Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Nevan Elam. Please go ahead.
Thank you and good afternoon. I am Nevan Elam, Rezolute's Chief Executive Officer and Founder. Before we begin, as a reminder, the information discussed during this call will include forward-looking statements which represent the company's view as of May 4th, 2022. We undertake no obligation to update or revise any forward-looking statements to reflect new information or future events, except as required by law. Please refer to today's press release, as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements. Thank you for joining us today as we offer an overall update on our business and an opportunity for you to ask us questions. Needless to say, it's only Wednesday, but it has already been quite a week for us at Rezolute.
On Sunday, at the Pediatric Endocrine Society's annual meeting, Dr. Paul Thornton presented compelling data from our phase II-B RISE study, treating patients with congenital hyperinsulinism. Later that evening, we announced a $130 million raise to fund our ongoing efforts. First, I'll briefly recap the results from the RISE study. We enrolled 23 patients across diverse genetics, gender, and age. The patients on average were 6.5 years old, and the youngest was two. One third of the patients enrolled were on diazoxide, and approximately half were on somatostatin analogs, both as background therapies. All patients had to meet our robust screening criteria to ensure that they were experiencing a substantial amount of hypoglycemia, regardless of whether they had pancreatectomies or were on background therapies.
Based on data gathered at baseline, we learned that patients on background therapies had some hyperglycemia, while also spending a significant amount of time in the hypoglycemic range. In fact, about 25% of the time. Going into the study, we hope to achieve a reduction in hypoglycemia of at least 25% from baseline, as this is a magnitude of correction that would be expected to translate into meaningful clinical benefits to patients. Our antibody was highly effective at correcting hypoglycemia, as even our starting dose of 3 mgs per kg achieved approximately a 25% reduction in hypoglycemia. Substantial improvements in hypoglycemia of approximately 75% were seen at the 6 and 9 mgs per kg dosing cohorts. Target and expected RZ358 concentrations were achieved in the study, and dose exposure dependent responses were also observed.
Importantly, RZ358 was generally safe and well tolerated, and there were no adverse drug reactions. With these results, we believe that there is clear potential for RZ358 to be a monotherapy for patients with congenital hyperinsulinism, as well as other forms of hyperinsulinism. With these strong study results in hand, we thought that now was an opportune time to confidentially approach the investment community, and those efforts culminated in the closing of the financing today. Nice to see that our enthusiasm for the program is shared by investors. The financing not only funds phase III for RZ358, but it also allows us to progress our small molecule platform, our oral plasma kallikrein inhibitors, and in particular, RZ402 for DME.
In fact, it would be useful to remind everyone of the status of RZ402 since we announced positive results from a phase I multiple ascending dose study a few months ago. I'm going to go ahead and ask our head of clinical, who's here with me today, Dr. Brian Roberts, to offer some perspective on the program.
Thanks, Nevan. Happy to do so. Our small molecule platform consists of a portfolio of oral plasma kallikrein inhibitors or PKIs. RZ402 is our most advanced PKI that we're developing for diabetic macular edema or DME. DME is the leading cause of blindness in the U.S. Like all microvascular complications of diabetes, it is a disease of blood vessels with collateral consequences to the end tissue, in this case, the retina. Leukostasis ultimately leads to inflammation, disruption of the blood-retinal barrier, and the subsequent leakage of fluid into the retina. The accumulation of this fluid at the macula, which is responsible for high resolution central vision, can lead to progressive loss of vision and blindness. The current standard of care therapy for DME are the anti-VEGF therapies, which require recurring injections into the affected eyes by a retinal specialist.
These therapies have substantially improved the treatment of DME, but still leave many patients undertreated. Half or more of patients do not adequately respond and subsequently are at risk for ongoing visual loss and blindness. Lack of response is likely due to a combination of delayed initiation, intermittent dosing or suboptimal regimen compliance, or simply the fact that other non-VEGF dependent pathways are involved in the disease. Thus, there remains a substantial need for better therapies beyond additional approaches targeting VEGF. An oral alternative with a different mechanism of action has the potential to address VEGF independent processes, enhance convenience and compliance, treat DME sooner and in a manner more aligned with the preventative care of other diabetes complications. Reach more patients and therefore achieve better overall outcomes. The kallikrein-kinin system, or KKS, is an alternative target to treat DME.
