Race Investor Update March 2021

On March 31, 2021 Race Oncology Limited ("Race") reported to update our shareholders on progress of our clinical and preclinical programs under the Three Pillars strategy, originally outlined at the Annual General Meeting of shareholders on 30 November 2020 (Press release, Race Oncology, MAR 31, 2021, View Source [SID1234577555]). Today’s update confirms committed and planned programs to maximise the significant opportunity offered by Bisantrene as both a targeted precision oncology drug and as a differentiated chemotherapeutic, with the objective of delivering better therapeutic outcomes for patients.

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Pillar 1 – FTO (Fat mass and obesity associated protein), a transformative opportunity
At the 2020 AGM Race announced its Pillar 1 program focused on Bisantrene’s ability to act as a potent inhibitor of FTO, a protein understood to play a key central role in the proliferation of many cancers. Two clinically relevant proof-of-concept cancer indications were identified, melanoma and clear cell renal cell carcinoma (ccRCC). Our intention was to undertake preclinical studies in both these indications to support the initiation of FTO-directed Phase I/II clinical trials in CY 2022.

FTO-directed melanoma pre-clinical study
In March 2021 Race announced that renowned melanoma cancer researchers, Professor Xu Dong Zhang and Associate Professor Lei Jin of the University of Newcastle would undertake a collaborative preclinical melanoma research program (ASX announcement: 19 March 2021).

The program’s purpose is to explore the use of Bisantrene as a novel FTO-directed treatment for melanoma using cellular and mouse models to identify drug combinations that improve melanoma treatment, with a focus on treatment resistant cancers. Previous independent published studies have observed that FTO is overproduced in approximately 50% of metastatic melanoma cancers and that the inhibition of FTO can overcome PD-1 immune checkpoint inhibitor resistance in mouse models of melanoma.

This preclinical project will report results over the coming 12 months, which will be shared with the market as received. The results of this study will support a Phase II FTO-directed human trial of Bisantrene in melanoma, currently scheduled to begin in Australia in CY 2022.

FTO-directed clear cell Renal Cell Carcinoma pre-clinical (ccRCC) study
In March 2021 Race announced eminent cancer researcher, Associate Professor Nikki Verrills, who successfully ran Race’s preclinical breast and ovarian cancer programs, would undertake a collaborative preclinical ccRCC-focused research program (ASX announcement: 25 March 2021).

The purpose of this research program is to use cellular models to explore the potential to use Bisantrene as a FTO-directed treatment of ccRCC, a devastating form of kidney cancer. Previous studies have observed that FTO enzyme activity is essential for ccRCC cell survival and the inhibition of FTO can directly kill more than 90% of ccRCC cancers.

The results of this study will support a Phase II FTO-directed human trial of Bisantrene in ccRCC patients, currently scheduled to begin in Australia in CY 2022. This preclinical project will report results over the coming 12 months, which will be shared with the market as received.

Other activities
Race is exploring the initiation of a Phase I dose escalation clinical safety trial of Bisantrene in CY 2021, directed at showing its capacity to inhibit FTO in patients with advanced cancers. Founded upon supportive data, such a trial could accelerate the Phase II proof-of-concept trials planned for CY 2022. Race will update the market on the progress of this proposal once finalised.

Pillar 2 – Breast Cancer and Bisantrene as a differentiated chemotherapeutic
In December 2020 Race tasked the clinical research organisation (CRO), George Clinical, with advisement on an optimal clinical trial design for the Pillar 2 breast cancer program (ASX announcement: 26 November 2020). After extensive consultation with Race’s clinical management team, George Clinical, and key opinion leaders (KOLs) in the breast cancer space, together with data from Race’s recent preclinical breast cancer program (ASX announcements: 24 November 2020 and 9 March 2021), a two-path clinical program has been developed.

Australian Phase II trial in late-stage metastatic breast cancer patients
The first path involves initiation of a Phase II clinical trial of Bisantrene in late-stage metastatic breast cancer patients (who have had three or more lines of prior therapy) in Australia, leveraging Race’s recent preclinical data that demonstrated Bisantrene can kill breast cancer cells resistant to current standard-of-care drugs. These data support the potential clinical utility of Bisantrene in treating late-stage breast cancer patients with treatment resistant tumours.

