BeyondSpring Inc. Ordinary Shares FDA announcement

Good morning, everyone, and thank you for joining us today. First, let me briefly introduce BeyondSpring Inc., which was founded in 2010, is headquartered in New Jersey, and was listed in Nasdaq in 2017. BeyondSpring holds an equity interest in Seed Therapeutics, which is a clinical stage molecular glue company with investments from global pharmaceutical companies Eli Lilly and Eisai. In addition, we are developing a first-in-class anti-cancer small molecule agent, Plinabulin, which has composition matter pattern protection through 2036 in over 40 jurisdictions, with potential to extend to 2041 based on Hatch-Waxman rule. Plinabulin has an extensive safety package. More than 700 cancer patients have been treated with Plinabulin. We plan to initiate DUBLIN-4, a confirmatory phase III study in second-line squamous non-small cell lung cancer, post-immune checkpoint inhibitors, or ICI. A 442-patient study with OS as the primary endpoint.

We believe this study to be supported by its unique mechanism and the previous encouraging clinical evidence. This is a patient population with significant unmet medical needs. Recently, 12 phase III studies have failed to demonstrate an OS benefit over docetaxel, the current standard of care. Plinabulin, combined with docetaxel, demonstrated OS benefit versus docetaxel in a phase III study in non-small cell lung cancer, DUBLIN-3, which was published in "The Lancet Respiratory Medicine" in 2024. Learning from DUBLIN-3, we have designed DUBLIN-4 to focus on Plinabulin mechanism-targeted non-small cell lung cancer patients. Today, we are excited to share with you the news that the FDA has granted Fast Track designation to Plinabulin plus docetaxel for the patient population being studied in DUBLIN-4.

In addition, we entered into a strategic transaction to receive access to clinical data from around 50% of the 442 patients planned for DUBLIN-4 by selling our ownership in Greater China subsidiary. We believe this represents a more capital and execution-efficient path toward DUBLIN-4 interim analysis of 221 PFS events. After this strategic transaction, BeyondSpring still owns global rights of Plinabulin outside of Greater China. Today, we would like to explain the scientific and the clinical rationale for DUBLIN-4, what the Fast Track designation means for this program, and how the strategic transaction is expected to support this global Phase III study. I will now turn the call over to our CEO, Min, to begin the presentation. Min, please go ahead. Thank you, Elaine.

Good morning, everyone. As Elaine mentioned, today I will focus on two important developments for BeyondSpring and our DUBLIN-4 program, the FDA Fast Track designation and strategic transaction related to the China portion of DUBLIN-4. I will first outline the key messages, then turn the presentation over to Jun Lu, our Chief Scientific Officer, to review the unmet need, the mechanistic rationale for Plinabulin, and the clinical evidence supporting DUBLIN-4. After that, I will return to review the DUBLIN-4 study design and summarize the path forward for Plinabulin and DUBLIN-4. Let me begin with the key takeaway from today's update. We have two important developments that we believe strengthen the path forward for DUBLIN-4.

First, the FDA has granted Fast Track designation for Plinabulin plus docetaxel for the same patient population being studied in DUBLIN-4, second and third line non-squamous NSCLC following ICI treatment and platinum-based chemotherapy and without actionable genomic alterations. The designation provides opportunities for more frequent interaction with the FDA during development and may allow rolling review of a future regulatory application, as well as potential eligibility for priority review if applicable criteria are met. Second, we have entered into a strategic transaction involving the sale of our Greater China subsidiary interest to Biolin Investment Limited. Under this arrangement, BeyondSpring expects to receive access to clinical data from approximately 50% of the planned 442 patients in DUBLIN-4, supporting progress towards the study's interim analysis. Importantly, BeyondSpring continues to retain the global rights to Plinabulin outside Greater China.

Together, these two developments are designed to improve the capital and execution efficiency of DUBLIN-4 and advance the study toward its next major clinical milestone, the pre-specified interim analysis at 221 PFS events. With that overview, I will now turn it over to Jun, our Chief Scientific Officer, to review the unmet need, the mechanistic rationale for plinabulin, and the clinical evidence supporting DUBLIN-4. Jun, please go ahead. Thank you, Min.

