Operator
Ladies and gentlemen, thank you for standing by, and welcome to the Aldeyra Therapeutics conference call to present the positive Phase II results of ADX-629 in chronic cough.
I would now like to turn the call over to David Burke, Head of Investor Relations. Please go ahead.
David Burke
Thank you, Mandy, and good morning, everyone. With me today is Dr. Todd Brady, President and Chief Executive Officer of Aldeyra. This morning, we issued a press release reporting top line results for the Phase II clinical trial of ADX-629 in chronic cough. A copy of the press release is available on the Investor and Media section of our website, www.aldeyra.com. Press release contains important information and should be [indiscernible] and considered in conjunction with the slides presented in the prepared remarks made on today's call, please note that we will not discuss or answer any questions regarding the clinical regulatory status of ADX-2191, including the Phase II clinical trial top line results in retinitis pigmentosis expected to be released later this week.
Turning to Slide 2. This presentation and various remarks, which may be made during this presentation contain forward-looking statements regarding Aldeyra investigational drug candidate including ADX-629 and its plans and expectations. 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, they are based on assumptions and subject to risks and uncertainties, including the development of clinical and regulatory plans or expectations for Aldeyra's investigational drugs, including ADX-629. There are risks that results from earlier clinical trials or portions of clinical trials may not accurately predict the results of future trials for the remainder of the clinical trial and others continuing our [indiscernible] and quality analysis of clinical data, including p-value estimate. Aldeyra assumes no obligation to update these statements 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 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 in our filings with the Securities and Exchange Commission.
I would now like to turn your attention to Slide 3 and introduce Dr. Brady.
Todd Brady
Thank you, David. Today, we have the pleasure of announcing the results of yet another positive clinical trial, supportive of the potentially broad-based immune modulating activity of ADX-629, the lead drug product candidate and our orally administered RASP modulator platform this time in a Phase II clinical trial of patients with chronic cost, a disease that currently has no approved therapy and it's thought to be mediated at least in part by recurrent inflammation. Achievement of all continuous cost reduction endpoints highlights the potential of RASP modulation as a new approach for the treatment of systemic immune-mediated diseases comorbid with coughing.
The primary endpoint of safety was met. ADX-629 was well tolerated and no safety concerns were identified. The key secondary endpoint of a weight cost frequency was met. The secondary endpoint of 24-hour calf frequency was met, and related POC assessments of awake and 24-hour cough counts were met.
At a high level, the results provide for novel evidence and support of anti-inflammatory approaches distinct from neuromodulatory approaches for the treatment of persistent coughing.
The results of the Phase II trial in chronic cough were consistent with previously disclosed evidence of activity of ADX-629 in other inflammatory conditions, including psoriasis, asthma and COVID-19 as depicted on Slide 4, all of which were presented in detail our Research and Development Day last year.
Slide 5 describes the protocol of the trial, a multicenter randomized sequence 2 period, double-blind crossover design, comparing 300 milligrams twice daily of ADX-629 to matching placebo. The design was comprised of 2 weeks of treatment in the first period, followed by 2 weeks of washout followed by 2 weeks of treatment in the second period with whatever test article was not received in the first period. Among other enrollment criteria, patients must have had refractory or otherwise unexplained cost for more than 1 year as well as at least 10 coughs per hour at baseline. The primary endpoint was safety as assessed by adverse events. The key secondary endpoint was awake cough frequency, which is total cough while away divided by hours awake. On secondary endpoints included 24-hour cough frequency, quality of life and clinical impression scales.
As indicated on Slide 6, baseline characteristics were generally balanced across both sequences mean baseline cough frequency was similar, although a wide range of baseline cough frequencies were enrolled in each sequence. Patients in the ADX-629 to placebo sequence had a longer history of chronic cough.
Slide 7 summarizes the safety results of treatment with ADX-629 and placebo. The primary endpoint of the trial was achieved. ADX-629 was well tolerated and no safety concerns were identified. No serious adverse events were reported Adverse event frequencies were similar across treatment groups and no patients discontinued due to adverse events. Importantly, no patients reported taste disturbance.
