Good morning. Welcome to Lyra Therapeutics' Conference Call and webcast to discuss top-line results for Enlightened II phase III trial of LYR-210 in chronic rhinosinusitis. My name is Kevin from Notify Conference Call Service, and I'll be your operator today. This webcast is being recorded. This webcast will be available on Lyra's website for a limited time. Currently, all participants are on a listen-only mode. Earlier this morning, Lyra announced results from Enlightened II phase III trial in a press release. The press release is available on the investor relations page of the company's website at www.lyratherapeutics.com. On this conference call today, members of Lyra's management will make prepared remarks about the Enlightened II phase III trial results with the accompanying slide presentation and the webcast. Today's speakers from Lyra Therapeutics will be Dr. Maria Palasis, President and CEO, and Jason Cavalier, CFO. Following the prepared remarks from Dr. Palasis, we will have a Q&A session. To ask a question at that time, please press star one one on your phone. I will now turn the call over to Mr. Cavalier.
Good morning. During the course of this call, we expect to make forward-looking statements, including statements related to the clinical development of the company's product candidates, business strategy, potential regulatory submissions, and potential commercial plans for its candidates, including estimated addressable market opportunity. These forward-looking statements are based on the company's current expectations and inherently involve risks and uncertainties. Lyra's actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. Factors that would cause results to be different from these statements include factors that the company describes in the section entitled Risk Factors in the company's quarterly report on Form 10-Q filed with the SEC on May 6, 2025, and its other filings with the SEC. I will now turn the call over to Dr. Palasis.
Good morning. We are very excited to share the positive results from the phase III Enlightened II trial, which evaluated LYR-210 for the treatment of chronic rhinosinusitis, or CRS. Before I take you through the presentation, I want to take a moment to thank our employees for their perseverance and dedication to the continued development of LYR-210 following the Enlightened I trial setback in May 2024. In addition, I want to thank our investigators and patients upfront. Their continued belief in the potential of LYR-210 allowed us to complete the Enlightened II study and collect the data that I am sharing with you today. We will start on slide three to briefly discuss CRS for those unfamiliar with this disease. CRS is characterized by inflammation that is localized within the nasal sinuses. It is widespread and challenging, with approximately eight million patients treated annually in the U.S. alone.
50% of these patients, which amounts to four million patients annually, fail today's available medical therapy and represent our market opportunity. It's estimated that the annual healthcare expenditures related to CRS are approximately $60 billion. Generally speaking, CRS has two phenotypes: patients without nasal polyps, which represent about 70% of the market, and patients with nasal polyps, which represents the remaining 30% of the market. Patients with CRS experience chronic nasal obstruction and congestion, facial pain and pressure, nasal discharge, and reduced sense of smell. These symptoms are referred to as the cardinal symptoms of CRS, and they are relentless and debilitating to patients in their daily lives. On slide four, I will briefly review our technology and product candidates. Our novel technology is an engineered elastomeric matrix that is designed to dynamically conform to the anatomy of the sinonasal passages and is designed to provide long-acting localized drug therapy.
Our lead product candidate is LYR-210, which is the smaller version of our product candidate. It's designed to accommodate patients with a narrow ethmoid cavity. LYR-210 is formulated to deliver 7,500 micrograms of mometasone furoate, a well-known anti-inflammatory steroid, over 24 weeks. Upon completion of our phase II dose-ranging study, LYR-210 was studied in our pivotal phase III Enlightened program, which we are sharing today. We have designed LYR-210 to be the new standard of care for CRS patients that have failed medical management. Within the CRS treatment community, it's well established that steroids work and are the mainstay of treatment. However, these treatments are inadequate for many patients due to limitations in delivery and administration. Oral steroids have well-known systemic safety issues, and steroid nasal sprays don't reach the site of inflammation that is deep within the sinuses.
