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spk_0: i know your shit
spk_1: greedy greedy and than welcome to ramada therapeutics fourth quarter and four year twenty twenty two earnings conference call at the time all participants run alison only mode a question and answer session will fall the formal presentation defending what your car operator assistance during the conference please press charges on your telephone keypad as a reminder this conference is being recorded
spk_2: i would now like determine the carpets over to your host
spk_3: he is me mister kim mccarthy thank you may begin
spk_4: thank you operator and thank you all for joining us afternoon with me on today's car chief executive officer sergio to versa chief medical officer doctor cedric a gorman and chief financial officer magazine outta this afternoon ramada issued a news release providing a business update announcing finance results with three and twelve months ended december thirty first twenty twenty two please note that certain information discussed on the call today is covered under the safe harbors provision of a private security location reformat because some listeners that during this call reminds management team will be making for looking statements as results could differ materially from those dated or implied by this for the statements to the risks and uncertainties associated with the company's business is for looking statements are qualified by the cautionary statements contained in ramada's press release issued today and in the companies as to see filings putting the and report on form ten guy but the year and it's cemetery first twenty twenty one and subsequent balance skanska also contains time sensitive information that is accurate only as a the date of this live broadcast march twenty third two thousand twenty three ramada undertakes no obligation to revise or update any for looking statements to reflect events or circumstances after the date of this conference call now that i turn the call resurgence sergio
spk_5: thank your name is always and good up the known to everyone athletes to welcome you to their i'm not a fourth quarter and fully at twenty twenty two conference call we're coming off from a challenging twenty twenty two but we have learned a great deal from our completed studies and believe that these learnings better enable us to realize the potential arrest and seventeen for the treatment of mvp following the availability of top line results for read and seventeen he really has one or study real your one in december twenty twenty two we have spent the last three months analyzing these data and considering the appropriate next steps is a reminder rely as one or studied three zero one and realized too or a study three zero to had to say three sister to arm but vivo control be with us studies evaluating wealth and seventeen at twenty five milligrams isn't a junkie prevent or mbd thirty be a to is ongoing we are confident that we have you then be the key issues that led to the face every day they studied three or one refrain from the positive results seen and paste you as such we tend to focus on read than seventeen isn't a junkie treatment based on the data generated to date and market potential and will initiate one you trials studied three zero for and implement really go creepy guy changes to the ongoing study three zero two i was thirty three oh two protocol amendment as been finalized and is ready to be implemented immediately and our new study three or four process of has been drafted and would be rated to he said by mid twenty twenty three i would like to emphasize that broadly we ever learn that the two most important drivers for a successful depression trial on recruiting the appropriate patients with them dd and controlling the placebo response it is propose that around ten seventeen i like conventional all anti depressant excess it's anti depressant effect by inhibiting and correcting the consequences of i practice with them an edge exactly it does not affect moved by out three neurotransmitter levels and it is thought not to have a boutique effect in the absence of underlying empty the battle physiology namely good them an edge is fucked this suggests that a dried would therefore have no effect in this situation is depressed or in those without it through diagnoses of major depressive disorder the epic us a signal or read them seventeen in a clinical trial would therefore be expected to be reduced directly proportional to the percentage of inappropriate subject and role in detroit you will see from the day that we're going to share with you today the impact that creek a trial subject quality head on bad outcome you a today's called cedric our new chief medical officer will provide the key details or our analysis of studied the one that generated many valuable insight which is where's our future blame wrote and seventeen teeth cleaning up problem he was buried you the changes were making to study three or two and we also be implementing in our study new study three or four point seven comment magazine without a chief financial officer with a view of our financial results and balance sheet but i will say that we are sufficiently funded to fully execute our plan to reach day that he doubts for both phase three trials we will then take your question and that i will now turn to call over to cedric seven sages all yours thank you so you and first flight please to begin you will recall that in study three or one rally ten seventeen did not meet statistical significance on the primary endpoint treatment with well ten seventeen did result in a fifteen point one points change from baseline on