Good morning or good afternoon, all, and welcome to today's call. Aldeyra reviews clinical trial development plan for reproxalap in dry eye disease. My name is Adam, and I'll be your operator for today. If you'd like to ask a question during the Q&A portion of today's call, please press star followed by 1 on your telephone keypad. I will now hand the call to Laura Nichols to begin.
Thank you, and good morning, everyone. Today we issue the press release announcing an updated development plan intended to enable resubmission of a new drug application of reproxalap, an investigational new drug for the treatment of dry eye disease. A copy of the press release is available on the investor and media section of our website, www.aldeyra.com. The press release contains important information and should be read and considered in conjunction with the slides presented in the prepared remarks on today's call. With me today to discuss the development plan is Dr. Todd Brady, President and Chief Executive Officer of Aldeyra. Turning to slide 2. This presentation and various remarks which may be made during this presentation contain forward-looking statements regarding Aldeyra, its investigational drug candidate reproxalap, and its plans, expectations, and opportunities including potential clinical trials and regulatory activities.
Forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause Aldeyra's actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. These statements are based upon the information available to Aldeyra today and reflect Aldeyra's current views with respect to future events and are based on assumptions and subject to risks and uncertainties including the development, clinical, and regulatory plans or expectations for reproxalap. There are risks that results from earlier clinical trials or portions of clinical trials may not accurately predict the results of future trials. There are also risks that the positions expressed by the U.S. Food and Drug Administration or FDA may change at any time, and that such changes, if they occur, could substantively alter our plans to diminish the feasibility of resubmitting a new drug application for reproxalap.
Aldeyra assumes no obligation to update oral or written statements made today as circumstances change. Future events and actual results could differ materially from those projected in the company's forward-looking statements, including the results of operations and financial position. Additional information concerning the factors that could cause results to differ materially from our forward-looking statements are described in greater detail in the press release issued this morning and our filings with the Securities and Exchange Commission. I would now like to turn your attention to slide 3 and introduce Dr. Brady.
Well, thank you, Laura. Following review of a new drug application or NDA of topical ocular reproxalap for the treatment of dry eye disease, the FDA issued a complete response letter in November of last year which stated that at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye needed to be conducted. The letter did not identify any other substantive review issues. In response to the letter, we submitted for review under the 45-day Special Protocol assessment program, a crossover design dry eye chamber clinical trial. In the clinical trial, each subject was to receive both reproxalap and vehicle, that is, the drug product without the active ingredient, and ocular discomfort score, a dry eye disease symptom, was to be reported by patients during exposure in the dry eye chamber.
Following the FDA's review of the protocol, in our opinion, the key recommendation was to change the crossover design to a parallel group design such that each patient received either reproxalap or vehicle following randomization. Per FDA guidance, sponsors may elect to meet with the FDA instead of resubmitting protocols for additional 45-day reviews, and accordingly, we modified the protocol per the FDA's recommendation and met with the FDA. As a result of the written protocol review, the written comments from the FDA prior to the meeting, and the minutes from the meeting, we believe that we have addressed the substantive recommendations of the FDA regarding the protocol. In the first half of this year, we intend to initiate a dry eye chamber clinical trial similar to dry eye chamber clinical trials that we've conducted previously with reproxalap, with patient-reported ocular discomfort score as the primary endpoint.
Results from the trial, if positive, are intended to enable a resubmission of the NDA in the second half of this year. The duration of FDA review of the resubmitted NDA, if such resubmission occurs, is expected to be six months. As part of a contingency strategy to account for disease heterogeneity and potential differences across clinical sites and environment, we also intend to conduct an additional dry eye chamber trial and a traditional six-week field trial in parallel with the dry eye chamber trial discussed with the FDA. The randomized, double-masked, vehicle-controlled dry eye chamber trial design is illustrated on slide 4. The trial is comprised of four visits. Visit 1 is a medical screening to qualify dry eye patients for visit 2. During visit 2, patients will receive vehicle before and during a dry eye chamber of approximately 100 minutes in duration.
Qualifying patients will advance to visit three and will be randomized to receive either vehicle or reproxalap four times during the visit. The next day at visit four, patients will receive randomized treatment before and during an additional dry eye chamber. Approximately 100 patients are expected to be enrolled. The trial design is substantially similar to that of four previously conducted dry eye trials with reproxalap, which primarily assess dry eye signs as primary endpoints. Slide five presents pooled ocular discomfort data from the four previously conducted dry eye chamber clinical trials using the planned clinical trial endpoint and analysis. As with the planned dry eye chamber clinical trial, randomized treatment was administered before and during the chamber, and subjects reported ocular discomfort score at regular intervals throughout the duration of the chamber.