The KKS is part of the first line of defense against injury or infection by coordinating the closely linked processes of increasing vascular permeability and the influx of inflammatory cells and mediators from blood vessels to respond to the nearby tissue insult. In response to vascular injury or insult, kallikrein is formed from its precursor prekallikrein and in turn cleaves kininogen to bradykinin. The KKS is highly implicated in DME as demonstrated in animal and human studies. Specifically, several studies have shown that the KKS is a separate and VEGF-independent pathway involved in the development of DME. There are two different approaches to inhibiting kallikrein in the setting of DME. Programs targeting intravitreally delivered PKIs have taken the first step. They have shown proof of mechanism and concept in early clinical studies and thus further validated the KKS as a target.
However, in falling back to recent treatment paradigms within the ophthalmic therapeutic area of using injections into the eye, these programs may also be missing the target, so to speak, by failing to achieve adequate and sustained plasma kallikrein inhibition at the retinal vasculature behind the eye. These intravitreal approaches may be further hampered in the proof of concept stages of development by the necessity to study and treat a higher hurdle VEGF non-responsive patient population, which is the population that would need another intravitreal therapy. This is something that may be avoided with an oral administration route. The advantages of an oral small molecule PKI go beyond the obvious convenience factor. Rather, it is our belief that high systemic exposure is in fact necessary to unlock the full potential of a PKI.
Simply put, the KKS is a vascular target for a vascular disease and therefore requires a vascular approach to treatment. In fact, in our studies completed thus far, RZ402 achieves substantial decreases in retinal vascular leakage in animal models utilizing this systemic hypothesis without meaningful drug concentrations in the eye itself. RZ402 is a potent and selective PKI, which has been extensively characterized in animal pharmacology models of DME, and to our knowledge, is the most advanced and differentiated oral systemic PKI in development for this indication, having now completed Phase 1 clinical trials. While the field has often focused on HAE, or hereditary angioedema, we have had an early emphasis on DME and believe that we have highly characterized and best-in-class compounds.
Kallikrein inhibitors developed in an HAE setting have primarily relied on ex vivo plasma kallikrein inhibition assays and other biomarker assays for potency estimates, and these do not always translate well into clinical efficacy. While RZ402 is potent in these traditional assays, including in our recently completed multiple ascending dose clinical study, our studies in animal models of diabetic retinal vascular leakage demonstrated that RZ402 is even more potent in vivo. In fact, in vivo it's about tenfold more potent than in the in vitro assay, which is likely a result of localization to the vascular site of action, and is an important observation because these highly effective concentrations represent a more relevant benchmark for targeting human concentrations of RZ402. Systemic administration of RZ402 consistently inhibited retinal vascular permeability and leakage by up to 90% in animal models.
Further, RZ402 was effective in both preventing retinal vascular leakage as well as treating retinal edema and leakage that has already occurred. Not surprisingly, we put more relative weight in animal studies of DME than in in vitro activity or inhibition assays and are optimistic that RZ402's high potency in these models can translate well into clinical efficacy. Our Phase 1 single ascending dose and multiple ascending dose studies with RZ402 in healthy volunteers concluded earlier this year. Single doses between 25-250 milligrams were evaluated, while in the multiple ascending dose study, the top dose was increased to 500 milligrams due to excellent safety observed in the previous doses. Between both studies, a total of 70 participants were enrolled and 56 have received RZ402.
With a focus on the multiple ascending dose study, four sequential ascending dose cohorts between 25- 500 milligrams were enrolled in a randomized, double-blind, placebo-controlled fashion, with each cohort comprising 10 participants of eight active and two placebo subjects. Dosing was once daily by mouth for 14 days. The main study objectives were to evaluate repeat dose safety, tolerability, and pharmacokinetics, while an exploratory pharmacodynamic endpoint included an ex vivo kallikrein inhibition assay to evaluate target engagement. The results of the multiple ascending dose study in healthy volunteers affirmed the single ascending dose study findings while safely exploring even higher exposures over 14 days. Specifically, RZ402 was safe and well tolerated across the entire dose range, and there were no serious adverse events, adverse drug reactions, or discontinuations due to adverse events in either of the clinical studies.
