BYSI

BeyondSpring Inc.

NASDAQ · HEALTH CARE · PHARMACEUTICAL PREPARATIONS

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MKT CAP $17.7MP/E —DIV YIELD —FCF YIELD -94.49%REV TTM —NET INCOME −$6.7MNET CASH $530K52W 0.43 – 2.35SEC XBRL · TTM TO Invalid Date

How BYSI rewrote its risk factors

10-K ITEM 1A · FY2024 → FY2025

Text kept

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Length

−2,271

words, now 82,946

New in FY2025

Our first-in-class lead asset, Plinabulin is a novel brain-penetrant microtubule modulator with dendritic cell maturation and vasculature modulation mechanism, which has the potential to help mitigate “acquired resistance” from prior immune checkpoint inhibitors (ICI) treatment in cancer patients.
Plinabulin has been administered to over 700 cancer patients with generally good tolerability and is being developed as a potential “pipeline in a drug” in various cancer indications as a direct anti-cancer agent with safety benefit of reducing chemotherapy-induced neutropenia (CIN).
After a successful phase 3 study (DUBLIN-3) in NSCLC, Plinabulin regimen is in a confirmatory global phase 3 study in second- and third-line NSCLC with epidermal growth factor receptor (EGFR) wild type after progression on prior immune checkpoint inhibitors, a severe unmet medical need.
SEED has advanced its wholly owned lead oncology asset, a novel RBM39 degrader into phase 1 clinical studies in January 2026.
Plinabulin is a differentiated microtubule modulator with different binding and kinetics from other microtubule stabilizing or depolymerizing agents.
By depolymerizing microtubule, it activates the immune defense protein GEF-H1, which leads to induction of innate and adaptive immunity via dendritic cell (DC) maturation.
In June 2025, we published in Cell Press “Med” Plinabulin’s DC maturation benefit to responding patients in eight cancers, based on our multi-year collaboration with The University of Texas MD Anderson Cancer Center, or MD Anderson.
In January 2026, our research collaborator Dr.
Steinmetz group published in “Cell” on the structural basis of microtubule-mediated signal transduction, which suggests the important role of microtubule as signal sensors to regulate cellular function, further supporting Plinabulin’s unique biological function.
With this unique immune mechanism, Plinabulin is being studied as an anti-cancer agent in a number of company-sponsored studies and investigator-initiated studies in late-line and first-line cancer treatments, including targeting patients progressed on checkpoint inhibitors in NSCLC with EGFR wild type, which we believe presents a severe unmet medical need.
The current standard of care for first-line EGFR wild type NSCLC is PD-1/PD-L1 antibodies with or without platinum doublet.
However, over 60% patients progress on these therapies, defined as “acquired resistance” due to “T cell exhaustion” and/or “antigen presenting cell (APC) pathway mutation” (Memon et al., Cancer Cell 2024).
Once patients progress on these regimens, docetaxel, a drug approved over 25 years ago, is recommended in the second- and third-line, but it has modest clinical benefit and high severe neutropenia.
Recently, 11 phase 3 studies, with agents including PD-1/PD-L1 antibodies combinations or Antibody Drug Conjugate (ADC) have failed to surpass docetaxel in overall survival (OS) in this population.
We believe that Plinabulin’s mechanism of DC maturation could help mitigate ICI acquired resistance, as DC is the most potent APC and it can prime T cells.
To address the significant unmet need in this population, we have been conducting multiple studies on Plinabulin combinations.
First, we completed a randomized global Phase 3 study of Plinabulin in combination with docetaxel compared with docetaxel alone for second- and third-line treatment of NSCLC, with EGFR wild type (DUBLIN-3 Phase 3 registration study).
The DUBLIN-3 study enrolled 559 patients at 58 clinical sites globally and the final results from the study showed that the Plinabulin and docetaxel combination had statistically significant and clinically meaningful overall survival benefit compared to standard of care (SOC) docetaxel alone with doubling 2-year and 3-year OS rate.
It has more pronounced overall survival benefit in plinabulin-mechanism targeted non-squamous patients (OS HR 0.72 after additional 2-year follow-up, p=0.0078).
Key secondary endpoints were also achieved with additional clinically significant benefits in progression free survival (PFS) and objective response rate (ORR), coupled with a significant reduction in grade 4 neutropenia, with over 80% reduction from over 33% to 5% (p<0.0001).
Because DUBLIN-3 study had over 80% patients from Asia, we plan to initiate a confirmatory global phase 3 study in second- and third-line non-squamous NSCLC with epidermal growth factor receptor (EGFR) wild type after progression on prior immune checkpoint inhibitors, based on productive discussion with US regulatory agency.
