Good morning, and welcome everyone to the BeyondSpring R and D Day. At this time, all attendees are in a listen only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q and A text box at the bottom of the webcast player or by emailing your questions to questions. Lifesciadvisors.com.
As a reminder, this call is being recorded and a replay will be made available on the BeyondSpring website following the conclusion of the event. Before we begin, I would like to remind you of the company's forward looking statements found here and in their filings with the SEC. 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 the view of the currently available information, you are cautioned not to place undue resilience 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 20 F and other filings with the SEC, which are available on the Investors section of BeyondSpring's website.
Today's presentation will begin first with an introduction from Doctor. Lan Huang, BeyondSpring Co Founder, Chairman and Chief Executive Officer Doctor. Ramon Mahanlal, Executive Vice President, Research Development, will follow with an overview of the company's development program. We will then turn the call over to our esteemed key opinion leaders, Doctor. Steven Lin and Doctor.
Trevor Feinstein. After the presentation and company remarks, we will open the call for a question and answer session. It is now my pleasure to turn the call over to Doctor. Lan Huang, Co Founder, Chairman and Chief Executive Officer of BeyondSpring. Lan, please go ahead.
Thank you. Thank you, everyone, for joining our R and D day, etcetera, early morning and thank you for your continued support. We are very honored and privileged to have 2 of the leading experts to come with us and discuss Plinabulin clinical development with you. And first, Doctor. Lin, who is a very well respected radiation oncologist from MD Anderson, He has been working on Plinabulin's immune mechanism for the last almost 4 years and also as a PI for the IIO combo in 7 different cancers, which has started at MD Anderson.
So in addition, Doctor. Feinstein has been with us for the last 5 years in the Dublin 3 study as a PI for the study, and he is a Board Certified Medical Oncologist from Piedmont Cancer Center. So thank you, Doctor. Lin and Feinstein for joining us. And next slide please.
BeyondSpring is committed to raising the standard care for cancer patients with 1st in class treatment that improves lives and clinical outcomes for millions of patients in life. And we have a very robust pipeline with lead asset Plinabulin currently in 2 near term NDAs and also 3 preclinical IO agents. We also have a targeted protein degradation, molecular glue discovery platform, which was recently validated with a recent $800,000,000 R and D collaboration with Eli Lilly, and that's in our subsidiary, Seed Therapeutics. Next slide, please. So we are developing pemplevalent as a pipeline in the drug.
As you have already seen, CIN has been proven in 6 clinical trials in over 1200 patients, and we just received priority review from US FDA with a FADUFA date November 30, 2021. And this indication also received ReXtrual designation last fall. In addition, Plinabulin has potent immune anticancer activities. So we are expanding Plinabulin into other anticancer indications, including the Dublin Street study in non small cell lung cancer and also in a few different cancers in IIII combo, which will be transforming opportunity for Plinabulin and potentially making Plinabulin cornerstone therapy in the IO treatment landscape for cancer. Next slide.
So now let me give you the journey of Plinabulin, which we are developing as a pipeline drug. Plinabulin is a 1st in class selective immunomodulating microtubule binding agent. We call it SYNBAP. Next slide. And we have been developing Plinabulin from the treatment of chemosurfing II side effects to the direct anticancer therapeutic effect.
So let me give you a brief overview where we are in the CIM prevention indication. Next slide, please. Chemotherapy kills fast dividing cells, including neutrophil in the bone marrow. So therefore, CIN is a problem for bone marrow, independent of chemotherapy type or cancer type. We believe that the data and the mode action of Plinabulin support the broad use of Plinabulin for protection against CIN in week 1 when G CSF are not effective.
We call the week 1 as the neutropenia vulnerability gap. G CSF approved for the broad label is effective in week 2 and it provides the base protection for CIN for the combination regime. So as such, our proposed label for the Plinabulin GCSE combination is for all solid tumor and all chemo for prevention of CIN. Next slide please. Here is a detailed description of the favorable benefit risk profile of Plinabulin and G CSF combination, which elevates standard care in CIM prevention in 30 years.
In short, compared to TCS alone, Plinabulin and TCSF combination has improved efficacy in AAC based endpoint and in clinically meaningful endpoints such as reduction of incidence and severity of febrile neutropenia and hospitalization and very importantly, also with improved safety, including reduction in bone pain. Next slide. So as such, we have filed NDA for the CI indication using 6 clinical studies in over 1200 patients. And we are very honored and also grateful to FDA's support to give us prior to review and the PDUFA date is end of November. Next slide, please.
So as you see that Plinabulin anti CSL combination is elevating standard care in the last 30 years, and we have very targeted approach to marketing. And as you see, the current U. S. Is very focused in 360 multi centers accounts to 81% of GCS use and just 150 sites on the networks actually accounts for $2,100,000,000 of GCS sales. And also just in 4 cancers, that accounts to 79% of the GCS abuse.
So our go to market strategy is very targeted. We let disease awareness to be the champion, so really educating the market on neutropenia vulnerability gap and positioning Plinabulin in the right manner and also with a very targeted market access program. So with that said, I'm going to turn the baton to Ramon. Next slide, please. So Ramon is our Head of R and D and he really has been developing Plinabulin as his brainchild for the last 5 years.
So let him take you through our strategies and all the thinking behind developing Plinabulin as a pipeline in the drug. Raymond?
Thank you, Lan. As we are continuing to work with both the U. S. FDA and the China FDA in getting the CIN application approved. We will increasingly now also direct our attention to the anticancer development program of Plinabulin.
This here is an overview of our plans how to develop Plinabulin as a triple IO combination. So as a start, a brief summary about Plinabulin. Plinabulin is a small molecule. It is a simple manufacturing process, 3 step synthesis. Plinabulin is given by IV infusion on the same day of chemotherapy.
Regarding the mechanism of action, Plinabulin acts primarily through immune enhancement for the anticancer application. I will show you in the next slide more detail about how Plinabulin helps to activate and maturate the dendritic cell. In addition to being an immune enhancing agent, Plinabulin also has direct anticancer activity in a number of cancers, which you see listed here. On the top, you see small cell lung cancer, and that is the reason why we initiated the triple combination with nivolumab and ipilimumab in small cell lung cancer. In the box on the right at the top, you can see that Plinabulin currently through all clinical trials has been exposed to more than 700 patients and is demonstrating a favorable safety and tolerability profile.
Next slide, please. Regarding the mechanism of action, on the left at the top, you can see in that box Plinabulin, which essentially binds to Tubulin. Tubulin is depicted by those blue lines, the light and the dark blue lines. And upon binding to tubulin, Plinabulin releases a signaling protein called GEFH1 depicted in orange in that orange oval. GEFH1 next triggers an intracellular cascade of signaling through the Rho pathway and the Gnk pathway.
An important target cell for Plinabulin for its activity is a dendritic cell, which is depicted at the bottom in the middle as a purple star type of cell. So that is a dendritic cell and that is where Plinabulin primarily acts. It maturates and activates dendritic cells, which, as you will be aware, are critical to present tumor antigen to T cells. The T cells are depicted as that orange cell at the bottom. Upon activation of the T cell, they are then next primed and enabled to target and kill cancer cells, which you can see at the left.
On the right, what we show is a mechanism of action for the prevention of chemo induced neutropenia. Essentially, what Plinabulin does is it protects bone marrow progenitor stem cells against the insult of chemotherapy of myelospecific chemotherapy. And by doing that, it preserves bone marrow stem cells so that they can produce neutrophils. You will be aware that Plunabulin has a very fast onset mechanism of action for CIM protection, and this is the basis of that protection. And that's why Plunavulin is a very good addition to G CSF, which, as we know, has a late onset of mechanism of action.
