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.

On March 31, 2021 Charles River Laboratories International, Inc. (NYSE: CRL) reported that it has acquired Retrogenix Limited, an early-stage contract research organization (CRO) providing specialized bioanalytical services utilizing its proprietary cell microarray technology (Press release, Charles River Laboratories, MAR 31, 2021, View Source [SID1234577537]).

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Based in the United Kingdom, Retrogenix offers cell microarray services for target receptor identification, off-target profiling, and target deconvolution on a wide range of novel therapeutics including biologics, cell therapies, and small molecules. Retrogenix’s proprietary cell microarray technology provides a fast, accurate, and effective solution for identifying specific cell surface and secreted protein interactions in human cells. Retrogenix’s technology allows global biopharmaceutical clients to overcome the critical deconvolution step in phenotypic drug discovery; uncover novel, high-quality and exploitable drug targets; and explore preclinical safety liabilities of lead candidates using a comprehensive, off-target screening platform. As part of its cell microarray technology, Retrogenix offers one of the largest protein libraries with over 6,200 human plasma membrane and secreted protein clones, which provides a unique screening tool for discovering primary target receptors and assessing potential off-target binding issues.

The acquisition of Retrogenix enhances Charles River’s scientific expertise with additional large molecule and cell therapy discovery capabilities. Retrogenix provides the premier platform for off-target screening for preclinical safety assurance in CAR T cell therapies. Combined with Distributed Bio’s large-molecule discovery platform, Retrogenix’s capabilities will further strengthen Charles River’s integrated, end-to-end solution for therapeutic antibody and cell and gene therapy discovery and development.

James C. Foster, Chairman, President and Chief Executive Officer of Charles River Laboratories, commented, "The acquisition of Retrogenix strategically expands Charles River’s existing discovery capabilities by adding a proprietary cell microarray technology to accelerate target identification and provide preclinical safety assurance for novel therapies. In addition to enhancing our position as the premier, single-source provider for a broad portfolio of discovery services, Retrogenix enhances our ability to support clients’ early-stage drug research efforts in advanced drug modalities, including cell therapies. Retrogenix’s goal is to become the industry standard for receptor identification and off-target screening solutions for biotherapeutics and cell therapies, and we believe the combination with Charles River’s extensive early-stage expertise will enable them to achieve this goal. We are pleased to welcome Retrogenix and its talented staff to the Charles River family."

Financial and Transaction Details

The purchase price was approximately £35 million in cash (or approximately $48 million based on current exchange rates), subject to customary closing adjustments. In addition to the initial purchase price, the transaction includes a potential additional payment of up to £5 million based on future performance (or approximately $7 million based on current exchange rates). The transaction is not expected to have a material impact on Charles River’s 2021 GAAP or non-GAAP financial results. Retrogenix has become part of the Company’s Discovery and Safety Assessment segment.

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 BeyondSpring Inc. (the "Company" or "BeyondSpring") (NASDAQ: BYSI), a global biopharmaceutical company focused on the development of innovative cancer therapies, reported the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) and the China National Medical Products Administration (NMPA) for use of plinabulin in combination with granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia (CIN) (Press release, BeyondSpring Pharmaceuticals, MAR 31, 2021, View Source [SID1234577501]). Plinabulin in combination with a G-CSF therapy, which received breakthrough therapy designation from the U.S. FDA and the China NMPA for "concurrent administration with myelosuppressive chemotherapeutic regimens in patients with non-myeloid malignancies for the prevention of CIN," has the potential to raise the standard of care in CIN for the first time in 30 years.

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CIN remains a severely unmet medical need. Treatment or prevention of CIN with G-CSF has been the standard of care since Neupogen was approved in 1991. The main benefit of G-CSF treatment, however, is in Week 2 after chemotherapy. Week 1 after chemotherapy is considered the "neutropenia vulnerability gap" where over 75% of CIN-related clinical complications occur, including febrile neutropenia, infection, hospitalization and death. Plinabulin is the first agent seeking FDA approval that has the potential to fill this gap by working in Week 1 to prevent the onset and progression of CIN. Therefore, combining plinabulin and G-CSF may maximize the protection of patients for the full cycle of chemotherapy, as demonstrated in the PROTECTIVE-2 Phase 3 registration study.

"CIN is a major concern for physicians and their patients undergoing cancer treatment. Plinabulin provides benefits above and beyond what is currently available on the market and has the potential to be a game-changer for patients undergoing chemotherapy treatment," said Dr. Douglas Blayney, Professor of Medicine at Stanford University Medical School and global PI for CIN studies. "CIN, which can lead to life-threatening infections, is the number one reason for the 4D’s in chemotherapy (Decrease, Delay and Discontinue dose and Downgrade regimen). We hope plinabulin will allow patients to better tolerate chemotherapy, thus enabling patients to stick to their optimal treatment plan and avoid serious CIN complications."