They don't reside in the local tissue for long periods of time and are dependent on daily patient adherence, which can be challenging for these patients. Lyra's product candidates are designed to address these limitations, and if approved, we believe that LYR-210 is positioned to be the first long-acting product for CRS designed to provide six months of therapy with a single administration. Moving to slide five, the Enlightened program consists of two phase III clinical trials, Enlightened I and Enlightened II, to evaluate the efficacy and safety of LYR-210 for the treatment of CRS. Each trial was designed to evaluate approximately 180 CRS patients who have failed medical management and who have not had ethmoid sinus surgery, randomized two-to-one to either 210 or sham procedure control over 24 weeks.
An important difference between the two trials was that Enlightened I had a 28-week extension stage where patients continued to be blinded to treatment and was intended to demonstrate safety in repeat usage as well as duration of effect, data for which we have previously disclosed. In addition, the sham patients at 24 weeks crossed over in treatment. While the Enlightened program included patients with and without nasal polyps, it's important to note that the primary endpoint was a change from baseline in the three cardinal symptoms, or 3CS, at 24 weeks in patients without nasal polyps. Key secondary endpoints include a change from baseline in the three cardinal symptoms and SNOT-22 score at week 24 for the full population of patients with and without nasal polyps.
Moving to slide six, as you can see in the table, patient demographics and baseline characteristics were similar across the LYR-210 treatment and sham group. In terms of region, 55% of the patients were in North America, 45% were in Europe. Baseline 3CS score was slightly higher in the sham group at 7.2 points compared to 6.5 points in the treatment. Baseline SNOT-22 score was very similar, with a score of 45.3 in the treatment group compared to 45.7 in the sham group. Moving to slide seven, in terms of safety, the Enlightened II study shows a favorable safety profile with no product or procedure-related serious adverse events. This table shows the most common treatment-emergent adverse events reported in the study. These were generally mild to moderate anticipated side effects.
The most common adverse effect was epistaxis or nosebleeds, which is a common adverse event for nasal steroid treatments and procedures. These resolved on their own without need for intervention. Moving to slide eight, the primary endpoint of the Enlightened II study was a change from baseline for the 3CS at 24 weeks in the non-polyp patients. The study showed consistent improvement over sham control starting as early as week eight, with a p-value of less than 0.05 at weeks 20 and 24. At week 24, 210 showed statistically significant improvement, with a 1.13 improvement over sham, representing a p-value of 0.0078. Slide nine shows the results of the first key secondary endpoint, which is a change from baseline in 3CS at week 24 for the full population of patients with and without nasal polyps.
Again, we see consistent improvement over sham starting at week 12, with a p-value of less than 0.05 at weeks 12 through 24. At week 24, 210 showed statistically significant improvement, with a 0.9-point improvement over sham, representing a p-value of 0.0209. Slide 10 shows the results of the second key secondary endpoint, which is the change from baseline in SNOT-22 score at week 24. This is the data that our investigators are most excited about, as SNOT-22 is a clinically validated assessment used by clinicians to measure the symptoms and impact on a patient's quality of life. 210 shows consistent improvement over sham control starting as early as week four, with a p-value of less than 0.05 at weeks four through 24. At week 24, LYR-210 showed statistically significant improvement, with an 8.7-point improvement over sham, representing a p-value of 0.0101.
For the SNOT-22 score, the minimal clinically important difference has been established as 8.9 points. Our 22-point improvement over baseline represents more than double this clinically meaningful benchmark. Moving to slide 11, here we show the change in % ethmoid opacification at week 20, which was our third key secondary endpoint and is an objective endpoint looking at level of disease in the ethmoid sinus on CT. In the Enlightened program, the inclusion criteria did not require a high level of disease on CT. Despite that, we observed a numerical improvement of approximately 2.2 points in % ethmoid opacification by CT over sham. Moving to slide 12, as a reminder, we pooled and analyzed separately the 64 patients with grade 1 nasal polyps across the Enlightened I and Enlightened II trials. This was a pre-specified as opposed to post-hoc analysis.
