RBC Capital Markets. Welcome to our last session of the day, but not least, with MBX Biosciences, represented by their CEO, Kent Hawryluk. Kent, thanks again for joining us.
Thank you. Appreciate the opportunity to talk about MBX and what's looking like our most important year to date.
Yeah, so maybe just to kick things off, for those who may be less familiar, can you briefly introduce the story and maybe give a little bit of background on what you guys are doing? I want to dig more into the indication that you're going after and some of the data you've seen so far, but maybe just start big picture for those who may not be as familiar.
I'd be happy to, and I'll just remind everyone that I'll be making some forward-looking statements and encourage everyone to look at our risk factors and other disclosures in our recent SEC filings, which are on our website. MBX Biosciences is a clinical stage biopharma company. It's a continuation of a 20-year collaboration with Dr. Richard DiMarchi , who's our scientific co-founder, preeminent peptide chemist, invented Humalog and the first GLP-1/GIP co-agonist . In previous companies, Richard and I were able to transact and sell to Merck, excuse me, partnered with Merck, sold to Roche and Novo Nordisk. This company is really looking to take full advantage of the modality of peptides, understanding that they have short half-lives and so need optimization. Our approach with our precision endocrine peptide or PEP technology platform is to provide continuous infusion-like exposure to drug with convenient and frequent dosing.
This PEP technology has already generated two clinical stage programs that are addressing significant unmet need in rare endocrine diseases. We have a third program that we expect to enter the clinic in obesity later this year. We're well funded, so we have $240 million as of the end of last quarter. We've indicated that we expect that to support our operations into mid-2027, and that includes just a number of value inflection point milestones.
Great. Maybe starting with your lead indication, hypoparathyroidism, can you give us a little bit more background on its etiology, what some of the recent developments have been with regards to the standard of care, and then maybe the mechanism of action for your lead asset, canvuparatide?
Great. It's a really interesting time to be discussing chronic hypoparathyroidism. This is a serious disease that, while rare, affects over 250,000 people in the U.S. and EU. Surprisingly, today, the standard of care is not hormone replacement therapy, as you typically see in endocrine disorders, but supplements. Large doses, seven or eight times a day, night, active vitamin D, calcium supplements. We hear of patients having to set their alarm clock for the middle of the night to wake up and take a handful of pills. These are short-acting, and they don't importantly address the cause of disease, which is PTH deficiency. Even with these supplements, we hear patients say they don't feel normal, stable, even if they are able to keep their serum calcium in a normal range. Typically, they're going to get fluctuations, hypo-hypocalcemia, symptomology, tetany, seizures, brain fog.
More significant are the long-term complications affecting kidneys and other organs. Good news is that it's changing, right? Fairly recently, we now have an approved once-daily PTH replacement therapy available to HP patients in the United States. It's called Yorvipath. We see the launch going well. It's early days. We can talk more about that. Opportunities to do better. Canvuparatide is a once-weekly PTH replacement therapy prodrug. In addition to the convenience of once-weekly, we see other ways that we can differentiate. When you look at other endocrine disorders, there's a pretty rapid uptake of a once-weekly when it becomes available.
What are some of the preclinical data that give you confidence in the drug? What have you seen in some of the rat models, the PTX rat models you've utilized in terms of things like calcium reabsorption? What about other biomarkers like phosphate levels, vitamin D? What's safety look like?
We looked at a lot preclinically, and we're very pleased that it supported the PEP design, this prodrug approach. First of all, we saw that in cynomolgus monkeys, we had this continuous infusion-like drug exposure. We also saw that the active drug had comparable potency at the PTH1 receptor to PTH1 to 34 or PTH. We saw safety in the two species with the IND enabling tox studies. Felt really well positioned. The PTX model is really interesting. This is one we developed where we could actually excise the parathyroid glands from these rats. Pretty hard to do. They're very small. That kind of created a model for the disease. What we found is we could actually reverse the disease in this model. We looked at that in terms of bringing back calcium to the normal range, phosphate. We looked at trabecular bone.
After treatment with Canvu, it resembled the control versus this very dense bone that you see in PTX rats, which you also see in HP patients. That was quite validating. I'm pleased that that's also carried through our phase I as well.
Yeah. Speaking of the phase I, you have reported healthy volunteer data for Canvu. What were some of the key takeaways to this? I guess, did the serum calcium level measurements from the MAD study meet your expectations? Can you talk about the effects on calcium at the higher dose levels that you tested? Anything to call out on safety there?