the mattress total score or placebo treated patients variants of an improvement of twelve point nine points representing a high placebo response it is widely accepted by experts that it's the placebo change on the madras total score exceeds about ten points you have failed to adequately control placebo response despite this hyper siebel response the placebo just a doubt to favorite well ten seventeen and was two point three points a clinically meaningful difference met analysis showed that the average drug placebo difference that has resulted in the approval of oral anti depressants over the past decades has been approximately two points next flight please we did see and study three or one that a statistically significantly greater proportion of patients treated with ral ten seventeen experience therapeutic response defined as a fifty percent or more improvement in the mattress total score from baseline at day twenty eight forty percent with row well ten seventeen treatment first twenty seven percent for placebo with a p value and zero point zero four for next slide please now let's take a look at the per protocol analysis of studied three or one it is important to note that this was a pre specified analysis per protocol refers to the population of patients who were treated today twenty eight and who did not have any major protocol deviations this priests specified analysis only resulted in the exclusion of twenty nine patients and demonstrated a three point one siebel it's just a difference in favor of route and seventeen at a twenty eight with a p value of zero point zero five one approaching statistical significance the total and in this pre specified analysis was a robust one hundred ninety eight patients first as the two hundred and twenty seven patients in the intend to treat primary analysis from the primary and priests specified analyses including response rates and per protocol said we believe the signal for efficacy with route and seventeen is clear and robust and that the continued development of route and seventeen for the treatment of major depressive disorder is warranted and justified after obtaining the phone data third and final study reports for study three or one we further analyzed the results in a post hoc manner to see what insights we could leverage to help us as we continue to develop route and seventeen we believe the following learnings will be a substantial driving force to optimize the likelihood of success for route and seventeen
spk_6: next flight place
spk_5: as previously communicated to of our highest and rolling sites were particularly impacted by paradoxical days and placebo response when we excluded data from these two sides the population was reduced by only approximately forty subjects and we saw a four point one point placebo just a difference at a twenty eight on the mattress total score favoring route and seventeen with a p value of zero point zero one nine next flight please we also found striking results when evaluating data from subjects coming into the study from different sources of referral which for the purposes of this analysis be divided into verifiable vs on verifiable sources of recruitment verifiably source patients were defined as patients who were known to the size such as a current patient patients found within the site database and referrals coming directly from healthcare professionals verifiably source subjects were those engaged to radio and tv ads social media internet searches and recruitment companies the prior studies had relied on self reported medical history from the subjects regardless of the source of recruitment being verified or unverified as a result we people yeah that subjects recruited true unverifiable sources were not adequately vetted by the use of medical or pharmacy records to confirm the accuracy up their mvp diagnosis moving forward for our trials medical and pharmacy records are mandated regardless of source of recruitment
spk_6: next slide please
spk_5: here we present the change from baseline on the map with total score when assessing patients on verifiable sources first as non verifiable sources we observe that verifiably source patients had a change from baseline of seventeen point two points on the madras ten total score day twenty eight first is eleven point eight points for placebo this amounts to a five point five point difference versus placebo with a p value zero point zero one six again this is a post hoc analysis but from these days it it is clear to us
spk_7: that in clinically depressed patients from verifiable sources of recruitment route and seventeen has a strong signal of efficacy next flight please
spk_5: it is also clear to us that the coven nineteen pandemic had a negative impact on trial results this has been seen by other researchers in the empty space we believe that it during the pandemic many patients had situational depression most likely related to isolation another pandemic related issues when we cut the data using april first twenty twenty two when called it's restrictions were largely listed as the demarcation point we saw a placebo adjusted difference or four point one points favoring route and seventeen on the day twenty eight madras score for the post pandemic
spk_8: subgroup
spk_6: next slide please
spk_5: finally we consulted with various internal and external stakeholders for additional perspective these experts concluded that site visits and study three or one for too long and duration with too many assessments thriving up placebo response the stakeholders also agreed that the highest and rolling sites with hyper siebel response for overrepresented in the final dataset additionally there were elements of the screening eligibility oversight that put have been improved to be more centralized rather than outsourced
