Q3 2020 Arena Pharmaceuticals Inc Earnings and ADVISE Trial Update Conference Call
I should have calls corporate conference call. This call is being recorded.
I'll now turn the call over to you back in the White, Vice President Investor Relations and corporate Communications at Arena. Please go ahead.
Good afternoon, everyone.
And thank you for joining US today, we hope you had a chance to review the press release that we issued this afternoon announcing both our third quarter 2020 financial results as well as the topline results from our phase to be advise trial Jordan.
Joining me on today's call are Amit Munshi, our president and Chief Executive Officer, Laurie Stelzer, Our Chief Financial Officer, Dr., Chris Campbell, Our Chief Medical Officer, and head of research and development and Rob Lisicki, Our Chief commercial officer.
Before we begin I would like to remind you that we'll be making forward looking statements that involve risks and uncertainties about our goals expectations plans beliefs timing of events or future results, including those risks and uncertainties related to our pipeline financial projections 2020 financial guidance.
And the COVID-19 pandemic and its potential impact on our business forward looking statements involve certain assumptions risks and uncertainties that maybe beyond our control and could cause actual results to differ materially from these statements.
Script, one of these risks can be found in our earnings press release, and our latest FCC disclosure documents.
All forward looking statements are based on information currently available to arena and we disclaim any obligation to update these forward looking statements.
Now I'd like to turn the call over to Aldo.
Thanks, Pat and good afternoon, everyone I hope you've had a chance to review our press release announcing our compelling topline results from the phase two be advise trial for TRASM on any topic I'm kinda this already.
This is the first study of an S. One p. one modulator in this indication.
Critically as we know from our extensive market research patients and physicians continue to demand a safe and effective oral agent for the treatment of 80.
Chris will be going through this trial in greater detail in a few moments, but before he does I'd like to provide a high level summary of the findings and results of this trial.
The advise trial recruited a moderate patient population with 83% per participant having a baseline AG score of three.
This is different than population studied in recently conducted a topic during trials with advanced therapies.
Importantly, the moderate patient population represents approximately 40% of the entire atopic dermatitis market.
Participants into two milligram groups show statistically significant improvement compared to placebo at 12 weeks on the VI G. a responder criteria.
Which as you know is the stringent ft, a phase three primary endpoint free topic dermatitis.
And Trustmark did not meet the phase two primary endpoint of percent change and easy from baseline at week 12 compared to placebo in the full analysis that.
We're pleased to observe a TRASM much rapid onset of action as seen in study of other indications was confirmed in this trial and in this condition and.
A week for participants in the two milligram treatment group achieved statistical significance across easy.
Easy 75, and pre write us endpoints.
Overall, the 12 week study showed no plateau of effect and very importantly, the safety profile, which Chris will cover in more detail, what's consistent with previous trials of the crowds might including low first those heart rate effect with no titration and no serious adverse events across the groups.
Be advised travel was impacted by an unwarranted dose interruption, which generally took place between weeks foreign aid in 19% or nine participants India TRASM My two milligram group.
Adjusting for this interruption the post hoc computer analysis would participants who receive full therapeutic exposure of the Cosmos. Two milligram showed statistically significant effect on the percentage change in easy from baseline it Weve week 12 compared to placebo.
The analysis of this corner participants, we experienced a dose interruption.
Allowed us to visualize what turned out to be an unintended, but serendipitous withdrawal type study design.
This data illustrated the diminishing clinical effect upon withdrawal of a TRASM my two milligram and a recapture effect upon the resumption of study drug.
Cross this complete response that the effect of critical parameters, including B.I.D.A. easy sometime Pruritis is in the recently approved advance in the range of recently approved advanced therapies and therapies currently latter stages of clinical development.
As we set out to conduct the advise trial, we had three objectives first we aim to ensure that the transmode was safe and well tolerated in a atopic dermatitis population as I mentioned. This is the first that's one p. one receptor modulator tested into syndication SEC.
Second we sought to determine whether kosmos could provide an efficacy signal and a dose response that would inform the decision to move into a phase three program.
And finally, we sought to ensure that we would have a profile that would eventually be commercially viable.
We are certain that we have met these objectives and the totality of the data emboldens, our conviction to move expeditiously into a phase three Registrational program.
In the past 48 hours, we've spoken to a number of global thought leaders, who are impressed by the safety and efficacy demonstrated by TRASM odd as an oral agent in this advise trial.
[noise] fees.
Global thought leaders, we're highly supportive of moving forward to a phase three program.
Chris and Rob will be reviewing our topline data and market implications for advice follow.
Following Chris and Rob I'll provide some key program updates and then Lori will provide an overview of third fourth quarter financial performance.
And then following their prepared remarks as always we will hold a Q and a session. So with that I'm going to go and hand, the call over to Chris.
Thanks, Tom and good afternoon, everyone. Today I'm pleased to take you through the topline data from the advise trial a phase to be placebo controlled dose finding trial to assess the safety and efficacy of a TRASM odd in patients with moderate to severe atopic dermatitis.
And advise we enrolled 140 participants across the U.S., Canada and Australia.
The advocacy measures for this trial included the percent change in the eczema area and severity index or easy from baseline to week 12.
The proportion of participants achieving easy 75 from baseline to week 12.
The proportion of participants achieving the validated investigator global assessment or VI GA.
Zero or one and a reduction from baseline greater than equal to two at week 12, and the percentage change and people rights.
Inclusion criteria for the study were as follows.
Male and female participants between the ages of 18 and 70 years of age.
Baseline a topic dermatitis scores of easy greater than equal to 16, I G. a grid any go to three and body surface area or B.S.A. involvement of greater than or equal to 10%.
[noise] patients were screened over a four week period, and then randomized in a one to one to one fashion.
Between placebo, one milligram or trials Mod and two milligrams of Etrasimod.
A four week screening was followed by 12 week double blind treatment period.
After completing the 12 week period study drug was discontinued for a four week safety follow up.