A Principal Investigator (PI) has been recruited to run this Phase II trial and advanced preparation for this trial has been completed including trial design, synopsis generation, CRO selection, patient inclusion/exclusion criteria, budgeting, and clinical trial site selection.

Final contract signing and initiation of this trial is expected to be completed in Q2 CY 2021 and patient treatment is expected to begin in the second half of CY 2021. Further updates to the market on this trial program will be made over CY 2021.

European Phase IIb trial in anthracycline-naïve metastatic breast cancer patients
Discussions with key opinion leaders in the breast cancer field identified an important clinical need to further demonstrate the historical heart safety of Bisantrene in a modern treatment environment if Bisantrene is to be used as a frontline replacement for the current cardiac muscle-damaging anthracycline chemotherapeutics. Patient exposure to anthracyclines can result in both acute cardiac muscle damage at the time of treatment, as well as a delayed damage response that can take months or even years to manifest1. To provide robust data on cardiac safety it is essential that Bisantrene is trialled in a patient population that has not been previously exposed to anthracycline chemotherapeutics. Such a patient population is not recruitable in Australia. Initial research has identified Eastern Europe as being able to provide anthracycline treatment naïve breast cancer patients.

After detailed discussion with a number international breast cancer KOLs, George Clinical has been tasked by Race with developing and costing a Phase IIb double-blinded clinical trial of Bisantrene verses doxorubicin in geographies where anthracycline naïve patients can be recruited.

George Clinical will provide a detailed, costed proposal to enable gated decision making around the potential to run such a Phase IIb clinical study. This report is expected within three months and Race will update the market once received.

1Kimmick, G., Dent, S., & Klem, I. (2019). Risk of Cardiomyopathy in Breast Cancer: How Can We Attenuate the Risk of Heart Failure from Anthracyclines and Anti-HER2 Therapies? Current Treatment Options in Cardiovascular Medicine, 21(6), 30.

Other Activities
Race is exploring low-cost collaborative preclinical studies focused on understanding the molecular mechanism of action of Bisantrene’s heart safety profile. Advanced discussions are underway with a leading Australian team specialising in anthracycline cardiotoxicity research. Race expects to update the market on the outcome of these discussions in early Q2 CY 2021.

Pillar 3 – Acute Myeloid Leukaemia (AML), an FDA approval pathway
Significant progress has been made on the Pillar 3 program during the quarter. Race has committed in principle support to initiate in 2021 two Phase I/II clinical trials in relapsed/refractory acute myeloid leukaemia (r/r AML) in Australia and Israel. In addition, significant progress has been made in exploring the potential use of Bisantrene in paediatric AML that may enable Race to generate the required data needed for award of a Paediatric Priority Review Voucher (ASX announcement: 18 July 2018). Previous vouchers have been sold on the secondary market for between US$80 and US$200 million.

Phase I/II clinical trial of Bisantrene in combination with Clofarabine and Fludarabine in relapsed or refractory AML (Israel)
Race has reached in principle agreement with Prof Nagler of the Chiam Sheba Medical Center to undertake an open label Phase I/II combination clinical trial of Bisantrene in r/r AML patients.
Prof Nagler led the Phase II single agent open label r/r AML trial of Bisantrene which reported a 40% clinical response rate in a very difficult to treat population of r/r AML patients (ASX announcement: 16 June 2020).

This Phase I/II trial will enrol 29 patients and involve the use of Bisantrene in combination with the nucleoside analogues, clofarabine and fludarabine. Unpublished preclinical data from Professors Andersson and Valdez of the MD Anderson Cancer Clinic in Houston, Texas has identified strong synergistic killing of AML cells using this three-drug combination.

Human ethics approval for this trial has been granted and the first patient is expected to be treated in Q2 CY 2021. The trial is scheduled to run for up to 36 months, but Race will release progress updates on patient responses as they are received.

Trial contract details are currently being finalised and Race expects to sign in early Q2 CY 2021.