spk_6: next flight please
spk_5: based on these critical learnings and analysis we intend to implement changes to our clinical programs going forward with a protocol amendment for the ongoing study and study conduct changes these changes will allow us to more accurately identify and in rotations with a verified diagnosis of them d d and will allow us to screen failed subjects with transients are situational depressive symptoms we will only and rotations from verifiable sources more specifically we will require medical and pharmacy records from perspective subject to verify depression diagnosis an antidepressant treatment history as previously mentioned in the past we have relied solely on patients self report in these regards in addition we will be making site selection improvements we now have a wealth of data on site performance from our recent trials and input from i thought leaders that will be drawn upon to select better quality sites going forward moreover we intend to limit the number of patients per perseid so no single size can have a disproportionate effect of study items we also plan to make changes to the protocol to reduce the duration of site visits and assessments previously there were too many assessments and procedures that resulted in lengthy and burdensome site visits between extensive safety evaluations and secondary assessments the so thirty visits last very long by this is great in the sense that we now have an abundance of safety valuations which looked very good for route and seventeen in comparison to placebo is hindered subject and site recruitment and heard signal detection we will also be dramatically simplifying are protocols going forward again with the go goal of reducing expectation bias to see where response and enhancing signal detection we also know that a simplified study design improve patient recruitment again just to reiterate the positive for completed studies provide us with very important controlled safety data which looks very good with ten seventeen with route and seventy and exposure and that is not insignificant data when it comes to filing or engage in the ongoing study through your to we are planning to enroll approximately three hundred patients and currently expect that trials complete and first half of twenty to twenty four currently we have enrolled one third are approximately one hundred a
spk_9: and into this study
spk_5: we also intend to initiate a new study three or four in made twenty twenty three also with a plan to moment of approximately three hundred patients with completion anticipated and the second half of twenty twenty four are open label one year safety studies on scheduled for completion and data released in may age twenty twenty three with that i will now turn the call over to maggot for a review of the financials
spk_10: thank you set it
spk_7: they were issued a press release announcing our business and financial results
spk_10: the three and twelve months ended december thirty one twenty twenty two which i will now review
spk_7: for the fourth quarter ended december thirty one twenty twenty two total research and development expense was approximately twenty six point nine million dollars compared to twenty five point three million dollars for the comparable period of twenty twenty one the increase was primarily related to an increase in stock based compensation this now on cash charge total two point two million dollars and most recently completed fourth quarter
spk_11: total general and administrative expenses for the fourth quarter ended december thirty one twenty twenty two with approximately eleven point eight million dollars as compared to eight point nine million dollars for the comparable period of twenty twenty one an increase of approximately two point nine million dollars increases primarily good
spk_7: riven by an increase in stock based compensation this non cash charge total of nine point four million dollars in the most recently completed fourth quarter
spk_10: for the fourth quarter ended december thirty one twenty twenty two the net loss was thirty seven point nine million dollars or one dollar twenty eight cents for basic infrastructure compared with a net loss of thirty four point four million dollars or one dollar and eighty cents for basic and diluted share in the comparable period of twenty twenty one
spk_7: going to the results for the for your december thirty one twenty twenty two total research and development expense was approximately one hundred and thirteen point three million dollars as compared to ninety point six million dollars for the comparable period and twenty twenty one
spk_10: the increase was primarily related to an increase in costs associated with the execution of a broader clinical program for route and seventeen for the year ended december thirty one twenty twenty two total general and administrative expense was approximately forty seven point nine million dollars as compared to thirty five point one million dollars for
spk_7: the capital period of twenty twenty one the increase was primarily driven by an increase in stock based compensation
spk_11: the the year ended december thirty one twenty twenty two the net loss was approximately one hundred and fifty seven million dollars or five dollars and thirty cents for basic and diluted share compared with a net loss of one hundred twenty five point eight million dollars for seven dollars and sixteen cents a basic and diluted share in the capital period of twenty twenty months