All participants completing the four week follow up period were eligible to enter a 52 week open label extension evaluating two milligrams of Etrasimod followed by the final four week safety follow up.
The day to discuss today will only include advocacy through week 12.
And then safety through week 16.
We will now turn to demographics and baseline characteristics.
As you can see from this table the treatment arms were well balanced.
The overall population was more moderate than severe with 83% of participants having an I.G. score of three at baseline.
From a safety perspective, the TRASM audit was shown to be well tolerated with a strong safety profile.
Similar to that seen in previous studies with most of the adverse events classified as mild.
We monitor specific adverse events of special interest for AG size for the S. One p. receptor modulator or class and a TRASM bought in general.
As you can see from the data shown here there were no. He sighs of concern in the advise trial spin.
Specifically there were no cases of macular edema.
There was one case I'm just me end up supergroup as well as one case and the two milligram of Transmode group.
There are no eight years related to heart rates for cardiac conduction.
There are two participants with non disseminated herpes zoster or shingles and both of these were in the placebo group.
In terms of a size for the broader immune modulator classes. There were no reports of conjunctivitis acne.
Venous thromboembolic events and no opportunistic or serious infections.
Overall, the safety profile of Etrasimod was favorable and as expected and the advise trial.
And taking a look at the attracts about impact on heart rate, we observed a placebo corrected Maxwell mean heart rate change from baseline at two hours.
The one milligram group there was a decrease of 1.5 beats per minute and a decrease of 6.7 beats permitted in the two milligram group.
These single digit heart rate changes were not associated with any blood pressure changes for symptoms.
After the first dose the heart rate differences across the three groups came together very weak one and were near identical from weeks two through 12 similar to previous observations.
One participant in the two milligram of Trustmark group had a transient second degree Avi block type, one which was self limited and asymptomatic.
The participants went on to further trials about dosing without any cardiac changes or symptoms.
These events have been very rare in our clinical trials and have been clinically in significant.
As as well characterized lymphocyte reduction isn't expected and on target effect of Etrasimod.
Through this process that the trials about effects inflammatory disease and potentially provides clinical benefit.
And the advise study there was a maximal reduction in the peripheral lymphocyte count into two milligram group of 43.6% at week two which.
Which was consistent with our previous studies evaluating and TRASM odd.
Three weeks four and eight as noted in the yellow box. There was an unanticipated increase in others like count with a gradual reduction in lymphocytes from weeks eight to 12.
This unanticipated finding led to further analyses.
As previously mentioned lymphocyte reduction isn't expected on target effect of Etrasimod.
As per protocol study drug could be interrupted at the lymphocyte count decreased to see T. C. H E criteria grade four which is less than 200 lymphocytes per microliter.
During the study starting around a week for a small number of investigators with a cluster at a single site. This continue to study drug and nine participants because of lots of lymphocyte counts only meeting CTC AG criteria grade three.
As you would expect and consistent with the TRASM as mechanism of action. These nine affected participants were all receiving two milligrams of etrasimod, representing 19% of the total two milligram population.
Importantly, these participants evidenced no other clinical symptoms or adverse events that would have warranted stopping study drug.
Notably the study protocol did not specify started or just continuation for these levels of lymphocyte reduction.
These actions were taken by the investigator.
Investigators without how many awareness by arena study personnel because the company was blinded to lab values like lymphocytes that would indicate which patients were taking active drug.
As seen in the lower Red line, there was a rapid rebound and lymphocyte counts between weeks for an eight and this group of nine participants.
And the majority study drug was resumed by week eight with subsequent decreases in lymphocyte count between we between weeks eight and 12.
As will be discussed in subsequent slides. It is clear from reviewing the data from this group of participants that stopping the transmode led to a clinical rebound or worsening of atopic dermatitis and restarting etrasimod resulted in the resumption of clinical benefit.
[noise] study drug discontinuation was clearly unwarranted and in fact was directly counter to the kind of benefit that participants were receiving.
We plan to incorporate this important learning and apply it to the phase III program to avoid unnecessary study drug discontinuations.
Now, let's take a look at the efficacy results.
And the primary endpoint in the primary endpoint analysis of the percent change in easy from baseline to week 12. The overall response rate was 57.2% in the two milligram group, which was not statistically significant.
No in the smaller patient population there was a relatively high placebo rate.
In the analysis of the FDA regulatory endpoint of the proportion of participants achieving IBG success defined as I g., a zero or one with a greater than or equal to two point improvement from baseline.
29.8% of participants achieved good success versus 13% in the supergroup, which was a change of 16.8% and was statistically significant.
Hi, Jay success criteria is the more stringent and more conservative endpoint when compared to easy.
Even so even though the study was not powered Friday, a there was a significant difference.
And the analysis of the proportion of participants achieving at least a 75% reduction easy from baseline 38.3% of the two milligram of trials My group achieved easy 75 versus.
Versus 26.1% in the Pacific Group, which was not significant.
To understand the impact arbitrage about treatment overtime, we analyze the easy chance from baseline at each clinic visit through week 12.
Easy improved in all three groups through 12 weeks.
And the trials about two milligram group the easy improvement was statistically different from placebo at week four.
In this group between weeks four and six the treatment effect treatment effect plateaued with recovery of treatment effect from weeks eight to 12.
The trajectory of improvement did not return to the same level seen through week for.
This observation was similar to the Olympus I change as previously reviewed where there's an increase in lymphocyte count beginning at week four due to the 19% to participants that have treatment interruption in the two milligram group.
From a mechanistic standpoint this observation is important.
Because it shows that with treatment withdrawal advocacy is lost and with treatment renegotiation. There is there is a recovery of treatment effect.
Similarly, we analyzed Ida and easy 75 overtime.
For both of these assessments. It is notable that into two milligram group. There was a change in the trajectory of treatment effect between weeks foreign aid with recovery after a weekend.
And the two milligram group the different from placebo was significant for I.G.A. at the week 12 time point.
For easy 75, similar to percent change in easy overtime. The difference from placebo was significant at week four.