On Slide 8, achievements of the key secondary endpoint of awake cough frequency with a p-value of 0.01 is presented on the left side of the slide, while the corresponding cough count across treatment groups is presented on the right side of the slide, with a p-value of 0.001. Unlike other trials in chronic cough, cough count increased during treatment with placebo and may have been due to a modestly different enrolled population or the presence of viral diseases, pollen or other uncontrolled factors that have not been identified.
Further, a carryover effect was observed such that activity in the second period dependent in part on the treatment of the first period. For example, placebo response in patients previously treated with ADX-629 was higher than patients treated with placebo in Period 1 and as has been reported in other chronic cough trials, the baseline of Period 2 was statistically lower than that of Period 1.
To control for the influence of baseline and the carryover effect, statistical models were adjusted for baseline and previous treatment. Although not presented here, the superiority of ADX-629 versus placebo in the first period alone for awake cough frequency was highly statistically significant with a p-value of 0.004 in favor of ADX-629. And Importantly, the so-called placebo-adjusted drug effect, which is the change from baseline of ADX-629 minus the change from baseline of placebo represents an approximate reduction of 14 to 15 coughs per hour. Divided by the baseline values reported today, the percentage reduction in awake cough frequency is in the range of 30% to 35% and which is remarkably consistent with the reported reductions in Phase IIb clinical trials of other chronic cough drugs in development, including the neuromodulatory P2X3 receptor antagonist class of compounds.
And consistent with the awake cough frequency and cough count results, Slide 9 presents achievement of the secondary endpoint of the 24-hour cough frequency with a p-value of 0.001 on the left side of the slide and the corresponding 24-hour cough count with a p-value of 0.001 on the right side of the slide.
Other secondary endpoints of quality and life and clinical impression scales were inconsistent across groups over the 2-week period, perhaps reflecting the immunomodulatory rather than the neuromodulatory mechanism of ADX-629.
Separate from cough, Slide 10 presents a statistically significant reduction of LDL to HDL ratio in ADX-629 treated patients relative to placebo-treated patients. The finding is surprising given that enrolled patients, though on average, overweight were generally ulipidemic. The lipid results are, however, consistent with the Phase I clinical trial and Phase II clinical trial of ADX-629 in psoriasis presented on Slide 11.
Reduction in inflammation, including inflammatory lipophilic and prolipidemic RASP may explain the normalization of lipid levels in certain clinical settings and may have applicability in the treatment of diseases, co-morbid with dyslipidemia and obesity.
As illustrated on Slide 12, we believe our list of upcoming planned milestones remains robust. And with regard to ADX-629 is highlighted by the announcement of Part 1 results of Phase II clinical trials in atopic dermatitis and nephrotic syndrome and initial results from a Phase II clinical trial and Sjögren-Larsson syndrome in the second half of this year. And separately, this week, we expect to announce Phase II results of ADX-2191 and retinitis pigmentosa, a site-threatening orphan retinal disease for which there is no currently approved therapy.
Operator, I would now like to open the call for questions.
Operator
[Operator Instructions] Our first question comes from the line of Yigal Nochomovitz from Citi.
Unknown Analyst
This is Carly on for Yigal. Two from our end. First, we were just hoping you could maybe elaborate a little bit more on your thoughts on the worsening you saw in the placebo arm given typically we've seen a placebo response in other trials in chronic coughs. So I know you touched on it a bit in your prepared remarks, but maybe if you could just go into a little bit more detail on why placebo may have worsened in the study? And then the second question is if you can speak to how you're thinking about next steps for chronic cough with 629 as well as potentially with the next-gen program, 246?
Todd Brady
Well, Carly, and thanks for the excellent questions. Firstly, I'd like to say we're absolutely thrilled with these results. As I mentioned in my prepared comments, I think this is some of the first evidence that a non neuromodulatory activity in chronic cough may have some applicability in treating these patients with such a persistently disturbing condition. I guess the reason we run placebo-controlled trials is to compare placebo to drug and that comparison here was quite successful. Why placebo elevated in this trial versus other trials, as we mentioned in my prepared comments, they have to do with a slightly different population. Most of our clinical sites were spread across the southern half of the United States. Most of the patients were enrolled in the winter season. There are a variety of uncontrollable factors as we happen to know here at Aldeyra Therapeutics having to do with seasonality, the pollen counts, co-morbid viral diseases and other factors that are really difficult to account for in this setting. I think what really matters, though, and what has been reported in the chronic cough literature is the so-called placebo-adjusted difference relative to drug, placebo minus drug here results in about 15 coughs per hour, and that in turn translates to changes from baseline that have been reported for their chronic cough drugs in the literature. So to that end, the change relative to placebo is quite consistent.