Next slide, please. The immune mechanism, as you will be aware, is a cascade of events. It is not a single step process, but a cascade. On the far right, depicted as the number 3, you see the step with checkpoint inhibitors. And checkpoint inhibitors, in fact, optimize T cell responses after they are primed and activated.
With the immune response, it always starts with step number 1 at the bottom, which is the generation of antigens, which are also called immunogens, if they are capable to stimulate the immune system. It always starts there in immunology, the generation of antigens. Antigens can be generated in many ways through radiation therapy, through chemotherapy. I mentioned there are occasions that Plunabulin also has a direct anti cancer effect. Then of course, there are tumors that naturally have a high level of immunogens such as melanoma and renal cell carcinoma, But it always starts here.
Generation of antigens that then need to be presented to the T cells in order to make the T cells active against these antigens. The presentation of these antigens to the T cells occurs in step number 2 on the left. And that is principally where Plinabulin acts. Antigen presentation is done by deadweight cells, which are sometimes also called antigen presenting cells, APCs. And Plinabulin enables dendritic cells to effectively present the tumor antigens to the T cells in order to get T cell specific activation against those antigens.
Based on this cascade, it is clear to us that steps number 1, 23 are very critical components to obtain an optimal immune oncology response. And this has become the basis for our development strategy in immunotherapy because we mimic with our immunotherapy strategies exactly these three steps: number 1, antigen presentation number 2, presenting these antigens through dendritic cells to the T cells endometri optimization of T cell responses. Next slide, please. So with cancers, we know that we have what we call hot tumors on the right, which essentially are cancers that intrinsically harbor a large number of mutations and therefore have a higher probability to have antigens and immunogens that are capable to stimulate the immune system. Generally, we call that hot tumors because they are able to stimulate the immune system.
On the left, you can see that in that box in that much larger box, these are tumors that we call cold tumors because naturally they do not express antigens or immunogens to the extent that they can effectively activate the immune system. You can see this is a much bigger box than the box on the right. And in our opinion, this is where the future lies with IO therapy strategies that we must make an inroad and also access these cold tumors with IO therapy. And therefore, they will also become a candidate for the classical checkpoint inhibitors, PD-one inhibitors and CTLA-four inhibitors. You can see at the bottom the notion that here at BeyondSpring, we have started to work on this exciting field that we believe will be an important next wave in the overall IO strategy.
Next slide, please. So in the next few slides, I will focus a little more on the hot tumor development strategies that we are currently employing because they are already clinical stage. Here, again, to summarize what I just said, our tumors essentially are immunoresponsive. They harbor intrinsically immunogens and antigens and are currently candidate for checkpoint inhibitors. The cold tumors at the bottom are not immune responsive or not very immune responsive, and they happen to be the majority of human cancers and currently not candidate for classical PD-one, PD L1 and CTLA-four inhibitors.
And therefore, an important aim has to be to convert these cold cancers into hot cancers so that therefore they will become candidates for immunotherapy. Next slide, please. So as I mentioned, our hot tumor development strategy is clearly the stage and that is why I will focus a little more on this program.
I mentioned that
the core foundation of our approach is a triple IO combo that is comprised of those three elements: something that generates antigens flunabulin that helps dendritic cells to present the antigens to the T cells to activate the T cells and something that optimizes T cell responses. This is the principle that we are employing, the triple therapy principle that we are employing in a number of different scenarios because different pharma companies, they have different approaches in their checkpoint inhibition strategy. On the top, you see the combination of Plinabulin radiotherapy plus PD-onePD L1 inhibitor. Doctor. Stephen Lynn will talk in more detail about this combination.
This combination is employed by certain pharmaceutical companies. And of course, this is something that we will strongly develop further. Doctor. Stephen Linn will also point out that we have proof of concept of this triple that I described, something that generates antigen, then generates cell mediated presentation to T cell and optimizing T cell responses, we have a proof of principle that if we have these 3 components in the mix, we have the best possible immune responses better than other combinations with PD-one inhibitors. I'll save that for Steven then.
Number 2 is the combination Plinabulin with chemotherapy, which is employed by Burke and other companies and checkpoint inhibitors PD-1s. So we have a number of studies here also that we are currently preparing, and we will announce that very shortly. At the bottom, you see yet another type of triple combination that is being employed here specifically by BMS, who likes the concept of chemo free IO strategies with PD-one inhibitor and CTLA-four inhibitor. And here we add Plinabulin to the mix. So Plinabulin here has a dual role.
Not only is it capable in this select number of cancers that you see listed here to be the drug that generates the antigen, but it is also the same drug that helps the dendritic cells to activate to be activated and present these antigens to the T cell repertoire. This trial now has finished Phase 1, was recently presented at ASCO, and we will present some of that data here for you. This trial now has progressed into Phase II. Next slide, please. So where do we see Plinabulin positioned moving ahead and looking forward, looking actually many, many steps forward.
The way we view Plinabulin is that it is the perfect candidate for us to become a universal add on to any kind of cancer therapy. Plunabulin is very unique that not only does it have anticancer properties activity, it helps the dendritic cells to present antigens better and make checkpoint inhibitors work better. Plinabulin, as we know, is also an agent that prevents chemo induced neutropenia. So if it's added on to a chemotherapy backbone, it will not only help the chemotherapy to work more effective because the antigens generated by the chemotherapy will be presented in a more effective manner to our innate and adaptive immune system. But it also will prevent the chemo therapy induced neutropenia that comes from that chemotherapy.
If the backbone is immunotherapy and we add Plinabulin to that, what we expect is that Plinabulin will not only enhance the anticancer activity, but also, as I will show you in the next few slides, help to prevent the classical side effects with immunotherapy, which are immune related AEs. So the solphenavulin being an anti cancer agent, the agent that helps dendritic cells and also an agent that prevents chemo induced neutropenia and immune related AEs, we see that as a perfect add on to any given backbone moving forward. And with that profile, it is hard to imagine why we shouldn't add Plinabulin to any given cancer regimen. Next slide, please. So with immune related AEs, we are aware that these are the most commonly occurring adverse events with immuno oncology.
What CIN is for chemotherapy, the equivalent for IO immunotherapy is immune related AEs. AEs. Immune related AEs, when they happen to be Grade 3 or 4, they lead to permanent discontinuation of immuno oncology treatment. With nivolumab and ipilimumab, that is around 40% in the case of small cell lung cancer and other cancer types, which means that 40% of patients will be taken off this treatment forever. If there is a tool, if there is a way that we could prevent this immune related ATs, that will be a tremendous advancement in the field of immunotherapy.
And we have initial evidence that Plinabulin is able to prevent immune related ADs due to the inhibition of an inflammatory pathway called PDE4 inhibitor. Next slide, please. In terms of development strategy in Evian Spring, we typically avoid doing large head to head comparison trial because typically they require large sample sizes. And the signal to noise ratio typically is not that favorable. Instead, we prefer to have an approach that you see at the bottom, where the patient serves as their own control in a concept that is called reversal of resistance of PD-onePD L1 therapy.
A number of patients who receive PD-onePD L1 therapy, they become resistant over time. And an important objective for us, therefore, is to convert that and to make the patient again responsive to these checkpoint inhibitors. So this is an important strategy that we are employing also in the trial of Doctor. Stephen Lynn and the small cell lung cancer trial. These are typically small trials because the patient serves as their own control.
The next slide, please. These are the current studies that we are conducting, and Doctor. Trevor Feinstein will talk about Dublin III. I will talk a little more about the Big 10 study. Doctor.
Stephen Glynn will talk about the Anderson and the Anderson triple combination. And we have an additional number of studies in preparation. Next slide, please. Next slide, please. So regarding the BIG10 study, Doctor.
