Good day, ladies and gentlemen. Welcome to CANbridge's omoprubart CAN106, phase I-B preliminary data readout call. It's our great honor to have the following management with us here today. Dr. James Xue, Founder, Chairman, and CEO of CANbridge Pharmaceuticals. Dr. Gerald Cox, Chief Development Strategist and Interim Chief Medical Officer. Glenn Hassan, Chief Financial Officer, and Pauline Li, Senior Vice President of Clinical Development and Operations. Management team will give us a presentation on the latest company development, and then we're going to have the Q&A session. I will hand over to James to start the presentation. Thank you.
Thank you, moderator. Good morning, good evening. Welcome to the CANbridge presentation, omoprubart CAN106, phase I-B update. We recently released the preliminary result through a press release on omoprubart CAN106, phase I-B trial in paroxysmal nocturnal hemoglobinuria, PNH, in China. Today we're going to walk you through more details of the data. Mostly will be done by Dr. Gerald Cox, our Chief Medical Officer. We can provide some question and answers at the end. Just briefly about CANbridge. CANbridge Pharmaceuticals is a China and U.S.-based and global-oriented specialty pharmaceutical company with a focus on rare genetic disease.
Over the past 11 years, we have built an integrated platform from research, development, manufacturing, commercialization, of a robust pipeline that involved products would address the highly unmet medical need in China and the rest of the world for rare diseases. The company has been led by a seasoned management team that have decades of complementary experience in research, development, and commercialization of a global assets. We have recently pivot from China focus to a more global focus orientation, and CAN106 is one of those examples, what we call in China for global. CANbridge owns the global right for development, manufacturing, and commercialization of CAN106 through the agreement with previous U.S.-based startup biotech company and WuXi Biologics. We have conducted phase I study in Singapore in healthy volunteer before we initiated the phase I-B in PNH in Mainland China.
Our goal is to develop CAN106 to its fullest potential, and firstly, to address the disease that we think has the most dire medical need in China or markets like China. We also emphasize on differentiated innovation, that today you are going to learn more about how we think CAN106 would have its own advantage and differentiating factor against other market products. With no further ado, I will let Dr. Gerald Cox to give you the full walkthrough of our phase I-B study. Gerry?
Thanks, James. Good morning and good evening, everyone. It's my pleasure to share with you these preliminary phase I-B results on omoprubart for the treatment of PNH. This is an anti-C5 monoclonal antibody that has an extended half-life that we're developing not only for PNH, but for other diseases where the pathophysiology is driven mainly by complement activation. We call this a pipeline within a product because we can potentially use the same drug for many different indications, many of which are listed here in this figure. I want to highlight some of the names of the diseases in green, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder. These are four indications for which anti-C5 therapies are approved.
As you can see, there's a host of other potential applications for anti-C5 therapies. In China, there's a very large population of patients that have these various disorders. Some of them number in the thousands, such as PNH and NMOSD, up to 20,000-25,000. There's also other indications like generalized myasthenia gravis, lupus nephritis, and IgA nephropathy, where there's some evidence that anti-C5 therapies may be beneficial. These patients number in the hundreds of thousands, up to 1 million patients in China. Altogether, we believe that by 2025, the global market will be more than $9 billion for these anti-C5 therapies. Next slide. Just a little background on the complement pathway.
When we inhibit C5 with a monoclonal antibody, we're inhibiting the terminal pathway of complement activation. This terminal pathway has two main roles. One is to lyse cells through formation of a membrane attack complex. The other is to induce inflammation. It is stimulated by the proximal pathway that converges on C3 complement. There's three different pathways. The classical, activated by antibodies, the lectin pathway, activated by sugar residues on cells and bacteria, and the alternative pathway, which is activated by tissue damage. They all feed into C3, which has three different roles. One is opsonization, where it coats cells that are then phagocytosed by the immune system. It induces inflammation, and then it also activates complement C5.