The NDA submission is based on positive data from BeyondSpring’s PROTECTIVE-2 Phase 3 registration study which showed that plinabulin in combination with pegfilgrastim demonstrated superior CIN prevention benefit, compared to pegfilgrastim alone. The study met the primary endpoint, with a statistically significant improvement in the rate of prevention of grade 4 neutropenia (improved from 13.6% to 31.5%, p=0.0015) and met all key secondary endpoints, including duration of severe neutropenia (DSN) and absolute neutrophil count (ANC) nadir. In addition, the combination reduced clinical complications such as incidence and severity of febrile neutropenia (FN) and incidence and duration of hospitalization for FN patients. The combination is well tolerated, with an over 20% reduction of grade 4 Treatment-Emergent Adverse Events (TEAE) in the combination compared to that of pegfilgrastim alone. The NDA submissions will include five supportive trials that show consistent CIN prevention in various chemotherapy regimens and cancers in over 1,200 patients.

"This NDA submission is the culmination of years of research to prove that plinabulin can improve the long-established standard of care and address an unmet medical need to further alleviate the risk burden of CIN for patients receiving chemotherapy," said Dr. Lan Huang, co-founder, CEO, and chairman of BeyondSpring. "With CIN responsible for potentially delaying treatment and causing life-threatening infections, we hope that receiving the improved care represented by the plinabulin and G-CSF combination will allow patients to better tolerate chemotherapy and potentially see increased treatment success rates. We are grateful for the patients’ participation in plinabulin’s clinical trials and the participation and contributions of our investigators and our many other clinical partners."

Each year in the U.S., 110,000 patients receiving chemotherapy are hospitalized after developing CIN, a severe side effect that increases the risk of infection with fever (also called febrile neutropenia, or "FN"), which necessitates ER/hospital visits. Due to the COVID-19 pandemic, the updated National Comprehensive Cancer Network (NCCN) guidelines expanded the use of prophylactic G-CSFs, including pegfilgrastim, from high-risk patients only (chemo FN rate >20%), to include intermediate-risk patients (FN rate between 10-20%), to reduce the number of hospital/ER visits related to CIN. The revision of the NCCN guidelines effectively increases the addressable market of patients who may benefit from treatment with plinabulin, if approved, to approximately 440,000 cancer patients in the U.S. annually.

There is a large unmet medical need and a growing market for CIN prevention and treatment in China as well. According to Lancet Oncology, 60% of East Asia cancer patients are treated with chemotherapy1. In 2020, there were 4.6 million new cancer patients in China which could correspond to 2.8 million patients using chemotherapy and needing CIN prevention agents. According to IQVIA data, the G-CSF drug market (for CIN treatment) in China is growing at over 30% a year.

About PROTECTIVE-2 (Study 106) Phase 3 Registration Study
The Phase 3 portion of PROTECTIVE-2 was a double-blind and active-controlled global registration study. It was designed as a superiority study to compare the safety and efficacy of plinabulin (40 mg, Day 1 dose) + pegfilgrastim (6 mg, Day 2 dose) versus a single dose of pegfilgrastim (6 mg, Day 2 dose) in patients with breast cancer, treated with docetaxel, doxorubicin and cyclophosphamide (TAC, Day 1 dose) in a 21-day cycle. TAC is an example of high FN risk chemotherapy and is the regimen used in all G-CSF biosimilar registration studies.

The primary endpoint was the rate of prevention of Grade 4 neutropenia and secondary endpoints included DSN and mean ANC nadir in Cycle 1. Literature shows that despite the use of pegfilgrastim, 83 to 93 percent of patients treated with TAC still suffer Grade 4 neutropenia (or rate of Grade 4 neutropenia prevention at 7-17%), which demonstrates the severe unmet medical need for improved treatment2,3.

The ANC data, which are used to calculate these endpoints, were obtained through central laboratory assessments by Covance Bioanalytical Methods using standardized and validated analytical tests. Covance was the clinical contract research organization (CRO) for patient recruitment and monitoring of global sites for this study.

About CIN
Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in cancer patients who receive chemotherapy and is the primary cause for the 4D’s (Decrease, Delay, Discontinue dose and Downgrade regimen). The 4D’s lead to a decrease of the anti-cancer benefit of chemotherapy, e.g., >15% of dose reduction correlated to >50% survival reduction4. The National Comprehensive Cancer Network (NCCN) recently updated its treatment guidelines for CIN prophylaxis using G-CSFs to include both high- and intermediate-FN risk patients treated with chemotherapies, to preserve hospital and ER resources for COVID-19 patients, and to maximize protection from CIN. The NCCN’s action effectively doubled the number of patients recommended to receive CIN prophylaxis.

