Greetings. Welcome to the Ralmana Therapeutics Incorporated 4th Quarter and Full Year 2020 Financial Results Conference Call. At this time, all participants are in a listen only mode. A question and answer session will follow the formal presentation. Please note this conference is being recorded.
I will now turn the call over to your host, Tim McCarthy. Please go ahead.
Thank you, operator, and thank you all for joining us this afternoon. With me on today's call are Chief Executive Officer, Doctor. Sergio Traversa Chief Financial Officer, Maga Chanuta and Chief Accounting and Compliance Officer, Chuck Ents. This afternoon, Ramada issued a news release providing a business update and announcing financial results for the Q4 and full year ended December 31, 2020. Please note that certain information discussed on the call today is covered under the Safe Harbor provision of the Private Securities Litigation Reform Act.
We caution listeners that during this call, Ramada's management team will be making forward looking statements. Actual results could differ materially from those stated or implied by these forward looking statements due to risks and uncertainties associated with the company's business. These forward looking statements are qualified by the cautionary statements contained in Romano's press release issued today and the company's SEC filings, including in the annual report on Form 10 ks and subsequent filings. This conference call also contains time sensitive information that is accurate only as of the date of this live broadcast, March 23, 2021. Ramada undertakes no obligation to revise or update any forward looking statements to reflect events or circumstances after the date of this conference call.
Now, I'd like to turn the call over to Sergio. Sergio?
Thank you, team, and good afternoon to everyone. I'm very pleased to welcome you to Ramada's first ever earnings conference call. We do believe that the company has reached a maturity time that is a good time, a right time to have a call. And since we expect a significant number of near term catalysts moving forward, we intend to host update calls on a quarterly basis. The plan for today, because this is our first earnings call and some of the people connected may not be very familiar with the company.
I will begin with a brief overview of Remada, our promising lead product candidate for the adjunctive treatment of depression, rel1017, and the large market opportunity that we are targeting. I will then turn the call over to Maggie for his review of our financials and after that I will provide an update on our most recent accomplishment and review upcoming milestones and do my best to leave as much time as possible for your question. As a brief background on how we arrived at this critical point in our corporate evolution. The Ramada is a late stage central nervous system CNS company focused on the development of RAL1017, which has the potential to address the significant unmet medical needs of major depression disorder, MDD. There are about 17 or more 1,000,000 people in the U.
S. They are affected by MDD. And they have limited safe and effective therapeutic option. Standard antidepressants can take up to 4 to 6 weeks to show efficacy and up to 65% of the patients do not respond or do not respond well to their first antidepressant treatment. And there are about 30% of the patients that don't respond up to 4 different antidepressant treatments.
Rel1017 is being developed as a new chemical entity and it's orally administered as a once daily pill. We have patent protection up to 2,033 with additional patents filed that could extend exclusivity to 2,000 and 38 and beyond. We have over 50 issued and filed patents for rel=ten seventeen and fast track designation for the adjunctive treatment of MDD. So based on the novel mechanism of action and Phase II data that showed statistically significant rapid and sustained antidepressant effect with a favorable safety and tolerability profile. We do believe that rel1017 has the potential to be the 1st FDA approved antidepressant for the adjunctive treatment of MDD.
In the Phase II study, rel=ten seventeen achieved statistically significance compared to placebo and all evaluated efficacy measure. Specifically, there were solid effects we observed on the MADRA scale that is a well established measure of the severity of depression with p value below 0.03 and the large effect size 0.7 up to 1 from day 4 to day 14. The extended efficacy up to 14 days was well beyond the 7 days of dosing in the study and it may suggest a potential neuroplastic and synaptogenic effect. Very importantly, there were no notable adverse events observed in the trial with no evidence of treatment induced dissociative psychothermometic or opioid withdrawal symptoms. In December last year, we initiated RELIANCE-one that is the first trial in our Phase 3 program of rel=ten seventeen for the adjunctive treatment of depression.
I will review the ongoing Phase 3 program and discuss the upcoming milestone shortly. But before I do that, I will turn the call to over to Magad for his review of the financial. Maggot, it's all yours.
Thank you, Sergio, and good afternoon, everyone. Today, we issued a press release announcing our business and financial results for the Q4 full year ended December 31, 2020, which I will now review. For the Q4 year ended December 31, 2020, total research and development expense was approximately $14,900,000 $36,000,000 respectively, as compared to $1,600,000 $7,900,000 for the same periods in 2019. The increase was primarily related to an increase in costs associated with the execution for our broader clinical program for rel=ten seventeen. Total general and administrative expense for the Q4 year ended December 31, 2020 was approximately $6,000,000 $24,900,000 respectively, as compared to $2,900,000 $7,200,000 for the same periods of 2019.
