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00:03 Good morning, and welcome to Evelo Biosciences Conference Call to discuss its Third Quarter twenty twenty one Business Highlights. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the company's request.
00:25 At this time, I’d like to turn the call over to Kendra Sweeney of Evelo. Please proceed..
00:32 Thank you. This morning we issued a press release that outlines the topics we plan to discuss today. This release is available at www.evelobio.com under the Investors tab.
Today on our call Simba Gill, Chief Executive Officer; Mark Bodmer, President of R&D and Chief Scientific Officer; and Jonathan Zung, Chief Development Officer will review our recent business highlights and third quarter twenty twenty one financial results.
01:14 Before I begin, I'd like to remind everyone that statements made during this conference call that do not relate to matters of historical facts, including statements about our objectives and anticipated clinical milestones, the impacts of any of our product candidates and the timing and results of any clinical studies should be considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of nineteen ninety five.
Such forward-looking statements are intended to be subject to the safe harbor protection provided by the Reform Act. Actual results could differ materially from those indicated by the forward-looking statements due to their impact of many factors.
01:54 Participants are directed to the risk factors set forth in Evelo's quarterly report on Form 10-Q for the quarter ended September thirty, twenty twenty one, and the company's other filings with the Securities and Exchange Commission. Any forward-looking statements made today speak only to Evelo's operations as of today.
Evelo disclaims any duty to provide updates to its forward-looking statements even if subsequent events cause the company's views to change. 02:23 It is now my pleasure to pass the call over to Simba..
02:27 Thank you. Kendra. Good morning, everyone, and thank you for joining us to review our progress during third quarter. A major news for last quarter was of course the positive top line results of a Phase II trial of EDP1815 in patients with mild and moderate psoriasis.
02:48 The Phase II clinical data proves beyond reasonable doubt that we can indeed harness SINTAX to create medicines. I can't emphasize enough the importance and value of these data. The trial address the central question we have been asking since we first started Evelo.
Can targeting SINTAX be the foundation for new profile of medicine? The answer is, yes. With EDP1815 we have now shown in a well-controlled Phase II clinical trial that we can harness SINTAX to make a clinical impact on patients with an oral product candidate with safety and tolerability data comparable to placebo.
03:35 Together with affordable manufacturing these data support the potential of SINTAX medicines to address an enormous unmet need in the global treatment of patients with mild and moderate inflammatory disease. The data from the Phase II trial underscore two drivers of value.
The first is the potential of EDP1815 as an important new medicine in the treatment of psoriasis. Based on the data we are advancing EDP1815 towards registration trials in mild and moderate psoriasis. The primary unmet need in psoriasis is for this segment of patients.
There are over fifty five million patients with psoriasis worldwide and patients with mild and moderate disease represent over ninety percent of this patient population. 04:33 The second driver of value is that, this is proof of concept for the SINTAX’s platform in a Phase II clinical trial. The potential implications of this are immense.
It reveals a previously unknown branch of biology which touches on a broad mechanism for the resolution of inflammation, which impacts a considerable number of diseases, and for which we have shown a new type of medicine that works in humans.
05:06 In dermatology alone there are globally over two hundred million people who suffer from mild and moderate diseases for which there are limited treatment options. In broader inflammatory diseases, including arthritis, asthma and chronic obstructive pulmonary disease, there are about a billion people worldwide in need of better treatments.
05:31 I'd like to touch on one specific aspect of SINTAX based products as a new type of medicine. We are developing orally delivered microbial products that are non-live bio therapeutics. This is a completely different concept of bio therapeutics and the microbiome. There is no colonization or modification of the microbiome.
They have a direct pharmacological effect through interactions with host cells in the gut, which in turn modulate systemic inflammatory responses throughout the body via the small intestinal axis.
06:12 The clinical responses to EDP1815 opened the door, both to EDP1815 as a potentially important medicine in dermatology and to the broader potential of the platform. Our aim has always been to develop an entirely new profile of medicine that will transform healthcare rather than another incremental improvement to what already exists.
We did not invent the small intestinal axis, we discovered it by inventing SINTAX medicines, which harness this extraordinary natural system, which controls inflammation throughout the body. 06:51 What we have discovered is harness nature to create something that has never existed before.
We have discovered and pioneered new principles and new approaches for developing and manufacturing SINTAX medicines. 07:07 Our Phase II data, together with other clinical and preclinical data we have generated gives us high confidence that we will realize our vision to transform global healthcare.
Let me repeat the core point, we have demonstrated that we can harness SINTAX to drive clinical effects throughout the body with an orally delivered gut restricted agent. 07:32 SINTAX Medicines are a substantial new platform in our industry with the potential to help hundreds of millions of patients globally at all stages of disease.
Most of these patients have so far not received the benefits of biotech innovation. 07:49 Think of this in terms of combining the discovery of cytokine biology, with the discovery of therapeutic antibodies, newly discovered biology underpinning many diseases together with the means to do something about it.
And then delivering it to patients as a convenient oral pill. 08:08 With that, I will hand over to Mark..