Jyoti Malhotra was not able to attend this meeting. And therefore, I will send the data to you. This poster was presented to at ASCO several weeks ago, as you will be aware. Next slide, please. On the top, you can see that with this small cell lung cancer trial, the Phase I has been completed.
And now we have advanced the trial, you can see that in that middle row, into Phase II. At the bottom, we also have employed another triple combo, and that is a combo that Doctor. Stephen Lynn will talk about. Next slide, please. So briefly about the design of this trial.
This was a Phase 1 trial. And of course, because this was the first time we put these agents together, Plinabulin, nivolumab, epilimumab, the objective therefore always has to be safety first, which was the primary objective, to determine the safe dose to go into Phase 2, which we determined to be the 30 milligram per square meter dose, which is exactly the same dose that we are using in the anticancer trial, Doblin III. Secondary endpoints included efficacy measures, ORR, PFS. But also a predefined secondary endpoint was the frequency of immune related AEs. Next slide, please.
So this is a summary of the efficacy analysis that has been shared with you. The waterfall plot you can see on the right, the orange bars, those are PD-onePD L1 resistant patients who received the triple combination of Plinabulin, vivolumab, evilimumab. And the blue bars are the PD-onePD L1 naive patients who then next receive this triple combination. And you can see that although this is a small Phase I trial that we have highly promising overall profile of efficacy, which is summarized in the table at the top, where in the middle you can see the summary for the PD-onePD L1 therapy naive patients. And there we observed a response rate of around 50%.
In the patients who became PD-onePD L1 resistant, and that's the column on the right, who were resistant. And what that means is that they started to have the ceased progression under checkpoint inhibition. When we gave Plinabulin, vivolumab and ipilimumab, we flipped that. We made them back responsive to immunotherapy in 43% of cases. Next slide, please.
So this is in brief summary. Efficiency summary on the right in green, the combination Plinabulin, nivolumab, ipilimumab, the numbers are close to 50% in terms of response rates. Nivolumab and epilimumab, you will be aware it has been withdrawn from the market because the pivotal Phase III trial didn't meet its primary endpoint for efficacy. But you can see that here, if we add Plinabulin to that same nivo and ipi combination, we more than doubled response rates. At the bottom, you see the immune related AE summary.
Typically, it's around 37% of subjects of patients who have Grade 3 and 4 immune related AEs at the left in blue. And here in this trial, with aducanabulin to divolumab and ipilimumab, we had 12.5% of patients with Grade 3four immune related AEs. This is early data. We hope to confirm this data in Phase II. Next slide, please.
So in short, I showed you the data about the triple. And on the right, you can see with conclusions that with adenclinabulin to immune therapy, we can re synthesize the immune system. We can help to increase antigen presentation to enable more effective T cell activation. But also, we have cases here with very long treatment response, 18 months and longer, by adding Plinabulin to divolumab. At the bottom, you can see that where we start here is with small cell lung cancer.
But it is our belief that if it works here, it will work in many other cancer types That is listed at the very bottom, where fermabulin has demonstrated to also have direct anti cancer activity. Next slide, please. So that concludes my presentation, and I would like to invite Doctor. Stephen Lynn to give his presentation. Thank you.
Thank you, Ramon. Next slide, please. So it gives me a great pleasure to introduce this basket early phase study here at MD Anderson that was activated recently. For the interest of time, I'll be quite brief in the preclinical rationale as well as the summary of the clinical trial. The PI is Vivek Subhaya, who is actually an associate professor in investigating therapeutics and I'm from radiation oncology.
Next slide. So the reason for this and the scientific rationale for this trial is that there is a significant interplay of cytotoxic agents with the dendritic cell maturation. So in this case, we were specifically focused on radiation therapy. And radiation is well known to actually not only stimulate the pro inflammatory cytokines within the tumor microenvironment, but also on the tumor cells, it can release tumor antigens as well as actually damage associated molecular patterns that can activate dendritic cells and in combination with blockers like anti PD-onePD L1 agents can actually also reverse the immunosuppression within target tumor microenvironment and synergize with dendritic cell maturation in order to enhance systemic immune responses. And of course, we are interested in Plinabulin because Plinabulin is a dendritic cell maturation agent that can play a role and also synergize with radiation and other cytotoxic agents.
Next slide. But the key question is actually, is there a role for the sequencing of radiation or cytotoxic agents with the Plinabulin for AMR effect. So is it necessary for pre activating dendritic cells with Plinabulin to enhance RT response or is RT priming in terms of doing conducting radiation prior to stimulation and activating with Plinabulin needed to actually enhance the response. Next, to answer this question, we Next slide please. To answer this question, we did conduct experiments to actually to examine the sequencing, the optimal sequencing with Plinabulin to elicit dendritic cell activation.
So either pre treating these cells with Plinabulin and followed by radiation or to actually add radiation for several time points prior to Plinabulin treatment. And what we found is that it's really the pretreatment of radiation, actually adding radiation to prime the system before dendritic cell activation. This is where we see the optimal dendritic cell activation. It's particularly within this window of 3 to 6 hours before Plinabulin treatment would be optimal to stimulate dendritic cell maturation and activation. Next slide.
We also found that in vitro that this type of sequencing also enhances T cell proliferation in a mixed lymphocyte reaction that you don't see particularly with either radiation alone or Plinabulin treatment alone. Next slide. But besides actually dendritic activation, which is actually based on we use the marker CD1886, There are other co stimulatory as well as actually inhibitory molecules that are also stimulated upon denture cell activation. So we examined a number of these other molecules as well with penadolene treatment. Next slide.
So in addition to what's expected of course is the CD40 and other MHC class molecules that's associated with intercell activation. We also found actually PD L1 is also co activated and post stimulated with financinib treatment. And radiation does also somewhat enhances and increases PD L1 expression, but actually the greatest stimulation is also from plinabulin itself. Next slide. This is actually so the previous slide was actually on mouse dendritic cells.
We actually went on to validate this in human derived PBMCs and these are differentiated cells in vitro from peripheral blood mononuclear cells. And what we found is that pinabulin also with dose dependent manner also stimulated not only dendritic cell maturation, which we see here from between 1 10 micromolar per annumabular. Next slide. But we also saw that with the same concentration, PD L1 is also stimulated with this type of with these in vitro stimulated and differentiated dendritic cells. Next slide.
This is important because it's actually well known that the induced PD L1 activation on dendritic cells, not only by cytotoxic agents, but in this case, but possibly by pinnadren may necessitate the need of a concomitant anti PD-onePD L1 blockade. So this is actually this type of research was recently discovered in a couple of high impact journal articles demonstrating that the PD L1 expression on dendritic cells is really important and they play a key role as a regulator of T cell immunity in cancer. So and therefore, the rationale for the triple combination concept, which is adding an IO, anti P1P1P1 agent along with agents like radiation along with phenyabulin to optimize the immune stimulation effect. Next slide. So we tested this in the lab in vivo in animals in a syngeneight tumor model and what we found that in comparison to single agent or double agents with either anti PD-one with radiation or plenabulinumablation, you see some local tumor response.
However, you don't do not see as great a systemic immune response. However, it's only in the triple combination approach that you see the effective systemic response, not only an excellent local tumor response, but also a systemic immune response. Next slide. This is further actually replicated in other experiments and this again shows that the antitumor response, the local tumor response is significantly enhanced with a triple combination approach. And also even an untreated, uneradiated tumor, what we call the scopal tumor, contralateral to the side that's irradiated, you see actually a kind of an induced anti tumor response only in the triple combination approach.
Next slide. What we found is actually when we dissociated and did single cell analysis of the inter tumor cells, only in the triple combination do we see an enhanced T cell infiltration and immune stimulation in the triple combination approach that is not seen with double agent or single agents. Next slide. So this is the working hypothesis for this clinical trial is that the RT priming followed by Plinabulin as well as concomitant anti PD-onePD L1 agents will have a synergistic effect of stimulating immune response to what we call the combination concept. Next slide.