No adverse events emerged as being related to study drug or as a potential side effect of RZ402. Results with respect to the pharmacokinetics demonstrated that RZ402 is bioavailable, with dose-dependent increases in systemic blood concentrations being observed. Steady state was achieved with less than two-fold accumulation, and the half-life ranged between 20-25 hours across the dose groups. High plasma concentrations were achieved that far exceeded target concentrations both at peak and throughout the intended 24-hour dosing interval, thus supporting the potential for once daily oral dosing. Consistent with the observed human safety, the concentrations were well below safely tested concentrations in animal toxicology studies. The study showed that daily dosing with RZ402 inhibited plasma kallikrein in human plasma at a magnitude that benchmarks comparably to other kallikrein inhibitors that have been developed for HAE.
However, more importantly, since RZ402 is more potent in vivo, the observed concentrations at all dose levels far exceeded target concentrations that were highly effective across multiple animal models of DME and related conditions. We believe the availability of these in vivo and modeled estimates increases the likelihood of clinical success in DME relative to relying solely on in vitro assays. These results have enabled the advancement into Phase 2 proof of concept studies in DME patients. Thank you, and I'll turn it back to Nevan.
Thanks, Brian. While this week has definitely been a focus on the RISE study and our Phase 2 B data for congenital hyperinsulinism and the unveiling of that data, we are really pleased about the results from both of our programs, both of our platforms, and very encouraged on our forward-looking journey. With the completion of the $100 million raised today, we are well funded to take RZ358 and RZ402 into the next stage of the development. Specifically, we plan to commence the phase II study for RZ402 in DME in Q4 of this year, with an expected readout in Q4 of 2023. While we're still putting the finishing touches on the phase two study design, in general, the study will be designed primarily to demonstrate proof of concept in patients.
Namely, that, you know, taking a kallikrein inhibitor by mouth can reduce macular edema as measured by an OCT scan. We wanna show the potential of this approach in a clean monotherapy study. With those objectives in mind, the study will be a randomized, double-blind, placebo-controlled parallel arm study comparing two to three dose levels of RZ402 versus placebo in patients with DME who are not taking or haven't recently taken anti-VEGF therapies. Dosing will be once daily for three months. The primary endpoint will be changed from baseline in central subfield thickness on OCT scan, with secondary endpoints including best-corrected visual acuity and diabetic retinopathy severity scale. Given the size of the market and significant unmet need in DME, we believe that RZ402 has the potential to be a game-changing oral therapy that could significantly disrupt the current treatment paradigm.
With respect to RZ358 and the RISE study, we're still finishing up the study, including patients that are completing the follow-up safety period. Thereafter, we'll begin interactions with regulatory authorities in the U.S. and Europe in an end of phase II meeting setting. Planning for alignment with regulatory authorities, we are already considering starting the phase III registrational study in Q1 2023. The size of the study and duration of treatment will be discussed with the regulators, but we currently believe that we are likely to have three dosing arms, including two dose levels of RZ358, namely the 6 mg/kg and the 9 mg/kg, which will be added on to standard of care, and a third control arm of continuation of standard of care only. We expect enrollment to take 12 months and are planning to have top-line data in the H2 of 2024.
Based on precedent and the RISE study results, we would expect the primary endpoint to be the change in number of hypoglycemic events per week based on BGM or point of care blood measurement, with multiple secondary endpoints such as time and hypoglycemia measured by continuous glucose monitoring. Hopefully, what we've outlined here for you today provides you with a good overview of our current status. Now we welcome any questions that you may have.
We will now begin the question and answer session. To ask a question, you may press star and then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. If you have a question that you would like to send in, please email it to rezolute@argotpartners.com, where argot is spelled A-R-G-O-T. That is rezolute@ argotpartners.com. At this time, we will pause momentarily to assemble our roster. Our first question today will come from Kevin DeGeeter of Oppenheimer. Please go ahead.
Thanks for taking our questions and appreciate the really detailed update here, and you know, congratulations on a really spectacular race. So I guess just with regard to you know, 358 and CHI, you know, how should we think about the clinical relevance of time and range, you know, the primary from the II-B study, you know, given the infrequent incidence of kind of low grade you know, hyperglycemia. Is that a useful metric to think about for phase III development? And can you kind of you know, describe the II-B data on that metric in a little more detail than was provided in the press release?