About Plinabulin
Plinabulin, BeyondSpring’s lead asset, is a selective immune-modulating microtubule-binding agent (SIMBA). A global Phase 3 clinical trial in CIN (PROTECTIVE-2) with plinabulin in combination with pegfilgrastim versus pegfilgrastim alone has been completed and is the basis for an NDA filing in the U.S. and China for the prevention of CIN. In this trial, plinabulin reduced the "neutropenia vulnerability gap" associated with G-CSF therapy alone. Additionally, a global Phase 3 study for the treatment of later-stage NSCLC in EGFR wild-type patients (DUBLIN-3) is now fully enrolled and will evaluate the combination of plinabulin and docetaxel versus docetaxel alone for overall survival in NSCLC patients. Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: first is a durable anticancer benefit due to the maturation of dendritic cells resulting in the activation of tumor antigen-specific T-cells to target cancer cells5,6 and the second is early-onset action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells (HSPCs)7. Effects on HSPCs could explain the potential for plinabulin not only to prevent CIN but also to increase circulating CD34+ cells in patients. As a "pipeline in a drug," plinabulin is being broadly studied in combination with various immuno-oncology agents that could boost the effects of the PD-1 / PD-L1 antibodies.

On March 31, 2021 Rodeo Therapeutics Corp., a drug-development startup founded by two leading researchers from Case Western Reserve University School of Medicine and a third scientific partner, reported that has been sold to Amgen Inc., a publicly traded international biopharmaceutical company (Press release, Case Western Reserve University, MAR 31, 2021, View Source [SID1234577491]).

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Under terms of the agreement, Amgen, based in Thousand Oaks, California, will acquire all outstanding shares of Rodeo for $55 million, plus "future contingent milestone payments potentially worth up to an additional $666 million in cash," the companies announced today. Total consideration to Rodeo stakeholders could potentially be worth up to $721 million in cash.

Rodeo Therapeutics is a privately held biopharmaceutical company based in Seattle that develops small-molecule therapies designed to promote regeneration and repair of multiple tissues. The therapies have the potential to help address conditions like colitis, among many others.

The company was created based on discoveries published in the peer-reviewed journal Science by three scientific founders: Sanford Markowitz, the Ingalls Professor of Cancer Genetics and Distinguished University Professor at Case Western Reserve; Stanton Gerson, interim dean of the Case Western Reserve School of Medicine and director of the Case Comprehensive Cancer Center; and Joseph Ready, a biochemistry professor at the University of Texas Southwestern.

"Amgen’s purchase of Rodeo marks a giant step forward toward bringing this Case Western Reserve-developed technology to patients," Markowitz said. "We are thrilled to be partnering with a world-class pharmaceutical company like Amgen, and to be able to benefit from its team of outstanding scientists and drug developers—as well as the company’s financial resources—to speed the development of this promising new class of drugs."

Initial studies will likely be done in patients with colitis and then hopefully expand to treating other diseases, Markowitz said.

The sale also marks the latest success story in Case Western Reserve’s efforts to "spin out," or transfer, university-based research and innovation from the lab to the commercial marketplace, especially in the biomedical field.

"This technology and these results are an example of how our process of identifying and investing in our own discoveries is working and is being recognized by the biotech industry," said Mark Chance, the School of Medicine’s vice dean for research. "Rodeo is only one example of the many companies started by Case Western Reserve University that are attracting the investors and investments needed to get our medical breakthroughs to patients."

The university’s technology transfer process has supported the emergence of such companies as Convelo Therapeutics Inc., a biotechnology firm discovering medicines for neurological disorders that announced a partnership with Genentech in 2019, and CardioInsight Technologies Inc., a medical-device company sold to Medtronic for about $93 million in 2015.

Rodeo’s science is based on the founders’ research, which showed how a drug-like molecule (called SW033291) could accelerate the recovery of damaged tissue in laboratory animal models of several human disease and medical conditions including healing of colitis and recovery from liver surgery and bone-marrow transplantation. Subsequent studies have shown that the compound can heal tissues in multiple additional disease settings.

Based on this science, Rodeo was co-founded in 2017 with Accelerator Life Science Partners, a venture capital firm that catalyzes the creation of high-quality, cutting-edge life science companies. Rodeo was focused on the development of versions of SW033291 to test in humans.

In the deal, Amgen acquires the license for the original Markowitz, Gerson, Ready and Rodeo-developed technologies, plus the rights to related technology developed by additional Case Western Reserve University School of Medicine faculty members Andrew Pieper, Amar Desai and Derek Taylor.

"Rodeo’s program is a strong strategic fit with Amgen’s inflammation portfolio and efforts to develop first-in-class therapeutics for patients," Amgen said in its announcement.

The final payout is based on reaching certain undisclosed milestones tied to the drug’s clinical and commercial success.