The first generation of products used to block the complement pathway have all relied on the terminal pathway inhibition. More recently, there was an anti-C3 peptide approved for PNH called pegcetacoplan. There's also factor B and factor D inhibitors. These are all considered proximal pathway inhibitors. When we think about the differences between proximal versus terminal pathway inhibition, I would say that the terminal pathway inhibitors really preserve the proximal pathway functions of opsonization and inflammation, which are used to ward off infections. I would say the proximal inhibitors, because they are able to block opsonization, there have been some additional gains in hemoglobin levels that have been seen in PNH.
With that also comes a potential cost because now that opsonization is blocked, it allows the PNH clones of red cells to increase to very high percentages. Under conditions where there's inadequate drug exposure, such as a missed dose or potentially an infection where a complement is stimulated, there's a much larger population of red cells that is now available for hemolysis or breakthrough hemolysis. What's been seen in trials to date is that with the proximal complement inhibitors, when there is breakthrough hemolysis, it tends to be pretty severe. We think that there's still a very important role for terminal pathway inhibitors, which provide not only efficacy, but also preserve the size of the red cell clones that are not as prone to hemolysis as with the proximal inhibitors. Next slide.
What is PNH? This is a disease that begins in the blood. Patients with PNH are lacking protective factors on the surface of their red blood cells that prevent complement activation from taking place. When those factors are missing, complement binds to the red cell surfaces and induces cell lysis, producing hemolysis. This results in severe anemia, increased risk of blood clotting, end organ failure, fatigue, and premature lifespan. The disease typically begins in early to mid-adulthood. In China, we believe the prevalence is higher than in the West, with about 23,000 patients in China. There is one approved anti-C5 monoclonal antibody approved in China, eculizumab, but it's never been launched for market access reasons.
We're developing omoprubart to fill that unmet need and to do better by providing a therapy that can be dosed less frequently, once a month, versus every two weeks for eculizumab. Next slide. This is the overall design of our phase I-B dose escalation study. We enrolled subjects with PNH who are complement inhibitor naive. We had three different cohorts with three different doses that we're investigating. Cohort 1 enrolled four subjects, and after induction doses of 12 mg/kg and 16 mg/kg of body weight, they went on to a maintenance dose of 20 mg/kg every four weeks. Cohort 2 enrolled four subjects as well, with an induction dose of 30 mg/kg and a maintenance dose of 40 mg/kg.
Twice that of cohort 1. Cohort 3 enrolled a larger number of subjects, eight, with both induction and maintenance doses of 80 mg/ kg, twice that of cohort 2. The primary analysis period was 26 weeks, upon completion, both cohorts 1 and 2 have gone into a long-term extension. Cohort 3 is halfway through the primary analysis period, I'll show you the data up through week 13. The primary objective of the study was safety, the primary endpoints that we're looking at are pharmacokinetics, pharmacodynamics, and efficacy in terms of reducing LDH as an indication of hemolysis inhibition, and improvement in hemoglobin levels as an indicator of transfusion avoidance. Next slide.
These are the baseline characteristics and demographics of the patients, and I'll focus mainly on the last column, which gives you the overall view of the study population. Mean age was 30, and they'd been diagnosed with PNH for about six years. There were roughly equal numbers of males and females that had normal body weights. Over 80% of the patients had received blood transfusions within the past 12 months. On average, three occurrences. The PNH red cell clone size was 50%, which is considered large. You can see that in terms of their red cells, they had severe hemolysis, as indicated by a mean LDH level of 1,553, which is about 7x the upper limit of normal.
LDH is a protein that's found within red blood cells and is released upon hemolysis, and this decreases the lifespan of red cells, and you can see the hemoglobin level of 7.8 g/ dL. This is about 4 g/dL-5 g/ dL below the lower limit of normal. These patients are severely anemic despite getting blood transfusions in the past. The blood transfusions just don't last for a long time. Next slide. Starting with safety, the drug was well-tolerated and safe. Again, pointing to the last column, during the course of the study, we had 14 subjects who experienced 59 treatment emergent adverse events, and of these, six subjects reported 18 adverse events that were assessed as drug related.