So this is a Phase 1btwotwo study to evaluate the safety or adding Plinabulin with RT and IO agents in IO progressing solid tumors. The primary objective for this Phase 1 study in the Basket trial is to assess the safety and tolerability of combining Plinabulin with our radiation in IO and as well as to assess the overall response rate. There's also secondary objectives to look at disease control to determine the progression free survival time as well as overall survival. There's a number of exploratory objectives that we incorporate into the study, which I will go over in the next few slides. Next slide.
We are targeting 7 cancer types and these are all and what's special about these 7 cancer types is that these are all cancer types that currently have as a first line status, a first line indication to incorporating IO agent either in as a single agent or in combination with systemic chemotherapy. Next slide. So this is a trial schema. Up to 5 lesions will be treated with radiation. However, what's important is that there is at least 1 or more lesions that would not be targeted by radiation where we will use to assess the overall response rate.
Plinabulinum will be added of course after radiation and this will be optimized based on our preclinical data will be administered 3 to 6 hours after completing the days of radiation. Therapy, anti PD-one agents or PD L1 agent will be administered at the same time. There will be an option to administer radiation again at the next cycle of Plinabulin with anti PD-onePD L1 agents, as well as subsequent cycles until progression or toxicity. Next slide. So here are the inclusion criteria, the 7 histologic and cytologically confirmed neoplasms that progressed on previous immunotherapies, now anti PD-one PD L1, but also anti CTLA-four agents.
Like I said, at least one lesion will be amenable for radiation and as well as at least 1 additional non continuous lesions will be amenable for radiographic evaluation. And then we also collect tissues to conduct translational studies. Next slide. We will administer 3 to 5 fractions of radiation along with the combination of Plinabulin with IO agents. And then as I alluded to the schema, this will continue with Plinabulin in PD-one and PD L1 in subsequent cycles.
And there will be an optional of sequential RT for other untreated lesions as well. Next slide. We will start with a starting dose of 30 milligrams per meter square per the other studies that's actually that the BeyondSpring has conducted in other cancer patients. And then the Phenabulin again will be dosed 3 to 6 hours after radiation therapy. Next slide.
I won't go into detail. However, this is based on a novel statistical design using Bayesian optimal interval design to re identify the NTD for all comers. Next slide. The Phase 2 will be conducted after completing the Phase 1 in the STASKA trial 7 tumors. And based on the response rate, we will expand that cohort to an additional possibly 102 patients that we randomized per the control arm, which is the anti PD-onePD L1 with radiation versus a triple combination approach.
Next slide. We'll conduct a number of translational study, including intratumoral TCR sequencing, single cell RNA sequencing, as well as a number of objectives and translational endpoints looking at the whole blood samples to look at now immune profile and TCR sequencing, the dreidel activation, Luminex cytotoxic cytokine assay as well as ctDNA analysis. Next slide. So this is my last slide. The trough stat, we just activated a couple of months ago.
We have conducted we have now consented 5 patients, 4 noncellus lung cancer patients, 1 renal cell carcinoma and 2 patients have already received the 1st cycle of triple combination therapy without any adverse events. So we're very happy for the activation of this study and we're very optimistic to proceed forward to see exciting results in the future. Hopefully, we report in a subsequent meeting. Thank you very much for your attention. And actually at this time, next slide, I'll be happy to introduce Doctor.
Trevor Feinstein, who will introduce to us the Dublin's 3 results. Thank you.
Hello, I'm Trevor Feinstein with Piedmont Cancer Institute and I want to present some of the clinical data of Plinabulin in non small lung cancer. Next slide. So as a medical oncologist, when I see patients with advanced non small cell lung cancer, we need to look at the histology, we assess for driver mutation and then we assess PD L1 status. Simply when we look at we differentiate between squamous and non squamous histology. This talk is going to be focused on patients without driver mutations, but a patient with high PDL expression, we tend to treat with a checkpoint inhibitor, although some will use a combination of chemotherapy with a checkpoint inhibitor or an IO therapy with nivolumab and nivolutumab.
Lower expression of PDL tends to enroll a backbone of chemotherapy plus a checkpoint
inhibitor
with the chemotherapy being the different platinum based in the adenocarcinomas, we tend to use pemetrexate for first line and squamous, we tend to use ataxine. Next slide. So when we look at non small cell lung cancer, excitingly, we see a decline in mortality and this is probably from reduced incidence of lung cancer from decreased tobacco and we've seen that some of our novel treatments are extending survival. Unfortunately, lung cancer remains a leading cause of cancer related death. Most of this is because most patients present with very advanced state and about a quarter of patients who present with advanced non small cell lung cancer do not receive treatment.
And older data seems to suggest only about a third percent of patients will receive second line treatment. Although I do feel that with more modern treatments, more patients will receive treatment and more patients will be receiving second line treatment. Let's advance. So as a medical oncologist where we're stuck at is after our patients have exhausted platinum based therapy and immuno therapy, we're left with some challenging options into where to treat next. In non squamous approved drugs are pemetrexate or docetaxel or docetaxel plus remissiramab.
Most patients have received pemetrexate kind of first line with the platinum based treatment. Treatment. So at least mostly docetaxel based treatments. And our squamous cell histology, it's mostly docetaxel. Next slide.
So docetaxel is approved as standard care based off of trials in the 1990s. The trial that led to approval was a prospective trial, which was patients with a randomized the most viewed best supportive care or docetaxel. Patients were excluded from going on this trial if you had a part of taxane. And at that time, we were trying to figure out the right dose of docetaxel. Half the patients randomized to docetaxel had a very high dose at 100 milligrams per meter squared and the other half had 75 milligrams per meter squared.
In the trial, only 6 patients, about 7% had a partial response and they were split evenly between the two doses of docetaxel. Comment on the timing of progression that led to approval versus best supportive care was 6.7 months increased to 6.7 weeks to 10.6 weeks. So you're talking about a less than a 1 month PFS benefit. When you look at median overall survival, it went from 4.6 to 7 months. And what was noted is that the docetaxel at 100 mgmt2 was too toxic and this is panned out in other disease types too.
Next slide. More recently, I was looking at ramsirmab, which is a monoclonal antibody against VEGF2. And this large trial looked at over 1200 patients and patients here were randomized and this is after failure of like platinum, but there was not immunotherapy given in this trial. Patients were randomized to docetaxel alone at 75 milligrams per meter squared or dose that was plus placebo or docetaxel plus revisirimab. And here you did see a survival benefit increasing from 9 months to 10.5 months with the combination and you saw a slight benefit of progression free survival from 3 to 4.5 months.
However, with aramitirumab, there was significant increase in toxicity, there was increased bleeding, hypertension, there was increased intestinal perforation, arterial thrombus and most medical oncologists do not use this combination therapy maybe in an exceptional patient with a high performance status. Next slide. So here's a heat map if you're not familiar with looking at the warmer the color, the greater the benefit is compared in the cooler the color, the less benefit. Here what you see is that despite spending 20 years of trying different combinations, nothing has really shown to be any better in afterpartan filler than docetaxel. Next slide.
So here we are now in the 21st century and we're still treating after platinum failures still with docetaxel. We've not made any improvement and when we're talking about 2nd or third line treatment as medical oncologists and as patients alike, we want to increase their survival. We want to find a drug that's safe and most importantly improve their quality of life as we see that most of these patients don't usually have a long life expectancy. Next slide. So I just want to highlight Study 101, which is just looking at penabnorm, that time it's called MPI-two thousand three hundred and fifty eight.
