Q1 2022 Aldeyra Therapeutics Inc Earnings Call
<unk> assumes no obligation to update these statements as circumstances change.
<unk> events and actual results could differ materially from those projected in our forward looking statements, including the current and potential future impact of the COVID-19 pandemic on our business results of operations and financial position.
Information concerning factors that could cause results to differ materially from our forward looking statements are described in greater detail in our press release issued this morning, and our filings with the SEC.
As many of you know next week I'll be leaving out there to take a position as CFO of another publicly traded company in the life Sciences space.
Though the timing was less than ideal it was an opportunity I cannot let path.
While transitions are a natural part of this business you always relish to friendships you make in the skills gained along the way.
<unk> provided both.
It has been gratifying to work with Todd the board of directors and our entire team over the past three and a half years.
I'm exceedingly proud of what we accomplished and look forward to seeing the company's continued success.
Bruce Greenberg out there as incoming CFO is highly qualified.
For the post.
I've taken particular pride in helping build a strong finance team metal Dara with more than 25 years of finance and operating experience much of that public companies Bruce.
Bruce exemplifies that depth of knowledge, having hired Bruce is our controller in 2019 and working closely with <unk>.
I know that he'll do an outstanding job.
I will now turn the call over to Dr. Brady.
Thank you Joshua and good morning, everyone. Thank you for joining us as we review the recent progress of our.
Clinical programs and discuss our first quarter financial results, but before we do that.
Let me convey my sincere appreciation to Joshua for his work and dedication.
Over the past three five years.
Now all of us at <unk> wish him much success as he begins the next chapter.
Of his career.
I also want that can drive congratulate Bruce on his appointment as Vice President Finance interim CFO and treasurer.
I expect that Bruce his knowledge of our business over the past several years, coupled with deep industry and financial experience.
We will make this a truly seamless transition.
Turning to our recent research and development highlights between our clinical accomplishments and our R&D day Q1 was an exciting quarter for Aldara.
It marked the start of what we believe will be a catalyst rich year for our company.
One in which we plan to continue executing on our key strategic milestones in our ocular systemic and retinal disease programs.
We are continuing to advance for proxy lap toward an expected mid year NDA submission in dry eye disease.
<unk> is the lead asset in our drug discovery and development platform targeting RASK.
Which represent a novel pharmaceutical target comprised of pro inflammatory small molecules.
That are implicated in a wide range of immunological diseases.
Dry eye disease affects an estimated 39 million adults in the U S. A large percentage of whom are dissatisfied with current standard of care treatments.
It's been nearly 20 years since the first approval of a prescription drug for dry eye disease.
Currently available topical therapies, often require months to demonstrate even modest efficacy.
As a result, the dry disease market remains significantly underserved.
We envision introducing a new therapy that changes that pattern.
We took another step towards that vision in first quarter completing enrollment in the phase III tranquility to trial of approximately <unk> <unk> in dry eye disease.
We have received many questions from investors on tranquility too and I want to spend some time, describing the precise nature of the trial the criteria for success the potential implications for our product label if approved.
And the timing of planned FDA interactions regarding our dry eye disease NDA submission.
The primary endpoints of tranquility to our Schirmer test on the first day of dosing in ocular redness on the second day of dosing.
<unk>, a dry eye chamber.
Because we've implemented an alpha sharing mechanism per FDA multiplicity guidance.
The distributes alpha roughly equally across both endpoints, if either readiness or schirmer test has achieved the primary endpoint of tranquility too we will have been met.
Based on the results of the previously completed phase two and tranquility trials.
Simulations of tranquility to indicate that in at least 90% of the potential outcomes. The.
The simulated trial was positive that is statistical significance of drug over vehicle for either ocular redness or Schirmer test was achieved.
We're continuing to review of the train quality data to confirm the analytical plans for tranquility too.
And we remain on schedule to report results of tranquility too in the second quarter.
Our next major interaction with the FDA is expected to be the type B pre NDA meeting following the results of tranquility too.
We may submit two pivotal trials for either ocular redness or schirmer test or two trials for both signs if ocular redness and Schirmer test are achieved and tranquility to Penn.
Pending the outcome of tranquility to approximate app could represent the first time.
<unk> drug will it qualified for the demonstration of activity for two objective signs in addition to symptoms.
Two additional trials are ongoing a crossover chamber trial and a one day Schirmer test trial either of these trials could also serve as pivotal trials in support of an NDA submission.
Both trials are designed to generate results soon after tranquility too so as not to significantly impact NDA submission timing.
In addition to dry eye disease with <unk> is also in a phase III clinical trial in allergic conjunctivitis, a condition that affects at least 66 million adults in the U S alone.