08:13 Thanks, Simba. We'll often ask the reasonable question, what are risks of success of Evelo’s medicines. Of course there is one overarching risk is SINTAX biology important and SINTAX medicines work. Yes, it is important. And yes, EDP1815 was observed to have a critical impact on patients with psoriasis.
08:37 We've also the risks around manufacturing and regulatory part for the clinic, both potentially significant hurdles for new modality. These two have been over overcome. The Phase II results take us pass these fundamental risks on the practical challenges of making SINTAX medicines work for the largest numbers of people as effectively as possible.
09:00 The breadth of opportunity that Simba talks about comes directly from the breadth of the mechanism of action, that is, the coordinated resolution of multiple pathways involved in the inflammatory response.
09:12 Now that we have shown SINTAX functions in humans to modulate systemic immunity, it's reasonable to expect that SINTAX medicines may be beneficial in almost any condition in which inflammation plays an adverse role, which is most diseases.
As an example, two weeks ago the effective EDP1867 in a mouse model of neuroinflammation represented at the European Model Sclerosis conference, these were extraordinary data showing that gut immune system reaching into the central nervous system under the influence of one of our drug candidates.
It is the same principle that allows the gut to reach into the skin. 09:50 The apparently disparate effects in skin and CNS, other result of the catastrophic mechanism which is a glue that holds together this whole concept with the small intestinal axis can impact information throughout the body.
10:05 I'm not going to turn to two related topics that are part making EDP1815 and future SINTAX medicines work as effectively as possible. The first topic is to do with a responder rate to EDP1815 that we observed in the Phase II psoriasis trial.
As you recall, approximately thirty percent of patients who received EDP1815 in the trial achieved a PASI-50 response by the sixteen week endpoint. While this does not mean that EDP1815 does not have any effect in the other seventy percent of people.
10:41 There was a continuous distribution of PASI responses, the thirty percent who were reported as PASI-50 responders is simply a cut of our overall distribution up for sixteen weeks of treatment. The Phase II study show that efficacy accrued hence patients continue to taker EDP 1815.
This suggests that treating for longer could result in higher response rates. A rising tide lift all boats, anything that increases overall response rates has the potential to benefit more patients. 11:15 We've also done further sensitivity analysis since the Phase II date were released last month, and I'd like to highlight one of them.
The proportion of patients who achieved IGA zero or one after stratifying their baseline body surface area psoriasis was evaluated. IGA zero and one are respectively clear and nearly clear skin. These are the targets of treatment in patients with mild and moderate psoriasis.
11:42 Mild disease is to fine the body surface area less than or equal to five percent moderate disease is greater than five percent. The proportion of patients with moderate disease that is greater than five percent who reached IGA zero or one compared to placebo had a P value of less than zero point zero five.
12:06 Patients with mild disease also trended to efficacy with a P value that was not significant. Across the entire study population, stratifying by BSA Group at baseline EDP1815 was also found to be significantly better than placebo in a number of PGA zero or one responders with a P value less than zero point zero five.
This was an important result, it does not mean that EDP1815 doesn't work in milder patients. It does mean that the effect is more readily detected in patients with more extensive disease, not surprising since there as a larger window for leading the effective treatment.
12:47 The observed response rate in the Phase II study it was already within a clinically and commercially attractive range for mild and moderate disease, reinforced by placebo like safety and tolerability. These further analyses are evidence for additional improvement of efficacy in future studies based on clinical data that we already have.
13:11 The second broad point about making SINTAX medicines work as effectively as possible is based on the observation in the Phase II psoriasis trial where we saw continued improvements in some patients after the end of the treatment period.
Generally, drug levels need to be maintained to suppress the target pathway when dosing is stopped the is often no rebound in disease symptoms. 13:35 The mechanism of action that allows us continued effect with EDP1815 ties into broad inflammation resolution that I was talking about a month of the ago.
EDP1815 and several of our other product candidates infuse a regulatory phenotype when circulating immune cells. We can show this experimentally in preclinical studies by isolating peripheral immune cells from animals that have treated with drug.
If we then transfer these isolated sales in the animals that have not treated drug, that means non drug treatment animals have the same anti-inflammatory inflammation resolution as this Phase have treated. The transferred cells mediate the information resolving effect of the drug.
This is called adaptive cell transfer, and it is a core proof of mechanism for the therapeutic cellular phenotype infused via SINTAX. 14:34 Consider what this means.
The efficacy of a gut restricted drug is carried out on modified immune cells in the periphery are evidence for this mice is the adoptive cell transfer, our evidence for this humans is a continuing effect after the drug is stopped.
Induced regulatory cells continue to overcome the effect of the inflammatory cells residents in the skin leading to skin healing after the administration of the drug is ended. 15:04 The modified immune cells can last for weeks in circulation perhaps longer, we don’t knoe the duration response yet.
So consider again what this means, we have created a regulatory cell phenotype, which is induced in tissue by product candidate EDP1815 that is observed to have to placebo like tolerability and safety and that can be manufactured at scale.