Notably we did not see a positive effect between weeks eight and 12.
From our experience and you see we have seen continued improvement in efficacy overtime in our completed trials.
Based on the trajectory of the response from weeks eight to 12, we would expect continued improvements in AG and easy.
And we will take this into a consideration in our phase three planning, which will likely be 16 week studies.
[noise] in a similar fashion looking at the price changes over time, there was an early and significant effect through week six with continued improvement through week 12.
[noise] [noise] further understand the impact of the treatment interruptions, we analyzed the key outcome variables and the two milligram TRASM by group that received complete therapeutic exposure, which was 38 participants.
For the percent change in easy overtime, there is clear and early separation into two milligram group versus placebo, which was significant at four weeks and continue to show separation out two week 12, which was also statistically significant.
[noise], we analyzed the proportion of participants achieving gay in easy 75 response at week 12, excluding those participants with dose interruption.
For RG, a there was a 23.8% improvement versus placebo, which was statistically significant.
Of note as you remember in the full analysis that previously presented there was a greater than two fold improvement in Nigeria.
At week 12 and win.
Analyzed for the group they had the full treatment exposure there was nearly three fold improvement in Nigeria at week 12.
For easy 75, there was a numeric 16 point improvement over baseline.
In a similar fashion looking at the price changes overtime, the TRASM by treatment group when compared to placebo was statistically significant from weeks two through eight.
I will now hand, it off to Rob to provide some commercial context, Rob over to you.
Thanks, very much Chris and good afternoon to everyone you should be seen a slide that is titled Cross trial comparisons are just a few comments to share on some of the different data that you may see from these phase two results I just to be clear. This is an indirect cross trial compare.
Chris in the select station studies and a topic dermatitis.
These studies have been conducted at different times, and then they have differing protocols as well but.
But in part it demonstrates the heterogeneity.
The study design and the baseline patient demographics across these studies. It's also notable that both the TRASM.
And I was sitting at studies were 12 weeks.
All of the other studies were 16 weeks of drug exposure for patients. In addition to that the Baricitinib study included topical corticosteroids.
What's particularly of note in this data is the trust my baseline Ita score, which clearly demonstrates that this is largely a moderate group of patients that becomes meaningful because moderate patients as a group in the U.S. represent roughly 65% of the moderate to severe total paid.
From an opportunity that's.
Thanks, Good advance to the next slide for me please.
So we'll look at one particular when you look at one particular endpoint atopic dermatitis competitive landscape.
Well you the endpoints that were choosing here the IDH zero why does it's a phase three primary endpoint and again just as a reminder tries a modern adversity reflects 12 weeks of exposure other agents have 16 weeks of exposure.
And that included topic of course, corticosteroids, Hello, understanding and appreciating that there always limitations of indirect comparison, we do note that attracts not demonstrated a statistically significant effect in advise.
And as you can see in the blue box that surrounded by the bars, we highlighted that effect size for a TRASM odd is in our opinion commercially attractive delta up 24%.
While indirect effect size for TRASM observed in the study demonstrates a result that is largely in line with other studied agent in phase two studies now I'd like to hand, the call back down it will provide a summary and key program updates.
Thanks, Rob.
As you've seen by the totality of the data and oral once daily PRASM I represent a novel therapeutic option for patients with moderate to severe atopic dermatitis.
The advise trial despite unnecessary interruptions in dosing of a subset of Transmode two milligram participants should a consistent in early effective treatment and very importantly, a TRASM unmet the idea of responded criteria the stringent FDA phase three primary endpoint.
Overall, the Transmode rep demonstrated rapid onset of action.
It was filled by patients the two milligram group achieving statistical significance, if you're right as easy and he 75 a week for.
And in the post how complete or analysis patients who received the full therapeutic exposure throughout the study achieved statistical significance in easy Big change from baseline at week 12, multiple time points and provide us further improvements on AG from baseline compared to see Bob.
Participants with dosing interruptions as Chris pointed out experienced disease recurrence, but recaptured response upon restatement of treatment.
Safety profile remains commensurate with previous trials.
And overall, the efficacy and safety profile, a potentially strong competitive profile and rationale to advance to a phase III program.
As you can see we're excited about the advise data and we'll be happy to address questions relative to the full dataset. During the question and answer session, but before we get there I'd like to walk you through key updates on other core programs.
Despite the COVID-19 pandemic arena continues to make strong progress on all fronts clinical operational and financial overview.
For the quarter, we reached several clinical development milestones across our programs.
Let's start with the Transmode Gi franchise in September we announced the first subject dosing the Olivier you see study.
You see 12 study the second of two pivotal trials within the elevator within the face we elevate ulcerative colitis program.
The other big you see 52 study remains on track to complete enrollment by the end of this year with the expected completion of the 52 week.
Treatment period by the end of Twentytwenty, one and top line data readout shortly thereafter.
You see 12 continues to make strong progress and we expect data in the same timeframe.
As you might expect we will continue to monitor the impact of the COVID-19, we surgeons on study enrollment for both you see 52 and you see.
For both of our studies and the other way you see program has been our plan to study a contemporary patient population and as such we chose not to pre specified limit the mix of patients in our protocol.
We continue to monitor the distribution of patients closely and we currently expect the patient distribution to be approximately 70% naive and 30% previously treated with advanced therapies.
Importantly by letting the patient mix evolve with contemporary treatment patterns, we maybe learning about were TRASM I might eventually be used in the marketplace.
In September we announced a new trial Gladiator you see to evaluate the TRASM on in a less severe patient population.
Elevate you see program.
Glad he gladiator you see is designed to enroll more moderate patients as defined by modified meals for four to six but.
But those revenue endoscopy score greater or equal to one as well as patients screen fail elevate you see.
Gladiator study addresses a broad unmet need for patients that are suboptimally controls or have failed conventional therapies that are resistant to the risk benefit profile of current biologics or JAK inhibitors.
Our TRASM all in TRASM, our dermatology franchise continues to advance in addition to the progress of the advise trial in September we announced our first patient dose in the phase two trial value TRASM and Alipay Shahriar ATA.