Sure, Kevin. This is Brian. Thank you. Time in range was of interest, and we thought it would mirror the hypoglycemia improvements in this study. What we didn't appreciate is the magnitude of mild hyperglycemia in the background on standard of care therapies. If you might recall, our previous phase II-A study was in fact a monotherapy study where we washed out a standard of care. In that study setting, we saw hypoglycemia improvements that really mirrored the time in range improvements. In this setting on background therapies, with RZ358 being so highly effective at raising glucose across the board, we did see a modest increase in mild levels of hyperglycemia. At baseline, hyperglycemia occurred at about 3% of the time, and after treatment with RZ358, it was about 8% of the time.
Well below levels that are guided even in diabetes patients, where hyperglycemia is the main concern. Also importantly, the magnitude of the hyperglycemia was in the mild range. We had no clinically relevant hyperglycemia, no events greater than 250, no adverse events and no metabolic consequences associated with the hyperglycemia. As it pertains to the time and range endpoint, we again thought that would mirror hypoglycemia. The hypoglycemia corrections were so pronounced that the endpoint became irrelevant in this study setting. We really do believe that the study showed the potential for RZ358 to be a monotherapy. We would expect the time and range, again, with it not being a clinically relevant endpoint, it was an endpoint that was of interest to us in the phase II setting.
We would not anticipate that to be a you know a primary or secondary endpoint in the phase II program and would not expect the FDA to want that either.
No, great. That's really informative. Then just on DME, really appreciate the detailed discussion there. Just any high-level thoughts on how you're thinking about, you know, business development around that program, particularly in light of, you know, a much stronger balance sheet, you know, to drive internal clinical development forward.
Yeah. Thanks, Kevin. This is Nevan. You know, we will absolutely be opportunistic as we look to bring that program forward. It is a, it's very different than the congenital hyperinsulinism disease because DME is a large indication. Just given the amount of interest in the last year and a half, since Brian and his team have done a wonderful job bringing that through phase I and demonstrating importantly the first step, the PK profile, it being bioavailable. Now it's really all about generating this proof of concept in the phase II study in DME patients. With those study results in hand, you know, thinking forward, we, you know, we will look to one, potentially push that forward even further ourselves to capture as much value as possible.
Of course, you know, we will always be open to the potential for, you know, opportunistic relationships that could make sense for us in a non-dilutive setting.
Well, great. I'll get back into queue. You know, congratulations. It's tremendous amount of progress in the last several days and weeks.
Thank you, Kevin.
Our next question today will come from Michelle Gilson of Canaccord. Please go ahead.
Hello, team. This is Michael on for Michelle. Congrats on the great news from Sunday, and we have a couple of questions ourselves. Regarding the regulatory path forward, you provided some details about what your primary endpoint will be. A competitor used the endpoint of rate of hyperglycemia when assessed by intermittent self-monitored plasma glucose, and there's a couple of different metrics, I guess, or endpoints that could be used. I guess, what do you think about would be the most reliable? I suppose it's the one you chose, but about also what may be recognized by regulators. In addition, about what proportion of patients would be from the US versus ex-US in the phase III study?
Hi, Michelle. This is Brian. I'll take the question. Thank you. So with regards to the endpoint and the competitor's endpoint, the results and the endpoint we're referencing, which is change in hypoglycemia events per week by point of care blood glucometer, is the same endpoint used. The only precedent there is in a competitor program. Based on, you know, the results from the RISE study, we feel quite confident that that endpoint is one that we can meet. We also think that there's significant importance in time in hypoglycemia, which is monitored continuously through a CGM. And that's an important clinically relevant endpoint as well as an endpoint that we think would be in the phase III study as well.
We'll have a discussion with the agency on which of those two makes the most sense, based on the precedent. That very well may be a change in hypoglycemia events by BGM. You know, again, we feel confident we can monitor that and capture that and demonstrate benefit.
Excellent. Thank you.
The, uh.
Oh, sorry, go ahead.
With regard to. Remind me your other question.
Number of patients.
Thank you.
You know, we're right now, I think we're in the early stages of evaluating where the patient, patients will come from, both between Europe and the U.S. You know, we had sites enrolled in the U.S. as well as in Europe in the phase II= B. It'll be really about where we find the patients that present with the background characteristics that are necessary to meet enrollment criteria, whether that is in the States primarily or in Europe primarily. All of that, I think, to be determined.