I would like to expand on what Lan and Min just mentioned about the clinical need and the patient population that DUBLIN-4 is designed to address. Immunocheckpoint inhibitors, or ICIs, have become a major part of the standard of care for treatment of non-small cell lung cancer. However, almost 60% of the patients eventually progress after ICI treatment. For patients who do not have actionable genomic alteration, or commonly referred to as driver negative, treatment options are limited once they progress after frontline ICI and platinum-based chemotherapy. In this setting, docetaxel remains an important standard treatment option. However, historic outcomes with docetaxel remain modest, with a median overall survival of approximately 9-11 months and significant hematologic toxicity, including over 40% severe neutropenia, which may limit docetaxel dose intensity and treatment duration.

Importantly, 12 phase III studies using different treatment approaches, including eight PD-1, PD-L1 inhibitor combinations and four antibody drug conjugate monotherapy in similar patient populations, have failed to demonstrate an overall survival extension beyond docetaxel. This highlights the significant unmet need in the post-ICI setting. Based on our projections, the post-ICI target population across the U.S. and the five major European markets of Germany, France, the United Kingdom, Italy, and Spain could reach approximately 135,000 patients in 2037, at the projected peak sales, if approved, which represents a meaningful patient population that DUBLIN-4 is designed to address. Before reviewing the clinical data, I would like to first highlight the mechanistic rationale for plinabulin in the post-ICI setting.

First is the structural basis of plinabulin as a first-in-class, first-off microtubule destabilizer with a distinct mechanism and a tolerability profile differentiated from other microtubule targeting agents on the market, such as taxanes, auristatins, and vinca. Researchers now know that microtubules are not just structural elements of the cell, but also serve as dynamic sensors in response to stress signals. Plinabulin's interaction with microtubules triggers the release of guanine nucleotide exchange factor GEF-H1, a key signaling protein that drives dendritic cell or DC maturation, antigen-presenting cell or APC activation, and a subsequent anti-tumor immune response. This is especially the case when plinabulin is combined with standard of care chemotherapy or radiation that induces real-time tumor cell death and the release of tumor neoantigens. In other words, plinabulin's immunomodulatory effect improves tumor antigen presentation that is necessary for sustained tumor-specific T cell response to help overcome ICI resistance.

We have early clinical data that Plinabulin also modulates tumor vasculature, which provides additional mechanistic rationale for going after non-squamous non-small cell lung cancer where anti-VEGF drugs are used. Finally, Plinabulin has demonstrated neutropenia-mitigating activity, which may help support chemotherapy dosing intensity and treatment continuity. Together, these complementary mechanisms provide the biological rationale for evaluating Plinabulin-containing regimens in the post-ICI setting. Let me now turn to the clinical evidence supporting this rationale. DUBLIN-4 is supported by encouraging clinical evidence from our DUBLIN-3 study, together with the prospective data from Study 303. First, in the overall DUBLIN-3 phase III population of intention to treat 559 patients in second and third line EGFR-type non-small cell lung cancer with one-to-one randomization. Plinabulin plus docetaxel demonstrated a statistically significant overall survival benefit with a hazard ratio of 0.82.

We also observed a long-term survival benefit with higher 24 and 36 months survival rate than docetaxel alone. Second, in a non-squamous population of 332 patients, which is more relevant to DUBLIN-4, the observed overall survival hazard ratio was 0.72, with a median extension of approximately 2.5 months. Third, a post hoc analysis of DUBLIN-3 revealed an encouraging efficacy signal in the post-ICI subgroup. The median overall survival was 15.8 months with Plinabulin plus docetaxel compared to 11.7 months with docetaxel alone. The median progression-free survival or PFS was 5.6 months versus 3.8 months, and the objective response rate or ORR was 18.2% versus 8%. In addition, Study 303 evaluated a Plinabulin-containing regimen with docetaxel in the post-ICI setting. It reported a median PFS of 7.0 months, an ORR of 18%, a disease control rate of approximately 80%, and a two-year overall survival rate of 58%.