Beyondspring Inc (BYSI) 2018 Q2 法說會逐字稿

Good day, everyone, and welcome to BeyondSpring, Inc.'s Operational and Clinical Update Conference Call. My name is Dimitrius, and I will be the operator on today's call. Please be advised that today's call is being recorded.

At this time, I would like to turn the call over to the host for today's call, Joe Rayne of Argot Partner. You may begin.

Thank you. And thank you, everyone, for joining today's call. Before turning the call over to management, I would like to introduce today's speakers and their agenda for today's call. Dr. Lan Huang, Chairman and CEO of BeyondSpring, will begin today's call and provide a review of the Phase II 106 Study data reported today, as well as a brief review of the recent Plinabulin data. Richard Daly, BeyondSpring's Chief Operating Officer, will provide a brief update on regulatory plans and timelines for the Plinabulin program and an overview of the market opportunity for the company's Plinabulin franchise. And Dr. Douglas Blayney, Global Principal Investigator for BeyondSpring's chemotherapy-induced neutropenia, or CIN, development program and Professor of Medicine at Stanford University Medical Center, will provide his perspective on the potential role of Plinabulin in enhancing patient outcomes in the treatment of CIN. We will then open the call for questions. Dr. Ramon Mohanlal, the company's Executive Vice President of R&D and Chief Medical Officer; and Edward Liu, Chief Financial Officer, will be available to answer questions during the Q&A portion of today's call.

I would like to also advise listeners that remarks made on today's call may reflect forward-looking statements relating 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. These statements are based on currently available information and management's current assumptions, expectations and projections about future events.

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 section of the company's 20-F and other filings with the SEC, which are available from the Investors section of BeyondSpring's website. A slide deck will be referenced on the call and is available on the IR section of the company's website.

It is now my pleasure to turn the call over to Dr. Lan Huang, Co-Founder, Chairman and CEO of BeyondSpring. Lan?

Thank you, Joe, and thank you, everyone, for joining us today. The past few months have been extremely productive from a clinical execution and a data rollout perspective, with multiple data results and presentations at pivot meetings and new emerging clinical data from our lead asset, Plinabulin, which further reinforce what we believe to be a potentially game-changing product profile for Plinabulin. We have learned how to use our lead asset first-in-class agent, Plinabulin, in our CIN clinical studies.

Please look at slide Page 1. For the intermediate risk chemotherapy patient, where no therapy is the current standard of care, monotherapy of Plinabulin will be developed as shown in Study 105 design. Plinabulin potentially will have a superior overall profile than Neulasta in similar efficacy and significant better safety in bone pain, prevention of thrombocytopenia and positive impact of immune system. All this positive data were presented at the recent ASCO, IASLC, ESMO meetings.

For high-risk chemotherapy patient, as shown in Study 106 design, Plinabulin combined with Neulasta has shown superior efficacy and safety profile, which I will detail in the call today. Today, we unveiled for the first time exciting and potentially paradigm-shifting new data from Study 106, our Phase II study of Plinabulin and Neulasta in the prevention of CIN in high-risk chemotherapy patients. This data are extremely compelling, and the potential clinical implications of this data cannot be ignored. Dr. Blayney graciously agreed to join us today to discuss this data and their potentially far-reaching implications to treating CIN. Importantly, this data suggests a new approach to optimizing chemotherapy by minimizing CIN and bone pain, providing a roadmap for how Plinabulin can be used in combination with Neulasta to improve patient care.

Let me briefly review the data from the trial. This study is evaluating the combination of Plinabulin with Neulasta versus Neulasta alone to prevent CIN and bone pain in patients receiving high-risk TAC chemotherapy, which is the triple combination of Taxotere, doxorubicin and cyclophosphamide. The result to-date analyzed data from 72 patients across 4 arms, evaluating Plinabulin at 20 milligram per meter square with either 1.5 milligram or 3 milligram or 6 milligram of Neulasta versus Neulasta 6 milligram alone.

Please look at slide Page 2. Beginning with the efficacy data, we observed improvement in the incidence of grade 3 and 4 neutropenia in the combination arms versus Neulasta alone, with a clear dose dependency in the combo arms. We saw the most significant impact on grade 3 and 4 neutropenia in the 6-milligram combo arm, with only 50% of patient experiencing grade 3 and 4 neutropenia in the 6-milligram combo versus 81% with Neulasta monotherapy, which is a significant 38% reduction in severe neutropenia.

This result was statistically significant, with a p-value at 0.0456. Secondly, the duration of grade 3 and 4 neutropenia was also very low, much lower, with only 0.94 days in the 6-milligram combo versus 1.38 days in the Neulasta monotherapy arm. This is over 30% reduction, which is clinically meaningful.