It very much, the MAD data very much met our expectations. We saw dose-dependent increases in serum calcium and a corresponding decrease in endogenous PTH. It's important to keep in mind that healthy volunteers have their parathyroid glands intact, so they have endogenous PTH. They're also coming in with calcium in the normal range or even the higher end of normal, right? You're pushing calcium with the exogenous PTH. That's the point of the phase I, primarily to look at safety. We saw that this corresponded, this PD effect with the PK. It's worth touching on that. With the PK, it was exactly as we designed it. We saw this long time action, half-life of eight to nine days, which very much supports once-weekly.
We saw a peak to trough at steady state over a seven-day period that was comparable to Yorvipath over a 24-hour or one-day period. KOLs and we view that as more continuous infusion-like than Yorvipath.
How does the phase I data influence your phase II design? Can you talk about maybe start with the dose levels that you've selected out of the phase I, how titration may work there?
Yes. In the phase I, we explored 200 µg to 900 µg. Again, we saw the dose-dependent increases, and that guided us toward the starting doses for our phase II to be 400 µg -800 µg, just kind of round it a bit. We have a fixed dose period for four weeks. That is informed by our PK profile, where we saw and we had predicted that you get to steady state after the third or fourth dose. In our 12-week AVAIL phase II trial, we have a four-week fixed dose period. You are keeping the dose of Canvu constant and you are reducing supplements. After the four-week fixed dose period, you have an eight-week dose adjustment period. Here we have four chances to adjust the dose of Canvu by 200 µg every other week. A total potential increase of 800 µg.
That could take the 400 µg cohort up to 1,200 and the 800 µg up to 1,600 if needed. Now, beyond the 12-week AVAIL placebo-controlled trial, we have a two-year open label extension, an additional two years to look at long-term exposure and to be able to report at time points that are familiar to people from our peers, like six months and a year.
Got it. Tell us more about what endpoints you're going to be looking at in that study and maybe how those endpoints relate to the different dose, like I guess the dosing schema, whether everyone gets pooled or there's going to be specific correlations made between the doses that patients end up on and what the endpoint measures look like.
Right. We believe that AVAIL is very well designed to show a clear and convincing clinical proof of concept and demonstrate its potential to address the unmet need in HP. We have designed this and powered this to show a statistically significant pooled treatment response rate of at least 55% or 48% placebo-adjusted after 12 weeks of treatment on Canvu. This was deemed by our KOLs to be clinically meaningful and to be supportive of dose selection for the phase III pivotal.
Got it. What types of patients are you enrolling in the study? How does that compare to what others have looked at?
Very similar to others, the inclusion and exclusion criteria. It will look at patients who are diagnosed and stratified with first post-surgical chronic HP. That's the majority overall in the etiology. Also the congenital and autoimmune HP.
How has the study conduct been thus far? I know you've got a couple of ex-U.S. sites in there as well. Is that helping with enrollment? Was there a specific reason to kind of add those in, get kind of those experiences outside the U.S.?
It's going really well. We were pleased to report that in March, we reported that the study was, in fact, over-enrolled. We had started with a target of 48 patients, and we ended up successfully randomizing 64 patients. I think that's a strong testament to the interest from patients and to the investigators in new treatment options. We are on track to provide top-line results in Q3. I think this will be just a transformative milestone, not only for the company, but I think it's big in the field, right? HP patient data for the first once-weekly PTH replacement therapy. The sites abroad were always planned. It's important. We wanted to set the stage for phase III, where we will do even more outside the US.
Got it. You touched on this maybe a little bit at the beginning in your opening comments, but can you talk a little bit more about the competitive landscape? I guess, what do you make of Yorvipath's early days into the launch? How do you, I guess, is there a proportion of patients who or a type of patient who would be a candidate for a therapy like this versus staying on supplements?
First, this is just every patient's our North Star. And so we're always focused on their care and very pleased that there is now a PTH replacement therapy. We're not surprised that the launch of Yorvipath seems to be going well. As you point out, it's early days. One quarter, full quarter of sales reported, I believe, about $50 million , almost a couple thousand patients on drug. I think this is the tip of the iceberg. When we talk to HP patients, they are clamoring for a PTH replacement therapy because the supplements are not doing the job. As I mentioned, they don't feel healthier or well-controlled with the supplements. I think some kind of reject that sort of label of well-controlled. So I think beyond just the most severe HP patients, you're going to see greater adoption across the population with a PTH.
I think a weekly can expand that. It's more convenient. We believe also at maintenance that we could provide potentially more homeostasis, more steady stability, less excursions in the hyper and hypocalcemia.
Makes sense. Payers, how much on board are they, or is there kind of education that's required to go from maybe less convenient generic to a much more convenient, more disease modifying, the concept of a much more convenient disease modifying, but branded price therapy?
As far as we know, the reimbursement is progressing. We're very happy for success with a PTH replacement therapy in the market. That just, it'll be good for patients and frankly, good for MBX.