For 3CS, we observed a consistent positive trend starting in week four and further improvement at weeks 20 and 24 in this small sample size of 64 patients. At week 24, interestingly, the 1.13-point improvement over sham is identical to what we saw in the non-polyp patients. On slide 13, a similar consistent positive trend was observed in the SNOT-22 score starting in week four and throughout week 24, with a p-value less than 0.05 at week 20. At week 24, similar to the non-polyp patients, LYR-210 showed a greater than 20-point improvement over baseline, which represents more than double the clinically meaningful difference of 8.9 points. Slide 14 shows a change from baseline in nasal congestion score at week 24 for subjects with baseline nasal congestion that is greater than or equal to two, which represents patients with moderate to severe congestion.
Change in nasal congestion score would be a primary endpoint for a future polyp trial. Again, we observed a consistent positive trend of improvement in nasal congestion score starting in week four and throughout week 24, with a p-value less than 0.05 at week 20. Moving to slide 15. In conclusion, the Enlightened II phase III pivotal trial met its primary endpoint and key secondary endpoint of change in 3CS and SNOT-22 in the full study population. A numerical improvement in the key secondary endpoint of change in percent ethmoid opacification by CT was also demonstrated. In the pooled Enlightened I and Enlightened II patients with grade one nasal polyps, a consistent positive trend was observed in symptomatic endpoints starting in week four and throughout week 24. Finally, LYR-210 was well tolerated, with no product-related serious adverse events reported in the study.
Needless to say, we are excited about these results as we believe that they support the robustness of our drug device technology to potentially treat CRS patients. We believe the positive data from our Enlightened II phase III study enables us to advance our regulatory strategy toward FDA approval for LYR-210. It renews our vision to bring new therapeutic solutions to millions of patients who struggle with CRS in their daily lives. We intend to meet with the FDA in the second half of 2025 to align on the strategy for CRS without nasal polyps, as well as initiating a phase III trial with nasal polyps in the first half of 2026, pending additional financing. We plan to present the data from the Enlightened II study at the American Rhinologic Society annual meeting in October. We will now open it up for Q&A.
Thank you, ladies and gentlemen. If you have a question or a comment at this time, please press star one one on your telephone. If your question has been answered or you wish to move yourself from the queue, please press star one one again. We'll pause for a moment while we compile our Q&A roster. Our first question comes from Lachlan Hanbury- Brown with William Blair. Your line is open.
Hey, thanks for the questions and congrats on the good data here. I guess the first question that I think we've probably discussed over the past year is, can you just elaborate on sort of anything you've seen that may explain why Enlightened I and II were different? I know I'm sure you've got plenty more analysis to do on this data, but anything you've seen at this point that may help explain the difference would be appreciated.
Hi, Lachlan. Thank you for the question. Let me start with, you know, we're thrilled with the results, clearly, of Enlightened II, and they're very much in line with what we expected, right? What we expected out of this trial and what we expected out of Enlightened I. The effect size of greater than 1.3CS, and very importantly, the SNOT-22 score throughout the treatment duration and, you know, in the magnitude of improvement. You know, we know that there's an enormous need for non-polyp patients with the 2.8 million failures per year. And these patients, really, they don't have anything other than one nasal spray that's been approved. There's no other drugs other than sprays. Our plan is to move forward with Enlightened II with the data, Enlightened II data supporting the non-polyp and Enlightened I data. First of all, you know, what is consistent?
Enlightened I, as you know, we looked at the different populations in Enlightened I, and we have reported that we had seen an improvement in the European patients. This was consistent with our phase II study. Now in Enlightened II, we again see very consistent improvement in our European patients, and we see consistent improvement in our U.S. patients in Enlightened II. In Enlightened I, the U.S. patients had a much greater sham effect. That's what we've noticed. You know, why is it that the European patients, we see consistent improvement? We have said before that there's a, we believe, a higher level of disease burden in the European patients. They have lesser access to disease, to treatment. We believe that the U.S. population, non-polyp population, there's more heterogeneity in that population, and we may have had more transient patients with transient disease.
In terms of the clinical study, you know, the designs were very similar. We did have different sites, right? Because the studies were executed for the most part in parallel, they were staggered, we had to use different sites. We had slightly more academic sites in Enlightened II than we did in Enlightened I. So those are the differences. We're going to continue to dig into the data just like we did in Enlightened I. I think what is critical is, you know, we intend to go to the FDA with a totality of our data. We believe that the risk-benefit profile supports moving to an NDA. The FDA may require us to do an additional study.