At every time point in the chamber, including the first time point, ocular discomfort scores of reproxalap treatment were lower than those with vehicle treatment. Both prophylactic effects of reproxalap occurring prior to the chamber and treatment effects of reproxalap occurring during the chamber at the time of peak symptoms were observed, and the activity of reproxalap relative to vehicle increased over time. The improvement of reproxalap over vehicle assessed across all 110 patients from previous trials that would qualify under the planned dry eye chamber trial protocol was highly statistically significant, with a p-value of 0.0003. Based on the results from the previously completed dry eye clinical trials, the planned dry eye chamber trial is expected to be more than 90% powered to detect a difference between treatment groups.
As is summarized on slide 6, results from the planned dry eye chamber trial, if positive, could lend further support to the key potential differentiating characteristics of reproxalap relative to the dry eye disease marketplace: rapid onset of activity, broad symptomatic effect potentially encompassing both dryness and discomfort symptoms, and rapid reduction of ocular redness, which may be the only dry eye disease sign that is of primary importance to patients. Dry eye disease remains a pervasive and debilitating disease that is growing in prevalence, and the clinical need remains for treatments that work quickly with sustained activity. The Aldeyra product candidate pipeline is illustrated on slide 7.
Across all therapeutic areas, including dry eye disease, allergic conjunctivitis, systemic inflammatory diseases that include atopic dermatitis and alcoholic hepatitis, and retinal diseases that include the dry form of age-related macular degeneration and the orphan disease retinitis pigmentosa, Aldeyra remains a well-capitalized biotechnology company with a diversified pipeline of novel clinical stage therapeutic approaches. Per previous guidance and based on our current operating plan, our cash and cash equivalents are expected to enable operations beyond 2026. Our milestones are listed on slide 8 among a variety of clinical trial results and initiations across a number of clinical indications. The reproxalap dry eye program discussed today is expected to be initiated in the first half of 2024, with results and potential dry eye disease NDA resubmission for reproxalap expected in the second half of this year. Operator, I'd now like to open the call for questions.
Cool. As a reminder, if you would like to ask a question today, please press star followed by one on your telephone keypad now. When preparing to ask a question, please ensure your headset is fully plugged in and unmuted locally. Our first question today comes from Yigal Nochomovitz from Citi. Yigal, your line is open. Please go ahead.
Hi guys. This is Ashiq Mubarack for Yigal. Thanks for taking my questions and congrats on the updates. Just a couple of quick ones from us. Can you give us any color on why the FDA felt strongly about a parallel assessment design rather than a crossover? What was the specific pushback on a crossover design? Thanks.
Thanks for the question. Good morning. The primary concern of the FDA, which is also the primary concern of clinical trialists regarding crossover trials, is carryover effect. Carryover effect is a concept where once patients receive drug, they then continue to either have drug in their systems, in this case in their eyes, or there's some sort of learning effect that occurs after receiving drug that then carries over into the next period when they receive vehicle. The problem with carryover effect is that it's difficult to interpret the vehicle results if there is either still drug in the system or some sort of learning effect occurred in the first period. The way around that is a parallel group trial where there is no carryover effect because, at least in our case, patients that receive drug are not subsequently treated with vehicle.
That's exactly the recommendation from the FDA that we followed with the design that you see illustrated on slide 4.
Okay. That's very clear. Maybe one more. We were wondering about the need for the sort of backup trials you have. It looks like you have one additional dry eye chamber study and then a traditional six-week field study expected to conduct later. What's your thinking behind those and whether or not you need to pull the trigger on actually running those if this upcoming study turns out to be successful? Thanks.
Well, I'm an old man, and I've been involved in a lot of clinical trials, and let me tell you, dry eyes are tough to treat. The disease itself is multifactorial, probably involving ocular physiology as well as more central physiology. The disease itself is heterogeneous, meaning that one person's dry eye is quite different from another dry eye. Compounding those concerns is the fact that dry eye may change from person to person, patient to patient, depending on environmental conditions, which may include pollen or pollution, and different clinical sites may have slightly different patient populations as well. For those reasons, we think backup plans are prudent. These chamber clinical trials are not terribly expensive. That enables us to run a backup chamber trial at a different chamber, a different clinical site, as well as run a field trial. In the past, we've run 12-week field trials.
