On March 21, 2022 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 it has established a global clinical collaboration with Bristol Myers Squibb to evaluate the combination of TST001, an investigational humanized monoclonal antibody targeting Claudin18.2 developed by Transcenta, with Opdivo (nivolumab), Bristol Myers Squibb’s anti-PD-1 therapy, for the treatment of patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction cancer (GC/GEJ) (Press release, Transcenta, MAR 21, 2022, View Source;gastroesophageal-junction-cancer-301507217.html [SID1234610496]).

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This collaboration includes two global phase I/II open-label, multi-center studies, one to be held in the U.S. and one to be held in China, to evaluate the safety, tolerability, and anti-tumor efficacy of TST001 in combination with Opdivo in patients with unresectable locally advanced or metastatic Claudin18.2 expressing gastric / gastroesophageal junction cancer with or without previous treatment.

Under the terms of the agreement, Transcenta will be the sponsor of the trials and Bristol Myers Squibb will supply Opdivo to Transcenta for use in its combination therapy studies with TST001.

Metastatic GC/GEJ is one of the highly prevalent cancer types globally and there is urgent need for new therapies that can improve patients’ survival. Claudin18.2 is a pan-cancer target and is highly over-expressed in gastric cancer, pancreatic cancer, gallbladder and biliary tract cancer, esophageal cancer, and other tumor types. TST001 is a high affinity humanized antibody developed by Transcenta in house, specifically targeting Claudin18.2 expressing tumor cells and can elicit strong NK cell mediated antibody dependent cellular cytotoxicity. The combination of TST001 with checkpoint inhibitor such as Opdivo could provide greater clinical benefits to patients with locally advanced or metastatic gastric /gastroesophageal junction cancer.

"TST001 is a high affinity humanized monoclonal antibody targeting Claudin18.2. It has shown to be safe in ongoing trials as monotherapy or in combination with chemotherapy and displayed encouraging anti-tumor activity signals in gastric cancer and other solid tumor patients expressing Claudin18.2. TST001 works through NK cell mediated antibody dependent cellular cytotoxicity to exert its anti-tumor activity, and the addition of PD-1 inhibitor and chemotherapy have resulted in synergistic effects in preclinical models. We are excited to test the combination of TST001 with Opdivo for the treatment of metastatic gastric / gastroesophageal junction cancer as a new potential treatment option for these patients." said Dr. Michael Shi, EVP, Head of Global R&D and CMO of Transcenta.

Opdivo is a trademark of Bristol-Myers Squibb Company.

About TST001

TST001 is a high affinity humanized anti-Claudin18.2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities and potent anti-tumor activities in tumor xenograft models. TST001 is the second Claudin18.2 targeting antibody therapeutic candidate being developed globally. TST001 is generated using Transcenta’s Immune Tolerance Breaking Technology (IMTB) platform. TST001 kills Claudin18.2 expressing tumor cells by mechanisms of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Leveraging advanced bioprocessing technology, the fucose content of TST001 was significantly reduced during the production, which further enhanced NK cells mediated ADCC activity of TST001. Clinical trials for TST001 are ongoing in China and US (NCT04396821, NCT04495296/CTR20201281). TST001 was granted Orphan Drug Designation in the US by FDA for the treatment of patients with gastric cancer or gastroesophageal junction (GC/GEJ).

On March 21, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that its novel MDM2-p53 inhibitor, alrizomadlin (APG-115), was granted a Rare Pediatric Disease (RPD) designation by the US Food and Drug Administration (FDA), for the treatment of neuroblastoma (Press release, Ascentage Pharma, MAR 21, 2022, View Source [SID1234610495]). To date, alrizomadlin has received a total of six Orphan Drug Designations (ODDs) and two RPDs by the FDA.

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The Food and Drug Administration Safety and Innovation Act (FDASIA), came into effect in 2012, established the rare pediatric disease priority review voucher (PRV) program to reward sponsors for the development of novel therapies for the treatment of rare pediatric diseases. FDASIA defines RPDs as rare diseases or conditions (diseases with a prevalence of less than 200,000 patients in the US) primarily affecting individuals aged from birth to 18 years, including age groups from neonates, infants, children, to adolescents. Being qualified for the PRV is one of the main benefits of the RPD designation, as sponsors who are rewarded with the PRV are eligible for priority review of future New Drug Applications or Biologics License Applications, and they may also choose to have the PRV transferred to another sponsor, at an estimated value around several hundred million US dollars.

