients with advanced solid tumors with the KRAS G12C mutation.

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The Phase 1/2 study will include a dose escalation period followed by dose expansion and optimization, and is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of BBP-398 in combination with LUMAKRAS. Under the terms of the non-exclusive collaboration, BridgeBio will sponsor the study and Amgen will provide a global supply of LUMAKRAS.

BBP-398 is a potent small-molecular inhibitor of SHP2 developed in collaboration with The University of Texas MD Anderson Cancer Center’s Therapeutics Discovery division. SHP2 is a protein-tyrosine phosphatase that links growth factor, cytokine and integrin signaling with the downstream RAS/ERK MAPK pathway to regulate cellular proliferation and survival. By combining SHP2 inhibition with KRASG12C inhibition in patients with the KRAS G12C mutation, there is potential that the investigational combination could prevent oncogenesis and overactive cellular proliferation.

"Overactivity of the MAPK pathway is a significant cause of many types of difficult-to-treat cancers and by combining these two agents, we aim to reduce the oncogenic potential of tumor cells," said Frank McCormick, Ph.D., chairman of oncology at BridgeBio. "Building on our collaborations with Bristol Myers Squibb and LianBio, we are excited to be working with Amgen on this new collaboration. By harnessing the power of BBP-398 as a potentially best-in-class SHP2 inhibitor with LUMAKRAS, we are hopeful that we will be able to provide substantial relief for cancer patients in need. We will continue to pursue additional collaborations that we believe hold promise for patients."

KRAS mutations occur in approximately 17% of malignant solid tumors. BBP-398, as a monotherapy or in combination with other targeted therapies, could potentially be a promising therapy for patients with the KRAS G12C mutation.

BridgeBio is currently advancing its Phase 1 clinical trial of its SHP2 inhibitor, BBP-398, in patients with solid tumors driven by mutations in the MAPK signaling pathway, including RAS and receptor tyrosine kinase genes. BBP-398 is part of BridgeBio’s growing precision oncology pipeline and is one of 14 programs in the broader portfolio that are being advanced in the clinic or commercial setting.

About BBP-398
BBP-398 is a potentially best-in-class SHP2 inhibitor. Earlier this year, BridgeBio entered a non-exclusive, co-funded clinical collaboration with Bristol Myers Squibb to evaluate the combination of BBP-398 with OPDIVO (nivolumab) in patients with advanced solid tumors with KRAS mutations. BridgeBio previously also entered into a strategic collaboration with LianBio for clinical development and commercialization of BBP-398 in combination with various agents in solid tumors such as non-small cell lung cancer, colorectal cancer and pancreatic cancer in mainland China and other major Asian markets.

On January 13, 2022 AstraZeneca reported that it will present new data in liver, biliary tract and prostate cancers illustrating its ambition to revolutionise cancer care at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) and the 2022 ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium (ASCO GU) (Press release, AstraZeneca, JAN 13, 2022, View Source [SID1234598652]).

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A total of 35 abstracts from AstraZeneca will be featured across the two meetings. There will be two oral presentations at ASCO (Free ASCO Whitepaper) GI taking place 20 to 22 January, and an additional two oral presentations at ASCO (Free ASCO Whitepaper) GU taking place 17 to 19 February.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "There is an urgent need for new effective treatment options to delay disease recurrence and improve survival for patients with advanced liver, biliary tract and prostate cancers. Our data for Imfinzi and Lynparza at these two meetings will illustrate how AstraZeneca is extending the benefits of our medicines into new areas where progress for patients has been limited."

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "Our data will demonstrate the potential of our medicines to transform patient outcomes in liver, biliary tract and prostate cancers. Results from HIMALAYA and TOPAZ-1 will underscore our commitment to improving long-term survival for patients with liver and biliary tract cancers, and data from PROpel will raise the bar in treating 1st-line metastatic castration-resistant prostate cancer."

Aiming to transform treatment of liver and biliary tract cancers with immunotherapy combinations at ASCO (Free ASCO Whitepaper) GI
A late-breaking presentation will feature results from the HIMALAYA Phase III trial showing a statistically significant and clinically meaningful overall survival (OS) benefit with a single priming dose of tremelimumab added to Imfinzi (durvalumab) in 1st-line unresectable liver cancer.

