All right. Welcome everyone to H.C. Wainwright's 28th Annual Global Investment Conference. My name is Matthew Caufield. I'm a senior biotech analyst here at H.C. Wainwright, and we're very pleased to be joined by Zenas BioPharma and Lonnie Moulder, CEO at Zenas. Lonnie, thank you very much for joining us.
It's great to be here. Thank you for the invitation.
Absolutely.
We're looking forward to a really productive day. It's a jam-packed schedule, so thank you.
Excellent.
I'll just refer you to our SEC filing, since we may be making some forward-looking statements today. I have just a few introductory comments here. For our pipeline, we have a lot that is going to occur in the next several months, and I just want to give people a sense of what's coming. First of all, we have, of course, our BLA under review for obexelimab for IgG4-related disease, with a PDUFA date at the end of May and a lot of activity preparing for the potential launch of that drug in this important indication. We have an upcoming investor event on September 29th and invitations have gone out, and additional invitations will go out where we have Dr. Guy Katz from Mass General, who will be talking about the disease, the obexelimab clinical data in IgG4-related disease.
We'll outline more details on our commercial planning and execution and how we view the marketplace. We'll then follow that up with some clinical evidence at both the International Symposium on IgG4-Related Disease in Boston, hosted by Dr. John Stone out of Massachusetts General Hospital. This is the gathering the world's experts on IgG4-related disease, followed by the American College of Rheumatology Conference. Data that will be coming out of those conferences includes our open label extension, flare protection data. You may recall that the INDIGO phase III study for IgG4-related disease with obexelimab reported out the randomized control portion of the study, but all patients had the opportunity to enter a three-year open label extension, and important data from that is the probability of 12-month flare. So we'll have that data.
We had previously reported the six-month flare protection at 92%, which I think really sets us up well to make a difference here in this disease over time with extended information from the OLE. A vaccine sub-study dataset will be available. The vaccine sub-study involves patients that are in the open label extension, where their obexelimab is paused over time, and they're administered a flu vaccine, a COVID vaccine, or both, given two weeks to elicit a vaccine response. Antibody titers are measured for protection, and then the drug is restarted. We think that's really important information for clinicians over time. We'll have the SunStone Lupus, SLE, phase IIb top-line results for the overall and biomarker population reporting out in the fourth quarter. We're looking forward to that.
As you know, we're in two large phase III trials for our other late-stage molecule, orelabrutinib, the highly brain-penetrant BTK inhibitor, both a primary progressive MS or PPMS and a non-active or naSPMS trial. I'll wrap up on this slide with the introduction that ZB021, our oral IL-17AA/AF inhibitor, is moving rapidly through phase I through the SAD cohorts. We're now into the MAD or multiple ascending dose study cohorts. In the fourth quarter, we will report out the safety, tolerability, exposure, all the information one would get from a PK study. With a validated mechanism such as IL-17, we think that's really important to identify that we have a medicine that can move forward into development. Next year we'll move into a proof of concept study in a patient population.
ZB014 is our extended half-life molecule that also binds CD19 and Fc-gamma RIIb, just like obexelimab. That half-life extension preclinically would suggest that it could be monthly dosing in humans. Obviously we'll investigate that next year as we move into the SAD and MAD studies and report some data out of the SAD study. ZB022, our brain-penetrant TYK2 inhibitor, we're doing IND-enabling work now, and that'll move into the clinic next year.
Excellent. A very helpful overview. Appreciate that. A lot going on.
Yes, there is.
It is very exciting. So maybe taking a step back. Monoclonal antibody obexelimab binds both CD19 and Fc-gamma RIIb, which are broadly present on the B-cell lineage. Can you help some of our investors understand the main strategic advantages of the B-cell inhibition versus depletion, as that is kind of a key crux to the thesis?
As you described, this mechanism is novel. The antibody binds the CD19, which is prevalent on a large range of B-cell lineage, of course, and anchors the antibody so that the Fc portion of the antibody can bind Fc-gamma RIIb. Fc-gamma RIIb, otherwise known as CD32B is really the only inhibitory pathway in B- cells. If you can block that pathway, you impact the B- cell's ability to produce antibodies, autoantibodies in this case, cytokines to process and present antigen to T cells, and then to progress to other later lineages of B- cells. With this potent approach, obviously across a variety of potential diseases, IgG4-RD, an earlier phase IIa lupus study, a multiple sclerosis, specifically an RRMS study that we conducted.
Back in time, in the MAD study, rheumatoid arthritis population, the drug obviously showed that it has substantial clinical activity balanced with safety. That's where it can differentiate from the depleting antibodies, those antibodies that target CD19 or CD20, but their mechanism of depletion being either ADCC or CDC, a cytotoxic mechanism to kill B- cells. With our mechanism, you could think about it as an on/off switch where clinicians can administer, get the potent inhibition for a potential disease, but at any time, turn it off and have B- cell activity restored. That might be important in patients that have comorbidities, if a patient has an infection, or potentially if there's a need to pause and vaccinate.
Many patients with these diseases, such as IgG4-RD, are older, and it is appropriate for them to receive annual vaccines. It is seen as an approach that could bring some safety advantages to different patient populations.