Phase I/II Clinical Trial of Bisantrene in Extramedullary AML (Australia)
Race has reached in principle agreement with Associate Professor Anoop K Enjeti, Director of Haematology at the Calvary Mater Newcastle and John Hunter Hospitals, to undertake an open label Phase I/II clinical trial of Bisantrene in patients with the extramedullary form of AML. Extramedullary AML occurs when the leukaemia spreads from the bone marrow and forms solid tumours in tissues such as the skin, breast, kidney, brain, or other organs. A 2020 prospective positron imaging trial identified that up to 22% of AML patients have the extramedullary form.

Dr Enjeti is a highly experienced clinical haematologist having designed and led more than 25 clinical trials. Dr Enjeti is the co-chair of the MDS/AML working party for the Australasian Lymphoma and Leukemia Group (ALLG) for Cooperative Clinical trials. He has published more than 45 papers in the haematology field and attracted more than $3.5 million in grant funding.

This two-armed Phase I/II trial will involve the use of Bisantrene as a high dose single agent treatment of extramedullary AML patients able to endure high intensity chemotherapy, or alternatively as a low dose Bisantrene treatment in combination with a hypomethylating agent in the less fit patients. The trial will recruit 40 patients at 10 clinical sites across Australia and New Zealand.

The trial is expected to received human ethics approval in Q3 CY 2021 and treat the first patient in late 2021. The trial is expected to run for 18 months. Results of this trial will support parallel pivotal Phase II/III clinical trials in the USA and EU with the aim of achieving rapid FDA/EMA label approval of Bisantrene for use in r/r AML. Furthermore, this trial may be expandable into a paediatric extramedullary AML population and enable Race to receive a US Paediatric Priority Review Voucher.

Phase I/II clinical trial of Bisantrene in combination with Fludarabine and Cytarabine for children with r/r AML (USA)
Race is in advanced evaluation on the prospect of initiating a pivotal Phase I/II trial of Bisantrene in combination with fludarabine and cytarabine in children with first or second relapse of AML. In principle support has been received from the USA Children’s Oncology Group (COG) and a proposed trial design has been provided to Race by COG for evaluation. The trial is expected to run for 36 months and requires FDA IND approval before it can be initiated.

While this trial may enable Race to meet the conditions required to be granted a Paediatric Priority Review Voucher, additional research and communication with the FDA is required to determine if the trial can be completed before the September 2026 sunset of the Rare Paediatric Disease Voucher program. Race will update the market as to the outcome of this research when complete.

Preclinical Extramedullary AML Study
In March 2021 Race announced Associate Professor Nikki Verrills, would undertake a collaborative preclinical extramedullary focused research program (ASX announcement: 30 March 2021).

The aim of this project is to support the clinical use of Bisantrene as a novel treatment for extramedullary AML, a difficult to treat form of AML, using an extramedullary mouse model developed by A/Prof Verrills’ team.
The results of this study will provide support for a pivotal (Phase II/III) trial of Bisantrene in extramedullary AML patients with the aim of providing a rapid path to FDA approval for Bisantrene as an orphan drug under the 505(b)(2) track.

This project is to start immediately with the results expected to be reported over the coming 12 months.

"Following on from the November 2020 AGM, we have evaluated how to best maximise the exceptional asset that Bisantrene represents. The 2021 program capitalises on Bisantrene’s significant FTO opportunity while also pursuing its differentiated chemotherapy profile. We propose that the strategy outlined today minimises risk while maximising commercial and therapeutic upside, particularly with respect to the potential we see in FTO. The 2021 committed program is fully funded and will generate actionable data by year-end, so supporting an expanded 2022 clinical program thereafter."

Chief Executive Officer, Mr Phillip Lynch and Chief Scientific Officer, Dr Daniel Tillett
Shareholders can expect continued updates to results as they read out, and in later 2021 specific communication on expanded FTO-focused clinical programs.

CStone Announces China NMPA New Drug Approval of Precision Therapy AYVAKIT® (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor

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.

Charles River Laboratories Acquires Retrogenix

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.

Yingli Pharma announce promising topline results of a Phase II registration study for treatment of relapsed/refractory follicular lymphoma with the once daily oral PI3Kδ inhibitor, linperlisib

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."

BeyondSpring Announces Submission of New Drug Application to U.S. FDA and China NMPA for Plinabulin and G-CSF Combination for the Prevention of Chemotherapy-Induced Neutropenia (CIN)

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.