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spk02: Thank you, everyone, for joining today's call.
spk08: I would like to advise listeners that comments 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 risk factors sections of the company's 20F and other filings with the SEC, which are available on the Investors section of BeyondSpring's website. Joining us on today's call is Dr. Fland Wong, BeyondSpring co-founder, chairman, and chief executive officer. Dr. Ramon Mojano, executive vice president, research and development, and chief medical officer. Richard Daly, chief operating officer. And Elizabeth Serpak, chief financial officer. It is now my pleasure to turn the call over to Dr. Lan Huang. Lan?
spk09: Hello, everyone, and thank you for joining today's call. We're very pleased to be here today reporting our second quarter results and providing an update on the many meaningful events in the recent weeks. Everyone here at the company is very excited as we have accomplished so much But most importantly, we're most excited for patients who are our North Star, who can be helped by our lead asset, Penabalin. Penabalin is a first-in-class selective immunomodulating microtubule binding agent, or SIMBA. With clinical evidence from Dublin Street and our CIN studies, we have revealed the dual benefit of Penabalin. in a direct anti-cancer benefit of significantly extending overall survivor while also significantly reducing severe neutropenia induced by chemotherapy, which would be beneficial to patients in need. From the execution point, we have much more to look forward to in the next 6 to 12 months, including, first, our FADUFA date is on November 30th this year for penicillin and GCSF combination in CIM prevention and upcoming commercial launch in first quarter next year. Second, a planned MDA filing for penicillin in non-sponsored lung cancer in the first half of 2022. And third, continued development of a rich and deep pipeline, including Pnebulon in IIIO combo in various cancers. Each of our upcoming milestones has the potential to provide significant shareholder value. Let me begin today by recapping the very meaningful events and data from the recent few months. I will then provide a few highlights of what to expect for us in the coming weeks and months before handing over to Ramon and Rich to provide more detail on our scientific and clinical accomplishments and commercialization plans. Again, the past few weeks have truly been transformational for us at BeyondSpring. Most importantly, we were thrilled to announce positive data from our registrational trial of Dublin-3 in penicillin in second and third line non-small cell lung cancer, which showed significant improvement in overall survivor, especially in doubling the two-year and three-year survivor in the penicillin and docetaxel combination arm versus docetaxel alone. This underscores penicillin's immune durable anti-cancer benefit and makes us optimistic for its potential in other cancer combinations like IIIO combos. We have always believed penicillin to be a pipeline in a drug with the potential for approval in several indications. With the direct anti-cancer data in non-small cell lung cancer, were well on our way to realizing our vision for Penabulum. I will let Ramon provide more color on the study and some high-level data. We are presenting additional data in 10 days at the late-breaking oral presentation at ASMO on September 20th. We are planning to host the call after the ASMO presentation. Another meaningful recent announcement was our strategic partnership between Fanchun Buling, our 58% owned China subsidiary, and Henre, a leading R&D and commercialization company with top expertise in oncology in China for the commercialization and co-development of Pnebulin in Greater China. This landmark partnership serves as a validation from a well-respected leading pharma for penicillin as a pipeline in the drug. Over the past 40 years, Henry has successfully grown to become the largest oncology drug sales company in China with the top-selling PD-1 inhibitor and docetaxel product and one of the top three GCSF products. Penabulin's potential for use in combination with these agents represents significant synergies and facilitates the development of Penabulin in additional indications, thereby accelerating and increasing the treatment of peak cells in Greater China. Important to note, Not only have we partnered with the most respected company with the widest and deepest reach in the oncology space in China, we have done so at favorable terms for us. We retain manufacturing rights and have the right to receive 100% sales proceeds while paying a reasonable percentage of the net sales to Henry and having all the commercialization costs covered by Henry. Additionally, we will receive significant upfront and 50% cost sharing of development costs. Of note, we will retain 100% of our benevolent rights in all other global markets outside of China. Finally, the deal has attractive financial terms which gives us more cash runway. This includes an upfront payment of around $30 million and milestones of up to around $170 