FDA Submission to Change the Primary Endpoint into an Industry First and Robust Clinical Measure for Superiority of CIN Phase 3 Study
The Potential for Superior and Rapid Onset Protection from Infection with Plinabulin-G-CSF Combination Marks First Significant Enhancement in Preventing Neutropenia in 30 Years
NEW YORK, April 29, 2020 (GLOBE NEWSWIRE) -- BeyondSpring Inc. (the “Company” or “BeyondSpring”) (NASDAQ: BYSI), a New York-based global biopharmaceutical company focused on the development of innovative immuno-oncology cancer therapies, today announced that, following discussions with the U.S. Food and Drug Administration (FDA), the Company has formally changed the primary endpoint for its Study 106 Phase 3 superiority clinical trial with first-in-class lead asset, Plinabulin, for chemotherapy-induced neutropenia (CIN) prevention. For more than 20 years, the standard primary endpoint for CIN trials has been the duration of severe (Grade 4) neutropenia (DSN). The new primary endpoint will be the rate of the prevention of Grade 4 neutropenia – a more clinically meaningful and trial-sensitive endpoint – and will be used to establish superiority of the Plinabulin-G-CSF combination over G-CSF alone.
A robust plan will be submitted to the FDA to prospectively validate this new primary endpoint against clinical outcome measures. If successful, Plinabulin could provide clinicians and cancer patients with powerful tools to fight cancer.
“This new primary endpoint is a better representation of clinical benefit to accurately capture superior protection against CIN, compared with G-CSF monotherapy, which is the current standard of care,” said Dr. Douglas Blayney, global principal investigator for BeyondSpring’s Plinabulin CIN studies and Professor of Medicine at Stanford Medical School. “The new endpoint not only has a larger dynamic range compared with DSN but also has greater clinical relevance. This signifies the start of a new, more patient-centric era in high-risk CIN prevention that I hope will lead to a new standard for evaluating this and other therapies. In the current COVID-19 pandemic environment, for cancer patients treated with chemotherapy, maintaining their neutrophil counts and preventing infection/hospitalization are even more important to physicians, patients and the healthcare system at large.”
“The primary endpoint for the CIN indication has evolved over the last 30 years,” added Dr. Lan Huang, BeyondSpring’s co-founder, chairman and CEO. “It began with the febrile neutropenia rate when Neupogen was compared to no therapy, then to DSN as an appropriate standard for the Neulasta and biosimilar G-CSF non-inferiority trials. To assess a new superior therapy regimen, it was evident that a new endpoint was needed to better evaluate clinical CIN superiority. As such, this is a timely advancement in clinical trial science for our program. While CIN is the most frequent cause for change in chemotherapy doses and regimens, the Plinabulin-G-CSF combination has the potential to revolutionize the chemotherapy treatment landscape by improving the standard of care and overall patient quality of life in a clinically impactful manner.”
Improved Prevention of Severe Neutropenia – Grade 4 neutropenia (absolute neutrophil number <0.5x10^9cells/L) is directly correlated with infections, febrile neutropenia (fever in a patient with an abnormally low number of circulating neutrophils), bacteremia and death, according to literature. BeyondSpring’s Study 106 Phase 2 trial demonstrated that 62.5 percent of the patients treated with the Plinabulin-Neulasta combination had Grade 4 neutropenia prevented versus 37.5 percent of patients treated with Neulasta alone. This represents a 67 percent increase in protection in terms of complete avoidance of severe neutropenia, which provides the basis of potential superiority of the Plinabulin-G-CSF combination therapy versus monotherapy G-CSFs.
Rapid Onset of Action – Clinical data indicates that Plinabulin’s differentiated mechanism of action (MoA), when combined with G-CSFs, appears to provide patients with maximum protection from neutropenia. Plinabulin protects from Day 1 through Day 8 of the first chemotherapy cycle, consistent with a rapid-onset MoA. In contrast, Neulasta as a single agent offers total protection beginning only on Day 9, consistent with a late onset. Grade 4 neutropenia prevention in Cycle 1, Day 1 through Day 8 for arms with Plinabulin use (n=93) were 68.8 percent versus 40.9 percent with the Neulasta 6mg monotherapy arm (n=22) (p=0.0149) in the Study 106 Phase 2 trial. Because of the complementary onset of CIN protection and mechanisms of action, combining the two agents together offered superior and maximum protection throughout the entire chemotherapy cycle.
About Plinabulin in CIN Studies
Study 105 and Study 106 trials are both multicenter, double-blind Phase 3 trials to support Plinabulin’s broad application in preventing CIN to be used with all chemotherapy and for all cancers.