spk_10: as of december thirty one twenty twenty two we have cash cash equivalents and short term investments of approximately one hundred and forty eight point three million dollars
spk_7: eric cash cash equivalents in short term investments of approximately two hundred and eleven point nine million dollars as of december thirty one twenty twenty one
spk_10: based on the updated clinical development plan sergio and separate shared earlier or current cash position provides us with ample runway are approximately two years of cash on now trying apollo for the searchers searchers
spk_5: thank you may get then the take us every fucking summary we are confident that we haven't a clue about drugs and need to focus on clinical trial execution based on the result of thirty three or one we now know how to identify the most reliable sites the most suitable patients and greatly improve our study brothels also importantly all other preclinical clinical and cmc pieces are in place for a successful in the a fairly for rather than seventy additionally has stated earlier we are sufficiently funded to fully execute on our plans or rather than seventeen development as we ended twenty twenty two with approximately hundred and forty eight million in cash cash equivalent and short term investments we look forward to reporting on province we studied three or two and
spk_12: three or four through the it
spk_5: it now we live the greatest please open up the corporate questions operator
spk_2: thank you at this time will be conducting a question and answer session
spk_1: like ask a question please press dar one on your telephone keypad a confirmation know when the gay line is in the question que you may press start to feel like to remove your question from the que for better spent use a speaker equipment it may be necessary to pick up your handset before pressing the store keys one moment please where we polled for questions i first question comes from who year with mizuho please proceed with your question
spk_13: hey guys thanks for taking my questions take us out my first question is i'm a human indicated that for real to the protocol is on his for much finalize and a meal and is you're ready so immediately so have you started well real rolling and reducing the patients and three old you an arm secondly i'm for three or four you need the f t a blessing before you can start the trial and i and i guess my third question is am on the open label study you know what what data i'm glad you do you think it would be helpful i guess for investors to look at and to gain greater confidence in
spk_5: your molecule thanks they give you a video cedric this question that them the for you absolutely thanks to the question the sand am of i'll i'll address them in the order they were as so israel to open for recruit and yes it is it was moving a little bit more slowly over the past quarter as we have worked to streamline the existing protocol and make the necessary amendments to add to make a day and more efficient study and we will add sites to to get that study at moving ahead at a at a at a nice pace so it was never it was never closed or paused it was open for recruitment and now we will be energize the efforts on that trial with the amended protocol or with regard to the new study and dad the requirement for ft a blessing to run the study
spk_7: all studies that we design are submitted to the ft a and so they do have the opportunity to come back and give us the thoughts of the recommendations or but you know as you can imagine a we've already had quite a bit of dialogue with the ft gay and we have quite a lot of understanding of a what these trials need to look like
spk_6: so the wouldn't be any anticipated sam
spk_5: divergence from what the fk would expect him to try like this so it's it's pretty straightforward
spk_6: and as to what kind of data come from the open label study would be of interest to add the community am i suppose the very fact that running at the top model for label city allows you to get your necessary safety exposures that's important for for the and be a filing are looking at a in an open label says
spk_14: adding we were setting rates of adverse events with contextualize what patients might expect wants to get this treatment in the future and discontinuation rates are all this of interest and have from the advocacy perspective it's real world efficacy findings
spk_7: you can look at the the timeline of treatment effect and also then to cause it's a long term openly the study you can sam
spk_3: learn quite a bit about as sustained our response and or treatment that to at twelve months some
spk_2: thank you
spk_15: or next question is from mark goodman with as the be security please proceed with your question
spk_5: i sent through to can question ceridian like a mac that how question regarding study rio two you mentioned us that he already you know around one hundred patients so i should be think about impact of the new roman criteria is as he knows patients who are road i'll sit and talk by the powering for both studies miss your new particle
spk_7: but take your cedric am doing great amount to deserts for you to thanks rudy am and if i understood your question cause of as a little bit of kind of
spk_5: metallic as sounds to your voice but am i think you were saying what to learn from or the first hundred patients that study and how one should think about the and the next two hundred for i will say is that the that the most important outcomes for this study
spk_7: around the primary efficacy analysis or there are not changes in that regard as so basically the amendments aware were aimed at reducing the amount of the the amount of time that the that the patients are spending at the site in order to you
