Everyone, thanks for joining us. Welcome to day one of Jefferies Global Healthcare Conference. My name is Fiona. I cover SMID-cap biotech companies at Jefferies, and it is my greatest pleasure to welcome to the stage with me, MBX Biosciences CEO, Kent Hawryluk, and CMO, Dr. Sam Azoulay. Welcome, gentlemen.
Thank you.
I believe before I put you guys in the hot seat, Kent is going to give us some overview of the setup for MBX.
First, I'd like to thank Fiona and the Jefferies team for inviting us to participate in the Jefferies Global Healthcare Conference. MBX is pioneering a novel platform technology we call Precision Endocrine Peptides, or PEP. We use this to design therapeutics to provide tailored and precision treatment of metabolic and endocrine diseases, ultimately to help patients live fuller and healthier lives. This is our most catalyst-rich year. We are experiencing a lot of excitement following our recent obesity day, where we pointed the way toward our exciting 12-week MAD data for our once-monthly GLP-1/GIP agonist prodrug in Q4. Additionally, next quarter, we are on track to expand our obesity portfolio by selecting our third obesity candidate, a Triple G, GLP-1/GIP glucagon prodrug, and again, once monthly. This is supporting our aspiration to become a global leader in obesity.
Additionally, we have an exciting event coming up next week. We are presenting AVAIL phase II data and one-year OLE follow-up data at ENDO. For investors who aren't able to attend in Chicago, we'll make available a conference call, and very excited about that. We're on track to initiate our phase III next quarter. I'll mention that I'll be making forward-looking statements, and Sam Azoulay as well, so please refer to our risk factors and other disclosures in our SEC filings on our website. We're in an enviable cash position, with cash into 2029, and that funds the advancement of all of our programs to key milestones. Great. Just as an overview, we have multiple clinical stage programs. These are designed to address multi-billion-dollar markets.
They are leveraging this PEP platform with extended duration of action, the consistent drug exposures, and less frequent dosing, you'll see that reflected in some of the data we're sharing in obesity. Additionally, we're on track for the phase III study, the phase II that we reported last September is really best in class, we believe. In fact, our phase III study, we view as basically building on the phase III confirmatory. We have an expanding monthly obesity portfolio, I mentioned, the PEP platform is clinically validated. Getting into canvuparatide, our lead program, let's just reflect that hypoparathyroidism is a serious rare disease that many are aware of because it affects over 250,000 people in the U.S. and Europe. It is caused by a PTH deficiency, which is the key regulator of hormone, or rather, of calcium.
The standard of care today is absolutely antiquated. It's very burdensome pill supplements, which are taken throughout the day and night and do not address the underlying cause of disease. Importantly, leave the patients at risk of serious long-term complications affecting kidneys and other organs. There is a sea change coming with the advent of PTH replacement therapies once daily. Where we're different is that we have a once-weekly PTH replacement therapy prodrug, and in our AVAIL phase II study, we demonstrated that it served proof of concept as it was designed using our PEP technology. We achieved 63% responder rate at 12 weeks. That met the primary endpoint with statistical significance, and that only improved at six months to 79% in the open label extension. We had a very high rate of opt-in for the OLE.
94% of the patients completing the phase II elected to enter the OLE. We view that as a very encouraging indication of how patients are feeling on the drug and their interest in a once weekly. We also saw that we had excellent safety and tolerability and believe that the trial is on track to initiate in the third quarter, as I mentioned. The phase III study, as I said, confirmatory. We say that because it's designed quite similar to the phase II study, with a key difference that it is 26 weeks versus 12 weeks for the primary endpoint. We have a four-week fixed dose period, where the starting dose is the 600 microgram, which was the middle dose from our phase II. This had the optimal balance of safety and tolerability. There is additional 18 weeks for the patients to titrate and achieve their optimal dose.
There is another twist. We have a key secondary endpoint of urine calcium. We think this is important as we have conversations with doctors and patients. This is something that is not in the once daily label, and we believe could be transformative in terms of our differentiation if we achieve this key secondary endpoint of reducing urine calcium while maintaining normalization of serum calcium independent of the standard of care I mentioned. The study will kick off next quarter with an enrollment target of 160 patients, which is overpowered for our primary endpoint. It's appropriately powered for this key secondary endpoint that we aim to achieve. We have invested already quite a bit in our pre-commercial activities. I'm joined here today by Mark Soued, our relatively recently added Chief Commercial Officer, previously head of U.S. for Alnylam.