Neuroblastoma is a type of embryonic tumor arising from the peripheral sympathetic nervous system. It is the most common extracranial solid tumor in children and the third most common pediatric cancer[1]. According to the American Cancer Society (ACS), there are about 700 to 800 new cases of neuroblastoma each year in the United States. This number has remained about the same for many years. Due to its aggressive nature and high risk of metastasis, neuroblastoma accounts for up to 15% of all deaths caused by pediatric cancers[2]. It is mostly diagnosed in infancy with 41% of patients diagnosed in the first three months after birth, and most patients are diagnosed by the age of 5 years with a median age of diagnosis around 18 months[3].

Neuroblastoma is a serious condition that can be life-threatening to pediatric patients. Patients diagnosed as low-risk usually have a good prognosis. However, those diagnosed with high-risk disease are difficult to cure, with a large proportion of these patients eventually experiencing disease recurrence. Despite intense multimodal treatments, patients with high-risk neuroblastoma have a poor prognosis with an Event-Free Survival (EFS) of less than 50%. Patients with relapsed or refractory neuroblastoma are extremely difficult to cure, and there is no standard treatment for these patients.

Being developed by Ascentage Pharma, alrizomadlin is an orally administered, selective, small-molecule inhibitor of the MDM2 protein. Alrizomadlin has strong binding affinity to MDM2 and is designed to activate tumor suppression activity of p53 by blocking the MDM2-p53 protein-protein interaction. In earlier studies, APG-115 as a single agent has shown antitumor activity in in vitro and in vivo models of neuroblastoma, demonstrating a mechanism of action that supports the clinical development of the drug candidate in patients with neuroblastoma.

Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma, said, "In addition to the benefits provided by the ODD, the RPD designation offers sponsors the additional incentive of priority review status for their future marketing applications, encourages the drug development for the treatment of rare pediatric diseases. Alrizomadlin is a key drug candidate in our apoptosis-targeted pipeline. It has already been granted six ODDs, one Fast Track Designation (FTD), and two RPDs by the US FDA, thus signifies this asset’s clinical potential. This RPD will qualify this program for a PRV, which should help us better communicate with the FDA to hopefully accelerate the clinical development of alrizomadlin. We will initiate the clinical study in neuroblastoma as soon as possible in order to develop a new treatment option for those pediatric patients in need."

References

American Cancer Society. Cancer Facts & Figures 2014. Atlanta, Ga: American Cancer
Ward E, DeSantis C, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. Mar-Apr 2014;64(2):83-103.
Shohet J, Foster J. Neuroblastoma. BMJ. 2017 May 3;357:j1863.

On March 21, 2022 KIYATEC, the leader in clinically correlated, published functional precision oncology technology reported that CEO Matt Gevaert, Ph.D., will present virtually at the KeyBanc Capital Markets’ Life Sciences & MedTech Investor Forum on Wednesday, March 23, 2022, at 1:30 PM Eastern Time (Press release, KIYATEC, MAR 21, 2022, View Source [SID1234610494]). KIYATEC’s participation includes virtual one-on-one meetings with investors during the two-day event which begins Tuesday, March 22nd.

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Leveraging its innovative 3D cell culture technology platform for both clinical and pre-clinical use, KIYATEC recently introduced its first commercial assay in the US, 3D Predict Glioma. The Company is adding commercial and business development capabilities to secure payer reimbursement and coverage while generating demand for these services among clinical and pre-clinical customers. Recently, KIYATEC began a facilities expansion to support the Company’s five-year growth plans to increase laboratory capacity and accelerate product development.

On March 21, 2022 Promega reported that Research in Nature Chemical Biology reveals new opportunities for using small molecule drugs to target KRAS, the most commonly mutated protein in cancer (Press release, Promega, MAR 21, 2022, View Source [SID1234610493]). Promega research scientists collaborated with the University of California – San Francisco research group led by Dr. Kevan M. Shokat, a global leader in KRAS biology, to study the binding of potentially therapeutic molecules to common mutants of the KRAS protein. This study represents the first observation and quantification of direct target engagement of KRAS(G12D) and other hotspot oncogenic mutants of KRAS in cells using reversible binders.