spk_5: of control for those issues that we saw strictly placebo response and so the the primary outcome of in first epic see measurement is unchanged and the approach to go saying and evaluating the patience to the purpose of that are is very much the same so as it with regards to
spk_6: learning from the trio one study obviously we can work to if if one were to assume that maybe the beginning of trio to your to was similar to three or one obviously there there are there are ways we feel confident having having discussed it internally and and with them clinical trial as
spk_2: design a more efficient a second leg of this ongoing studied you like to add to bring us to spam a a positive study and so that's that's what we have set out to do by amending this protocol and with regards to at this point powering up to death
spk_16: full analysis out we just would not be ready at this at this moment to get into those details
spk_5: the next our next question this from andrea tan with goldman sachs please proceed with your question
spk_7: the one thing for teach my question and maybe another one first cedric on if you don't mind just curious given the receptivity for as melody so far just wondering if you could speak on updated thoughts on how you would see well ten seventeen existing and between and landscape there and are there any left learning even heat from the early launched so far andrea thank you for the grass emissary the definitely for you well i just i think it's tremendous to see a new drugs being approved the new mechanism of action
spk_5: cmd the patient population continues to be underserved and so i think it's terrific the more has the more opportunities we have for approval the better am and obviously there are some similarities between wrote and seventeen been a and empty a receptor antagonists like think it's very excited thing for that particular realm of mechanisms that are set there's a bit those greater access and people are willing to add to develop these drugs and that night i don't think i would i will i haven't really any learnings or insights based on air early launch activity or anything like that i i focus on the clinical trial design here the andrei if i may add surgery here
spk_2: the or the the the position in in the marketplace of know the did read you mention and route seventeen if spread seventeen will be approved it will be quite a bit different
spk_17: the read this event is going to be a genteel so will be one single tablet they can be added to any other anti depressant used and are there is no anti depressant a proof of that indication side he added vog is a radio combination so it's unlikely that would be widely used as an adjunct the to a third antidepressant dumped out this answer your question you our next question is from andrew tie with jeffries please proceed with your question
spk_7: i ah thanks good afternoon at things retain my question i appreciate you are blocking lesnar the that these analyses that you did on first question is ah what would the very first three or three mana therapy study look if you are do if you were to do a similar set of post ah
spk_5: analyses on would you get a similar type of signal or unfavorable thing offer and seventeen and and secondly arm as we think about reliance to
spk_7: is there a way to know is the first hundred patients indeed are not tainted there's no issues basically
spk_5: or said another way why should we feel confident and the first thirty percent of patients are so who have and wrong and realize to ah mall hurt the study outcome get because i'm technically some of them could have come from air unverifiable sources crack thanks eric
spk_6: okay thanks hundred am so the first question about mana therapy and yes we did we we did apply the same am
spk_7: the narrative to the mana therapy study and again even in the mana therapist that he had a much higher mean change from base my for placebo about fourteen points and and drug i performed placebo by approximately one point of so what had a higher placebo problem but the doubt delta was also a little less than will be some the chanted are but you're right when we left a verifiable unverifiable pre pandemic posts pandemic am and and and difference that the data and sites
spk_5: when we definitely saw the same issues so we don't feel that the issues were unique to the chance to true to study for rather broadly across the reliance program the decision to pursue a adjunctive was was strategic decision really are based on fact that a three or two was on going with the with the you know as as you pointed out a third of patients enrolled and i am
spk_6: you know improving that design starting with a new streamlined adjunctive study a new study that would be the clearest and quickest path to filing of for at the indication of the chunks of treatment of them dt with the agency now the question as to whether you know can you know anything from the first one hundred subject was you can't really because it blinded first what you can you watch can work on his you can
spk_18: look at how your studies did over time and we we spend a little bit of time pointing out that the creep their maker or after the restrictions were lifted and the impact and on that have the the delta improved and so we do think that
spk_5: maybe the later part of the three or one study is more reflective of the early part of the first hundred patients that we we have in three or two and some other thoughts about a sample size and i gave us confidence to say well you know if we had an original target of the by three hundred patients
