Xeris Biopharma Holdings, Inc. (XERS) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to today's Top Line Phase I Study Results of XP-8121. My name is Drew, and I'll be coordinating your call today. [Operator Instructions]. I'm now going to hand over to Allison Wey, Senior Vice President, Investor Relations and Corporate Communications, to begin. Please go ahead.

Thank you, Drew. Good morning and thank you for joining us to discuss the results of our Phase I study of XP-8121. A press release was issued earlier this morning and can be found on our website. We are joined today by Paul Edick, Chairman and CEO; and Ken Johnson, Senior Vice President of Global Development and Medical Affairs. Paul will provide opening remarks, and Ken will review the study design and results, and then we'll open the line for questions. Before we begin, I would like to remind you that this call will contain forward-looking statements concerning Xeris' business practices, Xeris' future expectations, plans, prospects, clinical approvals, commercialization, corporate strategy, performance and the impact of COVID-19 on Xeris' business practice, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including the effect of uncertainties related to COVID-19 pandemic on U.S. and global markets; Xeris' business, financial conditions, operations, clinical trials and third-party suppliers and manufacturers; and other risk factors, including those discussed in our filings with the SEC. In addition, any forward-looking statements represent our views only as of the date of this call and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements. I'd like to turn the call over to Paul.

Thanks, Allison. Thanks to everyone for joining the call this morning and for your continued support as we execute on our growth strategy to build a substantial patient-centric, commercially focused, profitable biopharmaceutical enterprise with multiple products in multiple therapeutic areas, a highly targeted development pipeline that has significant long-term promise and value-added partnerships based on our unique technologies, meeting the needs of patients and caregivers. Today, we're pleased to report, we are encouraged with the results of the Phase I study of our subcutaneous injection for levothyroxine, the details of which Ken will take you through in a moment. Let me start by addressing the market opportunity for maintenance therapy in patients with congenital or acquired hypothyroidism who require thyroid replacement, hormone replacement, then take you through the value proposition of our subcutaneous injectable levothyroxine. At a high level, there are over 105 million prescriptions dispensed for oral levothyroxine annually. Of the people on levothyroxine who represent those 105 million prescriptions, 47% are frequently associated with combined comorbid GI condition impacting oral absorption, 21% concomitant medication known to interfere with absorption of levothyroxine, 17% admit to compliance issues and daily oral -- of the daily oral regimen, and with 15%, symptoms are very hard to control. Now those may not be individual and unique patients. There may be patients who have a multitude of those symptoms. But at the end of the day, if you only take 7% of that $105 million market, you end up with about 62 million weekly doses per year at an average prescription size and price. The opportunity here is close to $2 billion to $3 billion. Now for maintenance therapy in patients with congenital or acquired hypothyroidism, what is the value proposition of our potential once-weekly subcutaneous injection of levothyroxine? First and foremost, it would be the first injectable levothyroxine indicated for hypothyroidism. It would bypass the GI tract, avoid the spectrum of oral absorption challenges that I just mentioned, improve the regimen compliance with a once-weekly administration, demonstrate -- at some point, we will demonstrate safety and comparability in terms of exposure. And it's small volume, ready-to-use, room temperature stable, subcutaneous injection, which is enabled by XeriSol formulation technology, would be a significant advantage for patients. And as I mentioned, that would translate into a very significant market opportunity. And with that, I'll turn it over to Ken.