Study 105 was designed to evaluate the safety and efficacy in NSCLC, breast cancer and prostate cancer patients with risk factors, treated with docetaxel (Day 1 dose) in a 21-day cycle with a single dose of Plinabulin (40mg, Day 1 dose) versus a single dose of Neulasta (6mg, Day 2). Docetaxel is one example of an intermediate-risk chemotherapy. This is a non-inferiority study in CIN efficacy comparing Plinabulin and Neulasta in high-risk patients (intermediate chemotherapy plus one or more additional risk factor). Study 105 Phase 3 interim data had achieved statistical significance based on the primary endpoint of the Duration of Severe Neutropenia (DSN) in the first cycle.
Study 106 was designed to evaluate the safety and efficacy in breast cancer, treated with docetaxel, doxorubicin and cyclophosphamide (TAC, Day 1 dose) in a 21-day cycle with Plinabulin (40mg, Day 1 dose) + Neulasta (6mg, Day 2 dose) versus a single dose of Neulasta (6mg, Day 2). TAC is one example of high-risk chemotherapy. Plinabulin and G-CSF have complementary mechanisms in preventing CIN. This is a superiority study in CIN efficacy comparing the combination head-to-head against Neulasta and is currently enrolling. In the Phase 2 study, the combination had demonstrated superiority in CIN efficacy. Literature showed that the Grade 4 neutropenia rate for TAC and Neulasta at 6mg is 83 to 93 percent, which presents severe unmet medical needs [Masuda N et al., Support Care Cancer 23: 2891-2898 (2015); Lee J et al., Annals of Surgical Treatment and Research 94(5): 223-238 (2018)].
BeyondSpring is a global, clinical-stage biopharmaceutical company focused on the development of innovative immuno-oncology cancer therapies. BeyondSpring’s lead asset, first-in-class agent Plinabulin, is in a Phase 3 global clinical trial as a direct anticancer agent in the treatment of non-small cell lung cancer (NSCLC) and two Phase 3 clinical programs in the prevention of chemotherapy-induced neutropenia (CIN). BeyondSpring has strong R&D capabilities with a robust pipeline in addition to Plinabulin, including three immuno-oncology assets and a drug discovery platform using the ubiquitination degradation pathway. The Company also has a seasoned management team with many years of experience bringing drugs to the global market.
Plinabulin, BeyondSpring’s lead asset, is a differentiated immune and stem cell modulator. Plinabulin is currently in late-stage clinical development to increase overall survival in cancer patients, as well as to alleviate chemotherapy-induced neutropenia (CIN). The durable anticancer benefits of Plinabulin have been associated with its effect as a potent antigen-presenting cell (APC) inducer (through dendritic cell maturation) and T-cell activation (Chem and Cell Reports, 2019). Plinabulin’s CIN data highlights the ability to boost the number of hematopoietic stem/progenitor cells (HSPCs) or lineage-/cKit+/Sca1+ (LSK) cells in mice. Effects on HSPCs could explain the ability of Plinabulin to not only treat CIN but also to reduce chemotherapy-induced thrombocytopenia and increase circulating CD34+ cells in patients.
About Chemotherapy-Induced Neutropenia (CIN)
Neutropenia is an abnormally low blood concentration of neutrophils, a type of white blood cell, which may result from an abnormal rate of destruction or low rate of synthesis of white blood cells in bone marrow. Chemotherapy-induced neutropenia, or CIN, is a significant cause of morbidity and mortality in cancer patients receiving chemotherapy, as well as a significant factor in the interruption of chemotherapy. Annual global neutropenia treatment costs over $11 billion with an addressable population of 4 million high-risk patient chemotherapy cycles per year worldwide. Additionally, chemotherapy use is expected to grow by more than 50 percent by 2040 [Wilson et al. Lancet Oncology 2019; 20(6): 769-780]. G-CSFs are the predominant therapies in the CIN space but are limited by their inability to adequately address CIN and burdensome side effects. In preclinical studies, Plinabulin increased the survival of neutrophils.
Cautionary Note Regarding Forward-Looking Statements
This press release includes forward-looking statements that are not historical facts. Words such as "will," "expect," "anticipate," "plan," "believe," "design," "may," "future," "estimate," "predict," "objective," "goal," or variations thereof and variations of such words and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are based on BeyondSpring's current knowledge and its present beliefs and expectations regarding possible future events and are subject to risks, uncertainties and assumptions. Actual results and the timing of events could differ materially from those anticipated in these forward-looking statements as a result of several factors including, but not limited to, difficulties raising the anticipated amount needed to finance the Company's future operations on terms acceptable to the Company, if at all, unexpected results of clinical trials, delays or denial in regulatory approval process, results that do not meet our expectations regarding the potential safety, the ultimate efficacy or clinical utility of our product candidates, increased competition in the market, and other risks described in BeyondSpring’s most recent Form 20-F on file with the U.S. Securities and Exchange Commission. All forward-looking statements made herein speak only as of the date of this release and BeyondSpring undertakes no obligation to update publicly such forward-looking statements to reflect subsequent events or circumstances, except as otherwise required by law.
Caitlin Kasunich / Raquel Cona
KCSA Strategic Communications
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