We initiated the phase III invigorate, two allergen chamber trial earlier this year and expect results in 2023.
Enrollment criteria endpoints trial design and study conduct are substantially similar to our previously completed invigorate trial.
Which demonstrated statistically significant improvement in the primary endpoint of ocular itching and the key secondary endpoint of ocular redness.
Based on data from invigorate.
Emulation modeling of invigorate two indicates that more than 90% of outcomes achieved the primary endpoint of patient reported ocular itching.
At our R&D day in March we announced top line data from our proof of concept trials of <unk> six to nine our first in class oral <unk> modulator in psoriasis asthma in COVID-19 infection.
And those trials AVX six to nine demonstrated signs of Pharmacodynamic and clinical activity consistent with broad based reduction in pathologic inflammation.
As we announced at R&D day, we have advanced the <unk> six to nine to phase II clinical trials in four new clinical indications.
Our phase II clinical trials in ethanol toxicity and chronic costs have already initiated.
Phase two clinical trials in Sjogren Larsson syndrome, and minimal change disease are expected to be initiated later this year.
<unk>, our systemic program for multiple clinical milestones over the remainder of 2022.
And 2023.
We also continued to advance AVX 21, 91, or vitreous compatible formulation of methotrexate for orphan retinal diseases.
An investigator sponsored phase II clinical trial in retinitis Pigmentosa conducted at Duke University Medical Center has been initiated.
In addition in the first quarter, we completed enrollment in part one of the Phase III Guard trial in proliferative Vitreoretinal policy.
Results from both of these trials are expected in the second half of this year.
Now I'll turn the call over to Joshua after which I will summarize our recent clinical progress and our future potential and developing novel platforms the treatment of immune mediated diseases.
Thank you Todd cash cash equivalents and marketable securities as of March 31, 2022 were 202 hundred $16 $9 million based on our current operating plan, we expect our existing cash cash equivalents and marketable securities to be sufficient to fund currently projected operating.
Through the end of 2023, including potential new drug application submissions initial commercialization of <unk>, if approved and continued development of our product candidates and ocular and systemic immune mediated diseases.
Moving onto our first quarter 2022 results.
Net loss was $16 8 million or 29 per share compared with a net loss of $11 $3 million 25 per share for the comparable period of 2021.
Losses have resulted from the cost of clinical trials and research and development programs as well as from general and administrative expenses.
Research and development expenses were $12 $2 million compared with $7 7 million for the same period in 2021.
The increase of $4 $5 million is primarily related to increases in our clinical research and development expenditures.
General and administrative expenses were $4 2 million compared with $3 1 million for the same period in 2021 the.
The increase of $1 $1 million is primarily due to an increase in consulting expenditures.
Total operating expenses were $16 5 million compared with total operating expenses of $10 8 million for the same period in 2021.
Now I'll hand, the call back to Todd for closing comments.
Thank you Joshua.
We have begun 2022 with tremendous enthusiasm about our clinical progress.
As well as the clinical and regulatory milestones planned for the second quarter and the second half of this year.
Given a unique rapid onset of action and broad activity across symptoms and signs observed to date.
We believe there are approximately <unk> has significant potential to disrupt the dry eye disease market.
And we're looking forward to announcing the results of the phase III Tranquility trial later this year that affect this quarter.
Beyond <unk>, our systemic in retinal disease platforms represent substantial opportunities for near term and long term value creation that.
In our view remains significantly underappreciated.
With that we'd be happy to take your questions operator.
Thank you if you'd like to ask a question. Please press star one on your telephone keypad.
If you change your mind and wish to withdraw your question. Please press star two.
Our first question today comes from Justin Kim opening.
Justin Please go ahead.
Hi, good morning, and thanks for taking the question.
The overview on the possible of trials ongoing has been helpful.
As the team approach in the upcoming 10 quality to readout could you just discuss for us a little bit about the confidence in having a firewall data package on the basis of redness or schirmer tear test and could you just clarify the motivation for the two additional trials for training.
Boeing <unk> are these studies intended to serve in the peso and Colby one as it relates to sort of two pivotal studies.
Thanks.
Good morning, Justin and thanks for the excellent questions.
Based on our conversations with the agency, we're quite confident in the strength of our NDA submission package.
In fact, I would say.
Arguably the package, we intend to submit is the most comprehensive dry eye disease package ever submitted.
As far as weather.
Schirmer test or redness cancer, as an approvable defying I.
Dry eye disease.
Think there is plenty of precedent for either.
Most drugs beginning with Restasis many years ago have used schirmer test as an objective sign of dry eye disease.
Recently.