Excellent. Thank you. If I can just get one more, and that's a good segue from what Brian was saying. What do you say would be the bar for success for a patient staying on RZ358 chronically instead of moving into a pancreatectomy or partial pancreatectomy? We did notice that some patients are still spending about 10% of their time in hypoglycemia or about two hours per day. Obviously a drastic improvement, but does the two hours per day still pose a risk to patients?
In general, the trend toward pancreatectomy has been lessening over recent years. In a therapy that's safe and effective would be expected to, you know, further decrease the rate or the incidence of pancreatectomy used to treat the disease.
The recommended treatment goals are to keep the blood sugar above 70. That's what the Pediatric Endocrine Society recommends. That's what our principal endpoints are based on. The reason for that is because in this patient population, values approaching 70 or just below 70 can quickly become severe. It's very important to stay away from, you know, stay away from that by keeping the values well above it. I would say that although the patients do have some residual hypoglycemia on average, a significant number of patients in the study responded by a better than 75% improvement in hypoglycemia, so six out of seven at the top dose. I would also add that severe hypoglycemia was almost completely ablated for the average patient and for most patients across the study.
RZ358 was highly effective at particularly keeping glucose above levels that are more severe.
Excellent. Thank you for taking my questions.
The next question today will come from Douglas Tsao with H.C. Wainwright. Please go ahead.
Hi. Good afternoon, and thanks for taking the questions and congrats on the data and all the progress. Just, I'm curious, Brian, maybe as a follow-up to the last question in terms of residual hypoglycemia.
Sure.
It seems like for most patients, they had really strong responses. For the few patients that didn't see as good a response, was there anything noticeable about them? I mean, I guess it's hard to sort of figure out a trend just given the small numbers. But was there anything sort of maybe that indicated who would be a really strong responder and this was something that some of the non-responders lacked? I have a follow-up.
Yeah. Thanks, Doug. I mean, I wanna emphasize, again, it was nearly a universal response, and the response was strong. Of course, at a 25% sort of threshold, we had a 100% response at the top dose, I believe at the mid dose as well. A 100% response at the top dose for better than a 50% improvement. Just highly clinically significant. Again, only one patient did not achieve at least a 75% response. Really it was quite a universal response. I'd wanna caution you to say that there were non-responders as a whole. There may have been some patients with slightly less response, but really it was quite a pervasive response across the study.
With that said, you know, we're still digging into the data of course, but we haven't seen anything that's coming out in terms of, you know, responders or non-responders or intrinsic factors that are affecting response. Again, response was good across the study and we're really reassured because this is a diverse patient population we enrolled. It's young patients, you know, 16 patients between the ages of 2-6. All the usual genetics that you see in the population, you know, mix of gender. We're reassured by the efficacy and safety in this setting in terms of how that will translate going forward.
Just as a follow-up, you know, for the phase III study, I mean, certainly in RISE, you sort of demonstrated that RZ358 has the potential to be a monotherapy. It sounds like you're gonna, similar to RISE, so many patients or most patients in the phase 3 are gonna have background therapy as well. Just given, you know, the perceived downsides with diazoxide and some of the other current treatments, how do you think about potentially establishing RZ358 as a monotherapy just because it seems that it has great potential to really be a standalone agent?
Yeah, that's a great question. You know, this is a serious disease, of course, we're treating. Although the available therapies are, we've shown yet again, you know, not very effective, these patients do have to be on something. By the time that you pick them up in the clinical trial setting, you know, they're on background therapies and that becomes the execution pathway for these studies. I see two ways to continue to be able to show the potential for RZ358 as a standalone going forward. One is, you know, as we naturally advance the program, the patients will be younger and younger in the clinical trials. We'll, you know, begin to have the opportunity to put patients on RZ358 as a first therapy.
Secondly, in the pivotal study that we're in the process of thinking through and designing that we'll interact with the FDA on, there will be a controlled period, of course, where patients receive RZ358 add-on to background therapies compared to background therapies alone. We do expect that we're going to need to dose longer than is necessary for that controlled period as far as a glucose endpoint. During that phase where we continue to gather safety data, we believe there's an opportunity then to wean or potentially stop background therapies and to gather, you know, an additional supportive data set toward positioning RZ358 as a potential standalone.