The increase was primarily due to an increase in salaries and stock based compensation. For the Q4 year ended December 31, 2020, we recorded a net loss of approximately $20,800,000 or $1.28 per basic and diluted share and $59,500,000 or $3.31 per share basic and diluted respectively, compared to a net loss of $4,500,000 or $0.40 per basic and diluted share and $15,000,000 or $1.62 per basic and diluted share in the same periods of 2019. At December 31, 2020, the company had cash, cash equivalents and short term investments of $117,100,000 compared to $116,400,000 at December 31, 2019. We expect a strong cash position to support us through at least multiple data readouts we anticipate through the first half of twenty twenty two. I will now hand the call back to Sergio for additional remarks.
Sergio?
Thank you, Magath. As we had the recent announcement, I mean, last week, I would like to start with an update on the human abuse potential or HAP study. We recently announced that we early discontinued Study 120, which was assessing rel17 liking versus oralketamine as an active control. It's a pre planned and blinded analysis of the initial study completers, representing approximately 20% of the planned at 40 patients, showed that the large percentage of these patients did not separate oralketamine from placebo, which we believe was due to the poor bioavailability of oralketamine. Very important, no dissociative or psychotomimetic events were observed in any of the treated subjects in all arms.
To avoid futility, we discontinued this study and we will submit a new study design protocol to the FDA within the next month and proposing intravenous ketamine as an active comparator that has a very established very good and established history as an effective positive control. We anticipate the top line data from the IV ketamine controlled study by the end of this year. Again, we would like to underscore that neither in the discontinued study nor in the previous clinical studies in our program or historically in existing literature. S methadone has been associated with any cyclotomatic hallucinogenic effect and we are encouraged by the confirmatory effect of these results. The HAP Study 124 that is comparing RAS10-seventeen to oxycodone continues as planned and we will expect top line data from this study by the end of the second quarter.
This HEP study will be important in supporting the NDA submission for rel=ten seventy, specifically for the FDA evaluation and the DEA determinational schedule, but they will also represent an important opportunity to add to the existing strong body of literature that clearly differentiates rel1017 from methadone and any perceived association with dissociative symptoms or opioid effect. I will now share the key aspect of RELIANCE that is our Phase III program for rel=ten seventeen. The pivotal studies, RELIANCE 1 and 2 consist of 2 sister, 2 arm placebo controlled trial that include 3 64 patients per study across 55 sites. These studies will evaluate 25 milligram of rel=ten seventeen and placebo on top of the patient's existing antidepressant treatment. These are patients who have failed to respond to minimum 1 up to 3 previous courses of antidepressant therapy in the current depression episode.
The primary endpoint of this trial is changing MADRAS score at day 28. Key secondary endpoints include change in MADRAS score at day 7 and CGIS score at day 28. We believe that our Phase 3 program is optimized to reduce the placebo effect risk based on the design is a 2 arm study, the strong focus on site selection and their training and the multiple levels of screening to ensure accurate patient diagnosis. Our first Phase III trial RELIANCE 1 is evolving as expected and sites have come online nicely. We continue to anticipate the top line data from RELIANCE 1 in the first half of twenty twenty two.
The 2nd Phase III trial, RELIANCE 2, is a MIRROR study of RELIANCE 1 and is expected to begin immediately. Data from this trial top line are also expected in the first half of next year. RELIANCE OLS, the open label safety study, began recently and it is enrolling patients. This trial include patient from RELIANCE I, RELIANCE II, but also de novo patients. We are also on track to initiate our study evaluating the use of rel1017 as a monotherapy for MDD in the Q2.
We are currently evaluating option for this study design and we will provide greater details once this is finalized. As you have just heard, it is an extremely busy clinical development period of Ramnada with several key data readouts over the next 3 to 15 months. Importantly, as Meghan highlighted, we have a strong balance sheet with enough cash to support us through all of these expected data points. I would like to take a moment to express my gratitude to the Ramada team for their hard work and dedication to executing on our mission. I would also like to extend my sincere thanks to the patients and clinical partners involved in the rel=ten seventeen clinical trials for their efforts in advancing this important therapy through the clinic as expeditiously as possible.
With that, we will now open the call for questions. Operator, can you please open up for questions?
Absolutely. At this time, we will be conducting a question and answer session. Our first question comes from Andrew Tsai with Jefferies. Please go ahead. Andrew, your line is live.