15:25 Compare this to the current interest in cellular therapies with ex-vivo conditions regulatory T cells, we've skipped that entire process step and gone straight to with such new generation with an old product candidate, which uses the body's natural programming.
This is one of those scientific results that the family opened once time of reference. With gut restricted agent can create active regulation of systemic information who is not in immune suppression is restoration of the normal non-inflamed state.
15:57 I'd like to finish with some more forward-looking comments about our aspirations for the future of the SINTAX platform. EDP1815 is now nicely set up as a treatment for mild and moderate psoriasis, and that should also be true for other inflammatory diseases.
We have reported repeatedly that in preclinical studies, our drug candidates are as effective as the best standard of care biologics and oral. This suggests the potential also in severe inflammatory disease.
16:27 Our goal for future versions of SINTAX medicines is to reach biologic levels of efficacy and humans to take SINTAX medicines beyond mild and moderate and into severe disease. The preclinical data suggests this is biologically feasible, getting effective target engagement in humans is harder than in might.
The physics of the delivery of SINTAX medicines with the target in the larger human gut provide in particular challenges.
16:54 We think that extracellular vesicles, with a volume one thousand lack of a micro help to address these challenges The small size advantage of EVs allows them to diffuse more readily in the gut media and allows us to pack a higher concentration into each pill.
The size advantages will be combined with formulations that ensure that the drug is made as much as the small intestine as possible. It's a reasonable prediction that these factors, size, packing and formulation will combine to increase efficacy.
It's how we get the high levels of efficacy pre-clinically, and we are now learning how to do it in humans. 17:32 Our vision, the future of SINTAX medicines is efficacy, which is competitive to the best standard of care for all stages of disease with oral delivery and the safety and tolerability seen with EDP1815.
The scientific platform, which we've have constructed methodically over the last five years supports this possibility. 17:53 With that, I'll hand over the Jonathan to update you on our clinical programs..
Thank you, Mark, and good morning, everyone. I will provide an update on our ongoing clinical trials, upcoming readouts, as well as planned studies.
18:11 Part B of our Phase II trial in mild and moderate psoriasis is ongoing and assessing the durability of treatment response following completion of sixteen weeks of dosing in one hundred and twenty four patients. These participants are being evaluated monthly, and we look forward to learning more about the lasting effects of EDP1815.
We expect to report top line results in the first quarter of twenty twenty two. 18:39 The results from Part A and Part B of the Phase II trial will allow us to refine our next phase clinical plans for EDP1815 in psoriasis as well as seek feedback from health authorities.
Our Phase 1b trial of EDP1867 in a cohort of patients with moderate atopic dermatitis is ongoing. Trial participants are being dosed [Technical Difficulty] with a fourteen day follow-up period. We anticipate results from this trial in the first half of twenty twenty two based on slower than projected recruitment.
19:15 We previously reported that the U.S. FDA had requested additional information in a clinical hold letter in the EDP1815 Phase II atopic dermatitis trial in patients with mild and moderate and severe disease. We have satisfactory responded to the FDA request and the hold has been lifted.
The IND is now open and we anticipate dosing late in the fourth quarter. This trial will be sixteen weeks in duration with the primary endpoint of percent of patients who achieve an Eczema Area and Severity Index easy fifty score at week sixteen. In addition, we'll be collecting various physician and patient reported outcomes.
We anticipate reporting results from this trial in the fourth quarter of twenty twenty two. 20:03 Patients on active and placebo from this trial will have the opportunity to join an open label extension once they complete sixteen weeks of dosing. All patients in the open label extension will receive EDP1815 for up to fifty two weeks.
20:20 We remain on track to bring our first extracellular vesicles or EV candidate EDP2939 for inflammatory diseases into the clinic in twenty twenty two. We continue to recruit patients in the Phase II/III TACTIC-E for the prevention and treatment of life threatening complications associated with COVID-nineteen in hospitalized patients in the UK.
Brazil, Mexico and India. 20:48 TACTIC-E is progressing well and is very close the initial recruitment goal of one hundred and twenty five patients in each of the initial three arms of the trial, including EDP1815. Hitting this recruitment target will trigger an interim safety and futility analysis by the independent data monitoring committee.
21:08 Based on the progress and scale of TACTIC-E, we have decided to focus our efforts on this trial and to close our smaller U.S. Phase II trial evaluating the safety and efficacy of EDP1815 in the treatment of patients hospitalized with COVID-nineteen infection.
It is now clear that smaller trial will not make a meaningful contribution to our understanding of EDP1815 in hospitalized COVID-nineteen patients. 21:37 I'll hand it back to Simba for closing remarks..
21:41 Thank you, Jonathan. This is a pivotal moment for Evelo. We now have proof of concept from a Phase II study for SINTAX. We are advancing EDP1815 in psoriasis towards later stage development and potential commercialization. In parallel, we're advancing EDP1815 in a Phase II study in atopic dermatitis.
And our second anti-inflammatory microbial product, EDP1867 is in the clinic. Our EV development platform is making strong technical progress towards the clinic and we have shown preclinically the potential of SINTAX medicines in neuro inflammation.