Next, please look at slide Page 3. In this slide, you can see that the combo arm showed less incidence of bone pain versus the standard of care. Specifically, only 6% of patients in the 6 milligram combo arm experienced at least one day of bone pain versus 95% in the Neulasta arm. The results was highly statistically significant with a p-value of less than 0.0001.

When you look at patients who experience at least 3 days of bone pain, we saw a 0% in the 6 milligram combo arm versus 38% in the Neulasta arm. This result was also statistically significant with a p-value of 0.0056. The implications from these results are profound. With the use of a combination approach, the patients experienced less neutropenia and less bone pain, which means that over 30% patient may be better disposed to complete the full course of their chemotherapy and later better outcomes. That, in turn, is going to improve the patient care.

Long-term studies have shown that cancer patients receiving less than 85% of the relative dose intensity, or RDI, have expected survival that is 50% of that of patient receiving greater or equal to 85% RDI. A combination strategy for the treatment of CIN could ensure that patients receive their full course and dose of chemotherapy to most effectively treat their cancer.

This data builds on the impressive results we have reported in recent months that clearly articulate the potential for a superior overall product profile for Plinabulin over the standard of care Neulasta. I won't go into detail on each of this presentation today. However, a high-level overview illustrates how this successive tender of new clinical data support the significant potential of Plinabulin's differentiated mechanism action and clinical profile.

First, at the IASLC meeting, we presented data showing that Plinabulin mitigated both docetaxel CIN and thrombocytopenia in patients with advanced non-small cell lung cancer who participated in the Phase II portion of our Study 105. Then, we reported data on the differentiated mechanism of Plinabulin at the 2018 Joint Meeting of the Society for Leukocyte Biology and International Endotoxin and Innate Immunity Society last week.

Here, the data points to the potential IL-6 signaling in bone marrow and tissue microenvironment, suggesting that Plinabulin may be complementary to G-CSF therapy in CIN. This is the theory that has been borne out with our Study 106 data reported today. And yesterday, we had opportunity to share data at ESMO in a plenary session that demonstrated that Plinabulin has the potential to positively impact tumor microenvironment.

Immunotherapy plus chemo is emerging as the new trend in the treatment of cancer. And this data show that Plinabulin could be the preferred option to prevent CIN in an immune and chemotherapy combination. This is exactly what the panel concluded at ESMO meeting yesterday.

With that, let me turn the call over to our new Chief Operating Officer, Rich Daly, to discuss the potential business and commercial opportunities for Plinabulin given this robust and compelling data set.

Thank you very much, Lan. Good morning, everyone. In my view, the significance of the data that Lan highlighted cannot be overstated. I joined BeyondSpring just a few months ago, convinced that the data and the market opportunity that BeyondSpring has the potential blockbuster and a late stage development, which has the power to transform this company and, more importantly, [given these] data improved outcomes for patients in need of prophylaxis for CIN.

4 million cycles of monotherapy G-CSF are used worldwide each year to prevent CIN. And as Lan noted, there is an opportunity to improve on the current standard of care and improve the outcome for patients. Despite the current standard of prophylactic care in CIN with monotherapy G-CSF, although effective to treat mild neutropenia still, far too many patients develop grade 3 and 4 neutropenia.

When neutropenia develops, clinicians following the NCCN guidelines are faced with 4 choices that have been referred to as the 4 Ds: number one, decrease the dose of chemotherapy; number two, delay the next chemotherapy cycle; number three, downgrade the chemo regimen; or number four, discontinue chemotherapy. All of these choices can result in significantly worse outcomes for patients. As you can see, successfully improving preventative neutropenia matters to the oncologists and their patients. In our view, improving the prevention of neutropenia may be one of the most overlooked areas for the improvement of cancer treatment today.

Prior to the release of the 106 top line data, we reported a number of key differentiating factors for Plinabulin. These include: first, a favorable adverse event profile with reduction in bone pain, a significant side effect of G-CSF therapy; second, convenience, first-day dosing and infusion 30 minutes after chemotherapy; third, clinical data that suggests anticancer activity; fourth, a differentiated MoA with clinical data demonstrating protection against thrombocytopenia and immune suppression; finally, a potential IL signaling in bone marrow and tissue microenvironment that suggests that [complementarity] to other treatment modalities, including combination therapy with G-CSF, and now, clinical data that appear to support this thesis, showing statistically significant benefits in preventing neutropenia and bone pain in patients given Plinabulin 20-milligrams per meter squared and Neulasta 6 milligrams.

As both Lan and I have mentioned, data and the literature suggests that effective chemo treatment is dependent upon patients receiving their full dose and course of treatment. From our own market research, we know that many patients have their treatment interrupted or adjusted in response to neutropenia or bone pain. We believe that Plinabulin in combination with Neulasta can reduce the incidence of both, avoiding the events that trigger changes or suspensions in therapy. We believe this could ultimately translate into improved outcomes for patients.