All of these were mild or moderate and transient. None was severe, and none was considered serious. The most common adverse event seen during the trial was an increase in indirect bilirubin. This results from hemolysis. There were no drug-related serious adverse events and no serious adverse events that led to discontinuation from the study. We also saw no cases of anaphylaxis or meningococcal infection. Next slide. Looking at the pharmacokinetics of the drug, we can see that as we increase the dose from blue to orange to green, indicating the low, medium, and high doses, we saw a progressive rise in the drug plasma levels in the blood, and you can see the peaks and the troughs coming down.
The increase in concentrations in the blood was dose proportional, and what I mean by that is, if you look at the Cmax and the AUC in the table, with each doubling of the dose, we see a corresponding doubling of both the Cmax and the AUC. The drug is well behaved from a pharmacokinetic point of view. You'll also see from the graph that each peak corresponds to a dosing interval. For example, between day 21 and day 49 is a 28-day dosing interval, and that's what our study, the safety and efficacy is based off of, every four weeks dosing. Next slide.
The target of omoprubart is C5, and it's an antibody that binds C5, which means that if it's doing what it's supposed to do, there should be very little C5 circulating in the blood, and that's exactly what we see. Right after dosing, we see a dramatic decrease in the free C5 levels across all three doses. Importantly, we use a threshold of 0.5 mcg/ mL of free C5 as the threshold, indicating complete complement inhibition. You can see all three doses bring the free C5 level down below 0.5 mcg/mL, but with the low and the medium dose, we see rises in the free C5 before the next dosing interval.
This is most apparent with the low dose, but now you see that the levels are progressively getting lower with the medium dose, and by the time we get to the high dose, we're able to maintain both the peak and the trough levels of free C5 well below the threshold of 0.5 mcg/mL, indicating not only complete inhibition, but also sustained inhibition with this high dose. Next slide. We can see the effects of that free C5 inhibition on LDH levels. Just like with the free C5 going down very rapidly, we also see a rapid reduction in LDH, indicating inhibition of hemolysis. Again, we see a dose response with the lowest dose in blue showing 49% reduction by week 26.
The levels in general are still above the target threshold of 351, indicating complete hemolysis inhibition. As we move to the next middle dose in orange, you can see we're getting closer to that threshold, with some patients below and some above. Getting to the highest dose, we're able to bring the LDH level down into the target range. You'll note that on the green line at week 12, there's a slight blip. This refers to, or was induced by two patients who had COVID infections that were associated with some mild hemolysis. Within a week, the levels were back down again. What we see here is that dose-dependent inhibition of hemolysis with the highest dose cohort, bringing the target LDH levels down into the desired range. Next slide.
When you inhibit hemolysis, this allows the red blood cells to circulate for a longer period of time, and in PNH, this is evidenced by an increase in hemoglobin, as well as red blood cell levels. With cohorts 1 and 2, you could see that over the course of the first 26 weeks, we see a average increase on about 7 g/ dL up to about 9 g/dL, indicating an almost 2 g/ dL increase. At week 26, the first cohort dose was increased to the middle dose, and you can see a continued rise up through week 54, with nearly a 4-g/ dL increase. Eleven is approaching the normal range. We have some patients that are actually within the normal range, just with treatment of the drug, but no blood transfusions.
Similarly, the middle dose cohort continues to increase a bit through week 42, up to about 2.5 g/ dL from baseline. Cohort 3 in green, at the highest dose, these patients started off at a higher hemoglobin level at baseline, as we wanted patients to have recent blood transfusions before coming into the study, to see whether we could still see a hemoglobin increase. In fact, we do, with levels increasing by about 1 g/ dL by week 13. Again, in this cohort, at week nine, we see the levels are a little bit higher than, say, at 12 and 13. These, again, were influenced by the two subjects who had COVID infections, associated hemolysis, where the hemoglobin levels decreased in those patients.