Hey, good afternoon. Thanks for taking my questions and So maybe for those in the audience, help us understand, remind us at a high level, you have these 2 abuse liability studies reading out very fairly soon. So remind us what would you like to see on the VAST likability scores for both of these studies? What would positive data be like as we think about the 3,1017 doses versus the 2 comparators versus placebo? Just maybe talk us through that.
And I have a follow-up. Thanks.
Sure. Thank you, Andrew. Maggie, you want me to take this? Sure. So, very top down.
These are not very complicated studies. And if you look at like every study, the data point that we expect and that people should look at as soon as the data available is the each of the 3 different doses of RAL10-seventeen of esmetadone, so 25, 75 and 150 milligrams will have to be statistically different from the control. In this case, it's 40 milligrams of oxycodone and the Ketamine study, Ketamine IV in the 120 studies. This is really the two things that matters. One thing that I would like to clarify as a question that we have been asked sometime or frequently, S method to be deschedule or non settle, it does not need to be same as placebo.
It is an antidepressant. It is a CNS active drug. So it's possible and easily possible that it will differ from placebo. If you take many of CNS active drugs, they are not placebo. And but the key point is that there has to be statistically significantly control.
I hope I answered your question.
That's very clear, Sergio. Thank you. And my second question is, I don't know if you thought this through, but for the oxycodone study that's reading on Q2, I guess what would be some AEs of interest that would indicate euphoria, for example? And can we expect those AEs to be disclosed in the upcoming top line data beyond just likability scores? So basically, I'm just wondering how are you thinking about sharing the top line results when it happens?
Thanks.
Well, it's a good question, Andrew. We'll decide when we see the data, but top line, usually you receive really just very limited information, that's the one that matters. And then a few weeks later, you receive the more detailed data. I assume there is anything notable. The data will be provided to us, and we will of course, we will disclose it.
Ultimately, what really matters is the vast score and the statistically significant. We have treated many patients with s methodone now and we know how the profile looks like pretty well. So we have Phase 1, Phase 2. So we are not expecting any surprise from the maintenance profile.
Yes. Thank you, guys. Appreciate it.
Thank you, Andrew.
Next question comes from Marc Goodman with Leerink. Please go ahead.
Yes. Just to confirm a few things. One is, when the Oxy data comes out, that will be a press release. You're not waiting for the Ketamine data since now they're both not coming out near the same timeline, right? Is that true?
Yes, it's Mark. Good afternoon. Yes, it's absolutely true. Reason being that the oxycodone data is by far more they're both material, but the oxycodone is far more important than Right.
I just make sure that we will get that press release whenever it is in the Q2. And then secondly on Oxy, the HEP study. So, your view is that none of the doses can be relatively like oxy, right? I mean the 150 can't be like oxy, even though it's multiple times the 25 that you're going to be using in the real world, right?
Correct. Look, we have this is not really a that tossing a coin kind of trial. We have 13 patients treated with 150 in Phase 1. None of them showed any opioid like effect or oxycodone like effect. We have 21 patients in the Phase 2.
There was the 50 milligram arm that is loading dose they took 100, none of them showed any opioid like oxycodone like effect. And so we do have enough evidence that the one even the 150 does not have any even close to what the effect of OxyContinol can be. Of course, we have to show it in the CONTROL study. But we have quite a bit of evidence already out there.
And then lastly, could you just any update on enrollment? How many sites are up and running for RelianceOne? That's it. Thank you.
Yes, you caught me on that. This is evolving very quickly, so I don't have the exact number. Maggot, do you know we are getting close to oversight involvement because we will start very soon Reliance 2. So we wanted to wait to have Reliance 1 well up and running before to start the second one. I don't have the exact number, but it's close to having all of them up and running.
Thank you.
Next question is from Joon Lee with Truett Securities. Please go ahead.
Hi. Thanks for taking our questions and thanks for the update. So for the upcoming human abuse potential study, has there been a similar preplanned analysis for the HAP study using oxycodone as an active comparator as what was done for the ketamine study? And if so, was oxycodone arm behaving as they should be based on the historic data? And also, what's the explanation for the oral ketamine not separating from the placebo in your TREMELY HAB study?
And I have a follow-up. Thank you.
Okay. So the first one is, if the quality control yes, the answer is yes. We usually everybody I think usually does a blinded quality control data just to be sure that there is nothing like unexpected, nothing weird about data. And it's mostly done for safety. So and we have seen that with oral Ketamine, it was kind of also looking at futility that is like not very complicated to understand.