Sure. Very helpful. Then we will also get more into the details for separate BTK inhibitor or orelabrutinib. Just initially, at a high level, what do you presently see as the greatest unmet needs among progressive MS patients, which is a specific space within MS?
Right. Embedded in your question is somewhat the answer. I think the greatest unmet need in multiple sclerosis are the progressive types.
I think we have a good number of highly effective agents for RRMS. We could improve, and I think we could improve in the area of disability progression. But in progressive MS, what we're really measuring is disability progression. It's sort of this ongoing silent progression that leads to the disability over time in these patients. Whether it's a primary progressive MS, where that patient's first diagnosed already declining in physical capability, or secondary progressive MS patients that at one time may have been diagnosed with RRMS, but have gotten to the point where they're having this more silent disability progression, or really have transitioned to become a non-active SPMS patient. It's disability progression that we're seeking.
Right, independent of relapses, necessarily.
Yeah.
Yeah.
By definition, in PPMS or naSPMS, any disability progression benefit from a drug is independent of relapse.
Right.
Because if they are relapsing, they would be an RRMS patient.
Mm-hmm. Absolutely. Returning to the self-administered and subcutaneous obexelimab, that program could be on the verge of becoming a commercial stage asset, as you alluded to. Obviously, there is the PDUFA in May of next year.
You just mentioned the Investor Day coming up the end of this month. Can you talk to us a little bit about the IgG4-RD opportunity, in this first possible commercial step forward for the platform?
Sure. I think most people recognize now that this is a newer disease. It was only two decades ago it was first identified, interestingly enough, in Japan, where a number of patients that had presented with autoimmune pancreatitis were identified to have other organ involvement, and it was determined that there was some other inflammatory condition that was existing. It was not isolated just to the pancreas in those patients. Across the globe, other people began recognizing the disease, and ultimately, as a number of mostly rheumatologists got together to discuss it, they determined it was a very specific disease.
It is now recognized that way. Although it was not until 2019 that the very first diagnostic criteria, the ACR/EULAR guidelines were published. And actually not until 2023 was there an ICD-10 code in place. It is a newer disease, with substantial unmet need. Over the years to treat these patients, steroids were identified to be beneficial. I think you can replay many autoimmune or inflammatory conditions where that was the first attempt to treat these patients.
The problem with steroids, of course, are chronic administration is problematic, and IgG4-RD is a chronic condition. It flares from time to time, and the flares do not remit. You must treat. But even once the flare is tamped down and the patients in "remission", many of these patients continue to have ongoing inflammation in organs that is not always clinically apparent, but over time, there is a decrement in that organ function.
That is how these patients sometimes show up. Abnormal lab values during a routine physical, and then in further evaluation, it is determined that actually that patient has IgG4-related disease. The steroid treatment is effective, but you cannot dose it chronically. Along came some people that did some work and identified that targeting B- cells, specifically rituximab, could shut down the inflammatory state in a flaring patient such that they went into remission. So rituximab began to be used off label. There is no randomized phase III data, so the actual published evidence is limited, but it does work. Problem is, it is hard in the U.S. for patients to get access.
Some clinicians can get access. You have to appeal multiple times to the payer. There is, of course, some use. A lot of old DMARDs were tried. None of them have shown to have substantial benefit, but there wasn't anything else to utilize. Along came the first approval just 15 months ago, and that's an anti-CD19 antibody, a depleting antibody, as I discussed earlier, and that's the first approved FDA product. It's having nice penetration from a commercial standpoint, and it's helping patients. The current treatment paradigm is evolving.
Clinicians can think about using a B- cell depleting antibody, then they have to decide can they have access to rituximab, can they get the newly approved agent, which has really good payer coverage? We then hope to bring along an option here, and that is an inhibitory approach.
That in this patient population where 45% or so are 65 and older, over a third have comorbidities.
Right.
These are patients that are at risk of issues that could come along if someone is shutting down or eliminating a whole part of the immune system that is not reversible. Our market research indicates that this inhibitory approach could have a real place front line for these patients.
It is highly efficacious from the phase III results.
This opportunity to have the flexibility in patients that are older or have comorbidities gives the clinicians a level of comfort treating these patients long term.
Understood. Very helpful. There are also plans to submit the MAA application to the EMA during second half of this year, with potential for a possible launch in Europe independently. What are important distinctions between these IgG4-RD markets between Europe and U.S.? I also wanted to mention and ask you about the prefilled auto-injector pen. How that kind of plays into this narrative?
We do not see from an epidemiology standpoint much difference, many differences across the globe. If you look at the key markets in Europe and put the population together, and then think about the U.S. population, the markets from a patient standpoint are about the same. We know in the U.S., for instance, there are approximately 20,000 patients who are diagnosed and managed with IgG4-related disease.
The field believes, and some work that's been done in other parts of the world, that the actual population in the U.S. could be 35,000, 30,000-40,000 patients.
As a newer disease with an ICD-10 code that wasn't put in place until just a few years ago, we think that's highly possible. But let's focus on the 20,000 that are managed and treated today. The European population is similar.