We would expect that the levels to rise now that they've recovered from their COVID infections. Next slide. To summarize, the efficacy data, we see dose-dependent reductions that occur pretty rapidly and are very substantial across the three cohorts. We have, in the third cohort, LDH levels of averaging 295, which is below the 351 threshold for hemolysis inhibition. We see a, as we increase in the dose, a progressively increasing percentage of patients that have achieved the LDH reduction less than 1.5x upper limit of normal, at least once during the 26-week study. The hemoglobin levels have risen across all three cohorts and continue to rise throughout the first year of treatment.
The mean hemoglobin levels for each group are now at nine or higher. This is important because nine would be considered a threshold for transfusion independence in the West, and certainly in China as well. We see at least half the patients in the first two cohorts have had significant rises in hemoglobin levels. Next slide. To interpret what these hemoglobin level increases mean, I refer you in this table to the hemoglobin level greater than seven, which would be considered transfusion avoidance levels in China, and hemoglobin level greater than nine, which would be considered transfusion avoidance levels in the rest of the world. China has a very limited blood supply, their threshold for transfusion is much more rigorous than in the West.
You can see, particularly in the first two cohorts that have been treated and start off with low hemoglobin levels, that we're able to achieve transfusion independence, based on hemoglobin levels. Certainly for China and for several of these patients, also for the West. The patients in cohort three, they started off with higher hemoglobin levels, above that of China, for trying a transfusion, and in the West, we're seeing an increase in percentage of patients that would qualify for transfusion avoidance. Again, this is only through week 13, so we would expect this percentage to go even higher.
We believe that this is particularly important for China because the blood supply is so limited, being able to free up patients that don't require blood transfusions would be able to decrease the burden on the healthcare system. Next slide. The overall summary is that the drug was safe and well-tolerated, with a few drug-related adverse events that were all mild or moderate. None was severe or serious. We did see two cases of breakthrough hemolysis associated with COVID infections, but these were mild and resolved within a week. The drug had a dose-proportional exposure over the 20 mg/kg- 80 mg kg range. This led to dose-dependent inhibition of free C5, with at the highest dose, we saw both complete and sustained inhibition over the entire course of the four-week dosing interval.
In terms of efficacy, we saw dose-dependent reductions in hemolysis, to the point of complete hemolysis inhibition in cohort 3. This led to rises in hemoglobin values, which for many of the patients brought them into a range both for China and for the West of transfusion independence. We're very pleased to see these results in this phase I-B study. Next slide. What does this mean now? Well, now that we've been able to demonstrate really proof of concept with PNH, we believe that these results will be applicable for other indications, both approved as well as novel indications that we're looking into.
Our immediate next step is to communicate with the CDE and to align on the phase II trial design as the pivotal study for PNH approval in China. We're currently in mid 2023. I've just presented the preliminary results. The remaining patients in cohort 3 should complete the primary analysis period by the end of the summer. We are looking to start our phase II study by the end of this year in Q4, with top-line data available approximately one year later. Then we would plan to submit a new drug application in China in the first half of 2025. I thank you for your attention, and I'm happy to answer any questions that the audience may have.
Thank you, Gerry. Now, we are in the Q&A session. We look forward to having these interactions with our audience.
Thank you, management, for the presentation. We've now come to the Q&A session. Please make sure to change your name on Zoom to the format of institution name and your personal name for easy identification. If you have any questions, you can click the Raise Hand button. You will be placed in a queue. When the host announces your name, please state your name, the institution you belong to. You can ask your question. You can also type your question in the chat box. We will read it out for you. The first question comes from Jay Ma of Kira Pharma. What is the loading dose?
Sure. Thanks, Jay, for the question. We use different loading doses in the three different cohorts. For the third cohort, which we believe is the therapeutic dose, we're using a loading dose of 80 mg/ kg, which is the same as the maintenance dose.
Thank you. We will now take the next question from any investors. If you have any questions, you can click the Raise Hand button, or you can type in the chat box, and we will read it out for you. The next question is: There are currently several therapies available on the market for treating PNH. Some have already been approved, including those targeting C5 and C3. Could you please explain again the advantages of, CAN106, please?
