NovaBridge Biosciences (NBP) Earnings Call Transcript & Summary

[Audio Gap] Now as you can imagine, tumor has a very high level of metabolism leading to abandoned production of its product NOC and our accumulation of NOC within the tumor markering [indiscernible], and that's the issue we're dealing with. Now antibody modality has an advantage in complete inhibition of CD73 possibly. And the reason is that this inhibition is a noncompetitive. It's a lasting and sustained inhibition. And can need to complete shut out of [ Emerson ] possibly. Now if you look at the far end on the lower left corner, you can see that this particular experiment compares the effect of small molecule versus antibody, antibody is being the [indiscernible] represented by the [indiscernible]. It's a uliledlimab-based our CD73 antibody. And small molecule is a reference, small molecule. As you can see, when the increased levels of AMP, the effect of small molecule is overcome by the increased the level of AMP and around 10 micromolar level. Effect of -- the inhibitor effect of the small molecule is completely lost. On the contrary, if you look at the blue line, the inhibition through antibody effect is lasting and sustained throughout and this is not unique for a CD73 antibody. There are many examples in the literature for other proteins or energies. So from this type of data is quite clear that through inhibition of antibody for [ Arden ] antigens such as NSC, there's an advantage to use the antibody versus small molecule. Now the third message I like to talk about on this slide is really the key message that is our antibody, our CD73 antibody, uliledlimab, is a highly differentiated. Why we say highly differentiated? Now for CD73 antibody to work, there are 2 mechanisms, one that is called [ inter-gamma family ], meaning when CD73 antibody has to grab 2 molecules of CD73 in order to inhibit the [indiscernible] of a CD73. And this mechanism oftentimes works through a epitope located at a N-terminus. So it's a N-terminus epitope associated with this particular medicine. Now what is important to mention is that this particular mechanism inter-gamma bonding is associated with a paradoxical PK/PD relationship, meaning at a low dose of usually you to -- you should have -- typically should have a [indiscernible] prevent at a high dose paradoxity -- paradoxically through this mechanism that if that becomes lower. And this is so-called the hook effect. And that presents -- this particular mechanism presents clinical challenges to further develop such a molecule. The reason is that in the clinical setting you cannot use low dose because it does not give you a desired treatment effect. But you cannot use high dose because it also gives you a low effect. So that's the challenge in a clinical study. Now the other mechanism I'd like to mention is the so-called intra-dimer bonding. And through that mechanism, antibody needs to wrap one molecule in order to prevent normalization of CD73. So this mechanism is associated with epitope located at a C-terminus of the CD73 molecule. And this now becomes quite clear. Now our antibody, uliledlimab, works through this intra-dimer bonding mechanism. And now we have it already characterize our epitope, it's located at the C-terminus. Now if you look at the lower part of that figure, it becomes quite clear. Now the red line is associated with the hook effect. As you can see, above certain concentration, the effect, the inhibitor effect of CD73 antibody here is a reference CD73 antibody, the inhibitory effect is completely lost. And this is the so-called hook effect and the [indiscernible] challenges I just mentioned. Now our antibody is presented by the blue line, where you can see no [indiscernible] curve for the PK/PD relationship. So that presents certain clinical advantage because the clinical is saying, we don't have issues with the hook effect and we can determine an efficacious dose and then move forward with that dose. So we -- they saw the preclinical studies. We truly believe that this differentiation is critical and is clinically meaningful. Next slide. Now I'm going to switch gear to talk about our Phase I clinical data. Now our Phase I clinical trial is designed as a dose escalation study. It was conducted in the U.S., enrolling multiple clinical sites. Now the trial is designed as such that our CD73 antibody, uliledlimab, is given first as a monotherapy running for 3 weeks, followed by combination with atezo, a PD-L1 antibody, we have a cooperation with Roche. So the first part is really the monotherapy. And the second part is the combination therapy. And for that study, we focus on several aspects to look at the safety profile PK/PD relationship. We set the occupancy, even that this limited dose escalation study in this limited stage. We also wanted to see any efficacy signal from this study, which I'm going to elaborate further in my presentation. Last but not least, we also look at the biomarkers, more specifically, PD-L1, CD73, and to see how the expression of those biomarkers in-patient tumor samples would correlate with the clinical response. So this is really the clinical trial design. Now this slide, I just want to summarize some of the key data at the front before I take a deep dive to walk you through some of the data figures. So the first aspect is related to the safety. It's very clear from this study how CD73 antibody, uliledlimab, is safe and very well tolerated. We did not see DLT throughout the clinical study. The side effects are often milds, Grade 1, Grade 2. We did not see Grade 3 side effects. So the molecule is quite safe. The second aspect is about PK/PD relationship. And