A generic steroids has been approved for use in dry eye disease.
With redness at the site. So I think we have fairly clear precedent that the FDA will accept to either Schirmer test.
Or redness.
The additional trials I mentioned that is the crossover chamber trial and the one day Schirmer test trial.
<unk> designed to backup.
Tranquility too.
In the event that the data from tranquility to is for whatever reason not clear.
We will essentially have two more shots on goal.
Support the submission package.
Broadly as you know just in the FDA considers that preponderance of evidence.
And the stronger your package that is the.
Number of clinical trials.
The number of patients tested and so forth.
The better your odds of approval and I think alterra is in the very fortunate position.
Being able to run rapid one or two day clinical trials.
With nominal cost.
To support.
Our NDA submission package and thus I think running additional trial is a responsible and wise use of cash.
As we look to submit our dry disease package.
Got it got it.
Good.
Maybe just one more from me with regards to timeline.
I know you had mentioned that a mid year filing is sort of in the cards. Just wondering how the progress with the long term safety study is going and whether that sort of still remains on the critical path.
These safety trial remains on the critical path.
The safety trial.
Is the gating factor for the submission of the NDA as you know the FDA requires 100 subjects or 100 patients to have been exposed to your commercial formulation at year commercially proposed dosing regimen for at least 12 months.
We are masked as to how many patients are on drug versus vehicle. The safety trial is a two to one randomization that is drug to vehicle.
However.
Based on the information we have today.
We believe that we remain on track for a mid year.
The submission.
The NDA.
Great great. Thanks, Thanks, so much and congrats on the progress.
Yes.
Our next question comes from Marc Goodman of SVP Leerink. Please go ahead.
Yes. Good morning, two questions first the dynamics of the dry eye market. Todd can you just give us a flavor for whats happening there right now and how much if anything has changed if at all with Restasis going generic.
And then second.
Given that there is a transition CFO .
This is a product that potentially could be.
Licensed partnered can you give us a sense of confidence.
The relationship there.
Is there with Bruce or who is going to be the key drivers.
Making that deal. Thank you.
For sure Mark Thanks for the question and it's an ironic question for you because you were around when Restasis was launched and I recall you were involved in some of the initial.
Coverage of Allergan back in those days I think 2006 was the launch date for <unk>.
Restasis.
As you mentioned.
Restasis is now generic.
Which.
It has its pros and cons.
Con is that payers will almost certainly require generic step through as they would do in any disease.
When a generic becomes available.
Pro is many many many patients have already failed restasis.
The median discontinuation time.
<unk> is about a month.
After a year of therapy, approximately 70% of patients or so have discontinued risk basis, so stepping through.
Restasis and or a generic restasis I think will be less of an issue that might be.
Initially apparent.
Our goal is to position <unk> as the branded drug of choice.
Which is why we've now run two head to head trial versus <unk>.
Which is the only other novel topically administered a dry eye disease drug in one trial, we showed that approximately was.
Better tolerated than <unk> after a single dose over an hour faster.
The installation of that dose that there was.
Less blurry vision than zebra and there was less taste disturbance.
And all of those.
Findings.
Were statistically significant that paper has been published you can find it on Pubmed.
Free of charge.
The second trial, we ran head to head versus <unk> within a dry eye chamber, we were interested in seeing how well either drug protected the exacerbation of symptoms and a dry eye chamber. These chambers. Our noxious this is no humidity air.
<unk> essentially in the face we call that forced air in the face of subjects.
During visual tasking.
And what we showed was that.
Try a chamber does escalate symptoms, but that escalation is less and slower in <unk> treated patients patent with hydro treated patients.
Hence our positioning against a generic restasis again, our drug or our goal is to be the proud of drug of choice.
Let me answer your question about.
That partnering.
I think it's fairly apparent from my comments that there is considerable demand.
For a new <unk>.
Dry eye disease drug for two reasons.
One is today's market is not satisfied.
Either on the physician side of the fence or the patient side of the fence.
Given the.
Link fee.
Onset of action for today's therapies, and the fact that generally in many patients.
There is often only modest.
Activity.
Of either Restasis or <unk>.
And I think the second reason is if you look at the late stage dry eye disease.
<unk> pipeline.
It really isn't much.
Unfortunately.
Anterior segment ophthalmology drug development.
Is.
Not rife with innovation for approximately <unk> represents not only one of the few innovative drugs.
In front of the eye inflammation.
But also as representative as I said in my prepared comments.
A whole new pharmacology, a whole new class of drugs.
That can be applied broadly.
To diseases that affect not just the <unk>, but the rest of the body.
The business development.
