BeyondSpring Inc. (BYSI) Earnings Call Transcript & Summary

Greetings. Welcome to BeyondSpring's Corporate Update and Strategic Development Call. [Operator Instructions] 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 preclinical 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 section 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, 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, its headquarters in New Jersey and was listed in NASDAQ in 2017. BeyondSpring holds an equity interest in Seed Therapeutics, which is a clinical-stage molecular group company with investments from global pharmaceutical companies Eli Lilly and Eisai. In addition, we are developing a first-in-class anticancer small molecule agent, Plinabulin, which has composition of matter patent protection through 2036 in over 40 jurisdictions with potential to extend to 2041 based on Hatch-Waxman rule. Plinabulin has extensive safety package. More than 700 cancer patients have been treated with Plinabulin. We plan to initiate DUBLIN-4 a confirmative Phase III study in second-line, third-line non-squamous, non-small cell lung cancer post-immune checkpoint inhibitor, 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 towards 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 forDUBLIN-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 presence of DUBLIN-4. I will first outline the key messages, then turn the presentation over to June, 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 for start design and summarize the path forward for enabling and DUBLIN-4. Let me begin with the key takeaways from today's update. We have two important developments that we believe strengthens the path forward for DUBLIN-4. First, the FDA has guaranteed fast track designation for plinabulin plus docetaxel for the same patient population being started 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 interactions with the FDA during development and may allow rolling review of future regulatory applications 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 filing 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 return the global rights to plinabulin in Greater China. Together, these two developments are designed to improve the capital and execution efficiency of DUBLIN-4 and advance the start towards its next major clinical milestone. The prespecified interim analysis at 221 PSS 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. Immutep inhibitors or ICI 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 native, 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 outcome with docetaxel remain modest with a median overall survival of approximately 9 to 11 months and a significant hematologic toxicity including over 40% severe neutropenia, which may limit docetaxel dose intensity and the treatment duration. Importantly, 12 Phase III studies using different treatment approaches, including eight PD-1, PD-L1 inhibitor combination and the four antibody drug conjugate monotherapy in similar patient population has failed to demonstrate an overall survival extension beyond docetaxel. This highlights the significant unmet need in the post-ICI study. Based on our projections, the post-ICI target population, across the U.S. and the 5 major European markets of Germany, France, the United Kingdom, Italy and Spain could reach approximately 135,000 patients in 2037 as 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 platinum in the post-ICI setting. First, is the structural basis of platinum as a first-in-class fast off microtuble destabilizer with a distinct mechanism and a tolerability profile differentiated from other microtubule targeting agents on the market, such as taxanes [indiscernible]. Researchers now know that micro tugs are not just structural elements of the cells, but also serve as dynamic sensors in response to stress signals. Plinabulin interaction with microtuble triggers the release of grinninucleotide exchange factor, [ 81 ] a key signal protein that drives tender cell or DC maturation and is in presenting cell or APC activation and a subsequent antitumor immune response. This is especially the case when Plinabulin is combined with standard of care chemotherapy or radiation that induce this real-time tumor cell test and the release of tumor neoantigens. In other words, plinabulin's presence in new modulatory effect improved 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 moderates tumor vasculature, which provides additional mechanistic rationale for going after non-squamous lung small cell lung cancer, where anti-VEGF drugs are used. Finally, plinabulin has demonstrated neutropenia mitigating activity, which may help support chemotherapy dose intensity and the treatment continuity Together, these complementary mechanisms provided by large rationale for evaluating plinabulin containing regimens in the post-ICI study. 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 EGF-type lung small cell lung cancer with 1:1 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 the nonsquamous 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, post-half analysis of DUBLIN-3 reviewed 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 those 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 prevalent containing regimen with docetaxel in the post-ICI setting. It reported a median PFS of 7.3 months an ORR of 18%, a disease control rate of approximately 80% and a 2-year overall survival rate of 58%. These data suggest a more durable tumor response compared to docetaxel in similar patient populations as reported [indiscernible] and the COSTAR Phase III study. Taken together, the DUBLIN-3 subgroup funding 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 complementary global Phase III study in post-ICI drive negative nonscremers CRC, 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, where the control arm received those taxable. 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 enrollment is expected from China and approximately half from Western regions. BeyondSpring brings several execution capabilities to this program, including global oncology and regulatory experience, experienced completing Phase III studies and established clinical site and investigator network and direct operational experience from DUBLIN-3. Our currently disclosed development time line show started initiation around the end of 2026 to early 2027, with interim analysis expected in 2028. As interim analysis is event driven, its timing will depend on enrollment and the accumulation of PFS events. Let me close by bringing these elements together and highlighting what we believe creates a clear path toward creation for plinabulin. First, we have a differentiated clinical stage assets, 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. InDUBLIN-3, plinabulin plus docetaxel demonstrated a statistically significant OS benefit and its differentiated JFH1 mechanism provides both immunomonitory 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 nonsquamous and CRC population. Importantly, the FDA fast track designation and our strategic transaction related to the China region of DUBLIN-4 are expected to strengthen both the regulatory and execution framework for the program. Based on our current development time line, the beside interim analysis is expected in 2028, subject to enrollment and accumulation of the required PFS events. Finally, we believe DUBLIN-4 address is a large and underserved post-ICI CRC 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 toward the next major value-creating milestones for plinabulin and BeyondSpring. Our focus now is on displaying execution of DUBLIN-4 and advancing the program towards its prespecified 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.