And there was some patients with advanced non small cell lung cancer who have progressed in one prior line of therapy or 2 prior lines of therapy. Patients did not have to have measurable disease to go on the study and had to have an econ performance status of 1 or better. Patients were randomized to docetaxel or docetaxel plus pinapple. In the study, there was 2 different dosing of pinapplein at 20 milligrams or 30 milligrams per meter squared given on days 1 and 8. Dositax was given standard of care at 75 milligrams per meter squared every 21 days.
Next slide. And the study of the primary was to compare overall survival to see if Plinabulin had a benefit in survival. Secondary endpoints were looking at duration of response, progression free survival, overall response. And at that time, the PDL expression was not analyzed. Next slide.
So what we had noticed is that the 30 milligram dose of pinapline was more effective than the 20 milligram as an anticancer agent and post talk analysis in patients who have measurable disease, which turned out to be about a little bit more than 70% of the patients. And you looked at them with measurable lung diseases, I'm sorry. The response data is presented below in the table. So when you look at pnablon plus docetaxel, the median overall survival was over 11 months compared to docetaxel alone of 6.7 months. Slight benefit progression for survival, but what you do see here is a significant improvement in overall or you see an improvement in overall response from 10 percent to 18.4%, which compared back to the old docetaxel data, which was around 7%.
Next slide. And here's a look at your survival curve where you can clearly see in those who had measurable disease in the lung, the curves do separate suggesting that there is a benefit of this combination. Next slide. So one was looked at incidence of neutropenia in the docetaxel arm alone, 28.8% of patients had significant neutropenia versus when you look at the PANAP1 dose at 20 mgmt squared, only 5% of patients had neutropenia. Next slide.
What was also interesting is that you saw a reduced rate of patients becoming septic in severe infections with Plinabulin. And you also saw that there was significantly less dose reductions of docetaxel, meaning that in the pindambolone arm only 6% of patients had to have dose reductions of their docetaxel versus in docetaxel alone, 19% of patients had to have their docetaxel reduced. Next slide. So this leads to the Dublin III. Dublin III had both squamous and non squamous histology.
Patients had to have a ECOG performance of 2 or less. So if you're not familiar with ECOG, that means that someone is unable to perform a job, even a light desk job, but is able to perform their activities of daily living. Patients had to progress on at least one line of therapy, although you were able to progress on 2 lines of therapy. Patients needed to have measurable disease in the lung and was okay for prior checkpoint inhibitor therapy. So this is a more modern treatment regimen.
This is a randomized trial. It was global and it was stratified per region, Asia versus non Asia and second versus third line. And what was needed was a single blinded. So as physicians, we got to know what the patient was receiving, but patients were blinded with getting a placebo. Next slide.
And so the design of the study was a 1 to 1 randomization. It is fully enrolled, 559 patients have enrolled in the study. The final outlook is anticipated soon, but I want to highlight kind of what were our endpoints. The primary endpoint was overall survival, secondary endpoints for response for PFS, percent of patients without neutropenia on day 8. And then looking at cutoff rates at overall survival at 24 36 months, duration of response and then quality of life characteristics.
And then like at the bottom is proportion patients, how many patients were able to receive 8, 10, 12 cycles of docetaxel? Next slide. So treatment design was docetaxel was given 75 mg from your square on days 1 every 21 days and pinaablon was given on days 1 8 at 30 milligrams per meter squared. It was given 1 hour after docetaxel was completed. Next slide.
So unfortunately, the data is not out to present outcomes, but hopefully that will be out soon and I'll be able to present that in the near future. But I want to highlight 2 case studies of patients that I treated on the Dublin III study as this was not blinded to me a physician. So first one is a 75 year old man who had a tobacco consumption, who had a history of severe mitral regurgitation. In 2015, he presented with cervical lymphadenopathy, lymph nodes enlarged in the neck. They were biopsied and it was consistent with adenocarcinoma of the lung.
He was treated with carboplatin and pemetrexate and it was after 4 cycles and then he was placed on maintenance pemetrexate with disease progression. And that time he received second line treatment with nivolumab. And during his treatment of nivolumab within about 6 months, he developed brain metastases. The disease below the brain was stable and received whole brain radiation therapy and was kept on nivolumab. In May of 2017 or actually probably in April of 2017, he developed progression in the lung.
And at that time, he enrolled into double 3 and received docetaxel plus Plinabulin. He had stable disease and was able to receive 13 cycles with still stable disease. And at that time, unfortunately, his mitral valve regurgitation became significantly worse. He was recommended by cardiac surgery to repair his mitral valve and he declined at that time and enrolled into hospice. Very stable disease, which is excellent to say and there was no signs of any progression.
Had very stable disease, which is excellent to say and there was no signs of any progression at the time of him coming off a study. Next case. Next, I have a 78 year old man and this gentleman was a little bit worse performance asset than ECOG of 2, but presented with squamous cell lung cancer and had a history of significant GERD reflux. In September 2016, it was thought to be a very local disease and was planned for right upper lobectomy. Unfortunately, the disease was more advanced and he had to undergo a pneumonectomy and he had lymph node positive disease.
Normally, you would treat this with adjuvant chemotherapy, but he had significant complications after his pneumonectomy and adjuvant therapy was not given. Within 3 months after undergoing his pneumonectomy, he relapsed in the right bronchus stump, biopsy proven squamous cell. There was no driver mutation and low PDL expression. At that time, he was disease was not found outside of the lung and he was treated with concurrent chemoradiation utilizing carboplipemapaclitaxel and actually progressed during radiation. So then he was treated with pembrolizumab with progression after 9 cycles.
And then in October 2017, received docetaxelponablam. He had 2 cycles and then unfortunately had a gastric ulcer which perforated unrelated to his treatment. And after his perforation, he became very ill, went into atrial fibrillation. He was recommended to undergo surgery. He declined to undergo surgery and went into actually hospice at that point.
He did better in hospice without treatment and came out of hospice. And at that time, we decided to just watch him and he did not go back on any treatment. What I find fascinating is that his last treatment of Plinabulin was in November of 'seventeen and it was not until September of 2018 that I saw there was any evidence of disease progression. So you had someone who had almost stabilization for a year after 2 cycles of treatment. Go to the next slide.
And here you can see just part of kind of his disease and how extensive that was in the lung without really any signs of progression. Next. So I want to highlight next Study 105, which is designed for chemotherapy induced neutropenia, now small cell lung cancer, but I want to really focus on what are some of the supportive data showing here. Next slide. So in Study 105, this is a Phase 2 to Phase 3 randomized double blind study of pnabulin versus pettrogasmin in patients with receiving docetaxel after one line after progression after platinum based therapy.
So this is a 4 arm study, one arm received docetaxel standard of care plus pegfilgrastim and then there were 3 arms with 3 different doses of Plinabulin plus standard of care docetaxel. And in this we assess for absolute neutrophil count with multiple days during the first cycle. Next slide. So I want to highlight some things besides just kind of chemotherapy induced neutropenia that when you look at the study, what was interesting is that in the arm of patients who received Plinabulin, no patients had any thrombocytopenia lowering of the platelets. But 35% of patients who received peciforacinib had thrombocytopenia.
And thrombocytopenia is not a benign condition. Most patients with advanced non small lung cancer suffer from things like hemoptysis, so actively coughing up blood and he lowers his platelets that can increase. Next slide. When we look at neutropenia, when we look at the 105 study with docetaxel, you saw that 31% of patients had grade 4 neutropenia on day 8. And then in the arms receiving Plinabulin at the 20 30 milligram, it was only 2.6% of patients had Grade 4 neutropenia.
In the 105 study, when you look at comparing phenavalin versus pexobrastin, you basically find that there's similar benefits in prevention of significant neutropenia. Next slide. Now we know that piforacastin, one of the challenging side effects is bone pain. In this study, no patients were allowed to have bone pain at the time of entry. And when you look at the petrogrestin, 35% of patients reported bone pain and bone pain could be severe.