In this case, we've proposed a six-week field trial because the effects of reproxalap are relatively rapid, and we simply don't see the need to treat patients for 12 weeks. So in essence, we have a backup plan, and then we have a backup plan to the backup plan, which in dry eye disease, for all the reasons I've mentioned, I think is a very prudent strategy.
Great. Thanks for taking my questions.
The next question comes from Tom Shrader from BTIG. Tom, your line is open. Please go ahead.
Good morning. Thanks for the update. Maybe you can walk through this trial design a little bit. I mean, it's a chamber trial where everyone gets vehicle, and then a second chamber trial where half the people get vehicle. What's the FDA trying to get out of that, and how does the first trial or the first chamber trial contribute? How's the essentially standard deviation calculated? Is that what comes from the first trial or the first chamber experience? I'm just a little confused at what this trial is designed to get at.
I think that's a great question, Tom. Vehicle run-ins, which is essentially what we've described on slide 4, are quite common. That is, in many clinical trials, not just in eye but across the disease spectrum, patients will receive vehicle first. Patients that improve on vehicle or, in our case, do not exacerbate in a dry eye chamber on vehicle are excluded. It really doesn't make sense to treat patients with randomized treatment if on vehicle they simply don't exacerbate in the dry eye chamber. The dry eye chamber is an intense environment. It's forced airflow. It's low to no humidity. It's forced visual tasking. And so patients that just don't exacerbate are probably unlikely to respond to randomized treatment. And that's why we have the vehicle chamber in the beginning. The vehicle chamber also allows us to compare randomized treatment to vehicle.
You'll notice that the critical part of the design here is that we've addressed the FDA's concern about carryover effect and crossover design clinical trials by making this a parallel group trial. The other thing I'll add, Tom, is this is the same design, more or less, that we've run four times previously.
I guess I haven't thought about it enough, but what fraction of people fail the run-in trial?
I think about 15% don't exacerbate in the chamber.
So it's low. Okay.
Yeah, pretty low. You really have to wonder about those patients. I myself fly across the country. I sit in an airplane. I have that air vent blowing in my face. I watch a movie, and I feel terrible. My eyes feel terrible. Patients that don't exacerbate in the dry eye chamber, which is a more concentrated version of my airplane description, may have such mild disease that they just wouldn't qualify as moderate patients and certainly wouldn't respond to randomized treatment.
Got it. Great. Thanks for the detail.
My pleasure, Tom.
The next question comes from Marc Goodman from Leerink Partners. Marc, your line is open. Please go ahead.
Hi. Thanks for taking my question. This is Julian on the line from Marc. I just have a quick follow-up question on the design for the chamber trial. Can you provide a little bit more rationale for dosing the vehicle before and during the exposure to the dry chamber? And it sounds like you're going to have two more visits after that. So maybe provide a little bit of color there. And another question, you mentioned you're going to start another trial at a different chamber. So maybe talk about what are the key differences, and do you need data from this trial to resubmit and maybe the timeline for that? Thanks.
Perfect. Good morning, Rudy. Those are all outstanding questions. I'll see if I can remember them. Let me go through the visit schedule of the trial, which is outlined on slide 4. Patients first have to prove that they have dry eye, at least a history of dry eye, a history of taking eye drops. That's a medical screening visit. And then in visit two, the purpose of the vehicle chamber is twofold, as I explained with Tom's question. One, patients that don't get worse or exacerbate on vehicle probably should not advance and, in this case, will not advance to randomized treatment. That concept of vehicle run-in is very common. In fact, many clinical trials today and many pivotal clinical trials employ a vehicle run-in. The other reason is that we're able to compare patients' performance on randomized treatment to their performance on vehicle treatment.
Patients that randomized a vehicle will, in a sense, be compared to vehicle, and you wouldn't expect major changes there other than classic period effects in the chamber. I think the second question you asked was, how is the next trial in the dry eye chamber going to differ from this trial? I can tell you they're going to be more or less carbon copies of each other. That we're aware, in terms of a standardized, rigorous chamber environment, there are only two in the world. One is in Canada, and one is in the United States. And thus, we will be running trials at each of those clinical sites. And then finally, your question about timing is interesting and a good question. That is, if we're running two chamber trials and a backup field trial, how do all those shake out in terms of timelines?
The idea would be to resubmit the NDA with the first positive trial. The FDA has been very clear. In their Complete Response Letter, we have a single key deficiency, and that is the need to run an additional symptom trial. The first one that works will be included in the resubmission. As we've said today and consistent with prior guidance, we expect that trial to read out and that resubmission, if the trial is positive, to occur in the second half of this year.