He's giving extra focus on this area in building on our efforts to be commercial ready. We know that patients are very interested in a once weekly PTH replacement therapy, and we don't want to lose any time in getting this to patients once it's hopefully approved. More updates to come next week at ENDO. Hope to see you there.
Thank you, Kent. I'm going to now go through the obesity pipeline and really at MBX, we believe that there is a great opportunity for monthly administration with improved tolerability. With this in mind, we have developed a TPP, a target product profile, which is described here. That's the green curves. Green curves, that's what kind of expectation we can get from our PK profile. As you can see, as compared to tirzepatide in red and MET-097i in black, it's a very different curve. You see that both tirzepatide and MET-097i have an abrupt raise to the Cmax as compared to our target product profile, where we want to get a really smooth raise to the Tmax, and we know that this burst of effect is related to GI intolerability.
Again, if you look at the green curve, we want to get a flat curve with no peak, very flat and going down slowly to cover the months. Covering the months, you see the difference with tirzepatide, which is given weekly. We also know that the cycle in terms of PK, the cyclic change in concentration, are related to GI intolerability. If you look at and compare with MET-097i, they're claiming that time to reduce Cmax by half, the T half Cmax, is around 20-21 days, and we are aiming for 26 days. That's our target product profile. Now, with this in mind, I'm going to talk about the phase I study, which is ongoing and still blinded. I don't know the full data, but I'm going to share some preliminary data.
It's a phase I study, but in the target population of patient with BMI at or greater than 30. The target population. The study is divided in three parts, the SAD, single ascending dose, the MAD, multiple ascending dose, and the last section, which is a multiple administration over 12 weeks. Okay. Each step informs the next. We are progressing as we learn from each steps. Going fast, we have five dose that will be explored with the SAD, three dose regimen with the MAD, with the potential for even a monthly administration.
We have the 12-week that will be the most important part, which has not yet started, but we know that one of the cohort will be on the larger population of 30 subjects, 20 treated, 10 placebo, will be a weekly administration for four weeks, followed by a monthly administration, likely to be two monthly administration. This part, which has not yet started, is on time to have the results released and presented by the fourth quarter of this year. Okay. We have another cohort we are planning, but again, we learn as we go. The objective of the studies are clearly safety, tolerability, pharmacokinetic, and, thank you. Pharmacodynamic, which is weight loss, and clearly also to prepare for phase II. Next one, which is the initial results. That's already ahead of the game. No. Okay. That's the initial result.
That's a delay time to maximum concentration. What you can see here, that if you compare the 60 mg and the 90 mg single dose MBX, right, our product in respectively blue and green, you have exactly a PK profile which looks like the target product profile, the one we wanted to get by design. Here we have the smooth raise to the Tmax, right. Exactly as you wish. You have a plateau when the drug stays constant, the concentration stays constant. Very importantly, the Tmax for both tirzepatide and MET-097i is around two days. That's a burst of effect, right. That's when it gets really quickly to the Tmax. Our Tmax is 13-14 days. That's a big difference and also aligned with what we would expect in terms of the opportunity to reduce GI and improve tolerability.
Here you can see that the self-titrating PK profile, which is, as I said, supposed to improve tolerability. Here, that is a multiple dose already. That is a multiple dose in this slide. What you can see here is what we call the B1 cohort. That is the green curve. Keep in mind the green curve. The green curve is a 30 mg given weekly. Sorry, 30, three zero, milligram weekly, followed by 120 mg , four times the initial weekly dose. Four times. You can see in this curve how smooth rise even up to the fourth administration. Here, even when you give the 120 mg, you have again, this smooth rise to the Tmax, really exactly what you want to observe. The comparison here is with a 180 mg in orange given as a single dose, which was the maximum tolerated dose.
In terms of nausea, vomiting, et cetera. What you can observe here is that you reach the same concentration than the SAD, right? The single dose at 180 mg, but with a very, very different tolerability profile. I'm going to anticipate a little bit. On the left, the orange curve, the SAD 180 mg gives nausea, vomiting, and diarrhea. On the right, the multiple administration of 30 mg followed by 120 mg gives almost no GI effect, and I will show you later. Now, what we have here is the safety and tolerability of this MAD, the multiple administration I was talking about. Look at, in the tolerability section, one event only of diarrhea. In fact, was two days of loose stool, disappearing after the initial administration. No nausea, no vomiting, and reaching this type of Tmax. If you look also, it's blinded.