Our own practice, we prophylactically put all patients on Claritin to reduce their bone pain because it's significant. And the bone pain is not short. In this study here, you find that bone pain first became present about 3 days after receiving pilferograssmin and peaked on day 7 and but did still continue after day 7. When we look at the ponablon arm, no patients had any bone pain after day 3. Next slide.
When we look at quality of life, the global health status that we saw that patients receive pinaablon had a significant improvement of quality of life compared versus pexelgrastin and other important factors. Realize that this is all palliative treatment that we're giving patients is that patients receive phenabulin had significantly less fatigue, had significantly less pain and had significantly less insomnia compared to fegfilgrastim. Next slide. So just to kind of highlight here, docetax alone has a modest benefit. We've seen that in some of our trials that there seems to be a survival benefit.
And some of these survivals or some of these durations of these patients who respond can have very durable responses. In the last study I just presented, there was one patient who had a complete response that was durable. When we look at safety concerns, docetaxel is not a benign drug, it can be challenging, it causes 10% to 20% of patients will have neutropenic infections. There can be nausea, there can be thrombocytopenia with it. When we look at the combination, we find some hints that there's no increased toxicity.
We see that there's reduction in thrombocytopenia. We definitely see that there's reduction in neutropenia, less infections, we find that there's less dose reductions of the important chemotherapy drug. And also it's convenient in that it's a same day treatment versus new pecrogastin where a patient will have to come back to the office the next day to receive it or they have to go home with an antibody injector. And it's frustrating as a doctor when your patient calls you the next day and says, my antibody injector failed to deploy, then you have to bring them in for treatment. And then importantly is quality of life.
And I commend them to be looking at quality of life, but we see that there's superior quality of life with this combination, there's less bone pain and that patients complain of less fatigue, less insomnia and these are important things and the life. This concludes my part of the talk. Let's go to the next slide. And I want to welcome Elizabeth to kind of finish up the talk here.
Thank you, Doctor. Feinstein. Well, we've just heard an awful lot of specifics about why we believe Plinabulin truly can realize its potential as a portfolio and a product. And what I'd like to try to do now is to summarize the value of BeyondSpring and the value proposition that we offer. So BeyondSpring is committed to next slide, please.
BeyondSpring is committed to raising the standard of care for cancer patients in the largest global markets with 1st in class treatments that improve lives and clinical outcomes for millions of patients in need. Our value proposition includes derisked late stage assets with the potential launch of Plinabulin in CIN in early 2022 with Phase III data in non small cell lung cancer coming out in mid-twenty 21 and with our triple combo IO trials, which are underway. We target large markets, including CIN, solid tumors and IO combinations. We have 2 important advantages with our cost of goods as Plinabulin is a small molecule with a simple manufacturing process where we work with top CMOs and our broad and long IP coverage with coverage through 2,03636 jurisdictions. We have global capabilities with the U.
S. And China representing the 2 largest pharmaceutical markets. And finally, our cash position at March 31, 2021, was $90,600,000 which is sufficient for our clinical and prelaunch costs. Next slide, please. Plinabulin has value in CIN, where it targets a broad range of cancer and chemotherapy and can elevate standard of care.
It also has value in anticancer, specifically in non small cell lung cancer and in other cancers with an opportunity to establish Plinabulin as a cornerstone in IO regimens. And finally, I would like to remind you of our upcoming milestones, which include that we expect to report top line Phase III data in non small cell lung cancer in mid-twenty 21. We have our PDUFA date of November 30, which has been set by FDA for plenabulin in CIN. And we expect to maybe have early clinical data already in our IO combo in Q4 2021. And the big thing we're, of course, looking forward to is also our potential launch of Plinabulin and CIN in early 2022.
So we have a lot to look forward to. And I think at this point, I'll turn it back to the operator so that we can have our Q and A sessions. Thank you.
Thank you, Elizabeth. At this time, we will
be conducting a question and answer session. Box at the bottom of the webcast player or by emailing your questions to questions. Lifecycleadvisors.com. To our analysts, we invite you to join via Zoom now. Please hold while we poll for questions.
Our first question comes from Jason Gerberry from Bank of America. Please go ahead, Jason. Jason, I think you might still be on mute. Okay. Our next question comes from Fang Chi from Bank of America.
Fang, please go ahead.
Hi, this is Song Qi on for Jason Gerberry of BFA. Thanks for taking my questions. You hear me? I just want to make sure that I'm not on mute and hear me properly.
Yes, we can hear you.
Okay, awesome. Thanks so much. I guess the first question maybe for the KOLs. Curious if DEFLIN-three is able to replicate the data that we have seen from Phase 2 with Plinabulin chemo combination. Do you expect the combination to become the standard of care if approved in the U.
S? And then I have a couple of follow-up after that.
So it's for Doctor. Feinstein?
Yes, sure.
So if I understand your question correctly, if we find similar survival benefits in the Dublin III compared to 101, would this become standard of care?
In your practice, yes.
Yes. It would definitely come standard of care at that point because you've now kind of got the kind of home run. You've increased survival and you've reduced toxicity compared to you look at other combinations with minimal improvement of any overall survival and significantly increased toxicity. So yes, it would quickly become standard of care.
Sure. Maybe the same question for you as well, Doctor. Feinstein. You talked about 2 case studies. There was a patient with mitral valve insufficient in heart failure and other patients with gastric perforation, gastric ulcer and atrial fibrillation.
These patients discontinue these treatment these adverse events and can you confirm whether these treatments I'm sorry, these adverse event are adjudicated to be treatment related?
I don't believe they are treatment related. The patient with mitral route regurgitation had pre existing mitral route regurgitation before the diagnosis of lung cancer. I mean, there was an echo showing that it was severe before going on any treatment. I just think this is what happens to his mitral valve over time talking with his cardiologist. So it's not felt to be disease related or treatment related.
In regard to the gastric perforation, I don't think this was treatment related either. The gentleman had a underlying gastric ulcer that just happened to perforate. So I think it was just unfortunate timing of those 2. I don't believe they were treatment related.
Okay. Thank you very much for the clarification. I guess one last question from me for management. You talked about exploring Plinabulin triplet with IO therapies in other tumor segments beyond small cell lung cancer. And one of them is CNS tumor, which is a PD-one unapproved therapy.
I'm curious, can you talk about the scientific rationale for studying the treatment in CNS tumors? In particular, what consideration we should be aware of as it pertains to ability for each individual component to cross the blood brain barrier? Thank you.
Yes. This is Ramon. I'll take that question. So we have evidence also that Plunarim is active as a single agent in GBM. We also know that Plinabulin crosses the blood brain barrier.
GBM is an area of focus to us as will be of the CNS cancers and will be soviet for future trials.
Okay. Thank you very much.
Thank you, Chi. Our next question comes from Maury Raycroft from Jefferies. Maury, please go ahead.
Hi, good morning, everyone, and thanks for taking my questions and thanks for the event today. I had a question for Doctor. Feinstein. I was wondering if you can if you expect there to be differences in the checkpoint inhibitor naive versus experienced patients in Phase 3 Dublin? And what will you be looking for based on the stratification of these patients?
Wish I could answer that question without the data yet. But when you look at the preclinical, my suspicion is there might be some benefit of those who had prior checkpoint inhibitor therapy. My example is both those patients have very durable responses. And in other patients I treated on the study, I seem to find that same sort of response. But on a standard in the United States will be as almost every patient will have received a checkpoint inhibitor prior to going on any docetaxel, although in other countries that's not quite standard, although I think that will be that's becoming standard of care.