As a reminder, this is a phase two multi center randomized placebo controlled trial that will assess.
The safety and efficacy of once daily Cosmos, two milligrams in subjects with moderate to severe LP Sharia.
In all of these trials, we will continue to monitor for Discontinuations based on the lessons learned from the advise trial.
To date, we have not seen any similar type of issues and elevate 52 or 12.
Okay.
Moving onto a lower UNEV as a reminder, a learning curve as our investigational oral highly selective full agonist that it can have an i. type two receptor the potential people know visceral pain and a broad range of G.I. conditions.
Tobey, we announced that we have completed full enrollment in the cap to be trial evaluating three doses of a lower NAV for Domino pain in both ideas C and D.
We expect top line data for captivate to read out in mid Q1 2021.
I'm also pleased to announce that our cardiovascular franchise continues to progress ABT four we need our selective basis, we antagonism cardiaq mitral in development for treatment of acute heart failure reach completion of the phase one safety study.
PPD for me it was generally safe and well tolerated and we're in a phase two planning process.
We will also be unveiling a second clinical stage cardiovascular assets before the end of the year.
And finally at the end of October we announced the successful spin off of our neurology franchise with the exception of Longboard Pharmaceuticals, which we expect will unlock the value of these important programs.
I'd like to take this opportunity to congratulate Kevin Lin and wish him. The best of luck in leading this important endeavor.
Importantly arena shareholders will participate in the value of these assets renewed ownership in the entity as well as future royalty screens on the specific programs.
So with that I'll pass the call to Lori to review our financial results for the quarter Laurie. Thank you on it and good afternoon, everyone. I will provide a brief review of our third quarter 2020 financial result for more details regarding our results. Please refer to our earnings press release from earlier today and our 10-Q.
Revenues for the third quarter were $20000 compared to $1.4 million in the third quarter of 2019.
Research and development expenses for the third quarter totaled $79.8 million compared to $60.3 million in the same period in 2019.
This increase was primarily driven by advancement of our clinical trial programs as well as an increase in personnel expenses as we staff to support our program growth.
General and administrative expenses for the third quarter totaled $19 million compared to $20.4 million in the same period in 2019.
Net loss for the third quarter was $97.4 million compared to net loss of $72.9 million.
For the same period in the prior year.
Basic and diluted net loss per share for the third quarter was $1.69 cents compared to basic and diluted net loss per share of $1.46 cents for the same period in 2019.
And as of September Thirtyth, 2020, cash cash equivalents and marketable securities balance were approximately $1.2 billion compared to $1.3 billion at June Thirtyth 2020.
[noise] Arena continued to achieve clinical development and operational milestones, while reducing operating expenses through enhanced clinical trial efficiencies and focusing on optimizing our spend.
As a result, our guidance range for operating cash burn for the full year 2020 is expected to be $345 million to $355 million, which is down from our previous guidance of $400 million to $430 million.
That concludes concludes our prepared remarks, and now I'd like to open up the call for a brief question and answer session. Operator, Please open up the lines and we'll take our first question.
Sure, ladies and gentlemen to ask a question you will need to pass star one on your telephone. So we invite your questions asked about Oh gosh.
Our first question comes from the line of Jason Gerberry with Bank of America. Your line is now open.
Hi, Thank you for taking my questions. So I guess I wanted to follow up with my first question just the commentary around.
The.
Not not seeing I guess, the risk of dose modification in the U.S seat phase three you see trials.
Given it sounded like there wasn't a lot of visibility given the blinded nature of advice. So just curious what gives you guys.
Competent that there wouldn't be a risk of dose modification.
In the phase three you see trials and then.
How are you guys thinking about phase three eight topic term studies start time, you know would you think about commencing a phase three during over 19 surge would you wait for.
Situation to stabilize just sort of curious how you think about mitigating this risk in the phase three trial setting. Thanks.
Yes, Jason So just going back to our waste this would not have any discontinued discontinuations due to.
Great read live opinion, I'm going back to the the phase two study and looking forward into and so we know a lot about the gastroenterology community and and and how they think about it I think the real lesson. Here is there is a subset of dermatologist that are they require more education. There just in case, there are just more cautious and so the.
This we think this is much more of a dermatology specific thing that we're going to be mindful for as we go to phase three so let me ask Chris to lend them more color now that you got it I was just to say it.
In the elevate trial, we haven't seen any discontinuations relative simple premium and so we've kind of we've been looking about as we go again the issue here in these trials that were blinded to lymphocyte count obviously, because that was unblinded study to us and so we have to wait till these things show up in the electronic data capture record.
And so we are confident in the U C program, how things are moving so.
Get it really comes back to the different specialty Jason and how they are how do you how they view the specific types of agents and conservatism in general we've got a lot more extensive safety experience into gasoline logic in beauty, we haven't seen any any.
Any concerns from that side of the from that side of the fence.
In terms of starting a topic during its going to take us a while anyway.
To design, the study's work with external experts.
It'll be a global study and nationally will want to have a conversation with the various regulatory agencies. So well. We'll proceed along it's the most expeditious path we can.
And then we'll take a look at the external landscape and see if its prudent to start a study in that setting depending on where we are on the pandemic. So I.
I think we will continue our preparation and then we'll make that decision as we get to get close to initiating the trial.
Just if I kind of uncertainty externally.
Yes, if I can ask a follow up how do you try to mitigate this in the phase three setting is that all about a site selection to try to avoid.
Yeah, having investigators who might be more cautious and kind of why this sort of thing I imagine that you have to allow the physician have the discretion to dose modify in the phase three trial, just sort of curious how you navigate that.
Sure I think the first thing is when you're when you entering into these areas with a novel mechanism of action and if you looked at most drugs as they entered novel immuno agent dermatology setting.
There's a there's a finite subset of investigators who will engage and.
We will have a broader access to more experienced clinical trial sites as we go to phase III for sure. The other the burden on US is really on the education side on the mechanism of action and we'll be paying particular attention to that as we go into phase three.