In addition, we are conducting a number of investigator-initiated study (IIT) on Plinabulin in ICI progressed cancers, including NSCLC, head-and-neck cancer and Hodgkin’s Lymphoma, and first line ES-SCLC.
We provide financial support for these various investigator-initiated clinical trials as well as the drug supply of Plinabulin.
First, our collaborators at Peking Union Medical College Hospital in China are conducting an investigator-initiated Phase 2 study (Study 303) with the completion of all 47 patients enrolled: Plinabulin in combination with Keytruda® (pembrolizumab), a PD-1 antibody, and docetaxel for the treatment of NSCLC patients who progressed from PD-1/PD-L1 antibodies.
We presented clinically meaningful data of high disease control rate of 80% and prolonged PFS from this study at European Society for Medical Oncology (ESMO) 2024, Society for Immunotherapy of Cancer (SITC) 2024, and American Society of Clinical Oncology (ASCO) 2025.
Second, our collaborators at MD Anderson Cancer Center have completed a phase 1 IIT study in Plinabulin combination with PD-1 or PD-L1 antibodies and radiation for the treatment of patients in eight cancers who progressed from PD-1/PD-L1 antibodies, with disease control rate of 54%.
This paper was published in Cell Press “Med” in June 2025.
Plinabulin’s rapid DC maturation biomarker analysis was observed in responding patients.
Third, Plinabulin is being studied in a Phase 2 IIT study (Study 302) in combination with Keytruda®, etoposide and platinum for the first-line treatment of extensive-stage small cell lung cancer, or ES-SCLC, patients at Wuhan Union Hospital in China, where the current standard of care has limited median PFS.
Additional completed investigator initiated studies with Plinabulin include: 1) in combination with nivolumab, a PD-1 antibody, for the treatment of NSCLC at the University of California San Diego, or UCSD, and the University of Washington (Phase 1 completed); 2) in combination with nivolumab and ipilimumab, a CTLA-4 antibody, for the treatment of second line ES-SCLC at the Rutgers University and other U.S. clinical centers (both Phase 1 and Phase 2 completed).
It is a Selective Immunomodulating Microtubule-Binding Agent (SIMBA), which may provide multiple therapeutic opportunities.
By binding to a distinct pocket and depolymerizing tubulin, Plinabulin triggers the release of the immune defense protein, GEF-H1, which activates RhoA/ROCK (Rho-associated protein kinases) pathway and leads to two distinct effects: 1) a durable anti-cancer benefit due to the maturation of dendritic cells resulting in activation of tumor antigen-specific T-cells to target cancer cells and 2) early-onset action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells, or HSPCs.
As a potential “pipeline in a drug,” Plinabulin is being broadly studied in combination with chemotherapy, radiation, or various immuno-oncology agents that could boost the effects of the PD-1/PD-L1 antibodies and potentially allow patients who progressed on PD-1/PD-L1 antibodies to respond to Plinabulin regimen.
The elucidation of Plinabulin’s unique mechanism was a multi-year collaborative effort among us, University of Basel, Massachusetts General Hospital, and MD Anderson.
In these advanced cases, treatment is not curative, and patients with EGFR wild type (around 85% western patients and 50-70% Asian patients) are generally treated with first-line therapies including platinum doublet with or without PD-1/PD-L1 inhibitors.
However, over 60% patients could progress on these therapies and with docetaxel as the SOC after progression.
Recently 11 phase 3 trials failed to show OS benefit of new agents compared to docetaxel in patients with advanced and metastatic NSCLC after progression on ICI-based therapy.
These studies evaluated PD-(L)1 inhibitor combination with tyrosine kinase inhibitor (LEAP-008, SAPPHIRE, CONTACT-01), PD-L1 inhibitor with ATR inhibitor (LATIFY), PD-L1 inhibitor with VEGFR-2 antibody (PRAGMATICA-LUNG) , PD-1 inhibitor combined with Docetaxel with or without TIM3 inhibitor (COSTAR Lung), or novel bispecific antibodies (PD-L1x4-1BB, ABBIL1TY), or antibody-drug conjugates (TROPION-Lung01, EVOKE-1, CARMEN-LC03.
Therefore, docetaxel, a drug approved 25 years ago, with limited survival benefit of around 9 months and high severe neutropenia rate of over 40%, remains the standard of care, highlighting a significant unmet medical need.
Plinabulin in advanced and metastatic NSCLC Plinabulin is a Selective Immunomodulating Microtubule-Binding Agent (SIMBA), which activates immune defense protein GEF-H1, and leads to dendritic cell maturation and T-cell activation (La Sala 2019; Kashyap 2019) for anti-cancer benefit.