Got it. That's helpful. And then I also had a question on just when thinking about the total data for Plinabulin in the context of Dublin III, the Phase III Dublin study, how do you think about the contribution of Plinabulin's benefit on CIN versus the anticancer benefit? I guess if you took out the anticancer benefit, would you still expect Dublin to succeed based on just the CIN contribution alone? If I may,
professor Feinstein to also add his thoughts. So we through interim analysis, we did discuss this topic.
And
if we one way to address this question is to look at patients who have the full dose of docetaxel in both arms. Because obviously with CIM, the consequence will be that the dose, Saxel dose will be reduced. And that is the basis of your question, if that is the reason why in the platinum arm we have better results. So if we only look at patients with full dose, Dose XL in both arms, so that is constant, the chemo dose, and you add Plinabulin to that, we continue to see the benefit. So we know that it is Plinabulin that is causing the anticancer benefit and not strictly through its prevention of CIN.
Doctor. Feinstein, I don't know if you have something to add to that?
I mean, a little bit. I mean, I could add in that when you look at docetax alone, I mean, if you follow the NCCN guidelines, your risk of febrile neutropenia goes into an intermediate risk of 10% to 20%. Most of these patients have more than one risk factor over age 65 prior treatment, which would fall into a criteria where you should be using or considering growth factors. And we know the inherent toxicity with pefoclastin, just the inconvenience and the bone pain associated with it. So if you have something that can be given on the same day and has less toxicity and similar benefits in reducing of chemotherapy induced neutropenia, I think that is a benefit there.
And the day 8 infusion is not usually a big deal because most of these patients who do follow-up with them the next week anyways to make sure that they're doing okay.
Got it. That's all helpful. And I had one last question. When you were talking about the mechanism of action for CIN, you talked about the fast onset of benefit there. And I was just wondering if how you reconcile that fast onset with the bone pain improvement and how the mechanism works?
Maybe if you can talk a little bit more about that.
Yes. I can take that question. We indeed analyzed the neutropenia data from SOLI-one hundred and six further. And you're absolutely right in the basis of your question in that the bone pain benefit with Plinabulin indeed is coupled to the fast onset protection of CRM. We have the evidence through looking at the timing of when the peak of the bone pain occurs and the fast onset protection kicks in.
So we do have reason to believe indeed that the bone pain benefit that we see with Plinabulin is a direct consequence of its added CIN benefit and its fast onset mechanism of action.
Okay. Thank you for taking my questions.
Thank you, Maury. I'll now turn it over to Monique Cossy of LifeSci Advisors to read any questions that may have come over the webcast.
Thank you, Tara. First question here comes from Josh Schimmer of Evercore. It says, great overview. Based on the data and literature, which solid tumors would you expect to be most responsive to plinabulin antitumor effect? Also, any plans to combine the seed platform with plinabulin?
And can you discuss the commercial opportunity for Plinabulin in China?
Yes. I'll start with the question, which tumor types? So what I convey what we convey in this presentation is that Plinabulin would be a candidate virtually in any given solid tumor types. With the cold tumors, it's important to convert them to hot. With the hot tumors, we have different strategies employed here that would enable to, in an individual manner, target each solid tumor types, either through combination with nivoipi, with combination with radiation, with combination with chemo.
And that is where we would like to go with Plinabulin in the concept of a universal add on to any given anticancer regimen. I'll go next to the commercial question, and I'll ask Riz Daly to address that question.
Yes. Probably for the China question, I can take it first and then, of course, for Rich to add more. So China is a huge market. So for new cancer patients each year, it's over 4,000,000 new cancer patients. And then over 60% of them would use both therapy.
So that's the candidates and also patient we need to help. So that's why currently, but the biosimilar disease, I mean, China market is already $1,000,000,000 and it's growing over 30% a year. So that's for the CIM market, right? And as you know, Panab and adding to GCSF is elevating this standard care. So we could capture a large portion of this market and also helping patient with even good care.
Secondly, for the non small cell lung cancer, in China, almost 1,000,000 new lung cancer patients each year. And those are additional patients who can help. So that's the China question. Rich, you have anything more to add?
Lon, I think you covered it really, really well. I think the China opportunity is pretty significant. And I also think that the U. S. Opportunity as we've talked about extensively with the NCCN guidelines changing and increasing the adjusted full population by more than 100%.
And with the opportunity to combine with G CSF, I think it's a pretty significant opportunity. The base business of G CSF is in fact growing in the U. S. And so really excited by the data and the opportunity we have before us. So I think the combined opportunity of China and the U.
S, I think presents a really robust commercial opportunity for CIN and then obviously for the non small cell and all solid tumors as Ramon pointed out.
Yes. Thank you, Rich. I know, Josh, you also had another question regarding seed pipeline combination with Plinabulin. Well, see the pipeline currently still in very early preclinical studies. But as we move them forward, if in the cancer indications, there is a complementary mechanism, we will, of course, have the opportunity to combine, which potentially elevates standard care.
Thank you.
Thank you, Elizabeth. I'll move to our next question from Andy Xie at William Blair. It's I have a multipart question here. So several questions here. So just curious if there are plans to explore alternative ipi dosing or schedule in small cell lung cancer?
Second question he has is, how would you objectively choose tumor sites to radiate? And his last question here is, Doctor. Feinstein, do you rechallenge your non small cell lung cancer patients with checkpoint inhibitors in practice?
Thank you. Perhaps we should start with Doctor. Feinstein first and then address the other two questions. Doctor. Feinstein, this is about rechallenge.
I'm sorry. Do I rechallenge? My standard of care answer is no outside of a clinical trial. Have I done it before? Yeah, I have in a patient who might have had a early checkpoint inhibitor that was not approved and now with approval of 1 or sometimes where a patient had a very durable response and then went on chemotherapy progressed and sometimes we'll go back, but standardly, no, I would look for a clinical trial outside of rechallenging.
Thank you. Next, I would like to ask Doctor. Stephen Lim to comment on the question, which cancers are candidates for radiotherapy?
Yes. So how do we choose the size? I believe that was the question, if I understood correctly. Yes. So, yes, we specifically know from other studies we've done we have a number of trials that look that really trying to look at the epscopal effect, just PD-one and radiation alone in combination with a number of patients or actually many patients treated, 100 of patients actually by this point that started about 4 or 5 years ago.
And we know that certain sites, particularly the soft tissue sites are actually visceral sites are actually quite antigenic. And we actually see the greatest response. And we actually excluded bone mass actually as sites of antigen presentation or sites where we radiate for in terms of this enhancing immunogenicity. So we are so all the patients right now, what we examine is that they usually have one soft tissue site, either liver, adrenal gland, lung, etcetera. Those sites are actually preferentially radiated.
And then, however, other sites, including bone, will be used to assess for treatment response to assess overall response rate. And also another is also safety. Of course, we want to make sure the sites we're ready are safe for the patient. And that's how we usually choose when the Phase 1 group send us a patient to say they always send it to me to evaluate. I will look at the patient based on the number of sites, the sites of metastases to determine the sites to radiate.
And now either if I'm seeing the patient or one of my colleagues will be seeing the patient, we'll actually kind of decide and determine the Type 2 radiate and the Type 2 evaluator.
Thank you. And then there was a last question about the alternative dosing regimens for small cell lung cancer. So today, in this trial, we follow the nivo EP schedule and adapt clinabulin to that. Obviously, if the trial continues to be positive and that confirmation we hope to see in Phase II, we would like to continue with its schedule. But certainly, we will be open to explore other schedules.
Does that answer does this answer your question, Andy?