That process, which has been ongoing for many years of course, just given where <unk> status.
And the drive of these pipeline.
<unk> has involved not only development aspects, but also commercial aspects and much of the conversations now and the business development activity now is focused on.
Potential labels positioning.
Branding and so forth and those discussions are led by our commercial lead.
Kelly Miser.
Okay.
Thanks Mark.
Our next question comes from.
<unk> from Citi. Please go ahead.
Yes, Hi, Todd and team. Thank you very much for taking the question. So as you mentioned at the R&D day, you've announced the four new indications for 629 ethanol toxicity chronic cough minimal change in SLS.
It seems these four indications are mutually orthogonal in terms of clinical presentation, albeit obviously with the common underlying commonality of aldehyde involvement so with that being said if you were to rank. These four in terms of Pos which ranks highest in which ranks the lowest based.
On the role of aldehyde biochemistry and disease progression. Thank you.
Good morning, Thank all smiling as you asked that question because it's something that we think about a lot here.
In a sense the broad applicability of <unk> 69.
Is it a tremendous advantage.
That is we're able to.
Test diseases that as you pointed out are different.
Hi, <unk> complementary.
Because of the potential broad activity.
The drug RASK.
Mediate inflammation generally.
Which allows us to test different kinds of inflammatory diseases.
Obviously, what we're doing and have done with AVX six to nine.
And even that I think are most likely to derive benefit.
I would argue that.
Diseases that are particularly related to aldehydes that is sjogren Larsson syndrome.
<unk> toxicity.
Are probably.
More likely to demonstrate at least pharmacokinetics and pharmacodynamic activity.
If at all when we consume ethanol regenerate rasp.
And particular acetaldehyde, that's what's featured.
And at R&D day.
And.
<unk> nine should trap.
Acetaldehyde, and thereby diminish inflammation and sjogren Larsson syndrome, we have a an inborn error of metabolism.
That is caused by a genetic mutation in an enzyme that metabolizes fatty aldehydes.
Which have been shown to be trapped by AVX six to nine and other <unk> modulators.
So I would suspect that in terms of pharmacodynamic activity.
Best positioned and ethanol toxicity.
And.
And like diseases, such as SLS.
For the inflammatory diseases, which are minimal change disease, and chronic cough I'm also optimistic and I'm optimistic because of the data that we presented.
At R&D day.
We intentionally tested different kinds of inflammation. So on one end of the spectrum, we had an auto immune disease that is psoriasis on the other end of the spectrum, we had an allergic disease, which has asthma in each case I think we had either clinical or pharmacodynamic activity and thus we remain optimistic about our inflammatory disease.
As as well as a little bit like selecting your favorite child.
But in our case, we're optimistic about all four indications and look forward to discussing the results beginning with ethanol toxicity later this year.
Okay got it that's very very helpful incremental incremental color I, just had two kind of housekeeping questions on dry eye and shrink quality. So you made a comment in the press release that you are continuing to review the data from the completed shrink quilty trial to finalize analytical plants or shrink clearly too yes.
Just a little bit puzzled by that statement I guess I thought everything was pretty much hammered away in terms of how the co primaries for redness consumers would be analyzed in shrink quality too. So if you don't mind just elaborating on what you mean when you say.
Analytical plans still need some final level. Thanks.
While this answer will be near and Dear to your heart Eagle.
The simulation modeling you've done and kudos to you for.
Simulating the results an entree in quarter two so eloquently.
Additional analysis has to do with the alpha share.
That is how much alpha is allocated to readiness and how much alpha is allocated to schirmer test.
Typically the alpha is <unk> that is the P value has to be less than point out five.
To demonstrate.
A positive outcome.
When you also share you split the alpha.
So nominally you can divide the alpha in half and give 0.125 to readiness and.
<unk> <unk> five to Schirmer test.
However, the exact alpha allocation.
In our case will depend on ongoing simulations of the outcome of tranquility to based on the data.
From tranquility widened primarily because that is the largest.
The trials will be brought in to date.
That's what I mean by ongoing analysis.
We have not decided the precise alpha allocation across redness and schirmer test for tranquility to however IX.
I expect the allocation to be roughly.
One to one at this point.
Okay understood.
The refinement.
I will rebound much stimulation.
And then one other final question I think you sort of alluded to this before.
But just with the safety so a 100 patients on drug with 12 months of exposure.
My understanding correct that you are going to hit that goal, presumably middle of the year given your guidance for filing the NDA middle of the year.
Per FDA guidance. The NDA submission can occur with six months of data that is 100 patients with six months of exposure.
However.
The standard 120 day update.
Following NDA submission the remainder of the six months of exposure it needs to be submitted.
