On September 8, 2020 BeyondSpring Inc. (the "Company" or "BeyondSpring") (NASDAQ: BYSI), a global biopharmaceutical company focused on developing innovative immuno-oncology cancer therapies to transform the lives of patients with unmet medical needs, reported that its lead asset, first-in-class agent Plinabulin, has received the Breakthrough Therapy Designation (BTD) for the chemotherapy-induced neutropenia (CIN) indication from both the U.S. Food and Drug Administration (FDA) and China’s Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) (Press release, BeyondSpring Pharmaceuticals, SEP 8, 2020, View Source [SID1234585747]).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The FDA’s BTD is intended to expedite the development and review of a drug candidate that is planned to treat a serious or life-threatening disease or condition in which clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. The CDE in China established its BTD program in July 2020 to facilitate the research and development of innovative drugs that treat severe life-threatening or quality-of-life impairing diseases with no existing therapy or with proven evidence to demonstrate clear clinical benefits compared to existing therapies. Products with BTD from the CDE may be considered for conditional approval and priority review when submitting New Drug Applications (NDAs).
"Receipt of Breakthrough Therapy Designation from the FDA acknowledges both the significant unmet need among patients with CIN and the highly encouraging clinical results generated by Plinabulin," said Douglas Blayney, M.D., global Principal Investigator for Plinabulin’s CIN studies and Professor of Medicine at the Stanford University School of Medicine. "This should expedite Plinabulin’s move into the clinic, which is beneficial for patients. The currently approved CIN prevention agents are all G-CSF-based and not available to all patients. Even with the use of G-CSFs, over 80 percent of cancer patients undergoing chemotherapy may still experience Grade 4 neutropenia, which could lead to severe infection, hospitalization and even death. Thus, CIN still represents an unmet medical need."
"The clinical profile Plinabulin has shown truly represents a breakthrough in the CIN space since G-CSFs," added Ramon Mohanlal, M.D., Ph.D., MBA, Chief Medical Officer and Executive Vice President, Research and Development, at BeyondSpring. "We look forward to continuing to work with the FDA as we advance the development of Plinabulin to address this urgent medical need."
The Breakthrough Therapy application is based on the strength of the totality of the clinical data generated so far:
Positive interim analysis results from the PROTECTIVE-2 Phase 3 study – The clinically meaningful primary endpoint was the prevention of severe neutropenia, an "industry first," building on the previous standard for approval, the Duration of Severe Neutropenia (DSN). In the protocol-specified interim analysis, Plinabulin, in combination with Neulasta, was significantly better than Neulasta alone in achieving the primary endpoint with p<0.01, along with a well-tolerated safety profile and fewer Grade 4 adverse events, compared to Neulasta alone.
These results were further strengthened by the Company’s other CIN studies that have confirmed Plinabulin’s early onset action in Week 1 with protecting neutrophils in various cancer types and various chemotherapies, which is complementary to Week 2 neutrophil protection with G-CSFs.
The Company expects to report the full PROTECTIVE-2 Phase 3 topline data in Q4 2020 and file an NDA with the FDA by the end of 2020. The Company has submitted an NDA for Plinabulin for the CIN indication to the NMPA on a rolling basis in Q1 2020.
About Chemotherapy-Induced Neutropenia (CIN)
CIN is a common side effect in cancer patients undergoing treatment that involves the destruction of a type of white blood cell, the neutrophil, which is a patient’s first line of defense against infections. Patients with Grade 4 (severe) neutropenia have an abnormally low concentration of neutrophils, which may lead to infections, hospitalization and death.
G-CSFs are the current standard of care for CIN prevention. However, G-CSFs have limitations in reducing Grade 4 neutropenia with high-risk chemotherapy. Neutropenia, if severe enough, may cause doctors to lower target doses of chemotherapy, end therapy early and / or delay chemotherapy cycles, each of which has a negative effect on long-term outcomes of cancer care.
Despite these limitations annual global use of G-CSFs is more than 4.3 million cycles per year (CPY). The U.S. (1.3 million CPY) and China (1.6 million CPY) account for more than two-thirds of the global CIN market. Plinabulin’s demonstrated clinical profile in combination with G-CSFs has the potential to build on this existing base and improve the standard of care for patients and practitioners.
About Plinabulin
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 Plinabulin in CIN Study
The PROTECTIVE-1 (Study 105) and PROTECTIVE-2 (Study 106) trials are both multicenter, double-blind, active controlled Phase 3 trials to support Plinabulin’s broad application in preventing CIN: Plinabulin for concurrent administration with myelosuppressive chemotherapy regimens in patients with non-myeloid malignancies for the presentation of chemotherapy-induced neutropenia (CIN).
PROTECTIVE-1 (Study 105)
This study was designed to evaluate the safety and efficacy in non-small cell lung cancer (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.
PROTECTIVE-2 (Study 106)
This study 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 (40 mg, Day 1 dose) in combination with Neulasta (6 mg, Day 2 dose) versus a single dose of Neulasta (6 mg, Day 2 dose) alone. TAC is an example of high-risk chemotherapy. Plinabulin and G-CSFs have complementary mechanisms in preventing chemotherapy-induced neutropenia (CIN). This is a superiority study in CIN efficacy in the rate of Grade 4 neutropenia prevention (primary endpoint), comparing the combination head-to-head against Neulasta, and is currently enrolling. Literature shows that the Grade 4 neutropenia rate for TAC and Neulasta at 6 mg is 83 to 93 percent, which presents severe unmet medical needs.
Covance is the clinical contract research organization (CRO) for patient recruitment and monitoring of global sites for this study. The CIN studies are conducted in over 60 clinical centers in the U.S., China and Europe. In addition, Absolute Neutrophil Count (ANC) data, which is used to calculate these endpoints, was obtained through central laboratory assessments by Covance Bioanalytical Methods using standardized and validated analytical tests.