spk_17: these trials and it said the the opportunity for the drug to separate despite all the challenges of would have what would it would exist and so you know we we we've done a number of modeling exercises and talking to as statisticians and talking to the chemical sites and so am yes we are good chance your question directly we feel pretty confident that with the amended protocol and with the considerations around target sample size study at putting deposit
spk_6: nine and it but
spk_5: also consider that
spk_7: the if you look at it the the very top down the major impact on study to your one was vocalize localized on to states that wrong about forty patient together at these two sides the were not never been present study trio two right right okay and then a memorial just on and three or four study realize for are there any differences in the day design relative to reliance to the ongoing one
spk_5: and doesn't make sense his daughter alliance by the actually thanks
spk_19: well let me start with alliance for before we talk pipelines five but out with with am with with the three or four new study
spk_7: it you know it will be significantly different in terms of
spk_20: the various scales and assessments that we will
spk_2: we will be asking the the raiders and that the p eyes to administer with the with the patients now the a couple of standard things that you don't change like your primary emphasis epics the as the measure but again
spk_11: it's much easier to start with a blank slate than it is to amend the protocol and to to remove things though it it will be very similar
spk_7: in terms of to arm study for weeks and duration primary sk outcome the same and there will be less exploratory secondary and points just that it can really focus in on on the ask is
spk_6: my elbow thanking us
spk_5: our next question is from jails and with oppenheimer please proceed with your question
spk_6: oh you guys think through the updated takes her can course and first question history cedric could you could talk about and he due diligence that you did prior to making a decision to during real minor and would you learn from your ears or kill else
spk_7: you may have spoken to about route seventeen and would you consider to be the most important capabilities for the chief medical officer to optimize the probability of success stewart mbt clinical trials and and they had father want to thank you please
spk_9: thank you for that question and to him in i am delighted to be part of the ramada team they're very thoughtful professional group of people i've only been here in since january six but i already feel part of the family and that you know when sergio first reach out to me and and as would i be interested in taking the role of you're absolutely
spk_21: right i did one to a look at the day that and i'm under cd a and to understand what went wrong and the study and if i still believed that the drug had efficacy potential and if it did what could i reasonably come in and and suggests be changed in order to optimize
spk_7: the signal so was very obvious in my mind and that the t opinion leaders and thought leaders that you mention that when you know when i looked at the placebo response one and all acknowledge that this was an uncontrolled placebo response and very hard to draw any conclusions if you hadn't kept it to you about ten points
spk_5: and you you really couldn't say one way or the other am about the drug to then i wanted to look at the protocols as they were run and see if i have ideas coming into the design of the try that i feel i could actually be of help or bannister to them and so i think that by everything they were trying to do right
spk_7: now streamlining the the protocols i believe that can be and that can be achieved and done with the that the that the the second part your question ah that he does everything can take either super helpful i did have one follow up question on her wanted to see the results have you can't to evaluate patients who in room three vs post put a towel of men in and it's history powered for a subgroup analyses of pre vs
spk_22: first protocol
spk_23: and what influence you expect to see on the results and the for the common and you
spk_24: because every average of more answer that of the second part first to add to the the him the effect on the results i'm hoping to control for placebo response because i won't i won't feel like i've succeeded in my job unless i can bring placebo response down and or that will that should
spk_7: wyden the delta the trip the super difference because one thing that route and seventeen has had in common
spk_5: across all the trials is the same magnitude and trajectory of improvement and so she can she placebo down i would expect to add to see a nicer a nice separation and to am the first part of the question related to the mind me
spk_23: evaluating patients prefer so you can
spk_1: i've been were little we're definitely looking at that and intend to do that as part of the analysis plan but the specific that that i just would be ready to get into the details of the just yet with you but it's a it's a great an important
spk_5: demarcation in in terms of data the analysis by nj we we did a surge of yeah with the there we made a conservative assumption on the first one third of the patients we assume that so did the there will be similar to what we have seen into your one and the also made some conservative on what the next two thirds of the trial patients that
spk_1: they should be to make the study successful and breached the conclusion that is definitely worth a move forward and complete the dry
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