I think most sponsors typically submit the NDA with eight to 10 months of completion of exposure, which covers the initial six months and then allows the sponsor to submit 120 days later the remainder of the six months.
Got it okay very helpful. Thank you.
Thank you Paul.
Our next question is from Kelly see at Jefferies. Please go ahead.
Thank you for taking my question. So if only chevron's path to Henk, that's significant inflection call at each two trials and that will be included in the label and get into.
Sure Matt passes.
Glass Acer endpoint would.
One would be our strategy to convey that differentiation from other dry docks to prescribers.
Two new dry trials.
Trunk holiday to healthy neutral scenario. Thank you.
Hi, Kelly and good morning, that's a really interesting question that Kelly Mizer, and I have been exploring with a large number of key opinion leaders both on the optometry side and on the ophthalmology side I think it's important to remember that about 60% of the dry eyes.
<unk> derived from optometrists, so as a company we spend a lot of time with key opinion leaders and thought leaders on the automaton side as well as ophthalmology.
We spent a considerable amount of.
Our interactions.
In terms of dealing with.
Potential label scenarios, which gets right to your question.
<unk> Schirmer test is the Si.
Yes.
Redness is the sign.
The answer is consistent.
That is what matters is symptoms.
As a health care provider, if youre, an optometrist or an ophthalmologist.
Want your patient to feel better and you want your patients to feel better quickly.
And therein lies the key competitive advantage of approximately <unk> and Thats why we said in our prepared comments that we expect <unk> to represent a paradigm shift.
And the way dry disease is treated instead of having to wait a month or two months or three months for your patient to feel better. According to the head to head data we have versus Eyedrop, you can wait 90 seconds.
This is the key driver on the label.
Whether schirmer or redness is on the label.
<unk> to be obviously less relevant and really depends on the particular healthcare provider with.
With whom we are talking.
I think on the optometry side, there may be a slight preference for redness because patients complain of redness as I have said before readiness may be the only dry eye disease sign that patients care about.
On the other hand ophthalmologist seem to have a slight preference for schirmer test and Thats because of the fact that you mentioned Kelly that most drugs have used schirmer test as an indicator of activity in the past and it makes sense that if a drug can generate more tears.
Dry eye symptoms and signs should improve.
Alright, Thanks that is helpful.
Thank you.
Our next question is from Thomas Shrader BT RG Thomas Please go ahead.
Hey, good morning, sung and calling in for Tom. So I have two questions. One is kind of like a follow up question from earlier about six to nine.
So currently you guys have multiple indications, but any thoughts on which indications to prioritize and then whether it makes sense to potentially partner up towards like a bigger phase III studies.
And the second question is for 'twenty 191 in PBR, just thinking of a potential commercialization down the line.
Can you provide any color on salesforce sort of indication on whether there is any overlap with the drive the salesforce where potential synergistic effects.
Hi, Good morning, Thanks for the question My General bias.
Is that small companies.
Are better at commercializing orphan drugs than mass market trucks.
So in a scenario where for AVX 69.
All indications work and we're able to progress all indications.
The phase III clinical testing or certainly past phase III clinical testing.
I think as a company we would prioritize the smaller diseases that that is minimal change disease.
Dan Sjogren Larsson syndrome.
Partnering is always an option for us.
There is considerable demand for new.
Logical drugs.
Our specialty drugs that are safe I think a key message from R&D day was.
We were unable to identify across more than 30 or so patients tested any.
Adverse events that were clinically significant and related to drug.
So I do think that will have considerable business development opportunity and as a company. My belief is we would look to <unk>.
Entertainment partnering discussions around mass market indications.
Of the ones we've mentioned.
For Adi six to nine I would consider ethanol toxicity, which is a gateway indication too.
Alcoholic hepatitis or ash.
As well as chronic cough.
I think there are many many more indications that would apply to the brothers and sisters of AVX six to nine we spent a.
A little bit of time at R&D day talking about what we call project X, which is a drug discovery engine.
That and our belief is unparalleled design too.
Generate new Ras modulators I would look for the newer molecules to be tested in larger diseases and as I've mentioned previously those units would be candidates for partnering.
Great. Thanks, and then just regarding the 21 91.
Could you just provide color on the sales force required and then theres any overlap with the dry eye disease.
Of course right in those centers.
Yes, yes. Thank you for the reminder.
The answer is back office, Yes front office no.
Back office in terms of access and reimbursement.
Billing legal compliance et cetera.
Have considerable overlap.
For ophthalmology sales forces broadly.
<unk>, though in ophthalmology your sales force is either geared towards the front of the eye or the back of the eye.