In Plinabulin, we not only see a potential new treatment option for CIN and cancer itself, but a therapy with far-reaching benefits to allow more patient to successfully tolerate the chemotherapy that they need to treat their cancer. Late-stage clinical trials for Plinabulin in CIN and non-small cell lung cancer remain ongoing, with more data coming that will more broadly and completely articulate the profile of Plinabulin. Assuming these attributes continue to bear out and be supported by future data, taken together, these points support a potential blockbuster profile.

Our momentum is strong, and we are rapidly closing in on the critical milestones on the path to achieving this objective. In addition to advancing our clinical trials, we have been very active in setting a stage for multiple NDAs and potential market introduction beginning next year. This is a unique opportunity in the industry and underscores the competitive advantages intrinsic to BeyondSpring's China and U.S. dual market strategy, as well as Plinabulin's strong product profile.

We are on track and expect Phase III interim data for 105 Study this quarter and Phase III final data in the first half of '19. Our regulatory plan is to first submit a New Drug Application to the Chinese Food and Drug Administration, applying for marketing authorization for Plinabulin in China to treat -- for the treatment of CIN in late 2018 or early 2019. In China, with more than 5 million patients annually diagnosed with cancer, up to 65% of these patients are treated with chemotherapy. Our plan is to submit for a broad label for Plinabulin in CIN.

We are now preparing the NDAs which will integrate both 105 and 106 data. Our plan is to follow the CIN CFDA submission with an NDA submission to the U.S. FDA in the second half of next year, based on the full clinical development data package, following completion of the studies. Our regulatory and commercial strategies are completely aligned. Of the 4 million cycles of G-CSF used worldwide to address neutropenia as -- that I mentioned earlier, over 60% are used in just 2 markets, China and the U.S. By seeking approval in these 2 markets first, we expect to enable healthcare practitioners to optimize care for the greatest number of patients and provide the company with the best commercial path forward.

The non-small cell lung cancer regulatory strategy is very similar. Assuming favorable trends comparing overall survival benefit from the 2 treatment arms in Study 103, we plan to use that data in addition to the data from our earlier completed Phase I Study 101 on a basis -- as a basis for conditional NDA submission to the Chinese FDA in the first half of 2019, followed by a U.S. FDA submission targeted for 2020 based on a full and final data read-out from the non-small cell lung cancer program.

Assuming favorable data and regulatory reviews, BeyondSpring has the potential to be a commercial stage company as early as the second half of next year. We expect to look at global opportunities to maximize Plinabulin's potential worldwide and extend our reach to the millions of patients who we believe could benefit from Plinabulin. Our plan is to seek a commercial partner to augment our core competencies and familiarity with patient, provider and reimbursement landscape in China and explore our options for the U.S. market and other key markets.

We have had a period of significant news flows in recent weeks, and there is more to come, with critical data readouts and corporate milestones. Given my previous experience at standing up commercial companies and successfully launching products, I am thrilled to be here at such an exciting time and look forward to providing updates on our progress.

Let me now turn the call over to Dr. Blayney for his perspective on the recent data and potential role of Plinabulin in CIN. Dr. Blayney?

Great. Thank you, Rich, and thanks a lot for allowing me to participate in this call today. I'm a medical oncologist. I've been active in the chemotherapy-induced neutropenia space for approximately 25 years. And this is the first of what I think is exciting development in the field since the launch of Neulasta probably 20 years ago.

So the Phase II data from our 106 Study was announced today. I was pleasantly surprised to see these results when I saw them. Remember that the 106 Study is looking at chemotherapy with more than a 20% risk of febrile neutropenia. As you've heard today, Neulasta, given prophylactically with the first cycle of chemotherapy, is the standard of care. Nonetheless, in spite of our use of Neulasta in this space, a significant number of patients either have to decrease or delay chemotherapy, and many of them just abandon Neulasta, TAC or high-dose chemo -- high-risk chemotherapy treatment and move on to something else. And I don't think this is a good thing for patients.

Similarly, as you've heard, the combination of Plinabulin and a standard dose of Neulasta has shown not only a diminution in the stage -- grade 3 and 4 neutropenia, also shown a diminution in the grade 4 neutropenia. And surprisingly to me, and I'm very pleasantly surprised, it looks like the combination ameliorates the bone pain that patients have with Neulasta after chemotherapy.

Our study showed that Neulasta alone, almost all patients have some sort of bone pain. This is underappreciated by physicians. In my experience, when I treat patients, they typically minimize it because they are afraid I'm going to say no, let's change chemotherapy or do something else. That's often underreported [to] patients that our nurses hear about it a lot. And in our study, we designed a very careful questionnaire with patient-reported outcomes looking at bone pain.

