On March 31, 2021 Complix, a biopharmaceutical company developing a pipeline of transformative Alphabody therapeutics reported the publication in Science Advances of the results from a joint, multidisciplinary study with Belgian life sciences research Institute VIB and Ghent University (Press release, Complix, MAR 31, 2021, View Source;utm_medium=rss&utm_campaign=complix-and-vib-publish-pioneering-study-on-cell-penetrating-alphabodies-in-science-advances [SID1234577405]). The proof-of-concept study demonstrates the potential of Cell-Penetrating Alphabodies (CPABs) to efficiently penetrate the cancer cell membrane, disrupt an intracellular protein-protein interface, and cause an anti-tumor effect upon in vivo administration in relevant xenograft models.

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The article by Pannecoucke et al. can be accessed by clicking here.

CPABs are a revolutionary class of small proteins that have been designed to overcome the limitations of conventional antibodies and small molecules through combining the specific potency of biologics with the cell-penetrating capacity and stability of small molecules. Data available show that CPABs have the potential to address a wide range of disease targets, particularly intracellular targets, that are difficult for current therapies to reach.

The study, published in Science Advances, demonstrates that CPABs can be designed to efficiently penetrate the cell membrane, disrupt an intracellular protein-protein interface, and carry an albumin-binding moiety to extend their serum half-life to therapeutically relevant levels. The unique combination of these three features in a single protein scaffold is without precedent. In this publication a CPAB was engineered against MCL-1, an intracellular protein target in cancer.

The findings from this study provide strong proof of concept for the use of CPABs against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics.

Dr. Ignace Lasters, CTO of Complix, commented:
"We are pleased to see the publication of this important study, which is a clear validation of our platform and highlights the potential of CPABs to directly address intracellular drug targets in oncology. Reaching the intracellular space has been a critical limiting factor in broadening the therapeutic potential of current biologicals such as monoclonal antibodies. This proof-of-concept study clearly demonstrates the potential of CPABs as a transformative, "membrane crossing" technology to address a variety of cutting-edge and challenging intracellular disease targets. This holds the promise for the creation of an entirely novel class of therapeutics with applications in oncology and beyond."

Prof. Savvas Savvides, Group leader at VIB Center for Inflammation Research, and Professor of Structural Biology at Ghent University, said:
"Our study clearly extends the currently charted protein-based drug-targeting landscape by targeting the well-known intracellular drug target MCL–1, a protein upregulated in multiple tumor types and correlated with therapy resistance. It is very exciting and rewarding to see how our longstanding collaboration with Complix has matured to provide the essential knowledge needed to tackle such a major and important challenge in the design of novel therapeutics."

Scientific publication
Erwin Pannecoucke, Maaike Van Trimpont, Johan Desmet, Tim Pieters, Lindy Reunes, Lisa Demoen, Marnik Vuylsteke, Stefan Loverix, Karen Vandenbroucke, Philippe Alard, Paula Henderikx, Sabrina Deroo, Franky Baatz, Eric Lorent, Sophie Thiolloy, Klaartje Somers, Yvonne McGrath, Pieter Van Vlierberghe, Ignace Lasters, Savvas N. Savvides. Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. Science Advances, 26 March 2021: Vol. 7, no. 13.

On March 31, 2021 BioCanRx researchers Dean Fergusson, Justin Presseau, Natasha Kekre, Harold Atkins, Kednapa Thavorn, Rob Holt, Manoj Lalu, and patient representative Terry Hawrysh reported that they have recently published results in two medical journals from their BioCanRx-funded project, "Getting better Outcomes with Chimeric Antigen Receptor T-cell therapy (GO–CART): A BioCanRx Research Excelerator to Safely and Effectively Translate CAR T-Cell Therapy for Hematological Malignancies" (Press release, BioCanRx, MAR 31, 2021, View Source;utm_medium=rss&utm_campaign=biocanrx-funded-researchers-publish-results-car-t-csei-project [SID1234577433]).