million, plus a $15 million investment in rent and boolean at a pre-money valuation of around $560 million. As you are aware, our NDA for prevention of CRN had been accepted by China NMPA and the U.S. FDA with prior to review. Richwell provides more details on our plans for commercialization and launch in the U.S. in early 2022, assuming approval by the FDA on our November 30th for DUFA date. Looking forward, I mentioned the most important date BDUFA date of November 30th, 2021 for penicillin in CIM prevention. Additionally, our regulatory team are in high gear preparing for our NDA filing for non-small cell lung cancer indication, which we anticipate in the first half of 2022. Finally, with penicillin's unique immune mechanism as a SIMBA, and its durable anti-cancer clinical evidence shown in the Dublin-3 study, we have a well-planned path of development for penicillin in IO combos in various cancers to target unmet medical needs, which PD-1, PD-L1 could not help. First, in PD-1, PD-L1 fail patient. Second, the CRN issue in PD-1 and chemo combination. Third, immune-related SAE for iocombos, fourth, the cold tumors, and fifth, first-line cancers which need better efficacy in iocombos. We have undergone a few investigator-initiated studies to help to assess cannabinoids' role in addressing these biomedical needs. Ramon will talk more about this in his presentation. To summarize, I would like to thank our team for their commitment and tireless efforts. Everyone here believes in our mission and their passion has been driving us forward towards raising the standard of care for cancer patients in the largest global markets of our first-in-class treatments. We're closer than ever now to achieving this mission and we all look forward to advancing Penebulin and realizing upon our many opportunities to succeed. I will now turn the call over to Dr. Ramon Mohano for a brief review of our recent clinical developments.
spk10: Ramon. Thank you, Lan. As Lan indicated, we are easily awaiting the PDUFA date for the CIN application later this year. We were naturally awaiting the results from Dublin 3 to obtain confirmation of flanerbin's anti-cancer activity, which we have now. It was exciting to see that the flanerbin-dose-excel combination in Dublin 3 had met both the primary endpoint for overall survival and the key secondary endpoint for ORR and PFS. The significant reduction in grade four neutropenia by five-fold with the combination versus dose-excel alone supports plenibulin CIN prevention benefits. The four-year OS rate at 10.6% for the combination with plenibulin versus 0% with dose-excel alone underscores the durable anti-cancer benefit for penicillin and is consistent with its immune mechanism of action. I also would like to mention that we conducted WM3 at high-quality centers on the US GCP. We used quality CROs for the conduct of WM3. ICON was our global CRO for site selection, patient enrollment, and monitoring. All blood samples were sent to Covent Central Laboratory for pharmacokinetic and hematology assessments, including neutrophil count. Icon pharmacovigilance was used for safety processing. As Lan mentioned, Planabulin's next focus in our clinical development program is to develop IO combinations in multiple cancer indications. Earlier this year, we presented phase 1 clinical data with Planabulin in combination with nivolumab and epilimumab in small cell lung cancer, demonstrating a doubling of the anti-cancer results normally seen with nivolumab and epilimumab alone. In that study, we also demonstrated that trunabulin could reverse resistance to prior checkpoint inhibition therapy. Specifically, in this small cell lung cancer phase 1 data, which was presented at ASCO earlier this year, patients from US sites had an ORR of 46% in second and third line, and an ORR of 43% for PD-L1 inhibitors failed patients, which also had a long duration of response, as long as 18 months. And at MD Anderson, we are conducting an investigator-initiated trial in seven different cancers, evaluating the safety and tolerability of Trenabalin in triple IO combination therapy, with both PD-1, PD-L1 antibodies and radiotherapy in PD-1, PD-L1 failed patients. The first patient was enrolled in this phase 1B2 trial in June of this year. As was mentioned before, resistance to immunotherapy is a severe unmet medical need, and we believe Trenablin may have a potential synergistic anti-cancer effect when combined with checkpoint inhibitors and radiotherapy. Based on Frenabin's unique mechanism of action and early clinical data, we believe that adding Frenabin to checkpoint inhibitor therapy with or without chemotherapy has the potential to improve anti-cancer efficacy while reducing toxicity with IO and or chemotherapy. We believe that these early trials are providing collective evidence of an evidence role in addressing the unmet medical needs in immuno-oncology therapy. On the organizational side, we are rapidly building our medical affairs capabilities in support of the upcoming commercial launch efforts. With that, I will now turn the call over to Rich, who will discuss our commercial preparations.