Thanks, Paul. Next slide, please. So before we go into the results, I'd like to take you through a little bit of the background, objectives of the study and some of the simulations that we also performed at the conclusion of the study. So for background, we are taking an approach where we'll be very reliant on the previous approval for our listed drug, Synthroid. And in fact, that is the reference standard in this particular therapeutic category. So all of our comparisons that we'll be showing today will be versus the Synthroid product, and that is AbbVie's original NDA. Furthermore, there is a published guidance from the FDA that describes how to assess different forms of oral levothyroxine, which there are many generics on the market. And it focuses on the utility of studying 600 micrograms as a single dose in normal volunteers. This is important because you need to be able to have a measurable concentration on levothyroxine in normal volunteers above their own background or baseline thyroxine level. And then lastly, because this is the first time we've administered our subcutaneous formulation, we selected 3 ascending doses so we could confirm or ascertain the dose proportionality of this particular formulation over a range of doses that we feel will approximate current clinical practice. So the study objectives are really straightforward. We'll collect all the traditional pharmacokinetic variables associated with the subcutaneous injection as well as the oral. We'll do a formal assessment of dose proportionality. We're, of course, collecting safety and tolerability in these individuals. And then lastly, I'll show you our results of the population PK or pharmacokinetic modeling to approximate steady-state dosing. Next slide. So this is just a schematic of the design. We start out with a typical crossover design with 600-microgram oral to subcutaneous. This would be consistent with that FDA guidance I mentioned previously. After completion of those 2 periods, then all subjects went on to receive 1,200 micrograms of the subcutaneous 8121. And then following that, after we did an assessment of safety and tolerability in that group, we enrolled the final group at 1,500 micrograms, our highest dose. Next slide. So here, I'm showing you the line plots over 28 days for both 600-microgram doses. So in orange is Synthroid oral, in the circles. And you can see there, a typical rapid rise in the concentration of levothyroxine, followed by a rapid decline. A Tmax of about 3 hours, a Cmax of about 48. And then in comparison, the blue line is a 600-microgram subcutaneous 8121. You can see, it's a more prolonged Tmax up to 48 hours. About half the Cmax or about 22. But interestingly enough, when you compare the AUCs, there's actually about 35% more exposure with the subcutaneous in the later portion of the data collection. So you can see that blue line stays above the orange line at the later time points. Not on this slide, but a factor that we did calculate is the half-life, and the elimination and clearance of the drugs was similar between both. So that was not altered. So the conclusion here, other than what's obvious from these pictures, is that we have modified the absorption of this particular through this formulation. And we think that, that will fit very nicely with the profile we're trying to achieve. Go to the next slide. In this slide, I've kept both of the 600-microgram doses on the slide, but I've added the 2 ascending doses, the 1,200 and 1,500 of 8121 subcutaneous. You can see visually that there's a proportional dose-dependent increase, about 1,200 and 1,500. And we've documented that this is a linear relationship and confirming that we do have dose proportionality over this range. I have just a single bullet point there, but just to point out that in our safety assessments, we did have typical types of things seen in an oral volunteer study. But importantly, there was no difference between any of the groups. All of them are either mild to moderate. They resolved, they were transient, and they required no medical intervention. So now knowing something about the pharmacokinetic performance or profile that led to this exposure, we then -- please advance the slide, I'm sorry. We then use all the data that we had available to us to construct the population pharmacokinetic model. Some of you are probably familiar with this technique. It's kind of commonly I've used 5 sponsors and communication with the FDA, in particular, when there's a change in round of administration, change in the dosing regimen, and it's particularly useful when there's a well-established exposure relationship to the clinical effect, as is the case here with levothyroxine. So we had model parameters that were very well fit and met the criteria for moving forward with the simulation. In that simulation on this picture, you'll see what would be 5 weeks of oral therapy, 300 micrograms. That was an arbitrary dose that we picked, and we could certainly model other doses if necessary, but we started with 300. In that orange line, you could see what represent the kind of Cmax and Cmin over the course of 7 days. That results in a cumulative AUC that we wanted to compare to simulations of 1,100, 1,200 and 1,300 of a single once-weekly dose of XP-8121. And you can see, there's some overlap here. It could be 1,100. It could be 1,200, 1,300, probably not. But when we analyze the comparable AUCs, Cmaxes and Cmins, the best fit right now implied by this model is 1,200 or a conversion factor of 4x. So this gave us additional confidence that we probably have the right dosing interval, and we now have some measure of what the conversion would be for patients who are on a current oral dose to what they would receive as a commensurate subcutaneous dose. So with that, I'll turn it back to Paul. We certainly are moving forward and have a few next steps in place with the FDA, and I'll let Paul highlight that.

Thanks, Ken. Based on what Ken had shown you, we believe that our formulation enables a small-volume subcutaneous injection as an injectable maintenance therapy. It may facilitate very less frequent dosing and we believe may provide clinical advantages over the established oral daily route. As I mentioned previously, it's a large market opportunity. Oral levothyroxine is one of the most prescribed therapies in the U.S. with over 100 million prescriptions annually. We've demonstrated proof of concept of once-weekly subcutaneous injection of XP-8121 can provide the comparable exposure to daily oral Synthroid, supporting further development in patients with congenital or acquired hypothyroidism, require thyroid hormone replacement. The dose conversion ratio has been established. Chronic dosing simulation implies dose conversion of 4x. We have demonstrated at this level safety and tolerability. XP-8121 in healthy volunteers was generally well tolerated at all doses. And as for next steps, our FDA end-of-one-phase meeting has already been requested, and interaction with the agency is expected by year-end. Our anticipation is that what we will -- what we have submitted is very consistent with what has been the guidance in the past and what has been agreed to in the past with other sponsors. So with that, we thank you for listening, and I will ask the operator to open it up for questions.

[Operator Instructions] So our first question today comes from Oren Livnat from H.C. Wainwright.

Congratulations. It's pretty exciting stuff. Just first of all, you talked about already requesting an end of Phase I meeting with the FDA. Have you had any interactions with the agency before this to give you some guidance on your approach that you can comment on?

Oren, this is Ken. Well, we certainly had a meeting about our IND and what our initial Phase I study was then. Their questions there were about the safety of the subjects, what they consider to be new and different doses. So we did have that discussion. But that's kind of the [indiscernible].

Okay. And certainly, there have been bioequivalence pathway-developed drugs in the past, expedited fashion. You've highlighted repeatedly how big an opportunity this is. So I'm assuming, and you can correct me if I'm wrong, that such a large opportunity probably brings with it some rigorous, I guess, standards with regards to bioequivalence. So can you just comment on sort of what -- how this best fit modeling that you've done? How far down the road do you think that gets you pending FDA discussions towards potentially some pivotal bioequivalence work? What do you imagine conservatively would be the next steps?

Yes. Thanks, Oren. So I think if I just back up a second, there's sort of 2 points of view that we took in trying to understand what might be in front of us. One is, as I mentioned, there's a well-established guidance for oral levothyroxine therapy. But it's daily oral therapy but certainly points out what the parameters are for bioequivalents. So I think that will be on our minds as we sort of say what sort of range would we have to fall into. Of course, that's for daily and that's a once-a-day AUC, and we're doing a cumulative 7-day AUC. So that lend us to say, well, what of other sponsors who've gone from an oral therapy say once-a-day to less frequently administered parenterals. There are analogs outside of levothyroxine that we've found and stated as precedents. One of them, in particular, Adlarity was a once daily. It's now also available as a once weekly. And that was, again, with the well-established exposure, clinical relationship was done through a form of a bioequivalent. So I'll just use that term maybe more in air quotes. So comparable exposure with the change of route of administration with a different formulation, I think, is kind of our central thesis here for the program. But we're waiting for this interaction to occur, and we'll be following up with all of you when we reconcile what their feedback is.