You see the results that are with Neulasta. Almost everybody gets it. And with the combination, this is significantly reduced to almost no bone pain, which I think is going to do a lot for patients' compliance with the combination therapy as we go forward. So again, we have ongoing Phase III studies in the chemo in the high neutropenia risk patients which, with the combination, if the Phase II data is shown to be effective in Phase III, I agree this is likely to be a major step forward for patients and for doctors.

Similarly, in the intermediate chemotherapy risk, which is most chemo -- cytotoxic chemotherapies in use in this country and elsewhere, fall into this intermediate risk. And as noted earlier, many of the immunotherapies that are combined with chemoimmunotherapy also use immediate risk chemotherapy combinations as their backbone. I think this is an unappreciated market opportunity. So again, when we started with docetaxel, which is the point of our 105 Study, single-agent docetaxel, it was originally developed at 100 milligrams per meter squared, was the most effective dose.

A dose of docetaxel that's used today is 75 milligrams per meter squared. That's because the 100 could not be tolerated because of acute therapy-induced neutropenia risk. So I think the availability potentially of Plinabulin in the intermediate space is likely to transform intermediate chemotherapy -- intermediate risk chemotherapy as well.

So I'm excited about this data. I look forward to our Phase III -- completion of the Phase III studies. I've been impressed that the studies have accrued well with investigators, both in the United States and China and in Eastern Europe, enthusiastic about accruing to these patients -- to these studies. And Plinabulin, as you've heard, is fairly easy to use. There's not a lot of technical difficulty or things that -- new technology that we have to introduce to the investigators to get them to use the drug appropriately.

So with that, I'll conclude by saying I'm excited about the results. I look forward to what I think is a pretty aggressive time frame. And I think that can be realized, but I'm excited about seeing this data forward.

So with that, I'd like to turn it back to Lan and away we go.

Thank you so much, Dr. Blayney, for the overview. In the past 18 months, since our IPO last March, we have had significant development and growth at BeyondSpring. So we have successfully executed our clinical strategy and have built a world-class leadership team to support our transition to a commercial stage company. It's such an honor and privilege to work with such a stellar and a complementary team and with world-class KOLs, especially Dr. Blayney, to bring transforming medicine to treat unmet medical need.

For Plinabulin, we have enrolled over 550 patient globally in the last 18 months in our registrational trials. Multiple data sets have highlighted Plinabulin's compelling efficacy and safety profile in CIN compared to standard of care Neulasta, a $6 billion drug. This data collectively highlights how Plinabulin could truly drive a paradigm shift in the treatment of cancer. We look forward to building on this momentum in the near term and to move our robust pipeline forward in development.

We are now looking ahead to our Study 105 Phase III interim data this quarter, followed by our Study 103 Phase III top line interim data for non-small cell lung cancer early next year, which, assuming positive results, we expect to follow with NDA filings in China and the U.S. for CIN in the next 6 to 12 months and for non-small cell lung cancer in the next 12 to 18 months. We are very excited about opportunity for Plinabulin and our company, BeyondSpring. And we look forward to providing updates on our progress in the coming months.

Operator, we are now ready to begin the Q&A portion of our call.

(Operator Instructions) And our first question comes from Joe Pantginis with H.C. Wainwright.

3 questions, if you don't mind. First, with regard to 106, very nice to see the data. I was wondering if you could share any information regarding the other arms on the study. Obviously, there's relatively small amount of patients in each arm because you really are looking to ask a lot of questions here. So are you seeing any trends in the arms with the lower dosages of Neulasta?

Dr. Blayney, yes, please.

So thanks, good question. And so the answer is yes. The top line answer is yes. There seems to be a dose response in Neulasta, which is not a surprise given history of development of the G-CSFs. And in our study, particularly the lower doses were not -- by lower doses, I mean 1.5 and 3.0 milligrams fixed dose -- they were not as effective as the 6-milligram dose. So the answer to your question is that, yes, there seems to be a dose response in Neulasta. And this gives me personally confidence that our -- the Phase III data is likely to be confirmed by what we found in this smaller Phase II study.

That's helpful. Maybe a question for Richard. With regard to the upcoming CFDA filing, can you discuss what some of the -- what are keeping you guys busy right now other than waiting for the data? What are some of the rate-limiting steps , outstanding issues that could get you to the finish line?

Joe, it's good to talk you again, but I think it's probably best if Lan handles that question.