This trial used a novel dose and schedule called the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen. HIMALAYA is the first Phase III trial to show that a dual immunotherapy regimen has improved OS in this setting.

A second late-breaking presentation will highlight results from the TOPAZ-1 Phase III trial for Imfinzi plus chemotherapy in advanced biliary tract cancer, which was unblinded early at an interim analysis in October 2021 due to clear evidence of efficacy.

The combination demonstrated a statistically significant and clinically meaningful OS benefit versus chemotherapy alone in 1st-line advanced biliary tract cancer, making it the first immunotherapy combination to demonstrate superior clinical outcomes over standard of care in a global, randomised trial in this setting.

Also at the meeting, the first data from Imfinzi plus bevacizumab in the Study 22 Phase II trial will provide the efficacy and safety profile of this combination in unresectable liver cancer. This regimen is being tested in the EMERALD-1 Phase III trial of transarterial chemoembolisation in combination with Imfinzi alone and with bevacizumab in patients with locoregional liver cancer, as well as in the EMERALD-2 Phase III trial with liver cancer patients who are at high risk of recurrence after curative hepatic resection or ablation.

Challenging the status quo in prostate cancer with an industry-leading PARP inhibitor at ASCO (Free ASCO Whitepaper) GU
A late-breaking presentation will showcase the results from the PROpel Phase III trial of Lynparza (olaparib) plus abiraterone, which showed the combination significantly delayed disease progression in 1st-line metastatic castration-resistant prostate cancer (mCRPC) regardless of biomarker status. Lynparza is the first PARP inhibitor to demonstrate clinical benefit in combination with a new hormonal agent in this setting.

Additionally, an oral presentation will feature the results of the BAYOU Phase II trial evaluating the combination of Lynparza and Imfinzi in unresectable, Stage IV bladder cancer. Data will show comparable efficacy of Imfinzi monotherapy to that of other immune checkpoint monotherapy data in similar trial populations and will suggest additional research into a potential role for PARP inhibition in subsets of patients with specific gene mutations.

Harnessing the potential of antibody drug conjugates across HER2-targetable cancers
At ASCO (Free ASCO Whitepaper) GI, data will include an encore presentation of the OS results of the DESTINY-Gastric01 Phase II trial of Enhertu (trastuzumab deruxtecan) in HER2-positive metastatic gastric and gastro-oesophageal junction adenocarcinoma (GEJA), and initial results from the DESTINY-Gastric03 Phase Ib/II trial in HER2-positive gastric cancer and GEJA.

In January 2021, Enhertu became the first HER2-directed medicine approved for patients with gastric cancer in a decade.

Additional Enhertu data at ASCO (Free ASCO Whitepaper) GI will include encore results from the DESTINY-CRC01 Phase II trial showing clinically meaningful activity in HER2-positive unresectable and/or metastatic colorectal cancer. The overall safety and tolerability profile of Enhertu in DESTINY-CRC01 was consistent with that seen in previously reported Enhertu trials. There are currently no medicines approved to specifically treat HER2-positive colorectal cancer.

At ASCO (Free ASCO Whitepaper) GU, results will be shared from the primary analysis of a Phase Ib trial of Enhertu in combination with nivolumab in HER2-expressing bladder cancer.

Collaboration in the scientific community is critical to improving outcomes for patients. AstraZeneca is collaborating with MSD (Merck & Co., Inc. in the US and Canada) to develop and commercialise Lynparza, and with Daiichi Sankyo Company Limited to develop and commercialise Enhertu.

Key AstraZeneca presentations during ASCO (Free ASCO Whitepaper) GI 2022

Lead author

Abstract title

Presentation details

Immuno-Oncology

Alfa-Abou, GK

Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.

Abstract Presentation 3

Oral Abstract Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract

21 January 2022

17:07 – 17:17 ET

22:07 – 22:17 GMT

Oh, D-Y

A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1.