If out of 5 arms, there was no likability at all and one of the 5 arms even it was blinded, but it has to be CAT, I mean, because every patient takes every arm. So and it was pretty straightforward that there was an issue with the ketamine but behaving as a control, a valuable control. So we will do the we have not done it yet. And the oxycodone study started a couple of months after the decetamin study. The only reason being that the site that is doing, they need a little bit more time to get up and running.
They were beating with other things. So we had to wait a couple of more months. So at some point, we do the analysis. But if there is nothing notable, we will not even know it that it happened. They only will notify us something that will show that there is any unexpected effect or side effect or anything like it's happened with Ketamine that's look, this thing doesn't look it's going in the right direction.
So you were alerted because the ketamine arm didn't separate from placebo by whoever was conducting the study. But for the optocodone, HAP study using optocodone, you don't know and you won't know if there is no real issue with the study?
Right, right. We will only be notified if there is something that we the material that we need to know. We only side effects or something safety or something that make that the study will not generate any valuable useful results of lyketamine. Right.
And then following up on Mark's question, it's the 100 ampseptic arm or any one of the dosing arms actually does not separate from the active comparator statistically. Then do you automatically get a Schedule 2 or what's the sort of decision tree after that? I mean, the ideal situation would be as you described, none of the doses are likable. But if one of the doses happened to be likable, what's the process?
Yes. This is a great question, John. There are we are not hiding that the likability of the results of the study is important, but it's not the only factor that will determine the scheduling or non scheduling of esmetadone. There is a there are 8 factors that the FDA considers when they determine the recommendation for the DTA. One is likability and it's very important.
If you don't like something, it's more difficult, you get you abuse it or you get dependent on it. But there are other factors like, look, the FDA at the end is the real focus is on safety. And the reason that the oxycodone or the opioid, they are a lot more under scrutiny and the focus of the FDA is not because they are more abusable than ketamine or than alcohol or the PCP and it's because they are dangerous, right? You overdose an opioid, you can have respiratory depression and unfortunately you can have some serious consequences. If you overdose Ketamine, it happened, but you fell asleep or it's used as an anesthetic specifically because it does not give respiratory depression.
So and the dangers or the potential risk is a very important factor in determining the schedule. That's why ketamine is Schedule 3, not because it's less abusable than oxycodone, it's because it's less dangerous than oxycodone. There are 8 of these factors. So, likability is 1 and then you have dangers, the history, the pharmacology and so on. Clearly, likability is important.
To answer directly your question, if by chance, one of the doses of ex methadone will not separate statistically from 40 milligram oxycodone, then it will depend on the FDA overall analysis and how they will consider the other factor. Consider that esmethadone in the past has been used, not used, has been tested at 900 milligrams and nothing happened. People did not like it and nothing experienced an exterior side effect. 900 milligram is 36 times I believe is 9 times 4, is 36 times the therapeutic dose. And so definitely, we feel comfortable that safety is not the major potential risk for astigmatism.
Yes. So
it's not an automatic Schedule 2. It is one of the No. That's helpful.
Next question, Yatin Suneja with Guggenheim Securities. Please go ahead.
Hey, guys. This is Eddie on for Yatin. Thanks for taking the question. So just you talked about for Reliance 1 on sort of the checks that you are the screening multiple levels of screen that you're taking. So can you just talk a little bit more about these steps and how you're ensuring that you're not enrolling professional patients?
And then what would be a placebo range for the MADRS improvement that would give you confidence that you had a proper screening process? And then I have a follow-up on the human study.
Great. So let me take this one. So the how do we avoid or we reduce the risk of having non depressed patients in the Phase 3 in Reliance? Besides the 2 arms that is easier to the placebo effect is lower than multiple arms, specifically for the patient selection. And one point that we'd like to make, we have been advised by our advisor that the major risk in running a Phase III trial for depression is actually the patient selection because it's also connected with the placebo effect.
So we have multiple screening that the site select, they screen the patient and they propose that the patient meet the criteria to be enrolled in the study. Then we have the CRO that themselves, they will review the data and they will evaluate if there is any risk of having this patient is may not be depressed, may have some other issue or maybe a personality disorder. The data also seen by, I believe, our CMO and the for the safety control and clearly there is an opinion here. There is probably the most important of the steps beyond these 3 steps is the review done by a group. Magal, can I say the name?
Yes, it's not nothing. It's CT and I. It's a group that was I believe not from MGH or Harvard. And what they do, they re diagnose the patient. So only the site and CT and I, they have a contact directive is fixed.