Yes, this is much towards the CFDA side. So for the CFDA filing, this is -- as you know, for last October, CFDA has a new rule saying that the efficacy [trend] to apply for conditional approval in life-threat (technical difficulty) [diseases] indication, so Plinabulin in the CIN indication does [fit] that criteria. And so with that, the data we plan to file for CFDA, the conditional approval, is the 105 Phase III data and also the 106 Phase II data. So as you see, so we just shared with you the 106 Phase II data, which is positive, the top line, right, for the first cycle on the efficacy. And then the 105 Phase III, we are going to share this quarter, right. So we have the data ready for that filing from a efficacy point of view. For the safety point of view, we have enrolled over 450 patients in Plinabulin arm, so that fully meets the over 300 cancer patient requirement for the safety database, so that already complete on the data. And thirdly, for the CMC, we have already made all the registration batches for the API [and drug] product, we're already finished writing the CMC. And so those are the 3 packages we will have for the CFDA filing, and we are on track for that.

That's great. And then just a quick reminder, if you don't mind. With regard to the upcoming 105 Phase III interim data, can you remind us -- and I'm sorry, I don't recall if you've disclosed this, any potential stopping rules around that should the data be compelling?

So probably we should let Ramon to answer this question.

Yes. The Phase III of Study 105 has built in an interim analysis which was previously disclosed at around 100 patient, means 50 patients in each arm. That would trigger the preplanned interim analysis, which is currently ongoing. The conditions around the preplanned interim analysis indeed would allow for early stopping the study if we meet primary endpoint.

And our next question comes from Jason McCarthy with Maxim Group.

So I'd like to hear a bit more about the potential benefits of the combination, especially in the context of a now biosimilar Neulasta market. Given the difference in mechanism and the additive effects, is Plinabulin likely to be used to augment Neulasta rather than having to compete in this increasingly competitive neutropenia space?

So Jason, that's a great question. So I think I'll take it, and then I'll turn it over to Dr. Blayney, who can give you a clinician's perspective. So as I mentioned earlier, we look at 4 million cycles that are utilized worldwide, and then we look at the results of this clinical trial. And we see this as an opportunity to improve patient care. So Plinabulin is given 30 minutes after a chemo cycle, so a patient can get it right away. And then the physician can decide based on their judgment whether or not they want to give Neulasta. And obviously, these data point to the fact that this combination would give the patient the best opportunity to avoid a chemo-induced neutropenia. And then we can talk about the other benefits as well, the immuno-oncology benefit or the immuno benefits as well, but we just focus on avoiding the neutropenia and completing the chemo cycle. The focus here is on completing the chemo cycle at the target dose and on time and giving the patient the best potential benefit of gaining the true benefit from the chemotherapy.

So we look at this -- and when we think about -- if we were to go head-to-head straight up versus a G-CSF, you'd be thinking about market share. We're not thinking that way. We're thinking patient share because we see this as a polypharmacy approach because that's what benefits the patients the most. You reduce the bone pain. You reduce the febrile or the neutropenia and you have an opportunity to truly improve care. So we're agnostic to the G-CSF use here. We think it's best for the patient. And so we see this as a potential opportunity to really layer on top of, really become foundation. We are used first and then they add a G-CSF after. I hope that's helpful.

(multiple speakers), Dr. Blayney.

Yes, this is Doug Blayney. I think that's a nice way to frame it. Jason, as you pointed out, the mechanisms of action of the 2 drugs seem to be quite different. I think of it as pegfilgrastim and Neulasta provides protection maybe in the first week after chemotherapy and Plinabulin in the second week after chemotherapy. So you have sort of this overlapping mechanism. And sure enough, that's what showed up in our Phase II data. Again, the decision -- I think it is going to be a marketing challenge because many docs will think just like you did, gee whiz, should I pick one or the other? I think the stance is that this is -- the combination has a lot of benefits, including the bone pain, the chemotherapy neutropenia protection and potentially the anticancer effect and adding them, again, is best for the patient. So in the market with the high febrile neutropenia risk, this additive will be the way to go, and this will build on what I think is the approach in the intermediate risk, that almost everybody will get Plinabulin or could benefit from Plinabulin. So in the physician's mind, gee whiz, this is something we use for almost all of our chemotherapy, whether it's intermediate or high risk. I think that's the way to think about Plinabulin and its role with pegfilgrastim or Neulasta.

All right. And then just as a follow-up. I'd like to know -- because you saw that reduction in bone pain, I'd like to know how exactly you interpret that. Is Plinabulin itself actually reducing the bone pain? Or is it a byproduct of the reduced dose of Neulasta?

So probably, I can start and then Ramon can add and then some comment by Dr. Blayney. So as you see, Jason, bone pain actually comes from the overshoot of neutrophil of the G-CSF, right? So G-CSF sometimes makes too much of the neutrophil, and then you have too much neutrophil overshoot, pushing out the bone, and then you have this bone pain. But Plinabulin is different. Actually, what we see from the Plinabulin profile is it does eliminate -- attenuates the neutrophil overshoot of G-CSF. So that basically gets to the less of the bone pain. So that's what I can start. Probably, Ramon, you can add to it.