Abstract Presentation 2

Oral Abstract Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract

21 January 2022

16:45 – 16:55 ET

21:45 – 22:55 GMT

Wang, L

A phase 3 randomized, double-blind, placebo-controlled, multicenter, global study of durvalumab with and after chemoradiotherapy in patients with locally advanced, unresectable esophageal squamous cell carcinoma: KUNLUN.

Trials in Progress Poster Session A: Cancers of the Esophagus and Stomach and Other GI Cancers

Antibody drug conjugates

Yamaguchi, K

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2–positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01).

Rapid Abstract Session A: Cancers of the Esophagus and Stomach

Janjigian, YY

Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2+ gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03.

Poster Session A: Cancers of the Esophagus and Stomach and Other GI Cancers

Meric-Bernstam, F

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of select human epidermal growth factor receptor 2 (HER2)-expressing solid tumors (DESTINY-PanTumor02).

Trials in Progress Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract

Yoshino, T

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01).

Rapid Abstract Session C: Cancers of the Colon, Rectum, and Anus

Raghav, KPS

Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2 study (DESTINY-CRC02).

Trials in Progress Poster Session C: Cancers of the Colon, Rectum, and Anus

Key AstraZeneca presentations during ASCO (Free ASCO Whitepaper) GU 2022

Lead author

Abstract title

Presentation details

Immuno-Oncology

Rosenberg, JE

BAYOU: A phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC).

Oral Abstract Session B: Urothelial Carcinoma

18 February 2022

17:42 – 17:52 ET

22:42 – 22:52 GMT

Powles, T

A phase 3, randomized, open-label, multicenter, global study of the efficacy and safety of durvalumab (D) + tremelimumab (T) + enfortumab vedotin (EV) or D + EV for neoadjuvant treatment in cisplatin-ineligible muscle-invasive bladder cancer (MIBC) (VOLGA).

Trials in Progress Poster Session B: Urothelial Carcinoma

DNA Damage Response

Saad, F

PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Oral Abstract Session A: Prostate Cancer

17 February 2022

16:00 – 16:10 ET

21:00 – 21:10 GMT

Notes

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On January 13, 2022 AstraZeneca reported that has signed a collaboration agreement with Scorpion Therapeutics to discover, develop and commercialise precision medicines against previously hard-to-target cancer proteins, with the potential to transform oncology treatment (Press release, AstraZeneca, JAN 13, 2022, View Source [SID1234598651]).

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The new collaboration focuses on a class of proteins called transcription factors, which control gene expression and can regulate important cellular processes including cell growth and survival. Many transcription factors have long been identified as important targets for new cancer treatments and as drivers of disease,1 but have previously been considered ‘undruggable’ using conventional drug discovery approaches.

To overcome the challenges of targeting transcription factors and to reach underserved patient populations, the collaboration will combine Scorpion’s fully integrated discovery platform with AstraZeneca’s leadership in developing and commercialising precision medicines for cancer treatment.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Unlocking potentially transformative biology is pivotal for delivering the next wave of cancer treatments. Scorpion’s innovative platform is a strong strategic fit as we explore a range of new modalities across our broad drug discovery toolbox with promise to disrupt the activity of these highly-validated cancer targets."

Axel Hoos, MD, PhD, Chief Executive Officer, Scorpion, said: "We are pleased to enter into this collaboration with AstraZeneca, whose expertise in drug development and commercialisation complements our discovery platform, which leverages cutting-edge advances in cancer biology and medicinal chemistry, including chemical proteomics, structure-based drug design and machine learning. We expect this collaboration will accelerate Scorpion’s efforts to deliver the promise of ‘Precision Oncology 2.0’: optimised, transformational therapies for more patients living with cancer."

Under the terms of the collaboration agreement, Scorpion will lead discovery and certain preclinical activities. AstraZeneca has the exclusive option to licence worldwide rights for up to three drug candidates. AstraZeneca would be responsible for development and commercialisation activities worldwide following opt-in, while Scorpion would retain the option to co-develop and co-promote up to two of these programmes in the US under certain conditions, including if AstraZeneca exercises three licence options.