spk12: Thank you, Ramon. Our pre-launch activities and preparations for a commercial launch in the CIN market are building with our PDUFA date set for November 30th. Over the next several months, our seasoned commercial leadership team is preparing to deliver a fully integrated market preparation and launch program to support a successful launch of PNAVLA in early 2022. Complete with elements such as driving awareness of the unmet medical need, or what we call the neutropenia vulnerability gap, continuing our large account outreach, preparing for NCCN guidelines submission, KOL development, speaker mobilization, key stakeholder outreach including patient groups and federal, state, and local legislative initiatives, educational symposium, targeted advisory boards, and finalizing our patient support services to ensure broad access at launch. Specifically, We plan for a dedicated and focused team for the U.S. market. Importantly, we will have a field reimbursement liaison team supported by a patient services hub in place to ensure effective reimbursement from day one to provide support for both providers and patients. We believe this extensive commercial strategy will position us well to successfully launch penicillin combination therapy to capture long-term commercial success. We look forward to updating you on our progress with our prelaunch activities in the coming months.
spk11: And now I'll turn over to Elizabeth to take you through the financial results. Elizabeth.
spk07: Thanks, Rich. I will now briefly discuss our second quarter 2021 financial results. For greater detail related to these results, I refer you to our press release issued this morning and to our 6K filing both of which can be accessed under the Investors section of our website. With that, I will now highlight some of the key financial results. R&D expenses in the second quarter of 2021 were $11.3 million compared to $11.0 million in the same quarter last year. The increase of 0.3 million was primarily due to an increase in personnel cost and non-cash stock-based compensation expense, partially offset by lower clinical trial expense. G&A expenses were 9.0 million in the second quarter of 2021, compared to 2.6 million for the same quarter of 2020. The $6.4 million increase was primarily due to higher personnel cost, non-cash stock-based compensation expense, and higher costs associated with pre-commercialization activities for plenabulin. Net loss in the second quarter of 2021 was $19.3 million, compared to $12.8 million for the same period last year. Our cash balance at the end of second quarter was $51.3 million, and we had short-term investments of $25.0 million, which we believe will be sufficient to support our ongoing clinical programs over the next year, including our immune oncology pipeline and to prepare for the potential launch of Plenabulin in CIN in early 2022. In addition to reported available cash, we will also receive from Hanrei approximately $45 million for a $30 million upfront payment plus an equity investment into the China subsidiary related to the Plenabulin partnership in China, which Lan described. I do also want to mention that in the U.S., Rich has updated on our efforts to prepare for our own launch of Plenabulin in CIN, and we are also evaluating potential partnership opportunities in the U.S., Europe, and other parts of Asia outside of Greater China. We are only considering the very top companies who could bring great synergies and help us optimize the value of Plenabulin globally. With that, I will now turn the call back over to Lan for closing remarks. Lan.
spk09: Thank you, Elizabeth. We're very proud of our accomplishments thus far. We have had extremely busy and productive period recently, but we're just starting. Everyone feels the momentum building and our excitement grows as our vision of commercialization penicillin and expanding on our indications comes closer, with the potential to help many patients in need. We invite everyone to watch for us at ESMO on September 20th, where we will make a late-breaking presentation on doubling three, phase three data in non-small cell lung cancer. and our partners for their continued support as we work towards improving the current standard care for cancer patients worldwide. This concludes our prepared remarks today. I will now ask the operator to begin our Q&A session. Operator?