I remind you, it's blinded, so I can tell you that the weight loss is at 7%, all patients or all subject included in this analysis. The range is between 0% and 16%. Very exciting result in terms of both tolerability, demonstrating the monthly administration. I didn't tell you, but the time to reduce the half Cmax is 26 days following the repeated administration. We have demonstrated the three pillars of what we were expected. Monthly tolerability and really good potential for weight loss. Now I'm going to hand over to Kent.
Thank you, Sam. The great part about that preview that we shared with the community a few weeks ago and are today is that this is the PEP design now demonstrated proof of principle in the target population of obese adults, where you have this slowly rising and steady exposure. This translates to our obesity portfolio that is growing. We also, a few weeks ago, declared our amycretin. We use this term to describe our molecule that combines four plus mechanisms in a single molecule. The dual incretin agonist plus a taste of glucagon, so not as strong as the other mechanisms, and then DACRA, which is calcitonin and amylin. We believe that we will have true monthly dosing as well as this improved tolerability versus others in the amycretin class.
We are excited to move toward the clinic in there with this program, the data so far is showing, this is a non-human primates, that we have this very flat exposure, similar to what we've seen in the humans. Whereas the amycretin that is designed for weekly administration, you see, first of all, you have the burst effect, which leads to a GI intolerability, and then it doesn't have the exposure to cover a month. It has to be dosed weekly. More to come and off to a great start. We demonstrated that in non-human primates, we've seen a leading weight loss with persistence, noting that non-human primates turn over albumin three times faster than humans. Importantly, there was no nausea, vomiting, and diarrhea that you typically see with the drugs in this species. I've covered these catalysts.
I just would note that I believe MBX is unique in having multiple clinical stage programs in blockbuster markets, all supported by this clinically validated PEP platform and the cash to take these through meaningful value inflection points. Thank you, Fiona.
Thank you. There's certainly a lot to unpack there. I want to maybe just ask a few pointed questions on canvuparatide and also your obesity franchise, which are turning out to be the two pillars of the MBX portfolio. Starting from canvuparatide, we're just a week away from ENDO data, which is highly anticipated, and a lot of people are building expectations, particularly on the durability. What type of durability data should we be expecting? Based on your conversation with the KOL, what type of profile is considered competitive?
Let's start with the PTH replacement therapy. This is very known biology. As I said, PTH is an established mechanism. It's the deficient hormone. We've already established in our phase II that we have a full week coverage. We have the expected PTH biology, and obviously we met our primary endpoint. I also focus on the retention as well as durability. We had 94% entering the OLE. At six months, we had retained most of them. There was a few that for feasibility, they elected not to continue in the OLE. We will look at one year at how the patients are retained in the study, and we think that's a really good measure. We'll look at other markers as well to demonstrate the overall biology of the disease. Now, you mentioned durability.
Let's note that when we spoke to KOLs, to patients, through our own engagement, through primary market research, working with third-party firms, the consistent message is that if we are in the ballpark of the once daily with our once weekly, that is a best-in-class profile. Just in the ballpark of efficacy. That means it's the choice for PTH-naive patients, and in a large majority, it will drive switching. Right? Once weekly really matters. These patients are done with the standard of care, pills every day. They want a convenient weekly drug that fits their lifestyle and makes them function normally. That's really what we're looking at in the phase III to demonstrate the overall biology that we've established with our once-weekly PTH replacement therapy.
That's very helpful. Definitely looking forward to the data. As canvuparatide is heading into phase III, just around the corner, tell us more about this design because you have some very interesting components, particularly on the urine calcium, which is the secondary endpoint. Just tell us how important that is to have that in the label for HP patients and how much of an advantage it can offer you.
Happy to answer. Urine calcium is a very, very important parameter in hypoparathyroidism, Addressing this issue for patients will prevent a CKD in the long term. That's why we thought it was very important to focus on this endpoint. In this design, obviously, we are going to look at the responder rate as usual, In addition, we'll be looking specifically at the population of patients with elevated Urine calcium at baseline who normalize both urine calcium and serum calcium. It's a very important point that the study is designed with this purpose. That means it's a pre-specified endpoint. We have calculated the power of the study accordingly, During our meeting with the FDA, they didn't have any comment on our goal and objective.