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Gone since FY2024

Our first-in-class lead asset, Plinabulin, which has been administered to over 700 cancer patients with generally good tolerability, is being developed as a potential “pipeline in a drug” in various cancer indications as a direct anti-cancer agent.
Plinabulin binds in a unique pocket in tubulin which is different from other tubulin binders such as taxane, vinca, and colchicine, and releases an immune defense protein GEF-H1, which produces the potent effect of maturing immune dendritic cells, leading to T-cell activation for a potential durable anti-cancer benefit.
Therefore, we believe Plinabulin’s mechanism stimulates both innate and adaptive immunity.
We are applying these insights to our current clinical studies to target mechanism-based patient populations.
Plinabulin’s unique binding site has also led to clinical findings that have repeatedly shown significant reductions in CIN, which may provide added clinical and safety benefits to cancer patients.
Plinabulin is being studied as an anti-cancer agent in a number of company-sponsored studies and investigator-initiated studies.
We completed a randomized global Phase 3 study of Plinabulin in combination with docetaxel compared with docetaxel alone for second- and third- line treatment of NSCLC, epidermal growth factor receptor, or EGFR, wild type (DUBLIN-3 Phase 3 registration study).
The DUBLIN-3 study enrolled 559 patients at 58 clinical sites globally and the final results from the study showed that the Plinabulin and docetaxel combination had statistically significant and clinically meaningful overall survival benefit compared to standard of care docetaxel alone.
Key secondary endpoints were also achieved with additional clinically significant benefits in progression free survival (PFS) and objective response rate (ORR), coupled with a significant reduction in grade 4 neutropenia, with over 80% reduction.
The current standard of care for first-line NSCLC without driver mutations is chemotherapy plus PD-1/PD-L1 antibodies, with 60% patients progress on these therapies.
Once patients progress on these regimens, docetaxel is the recommended in the second line, but it has modest clinical benefit and high severe neutropenia.
To address the significant unmet need in this population, our collaborators at Peking Union Medical College Hospital in China are conducting an investigator-initiated Phase 2 study (Study 303): Plinabulin in combination with Keytruda® (pembrolizumab), a PD-1 antibody, and docetaxel for the treatment of NSCLC patients who progressed from PD-1/PD-L1 antibodies.
We presented the early data of disease control rate and prolonged PFS from this study at European Society for Medical Oncology (ESMO) 2024 and Society for Immunotherapy of Cancer (SITC) 2024.
Plinabulin is also being studied in a Phase 2 investigator-initiated study (Study 302) in combination with Keytruda®, etoposide and platinum for the first-line treatment of extensive-stage small cell lung cancer, or ES-SCLC, patients at Wuhan Union Hospital in China, where the current standard of care has limited median progression free survival.
Additional investigator initiated studies with Plinabulin include: 1) in combination with nivolumab, a PD-1 antibody, for the treatment of NSCLC at the University of California San Diego, or UCSD, and the University of Washington (Phase 1 completed); 2) in combination with nivolumab and ipilimumab, a CTLA-4 antibody, for the treatment of ES-SCLC at the Rutgers University and other U.S. clinical centers (both Phase 1 and Phase 2 completed); and 3) in combination with PD-1 or PD-L1 antibodies and radiation for the treatment of patients with various cancers who progressed from PD-1/PD-L1 antibodies at The University of Texas MD Anderson Cancer Center, or MD Anderson (Phase 1 completed and presented at SITC 2023).
We expect each of these studies to benefit from our previous investigation of Plinabulin as an agent that has been studied in two randomized, controlled Phase 3 clinical studies to have demonstrated a statistically significant reduction in CIN.
In total, over 700 patients have been treated with Plinabulin, where improvements in CIN have been repeatedly observed.
It is a Selective Immunomodulating Microtubule-Binding Agent, which may provide multiple therapeutic opportunities.
By depolymerizing tubulin, Plinabulin triggers the release of the immune defense protein, GEF-H1, which activates RhoA/ROCK (Rho-associated protein kinases) pathway and leads to two distinct effects: 1) a durable anti-cancer benefit due to the maturation of dendritic cells resulting in activation of tumor antigen-specific T-cells to target cancer cells and 2) early-onset action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells, or HSPCs.