this is really important for us to measure because we want to use in a clinical setting to really look at the -- whether our molecule has or has not -- have the focal effect. So to make a long story short, later I would present some data, our molecule has a favorable PK/PD relationship. We do not see the hook effect, which is commonly observed by other people with other clinical stages CD73 antibodies. The third aspect is about dosing and a receptor occupancy. It becomes quite clear through this study for our antibody, uliledlimab at 10-milligram per kilo and above, we can see a full saturation of the receptor occupancy. And this is very important for us to determine what is the RP2D dose to move forward. And through this study, now we can conclude. Most likely, our RP2D dose is about 20-milligram per kilo every 3 weeks. And this is the dose we are considering to move forward in our Phase IIb trial. And this is also very important information that we need to design our future studies. Now the first aspect is related to efficacy signal. As I mentioned earlier, this is a limited Phase I clinical study. It's designed for dose escalation for safety, PK/PD and other aspects. But we still wanted to see even, and as such, limited clinical study where we see clinical activity of this molecule. And to summarize, we're very encouraged by the clinical efficacy signal we are seeing on this Phase I clinical study. To summarize, out of 13 evaluable patients, we altered 1 CR, 2 PR and 3 SD in both PD-L1 naive and refractory patients. This is -- this level of ORR, so far, is the highest among all the clinical studies with CD73 antibody. And we're very encouraged by the data. Now in the next 10 minutes or so, I'm going to take a deep dive to give you more color on the efficacy signal of CD73 antibody in patients with advanced solid tumors. Now the last aspect among these is that through this study, we also observed a correlation of high co-expression of CD73 and PD-L1 in archived of -- tumor biopsy samples in the patients, and that correlates with the clinical response. And this is quite struggling to see even with a limited number of patients, there's a good correlation of a co-expression of both biomarkers in a clinical response. And I'm going to take a deep dive and to tell you why we're excited by this correlation and what we're going to do to use that information to move forward for our future clinical performance. Now let me first talk about PK/PD relationship, supported by the differentiated property of our CD73 antibody, uliledlimab. Now this figure is quite typical that basically you can see that 10-milligram per kilo and above, you see a saturation of receptor occupancy of CD73. And this data is from the analysis using peripheral B cells, so this is a newly [indiscernible] cell bound, CD73 levels. In parallel, we get similar studies with soluble CD73 serum, soluble CD73. The data are quite consistent between soluble CD73 and cell bound CD73. So the message is quite clear at 10-milligram per kilo and above is the receptor occupancy, and that provides some critical information for us to determine what would be the RP2D does were for. And the other critical information is that through this analysis, we are quite comfortable that our molecule has a no hook effect of both at a soluble level and the cell bound level of CD73. And this is quite exciting to see the data. Now the next slide shows you the PK profile. On the left side, it's a single dose PK. On the right side is repeated dose PK. And this is a very typical PK profile. It's a linear -- and that gives us pretty good confidence that we can take 20-milligram per kilo every 3 weeks to move forward. And that's the information supporting the future dosing. Now this is a exciting aspect. I'm sure you're all -- you're one to see. This is related to a efficacy signal. To summarize, in this among 13 evaluable patients with advanced solid tumors, we observed that 1 CR, 2 PR, ORR is at 23%, which I already mentioned. This is so far the highest ORR among all the clinical trials with CD73 antibodies. We also observed 3 SD. So that makes [ DCR ] of 46%. Now let me give you some more color about those patients. The CR patient is a patient with ovarian cancer, which is typically insensitive to PD-1 therapy. And this patient has been on trial for over 17 months. And it's always very exciting to see how patients can do well on the trial. Now for the 2 PR patients, both patients are patients with lung cancer, advanced lung cancer. One patient who failed the checkpoint therapy before entering our study and the other patient had a no prior PD-L1 treatment. And the 3 SD patients -- among the 3 SD patients, 2 of them failed the PD-L1 treatments prior to entering our study, and 1 is PDL-1 naive. So this is so far we've seen the efficacy signal we've seen from this clinical study. And we are very encouraged on the data because the efficacy signal is really associated with such limited clinical study because this is a dose escalation study. Now let me tell you about the biomarker studies. While we are quite excited started about the correlation. So as I mentioned earlier, in this study, we analyzed 3 biomarkers, PD-L1, CD73, A2A receptor, in archived tumor biopsy samples in those patients, okay? And then retrospectively, we look at the levels of CD73, PD-L1, A2A receptor and compare with the clinical response of the patients. Now the methods we use for the analysis is immunohistochemistry method, it's a standard method to measure the expression of the biomarkers I mentioned. And the scoring system we use is a standard TPS system. People often use to score the level of