Got it. Thanks. Very helpful.
Thanks, Rudy.
The next question comes from François. from Oppenheimer. François, your line is open. Please go ahead.
All right. Thanks for taking the question. I just had a quick one here, a couple of quick ones. Can you just talk about on slide 5, you just maybe give a little more color on the slopes here and just the clinical meaningfulness of the differences between the slopes in terms of, I understand the first dose is prior to the chamber, but how do you feel about the slopes being similar, I guess, before the second dose between the two arms?
Yep. Frank, thanks for the question. I think that's an interesting point you make about, A, clinical relevance, B, the slopes after the first dose versus the slopes after the second dose. And I think, in this case, as I said in my prepared comments, we have evidence for prophylactic effect. That is, you give the drug or you give the test article, whether it's reproxalap or vehicle, prior to the chamber. And what you can see at the first time point is that the ocular discomfort score is lower with drug. Now, the reason for that, we believe, is that drug is administered just before the chamber, and you have a day prior to the chamber where four doses of randomized treatment, that is, either reproxalap or vehicle, is administered.
So before that first time point in the chamber, in a sense, patients have had five doses of test article, and already you see at least a numerical difference between drug and vehicle. That difference is increased, fortunately, after the second dose. The intent of the second dose, as I said in my prepared comments, is to test the treatment effect of drug near the peak symptomatology in the chamber. You can see that both lines go down after that second dose. That's just a vehicle effect. That is, when you put water in the eye or liquid in the eye in a dry eye chamber setting, you're going to feel acutely better. But you can see that vehicle never reaches the low ocular discomfort scores of reproxalap. Then over time, after that second dose, the difference between vehicle and reproxalap increases.
That is, patients on vehicle get significantly worse. And then finally, I think your question about clinical relevance is also interesting. There is no defined clinically relevant difference in the visual analog scale for ocular discomfort or ocular dryness that we're aware of. And I don't think the FDA specifies such a difference. What they do require is statistical significance. And as you can see, we have that demonstrated on the graph on slide 5. Generally, though, a 10-point difference, that is, a 10% of scale difference, is considered clinically meaningful. I would say that is prolific throughout the literature, but again, not a regulatory requirement.
Okay. Great. And in terms of the chosen symptom of ocular discomfort, how much was this discussed with the FDA? Or was this something you got to pick? Just why that one?
Throughout our discussions with the FDA, it became clear to us, at least, that the FDA's concern isn't a particular symptom. I believe, from the FDA's perspective, a dryness is similar to discomfort, which is similar to grittiness and similar to stinging and burning and so forth. That is, we believe the opinion of the FDA is that symptoms are a personal thing in terms of how a patient describes those symptoms. What we like about ocular discomfort is that the patient-to-patient differences for the word discomfort are not as substantial as they might be for other symptoms or other words that you might use to describe symptoms. Discomfort is universally understood, and that's why we have the specified discomfort here.
You can rest assured that ocular discomfort, as a term, as a specific symptom, was specifically discussed with the agency, and that's why we're moving forward with that term here. Finally, as I mentioned in my prepared comments, were reproxalap to be approved, both of those symptoms, that is, dryness and the discomfort, could appear on the label indicating a breadth of symptomatic improvement that I don't think exists in the marketplace today.
Understood. Thank you.
Thanks, Frank.
The next question comes from Yale Jen from Laidlaw & Co. Your line is open. Please go ahead.
Good morning. Thanks for taking the questions, Todd. Just two quick ones. The first is that earlier, I mean, I think you guys had talked about the possibility of SPA. Would that still be anything possible, or you feel that not necessary at this moment? Then I have a follow-up.
The SPA guidance from the FDA, which I encourage investors to read, is quite prescient. It specifies that sponsors may continue to submit 45-day reviews, which, as you can imagine, could be quite time-consuming. We've heard of one case where seven different 45-day reviews were submitted, which takes a lot of time, not including the time between the submissions where protocol amendments are needed. I think you said it correctly, Yale. We simply don't believe that we need to continue to resubmit protocols. The FDA was quite clear. In our initial protocol review, we have essentially agreed to the FDA's recommendations, or at least we believe we've agreed to the FDA's recommendations, and therefore continue to resubmit. It's just simply not required from our perspective. And so I think, as you said, we have what we need to move forward.
Okay. Great. Maybe a follow-up here is that, as we know, AbbVie was potentially part of the deals. And any discussion with them and from your standpoint, what's your thoughts about how the collaboration, potential collaboration at this point? And thanks.