22:29 All of this is only the beginning, we have a better and better understanding of how to capture the full breadth of our SINTAX platform, and you can expect much more from our platform as we continue to grow Evelo towards our vision. 22:44 Thank you for your attention, and we will now open for questions..
22:50 [Operator Instructions] Our first question coming from the line of Chris Howerton with Jefferies. Your line is open..
23:13 Hi. Good morning, everybody, and thank you very much for taking the questions. For me, I think the first would be with respect to atopic dermatitis.
I'd be curious to hear the company's thoughts on both kind of the regulatory path of using EASI-50 as the primary endpoint if that would be possible? And then secondarily, what would be a clinically meaningful effect size on such an endpoint within, I guess, the mild to moderate patient population? So that would be question one.
23:49 And then question two is, with respect to cohort B of this psoriasis study. Maybe if you could just compare and contrast that to cohort A? And how that's going to inform the Phase III design moving forward it? Thank you..
24:08 Chris, this is Simba. Thanks for your question.
Sorry, could you just repeat the last question?.
24:13 Yes, sorry, the last question was, compare and contrast cohort A and cohort B for the psoriasis study? And what exactly in the cohort B results is going to help you kind of figure out the Phase III design moving forward?.
24:31 Okay. All right. Thanks. So let me take the middle one first, which was, what would be a clinically meaningful effect on EASI-50 side. As you know Chris, atopic dermatitis for mile and moderate patients does not have any approved oral treatments.
And atopic dermatitis patients essentially with mild and moderate disease are limited to taking a range of topicals, including topical steroids. We have a number of limitations. 25:04 The reason I'm leading with that, Chris, the bar is actually very low for a safe well tolerated oral drug.
And as long as we continue to confirm safety and tolerability, if we see EASI-50 responses or equivalent, and I'll hand over to Duncan in the moment who can answer your first question. 25:26 In a reasonable percentage of patients we have a very attractive drug.
I would say somewhat similar to psoriasis that we have effective EASI-50 or greater in twenty five percent to thirty percent of patients or more than we have an attractive drug as a general guidance for you, Chris. 25:48 We expect we have a good probability of doing better than that.
If you look at our Phase Ib data in atopic dermatitis we already had seven out of sixteen patients who are plus or minus at that EASI-50 level after only eight weeks of treatment. 26:08 So we're feeling confident right now that we'll get to that level or better, Chris, that I talked about.
I’d also emphasize that in psoriasis we did already see some patients at PASI-75 or even greater PASI-90. Different diseases, different biology, but it's certainly encouraging in terms of where we think we may end up. So that's the first point, Chris. And then I'll let Duncan answer your question on EASI-50 as a regulatory endpoint..
26:43 Yes. Chris, good question. So EV is well established scale, it's the scale that the authorities are very familiar with. In terms of the EASI-50 benchmark itself, it is a clinically meaningful change that patients with mild to moderate and ing fact sever disease will clearly notice some benefit from.
So, we have no concerns about that as a scale from regulator perspective. But member we'll also look at the Phase II study. We also will have SCORAD, we will have IGA and BSA. BSA is sort of key factor to the endpoints.
So what we will do is we will look at all of that data, we will understand which of those endpoints actually is the best end point to capture the benefit of EDP1815 in mild to moderate atopic dermatitis, and then we'll go and have those discussions with the health authorities.
But all the result are pretty well established and particularly EASI is a very well validated endpoint that we don't expect to have any concerns from the regulations of EASI..
27:50 And then Jonathan, do you want to do the Part B versus Part A?.
27:54 Sure. So, Chris, for the Phase II psoriasis study from the part A, we clearly weren’t dosing longer is going to be important to capture the whole breadth of activity of 1815. When we think about the Part B data. Part B bata will inform us around relapse, how along this benefit maintained.
Obviously that'll be incorporated in our thinking, but certainly as we think about the next study in the registration pathway, it will be longer dosing, right? We'll be looking at an endpoint, as we've mentioned before, most likely at six months and then extending out for another six months so we get a full year of data.
So the real I think data that will support the thinking behind that is Part A..
28:42 Thanks. Okay --.
28:44 Mark, do you want to add –.
28:45 Just one point of -- Chris, just one point for clarity that is, cohort B is not a separate cohort. It's the same patients from Part A of the study carried over into Part B. I just wanted to make sure you didn't went on the impression that we had a separate cohort of patients that we were looking at for longer..
29:02 Yes. No, that is helpful. I appreciate the clarification. And maybe I'll hop back in the queue and give other people a chance, but I appreciate you taking my questions..
29:15 Thanks, Chris..
29:20 Thank you. And our next question coming from the line of Matthew Luchini with BMO Capital. Your line is open..
29:30 Hi. Good morning, guys. Thank you very much for taking the questions and congrats on the continued progress. 29:37 So, maybe first on the Part B psoriasis.
Given everything that you've just talked about and the importance of looking beyond sixteen weeks, are you able to provide some preliminary perspective on the level of additional follow-up you expect to have beyond that sixteen week data point, when you release data will everyone be at six months or will the median be somewhere below that, and if so, around where? And then secondarily, want to know if you're able to provide any incremental color on the formulation work since the last update.