spk02: Thank you. At this time, we'll be conducting a question and answer session. If you'd like to ask a question today, please press star 1 from your telephone keypad and a confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for questions.
spk11: Once again, that is star 1 to ask a question. Thank you.
spk02: Our first question is coming from the line of Josh Schwimmer with Rivercore ISI. Please proceed with your question.
spk01: Great. Thanks for taking the questions. First, what type of information should we be looking for from the Dublin III trial at ESMO? And specifically, are we going to be getting the subset analysis, which investors have been very focused on? And then second, Investors are clearly concerned that the double and three trial may not suffice for FDA approval, given that the trial was run mostly outside the U.S. and in PD-19 patients. As you're discussing the program with partners, do you expect that you're going to need to wait for full approval by the FDA to capture the full value of the program and some kind of a partnership deal? Thank you.
spk09: Thank you so much, Josh, for your continued support, and thanks for this great question. So let me just touch on both of questions. Number one is for the asthma presentation, we are going to show the whole data, the ITT population with all the specific numbers with it. And in addition, we're also going to show the subset analysis everyone is so eagerly waiting to see, including the PD-1, PD-L-exposed patients, and also the Western patient subset. So that's number one question. Number two is regarding your question on the relevance of the study with limited patients from U.S., how it relates to the U.S. population. So we think that currently our patient population does capture the current landscape of treatment to the biggest extent because we do have patients who has exposed to PD-1, PD-L1. And from the previous experience in FDA approvals for oncology drugs, there were incidents of, you know, approval using limited patient data from the U.S. According to the IQVIA report, 27% of the U.S. FDA oncology drug approval actually used less than 10% data from the U.S. Of course, this is a review issue, so we will be eagerly discussing this with FDA in our planned pre-NDA meeting. We're planning for quarter four of this year. Regarding the partnership discussion, I think this, of course, is a very important topic to discuss, but we cannot give any details at this moment.
spk11: Okay, super. Thanks very much. Looking forward to the ESMO presentation. Yeah, thank you. The next question is from the line of Jason Gerbery with Bank of America. Please proceed with your question.
spk03: Hey, guys. Thanks for taking my questions. Two for me on Dublin. Probably not a big surprise, but just can you, Lon, maybe walk us through the history of the trial, the interim analyses, and and whether median OS or Kaplan-Meier OS were the pre-specified primary endpoint, and whether there were any protocol changes that occurred during the trial. And then my second question is just, there isn't much debate that Kaplan-Meier OS is a gold standard for measuring OS, but I think investors believe that supportive median OS is needed to ensure that the clinical benefit is meaningful. So just love to get your thoughts on the regulatory implications of support of median OS, particularly if it falls in a more gray area or even a negative p-value. Thanks.
spk09: Yeah, well, thank you so much, Jason, for your great question regarding the more details in the history of W3 and also the primary endpoint questions. So first is, you know, W3 has been ongoing for almost six years, so it has been a long trial because it is, you know, 551 patient enrollment globally in U.S., China, and Australia. So along the way, the treatment landscape has also changed, right? And there are PD-1, PD-L1 treatment approved during the study. So we did, during the study, we did update the protocol to include the allowance to have PD-1, PD-L1 failed patients in the study and stratify them. So that's why we are confident with the balancing of two arms with PD-1, PD-L1 exposed patients. And then secondly, regarding the primary endpoint. So the primary endpoint has always been over a survivor. It has never been changed. It's just the analysis of the data, you know, methods, right? So why is using the log rank p-value looking at the, you know, the whole PEPL-MR OS curve, but including in there, there will be, you know, medium OS shown. And in addition, we're also putting the restricted mean survival time, which is looking at the mean OS because penicillin is an immune agent. The mean potentially captures more of the OS benefit for penicillin arm, but both are going to be, you know, shown in the asthma and also with the NDA filing. So everything is transparent and everybody can see what is the profile for Pnevrin. So in the end, the drug is the profile from the KMOS graph, and that's the key. So along the way, we did have two interim analysis. So there is a little P-value hit, statistical hit for the final. p-value which we need to meet for the log-rank p-value, which is 0.046. And what we have said in top line is log-rank p-value for the Dublin-3 in the Neoprenabolin plus doxy-tetra versus doxy-tetra is less than 0.04, so that it does meet this statistical significance in extending overall survivor in the primary endpoint. So, of course, everybody was seeing more details in the asthma.