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The study, which began in 2017, aimed to bring together experts from different backgrounds as well as patient representatives to formulate a feasible, safe, effective, and economical trial protocol that addressed the pitfalls some early-phase trials have faced in the past. Its ultimate aim was to help BioCanRx scientists effectively use CAR T cells in Canada.

Read about the results of their research below:

Navigating choice in the face of uncertainty: using a theory informed qualitative approach to identifying potential patient barriers and enablers to participating in an early phase chimeric antigen receptor T (CAR-T) cell therapy trial

Partnering with patients to get better outcomes with chimeric antigen receptor T-cell therapy: towards engagement of patients in early phase trials

On March 31, 2021 Oxford BioDynamics Plc (AIM: OBD, the Company), a biotechnology company developing precision medicine tests for personalized healthcare based on the EpiSwitch 3D genomics platform, and Agilent Technologies (NYSE: A), a global leader in the life sciences, diagnostics, and applied chemical markets, reported that have signed a supply and resale agreement for the manufacture and sale of the new EpiSwitch Explorer Array Kit ("Kit") (Press release, Oxford Biodynamics, MAR 31, 2021, View Source [SID1234577450]).

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Under the terms of the agreement, Agilent will supply a custom-made SurePrint G3 CGH Microarray for the Kit, incorporating OBD’s proprietary 3D genome probes. OBD has exclusive rights for supply and distribution of the Kit.

Harnessing the strengths of Agilent’s microarray technology and OBD’s 3D genomic recognition algorithms, the EpiSwitch Explorer Array Kit provides results at a high throughput, with high resolution in a fraction of the time. The Kit simultaneously interrogates almost 1 million 3D genomic sites, providing over ten times more high-value data points than conventional, costly, time-consuming methods of detection, which are limited by high noise to signal ratio. This creates a highly reproducible, unbiased map, which can be used to identify, evaluate, or monitor 3D genomic biomarkers.

The newly launched Kit, which is for research use only, will enable a new level of whole genome screening, biomarker discovery, and profiling of the 3D genome. It can assist researchers by analyzing the genome’s 3D architecture and the crucial role it plays in gene regulation.

Improved understanding of the 3D genome could have a significant impact on patient diagnosis, prognosis of disease response, and determination of treatment options. The global epigenetics market size is expected to reach over $22 billion by 2025, with the kits segment anticipated to experience the greatest growth (>20% CAGR), driven by this need for biomarker development and accurate detection for personalized medicine [2].

The EpiSwitch platform has already been used to develop the recently launched COVID-19 Severity Test, EpiSwitch CST. Further tests are being developed in other areas including immuno-oncology response, rheumatoid arthritis and prostate cancer [3-8].

Dr Jon Burrows, CEO of Oxford BioDynamics, said:

"EpiSwitch is already well validated in pharma biomarker discovery and has proven capable of stratifying patients for many biological indications [3-8]. OBD has previously announced the expansion of its strategic focus [1] to bring the platform to the precision medicine market, starting with the launch of our COVID-19 Severity Test and the upcoming launch of an IO test. Alongside this strategy, we are keen that our technology and knowledgebase are made available for research and development by academic and clinical researchers worldwide."

He added: "Partnering with industry leader, Agilent, gives important third-party validation to our technology and working together will strengthen the commercial offering of our EpiSwitch Explorer Array Kit to the global research community."

Kevin Meldrum, VP/GM of Agilent Genomics said: "Agilent is the premier provider of custom microarrays and we are excited to secure this partnership with Oxford BioDynamics demonstrating how arrays can enable the development of new technologies, such as EpiSwitch, beyond gene expression and CGH."