And when you may be able to have something more concrete to say about your efforts here? 30:22 And then maybe lastly, if I could on 1867, just understand a little more of the recruitment challenges which are seen and maybe more broadly how the AD data will inform your development strategy not only for this drug, but for EDP1815 as well? Thank you much..
30:49 So, let me take a couple of those and I'll let Jonathan take the detailed questions on Part B. 30:57 On formulation, we expect we'll have next level of data and understanding of the next wave of that in Q1 next year. So I think we should be on track for that on that front..
31:15 On recruitment of 1867, we're trying to understand exactly why it could have been slower than we had expected. It may be because of COVID, that study is being recruited in the UK, and you probably known, there's been a rise of COVID patients. We don't know that math, it's definitely positive for us, but we're try to understand that right now.
We don't really have any additional information at this stage on that recruitment situation.
31:42 And then, Jonathan do you want to talk about the details on Part B?.
31:45 Yes. So, in Part B, we have one hundred and twenty four subjects who have rolled into that portion of the study. It goes out for an additional twenty weeks. We expect to have a fair number of those subjects who will be completing the twenty weeks.
We've got about seventy plus percent subjects who are now completing in that and we'll report the data in first quarter of next year. And what we'll have a large proportion of those subjects who will go out to the full twenty week..
32:16 Great.
And then actually Duncan, do you want to culminate into 1867 atopic dermatitis?.
32:22 Yes. Matt, it’s a good question. I suggest to be clear, we reusing atopic dermatitis here because that actually is a very useful and valuable kind early indication that we got from that inflammatory effect.
We will obviously have the 1815 data as well, but the intent to is not say that 1867 is another drug that will follow an exactly the same footsteps as 1815.
This is the Phase Ib study we want to demonstrate managing plans to effect and then actually there is obviously a whole range of indications that we talked about before, the good range classic immuno inflammatory diseases like inflammatory bowel disease [indiscernible] to diseases such as neuro information.
The key here is to just demonstrate the safety tolerability and the anti-inflammatory effect and then the future development plan will involve other indications..
33:20 Okay. Thank you for taking the questions..
33:23 Thank you, Matt..
33:28 Our next question coming from the line of Kristen Kluska with Cantor Fitzgerald. Your line is open..
33:35 Hi, good morning, everyone. Thanks for taking the questions. The first one I have is, I noticed that your most recent corporate deck expands and further emphasizes some of the comorbidities that are specifically associated with psoriasis in atopic dermatitis.
So as your recent dataset was important for your broad understanding of the potential of SINTAX medicine.
Curious as you are near starting the Phase II study in atopic dermatitis, if you will look to enroll some patients where perhaps some of these comorbidities are more apparent to even better understand some of the systemic impact?.
34:13 Yes. So Kristen, thanks for picking up on that point. We won't be specifically looking to recruit patients with comorbidities, obviously to the degree we pick it up anyway in the detailed analysis, we'll obviously be looking for those things in that context.
34:31 But beyond the Phase II, I think the more fundamental point that you're picking up on Kristen is, there's huge breadth of opportunity with 1815 on the SINTAX to treat many different types of inflammation, A.
And B, both psoriasis and atopic dermatitis are systemic diseases as your question suggest impact, not just skin that have comorbid conditions in multiple different dimensions. So we won't be looking specifically for that, no recruitment in Phase II. But the point is, an important one in terms of the potential treatment as we go forward..
35:10 Okay. Thanks. And looking at the profile differences between EDP1815 and EDP1867. Based off some of these trends you've observed post dosage in longer term with EDP1815.
Wondering it’s based on the differences with the [indiscernible], whether you might expect or look to see something similar with EDP1867? 35:34 And then as you think longer term here, how do you think about expansion opportunities for EDP1867, excuse me, in light of these recent preclinical findings you had, as well as the greater focus on EV candidates, given the recent patent could address both?.
35:54 Yes. So, I think three level of questions. So first of all, we need those human clinical data to see if we see similar or different responses with 1867 versus 1815 are different. And so the preclinically they are difference. So we'll be able to answer that question with data in then not update future, hopefully, Kristen.
36:18 In terms of how we think about 1815, 1867 expansion and the EV side of things. I think let me take that together. What we've talked about historically is that, we see where we are now. I talked about it earlier to today even as the equivalent of uncovering cytokine biology and discovery of antibodies.
I have been to have worked with Alex Zaboronok decade ago, Kristen, who started DNX is the first flight cytokine company in the world, fairly remarkable on recovery of central human biology, Mark and I worked, as you know, in the other stage antibodies when Mark headed up when it was first antibody engineering groups.
We are very much in the early days of uncovering the potential of SINTAX platform. And pushing thing forward, I’ll as Mark say a little bit more about this right now. 37:12 But as we start to understand more and more how the biology works, what the potential of EV is.