One other comment is just focusing on safety, we had established I think in this trial.
And dermatology dermatologic patients that the profile continues to be very consistent across all of our experiences a relative to the safety piece and Thats really critical and then just continued educate.
Dermatologists around the Olympia and how that plays into efficacy. While also being safe you can you know one of the things that's really interesting years, even with grade three and even grade four we're not seeing the.
Here is an opportunistic infections that you see with other oral agents and just being able to communicate that that we're maintaining immune surveillance, even though we're reducing T lymphocytes will be an important part of the education as we move to phase three.
Got it thank you.
Yes, thanks, Jason.
And our next question comes from the line of Olivia Young with Kantar. Your line is now open.
Hey, guys. Thanks for taking my questions and thanks for all the details today, maybe two from me one I think I might answer, but I. Just wonder is there any kind of additional sensitivity with their arms just in light of being in a kind of an environment and and lowering lymphocytes or is this kind of their default position and then can you talk a little bit about in the management of the VI Jay versus the 80 75.
You know being able to achieve the measure in one endpoint versus the other and just kind of how to think about those endpoints and the differentials into thanks.
Yes, let me take the first one though and the second one off when the inputs to Chris.
You know it is difficult to tell whether whether it was covered sensitivity or not covered sensitivity and we just don't have that line of sight as Chris mentioned it was a cluster of patients in a single clinical site that had the most of the effect here. So it is there is definitely additional says to the other side of the dermatologist and.
We'll just have to spend more time make sure that we're getting the more experienced clinical sites and doing a good job on the on the front end education.
Here with these with these clinical sites have Christy, we'll take the AG versus easy sure.
Yes, I think one of the key observations here is that there was a high placebo rate on the easy side, but not an idea.
It's not entirely surprising kind of on a couple of levels. One is that the placebo rate him and easy tends to be higher in modern HD and we had a fairly high moderate population in this particular study.
And that the other observation is that the placebo rate in easy in particular has been higher in phase two studies. When you have a novel I'm away, so kind of two things going on there, but again not high on the AG side.
That's also not surprising I G is more conservative more stringent and importantly, as the FDA regular regulatory endpoints and so it is going to be the gay treat.
Treatment effect.
Which is going to be driving our design and sample size calculations and so feel good about what happened on the AG side.
Lastly, as we answer your questions.
Yeah that was that was very helpful. Thank you great.
Great. Thank you really appreciate it.
And our next question comes from the line of Martine Oster with Credit Suisse. Your line is now open.
Yes, hi, everyone. It's it's Thomas on for Marty Thanks for taking the questions I guess, a two on a topic there from here.
Maybe first the knee is 19% of patients who had dosing interruptions can you clarify how those patients were hand to handle them. The full primary statistical analysis was that kind of a last observation carried forward or was there. Some other handling there and I'm I'm curious if you can contextualize kind of this this fast.
Sort of action.
It's on some key endpoints start Sega at week four can you put that in context kind of relevant relative to other agents in AG and how meaningful that might be clinically. Thanks.
Sure, Let me have Chris take the first part of that which is the.
The statistical for the full analysis.
On the phone also set those nine participants are 19%, we're not handled any differently than any any other subject in the trial. So we had two different analysis met.
Methodologies that we applied across the trial, whether was amputation or or not and.
And so they weren't handle any difference was only only subjects that were missing say that week 12 data and that didn't that was not dependent on whether they missed any doses or not so they are handled exactly the same as the rest of the population.
Then the second part of your question Thomas on the fast onset of action.
I think the real key here is that fast onset of action combined with the safety profile.
I'll ask Rob Mickey to provide some commentary on what we know about the marketplace and how those things we think are going to be important competitively Rob.
Thanks dominant hi, Marty the.
Certainly physicians want drugs that work as quickly as possible for these patients, but it is a chronic illness. So the long term profile of an agent is really important. So one of those components is going to be efficacy, but the two others will be long term exposure and any safety disadvantages that in Asia agent they potential.
They provide and the second is the relative ease of use of the age and.
Injection therapy is challenging for patients jacks are likely to have the current monitoring in AG. So when you think of the totality of those three attributes or efficacy safety and ease of use tourism out has we think a really attractive profile I specifically to your question.
See most of these studies start to separate by two weeks. So you do see statistical significance for some of the key endpoints.
Some studies that measure edge as soon as two days.
I think that in an acute situation, that's probably a valuable endpoint to have I think a little bit less so in a chronic situation or chronic administration for patients.
So that was my question on both thank you yeah. Thanks sure. Thanks, Tom.
And our next question comes from the line of Kennen Mackay with RBC capital. Your line is now open.
Hi, Thanks for taking the question.
Wondering if theres anything in terms of 60.
Your safety profile, but we couldn't derived from the one milligram.
Right.
Uh huh.
Group revenue.
On therapy across the entirety of the study just again thinking about back with.
What stands out most of you on the team about the yep.
Yep.
Profile. Thanks.
Yes, I think what's interesting about the one milligram, especially as we look at the complete our analysis of patients who received a full full threshold in terms of two milligram is that we see a nice dose response to a question on two looks better than one across most of those metrics.
So the interrupted patients on to.
Makes the curves look a little bit screen, but we do believe that too is better than one in.
Incursion for us.
Two was was sufficiently safe and it really does beg the question whether.
We pushed to two and three in the next stage of our of our evaluation so well.
Well, one looks interesting there.
There may be a one for one in terms of chronic therapy. It at some future point in time in terms of these these 12 16, we conduction trials, we'd be looking for a two and potentially even thinking about three and again.
We'll have data this year in patients in chrome setting from the three milligram, which allow us to just a little bit more informed about where we can go with that.
Now version.
The final point I'd bring up is both on two and three milligram as you know we have the transmode see our profile.
So we'll be exploring those this year too so it gives us lots of options to think about optimizing dose.
For these patients over over a longer period of time.
Got it thank you.