Right? So that's a population of IgG4-RD diagnosed patients that physicians will see from time to time because they're being managed. Now of that population, some of those patients are taking intermittent steroids. Some are receiving off-label rituximab or old DMARDs. But we believe in any one year, 10,000-12,000 of those patients are requiring therapy because they flare frequently enough. We size the market in the U.S. and Europe in that 12,000, that's the TAM, the 12,000, until more patients are diagnosed and we go from 20,000 to almost 40,000. 12,000 is the TAM in both markets, U.S. and Europe.
Okay.
The difference, of course, is pricing. Although we're submitting our MAA, we haven't made the strategic decision yet that we'll be commercializing because we need to see how MFN plays out.
Of course.
That's an important consideration. The pricing in the U.S. is approximately $300,000 annually, based on the currently approved product. Of course, the pricing in Europe would be less.
Those are some of the considerations there. You mentioned the auto-injector pen. The first format available in the U.S., the format that was submitted in the BLA, if the BLA is approved, is a prefilled syringe format. We will launch with the prefilled syringes. We have conducted a development program for the auto-injector pen. This is a 2-mL pen. We estimate the subcutaneous self-administered injection time being about eight seconds.
Pretty straightforward. It is interesting the percentage of the U.S. population that is very familiar in using auto-injector pens because of GLP-1s. Numerous rheumatology drugs are administered that way, so this is the normal paradigm in rheumatology to use an auto-injector pen. We have conducted the bioequivalence trial comparing the auto-injector pen to the prefilled syringes, and that was successful. We announced that last quarter. The human factors testing is complete. The CMC work is done. We are actually preparing to submit the auto-injector pen format in the MAA to Europe this half of the year.
That will be ready to go, and in the U.S., upon approval of the BLA, we would then submit the supplemental or sBLA and would anticipate potential approval within a year of the original launch.
Mm-hmm. Very helpful. Just in terms of data catalysts, I wanted to touch on Systemic Lupus, SLE, and that program. There is top line and biomarker results expected for obexelimab in fourth quarter of this year from the phase II SunStone trial. That trial assesses the BILAG-based composite lupus score at 24 weeks. What are some of the key points there in terms of that metric and how you would consider the outcome to be successful?
Yeah. So, whether you look at BICLA as a primary endpoint in a study, or you look at SRI-4 in an SLE study, what you see with other agents out there that have been successful is an effect size, the difference compared to the control arm anywhere in the mid-teens to low 20 points.
The currently approved drugs out there, and there are two, the effect size on their primary endpoints was in the mid-teens. The data that stands out to date in a randomized phase III trial would be the Roche data for their anti-CD20 antibody, where the effect size was 22%, 23%.
Whether it is SRI-4 or BICLA, the effect size that you would look for is something in probably the high teens to just over 20% is the range that is a reasonable range for an effective drug. That is what you are shooting for, right? Then the rest of the drug profile plays in, and we think the rest of our drug profile is highly desirable. You see that from our IgG4-RD phase III results. That is what you would look for in the endpoint. We will report out both BICLA and SRI-4. Remember, phase IIb, the purpose of that is to instruct you how to design your phase III program. We will learn from both of those. The other thing we will be reporting out, of course, is not only the overall results, but the biomarker population results.
Again, side by side, so everyone will view that. Then we'll take that information and decide if there is a path forward for phase III using either BICLA or SRI-4, a biomarker-only population, an overall population, or a combined study like one does in oncology, where you take an overall population in a phase III. You might analyze the biomarker population first, so you get a potential win there, and then you analyze, after taking a statistical hit, the overall population.
So you sort of have two shots on goal in a phase III, just like we have in our phase II. We have biomarker and overall.
Very helpful. Appreciate that. I know we're kind of short on time here, but I did just want to ask one final question. With many strategic shots on goal within the autoimmune diseases across obexelimab or orelabrutinib and the earlier stage pipeline that you mentioned, are there any specific points you believe investors might be missing out about the platform or some of these opportunities? Kind of underappreciated?
Yeah. I guess, where I sit, I should always think about investors perhaps underappreciating what we have. But I think as time passes, data comes along, and then there is greater appreciation. We are really excited about our late-stage programs. Obviously, transitioning to be a commercial company is exciting.
We have done it in our prior companies, and it is a special time in a company to do that, to bring a brand-new medicine to patients. But I would point to our earlier pipeline, the follow-up long-acting molecule potentially to obexelimab, could have potential in other indications, an even longer life cycle with monthly dosing. And then our ZB021 IL-17 inhibitor, I think that could be a really, really important program for us, and I think having the exposure data, the safety tolerability data just here shortly in hand and moving right to a patient population. With no mechanism like that, you could see a rapid path to actual registration studies there. So that perhaps is something that is underappreciated right now. But I understand maybe that greater appreciation will be there once we release some data.
Yeah, of course.
Yeah.
Well, some really exciting catalysts and opportunities with the platform. Thank you, Lonnie. Really appreciate your time, and thank you to Zenas BioPharma.
Thank you, Matt.
Thanks, everyone.
Appreciate it.