PD-L1 and some other biomarkers. So it's interesting to see, on the right side, when we plotted the co-expression of PD-L1 on the y-axis and CD73 on the x-axis, it becomes quite clear that there are only 3 patients out of 13 evaluable patients. Those 3 patients have a high spreadsheet of both CD73 and PD-L1 in their biopsy samples -- archived biopsy samples. And those 3 data points are represented on a blue dot and those 3 dots or those 3 patients are the only 3 patients who have clinical responders. So on 1 CR, 2 PR. And they happened to be those 3 clinical responders. So this is quite interesting to see this level of correlation. Of course, we have to -- we are making efforts now to move towards to validate this correlation with the additional set of samples in order to confirm this correlation. Now if this is confirmed, we believe we have a handle to use such biomarkers, CD73 and PD-L1, to move forward, to select and stratify patients in our future clinical studies in order to increase the probability of success. And this is, again, interesting to see. Now we went further to look at -- in the literature, what is the role of CD73, PD-L1 and how they are expressed in any tumor samples. And there's an ample evidence in the literature that expression of CD73 in tumor samples correlates with the poor prognosis in cancer patients. And if you look at this table on the left side, the p-value represents statistically significant correlation between high expression of CD73 and a poor progression in cancer patients. And there are multiple studies demonstrate -- consistently demonstrating the same conclusion. Now on the left side in that table, you can also see that both CD -- PD-L1 and CD73 are expressed in multiple solid tumor types that includes [indiscernible] cancer, lung cancers and many other cancer types. So the conclusion on this is that PD-L1 and CD73 are relatively progressed at high levels among multiple cancer types, and CD73 correlates with poor prognosis in cancer patients. Now on the right side, this figure, this slot really demonstrates the correlation of PD-L1 and CD73 expression in tumor samples. Where you see a high PD-L1 expression, oftentimes you see a high expression of CD73. And this is also critical information for us to use CD73 and PD-L1 as additive biomarkers in our future studies. Again, as I mentioned earlier, the purpose is to increase the probability of success through selection and stratification of patients using such predictive biomarkers. Now this is my last slide. I just my -- concludes, we are very excited with our CD73 antibody, uliledlimab. In our pipeline, this is another exciting asset after our CD47 antibody. And based on the clinical data and preclinical data we generated so far, we are very excited to move forward to get this [indiscernible] asset into Phase II clinical studies, both in U.S. and China. Our goal is to [indiscernible] those Phase II clinical studies to advance this molecule into registrational trials, both in U.S. and China. Now in U.S., our plan is to advance this study into a Phase II clinical trial focusing on 2 cohorts: One cohort is in patients with ovarian cancer in combination with PD-1 antibody. We have already completed our Phase I clinical study. Now it's time, and based on exciting data from our Phase I trial, its time move forward to initiate a Phase II clinical trial in the U.S., and we're ready to do that. Now in that study, we will have a second cohort. This second cohort is focused around biomarkers. As I mentioned earlier, in my data presentation, we have seen this exciting correlation between co-expression of the PD-L1, CD73 in a clinical response. In this Phase II study, cohort #2, we'd like to validate this finding, validate this correlation and also use this -- both biomarkers as to select and stratify patients. So cohort 2 is really what we call biomarker-driven study. So based on biomarker, we will select different asset types to be included in this study. Now in parallel, in China, we have just initiated a Phase II clinical trial with uliledlimab in combination with a PD-1 antibody in patients with -- primarily with lung cancer. We are quite excited about this clinical study. And the reason why we focus on lung cancer in China is based on our previous analysis and also the clinical data and also look at the expression of CD73 in lung cancer samples. In addition to the Phase II -- ongoing Phase II clinical trial in China, we are also considering to initiate another study where we're going to combine our CD73, uliledlimab, with a small molecule cancer drugs -- target molecule. And this is something we are in the process of looking at the data, looking at the analysis, making final decision to initiate that study. So all together, I like to conclude that with the preclinical data around the differentiation of our molecule. Now with Phase I clinical data around the differentiation and some of the efficacy signals and correlation of the biomarker with the clinical response, now we are quite excited. And we think we have a truly differentiated CD73 antibody that behaves differently from other CD73 antibodies and we go through Phase II and the future studies. We can't advance very quickly to registrational studies and also generate more data to share in the field. So the focus of this program at this point is that in U.S., we're going to initiate a separate Phase II clinical studies. In China, in parallel, we're also advancing Phase II clinical studies and initiate a new study with a small molecule drug. So I think I'm going to stop here to see whether you have a questions that we can -- as a group, we can address your questions.