As Mark said, we see EVs and the ultimate future of SINTAX platform as being an opportunity to have orally delivered agents that have antibody like efficacy whilst being safe, well tolerated and affordable. And all of the signs right now point us in a direction of that being a very real populated, and it's not too far away.
We'll have our first EV data sometime in a not too distant future as we said on the call. We are on track to go into the clinic with EVs next year in inflammation. And we have a good formal guidance of when that date will read out, but it won't be too far away. 38:02 And so that's where we see this going pretty quickly actually.
Right now, we have, as you know, 1815 that's looking like an attractive drug in psoriasis and quite probably in atopic bermatitis. But that's really the first wave we look at EVs as rapid follow-ons but that can have dramatically better potency.
38:23 In terms of 1867 and 1815 or indeed any of our other microbes and microbial extra cellular vesicles versus 1815. As you know, and again as Mark talked about today, the newer inflammatory side of 1815 is already looking very interesting. As Duncan said, we don't see 1867 as an atopic dermatitis drug.
Necessarily atopic dermatitis is a quick way of getting clinical information in human patients and then we will figure out how we move it forward depending on that data, but we see potential for 1867, for example, in your nuro inflammation as well as in a number of other areas.
39:03 And then Mark, always who like to remind everybody how lucky would we be to have 1815 and 1867 as great products. So, we look forward to that possibility obviously, Kristen and it’s great luxury if we do end up fast. So, hopefully that was helpful. I’ll have Mark say a little bit more about, actually your EV side of things.
Because as I said, all the signs right now is pointing us to that being an incredibly exciting possibility..
39:32 Yes. Thanks Simba. And Kristen, let play into to that with the first set of your question about 1815 and 1867 and the duration of effect. As Simba said, we don't know clinically, but preclinical we do. So EDP1867 induces this regulatory phenotype in treated animals that could be transferred to untreated animals at exactly the same way as EDP1815.
But it does it with a different molecular background, which is fascinating, which is driving a lot of our research and discovery, because there is -- there's some common parts of the pharmacological pathway here which were increased by different molecular pathways in the primary actions of the drugs.
It is not to say that we've identified specific targets, but we can look at differences in by any toll-like receptors, we can look at differences induction of various transcripts in the gut by the different agents. 40:25 We then take that to the EV part. We've been doing a lot of work on the extracellular vesicles of the micro that underlies EDP1867.
And that also does these things. It doesn't look molecular exactly like the current microbe, but pharmacological it does in a much lower level. So if you think about this from a dose point of view, exactly it was driving some of my comments about efficiency of movement of these things in the media to get to the target and the gut have also packing.
So, we did typically a dose of about ten to the nine microbial cells per day in an animal model with the EV from EDP 1867. We can take that down several orders of magnitude, ten to the six, ten the seven. And that's smaller at the same time. So the differential is about a million fold.
I mean this is quite an extraordinary fact, that's why we're so excited about the future of the EV platform, because we've got a base of efficacy with the microbial preparations, and then we have this additional way to go forward, which is why I talked about the potential to get -- to get into severe disease.
So I suspect this is all about dose inventory and where we are on the dose response in relation to formulation, in relation to the concentration of drug that's given to the target.
41:46 Then just very briefly, beyond that, actually most of our discovery work is now focused on looking at extracellular vesicles from quite a wide taxonomic range of microbes comparing the pharmacology that underlying molecular mechanisms to get a spectrum, which is going to support the future of the pipeline.
And by the way, critically importantly it supports the breadth of patent claim that we get around this. 42:13 And just to reemphasize that the patenting around the use of extracellular vesicles from mucosal and aerobic microbes as oral treatments is virgin territory. And so we're fighting very broadly on that. Nothing issued yet, of course.
But the discovery work which gives us the product candidates also gives us the breadth of support for those patent filing. So I hope that helps to give a bit of context to the whole thing..
42:41 Yes. Thank you, Simba and Mark..
42:45 Thanks, Kristen..
42:53 And our next question coming from the line of Gobind Singh with JMP. Your line is open..
42:59 Hi, thanks for taking the questions. So just a few from me. I think Mark you had – I wanted to bring the conversation back to the results.
I think you've have mentioned that BSA greater than five percent and below five percent and I'm just trying to figure out what the comparator is, if there is any? It just seems like the way Amgen has presented those results from the advanced trial. It looks really different compared to how they’ve kind of done things with other trials.
I don't even think there's a PASI of fifty or PASI of seventy five or any kind of traditional PASI ever presented from the advanced trials. So can you maybe give us some context to how to kind of view those results, and then one follow-up after that's..
43:42 Duncan, go ahead..
Yes. Gobind, thanks for the question. So, I can't really comment on why I'm Amgen chose particular endpoint that they chose. Obviously, they -- as there are [indiscernible] advance.
In terms of the body surface are threshold of five percent that they use, that’s sort of -- that's one of the ways in which people can sort of classified psoriasis into mild and moderate disease.
It's not necessarily true from patient perspective, it’s really from the physician perspective, we can sort of say that the body surface are is less than five percent in mile, it's greater than five percent in moderate. And I’m assuming that is the reason that they cut that at five percent.