As a potential “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 and potentially allow patients who progressed on PD-1/PD-L1 antibodies to respond to PD-1/PD-L1 combination with Plinabulin.
The elucidation of this mechanism was a multi-year collaborative effort among us, University of Basel, Massachusetts General Hospital, and MD Anderson.
In these advanced cases, treatment is not curative, and patients are generally treated with systemic therapies.
Initial first-line therapy is often based on broad chemotherapy drugs such as cisplatin with or without PD-1/PD-L1 inhibitors.
Most patients, however, do not obtain a long-term overall survival benefit.
For patients who failed first-line therapies and with no driver mutation, the current standard of care is still docetaxel-based therapies, with limited survival benefit of around 9 months and high severe neutropenia rate of over 40%.
Seven recent Phase 3 studies in patients with EGFR wild-type NSCLC who were previously treated with immune checkpoint inhibitors failed to show overall survival (OS) benefit compared with docetaxel (SAPPHIRE, LEAP-008, CONTACT01, EVOKE-01, CARMEN-LC03, and CANOPY-2, and TROPION-Lung01).
No new drug has been approved in this hard-to-treat indication in the last decade.
Therefore, we believe new treatments for advanced and metastatic NSCLC with EGFR wild-type after platinum therapy progression are urgently needed.
Plinabulin in advanced and metastatic NSCLC Plinabulin is a Selective Immunomodulating Microtubule-Binding Agent, which activates immune defense protein GEF-H1, and leads to dendritic cell maturation and T-cell activation (La Sala 2019; Kashyap 2019) for anti-cancer benefit.
This subset analysis was presented as an oral presentation at 2017 American Society of Clinical Oncology—Society for Immunotherapy of Cancer, or ASCO-SITC, conference and was selected as one of five highlights of the meeting.
For the non-squamous subset patients, median OS (mOS) in Plinabulin/docetaxel arm was 11.4 months vs. 8.8 months in the docetaxel arm, with mOS benefit of 2.6 months. ● Improved OS benefit with more cycles of treatment (≥ 4, 6, 8, 10, or 12 cycles): for patients who used at least 4 cycles of treatment, OS HR=0.64, p=0.0027, with mOS benefit of 4.8 months (Plinabulin/docetaxel arm n=133; docetaxel arm n=127). ● Plinabulin/docetaxel combination is well-tolerated: Treatment-emergent adverse-events occurred in 273/274 (99·6%) of patients in the Plinabulin group and 276/278 (99·3%) in the control group.
The global market size of PD-1 and PD-L1 inhibitors/ immune checkpoint inhibitors was estimated at $52.3 billion in 2024.
It is estimated at $63.7 billion in 2025 and $145.6 billion by 2030 at a compound annual growth rate (CAGR) of 18.0% (Modor Intelligence Research and Advisory 2024).
Around 60% of the patients who receive such treatment progressed from PD-1/PD-L1 antibodies in NSCLC (Cancer Cell 2024).
Current investigator-initiated studies on these Plinabulin combinations aim to help design an optimum registrational study for these indications for patients who failed PD-1/PD-L1 inhibitors, especially in NSCLC.
We believe that the activation of dendritic cells is a key to unlocking the next boost to the efficacy of immuno-oncology agents.
Activated dendritic cells, which are the most potent antigen presenting cells, present foreign tumor antigens to T-cells to induce cancer-directed immune attacks.
Even with the current PD-1 and PD-L1 antibody annual sales exceeding $50 billion, with most sales coming from lung cancer, around 60% of lung cancer patients could develop acquired resistance to PD-1 and PD-L1 antibody, and these patients currently have limited treatment options (Tamon et al Cancer Cell 2024).
Our anti-cancer strategy is to combine Plinabulin with checkpoint inhibition and immune activation from radiotherapy.
We believe the data strongly indicates that this triple combination has potential to help patients who failed or have progressed on anti-PD-1/PD-L1 targeted therapy, which represents a high unmet medical need.

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Sentence-level comparison of Item 1A in the two most recent 10-Ks (FY2024 ↗, FY2025 ↗). A reworded sentence counts as one dropped and one added, so heavy edits read as low “kept”. Headings and page furniture are stripped; nothing is summarised by a model.

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