In terms of next steps, as I mentioned in the press release this morning, we're thrilled to speak with the regulatory authorities about next steps in chronic cough. I think unlike other drugs in the chronic cough arena at the moment, we have the opportunity to discuss inclusion of patients with inflammation. Today's chronic cough is treated not with anti-inflammatory medications primarily, but with neuromodulatory medications, opioids anesthetics, drugs for neuropathic disease and so forth. Here, we have, I think, some of the first evidence that immune modulating activity could be important in this disease, and that allows us to treat a different class of patients where, as I mentioned in my prepared comments, inflammation may be comorbid with coughing. It also includes shorter versions of chronic cough, subacute cough, post-infectious cough, so-called intermediate coughing and so forth. And we look forward to discussing that range of options with the regulatory authorities.
Operator
Our next question comes from the line of Kelly [indiscernible] from Jefferies LLC.
Unknown Analyst
This is Sean Penn on for Kelly. Congrats on the data. So we have a question about the AE. Can you maybe give us more color on the AE profile? And also our second question is, given the non-overlap mechanism with neuromodulators, how do you think about the possibility of combination therapy?
Todd Brady
I'm happy to talk about the adverse event profile, which, as I mentioned in my prepared comments, we're balanced across treatment groups. The AEs were inconsistent and sporadic and generally mild, as you can see from the slides presented today. As I mentioned in response to Carly's question, the current treatment of chronic cough generally involves neuromodulatory agents, which are effectively anesthetics. And what you typically see with those drugs are changes in sensation. I don't just mean opioid like side effects, but in other cases, such as the P2X3 antagonist changes in taste. We saw nothing of that sort with ADX-629, that is because the mechanism of ADX-629 is related to anti-inflammatory activity or immune modulating activity and thus, we would not expect to see any sort of neurosensory changes like you might see with other drugs in development or that are currently used to treat chronic cough. Because of the different mechanism here that is an immune modulating mechanism with ADX-629, a relative to the standard of care in chronic cough today, I'm very bullish on polypharmacy. That is the ability to treat this disease, which is difficult to treat with 2 different mechanisms. As a medical community, we need more drugs in this class. The chronic cough is a persistently disturbing condition. It is often refractory to therapy. And as far as I'm concerned, and I think as far as most physicians that deal with this condition on a daily basis is concerned, we need more different kinds of therapies. And I think today's data provides hope that yet another mechanism may have applicability for the treatment of chronic cough.
Operator
Our next question comes from the line of Yale Jen from Laidlaw & Company.
Yale Jen
Congrats on the outcome, it is very impressive. Just 2 quick questions first here is why the quality of life readouts did not change much compared to the 2 groups? Do you have any theories behind that? And then have a follow-up.
Todd Brady
I'm sorry, Yale, could you restate the question?
Yale Jen
The quality of life of the 2 groups have not been changed much.
Todd Brady
Yes. I think the answer is the same answer that I gave to Sean's question, which is the ability to affect cough's frequency relative to the ability to affect quality of life and symptoms really relates to the mechanism of the drug. Today's chronic cough agents are neuromodulatory they affect sensation. They affect perception of sensation. And that is not consistent with the mechanism of ADX-629. So in general, with drugs that modulate inflammation typically over a short period of time, such as the 2-week treatment period featured in the present trial, that you wouldn't expect to see changes in quality of life or clinical impression scales, unless you had some sort of neuromodulatory therapy.
Yale Jen
Okay. Maybe 1 follow-up. The question here is given the landscape of the chronic cough at this moment, what would be your overall sort of comment and the thoughts and the positioning of 629 at this point?