Thank you very much, Dr. Zang, for the very detailed in-depth walk-through of the clinical data. Now we would like to start the Q&A session. [Operator Instructions] The first question is from Kelly Shi.

So this is [ Hao ] asking questions for Kelly Shi from Jefferies. I think my first question is really about the non-small cell lung cancer patients. So how many of them are enrolled in those 13 evaluable patients? What's the percentage of those patients have CD73 expression? And what's sort of the variation you see of CD73 expression among those non-small cell lung cancer patients?

Yes. Thank you. I want to ask Dr. Shen to elaborate on that question.

Okay. Thank you. This is a very good question. In total in amount of 13 evaluable patients, we have 3 [indiscernible] patients, 2 of them, as Zang has mentioned earlier, had TRs and 1 had PB. So in terms of the correlations of the PD-L1 and the CD73. So all those 2 PR and TRR patient have high expression of both PD-L1 and CD73. So in particular, the one with IO-resistant patients, which was at least for 4 systematic chemo treatment in addition to the 6 months of neuro treatment. This patient, particularly had a PD-L1 for 30% and the CD73 for 90%. The other one, with also TRR, which is IO-naive patients with [indiscernible] study at also high correlation. So PD-L1 expression is 90% -- 95%, and the CD73 expression is 90%. And the rest of the one I mentioned earlier with PD, which had a regular expression of both. So CD -- PD-L1 is only 5% and the CD73 is 10%. So all 3 patients are here.

Okay. Awesome. And my second one is regarding to the patient who has ovarian cancer had a CR. so could you provide maybe more color about the patient baseline and prior treatment for that patient?

Yes. these -- ovarian cancer, we made a T cell type time IO treatment naive, but the patient -- the T risk had failed 2 systemic chemo treatment. And then the patient also is a 58-year-old and had -- after he -- she went to the treatment, achieved TR after 2 months, 8 weeks of treatment. And then following that, become CR. So the patient continue to have treatment benefit after 500 days now. Now currently, the patient had a PD-L1 expression and also is 40%, and there -- for CD73 is at least 80%. So -- right, 50%. So all of these TR or CR patients have high expression for each.

Awesome. Maybe last one. So any other CD73 assets that presented a clinical update at ASCO, that maybe draw your attention?

Yes. We noticed that AstraZeneca presented their clinical data on their CD73 antibody, oleclumab. So it's also very interesting for us to see that data. I -- although it's hard to directly compare their data with ours criteria the patient populations are different. The molecule is different. But I can summarize some key points for you guys to consider. Now in their combination study, CD73 antibody with a PD-L1 combination therapy. Out of 15 evaluable patients, they did not see CR and then no PR. And I'd also like to mention that their CD73 antibody was given at a very high dose, 40-milligram per kilo every 2 weeks. It's more than double of our CD73 antibody given to patients. And the other data set is also interesting to see is that in that dose expansion cohort, out of 112 patients, those cancer patients with CIC or rectal cancer, EGFR-mutated lung cancer and pancreatic rectal -- rectal adenocarcinoma. Among 112 patients, they observe 2 CR and 5 PR, making ORR around 6%. So it's interesting in such relatively a large population of patients, such a combination therapy, you still can detect clinical efficacy signal. But again, I think our ORR level is much higher, but the caveat being, as I mentioned earlier, the different studies, different patient populations. It's hard to make a direct comparison. So it's done -- it's quite interesting to see the data, and we're encouraged to move forward with our CD73 because we truly believe our antibody has a differentiation and clinical advantages.

Our next question comes from Jill Wu.

Congratulations, Dr. Zang and management for the impressive data. So my questions are on the 3 SD patients. Could you please share with more details about these 3 SD patients. How were their prior lines of treatment? And what are their types? And if I may, I would also like to know how about their expression level of CD73?

Yes. Yes. Maybe Dr. Shen can summarize it.