If everything works well and if we meet our expectation, we can expect to have this differentiation in the label. That will be a big change for physicians.
Building on that, when we conducted this primary market research I referenced, it came through that going beyond weekly, if we're able to achieve this primary endpoint, which is not in the label for the once daily PTH, that would be, and they use this term, transformative differentiation. We're very excited to see how that plays out, and we've powered the study appropriately for it.
Definitely. It's going to be a very powerful analysis. Let's assume everything goes well and then canvuparatide gets approved. Based on your KOL interactions and the market research, what type of patients do you think are the most easily accessible, and what other layers of patients can potentially convert from daily PTH to canvuparatide?
We believe that we have a best-in-class profile, and when we conducted the primary market research, our phase II data was presented on a blinded basis compared to the label for the once daily, and hands down, it was chosen. We believe that this means that we can become the market leader for sure. I think it's interesting when you look at other indications where you move from a once daily to a once weekly. Not only does the once weekly become the leader, but it tends to expand the market. Perhaps patients who aren't ready to begin a therapy now come on therapy, and we look forward to serving as many of the PTH patients as possible.
If I may add something.
Yes.
I think this population for now is treated for symptoms. PTH replacement therapy offers the treatment of the disease. It's not only targeting serum calcium, but also targeting bone and kidney. We've seen this in our phase II. We'll demonstrate it in the phase III, and it's like treating the entire problem instead of really treating the symptoms.
That's a perfect segue to obesity, which is also building on the long-acting profile. Coming into this space, Kent, we know you have 20 years of experience, before obesity was even a thing. Looking at this space from your point of view, what kind of theme or any meaningful gaps that you can identify?
Thank you for that question. We, at MBX, have team members who have been in the field for 20 years and more. I would include Richard DiMarchi, our Scientific Co-Founder. We have anticipated that the next wave in obesity will be one on therapies that are once monthly, that provide the convenience that patients really want. What good is a drug that causes you to lose weight if it makes you feel lousy? What's also important, in addition to being once monthly, is that we have improved tolerability as a monthly drug. That is where I think the opportunity is. We know these mechanisms are very active, and we'll see the weight loss. It's not a race to weight loss. It's really sustained benefit. That's what the patients and doctors, and frankly, payers are looking for.
I'm pleased that we anticipated that, and we're already in the clinic. You've seen some of the data showing that this approach seems to be quite powerful.
Yeah, thank you for that. Looking at the blinded data, which is already very promising, and we did the math. If placebo behaved as it should, the weight loss will only look better. Looking into maybe longer term, how competitive do you think the weight loss need to be to support a monthly drug?
Well, I would say that 7% mean weight loss at eight weeks with our very first MAD cohort was pretty impressive. I go back to it's not a race. You want to see steady weight lowering that's sustained, that doesn't cause discontinuation, that supports adherence and long-term benefit. We know this is a chronic illness and that patients need to be on the drug really for the rest of their lives.
Makes sense. Now that you have multiple great assets in your arsenal, how do you see them complement each other, and then where is the direction that this obesity portfolio is headed?
We are seeing segmentation in the market. That's recognizing that obesity is a heterogeneous disease. Not all patients are the same. So you need various treatment options, much the way you have in treating cardiovascular disease. We're evolving towards that. We've also anticipated that different mechanisms will give you different benefits in different individual patients. We have our Triple G coming next quarter. We're excited about that because the data coming out of Lilly with retatrutide is promising in terms of the amount of weight loss that can be achieved, especially for really obese, highly obese individuals. In the case of retatrutide, you see it comes at a cost of tolerability. We think with our unique PEP approach that's been clinically validated, we can deliver the benefits of a Triple G with improved tolerability.
Perfect timing as we head into ADA next week. I think you'll get a lot of recognition from that as well. We already touched on the cash position, which is very solid, gives you a lot of opportunity and flexibility. Anything else you want to highlight to the audience?
Well, we are excited about ENDO coming up next week. This is our flagship program. You can see that we have conviction that we have a best-in-class once weekly PTH replacement therapy. We've brought in the big guns. Mark Soued and building out our commercial team, because we want to deliver this to patients, and I think you'll see us continue to move down that path. There's room for improvement with the PTH. We're glad that a once daily is available to patients, and we look forward to providing patients a better option if we're fortunate to get it approved.
Thank you, Kent, and thank you, the audience, for listening and watching. It's going to be a very exciting time for MBX.
Thank you.