Financial considerations
Scorpion will receive an upfront cash payment of $75m and is eligible to receive additional success-based payments in the form of option fees and milestone payments, as well as tiered royalties on net sales ranging from mid-single digit to low-double digits.

In the event Scorpion opts into co-developing and co-promoting a nominated programme, Scorpion will participate in the operating costs and be entitled to a proportionate share of the economics in the US, subject to certain adjustments.

Notes

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On January 12th, 2022 Epics Therapeutics S.A., a private drug development company, reported the initiation of a First-in-Human, double-blind, placebo-controlled, single and multiple ascending dose study of EP282 to evaluate oral pharmacokinetics, pharmacodynamics, safety and tolerability in healthy male volunteers (Press release, EPICS Therapeutics, JAN 12, 2022, View Source [SID1234628628]). Specific biomarkers will also be monitored to evaluate drug-target engagement at different dose levels. Successful completion of this Phase I study will enable the initiation of Proof-of-Concept Phase II studies of EP282 in patient suffering from gastrointestinal inflammatory disorders as well as establish dose levels for initial clinical evaluation for specific types of cancer. Phase II studies are projected to start mid-2023.

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EP282 is a proprietary, oral, small molecule FFAR2 agonist discovered and developed at Epics Therapeutics. "We are the first company to bring an FFAR2 agonist into clinical development. FFAR2 is the focus of numerous published reports from the research community as it is an exciting target linking the microbiome with defence against intestinal infection, inflammation and cancer remission. Our preclinical dataset, in agreement with the published reports, indicates that our drug candidate represents a safe and powerful new approach for addressing the unmet medical needs in the treatment of gastrointestinal disorders and certain cancers" stated Jean Combalbert, CEO.

On January 12, 2022 Simcere reported that the IND of a novel oral PRMT5 inhibitor (project number: SIM0272, product code: SCR-6920) in China for the treatment of advanced malignant tumors was accepted by NMPA (Press release, Jiangsu Simcere Pharmaceutical Company, JAN 12, 2022, View Source [SID1234619235]).

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The candidate is independently developed by Simcere with potential mechanism of Synthetic lethality, where the combination of two genetic events results in cell death or death of an organism

The "synthetic lethality" theory has great significance in fighting cancer. Tumor cells usually have a lot more mutations and gene replication errors than normal cells do. Inhibition of the corresponding "synthetic lethal" paired genes can result in precise killing of certain tumor cells without harming normal cells.

The successful development of PARP inhibitors in the clinical treatment of ovarian cancer, breast cancer and other Breast Cancer gene (BRCA) mutant tumors is a fine example. The global PARP Inhibitor market is valued at 2178 million USD in 2020 and is expected to reach 16180 million USD by the end of 2026, growing at a CAGR of 32.8% during 2021-2026.

SCR-6920 is targeting another pair of synthetic lethal genes with great therapeutic potential: methylthioadenosine phosphorylase (MTAP)/ Protein arginine methyltransferases (PRMT).

In 2016, two articles published in the Science magazine were the first to report the "synthetic lethal" effect of inhibiting PRMT5 in MTAP-deficient tumors.

PRMT5 is overexpressed in various cancers such as lung cancer, breast cancer, gastric cancer, colorectal cancer, ovarian cancer, leukemia and lymphoma. It is associated with the progression and poor prognosis of many types of cancer, indicating its potential to be a promising anti-tumor target.

Preclinical studies have shown that SCR-6920 with its highly selectivity over PRMT5, potently inhibited tumor cell proliferation against various hematological and solid tumor cells in vitro. In multiple mouse CDX models, SCR-6920 alone has significantly inhibited tumor growth. On the other hand, SCR-6920 has demonstrated good cross-species pharmacokinetic properties, good safety profile and a relatively large therapeutic window.

Simcere is applying for approval of a multi-centered Phase I clinical study to evaluate the safety, tolerability, efficacy and pharmacokinetic characteristics of SCR-6920 in human. Once approved, Simcere will rapidly advance clinical research, in hope of bringing new clinical drug options for tumor patients in China soon.