And as you saw, we've done something similar and looked at that. 44:36 PGA zero to one, so the ability to get clear or nearly clear skin both in the mild and the moderate disease. We've also actually done it using PGA two and PGA three, which is another way of categorizing mild to moderate disease.
And In both of those settings, we have a statistically significant result in terms of EDP1815 versus placebo and reaching clear or nearly clear skin.
So from our perspective, it's just another way of looking at the clinical benefit that we're getting with EDP1815 and seeing a sort of a clinically meaningful benefit to patient set, because that's usually -- that’s the targets of patients, they want to get to the clear skin or virtually clear six, it is quite hard to truly a clear skin.
But we -- the five percent it does reflect some of what Amgen did, but I can't tell you why they use PASI or did use PASI in that case, we used it because we used this early and it’s a well-established, well validated endpoint.
45:44 We will look at obviously all the endpoint in 201 and we will decide which one we view is the best in terms of capturing EDP 1815 activity, and that's what we’ll propose to the health authorities in terms of thinking about later stage development study..
46:02 Can I just add one comment Gobind. Actually you understand very well, what was important in this was that an orthogonal analysis to the PASI-50 showed robustness of the underlying data. So I like the comparatively primary PASI with the PASI-50.
This is a different dataset that was collected looking at BSA and looking at IGA and it reinforced the fact that there is an effect of EDP1815. This was separate from the question the proportion of responders, but they thought that all analysis picked it up as well.
So, it really for us in our evaluation of the study added a deal of robustness in our estimation of the effect of EDP1815..
46:53 That's helpful. And I know there was a mention about the lower, I guess, less than five percent BSA population not being statistically significant with the Bayesian Analysis. I mean, I'm just roughly following it. It’s about what, ten percent, twenty percent of your population? So I'm assuming the numbers are probably pretty small there anyway.
Can I confirm that with you guys and then maybe the follow-up would be I'm looking at those pictures that you guys presented earlier with like PASI and PGA and DOQI and PSI. And is the clinical effect, clearly we're having a microbiome drug, it's not shutting off the pathway, we are more normalizing the underlying disease process.
So one might imagine the time to kind of see the peak effect might be different than a small molecule like Tesla or Jack, is there any rationale or any precedent for how long this could take.
Like for example, with thirteen week, for example, be enough time for us to be able to see this? And then maybe is PGA the right way of looking at this not PASI or maybe DOQI or I don't know if you can comment, because the DOQI responses that you guys presented was pretty good.
And I think in advance they are focusing more on PGA and the other metric, it's not PASI..
48:13 Yes. Let me just say a few things and then Duncan can expand Gobind. So, first of all, you raised a really important point on small molecules versus our mechanism action.
And in Mark's comments today, he talked about the fact that we've been very elegant adopters of cell transfer studies preclinical that show that our effects are driven from immune cell impact versus classic impact of the antibodies or small molecules.
So we're pushing the immune system back to a homeostatic regulatory status through cellular effects on the immune system. 48:57 That is completely distinct that you're saying over anything else that it's got.
Very positive potential implications because obviously having a healthy homeostatic immune system is lot better than shutting down part of the immune system, which is essentially what antibodies and small molecule do. 49:14 As you suggest also likely means it will take a little bit longer for effects to kick in the then effects.
And that's part of what we're looking for in part B may well be sustained foe longer. So all those things are very positive for us.
We can't quantitatively answer your question – it’s twenty weeks the right time, we certainly already seen a twenty weeks and we reported out on this with the initial data to release from the Phase II psoriasis study that we see continued depth of response post dosing.
So that is already indicative of a likely cellular effect that persist and continues for presumably weeks after we stop dosing, but we don't have it quantified yet. 49:59 So, just a few initial comments there.
And then Duncan, you can answer the other process?.
50:05 Yeah. Just a couple of points on that. So just to be clear, when we talked about that data being statistically significant. What we were looking at that is, when we looked at the PGA zero and one across both the groups, I just split by BSA or actually split by that starting PGA a baseline of being two or three.
This is still -- it's a phase II study, it's a reasonable guide, but as you start to just sort look at the very sub set they can benefit to.
So it's not that we looked at each those individual subsets, what we've done is, we looked at the total population, but divided into either being PGA two or baseline or less than five percent, greater than five percent of baseline in the two analyses.
And when you analyze all of the data with that as a transportation variable in either of those two cases we see it statistically significant results. 51:04 In terms of what will be the best endpoint as we go forward, we'll keep continuing to look at the data.
The one thing I would say to you, if we look at the process where we get very nice clear kind of kinetics response to EGP 1815 the psoriasis flat you can see them actually clearing sort of earlier on and they tend to clear centrally which means the BSA is one of the later things actually shift, and we'll take that into account as we think about what the later -- so what the endpoint are for later trial.
It's a well-established way of psoriasis clearing and actually Benny, our Chief Investigator, what it is as well as our in-house dermatologists, and it's a fascinating way in which actually EDP1815 is essentially clearing and the last thing clear is the agent of the fact..