Yes. What I can add to that is that the fact that Plinabulin prevents the bone pain is a clear indication that the mechanism of action resides in bone, because, otherwise, it would not give that benefit. So Plinabulin works through a different mechanism of action, and our initial data shows that that relates to a pathway that is important in the formation of neutrophils and that pathway relates to interleukin-6 in the bone marrow itself. So our hypothesis is that these 2 pathways together, they smoothen the process of the production of neutrophils. As Dr. Blayney pointed out in one of our discussions, it looks like the mechanism of Plinabulin is a stem cell protective mechanism rather than a stem cell activating or proliferating mechanism. And therefore, we believe that these 2 mechanisms together will prevent bone pain at bone marrow level.

Yes. This is Doug, if I can maybe amplify. Remember, that the bone in the human and mice, too, in the central part of the bone is where the bone marrow lives, that's where the stem cells are, and the pain receptors are on the surface of the bone. So anyway, when you give G-CSF 2 or 3 days later, you get this expansion of the center part of the bone. And patients tell me, doc, my skin is too small or something, my bones just ache from the inside. So I think Plinabulin is not acting on the pain receptors, but it's preventing -- is this rapid expansion of the bone marrow or the hematopoietic compartment of the bone. And that's the reason why we don't get this bone pain, not seen. And that rapid expansion and the pouring out of neutrophils is what happens about day 8 after the chemotherapy. So I think the protection, as Ramon pointed out, of the hematopoietic stem cell from the insult of chemotherapy is responsible for not only the low bone pain, but also this absence of pouring out of neutrophils day 7 or 8 that we see.

All right. That was actually very helpful. So then I'd just like as a last quick one, so when you look at the -- just the high dose combination versus Neulasta alone, does the reduction in duration of neutropenia widen compared to when you look to the sum of the combination data?

Yes. Perhaps, I can take that. Yes, it does. We have a dose-dependent widening -- a dose-dependent shortening, sorry, with the duration of severe neutropenia, means that we have a dose-dependent benefit on duration of severe neutropenia. Because this is a small trial, with relatively small sample sizes, DSN is an endpoint that is best measured in larger sample sizes. So we see the trend already in this data set, dose-dependent benefit on DSN, and with Phase III, the goal is to confirm that.

This is Doug. I'd just add that the curve -- as you look, we haven't plotted the curves, but it's -- in the previous study, 105, if you look at the neutrophil curve, it's broad at the nadir. It's not as deep with Plinabulin. It's broader, but the protection from the neutropenia comes over more days with Plinabulin, and it's a completely different kinetic or time recovery curve than you see with either pegfilgrastim alone or with Plinabulin alone. The combination seems to be the best of both of the curves. (multiple speakers) Hopefully, we'll show that later or when we have more data, as Ramon says.

Yes. So in summary, we see a dose-dependent benefit on the duration of neutropenia, which becomes shorter with the higher doses. But also we see that the depth, the nadir of the neutropenia also dose dependently is improved. So the data is consistent in terms of the duration, but also the intensity of the neutropenia with the benefit of the higher dose combination.

(Operator Instructions) And our next question comes from Matthew Cross with JonesTrading.

Congrats on the good mix of data here from both Study 105 and 106. I wanted to focus primarily on Study 106 results here. And I was hoping you could comment on your plans for a broad label for CIN. Obviously, you've established monotherapy benefit for Plinabulin that's noninferior to Neulasta in the docetaxel setting. But do you feel you need to establish this as well for TAC chemotherapy and in other chemotherapy modalities outside of taxanes and microtubule disruption to kind of test this protective effect on neutrophils and claim that broader label?

Well, probably I can start, and then, Ramon, you can add to this. So for the high-risk chemo indications, currently we are using the TAC; it is an example of the high-risk chemo. So I think with this showing good benefit but also with additional preclinical studies, we have shown Plinabulin in reducing the neutropenia of many different other chemotherapies which has different mechanism from docetaxel, such as gemcitabine, Irinotecan and then other agents. So we think with these 4 cluster of data, potentially we could get a broad label of the -- in the combo against the high-risk chemotherapy. So Ramon, probably you can add.

Yes. So as Lan pointed out, the development strategy is to test Plinabulin against a number of different chemotherapies, which each have a different chemotherapeutic mechanism of action. And the goal of that is to demonstrate that the benefit of Plinabulin for neutropenia is universal. So that's the way the program is set up. Those studies are ongoing, and we expect that we see the benefit throughout all the different studies, which will be the basis for approval for this broad indication.