Okay, great. Thank you very much. In terms of the phase III, just if I may, background therapy would be allowed, but it wouldn't if a patient hadn't been treated already, especially as you go into younger patients, they wouldn't be excluded from the study.
That's correct. That was in fact the case in the RISE study. Even though it was add-on to background therapies, we had three patients who were not taking anything, and that was primarily because they didn't respond at all to these medications. You know, you have a safety risk with these without any benefit. The physicians had stopped these prior to study entry. In two of those cases, the patients actually had to have more than half of their pancreas removed. We're still having, as we know from the literature, substantial hypoglycemia that met the study entry criteria. Yes, we would continue to take the same approach into phase III.
Okay, great. Thank you so much.
Our next question today will come from Jason Butler with JMP Securities. Please go ahead.
Great. Thanks for taking the questions, and let me add my congrats on the RISE data. I guess just at a high level, you outlined the phase III design. Any significant or you know substantial changes you'd expect in design? And then just in that context, can you talk about any of the reasons for screen failures and any thoughts on that, you know any implications there in terms of the phase III trial design?
Sure, Jason. Thank you. I'll start with the second question on the screen failures. We actually had quite a relatively low screen failure rate in the study. It was about a third of the patients screen failed. About half of those screen failures did not have adequate hypoglycemia that met our entry criteria, so they weren't significantly addressable. The other half were a mix of reasons that were primarily sort of patient choice and family choice, particularly participating in the study in the setting of COVID and having to come to the hospital. You know, we think the screen fail rate was pretty low, and as a whole, we picked up you know, a lot of patients who were at need.
We would not expect significant differences from between the RISE study and the phase three study in terms of the design, particularly as it pertains to the patient population. We think, you know, we enrolled the right patients. We adequately and robustly characterized their hypoglycemia. We would expect to enroll, you know, more patients in phase III than in phase II on the order of approximately double the sample size, but we'll have that discussion with the health authorities. The other key difference I think has already been outlined. Rather than a sequential cohort design, it will be a parallel arm study that's controlled against standard of care alone. Of course, we will be dosing, you know, longer than the eight-week duration that we just dosed in the RISE study.
The last, I think, key difference is, as we would expect, as we move through the program and gather good efficacy and safety, particularly in young kids, that we will be able to continue to, you know, lower the age as we move into phase III.
Got it. Then, just thinking about the use of monotherapy, you know, and the potential in the real world to switch patients off of therapies like diazoxide, can you just talk about the time course of efficacy? How quickly did you see an impact? Just broadly, how do you think about, you know, the implications for switching patients onto RZ358 monotherapy?
Yeah. We see the onset of effect in a similar time course as we've seen it in the past in our earlier phase studies. There's generally a few days before onset takes effect, and then the improvement in hypoglycemia kind of builds over a two- to four week period and is optimal at that timeframe, and then of course continues through the duration of the RISE study. I would take the opportunity to comment and say that we saw kind of an offset of effect when RZ358 was withdrawn, which is reassuring to see in terms of evaluating the efficacy. I don't think that has any impact on the practice or how RZ358 might be used.
This is a chronic disease, and, you know, they're managed, these patients are managed through a variety of means and a kitchen sink approach of whatever works. What we've observed for our RZ358 in terms of the onset, I think would be fine and consistent with the way these patients are managed. In fact, the long half-life and the long biologic effect, if you will, also advantages our RZ358 in many ways, in terms of one, making sure that the drug is in with a 30-minute IV infusion, and then knowing that there's a buffer of effect that's sustained, you know, two or more weeks. We think it's actually an ideal time course.
Got it. Thanks. Just last one from me. Obviously, the numbers are relatively small here, but even on an anecdotal level, can you speak to any reports of improved function or quality of life by the, you know, from patients and caregivers?
Sure. We did not formally or robustly evaluate patient-reported outcomes in the RISE setting. That would be something that we would do as a pre-specified exploratory endpoint in phase III. With that said, it was an open label trial, and you know, we did hear anecdotes. For what that's worth, we did receive quite a bit of positive feedback from patients and families indirectly. Things like, you know, their children were sleeping through the night, they had an appetite for the first time and were requesting food. Remember, these patients from birth really are force-fed in many ways as a method of trying to treat hypoglycemia.
