Greetings. Welcome to BeyondSpring Corporate Update and Strategic Development Call. At this time, all participants will be in listen-only mode. The question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero from your telephone keypad. Please note that this conference is being recorded. At this time, I'll now turn the conference over to Min Qiu, CEO of BeyondSpring. Thank you. You may now begin.
Good morning, everyone, and thank you for joining today's call. Before we begin, I would like to remind listeners that remarks made on today's call may reflect forward-looking statements that are related to such matters as BeyondSpring's clinical and pre-clinical research and development activities and results, regulatory and commercial plans, industry trends, market potential, collaborative initiatives, and financial projections, among others. While management believes that its assumptions, expectations, and projections are reasonable in view of the currently available information, you are cautioned not to place undue reliance on these forward-looking statements. The company's actual results may differ materially from those discussed during this call for a variety of reasons, including those described in the forward-looking statements and the Risk Factors sections of the company's 10-K and other filings with the SEC, which are available on the Investors section of BeyondSpring's website.
Joining me today are our Chairman, Dr. Lan Huang, our Chief Executive Officer, Mr. Min Qiu, and our Chief Scientific Officer, Dr. June Lu. I will now turn the call over to our Chairman. Lan, please go ahead.
Thank you, Cedric. 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 non-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, Lan. Good morning, everyone. As Lan 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 June 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 June, our Chief Scientific Officer, to review the unmet need, the mechanistic rationale for plinabulin, and the clinical evidence supporting DUBLIN-4. June, 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. Immune checkpoint 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 two point five 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 five point six months versus three point eight 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%.
This data suggests a more durable tumor response compared to docetaxel in similar patient populations as reported TROPION-Lung01 and COAST phase III studies. Taken together, the DUBLIN-3 subgroup findings and the results from Study 303. Provide a clinical rationale for evaluating DUBLIN-4 in a more clearly defined, plinabulin mechanism-supported population of patients with non-squamous, non-small cell lung cancer whose disease has progressed following ICI treatment. With that, I will turn it back to Min to review the DUBLIN-4 study design and discuss how we plan to execute the program. Min, please go ahead.
Thank you, June. Let me now briefly review the design of DUBLIN-4. DUBLIN-4 is a confirmatory global phase III study in post-ICI, driver negative, non-squamous NSCLC. Approximately 442 patients are planned to be enrolled. Patients will be randomized one-to-one in the double-blind design. The experimental arm received docetaxel plus plinabulin, while the control arm received docetaxel plus placebo. OS is the primary endpoint, with PFS, ORR, and other important clinical and safety measures also included in the study. Approximately half of the planned enrollments is expected from China and approximately half from Western regions. BeyondSpring brings several execution capabilities to this program, including global oncology and regulatory experience completing phase III studies, an established clinical site and investigator network, and direct operational experience from DUBLIN-3. Our currently disclosed development timeline shows study initiation around the end of 2026 to early 2027, with interim analysis expected in 2028.
As the interim analysis is event-driven, its timing will depend on enrollments and the accumulation of PFS events. Let me close by bringing these elements together and highlighting what we believe creates a clear path to value creation for plinabulin. First, we have a differentiated clinical-stage asset supported by a substantial body of scientific and clinical evidence. More than 700 cancer patients have been treated with plinabulin across multiple clinical programs, providing an extensive clinical safety database. In DUBLIN-3, plinabulin plus docetaxel demonstrated a statistically significant OS benefit, and its differentiated GEF-H1 mechanism provides both immunomodulatory activity and the potential to mitigate chemotherapy-induced neutropenia. Second, we believe DUBLIN-4 provides a focused path to confirm this clinical benefit in the mechanism-targeted post-ICI non-squamous NSCLC population.
Importantly, the FDA Fast Track designation and our strategic transaction related to the China portion of DUBLIN-4 are expected to strengthen both the regulatory and execution framework for the program. Based on our current development timeline, the pre-specified interim analysis is expected in 2028, subject to enrollment and accumulation of the required PFS events. Finally, we believe DUBLIN-4 addresses a large and underserved post-ICI NSCLC patient population and, if successful, could establish a meaningful commercial opportunity for plinabulin and unlock plinabulin's potential as a differentiated anticancer agent in NSCLC and beyond. Taken together, we believe the clinical evidence, differentiated mechanism, focused phase III strategy, and recent regulatory and strategic developments provide a clear path towards the next major value-creating milestones for plinabulin and BeyondSpring. Our focus now is on disciplined execution of DUBLIN-4 and advancing the program toward its pre-specified interim analysis.