This was a written question, so I believe it does. We'll move on here. Joe Panginas at HCW has a question. He asks, can you please discuss your preclinical and
or mechanistic support for PDE4
inhibition in reducing
Yes. I'll take that question. So PDE4 stands for phosphodiesterase 4, which is a proven target today to treat inflammatory disorders. There are several drugs on the market that treat inflammatory skin disorders, but also pulmonary disorders through PDE4 inhibition. Immune related AEs, in fact, are autoimmune responses.
They are they mimic inflammatory disorders, as we know, and they are caused by the enhanced activity of the immune response induced by the combo, nivo and ipi. So the way we look at this and the way we also discuss this with BMS, who is contributing to this trial, is that immune enhancement follows a different path of mechanism of action as compared to inflammation. Those 2 are separate paths that have some extent of cross talk, but they can be considered separate. So we can have immune enhancement and enhance the anticancer efficacy with this combination, while with the PDE4 inhibition with Plinabulin, we can reduce inflammation and therefore prevent immune related AEs. So this is a concept.
This was a predefined secondary endpoint in this trial in the BIG10 trial. And we hope to confirm what we saw in Phase 1, which is a marked reduction of the Grade 3 and 4 immune related events to occur. If that would hold, we believe this will be a tremendous advantage for Plinabulin to be added to the nivo, ipi or PD-one, CKLA-four inhibition combination because we expect it will not only enhance anti cancer effect, but also prevent the most common side effect, which are the immune related AEs.
Thank you, Ramon. The next question is on the Dublin III trial versus 101, can you comment on the patient demographics differences between the two studies? What signal activity should we expect in the control arm? What are the main similarities and differences between the patient demographics of the Dublin III trial and the 101 study?
Yes, yes. I can start with your response and perhaps Doctor. Feinstein can add to that. So with Study 101, the majority of the patients were recruited outside China. In fact, we had no patients from China.
We did have Asian patients, but not from China. The majority was for patient. In Dublin III, the majority of the patients were of Chinese origin, but we do have Caucasian patients as well. We do not expect that we will have regional differences that would impact outcome. And we expect what we saw in Phase II with Study 101 that we would largely confirm that in Dublin 3.
I would like to point out that the trial was stratified for region so that therefore we ensure that the 2 treatment arms are balanced for the contribution of each region to each arm. We do not expect there is a basis for difference of the drug F-fifty between Asians and non Asians. An important part to confirm that is that we take intensive pharmacopinabic sampling and we compare if the Plinab and pharmacokinetics are different between regions. Thus far, we have no evidence that there is a difference. We do not expect that the two trials will have intrinsic differences.
And as pointed out, the way the trials are designed is that they are stratified for region and in this case also for the line the number of lines. So we expect the 1 on 1 data to be highly translatable to Dublin 3. Doctor. Feinstein, you have anything that you would like to add? I
think there's a few things, little differences, but I mean, you're right that most of it is fairly comparable between the two. The differences in Dublin, you've allowed checkpoint inhibitors to be given. And then also in the Dublin, you've taken a more kind of realistic patient population, you have ECOG2 patients versus in 101 with just ECOG01. So you're taking a more true third line patient population, people being a little bit sicker. And then the other sort of thing to highlight is the eligibility for the Dublin III, a patient had to have measurable disease in the lung and in 101 patients didn't have to have measurable disease in the lung.
So there's a couple of small differences, but overall there and then the other sort of thing is in the 101, you had 2 different doses of Plinabulin versus the Dublin III, you had one dose of Plinabulin.
Yes. Thank you, Doctor. Faitz here. And thank you for bringing the topic of the measurable long vision. Lesion.
So the data that we showed here was in the subset with patients with a measurable long lesion with a 4.6 month survival benefit. And it is that subset design that we employed in W3. I just wanted to clarify that point. Thank you. Perhaps you can go to the next question if you have time.
Yes. We'll take a couple more questions here. From the 101 study, what patients had a better benefit from the combo arm following what lines of treatment?
What's the question for the 101 study?
Yes.
So the 101 study, the study was obviously relatively small. It was Phase II. It will be difficult to split that data up in different segments and draw meaningful conclusions. But that study was also conducted in 2nd and third line in EGFR wild type patients. Obviously, at that time, checkpoint inhibitors were not yet approved.
So those patients, we are not in the mix. In terms of the key notion is that the type of patient population in terms of second- and third line EGFR wild type, we expect will be comparable in 101 comparing with 103. With 101, I would say, was a relatively small study, and it probably would not be advisable to define the data in further segments. The one segment that we did employ is to select patients with a measurable long lesion, which represented 70% 70 percent of the data set in 101. And the reason we selected this type of patients is because we can argue that these are the patients that are likely still immune responsive because they still have relatively earlier stage in the overall Phase IIIb IV spectrum of disease.
I hope that answers the question. It's phrased carefully because 101 is a small study. And to further subdivide that in segments will also be some will always be somewhat challenging.
Thank you, Ramon. Next question here is on the triplet rationale with XRT. Can you please comment on the direct effect of XRT plus plinabulin in cancer cells in preclinical studies? And does plinabulin plus XRT increase the tumor killing effects of XRT regardless of immune activations?
This question is for Doctor. Stephen Lin.
Yes. Thank you for that question. Actually, so the direct effect, and we know, of course, pylabalin has in some subset of tumors, it actually has a direct cytotoxic effect. And it occurs to radiation also has, of course, a direct healing effect. The combination, however, I think just to be frank, we have not looked at specifically using clonogenic survival assays to see if actually Plinabulin itself will be radiation enhancing directly on the tumor effect, tumor cells themselves.
So most of our focus has been on looking at the dendritic size or dendritic cell stimulation effect of Plinabulin and therefore it requires a kind of a tumor microenvironment in vitro assays to really into specific study that kind of question, but then also in vivo studies to look at the combination effects. However, the direct effect, radiation sensitizing effect is something that actually we're very interested to look at whether there would be a direct rule for that.
And in interest of time, this is going to be the last question here. What level of response would be needed in the Dublin study to be of use in the medical community? And how quickly or slowly could the oncology profession begin to use Plinabulin as an anticancer therapy, should there be improvement?
So with how much of a response was the first question And the adoption is the second question. I wonder, Doctor. Feinstein, if you would be comfortable to make a start?
Yes, I'll try my best at this question here. I guess the question is one has back is an improvement in what? I think if you find that the Dublin 3 met its primary endpoint of overall survival benefit, it will be rapidly employed quickly accepted throughout the community. If it fails to meet its primary endpoint, when we look at some of the secondary endpoints, it depends on how many of them are positive. I think that would kind of lead to how adoption in the community, just kind of having to adoption in the community.
Just kind of having to convince someone that with a new agent that there are differences and there are some benefits, But they're changing a habit. But if we do meet the primary endpoint, I think that would be rapidly accepted.
Thank you, Doctor. Feinstein. To add to that very quickly. So the profile that we are Dublin III with the combination Plinabulin plus dose itself is not only to have a survival benefit, but also the reduced safety concerns and importantly, improved quality of life. We have the Q Twist measure incorporated as a predefined secondary endpoint, which is a highly relevant endpoint for this population, which tends to be very sick.
To have a proposition here that we not only have survival benefit, but a longer survival at a high comfort level, at a high quality of life and minimize toxicity, we believe, is a very attractive proposition here that would enable rapid adoption. But of course, we all have to wait and see what the final data set what the final data results will show. But here, I think the key point is that we look at that profile in terms of survival benefit, but also importantly to demonstrate the quality of life Qtris endpoint and that reduce toxicity. Thank you.
Thank you, Ramon. That does conclude our question and answer session. I will turn it over to Lan for closing remarks.
Thank you, Monique. Thank you, everyone, for spending your precious morning time with us and really appreciate your support. And as you see, we have a few very exciting months coming up with a few very important milestones to be released. So stay tuned, and I hope you have a nice day and nice weekend.