I think what's important is if they do, that we are very confident that we can design a successful Enlightened, a next Enlightened trial if required, based on all the data that we have. I do want to mention we have a very big data set now in non-polyp patients. We have more than 300 patients that we can use. Our clinical team has been digging into Enlightened I. We know that a next trial, if we needed to do this, would be we would have a lot of European patients. We also would increase the severity of disease on CT, which we think will be important. We are going to validate all of this with our Enlightened II data. Let me just stop there and see if you have any follow-ups.
Yeah, thanks. That's very useful to hear all that. Definitely a lot to think about. I guess another question here is, you know, it's good to see the trends in the polyp patients, but you were only enrolled grade I, which I assume sort of caps the level of benefit that you could see. I guess, could you just comment on that? Do you have a sense of how much only grade I patients could be capping the efficacy there and maybe if you would expect anything different in patients with larger polyps?
Yeah, we are. That's a great question, Lachlan. We do believe that that is likely the case in the polyp patients. I think it's very interesting to see that both the three cardinal symptoms and the SNOT-22 score in the grade I polyps were very similar to the non-polyps. I think that helps us overall, right? We're showing consistency. And these grade 1 polyps are very small.
You know, showing the differences that we showed in the nasal congestion and we have important differences also in CT, I think it bodes well. We would expect that patients that have bigger polyps, grade II, grade III, grade IV, should show greater congestion, right? We have to prove that out in a pivotal study, and that is our plan. I also want to note that, you know, there have been many antibody trials that have been done in polyps, and those studies have, for the most part, not included grade I. They have included the larger grade of polyp. Our thoughts right now on a polyp program would be an adaptive study where we would understand the benefit of our product in those larger polyps, and then we would be in a position to do a sample size re-estimation for the pivotal stage of that program. That's a very, very important question. Thank you.
No problem. Anything I can squeeze in before passing on? In your communications with the FDA since Enlightened I read out, did you ever discuss the possibility of, you know, if Enlightened II was positive, what your options would be?
We did not discuss the non-polyp data with the FDA. We felt it was important to have Enlightened II read out first so that we knew what the full data set is. Now, having said that, we are planning to go to the FDA as soon as we can. Number one, we have to get all the data analysis on Enlightened II completed. The other thing I want to mention is that we have pre-specified pooled analysis between Enlightened I and Enlightened II that we can do, and this was included in our integrated summary of efficacy. These are planned analyses. We believe that this pooled data is going to be really important to share with the FDA. You know, we're going to do this analysis. We're going to quickly put in a meeting request with the FDA, and our intent is to meet with them in the second half and talk to them about our pathway towards an NDA for non-polyp patients.
Got it. Thanks for the questions, and congrats again on the data.
Thank you, Lachlan.
One moment for our next question. Our next question comes from Dennis Ding with Jefferies. Your line is open.
Hi, good morning, and congrats on the data. I just had a question just around the FDA. Just curious what precedence is there in the Division of Pulmonary and Allergy, where the FDA has allowed an NDA filing on only one positive phase III. Are there any differences in those examples relative with your own situation? How much can you leverage the fact that the steroid is already approved in those discussions with the FDA? Thank you.
Right. Dennis, your first question is, is there precedence? There is precedence. There has been a nasal steroid-eluting implant for patients with recurrent nasal polyps that has been approved off of one phase III study. There has also been an antibody, Nucala, which has been approved with one positive phase III study. Yes, there is precedence there. Your second part of your question was, can you repeat that, Dennis? I'm sorry.
Yeah, just, you know, when you compare those situations with your situation side by side, if there are any similarities or differences.