spk11: Thank you. Thank you. Our next question is from the line of Maury Raycroft with Jefferies.
spk02: Please proceed with your questions.
spk06: Hi, good morning, and thanks for taking my questions. To tie this subset analysis together, For PK bridging data between Western and China patients, is it possible you could disclose some of the PK bridging data at ESMO or at some other point prior to filing the NDA?
spk09: Yeah, thanks for this great question because this is very important for us to be able to combine the Western and Asian patient data for the NDA submission, not only for US but also for China FDA. So we had done extensive population PK Everybody in our CIN studies and also in lung cancer study, everybody has a population PK. So we have rich data for almost, you know, over like 700 patients on those data. So currently we have, you know, submitted those data to the regulatory agency and this is not the PK comparison data usually is not in the, you know, presentation or, you know, for the registration study or in the publications of course you know if everyone's very interested coming in the future we should you know have some kind of public you know review on this later but this is not it's not going to be discussed in the asthma but it is consistent where you know we're very confident with got it so you're you're confident in that consistency that you're seeing between the patient population Yes, yes. Yeah, they are comparable. They're similar in the population PK in Asian versus Western patients.
spk06: Got it.
spk09: We have shown that in many studies. And all the PK data came from Covance, right? We use Covance as our central lab.
spk06: Okay. And then one other question just for the CIN NDA that's under priority review. Can you talk more about the regulatory interactions and feedback and whether you've had a mid-cycle review communications and any label discussions yet?
spk09: Yeah, thanks for this great question. Everyone is eagerly waiting for the final date, which is November 30th. Yes, so HFDA has been communicating with us very infrequent matter and very supportive of our because we did have AOM meeting before the document has been successfully received by FDA. We also had mid-cycle review, and we haven't got to the label discussion yet because it usually is one to two months before the FDUFA date, then there will be label discussion.
spk06: Got it. Okay. Thank you very much for taking my questions.
spk11: Thank you. Next question is coming from the line of Andy Say with William Blair. Please proceed with your questions.
spk04: Oh, great. Thanks for taking my questions. And again, congratulations to the team on, as you said, transformative first half and a great start to 2021. So I have two questions really kind of related to Jason's questions before. One is really, Lon, maybe you can comment on just how Dublin is conducted from a quality control standpoint, data integrity standpoint. I think there's a lot of questions regarding that. And also since, Ron, you talked a little bit about the p-values, I wanted to kind of get your clarification in terms of the p-values listed in the presentation back several weeks ago. following the Dublin three top line results, I noticed that there were a lot of the p-values that basically provided a range and not basically like a single number. I just want to clarify that that is due to the fact that analysis was still ongoing and that was kind of like the top line results and we'll basically get detailed exact p-values at the ESMO conference.