Well, as you pointed out, we've disclosed that AbbVie has an option on reproxalap and all indications associated with reproxalap. And should they choose to exercise that option, we would enter into a co-development and co-promotion agreement with AbbVie with milestones that we've previously disclosed. I can assure you that our option holders are well-versed in our plan. AbbVie has been a pleasure to work with. And at this point, I believe Aldeyra needs to execute on this clinical plan. And what happens with the option agreement is up to AbbVie.
Okay. Great. That's very helpful. And again, thanks, Todd. Appreciate it.
Thanks, Yale.
Next question comes from Catherine Novack from Jones Research. Catherine, your line is open. Please go ahead.
Hi. Morning, Todd. Not to belabor the point, but I'm confused about the FDA feedback on the crossover data. Why were they okay with a crossover trial 2 years ago? It seemed like they were fine with the sign data that were submitted. What changed their mind about symptoms?
Catherine, that is a great question. You point out something that we are also curious about. That is, the FDA has previously reviewed a crossover trial in a dry eye chamber that we ran. I think the reason is, although we don't know for sure, is exactly what you said. That is, the prior crossover trial was about an ocular sign, specifically ocular redness. Blood vessels don't remember previous chamber treatments, so there's unlikely to be any sort of learning or psychological carryover effect. Our washout periods are typically 7-14 days, which is standard for dry eye chambers. You would not expect drug to remain in the eye.
My guess is, and again, we haven't asked the FDA this, but specifically, it is the notion that you raised, which is that the prior crossover trial involved a sign where you would expect less carryover effect than you might expect with a symptom.
Okay. And then I just have one more. It's not about reproxalap, but I see you have added an oral metabolic disease program to your pipeline. Is this a RAS modulator? Where does this kind of fit in with your development plans?
Happy to talk about our metabolic disease program, Catherine. The first thing I'd say is that for many clinical trials with ADX-629, which is an orally available or orally administered RASP modulator, we have shown consistently reductions in triglycerides, free fatty acids, and cholesterol. One of the activities of RASP is to generate fatty acids. That is, fatty alcohols are oxidized to fatty aldehydes, which are then oxidized to fatty acids, which is a precursor of triglycerides and fat. So what we may have in a systemically available RASP modulator is a fat-specific lowering agent. And that's something that we tend to explore directly in future clinical programs. And you'll hear more about that, I think, in the near future.
Okay. Looking forward to it. Thanks, Todd.
Thanks, Catherine.
The next question comes from Kelly Shi from Jefferies. Kelly, your line is open. Please go ahead.
Hi. Good morning. This is Yuan for Kelly. And thanks very much for taking the question. So just a few points to confirm. I believe you talked about the company can have the selection of having a meeting, but it looks like you're not going to have a meeting. So you just move forward with the current plan. And essentially, this is a proposed plan, but isn't it going to be helpful to have confirmation from the FDA? And the second question is, I just want to confirm that you're going to initiate the second chamber study and also the open field study before you have the top-line data from the proposed first chamber study. And are you able to share the size of the second chamber study and the open field study, please? Thank you.
For sure. Yuen, good morning. And thanks for the question. I just want to be very clear. We have met with the FDA. In fact, after receiving the initial comments on the crossover clinical trial design, we opted to meet with the FDA, discuss that particular point directly instead of resubmitting the protocol per the SPA process. So yes, we have met with the FDA. We have written pre-meeting comments from the FDA. We have written comments from the FDA on the protocol. We have minutes from that meeting. So as I was mentioning in response to Yale's question, we clearly believe that we have what we need in terms of FDA guidance to initiate the dry eye chamber protocol. The second part of your question is about the size of the other chamber protocol. It will be nearly identical, approximately 100 patients.
As I mentioned, we believe at this point, based on the four previously completed dry eye chamber trials, that 100 patients is an excess of 90% power to detect the difference between treatment groups. The backup chamber trial and the backup field trial will be initiated subsequent to the initiation of the first chamber trial. But the idea is to complete clinical development in the second half of this year and, depending on which trial works, enable a resubmission of the NDA also in the second half of this year.
Great. Thank you.
Thank you.
This concludes today's Q&A session. So I'll hand the call back to Dr. Brady for any concluding remarks.
Thank you, Adam. Thank you all for joining us this morning. As always, we appreciate your time and interest in Aldeyra and look forward to updating you soon on future developments.
This concludes today's call. Thank you very much for your attendance. You may now disconnect your lines.