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KRAS and Cancer

KRAS is a protein that serves as a "master switch" for regulating cell proliferation. It is the most commonly mutated protein in cancer. KRAS was long considered to be "undruggable" until 2013 when the Shokat lab identified covalent drugs targeting KRAS(G12C), a common mutant in which a glycine amino acid is changed to a cysteine. That discovery led to increased drug discovery research, and eventually the first inhibitors targeting KRAS(G12C).

Unfortunately, other mutants of KRAS presented different challenges. All of the known inhibitors of KRAS(G12C) relied on an inactive state of the protein that other mutants do not frequently exhibit. The G12C mutation also provided the opportunity to employ covalent drug discovery methods that would not apply to other hotspot mutants. For those reasons, alleles such as KRAS(G12D) and KRAS(G12V) continued to be considered undruggable.

Targeting Hotspot Mutants for Drug Discovery

The research published today in Nature Chemical Biology utilized a Bioluminescence Resonance Energy Transfer (BRET) assay to quantify target engagement of RAS complexes in live cells. They found that the switch-II pocket of KRAS was a privileged drug binding site for non-covalent ligands, and that this was not dependent on the activation state of KRAS. These results open new opportunities for targeting non-G12C mutants of KRAS in drug discovery.

"We’ve shown that some of these highly aggressive mutants are indeed vulnerable to small molecule inhibitors," says Matt Robers, Senior Research Scientist at Promega. "With our new target engagement method, we can measure binding within living cells and show that the binding we see at these hotspot mutants actually translates into anti-proliferative effects in the pancreatic cancer lineages."

In addition to the BRET methods for measuring target engagement, the paper also describes nuclear magnetic resonance (NMR) spectroscopy methods for observing reversible ligand binding in vitro and determining the state of the KRAS protein. The authors hope that the methods they describe will be a valuable tool for researchers to develop treatments for some of the most aggressive KRAS mutants previously thought to be "undruggable."

Promega offers a comprehensive selection of tools to accelerate RAS pathway drug discovery based on a sensitive bioluminescence platform. Learn more at www.promega.com/applications/small-molecule-drug-discovery/ras-oncogene/

On March 21, 2022 Chimeron Bio, an RNA company developing self-amplifying RNA (saRNA) vaccines and therapeutics designed on its proprietary ChaESARTM RNA delivery platform, reported it has signed a Non-Clinical Evaluation Agreement (NCEA) with the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH), to evaluate the potential of its vaccine for COVID-19 (Press release, Chimeron Bio, MAR 21, 2022, View Source [SID1234610492]). The Company’s lead candidate, CB-106, delivers the Spike gene as a self-amplifying mRNA. Preliminary data on this vaccine obtained in collaboration with George Mason University, demonstrated positive results in pre-clinical models with nanogram quantities of RNA, a significant dose advantage over other RNA based technologies. In addition to CB-106, other ChaESAR candidates under testing by the Company include particles co-delivering multi-variant antigens for viral and non-viral vaccines for broad spectrum protection.

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Under the current agreement, Chimeron Bio will utilize the pre-clinical services program offered by the NIAID. Chimeron Bio will provide the vaccine candidate to test in the hamster model of COVID-19 which has previously been used for the assessment of other COVID-19 vaccines. "A successful outcome from this study will further validate ChaESAR technology in pre-clinical models and boost the design of a next generation single shot RNA vaccine that is durable, low dose, low cost, scalable and can render broad-spectrum protection against multiple variants or infectious agents," said Thimmaiah Chendrimada, Co-founder and CSO of Chimeron Bio.

"We are grateful to receive NIAID’s support and work with NIAID funded world-class institutions. The COVID-19 program is Chimeron’s first foray into infectious diseases, and we expect the data from the current study to offer critical validation to advance CB-106 into non-human primates and demonstrate the applicability of ChaESAR technology for vaccines at large," said Jolly Mazumdar, Co-founder and CEO of Chimeron Bio.