spk09: Yes, thank you so much, Andy, for your great questions and also always your great support. So let me answer your three questions in sequence. So number one is we are very confident with our quality of the data because we are using the quality CROs to conduct the study, as what Ramon just related to you. So our global CRO is QICOM. which is in charge of site selection and patient enrollment and also the monitoring. And secondly, we're also using Covent Central Labs to look at all of our blood samples to evaluate the PK and also the blood chemistry, including the ANC numbers, because you know the ANC is actually important for our secondary endpoint looking into the grave for neutropenia reduction in penicillin arm versus the doxetaxel arm. And thirdly, we also use ICOM-PV to actually do the SAE reporting and also collect all the AE data for all the studies, including W3 and also CIN studies and all the ITT studies. And the last but not least, I also want to mention we also use CRT, which is a central lab company and they actually send all the ECG machines to all the sites to take triplets for the ECG to look at the cardio safety for the drug. So all of this is well validated CROs and also our conduct is under USGCP. So that answers your first question. And number two is the data integrity. So actually, we do use independent statistical company to do the analysis of the data. And also, it's also single-blinded study to the patients. So the patient, when you look at the quality of life data, it will be very trustworthy because patients do not know which arms they are on. So that's the second question. The third question is a great question, a classification. for the p-value in all the you know some of the primary and also the secondary endpoint which we actually had released in the top line because this is a top line right so and really we cannot disclose much because we are saving it for a big major medical conference which is coming up in asthma so that's why it was just only showing a range okay great thanks for all the detailed explanations Vaughn
spk04: Maybe just one more. You know, kind of heading into the ESMO conference, I wanted to get your perspective on how you would view the PFS data. Obviously, you know, whenever you look at OS, it's always kind of confounded by subsequent therapies. So, you know, maybe kind of a, you know, two-parter. One is maybe can you comment on, based on the geography, what are some of the subsequent therapies that patients could get on Dublin 3? And Also, how would you kind of interpret and look at the PFS results in the context of the positive OS?
spk09: Yeah, that's really a brilliant question, because for the clinical studies, I think the gold standard is OS, right? Because in the end, we want to provide the long-term survivor for patients. And that is what all the patients and FDA and also physicians are looking for. So OS is the gold standard. But in the end, in addition, we also want to use PFS and ORR also to look at the drug effect, right? And there's no noise from the later treatment. So that is what you are getting at. So do we see a drug effect? adding to the benefit of docetaxel in the PFS and as you see the p-value is less than 0.01 right from the directional p-value which we shared in the top line so we are seeing you know better improvement in cannabinoid adding to docetaxel not only in the PFS benefit, right, and also in the ORR, which also showed statistical significance. And your last question also asked about what's the later treatment after, you know, the patient's out of the study. As you know, it is a randomized study, so both arms are balanced, and patients, after they get out, of course, they do have a desire to live, so, you know, have a good therapy to be treated, so Afterward, they usually use, you know, TKIs and also they do have PD-1 or PD-LY exposures, but limited.
spk11: And also they're valid. Got it. Got it.
spk09: Thank you.
spk11: Okay, that's helpful. Thank you very much. Yeah, thank you. The next question is coming from the line of Joel Beattie with Baird.
spk02: Please proceed with your question.
spk05: Hi, congrats on the progress. For the CIN indication, there's been recent attention among investors that most of the patients in the trials were from outside the U.S. Could you discuss if FDA is okay with the number of U.S. patients in the CIN studies? And then also, could you discuss how closely the chemotherapy regimens used in those CIN studies resemble what's currently used in the U.S.?
spk09: Well, thank you so much, Joe, and thanks for initiating the report for us recently. Yeah, so this is a great question. So for the CIN indication, as you know, we're going after a broad label for penicillin combined with DCSS in preventing a CIN in all chemotherapy and all solid tumor, right? So it is a broad label. And, you know, study one or six phase three or protect two is a pivotal study which supports this label. In addition, we also have five other clinical studies to support this label from a safety point of view and also from Penabin's pharmacology in its working in protecting neutrophil in week one after chemotherapy as what RIPs 96 to 100%, you know, according to literature, right? So there's a lot of room to improve there. And so, but then, so in a way, it's not so relevant to show, you know, is TAC still used in the U.S.? It's more like it's using as a template to evaluate the drug effect for penicillin, you know, combination with DCSF or any new current, you know, any new agent in development for the CRN. prevention so coming back to the wild six phase three location population you know it is mainly you know coming from it's from the two countries around you know fifty percent
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