Okay. I'll try. So we've been -- among these 3 patients. The first one is the basal cell carcinoma, the skin cancer type. The patient actually had a very low PD-L1 expression, which is 2%. The -- also the CD73 is relatively high. If I remember, right, it's about 40%. However, this patient did fail IO treatment previously, in addition to a multiple systematic [indiscernible]. On this basal cell patient, actually the -- this treatment naive for IO, the patient is currently still continuing in the treatment after joining the study. This is the patient, I think, it's 75% -- 75-year-old. And then the other 2 patients, one is a cervical cancer patient, I think a 42-year-old lady, and she also had a low expression of PD-L1, which is 0 and a relatively higher CD73. And however, she did failed IO treatment previously. And then -- but was able to be kept on this treatment for at least 8 months, but then CT. And so there's another patient who is also a sarcoma patient and also failed the IO treatment previously. And then he was able to be on TP for -- as far as I know, 6 months, and then CT afterwards. So 3 patients.

Thank you, Dr. Shen. The next question comes from Louise Chen.

Okay. Congratulations on the data. So my first question for you is that we see very good biomarker correlation. How will this finding guide your future clinical trial designs? Secondly, are you considering a partner to develop this drug? What are your thoughts there? And then what kind of tumor types do you think your anti-CD73 will be best to treat? I know that the Phase II will prove that out, but any initial thoughts on that?

Yes. Those are very interesting questions. Well, first of all, based on the preliminary data, on this correlation of PD-L1, CD73 with a clinical response. We're quite excited to confirm this study. And as I mentioned earlier in my presentation, we are in the process of confirming this observation with a patient of samples. And in particular, in our Phase II clinical study, especially the biomarker-driven study, the biomarker-driven cohort, we will have a better answer as to how reliable of CD73, PD-L1 co-expression as a predictive biomarkers. We -- the idea is, as I mentioned earlier, we may have a handle on this. If the correlation is fully validated and we would have this 2 predictive biomarkers to select patients, to stratify patients to increase probability of success. And this is critical in our field, how to select those patients in order to have a better chance of success. So that -- this is something we're moving forward. Now what is the second question? Yes?

Cancer types.

Yes, the cancer types. So based on our analysis of all the data in the literature. And based on our own studies, including the Phase I clinical study and also based on other companies' study, at this point, we think we should focus on 2 cancer types. One is ovarian cancer. The other is lung cancer. So that's why I mentioned earlier, in the U.S., we're going to initiate very soon a Phase II study focusing on ovarian cancer. And in China, we have already an ongoing Phase II clinical trials in patients with lung cancer, both in combination with a PD-L1 or PD-1. So this is how -- at this point, how we focus on these 2 cancer types. Our U.S. study, as I mentioned earlier, we have a second cohort in our U.S. study. In that second cohort, we're going to use biomarkers, PD-L1 and CD73, to look at -- with more samples to look at correlation. And the outcome of the study may give us in-depth insight as to what additional cancer types we should focus on. And we are quite looking forward to start to studying this study and also look at the data [indiscernible].

Thank you, Dr. Zang. Due to time limitation, I think we will take one last question. So the last question comes from [indiscernible] at CICC.

This is [indiscernible] from CICC. And I have a small question is that following a successful collaboration with AbbVie on CD47 last year, any thoughts on the value and criteria of CD73 global partnerships? And is it still in discussion?

Yes. Thank you for the question. Our licensing global partnership with the global pharma for innovative proprietary assets is our strategy -- it's part of our strategy. And that is well demonstrated in the deal that we had with AbbVie last year regarding our CD47 antibody. So we internally developed that molecule. And validated clinical differentiation in a Phase I clinical study. And then we partnered with AbbVie. At the same time, we retained China rights using -- leveraging the clinical data generated in the U.S. and advanced very quickly through Phase II, Phase III and launched a product in China, and that has always been I-Mab's strategy. CD47 last year was first example. Now for CD73 antibody, we would follow exactly the same strategy. So based on the Phase I data, people are quite excited about this molecule. So we are in the process of discussing, negotiating with potential pharma partners. And at this point, I don't have any information to share because it's really pretty early. But when things approach to a certain point, we'll be very happy to share information with investors.

Okay. Thank you very much for the senior management for their time and a very detailed presentation and Q&A. Now at this point, I would like to thank everyone for joining our call. If you have any further questions about I-Mab or our pipeline or specifically about our CD73 asset, uliledlimab, please feel free to reach out to our IR team. Have a good day or evening depending on where you are. You may disconnect now. Thank you.

Thank you.

Thank you.