There are a lot of psychosocial issues and food aversions, and we were really surprised to hear this sort of feedback that the therapy had sort of normalized the dietary pattern and the kids were hungry. We had investigators and families who wanted to come off their background therapies. Of course, that was not the study design and no patients, you know, did so. That was certainly expressed to us. I think most importantly in telling is we have patients who want to stay on the therapy, and that's something that, you know, we're looking at now, as we think about an expanded access program and bridging that into our phase three trials and the availability of our RZ358.
Okay, thanks. Congrats again.
Thanks, Jason.
Again, to ask a question, please press star then one. If you have a question that you would like to send in, please email it to rezolute@argotpartners.com. The next question comes from Zegbeh Jallah of Roth. Please go ahead.
Hey, guys. Congrats on the progress and the raise. We should probably remove some financing overhang. We just have a few quick questions. I think the first one for us is about RISE. Can you state what the most common baseline therapy was or standard care therapy was, and then how the number of glycemic events may vary as a function of baseline or standard care therapy, and how many patients might you need to fully power the phase III study to show superiority? And then a tag along to that is just kinda commenting based on this new data that you have, how has that really changed your perception, if at all, about, you know, how much market share you could possibly gain? And then I have a couple follow-ups.
Okay. We're trying to jot these questions down, Zegbeh, so I apologize if we don't hit all of them, but just feel free to remind us. As far as the most common standard of care therapies in the background for the trial, those were somatostatin analogs. More than half of the enrolled patients were taking these therapies. We did not see really any effect or variability among the enrolled population in the background hypoglycemia based on their treatments. With the exception of, you know, the patients who had a pancreatectomy had obviously failed all of the therapies, and they were, they tended to be fairly severe. Again, it was really the case for the population that we enrolled as a whole.
It didn't seem to track toward any one therapy in particular. That's your third question, Zegbeh, if you could remind us.
Yeah. Just so based on the efficacy seen in the standard care arm, you know, how many patients do you think you might need to fully power the phase III study? Based on the new data you generated, you know, how has that changed your perception of what the market opportunity could be for 358 ?
Hi, Zegbeh. It's Nevan. I'll give Brian a break. I think for the phase three that we're really looking, probably in the neighborhood of, you know, 40 patients, plus or minus, depends on the study design, depends on our interaction with the regulators. It depends, quite frankly, on the view of this compelling data that we generated in the RISE study. We have a lot of questions in a positive way, a positive sense that need to be answered as we begin those into phase two interactions. I think one thing is clear, we do expect it to be one study. One pivotal study for phase III moving forward.
In terms of market share, we've generally taken a conservative approach to, as we think about the market, and we may be overly conservative in that regard. What I mean by that is, you know, diazoxide, as is noted, is a pretty tough drug in terms of side effect profile and the fact that it's still patients are left with residual hypoglycemia. Having said that, we really do exclude most of the patients who are on diazoxide from our kind of market projections. I think as we go into phase III generate more data, have more safety, that, you know, increasingly we are likely to potentially capture more of those patients from a market perspective moving forward. I always think about it the following.
It's a pharmacoeconomic exercise, but if I had my child on diazoxide and given that side effect profile, including the risk for a black box warning that exists for pulmonary hypertension, and there was an alternative therapy that was efficacious, you bet I would absolutely want my child to be on that. I think that's the view of, you know, the KOLs as well and the broader community, but those are bridges we'll cross as we move forward.
Only thing I would add.
Thank you, Nevan.
To what Nevan said about diazoxide is, just to remind everyone, every patient enrolled in this study was diazoxide unresponsive. Even though at least a third of them were on diazoxide and have probably traditionally been thought of as diazoxide responsive, meaning they have a genetic subtype that has the potential to respond to diazoxide. By definition, all 23 patients enrolled were non-responsive or inadequately responsive. We know that patients on diazoxide are not well served, not only from a safety perspective, but also from an efficacy perspective.