With that, I will turn the call back to Lan.
Thank you, Min, and thank you, June. We believe these developments represent important progress for BeyondSpring and DUBLIN-4. We remain focused on executing the global Phase III program and advancing plinabulin towards its next major clinical milestone. With that, we are ready to take your questions. Operator, please open the line for Q&A.
Thank you. We will now be conducting a question and answer session. If you would like to ask a question at this time, please press star one on your telephone keypad and a confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please for our first question. Thank you. And our first question is from the line of Sylvain Turcan with Citizens. Please proceed with your questions.
Yeah, good morning. Congrats on the transaction and the update here, and thanks so much for taking my question. Maybe just starting off big picture here, as you highlighted this, 12 phase III studies that showed no OS benefit, which points to this really big unmet need here, post-checkpoint inhibitors. Could you just maybe summarize one more time why DUBLIN-4 should work? Specifically, how did your prior observations and insights on the mechanism inform the trial, and how did you get to your powering assumptions from DUBLIN-3 and the Study 303? Then I will follow up. Thank you.
Yeah, thank you, Sylvain. I think I am going to turn the answers to Dr. June Lu, our CSO.
Yes. Thank you for the question. This is June Lu. Agree with you that given the type of data out there, this is a challenging therapeutic space competing against docetaxel in post ICI setting. I should also mention that in the recent COASTAR Lung phase III study, Jemperli or dostarlimab plus docetaxel did not surpass docetaxel in PFS and overall survival. But still, this space is very active with at least eight phase III studies, either ongoing or not yet recruiting, evaluating novel IO agents, ADCs, including those of novel targets by specific antibody or by specific ADC. To our end, we believe that plinabulin's mechanism supports the DUBLIN-4 program as the following. First, as docetaxel kills the cancer cells in the body, plinabulin is there to drive immunogenic DC maturation, breaking the immune tolerance, which is the key determinant to fully reverse T- cell exhaustion.
We also stack the deck in our favor, so to speak, by enrolling only non-squamous patients based on the efficacy data we saw in DUBLIN-3, Study 303 in post ICI non-small cell lung cancer patients and the tumor vasculature effect of plinabulin. Together with the same benefit of plinabulin that allows for more docetaxel dosing and a better bone marrow recovery, we think that plinabulin helps to refresh and sustain the cancer immunity cycle for a more durable anti-tumor immune response to help overcome IO resistance. Now, please come in.
Yeah. Thank you, June. Sylvain, you asked this great question. So we have been studying plinabulin for over 15 years in its immune modulating mechanism, and we believe that it differentiated DC maturation and also targeting vasculature and then finally reducing chemotherapy-induced neutropenia, really is perfect to combine this profile to get into this DUBLIN-4 population. From the study design and also patient number, we have worked with independent statistician to use the DUBLIN-3 study data, and also the OS hazard ratio for non-squamous population and also the post hoc analysis in ICI progression patient to determine this 442 patient one-to-one randomization with a power of over 85%. Yeah. Thank you.
Yeah. Great. Thank you. And maybe on the business side, did the FDA sign off on your DUBLIN-4 basically design and maybe the patient composition, right? So now you will have a significant number of Chinese patients and then rest of world patients. Did they sign off on it and specifically the 50/50 split that you can expect here in this trial?
So yeah, if I can just start and then Min can come in into the split of Western and Asian population split. From a study design point of view, our phase III protocol for DUBLIN-4 has been aligned with FDA in this population and also OS is the primary endpoint, and we are very honored to receive the Fast Track designation from FDA for this population. Secondly is, of course, it's always good to have more Western patients, but depending on where the patient come from, the speed and also cost efficiency and also the support for the global study and the package for the FDA approval, we actually utilized this 50/50 split, and they already have some examples before, for this successful regulatory strategy. Min, you can talk about those examples.