Yes, absolutely. That's right. There is a guidance document that the FDA has put out that guides towards one pivotal study as being sufficient. That guidance document states that if the drug is within the same pharmacological class as another drug that is approved for the same indication and the endpoints are similar, that you may be able to use one trial. What helps us, both for polyp and non-polyp, is that steroids are the foundational treatment for these patients. There is no doubt about that, right? Patients will go on steroids, nasal steroids for the most part. The fact that nasal steroids now are approved also in non-polyps, there has recently been a steroid spray that was approved in non-polyps. I think that really helps our company, right? It helps us leverage, you know, the data that is already in there for both non-polyp and polyp. You know, that's our intent is to, number one, use our data where we have very strong benefit-risk profile. We have a very strong safety profile with no serious adverse events that are product or procedure-related across any of our trials, right? We've done six trials to date. Leveraging all of our safety, all of our efficacy, and also the fact that there is precedence at the FDA, both in terms of having an approval off of one pivotal and using the guidance document in cases where there have been recent approvals of local steroid therapies.
Perfect. Thanks. If I can follow up with one question, if the FDA does require a new trial, how much will that cost and how will you bridge that funding gap? Thank you.
Hey, Dennis, this is Jason. If we do have to do another Enlightened III trial in non-polyp, again, depending on the feedback from the FDA on the sizing, we estimate about $20 million, which is roughly in line with our previous phase III trials. In terms of bridging the funding gap, I can't be specific about our financing plans, but, you know, we had $32 million of cash at the end of the first quarter of this year, which takes us to the end of this year, early into next year. Clearly, you can do the math and understand that we need to finance, but I can't be more specific about that right now.
Okay. Thank you and congrats on the data.
Thank you.
Thank you.
One moment for our next question. Our next question comes from Matthew Caufield with H.C. Wainwright. Your line is open.
Hi, good morning, Maria and Jason, and very excited to see the updates. Congratulations. From a practical standpoint in the clinic, I was wondering, what are your thoughts on the two matrix sizes at this point? If that approach is ultimately more practical for treating sort of the heterogeneity that exists among patients, what could be necessary to ultimately get both sizes across the finish line, you know, first for non-polyp and then ultimately for polyp? Is that something that could be implemented into the next stages, or is that something that would be thought about or pursued kind of down the line?
Hi, Matt. Thank you for your question. That's correct. We have two matrices, two sizes, a big and a small. LYR-210 is a small one. It opens up to about a diameter of 13 millimeters. Both matrices are in applicators that are about 3 millimeters, right? 210 opens up to 13 millimeters and 220 opens up to about 20 millimeters. It is important that we have the two sizes because one of the things that clearly we've learned is that no two patients are the same. They get surgery, and the surgery is more like an art. You know, each physician does the surgery differently. Sometimes they'll do a full ethmoidectomy. Sometimes they'll do what's called a partial ethmoidectomy. They may take out some of the ethmoid sinuses but leave the other ones intact. Some patients have polyps, some do not. You really get a sort of a range of anatomy. The great thing about our product candidates is that when they open up, they sort of bloom open, they adjust to whatever the anatomy is.
The small one will be better suited for surgically naive and also for post-surgical patients that have had some polyps and maybe have a narrow space, and the 220 will be more for those who have had a full ethmoidectomy. That is the heterogeneity, and that is why we need two sizes. With respect to how we are going to bring forward, we know that we have studied 220 in the BEACON study in patients who have had a prior surgery. Our intent right now is to focus on LYR-210 in the presurgical patients and patients without polyps. In the polyp study that we plan to initiate, that study would be 210 in both pre and post-surgical patients with polyps. We believe that we can access, you know, the majority of the market with those trials if we can get those indications. The 220 then would follow, right? So we would do that as a supplemental NDA to be able to bring another size in. We believe that could be done in a straightforward way. I mean, think about it like a drug-eluting stent where you'll test out one size, but then bringing in additional sizes requires a lower level of burden. That would be our strategy for 220.
Excellent. Very helpful. I really appreciate that and very excited to see next steps here. Thanks, guys.
Thank you. Thank you, Matt.
I'm not showing any further questions at this time. I'd like to turn the call back over to Dr. Palasis for any closing remarks.
Thank you, Operator. I want to thank everyone again for joining the call this morning. We look forward to sharing additional updates on our path forward as soon as we can. Thank you very much.
Thank you, ladies and gentlemen. That concludes today's presentation. You may now disconnect and have a wonderful day.