Sure. CAN106 was developed to be a long-acting anti-C5 monoclonal antibody, which we believe will decrease the burden on the healthcare system, particularly in China. Currently, the standard of care for PNH has been eculizumab, which is dosed every two weeks. Omalizumab is dosed every four weeks, so a 50% reduction in dosing frequency, which we believe will not only free up resources for healthcare systems but also decrease the burden on patients. In China, eculizumab is approved, but it's never been launched because of pricing considerations, and so we're looking to fill that niche in China. In terms of the other drugs that have been approved, there are biosimilars to eculizumab that are waiting in the wings for approval.
These will all be dosed every two weeks, so we feel that we have a competitive advantage there because ours would be dosed every four weeks. Other inhibitors of the proximal pathway are being evaluated or, you know, in the case of pegcetacoplan, have been approved as a treatment for PNH. Again, I would say these do have the added benefit of inhibiting opsonization, which will increase hemoglobin levels, but they also leave those red blood cells, the PNH clones, the cells, the clone size increases to almost 100%
That makes those cells particularly susceptible to hemolysis if there's a decrease in the drug concentration or if patients have a concurrent infection in which the immune system is stimulated, and complement levels rise higher than the drug can accommodate, leading to potential for severe breakthrough hemolysis. Some of the newer proximal pathway inhibitors are oral, like iptacopan, you know, twice daily dosing. Again, if patient is non-compliant, and they have a very large red cell clone or PNH cells, they could set themselves up for a severe hemolytic event. The other drugs, like I'd mentioned, pegcetacoplan, that is dosed twice weekly through a rather large subcutaneous infusion of 20 mL.
Again, that, you know, is associated with site reactions and also, you know, requires those rather large subcutaneous infusions on a very regular basis every week.
Thank you, Dr. Gerry. Once again, if you have any questions, you can click the Raise Hand button, and you will be placed in a queue. Otherwise, you can also type your question in the chat box, and we will read it out for you. The next question is, when is omoprubart expected to complete clinical trials? Could you tell us a little more about when we can enter the stage of applying for NDA?
Yes. We plan to meet with CDE in the very near future to align on our pivotal study design for PNH. We're looking to begin enrollment at the end of this year, and between enrollment and the standard 26-week evaluation period, we would expect to complete the study at the end of 2024 and then file for NDA in the beginning of 2025.
Thank you, Dr. Gerry. Once more, if you have any questions, you can click the Raise Hand button now, or you can also type your question in the chat box, and we will read it out for you. I repeat, if you have any questions, you can click the Raise Hand button, and you will be placed in a queue. You can also type your question in the chat box, and we will read it out for you. We will now hand over to James once again for some closing remarks.
Thank you, Gerry. Thank you, moderator, and thank you for the questions you raised. We are very pleased with the preliminary result from the omoprubart phase I-B study in PNH in China. We definitely will work hard to, you know, initiate and accelerate the remainder of the studies and to get this life-saving and life-changing therapies to the patients who need them in a very dire situation as quickly as possible. As we speak, CANbridge has invested also in efforts that allow us to expand the indications as well, the geographies, that would allow CAN106 to impact as many patients as we could. In particular, in late last year, we have established a world-class scientific advisory board to guide us on the existing unknown indications or any indication that would allow the anti-C5 complement pathway to become the handle.
Far, we're making progress. In particular, late last year, we received U.S. FDA's grant of orphan designation of CAN106, GMG, and this is just the beginning. Our goal is to let the most dire need patients to get the treatment, namely PNH, in China or markets like China. We're very pleased that not only we can match the current standard of care approved in China, but perhaps we also can allow CAN106 to have an edge. As Gerry's mentioned, 50% less of the frequency to reduce the burden to both healthcare delivery system as well as to patients. We're hoping, you know, similar characteristics can be defined for the rest of the indications that will bring change and positive impact to the healthcare market in rare disease and beyond, in China and beyond.
Again, thank you very much for joining us tonight and this morning, and we look forward to updating you on additional progress of omoprubart, as we completing the phase I-B study and initiating the future studies. Thank you.
Ladies and gentlemen, that does conclude our presentation for today. Thank you all for participating. You may disconnect now.