Got it. Okay. No, that's very helpful and I appreciate that clarity. And just to confirm then, there is no reason to believe you'd need to test Plinabulin by itself in this more aggressive chemotherapy in order to kind of contrast the benefits that you're seeing of the combination versus Plinabulin alone and what the contribution is there?

The effect of Plinabulin can be demonstrated in different types of study designs. It's not always necessary to test that separately. It's typically an arm that we include in the overall design [bid]. What we convey in this call is that the overall development strategy of Plinabulin will be as a combination product in combination with a G-CSF. The data collectively suggests that each of these 2 drugs, they have a different mechanism of action. And each of these 2 drugs, they have efficacy against CIN, but they do it in a different way, through different mechanism and also in a different time point in the cycle. Plinabulin primarily is protective in the first week and G-CSF in the second week. And together, we believe we can offer protection throughout the entire cycle. The benefit of monotherapy Plinabulin has already been demonstrated. We will further continue to study that. However, from a product development perspective, our opinion is that we should go for a combination to therefore create a superior product.

Perfect. Okay. No, that makes perfect sense and I appreciate you clarifying that for me. And then last one was just looking at the efficacy data that's presented from 106. Can you kind of comment on the openness of both the Chinese and U.S. FDAs to the use of incidences of severe neutropenia rather than DSN as an approvable endpoint? I just wanted to clarify that the reduction in DSN you saw at this stage for the combo versus Neulasta alone was clearly an improvement and clinically meaningful compared to Neulasta monotherapy, but not statistically significant. Is that correct? And then I also wanted to ask what way the DSN was calculated in this study, as there's been a couple of different ways used.

Yes. Perhaps I can start. So DSN indeed was numerically improved, better combination, and the improvement was larger with a higher G-CSF dose. If you look at the 2 arms, Neulasta alone versus Neulasta plus Plinabulin, we see a clear reduction in DSN. Because the data is not in the public domain, I probably don't have a lot of liberty to give you the exact numbers. The data is not only clinically significantly improved with the given -- with the right sample size, we will also be able to show that it is a statistical improvement, if this data would hold in Phase III. The other -- all other neutropenia-related endpoints, they improve consistently in same direction. So therefore, we have a high confidence that we are looking at a true effect here.

And our next question comes from Graham Tanaka with Tanaka Capital Management.

Dr. Blayney, good to hear you again. And it was last winter we met and you mentioned that the medical community might be not reluctant, but slow to embrace new therapy. But based on the new data, do you believe now? It sounds like you believe that the community might actually be more willing to accept this theory -- this therapy as maybe mainline?

Yes, thanks, Graham. Appreciate your question. So the short answer is yes. I think that there's a lot of benefits to Plinabulin, this data, and also the anticancer data is going to show. So as we talked about earlier, this data are driving a strategy of gee whiz, if we're going to use intermediate risk chemotherapy, which is what we use a lot, why not -- and we're going to add Plinabulin for the neutropenia protection, we will know the -- us as docs will know how to use it. And then when we do use in the high-risk settings for palliative chemotherapy, in other words, not the dose-dense Adriamycin, Cytoxan and the dose-dense AC, but when we use it in other high-risk chemotherapy, gee whiz, let's -- we know how to use G-CSF, now we know how to use Plinabulin. We're comfortable with using Plinabulin. So I think this data that you're seeing now, as well as the -- what I hope is an anticancer effect will ease the acceptance path by physicians and other clinicians to accept Plinabulin. There will be a lot of benefits to using it much more broadly. I hope that's responsive. But again, yes.

Graham, it's Rich. Good to talk to you again. So I want to add to Dr. Blayney's comments. I think that when you probably spoke, the thinking was probably along the lines of displacing the market leader by going pretty much head-to-head. And if you're thinking about this in general terms, I'm not speaking about Plinabulin versus Neulasta. In my experience, just in general terms, if you're trying to displace a market leader, it's really difficult if you're going in, you have sort of some differentiation, right. This is probably -- of the 10 products that I've launched previous to this, this is probably the most differentiated product that I've seen. And having worked in diabetes, cardiovascular, GI and all that, those are really tough spaces.

The really interesting play here is that we're not trying to displace anybody. By adding on now -- if you look at the way the organization is moving and the way the therapeutics are moving, we're adding significant clinical benefit. Based on these data, we would be adding significant clinical benefit. And so we're not trying to displace anybody. The challenge becomes how to change habit. And we have a 100 -- a 360-degree program planned around professional, patient and payer. And prior to market -- prior to coming to market, we can do things around medical education. We have many awareness tools for the company around medical education, publications, abstracts, outcomes, patient surveys, et cetera, that we can make available, so that we begin to set the field, if you will.