To accompany the Explorer Array Kit, OBD will also provide access to their online EpiSwitch Portal to enable array data analytics and provide biological context for readouts. This Portal comprises of two applications:

The EpiSwitch Analytical Portal (EAP) – to enable statistical analysis of 3D-array data with a wide range of tools
The EpiSwitch Data Portal (EDP) – to provide options to map data to the genome, allowing integration of analysis with other data types (SNPs, Hi-C, ATAC-Seq Chip-Seq, RNA-Seq, etc.) and biological interpretation
The EpiSwitch Explorer Array Kit is now available to purchase from OBD’s online store: View Source Here, users can also sign up and access the EpiSwitch suite of analytical portals. The Kit is provided with EpiSwitch-optimized sample preparation reagents for analysis of blood, PBMC and primary cell or cell line samples.

On March 31, 2021 Shanghai Yingli Pharmaceutical Co., Ltd. (Yingli Pharma) reported that topline results of a Phase II registration study of linperlisib, a PI3Kδ inhibitor, for the treatment of relapsed/refractory follicular lymphoma (FL) (Press release, Yingli Pharmaceutical, MAR 31, 2021, View Source [SID1234577528]). Linperlisib is a potent and highly selective oral PI3Kδ inhibitor that was developed for potentially more efficacious with a potentially more manageable and differentiated safety profile from other PI3Kδ class agents. The topline results of this single-arm Phase II study (NCT04370405) showed that linperlisib treatment led to significant clinical improvement for the patients with relapsed/refractory FL.

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The results of the study indicated an 80.9% overall response rate (95% confidence interval, 71.2-88.5%) for 89 evaluable relapsed/refractory FL patients, as a primary outcome measure assessed by an Independent Review Committee (IRC). In addition, a disease control rate (DCR) of 96.6% was observed. Safety data demonstrated that linperlisib 80mg QD dosing regimen was well tolerable and manageable with a differentiated and favorable safety profile.

Responding to the topline data of this Phase II registration study, Dr. Qiu Lugui of Institute of Hematology & Blood Diseases Hospital, Tianjin, China, and the leading Investigator on the clinical study, stated: "The Phase II clinical trial of linperlisib for the treatment of relapsed/refractory follicular lymphoma has demonstrated striking clinically meaningful results, suggesting that this new PI3Kδ selective inhibitor may be very well differentiated from marketed PI3Kδ inhibitors available outside of China. It is encouraging that infrequent and manageable adverse events were observed for linperlisib, indicative of the agent being safe and well-tolerated for relapsed/refractory FL patients. We are hopeful that linperlisib may soon be made available as a valuable treatment option for this serious disease, bringing hope to these patients and their families."

"We are very excited that linperlisib has demonstrated such outstanding therapeutic benefit in relapsed/refractory follicular lymphoma. These findings give us confidence in the performance of linperlisib for our other ongoing clinical studies for different types of tumors," said Dr. Xu Zusheng, President, Research and Development of Yingli Pharma. "We look forward to bringing this PI3Kδ inhibitor that has been premiered in China, into global development for patients around the world."

Full analysis of the data from the study will be forthcoming through medical conferences and publications and can be followed on the Yingli Pharma website. Yingli Pharma is planning to submit an NDA application to NMPA based on the results of this registration study.

About Linperlisib

Linperlisib (YY-20394) is a highly selective PI3Kδ inhibitor that has shown superior efficacy, PK, and good pharmaceutical properties in preclinical research as an oral once-a-day agent. Linperlisib received FDA Orphan Drug Designations for FL and CLL/SLL and has an IND for a Phase II study in r/r FL in the United States. Linperlisib was awarded NMPA Breakthrough Therapy status in China. Additional linperlisib clinical trials are ongoing in PTCL, other lymphomas, solid tumors, and in combination with gemcitabine/oxaliplatin in r/r DLBCL.

About follicular lymphoma

Follicular lymphoma (FL) is the second most common type of NHL worldwide and accounts for 10-20% of NHL in China. Although FL is generally an indolent disease on diagnosis, the relapsed and refractory forms of FL are more aggressive and require innovative therapies. Dr. Qui reflected on the status of FL treatments, "In recent years, immunochemotherapy has gradually replaced chemotherapy and radiotherapy for the initial treatment of FL and other lymphomas. However, because patients progress on frontline therapies, safe and efficacious agents are needed to prolong treatment benefit for these lymphoma patients."