Todd Brady
Well, I think it's was good to see that the reduction in cost relative to baseline is certainly consistent with what's been reported in Phase II trials, at least with the P2X3 antagonist, greater than that which has been reported in Phase III trials of chronic cough medications in the P2X3 class. I would say that in general, patients with concomitant inflammation which is common in chronic cough. The patients with underlying pulmonary issues, such as interstitial lung disease, asthma and so forth, would more likely benefit from an immunomodulating approach to treat cough than a neurosensory or neuromodulatory approach, which would not address underlying inflammation.
So the data today really open up a whole new market for the treatment of cough and that market has to do with the comorbidity of inflammation and coughing. So I would think that, sure, as Sean pointed out, we could administer these drugs together. But at the same time, to the extent we're interested in treating underlying causes where there is inflammation. I would expect immunomodulating approaches such as the 1 featured by ADX-629 would be far more relevant.
Yale Jen
Okay. Great. And again, congrats.
Todd Brady
Thank you, Yale.
Operator
Our next question comes from the line of Catherine Novack from Jones Research.
Catherine Novack
Congrats on the data. I had a question a little bit about the trial design. Is 14 days enough to see a therapeutic effect, albeit a different mechanism of action, but in P2X29 antagonist, we've seen the placebo-adjusted reduction definitely attenuates over time. How comfortable are physicians with just 2 weeks of data? And are you intending to look at longer time points in the future?
Todd Brady
Catherine, good day to you. As usual, you raise an excellent point. Most of our trials going forward with ADX-629, and I hope soon, ADX-246, which is another orally administered RASP modulator, will feature 90-day trials, which has typically been the Phase IIb endpoint and chronic cough 3 months of treatment or 12 weeks of treatment are far more relevant clinically as you point out than 2 weeks of treatment. I think in trials like these where patients are treated acutely for a chronic disease. What we're really looking for are signals I think we have identified those signals today that warrant future study. And as you correctly point out, future study will feature longer trials, including 90-day trials, which I think will be our next stop in clinical development.
Catherine Novack
Got it. That's very helpful. Congrats again on the data.
Todd Brady
Thank you, Catherine.
Operator
Our final question comes from Tom Shrader from BTIG.
Sung Jun Hong
Well, Todd, this is Sung Hong for Tom. So I have 2 questions. One is, could you provide additional color on where you are with dosing and whether a dose ranging study makes sense moving forward? And then the second question is, in a more -- in a broader context, [indiscernible] know whether the RASP VCs involved in these indications are the same or different? And if a specific type is identified, could they generate new [indiscernible] for the class?
Todd Brady
Sung, I don't expect we'll be doing too much dose ranging going forward. The reason I say that has to do with the second part of your question, which is RASP and RASP levels. Generally, an inflammatory disease is the levels of RASP at least in plasma are single-digit micromolar, which is the PK we attempt to match with our orally administered platform, including ADX-629. So we know that 250 milligrams to 300 milligrams administered twice daily approaches single-digit micromolar. There's a one-to-one stoichiometry between drug and RASP target. And thus, I think the therapeutic levels, at least as theoretically as they relate to levels of RASP have been achieved. I think it would be hard to argue that ADX-629 has no activity at these levels based on the data we presented at the R&D Day last year in psoriasis and asthma and COVID plus the data announced today. I think going forward, we typically run 90-day trials at the 250-milligram BID level, and I would expect the same here following our discussion with the agency.
In terms of the kinds of RASP that are involved in inflammation, the 2 main culprits are malondialdehyde and hydroxynonenal. An interesting exercise is to go to PubMed and type in, malondialdehyde or hydroxynonenal and pick your favorite inflammatory disease, and you'll often see levels elevated in those patients relative to healthy volunteers. And typically, as I mentioned, those levels are in the single-digit micromolar range, at least in plasma. There are probably other rats that are elevated that are less well described, but in general, those are the 2 targets that we believe are the main culprits in inducing inflammation.
Operator
I would now like to turn the call over to Todd Brady for closing remarks.
Todd Brady
Well, thank you, as always, for joining us this morning. We do appreciate your time and interest in Aldeyra. And as always, we look forward to updating you on future developments.
Operator
Thank you, ladies and gentlemen. This does conclude today's call. Thank you for your participation. You may now disconnect.
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