Thanks, Brian. The second question I have here is about the DME program. I'm at ARVO, so, you know, this is really exciting because this clearly talks about thinking about these diseases as systemic diseases and then also looking for more convenient treatment options. I think it's interesting that you're looking initially at structural changes instead of functional changes. Can you comment on the rationale for that, maybe as it relates to the MOA? How do you plan to pre-select patients for enrollment into the study, and at some point, would you consider a combo?
Sure, Zeg. The use of optical coherence tomography to look at central subfield thickness or macular edema is fairly standard as a structural endpoint at this stage of programs. While we do, of course, visual acuity is the ultimate registrational endpoint and will be an endpoint in the study. You know, there is a precedent here, and this is fairly standard. In terms of, I think to maybe broaden your second question out to the patient population, we're still working, you know, through some of the details. The general concept here is to enroll patients who are not taking VEGF therapies and to randomize them into either RZ402 versus placebo in blinded fashion. We wanna have a monotherapy study.
In our mind, that's the best way to evaluate an oral plasma kallikrein inhibitor as a target and to look at a structural endpoint, as you noted, on OCT. We are taking patients who are either gonna be naive to VEGF therapies or who are on them, but have not received VEGF therapies in the recent past. Meaning they would not have received the most recent dose within a certain number of weeks, you know, whether that's eight or 12, we're still looking at. And they would not have received more than a certain number of doses. What we're really trying to accomplish with that is making sure that we're not enrolling the very difficult to treat patients or the patients on VEGF therapies who are non-responding.
I think that's been one potential pitfall of the intravitreal kallikrein inhibitor studies. Unlike them, we have the ability to conduct a monotherapy study in placebo by addressing that population upstream.
Thank you. The last one here is just regarding catalysts post the initiations of these phase II studies. What kind of updates can we expect during 2023? For RZ402, is the HAE program or optionality really now off the table? Thanks again for taking my question.
Absolutely. This is Nevan jumping back in. You know, I think we can expect the milestones upcoming, clearly as we look to enroll and prepare for phase III. I think in the H2 of the year, we'll have milestones around endpoints, study design and phase III specific start timelines. I think that's one for the RISE study. And then as far as RZ402, given that that study will start the phase II proof of concept that Brian just outlined towards the end of this year and will read out in the H2 of 2023, that will be the first, I think, major clinical milestone that we would expect in that. Then to be followed exactly a year later by top line for phase III for RZ358.
With respect to alternative indications, we actually haven't ruled anything out, with respect to, you know, looking at, we have a suite of kallikrein inhibitors, some very potent kallikrein inhibitors. It's not just RZ402. We're looking at a variety of diseases when we think about expanded indications. It's really about us being resourced properly and making sure that we are keeping our eyes on the ball and staying focused on our lead programs. Whether it's the use of our antibody for an alternative indication that's associated with severe hypoglycemia or looking at other vascular complications that make sense for our oral kallikrein inhibitor.
Platform, we will actually, you know, look at those both and continue to evaluate.
Thanks, and then congrats again on the progress.
Thank you.
Our next question is a follow-up from the line of Michelle Gilson with Canaccord. Please go ahead.
Hi, Michael here again. Thanks for taking a follow-up. Just a quick question on RZ358. Obviously a pretty good safety profile. Did you notice any immunogenicity? How does that profile look like?
We're still analyzing. Well, accruing and then we'll be analyzing the anti-drug antibody data from the study. We don't have those data yet. However, we've done ADA assessments in earlier studies, have never seen any positive ADA levels in the clinical or in the non-clinical setting. Based on the pharmacokinetics from the RISE study as well as the glucose effects, I don't predict any development of ADAs or neutralizing ADAs because we haven't seen a decrement in the drug concentrations or the efficacy. Then the last point I would make on that question is a priori, RZ358 as an IgG2 and one that is cleared into the cell at the insulin-dependent target tissues, would have a low risk going in for immunogenicity.
What we did monitor very closely in the study were injection site reactions, both locally and systemically, and we also didn't see anything of concern in those assessments.
Excellent. Thanks again.
At this time, we are showing no further audio questions, so I'd like to turn back to Nevan Elam.
Thank you. Thank you everyone for joining us today to receive an update on the business. Thank you as well for the series of very thoughtful questions. We look forward to updating you on our progress as we continue making strides to elevate the standard of care. Thanks again.
The conference has now concluded, and we thank you for attending today's presentation. You may now disconnect your lines.