Because the physician populations are quite different not only in terms of their training and expertise in practice, but also in terms of their outlook on pharmaceuticals, and so forth.
I would say, though that the dry eye disease and allergic conjunctivitis are representative of more typical.
Sales force kinds of efforts.
Whereas AVX 21 91.
Different.
Injectable drugs for retinal surgeons are typically buy and bill meeting that the surgeons purchased the drugs and then get reimbursed for them later.
That is.
<unk> sales process typically involves a heavier emphasis on access.
So that we may not need to have your standard.
<unk> force.
Geared towards the launch and marketing and sales of <unk> 21 91.
Great.
Thank you.
Okay.
Our next question comes from Matthew Cross Alliance Global partners.
Please go ahead.
Hey, good morning, and thanks for taking a couple of questions from my best wishes to Joshua in the new role.
Wanted to drill down a little bit on the exact handling of these two primary endpoint <unk>.
The two now that you guys are fully enrolled.
I guess wanted to get a reminder, on for the handling of Schirmer.
I know youre looking at.
The analysis there before.
Before and after the fourth dose in particular as opposed to just straight baseline and post post dosing.
Which I know was related to what you saw in tranquility.
But given the base block III doses prior to that I, just wanted to kind of review the rationale for looking at that.
In that fashion and then on redness wanted to confirm.
That part of the equation, but this was as you've done in prior trials still.
Contingent on a majority of the assess time points.
Not all being Thats early successful relative to the comparator or if this is more strict given the significant split with <unk> and.
And on both fronts, whether the handling and frequently to should we expect it to be mirrored.
To some extent in these in these so called backups studies. Thanks.
Well, Matt as usual you've raised some interesting statistical nuances.
It turns out the answer to both questions is the same.
And that is.
I've never understood why companies pick single time point.
Single time points are riskier, they diminish or statistical power you throw away much of the data.
And theyre not clinically relevant.
Never have I asked the patient Mrs. Smith, how did you feel on day 37 and.
And I don't care about before after.
Instead, a more clinically relevant and statistically powerful approaches to include all the data.
And so both with Schirmer test and redness in the chamber.
We have more than one time point.
In particular with Schirmer test, you're absolutely right, we're assessing changed from baseline before the fourth dose and after the fourth dose.
But before the fourth dose accounts for the activity that may or may not be present with the first three doses.
And after the fourth dose accounts for the acute activity in the fourth dose. So we're sort of measuring two different things both of which are clinically relevant.
Both of those endpoints are incorporated in the statistical model, which increases power that is add data to the model and generally the slope of improvement over time can be assessed, albeit with only two points post baseline.
The readiness assessment is approximately 10 or so time points.
The dry eye chamber.
We include all 10 time points in the model as I've just mentioned one way to think about such a statistical approach with a slope that is generally is the patient getting worse, which you would expect in a dry eye chamber, but is that patient getting.
Worse than drug.
If youre on vehicle.
So the slope you would expect to be higher on vehicle.
On drug.
All of that is very clinically relevant as healthcare providers were concerned with how patients do over time.
We are not concerned with how patients do at a particular <unk>.
<unk>.
And thus both for statistical and clinical relevance reasons, we analyze.
Multiple time points the answer to your question about will tranquility to be mirrored.
The statistical approach for <unk> for the backup studies is absolutely yes.
We are intending to change absolutely nothing about the.
Physical plan in fact, the conduct of the study is largely the same the schirmer test trial doesn't kind of a chamber.
Crossover Chamber trial is the same as tranquility accept patients are crossed over that is patient may have vehicle and then come back some weeks later and get drug or vice versa and that sequences of course randomized.
Got it okay really helpful and put it on several fronts there Tom I appreciate it and if I can squeak in one one quick confirmation.
Great too and I know you mentioned that you'd already initiated that study. So just wanted to confirm.
Given your intention to kind of avoid isn't effective seasonality on those patients.
In terms of data variability.
Is that study enrolling or just initiated but planning to really enrolled the bulk of patients still in winter for 2023 readout. Thanks.
What we're learning about the front of the eye, whether it be tried to fees or allergic conjunctivitis.
Is that seasonality probably matters.
<unk> matters for allergic conjunctivitis, because during certain parts of the year.
We have pollen and during other parts of the year, we do not have pollen. Unfortunately.
To run a clinical trial in allergic conjunctivitis, you cannot have fallen in the atmosphere because the pollen in the atmosphere.
Compounds the exposure to pollen.
And the chamber and thus the results are confounded.
And thus we cannot enroll.
<unk> trial say in the spring or fall the answer to your question about enrollment for invigorate. Two is yes, we have begun enrollment enrollment has been robust which is always a good sign not only in terms of clinical operations, but in terms of commercial demand.