[Operator Instructions] Our first question is from the line of [ Silvan Turan ] with Citizens.

Congrats on the transaction and the update here. Maybe just starting off big picture here. As you highlighted, there's 12 Phase III studies that showed no OS benefit, which point is really big unmet need here post checkpoint inhibitors. Could you just maybe summarize on the time why Dublin 4 should work? And specifically, how did your prior observations and insights on the mechanism in form the trial? And how did you get to your powering assumptions from Dublin 3 and the Study 303. And then I have a follow-up.

Yes. Thank you, Steven. I think I'm going to turn the answers to Dr. June Lu, our CFO.

Yes. Thank you for the question. This is June. Yes, I agree with you that given the type of data out there, this is a challenged therapeutic space competing against docetaxel in post-ICI study. I should also mention that in the recent CoStar long Phase III study [indiscernible] of dopolumab plus docetaxel did not surpass docetaxel in PFS and overall survival. But still, this space is very active with at least 8 Phase II studies either ongoing or not yet recruiting, evaluating novel IO agents, ADCs, including those of normal targets by spec antibody or bispecific ADC. So to our end, we believe that plinabulin's mechanism supports the DUBLIN-4 program as the following: first, docetaxel kills the cancer cells in the body, docetaxel is there to drive inorganic DC maturation, breaking the immune tolerance, which is the key determinant to fully reverse T cell exaction. We also stacked the deck in our favor, so to speak, by enrolling only non-squamous patients based on the efficacy data we saw in DEBR3, Study 303 in post II non-small cell lung cancer patients and the tumor vestiture effector plinabulin. Together with the same benefit of plinabulin that allows for more docetaxel dosing and a better bone marrow recovery, we think that cable helps to refresh and sustain the cancer humidity cycle for a more durable antitammune response to help overcome IO resistance. Now please come in.

Yes. Thank you, June. Yes, Silvan, you asked this great question. So we have been studying Plinabulin for over 15 years in its immuno-modulating mechanism, and we believe that its differentiated the maturation and also targeting vasculature and then finally, reducing chemotherapy neutropenia really is perfect to combine this profile for this -- to get into this DUBLIN-4 population. And then from the study design and also patient number, we have worked with independent decision to use the DUBLIN-3 study data and also the OS has a ratio for nonsquamous population and also the post hoc analysis in progression patient to determine this 442-patient one-to-one randomization with power of over 85%.