Yes. Thanks.
[laughter].
And our next question comes from the line of Jessica Fye with JP Morgan. Your line is now open.
Hey, guys. Thanks for taking my question I'm sure they're going to try to include more ita for plus patients in the phase three.
Yes, so it's possible it could talk about how the admittedly small subgroup of more severe patients did in this trial relative to let's see though obviously.
Sure I'll take the first part of course to answer the second one.
The idea for patients.
You know we we in the phase three program will be looking for a little bit or stratification and understanding a little bit more about the AG three and four.
One thing we are encouraged with is is to see this type of idea response.
And moderate patients.
Is actually quite substantial and if.
If you look at the ideas scores across all the competitive programs and the magnitude of effect. It's all been in more severe patients were more severe patient group did not so the monitor patient population is is the more substantial numerical patient opportunity and being able to demonstrate that that change is important.
So will we have to balance that with the more severe or more serious patients. We know that the JAK inhibitors from our market research will be really reserved for for later in the duration of the disease or severe disease. We know that dupi is predominantly used in more severe patients who really need that moderate patient population.
Billable for in terms of market opportunity. So what's the balance those two things out what type of a subset of the idea for [noise].
But not a lot to say there yet I mean, we just have the topline data and certainly we're going to be looking at various subsets of patient populations and doing some sensitivity analysis to tease that out a little bit the AG fours will be somewhat limited in terms of the conclusive. This of those analyses just because we had a relatively small number of patients in that in those groups.
Okay. Thank you.
Thanks, Jess appreciate it.
And our next question comes from the line of Jason Butler with JMP Securities. Your line is now open.
Great. Thanks for taking the questions.
First one just on placebo rate I think you mentioned before the.
Higher placebo effects for.
Actions in phase two trials why is that and how do you think about managing placebo effect in a phase three study and then for the sites, where you had the dose interruptions was was there any other notable.
Findings from from the data those sites for example, the you know in the placebo arm and just to clarify where the placebo patients and and other data for the one milligram or from.
From those sites included into the complete or analysis. Thanks.
So I think three questions there if I if I got it right. So.
In terms of thinking through placebo rates for the phase three trial and why why are they higher.
And studies, where you have a novel mechanism.
So we don't really know the answer so just a conjecture would be that when you have a novel mechanism of action.
In a particular disease and then Harry tougher dermatitis in general the types of investigators that participate in those studies may be fundamentally different than the types of investors that participate in the larger studies. Once you already have an efficacy signal and so it may be that those sites that participate early aren't as experience in clinical trials and may not be able to.
Consistently perform some of these more detailed measurements and easy as a much more detailed.
Kind of intensive.
From a from a from an experience perspective measurement and so we see and lots of studies and phase two trials, where you have a novel mechanism thats, a placebo rates, particularly related to easier higher.
Not really concerned about that because again, we are going to be focusing on AG is our main.
And point, that's going to be critical and the phase three trial. So you will have to work through that we do think that site distribution from an experience standpoint will be different antibodies are trial relative to phase two.
Your last question had to do with how we analyzed.
Placebo at the sites, where there was studied discontinuation if I got that right now.
And we just we just have to analyze them like every other we didnt there was nothing else on the data that that was particularly of concern at those sites again, there was one site, where there is a cluster of drug interruptions and the rest were scattered across a couple of others and so there's nothing else in the data that let us to concern I mean did not exclude other patients from those sites from the.
Analysis.
Okay, great. Thanks for taking my questions.
Thanks.
And our next question comes from the line of patents and they have it's again high your line is now open.
Hey, guys. Thank you for taking my questions two for me.
You got to be.
Lymphocyte count reduction I think it was about 40, 45% in the study can you remind us what you saw in ways, you're going to be healthy volunteer studies that youve done any reason for a for a different here.
Then I have a follow no no no.
Looks just like Oasis really not much different.
Okay, and then with regard to the phase three I think you're saying it will be a 16 week study can you maybe point us to date that keeps you bet I'm sort of conviction to capture additional efficacy at week 16, and the reason I ask is that because if you look at the beta and I'm just focusing on be complete.
Across all end point it doesn't seem like there is a separation of getting a continued separation you know that some endpoints that hits that sets have been 10 point time point, but.
No significant that's why that's the case I wonder the data that gives you confidence on the 16 week, it's going to be better.
Yes, I'll answer that with so.
Our response can talk about specific.
The.
As we've seen the attraction Mad phase to an open label patients continue to improve over time.
And you continue to see effect and one of the challenges and is this complete responses because we.
The sample size gets smaller it's difficult to interpret but we do see continued response continued improvement in response.
Inpatient from the Oasis work in the open label. So there's no reason to think it would be otherwise.
In this patient population.
Yeah, I think that's exactly right and we did obviously, it's a it's a brief presentation had been in show you all of the grass, but.
But if you if you go back and review the graphs, particularly looking at I.G. response in the full analysis that there continue to be separation of gay from placebo in that group, even though oh.
20% of the paper patient population.
Had an inadequate therapeutic exposure and so from our experience with the TRASM on.
From a waste as in particular, we know that there continues to be.
Therapeutic benefit derived overtime and so we'll have a lot to do some modeling to look at the week 16, but we believe this in our previous experience and from the data that we see here that it is likely that you would see continue separation of the curves, particularly related to things like AIG, Jay, but also easy and that the overall Truman effect would be significantly higher.
At week 16, the other piece, that's going to come into play in our planning, which were not at liberty to discuss yet because the data.
Aren't cleaned and lock is that we will have open label extension data in this trial going out to be to be we'll be able to look at that data to get a sense of what happens with continue to TRASM got exposure. Obviously its open label slots to take that caveat into account as we plan, but there will be.
Against long term exposure data that will help us in our planning for.
Phase three.
Rob anything to add from the commercial side in terms of 12 versus 16.
I think two things the first if you look at the slope of the curves to Chris is point you see what appears to be improving separation between the two and the placebo Secondly, I think probably more importantly is when you look at the phase three programs across studies. They are 16 week studies. So it would provide a fair comparison.