Good. Maybe we could move on beyond Canvu. You've got a number of other drugs in the pipeline as well. Maybe on 1416, you're going after post-bariatric hypoglycemia there. What's the standard of care right now, the unmet need that you see, and how a GLP-1 antagonist could be differentiated and fit into that paradigm?
PBH, post-bariatric hypoglycemia, is a quite interesting market or condition. When we've done investigation into this, talking to endocrinologists, bariatric surgeons, we see a US prevalence that's pretty comparable to hypoparathyroidism in size. Here, there is no approved pharmacotherapy to treat it. You have basically a prescription of a very restrictive diet, which is hard for these patients to maintain. You have some off-label medicines that have poor tolerability, very little clinical data. Where do you go? It's very disruptive too. This is a case where this presents six months to three years after the bariatric surgery, which you're hoping to kind of transform your life in a good way. This comes along and it's quite disruptive. You don't really know when the hypoglycemia can occur.
It's triggered by the release of nutrients more quickly to the small intestine, but it's not always right after a meal, say. It could happen nocturnally too. With our approach, we have a long-acting GLP-1 antagonist. The purpose here is to cover the whole week. It has a 90-hour half-life according to the phase I data and cover both day and night, prevent this severe hypoglycemia that's triggered by the increase in GLP-1, which increases insulin and brings down glucose. We think it could be a game changer for these patients. We had positive phase I data. We were released last January, and we have plans to enter phase II with PBH patients in the second half of the year.
Great. The phase I data that you saw there, the SAD/MAD, remind us what you saw. Anything unexpected in terms of variability and exposure, injection site reactions, anything notable from that that you've learned to take away to the phase II?
Overall expected, first starting with safety, it was shown to be well tolerated with a favorable safety profile overall. We saw higher incidence of ISRs. Vast majority of these are mild to moderate, 88% mild to moderate. This is erythema or redness, not associated with any general symptoms. We looked at allergic response and didn't see any. The cases that were of ISRs that were graded more severe, again, it's on the size of the redness, but not other associated symptoms. We even did a biopsy of one of those and confirmed it's a type of hypersensitivity you commonly see with peptides. Importantly, it tends to disappear spontaneously with repeat use. It's possible that in our four-week MAD study, it wasn't long enough to have enough exposure to resolve that. In terms of the half-life, I mentioned 90 hours, so very supportive once weekly.
We saw overall dose proportion increases in concentration. What was great to see was a, and not necessarily expected, a PD signal in these healthy volunteers. This is a GLP-1 antagonist, competitive antagonist. What we saw was an accumulation of GLP-1, endogenous GLP-1. That was good to see. We think that's predictive, likely of a therapeutic benefit in PBH patients, and similar to what a different GLP-1 short-acting once daily saw in healthy volunteers as well.
Great. Maybe just in the last few minutes, if you could touch on your other program, 4291, part of the early stage obesity portfolio. As the obesity market is kind of shaking out in real time with a lot of developments there, where do you see this fitting in? What features may differentiate it most clinically? Tell us a little bit more about the approach.
Also a very interesting time in obesity. I think there's little debate that this is a very large market. You have an epidemic global. You have blockbuster successes. Let's look at tirzepatide or Zepbound, but also limitations. I think it's pretty well known if you have friends taking these versus GI side effect. And it's pretty real, the nausea, vomiting. It also is an encumbrance in terms of tirzepatide with the discontinuation rate, which is pretty high, right? According to JAMA, about 65%. And importantly, only about 10% are able to get to the highest dose. And so that limits the effectiveness. Our approach with this continuous infusion-like, this pro-drug kind of approach is we think that we can do better starting with once monthly as an important point of differentiation and potentially other areas such as better tolerability. We have a slower rise to Cmax or maximum exposure.
We hear from KOLs that that is a very important way to improve tolerability because it is not just the maximum concentration, how quickly you get there, that affects the GI tolerability. The other way we could differentiate is on overall weight lowering. If you can get patients to tolerate a higher dose and you have the activity of tirzepatide, which we believe our GLP-1, GIP co-agonist does, it would seem you could expect to get greater weight lowering as well. We have planned a phase I study where we can answer a lot of these questions. I am pleased to say we are on track to file an IND this quarter.
Got it. Great. Excellent. Look, I think we're just about out of time, last few minutes. I guess anything we didn't touch on that you think people are maybe missing from the story that you want to add?
I would hope that people would take away from this that this company has a clinically proven platform technology that's been able to reproducibly show that translate to the kind of profile in healthy volunteers that we designed it for. Now we'll look forward to seeing it in patients. I think this phase II milestone coming up next quarter is huge for the company. I guess I would say if you like Yorvipath, you should love canvuparatide.
Yeah. Looking forward to those data. Kent, thanks so much for being here. And thanks to everybody.