And we're trying to make, along with our partners -- and when I say partners, I mean partners in general in the G-CSF space -- improve therapy. So the opportunity becomes, how do we work with the G-CSF players out there and the physicians to improve therapy for patients. So by adding Plinabulin in, and Plinabulin is the base now because we're first, we really are creating a better opportunity. And I think there's going to be less resistance to that because you're not going head-to-head and trying to displace somebody. You're really trying to improve patient care.

That's very encouraging. Now, from a clinical point of view and a patient point of view, what -- this appears to be much better in side effect profile and patients will be less likely to go off their chemo. What expansion of the potential total market do you see now if the community and the patient population embraces this as a better bone pain free, et cetera, solution, so that more people beyond chemo, and therefore, the market might actually be better? Could you mention numbers?

Sure. So let me take that and then I think Dr. Blayney can give you his clinical perspective. So we mentioned there are 4 million cycles worldwide, so let me give you a little perspective. There's 4 million cycles that out there that are going on, and 60% of them are in the 2 major markets. We talked about the U.S. and China. Globally, 14 million patients were diagnosed roughly 2016, 2017 with cancer. 14 million patients diagnosed. 4 million of those patients received chemotherapy. Now these numbers are really tough to get, so it's taken us quite a bit of time to get these numbers. So 4 million patients received chemotherapy. So if you think, on average, patient is on about 3, 4 cycles, so about 25% of patients are, roughly, I'm just saying roughly, are getting a G-CSF for the neutropenia. We talked before about patients are getting delayed cycles and all that or they're dropping off. So about 20 -- what's that?

I'm just saying correct, yes.

So about 25% of patients experience a delay of 7 days or more because of neutropenia and about 35% of patients have their dose reduced. And that's not including what Dr. Blayney talked about. He talked about docetaxel. 100% of patients get their dose reduced, right. He said the dose that the company tested was 100 milligrams per meter squared, and their starting dose in the clinic is 75. But if you talk about in general, 35% of patients get their dose reduced by 15% or more. So that's a very complex world we're looking at. So some patients are getting stopped.

So we think that there's an opportunity to grow this market. And I think that's one the misnomers or misunderstandings about this market. People see this as a sleepy market. That's why I said in my comments, this is one of the overlooked areas of improving chemotherapy. Treating neutropenia is interesting, but that's not the goal. The goal is to improve chemotherapy and the outcomes for chemotherapy and to get a patient the best care possible. And so we really believe that this is a potential growth market. And if we're not duking it out with the G-CSFs and we're working to improve patient care, we can layer on top of it and now the CIN market becomes a growth opportunity. And we think that there's a lot of opportunity here. 4 million patients on chemotherapy and only 25% of them are receiving a G-CSF right now. If we can improve the side effect profile and reduce neutropenia, it becomes easier for a clinician to use the product together. Dr. Blayney?

Yes. I think that's well said. I think I'd draw the analogy too that 5-HD3, the antiemetics that were developed 20, 30 years ago. At that time also we had patients abandoning or stopping chemotherapy because of nausea. Doc, I can't take this anymore. I have been throwing up for 3 days. When the 5-HD3s came along, a remarkable change, much safer to administer chemotherapy, much better adherence. So the 5-HD3s -- dolasetron, granisetron, et cetera, and now palonosetron -- are used ubiquitously in -- as antinausea agents. So we don't have nausea and vomiting as a side effect of chemotherapy. Hardly ever anymore do we have to stop it, stop chemotherapy because of nausea and vomiting. I see Plinabulin as a analogous compound in neutropenia and dose reduction and dose delay, et cetera, as we talked about earlier. So the 5-HD3 is the analogy that I think you look at to really expand our ability to deliver chemotherapy because of -- because it's did away with a major side effect.

This is Ramon. If I can add one point to that. So this add-on strategy of Plinabulin in addition to G-CSF is also consistent with medical practice because Plinabulin is given on the same day of the chemo, 30 minutes after the chemo, and the Plinabulin infusion lasts about 30 minutes. So also from how to incorporate this strategy into the clinical practice, this is very doable.

Ladies and gentlemen, that now concludes the Q&A portion of our call. I would now like to return the call back over to Lan Huang for closing remarks.

Thank you all for joining us for today's operational and clinical update call, with a special thank you to Dr. Blayney for his participation today, as well as for his leadership in our clinical development program for CIN. BeyondSpring has the potential to change the face of CIN and cancer treatment, and I couldn't be more proud of our achievements to-date. Today, we are on the cusp of seeing the fruits of our hard work with multiple critical readouts over the next few months, which, if positive, will enable near-term NDA submissions with hopefully commercial launches not long thereafter, all tremendous achievements as we begin to transition toward a global, commercial stage biopharmaceutical company. Thank you.

Ladies and gentlemen, thank you for attending today's conference. This does conclude the program, and you may all disconnect. Everyone, have a great day.

Thanks, all.