Two other read outs for other agents that are either in market or in development.
Hi, Thank you go ahead.
Yes, Thanks, just an accretion.
And our next question comes from the line Shell BT with Citi. Your line is now open.
Hi, Thanks for taking the questions. The first one is for phase three would enrolling a somewhat larger percentage of more severe patients be something that might have the potential to.
Sure larger Jeff between treatment and placebo and then second question is with this data in hand, they have today, what's the outlook for expanding the study of a trust nod to other dermatitis indications.
Yes, so Joe I think on the your first question. The answer is absolutely, we'll we'll be looking at modeling that out and looking at that mix of patients and you.
It's a little early for us or thinking about other dermatitis indications I think we need to fully digest. This begin to and our phase three program here, but we will be looking.
Toward our ERP data and we'll be in Rio we study, which we continue to hope to start this year cobot dependent and ER and then over time as those data readout become a more robust and as Chris mentioned, we see more of the open label data.
We'll start thinking about other areas that overlap with these conditions, we we tend not to jump from dermatitis, the German dermatitis.
I think we.
We tend to try to follow the biology, we mentioned the bi directionality you see to eight topic derm, we know each topic Derbio you have bi directionality to.
Other conditions and Thats sort of how we'll approach it but you know as as.
The data is fairly fresh and we've got work to do to get phase three ready that's going to be our near term priority.
Great. Thank you.
Hey, Joel.
And our next question comes from the line of Joseph Schwartz as need be Leerink. Your line is now open.
Hi, Thanks very much.
Was wondering if you could talk about the reasons for the relatively moderate patients being enrolled in advise and whether you're confident that you can control that in phase three for a D.
Yes, Joe what one of the things.
That that happens, though is that the.
The number of sites that are open to new mechanisms actions.
Going into the first time, a relatively limited.
Those paid those sites tend to have more moderate patients there's more comfort with patients who are less but in general.
So now that we've got a strong safety database, we've shown evidence of so thats to see them effectively part of the study we think we'll be able to address a broader set of clinical sites more experienced sites sites that have both moderate and severe patients. The larger practices again to Chris' point, who are also more experience on the site. So.
We think it's a step in the right direction.
The clinical signal it is a.
Clearly provocative from our point of view and warrants moving forward and that was consistent with the conversations we had with yeah. The experts we spoke to so this.
This will all be a matter of just being able to get out and educate folks on the m. away. The safety profile, which we were incredibly encouraged with and we think that will give us access to a much broader range of sites and more experienced investigators.
Yeah, I mean, if I can just ask one quick comment to that the.
The opinion is supported by what you see in the phase two versus the phase III studies. If you look at the phase two studies across a D. You see this as I mentioned a lot of heterogeneity, but you also see in some cases lower rates of force Hooper for example, and there.
The other phase two study for their high dose arm, 26% of patients weren't getting four cents higher than the number we sought to trust them out, but again, it's not a significantly higher.
That's interesting Okay, and then what work will you be doing to determine the best dose or doses to take forward. What information do you have that you can.
Analyze and make that decision.
Sure. Let me start and then Joe have have Chris comment further, but we know the two milligram is active here. It was active in the you see study we know the corresponding what do you think this really interesting here is to look at the trend could the dynamics of the lymphocytes, both the dropped to four.
Recovery with the nine patients who were had the interruption and then again a.
The resumption of the slight decline.
And then watch to see clinical response actually mirrors that right. So so we usually have a really nice PD marker with the lymphocyte count dropping really look the shapes look very quite identical so.
So that gives us reason to understand the two milligrams is active we saw that exact same phenomena you see study we're seeing the exact same phenomenon.
So whether we push up in dose the three milligrams.
That's something that we'll have to discuss as I mentioned, where we're thinking about it we already began thinking about this week, whether we had a push the dose little bit. These are in general healthier patients that you see for example in Crohns and and we think our three milligram. We have a we have a broad therapeutic index with this compound.
There might be something worthwhile looking at it so well keep you guys updated we have a lot of work to do on the but two is definitely Laura we think is our sweet spot.
Yeah, the only thing to add into that is that because it's a relatively small phase two study we do have intensive.
Pharmacokinetic data to look at so that's going to take a little bit of time, but we'll look at that PK data relative to lymphocytes relative to clinical efficacy relative to other biomarkers and it's that totality of data that we'll use to think through dosing.
Okay, and then if I could just ask a housekeeping question how likely is it do you think that elevate you see.
52 in Htwo and it might slip early 22.
I'm, sorry would flipped literally 22, Joe that was your question.
I like your press release, you you noted that the data collection would be and Lake 21.
I just didn't know if the if the data itself.
If we should expect it to be reported.
21 as well.
Yes, we haven't completed enrollment in you see 52, we think it will be by the end of the year. Some of that is covered dependent but we do think it will be by the end of the year. Then you go to 52 weeks of treatment that takes us to the end of next year.
So we'll have data shortly thereafter, it's really hard to tell right. Now is as you know that the end of the study when you begin to close screening you get up you get a bolus of patients in the speed of those those patients.
Ongoing pandemic and then we got the second wave of pandemic in Europe for example, and in here in the U.S. those might always things that impact that were watching that carefully right. Now we will complete enrollment before the end of the year and I can't tell you. It's November December when when that's going to be.
And and then it'll take 52 weeks, which would push the data read into early 22 and that will just have to watch that over the next month or two.
Makes sense thanks for the color.
Yes, Thanks, Joe appreciate it.
And our next question comes from the line of Jim Birchenough with Wells Fargo. Your line is now open.
Hey, guys. Thanks for taking the question for all the detail I just a couple from me I guess, one I might have missed it but in the patients that didnt discontinue the 81% at the two milligram dose that Didnt just continue what with their easy 75 improvement versus placebo and I guess the second part is how do you benchmark that again.
For a more moderate population or things will get JAK inhibitors.
Yes so.
