New Preclinical Data Demonstrates Immune-Enhancing Effects of Triple I/O Combination Therapy with BeyondSpring’s Plinabulin

June 23, 2020

Research Presented at 2020 AACR Virtual Annual Meeting
The Triple I/O Combination of Plinabulin, Anti-PD-1 and Radiation Achieved a 100 Percent Complete Response in Anti-PD-1 Non-responsive Animal Model
Triple I/O Combination to Be Administered to Patients Who Failed I/O in Second Half of 2020

NEW YORK, June 23, 2020 (GLOBE NEWSWIRE) — BeyondSpring (the “Company” or “BeyondSpring”) (NASDAQ: BYSI), a global biopharmaceutical company focused on the development of innovative immuno-oncology (I/O) therapies, today announced new preclinical research findings that indicate BeyondSpring’s lead asset, Plinabulin, enhances immuno-radiotherapy for cancer patients. The results of this preclinical study was highlighted in a poster presentation titled, “Plinabulin, a microtubule destabilizing agent, improves tumor control by enhancing dendritic cell maturation and CD8 T cell infiltration in combination with immunoradiotherapy,” at this year’s American Association for Cancer Research (AACR) Virtual Annual Meeting on June 22, 2020.
Based on these preclinical findings, including a 100% complete response of the triple I/O combination of Plinabulin, anti-PD-1, and radiation in a PD-1 antibody non-responsive model, the compound is being advanced toward a Phase 1 clinical trial in patients who failed or progressed on PD-1 / PD-L1 antibody treatments. Principal investigator Steven H. Lin, M.D., Ph.D., associate professor of radiation oncology at The University of Texas MD Anderson Cancer Center, presented the research data.
“The experiments from my lab demonstrated that Plinabulin treatment in murine cancer models leads to activation of antigen-presenting dendritic cells,” said Dr. Lin. “The combination therapy with Plinabulin, anti-PD-1 therapy and radiation therapy further activated the immune system, resulting in increased T-cell activation, which is associated with increased tumor regressions.”

Additional data highlights include:

Preclinical effectiveness: The triple I/O combination of Plinabulin, anti-PD-1 and radiation achieved a 100 percent complete response in a breast cancer model that is not responsive to PD-1 antibody alone.
Sequential benefit: Plinabulin’s effects on dendritic cell maturation are greater when administered after each dose of fractionated radiotherapy, compared to administration before radiation, or administration only once after the first dose of radiotherapy.
Abscopal effect: The Plinabulin triple combination anticancer effects in both irradiated and non-irradiated tumors in the same mice indicate the activation of a systemic anticancer immune response. Notably, CD8 cell levels in the non-irradiated tumors were almost double in the triple combination group compared to anti-PD-1 and radiation alone.
Dendritic cell MHCII up-regulation and T-cell tumor infiltration: Plinabulin triple combination significantly increased dendritic cell MHCII expression and T-cell infiltration in the tumor.
I/O mechanism: AP-1 and NF-kB molecular pathways are crucial in the Plinabulin-induced maturation of dendritic cells.
The above data presentation is available on the Posters page of the BeyondSpring’s website at: https://www.beyondspringpharma.com/conferences/list.aspx?lcid=3.
Peer-reviewed 2019 publications in Chem and Cell Reports demonstrated that Plinabulin is differentiated from all other tubulin-targeted agents through its binding site and kinetics and is among the most potent agents that induce dendritic cell maturation. Dendritic cells are key immune cell types in the activation of the immune system against cancer cells, but currently approved immuno-oncology agents, such as antibodies to PD-1, only take the brakes off of T-cells without activating antigen-presenting cells that stimulate T-cells to attack foreign proteins expressed by cancer cells.
“We believe that the activation of dendritic cells is a key to unlocking the next boost to the efficacy of immuno-oncology agents,” said Dr. James Tonra, BeyondSpring’s Chief Scientific Officer. “Activated dendritic cells present foreign tumor antigens to T-cells to induce cancer-directed immune attacks. Thus, adding this critical step of dendritic cell activation in the immune cascade to the established effects of immune checkpoint inhibition therapies is expected to increase overall anti-cancer efficacy in the clinic. Our anti-cancer strategy was to activate dendritic cells and T-cells, in combination with checkpoint inhibition and to add onto the benefits of neoantigen generation and immune activation from radiotherapy, as Plinabulin serves as the key to reverse the tumor non-response to PD-1/PD-L1 antibodies. The data strongly indicates that this triple combination has enough potential to move into clinical testing to help patients who failed or had progressed on anti-PD-1/PD-L1 targeted therapy, a severely unmet medical need.”

About BeyondSpring
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 as an immune and stem cell modulator, 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.

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.

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.