Yeah. Thank you, Sylvain. Thank you, Lan. Yeah, of course, there are also recent FDA approvals supported by programs with a substantial proportion of Asian patients. For example, the recent TALVEY drug, talquetamab, was approved based in part on the study conducted entirely in China together with a global study that also enrolled a high proportion of Asian patients. Also a drug from HUTCHMED called savolitinib was approved based on the multinational study in which approximately 65% of the efficacy population was Asian. But I think which is most important for us is that DUBLIN-4 will apply the same protocol and evaluation standards across regions. PK and efficacy will be evaluated across Asian and Western populations to assess the consistency of drug exposure and treatment effect. So yeah, I think we believe our approximately 50/50 strategy is reasonable.
Yeah, of course, the ultimate acceptability of the data will depend on the actual study results and FDA's review. Thank you.
Great. Thank you. I'll hop back in the queue.
Thank you, Sylvain.
Just a reminder, if you would like to ask a question today, you may press star 1 from your telephone keypad. The next question is a follow-up from the line of Sylvain Turcan with Citizens. Please just use your question.
Great. Thanks. Yeah, one more question if I may be able to sneak that in. After obviously this transaction that you just did, can you just maybe summarize your cash needs and how that aligns with the time and operations and startup costs in the U.S. versus your first interim analysis in 2028? Thank you.
Yeah, so probably I can start and then Min can chime in. As you see that this study is a 442 patient study with the prespecified interim at a 221 PFS event. With this very important non-cash and also non-dilutive transaction with investors, then we are getting around 50% of the patient data, which is around 221 PFS events and OS events in the future. That definitely cuts down on the cost for BeyondSpring to generate data to get to the prespecified interim analysis, which is the 221 PFS event. The actual how much to be saved, of course, it is going to be determined by the study operation. But as you see here already, more than half of the study cost is reduced.
China has such a great population of non-small cell lung cancer patients. The speed is also going to add to our arrival at the prespecified interim analysis. Thank you for the great question.
Great, and sorry, one last one if I may. Obviously this is a small molecule, but it seems to do a lot of things. Maybe can you just summarize how, I guess, the mechanism of GEF-H1 kind of explains all of these and how does that line up with some of the side effects that you've seen in DUBLIN-3, such as the GI side effects and the hypertension? Thank you.
Yeah.
Yes. Hi.
Thanks for the question. June will comment.
Yes. I very much welcome this in-depth question. As Lan mentioned, we have been building our knowledge base over the years. First, I want to mention that people only recently recognized the sensory role of microtubules that may be as important or more important than their traditional architectural role. According to a recent cell paper published by our collaborator, Dr. Michel O. Steinmetz at the University of Basel, GEF-H1 is one of the key microtubule-associated signaling proteins, but there are others that are not yet explored. Second is GEF-H1 function is different in different cell types. Obviously, microtubules are everywhere, right? Biologically, its activity is highly regulated through four phosphorylation sites, depending on the timing, location, and environmental cue. Under myelosuppression condition, the bone marrow recovery or regenerative hematopoiesis is also a GEF-H1-dependent process.
As far as the side effects you mentioned, GEF-H1 regulates barrier integrity in the intestines and normal vasculature. The GI side effect is managed in the clinic by medication. We actually consulted with [uncertain] at UT Southwestern, who specializes in gastroenterology and gut health. He published in April this year that a long isoform of GEF-H1 is located in intestinal epithelial cells. So he believes that plinabulin's GI side effect may attribute to that. As far as the hypertension, the hypertension is transient, which often resolves within four to six hours after infusion. This is because GEF-H1 is at a tight juncture that its minor disturbance can cause transient endothelial disturbance shift. So I hope that answers your question.
Yeah. Thank you so much, and congrats again on the update.
Thank you. At this time, I'll hand the floor back to Min for closing comments.
Yeah. Thank you. Thank you for your questions and for joining us today. We appreciate your continued interest in BeyondSpring. We look forward to keeping you updated on the advance of DUBLIN-4 and the development of plinabulin to help patients with high unmet medical needs. Thank you, and have a good day.
Thank you. This will conclude today's conference. You may disconnect your lines at this time. We thank you for your participation.