52:00 Can I just add one comment Gobind related to what Simba said about the mechanism of action. Because you are actually asking a question about the duration of the hyperscale of the senator effects versus factor in inhibition.
So if on imagine for instance, an inflammatory response that’s driven by IL17 or TNF, one puts a direct inhibitor and takes that inflammatory drive out and as long as inhibitors that the drivers has taken away. 52:28 But it's not generating a remapping of the immune system, and its function.
So while the effect maybe a bit quicker, the durability will be less. So one of the things to imagine here from an logical point of view is, we got inflamed skin whether it psoriasis or dermatitis or an inflamed joint, our inflamed spinal cord, whatever it is. You've got a bunch of resident cells in there, which need to be suppressed and displaced.
52:58 Now, if you've got a direct inhibitor where the inflammatory effect so it will act on those inflammatory cells.
What we're looking at here is a different process where there's is a steady replacement over time of the inflammatory cells that are resident in the inflamed tissue with the anti-inflammatory regulatory cells that have been by the drug. And that's why Simba talks about the reprogram or the long-term effects.
This has been holy grail of inflammatory therapy for years. We haven't know how to get at it. So you can imagine what we saw the adopted cell transfer effective in mice and we saw the continuing accrual of effects in humans. This was a real eye opener for us.
I mean that was why I made the comment in the scripted remarks about profoundly changing the way want thinks about an area of science. Certainly we can do something in the system, which we known we wanted to do for decades, but haven't figured out how to do it.
That is not just to suppress the inflammatory response but to reprogram the immune system, so that it controls its own response.
So that is what the data are telling us are happening very clearly preclinical we can show it by direct methods and it reads on to what we're seeing clinically, which is consistent with what we're seen preclinical clinically..
54:18 Thank you..
54:21 Thanks, Gobind. Appreciate the question..
54:26 And our next question coming from the line of Keay Nakae from Chardan.Your line is open..
54:34 Thank you. Let me just further drill down on the effort to improve release kinetics. Obviously, I think the coating chemistries are well understood.
So what's really the gating item of that initiative?.
So, we're just generating supply key for the next wave formulations to test in the model that we touched on briefly on the last earnings call. So we just generated supply. And as I said, we should be ready to test different formulations in Q1..
55:17 Okay. All my other questions were answered. Thank you..
55:29 And our next question coming from the line Joseph Thome at Cowen. Your line is open..
55:35 Good morning and thank you for taking questions. Maybe the first one just a clarification on the Phase II atopic dermatitis data readouts that we're going to be able to see. I know with the Phase II we saw the data analysis for superiority, but then also maybe more a traditional P value comparison on that reach a certain PASI cutoff.
What should we expect in terms of the data readout for the atopic dermatitis, will this be sort of a traditional disproportion patients got the EASI-50 on drug versus placebo or is there a comparison that would be appropriate here as well? 56:13 And then Second, in terms of other formulation work, you can move that into in the Q1 the Phase II for atopic dermatitis is starting Q4.
Is there any way to expand the Phase II if what you're seeing with the novel formulations is interesting, to add that cohort or will these novel formulations be used kind of ready for the pivotal studies is path is supported? Thanks..
56:36 I'm going to let Duncan answer about those questions..
56:40 For the that question that we straightforward because it is a proportion analysis -- the number of subject to reach EASI-50. Actually basing approaches is a less well established and to that we will use the more traditional approach from that side. In terms of the potential to you, add a new formulation part to Phase II.
57:06 I think that would be very difficult to sort of do that and be able to sort of have a robust technical analysis for that. So we will run any potential new formulations in a separate study rather than trying and complicated the current study..
57:28 Great. Thank you..
57:30 So, Joe, I hope that hasn't stopped you from becoming an expert on basis statistical analysis, which I will -- it is not only in the future, it's the path. So probably we try to educate people something it’s three hundred years old, which is basically statistics but anyway, that's just my comment for the day, Joe..
57:51 Thank you very much..
57:58 I'm showing no further questions at this time. I would now like to turn the call back over to our speakers for any closing remarks..
58:06 Thank you, everybody for your attention. Thanks to all wonderful analyst for their attention and their excellent questions. As we said in the scripted remarks, this is a pivotal moment for us. We are thrilled with the Phase II in psoriasis, but is absolutely just the beginning of what we see as an incredibly exciting future for tax platform.
58:31 I will remind everybody that we are true pioneers, as Mark talked about the extracellular intellectual property, but we were the first company to uncover the small intestine. We're the first company to think of using non live microbes already delivered therapeutics.
We are the first company to think about he's orally delivered my microbial are selling the vehicles. So a goal is always been to be the pioneer and the leader forever.
And think about how to capture the value of the small intestinal access, which we now absolutely know plays a central role as even by still not widely appreciated by the scientific clinical community. And we now know that we can harness some exploring test access for clinical effects with something that is very safe.
And well tolerated to an extremely exciting moment for. Thanks very much everyone..
59:29 Ladies and gentlemen today thank you for your participation. You may now disconnect..