For such a therapy.
But again, we expect to enroll over two allergy free season that has two winters.
And.
Maybe perhaps during the middle of the summer with data coming out next year.
Great. Okay. Thanks, again I appreciate all the answers.
Yes, Thanks, Matt.
As a reminder, please press star one for any questions. Our next question is from Katherine Nowak with Jones trading. Please go ahead.
Hi, Thanks for taking my questions I just have a couple of quick ones. One I wanted to ask on R&D spend for the year with running additional trials with <unk> as well as the ongoing 69 studies.
How much should we be expecting for those studies and in particular the comp.
Craft slap studies.
Yes, thanks for the question Katherine.
Ill give some broad guidance regarding R&D spend.
All our planned activity in 2022 from tranquility to to invigorate too.
The <unk> six to nine trials in chronic cough.
Ethanol toxicity minimal change disease in SLS.
With the development in our retina programs as well as advancing our Ras platform broadly.
Should expect our spend particularly in R&D.
Increase compared to 2021 level.
Got it thanks.
And then just as we look forward to the train quality data trying to get a sense.
When do you expect that.
Given that in the short dosing period wondering is the database already locked and what else needs to be completed in addition to analytical plan.
Thanks for the question Kathy.
It's one that we get frequently.
Let me just take a step back and explain that.
Just how I think most sponsors.
<unk> analyzed clinical trials.
The first step is quality control of the data itself.
So following the last patient last visit which as you point out.
It's very close to be.
Last patient first visit I E. The completion of enrollment.
The data are QC, there is a specific process.
For analyzing.
Whether there are data for each.
Particular endpoint.
Which in our trial is complicated because there are many endpoints as I was discussing in response to Matt's question.
However, I am happy to report that I believe that that process is nearly complete.
Following quality control.
Completion, the database is locked.
Meaning that the database cannot be changed any further.
That the queries between the clinical sites in the <unk> and our sponsor have all been satisfied.
Following locking up the database, which has not yet occurred.
In the case of tranquility too.
The database has been sent to our statistical firm.
Third party statistical firm.
The statistical firm as the only group that has the randomization codes.
And what that means is.
Generally there is only one person.
Statistical firm.
Any one time nose.
What patient is on what test article that is whether a patient is on drug or vehicle.
After an initial QC process as a statistical firm.
When the randomization codes are released and applied to the data within the statistical firm.
There is a QC process that follows that.
Which is.
Hey.
Our QC process that involves the statistical analysis.
Then only following that process is the sponsor made aware.
Of the results.
So forgive me for that lengthy answer, but I think it's important for investors to understand exactly what happens when a trial is completed and how the data are analyzed and I hope. It gives you a sense of.
Where we are in that process, which in a nutshell, it's pre database lock.
Got it that's very helpful. Thanks very much.
Our next question is from Esther Hong Bahrenburg ester. Please go ahead.
Good morning, This is England Kim on for <unk>. Thank you for taking our question.
Can you just wanted to ask with the convenience of AVX 291, as a specific injection formulation.
Now that taxi, we were wondering if that would be enough to compete with the growing support.
<unk> itself is getting and a follow up have you gotten any feedback on our conversations with Kols have Terry Thank you.
Thanks for focusing on 'twenty 191.
Topics that I wish we had more time to discuss and more questions about.
The answer to your last question about feedback from.
Payers is in.
In absolute yes, we have been discussing with payers not only of Approx of lab, but AVX 21, 91, which we believe could be near NDA submission and we intend to update on the regulatory plans, particularly NDA submission plans for 'twenty 191 in the second half of this year.
The convenience of a GMP product.
Is one thing I think the safety of a GMP product is another.
Today before methotrexate is injected and patients eyes.
Save patients with furniture venture retinopathy or patients with ocular lymphoma.
The intravenous formulation of methotrexate has to be used.
So the vial of intravenous methotrexate is cracked open a certain amount of the solution has drawn up into a syringe and then that syringes used to inject the high the problem with that process is that it allows for the introduction of contaminants, which when you are injecting.
Into NII.
Is.
Potentially serious.
There is a condition called endophthalmitis, which is an infection.
Of your NRI that occasionally requires nucleation that is removal of the eye.
For treatment. So obviously very serious consequences for contamination, which is more likely to occur with non GMP product that is compounded.
Yes.
Product.
You would also add to payout.
I also appreciate your question about the use of methotrexate These days.
It's interesting because methotrexate is already to standard of care in ocular lymphoma.
What's more interesting is that the use of methotrexate is growing for.