Let me, let me just pull up that slide here to make sure I've got to be incorrect site. The the.
But just as one comment it's not that they discontinued there was dose interruption.
Right just to make that clarification, and then glad I'm 70, 75, we saw about a 16 delta.
Which Rob do you want to put that in some commercial context of competitive product.
Yes, so that would be a delta that is in the range of.
There are setting up.
On the easy 75 Delta so it's a little bit tough with Baricitinib because their study included topical corticosteroids, but if you look at those that didnt roughly in that same range. If you look at the I.G. a score.
It's in the range of low dose jacks the delta.
It's pretty much on top electric isn't that a eye on 13, and it's slightly little bit south of to tell you. Matt. So the idea was that a really strong read through.
In the easy 75 Delta is in the neighborhood of Ah Theres enough.
And then just on the Pharmaco dynamic dynamic effects are I can't remember if you took biopsies or if you could look at this in in the blood, but you know th one th th 17, cytokine responses and do you have any sense of either you know how the patient population.
Hughes between Th one th two until 17 and would you expect to collect some data on how you impacted though the different cytokines.
Yes, we do have Oh.
A lot of that type of data it'll be a while before we can analyze and share that with you, but we will do that over time again. This is topline data almost real time so are we.
We will definitely take a look that we're we're as curious as you are.
And just maybe just one final question just I recognize that a great 180 block in a single patient isn't a big deal, but just to contextualize that with what we've seen for most animate maybe just for proper context.
Yes, so Christian.
Yes. So you know we continue to observe very low rates of any cardiac issues relative to other restaurant P. modulators and the class plus upon a lot on ozanimod and we have nearly 1000 patient exposures and have seen a very low rates of cardiac conduction issues. In fact, it's actually lower than what you see in epidemiologic studies of healthy volunteer.
Sure so feel very good about the cardiac safety profile and again remember we have no titration closed on about double digit heart rate should be placebo adjusted out the date eight.
We're talking about placebo adjusted in that in that six beach range with no titration, we think thats substantially different also recall that goes on them on had multiple cases signed we trim going back to their phase one studies and again, we haven't seen any evidence of anything remotely that severe.
Great. Thanks for taking the questions.
Thank you [noise].
And our next question comes from the line of Alan Carr with Needham and company. Your line is now open.
Hi, This is Jerry on for Alan Thanks for taking our questions just a quick one can.
Can you disclose how many patients.
Entered the to make an open label extension. Thanks.
We haven't disclosed that and I'm not sure the data's been clean at this point so as soon as we have stayed on the open label will share with you again. This was designed to be top line on the.
The first 12 weeks that seem to 16 rigs to safety, but I soon.
Soon as we see the data and we can digest it and we'll be happy to look forward to sharing that with you.
Great. Thanks.
Thank you John.
And our last question comes from the line of Patrick Tequila with H.C. Wainwright. Your line is now open.
Thanks. Good afternoon, just a few follow ups from me in just the first one is is there a possibility of an increased level of ongoing monitoring by Derms post the potential approval and how should we think about that possibility from either a regulatory or clinical perspective compared to some of these other novel comp.
Sounds like the JAK inhibitors, and then secondly, you know.
How could this the advise data demonstrating the quick rebound on lymphocytes upon dose interruption, how can that factor into the phase three program and the potential label for troughs Mountain view in a deal if it's approved.
Yes, So just give me a bit of context, Rob can you talk about any tentative label profiles as it really monitoring ongoing monitoring early monitoring chest X rays and all of that.
Yeah, and I'm happy to do that so the so we'll talk about the Jack specifically so all of the Jackson I know everyone knows this have box carry box warnings for a month.
Malignancy opportunistic serious infections, TB and Z Keaton.
But they also carry a monitoring that can be rather onerous, particularly for a dermatologist when bulk will be disappointed as an example, all patients have to have baseline labs, which is normal and typical for any of these treatments in any of these patients but by labeled a recommended to test those patients every 12 weeks for.
Opinion, neutropenia hemoglobin changes or changes to lsts in changes to let this as well. So you can imagine that creates a lot of work that off as tracking down those patients. If you look at the S. One piece that are approved different category right and M.S. baseline labs are normal and required for all of those patients.
But there is no recommendation for ongoing monitoring for S. One piece, we think thats going to be an important difference in the market. We think that makes the molecule more attractive to physicians and to patients as well and.
And it's something that would be advantageous relative to a JAK inhibitor.
It's Robin I'll, just add brought hematologic changes, which are directly corresponding to serious opportunistic infections, that's just not going to see.
The TRASM Oddness, one p. modulation.
Decreases in lymphocytes or an on target activity, but they don't correspond to severe opportunistic infections. There's no.
Real pressing need to monitor it on an ongoing basis.
Clinical program you do that we do that in the Gi space and of course, we don't see the Discontinuations, we don't see the.
This comfort there because we're not seeing the infections and now that we have this data now that we can confidently speak to clinical trial sites about the fact that the drug is safe effective.
We think we think that will go a long way toward building the phase three program and making sure we have a strong comparative label.
Yeah. The other one I forgot to mention on but I apologize is herpes zoster you heard Chris mentioned that there were two cases in the placebo arm one of the challenges that the jacks have particularly in these 80 studies is high imbalances high rates of herpes zoster, sometimes five to 10 fold higher which can be disseminated.
It is quite challenging for patients and for physicians as well, so not seeing that and albeit a small phase two study is encouraging.
That's helpful. Thank you very much.
And there are no further questions I will now turn the call back over to Kevin Glenshee for closing remarks.
Great. Thank you.
I want to start by thanking our team internally for the tremendous effort.
Across the entire pipeline this quarter.
And our and the tremendous commitment while we all work remotely and work from home.
And deal with lots of external environment related issues I just want to take this opportunity to think the investigators advise trial the patients.
All the people involved in executing this program we learned a lot through this program. We are incredibly excited to move to phase three and with what we said details of our future plans with you on upcoming calls so thank you again everybody in the states.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating you may now disconnect.
[music].