So it's a phone interview and they administer a different scale. So it's not Hamilton, it's not Madras. They administer a scale called SAFR that is considered more the patient as an entity, right? For example, they look at the history of the patient that's been depressed in the past and or there has been an event that has generated the current episode of depression. So it gives a little bit more complete picture.
And they have the last say on the patient if it is suitable for the trial or not. So we have 4 different ways of which the one the last one, the CDNI, it's we do believe it's effective. We use it in Phase II and we have seen the results. It was pretty well done, pretty effective in a way.
I hope I answered it.
Yes, that's great. Thank you for that color. And then for the Ketamine abuse liability study, can you just give like a little more logistics on how they run a trial with multiple different routes of administration? And will the placebo also have to be IV or sort of how does that work in terms of making sure that patients are going to be an accurate comparator if they're getting oral versus IV drugs?
Thanks. Yes. The answer is yes. There's going to be IV placebo and the IV oral.
Okay. Thank you.
Next question, Shay Olsen with Oppenheimer. Please go ahead.
Hey, guys. Congrats on the progress and thank you for taking my questions. I was curious about the startup activities that remain to be completed before initiating the RELIANCE 2nd pivotal trial and also the Phase 2 monotherapy trial and whether or not you expect to initiate the Phase 2 monotherapy trial before or after RELIANCE 2 starts?
Yes. Maggot, Maggot is really helpful in looking at
the operation as entirely. Maggot, do you want to take this? Sure. Sure. Thanks.
Thanks, sir John. Thank you, Jay, for the question. So with regard to ALLIANCE 2, I can safely say that we're close to initiating that study. I think most of the operational pieces are in place right now. We're not quite there yet, but look for that to officially start kickoff shortly.
So with regard to can you repeat the second question, Shay?
I was wondering for your Phase 2 monotherapy trial, what remains to be done before you can initiate that study and should we expect that before or after RELIANCE 2 initiates?
So I'll answer the second question first. So expect that after Reliance 2 starts. We still have a fair amount of work. We've completed the protocol. We've submitted it to the FDA.
We're about to submit it to the FDA. And we have also selected a CRO. So I think a lot of the pieces are coming together, but our expectation remains that we'll start that study by the end of the first half.
Okay, great. Thank you. And are there any details about the study design for the monotherapy study that you could share with us?
I think we're not quite prepared to do that yet. So give us some time and we'll be able give you a more full characterization of the study. You can expect it to be very similar to the RELIANCE I and RELIANCE II studies and in that it will be 2 arms, placebo versus 25 milligrams of rel1017 de novo patients, but beyond that we're not ready to disclose number of sites and such and any limitations on patient selection.
Okay, got it. Well, look for
that. Yes, the biggest difference is going to be the patients. So adjunctive treatment versus monotherapy, that's going to be the case.
Okay, got it. Thank you again for taking the questions.
Thank you. Pleasure, Jay.
Our next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Hi, everyone. Thanks for taking the question. This is Andrea on for Salveen. Sergio, maybe a question for you just based off of what you saw from the oral ketamine study. Understand the positive control didn't separate here, but does this give you any increased confidence in the profile of rel1017 and what you might expect to see versus the oxy?
Well, good afternoon, Andrea, and thanks for the question. Well, yes, with the limited that is the limitation that was a blinded analysis. So we don't know who took what, but they all took all arms. So we have seen no evidence of dissociation, hallucination, delirium and out of body experience in any of the patient that's been reviewed. That was 20% of the plan in total.
So, I mean, if clearly, esmetadone did not show anything because even blinded, there was no sign of this in any of the arms. So, yes, it gave us a good level of confidence that the profile confirms what we have seen in the historically in the literature that we have seen in Phase 1 and in Phase 2. And clearly, we have to prove it, but we see it a little bit like unlikely that a drug will behave differently into similar studies just with a different control arm. So I mean, nobody liked it or nobody has experienced anything that could be likable in the ketamine study. Yes, totally possible, but we see it as unlikely that we'll change total behavior.
So yes, the answer is yes. K was, you know, supported the confidence that we have that smethidine is not a likable compound.
I would like to turn
the floor over to Sergio for closing comments.
Okay. Well, thank you, operator, and thank you all of you for joining our call today. It was our first one, so it will be remembered. But we look forward to the year ahead and we'll provide further update throughout 2021. So thank you all again and hope you will enjoy the rest of the day.
This concludes today's teleconference. You may disconnect your lines at this time and thank you for your participation.
Thank you.