On March 31, 2021 CStone Pharmaceuticals (CStone, HKEX: 2616), a leading biopharmaceutical company focused on developing and commercializing innovative immuno-oncology therapies and precision medicines, reported that the National Medical Products Administration (NMPA) of China has approved AYVAKIT (avapritinib) tablets for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Discovered by CStone’s partner Blueprint Medicines, AYVAKIT is China’s first approved therapy for patients with PDGFRA exon 18 mutant GIST specifically designed to target the underlying molecular driver of their disease (Press release, CStone Pharmaceauticals, MAR 31, 2021, View Source [SID1234577549]).

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"AYVAKIT is the second approved therapy in the same month for CStone and it is a first-in-class therapy for patients with PDGFRA exon 18 mutant GIST," Dr. Frank Jiang, Chairman and CEO of CStone, noted. "The approval of AYVAKIT in China reflects the collective efforts and accomplishments of the CStone team. We would like to thank all the patients and investigators involved in the clinical study and the NMPA for their support during the priority review. Together, we are aiming to solve Chinese cancer patients’ urgent unmet medical needs. With our first two approvals, CStone will strive to bring more first-in-class and best-in-class innovative precision medicines and immuno-oncology therapies to patients."

"Historically, there has been a lack of treatment options for patients with GIST harboring PDGFRA exon 18 mutations. AYVAKIT has shown effective anti-tumor activity and a generally well-tolerated safety profile in Chinese patients with advanced PDGFRA exon 18 mutant GIST," said Dr. Lin Shen, Vice President of Peking University Cancer Hospital and Institute, "We believe the approval of AYVAKIT in China may bring important clinical benefit to Chinese patients with advanced PDGFRA exon 18 mutant GIST."

The NMPA approval of AYVAKIT for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant GIST was based on an open-label, multicenter phase I/II bridging study, designed to evaluate the safety, pharmacokinetics, and anti-tumor activity of AYVAKIT in Chinese patients with advanced unresectable or metastatic GIST. Study results demonstrated effective anti-tumor activity, with evidence of tumor regression in target lesions among all eight evaluable Chinese patients with PDGFRA D842V mutant GIST who received 300 mg once daily (QD) doses of AYVAKIT, and the overall response rate (ORR) was 62.5%. AYVAKIT was generally well tolerated. Most treatment-related adverse events (AEs) were Grade 1-2.

About Gastrointestinal Stromal Tumor (GIST)

GIST is a sarcoma, or tumor of bone or connective tissue, of the GI tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction. About 5 to 6 percent of primary GIST cases are caused by a PDGFRA D842V mutation, the most common PDGFRA exon 18 mutation.

About AYVAKIT (avapritinib)

AYVAKIT (avapritinib) is a kinase inhibitor approved by the China NMPA for the treatment of adults with unresectable or metastatic GIST harboring the PDGFRA exon 18 mutation.

The U.S. Food and Drug Administration (FDA) has approved AYVAKITTM for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. This medicine is approved by the European Commission under the brand name AYVAKYT for the treatment of adults with unresectable or metastatic GIST harboring the PDGFRA D842V mutation.

AYVAKIT/AYVAKYT is not approved for the treatment of any other indication in China by the NMPA, in the U.S. by the FDA or in Europe by the European Commission, or for any indication in any other jurisdiction by any other health authority.

CStone and Blueprint Medicines have an exclusive collaboration and license agreement for the development and commercialization of avapritinib and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for avapritinib in the rest of the world.

Blueprint Medicines is developing avapritinib globally for the treatment of advanced and indolent systemic mastocytosis (SM). The FDA granted breakthrough therapy designation to avapritinib for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia, and for the treatment of moderate to severe indolent SM.