<unk> for the treatment of PBR.
Which made our phase III guard trial difficult to enroll as you recall the guard trial was a randomized trial.
Where subjects or patients were either randomized to receive methotrexate or nothing which is technically a standard of care.
It was difficult to convince our clinical sites and surgeons to.
Randomize patients to nothing.
Because of the ongoing belief.
Investigators.
That methotrexate is active for PBR.
I think we've continued to see a surge in the number of posters and papers and manuscripts that describe the use of methotrexate to treat PBR, which I consider a good news I think if given the choice lowest retinal surgeons that treat PBR.
Sure.
I would much rather use a GMP product than a compounded product for the reasons that I have.
Already discussed so thanks for your question.
Thank you.
Our next question is from Yale Jen from Laidlaw capital. Please go ahead.
Good morning, and thanks for taking the questions and best of luck with Josh.
Just two quick ones here, both about the study design.
In terms of the crossover chamber and one day sugars.
What's the study size.
Of this.
That study as well.
What might be the rough time, you will report data.
<unk> concluded two two.
As positive and then I have a follow up.
Yes.
The patient.
Patient numbers and the crossover trial are designed to roughly approximate the crossover trials, we have completed for allergic conjunctivitis.
I believe we have approximately 60 subjects or so in the crossover trial, but remember that's equivalent to 120 subjects in a standard parallel group trial with a one to one randomization.
In allergy and crossover trials and at least in the allergy chamber.
We saw a highly statistically significant changes.
And symptoms and signs using that crossover technique, which really just eliminates patient to patient variability what.
What you might think is uncomfortable is different from what I might think is uncomfortable and thus it makes sense to compare.
Drug to vehicle with in patients and that's why we're doing the crossover trial.
<unk> Schirmer study is.
Designed to mimic tranquility, so I would expect hundreds of patients.
In that trial.
Again, because we saw such a strong signal.
The tranquility trial regarding schirmer with about 300 subjects.
The trials are designed to readout.
Shortly after tranquility too.
Im not prepared to predict the exact timing because those trials are ongoing. However, the idea is that if for whatever reason the data from tranquility to our not interpretable.
Or ambiguous than.
We will have to.
Two different trials reading out shortly afterwards.
That in theory.
Would not impair our NDA submission timing, which we are.
Reiterating is mid year this year.
Okay great.
Very helpful and one more question here is therefore 629, you already started at no toxicity and I think you mentioned about chronic cough as well.
Could you give us a brief description of the study design.
Each of those studies.
Sure, Yes, absolutely we had reviewed some of that are.
At R&D day, both of those trials interestingly enough our crossover trials.
As you can tell.
We're big fans of crossover trials for the reasons I just discussed that is they generally eliminate subject to subject the variability that's especially important when youre talking about symptoms that is how does the patient feel about ocular discomfort, how does the patient feel about his or her coughing.
How does the patient feel after.
Consuming ethanol and those are different from person to person, which is why we have crossover trial. So both of those are our crossover designs that in terms of patient numbers are consistent with phase II or phase Iia.
Type clinical trials.
The range of 30% to 50 subject ourselves.
Okay, and maybe lastly, just to follow up on this and what might be the endpoint for each of those studies you put a phase II of the phase III.
Right.
We're also big believers in signs and symptoms.
I think typically over the past several decades, the FDA has moved toward a sign and symptom.
Our calculus for assessing.
Activity of drugs, and we agree with that shift in thinking so for each of these will have.
Subjective measure in the case of ethanol.
Standard ethanol exposure symptoms nausea dizziness.
Emphasis vomiting et cetera.
And then signs in the case of ethanol.
Washing appropriate exception tests acetaldehyde levels and other rasp level other markers of inflammation and involve deliver such as liver function tests. The same is true.
With regard to chronic cough.
The typical SBA endpoint for chronic cost seems to be a number of costs over 24 hours that can be measured objectively with the device.
That is attached to the patients chest.
Long size that sign or a whole bunch of symptoms quality of life.
Global impression of disease global impression.
<unk> and so on so that for each condition, we have both symptoms and size.
And is there a placebo involve in this study all of the business just the single arm.
Both of them are placebo controlled so the crossover is either drug.
And then vehicle or vehicle, I should say drug and placebo or placebo and the drug.
Okay, great. Thanks, a lot I appreciate and congrats on the progress.
Thanks for the question Neil Thank you.
We have no further questions on the call. So I will hand, the floor back to Dr. Brady.
Well. Thank you all for joining us today and as always we're.
We're excited about keeping you posted regarding our future updates and events.
This concludes the conference call. Thank you all very much for joining you may now disconnect your lines.