Greetings, and welcome to the Relmada Therapeutics Fourth Quarter and Full Year 2021 Earnings Call. At this time, all participants are in a listen-only mode. A brief question-and-answer session will follow the formal presentation. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Tim McCarthy of LifeSci Advisors. Thank you, Tim. You may begin.

Thank you, Paul, and thank you all for joining us this afternoon. With me on today’s call are Chief Executive Officer, Sergio Traversa, and Chief Financial Officer, Maged Shenouda. This afternoon, Relmada issued a news release providing a business update announcing financial results for the 3 and 12 months ended December 31, 2021. Please note that certain information discussed on the call today is covered under the safe harbor provisions of the Private Securities Litigation Reform Act. We caution listeners that during this call, Relmada’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 Relmada’s press release issued today, and the Company’s SEC filings, including in the annual report on Form 10-K for the year ended December 30, 2020, 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, 2022. Relmada 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, Tim, as always, and good afternoon to everyone. I’m pleased to welcome to the Relmada fourth quarter and full year 2021 conference call. During today’s call, I will review our recently achieved milestones and provide an update on anticipated clinical trial readouts time line for REL-1017, our lead product candidate, that we are currently studying as an adjunctive treatment and monotherapy for patients with major depressive disorder or MDD. Following my comments, Maged Shenouda, our Chief Financial Officer, will review the financial results and recently strengthened balance sheet, and we will then take your questions. Looking ahead, we expect 2022 to be a catalyst-rich year for Relmada. We kicked off 2022 by reporting top line results from the second human abuse potential or HAP study, which I will recap shortly. We intend to generate REL-1017 clinical data readouts beginning mid-year for the ongoing RELIANCE Phase 3 trial. We anticipate completing the enrollment of RELIANCE III, the ongoing monotherapy registrational Phase 3 trial, followed by top line data readout by midyear 2022. In the third and fourth quarter of this year, we expect top line results from RELIANCE I and RELIANCE II, respectively. These are two ongoing Phase 3 sister 2-arm, placebo-controlled pivotal studies evaluating well REL-1017 as a potential adjunctive treatment for MDD. The goal of this comprehensive development program is to address the significant need for a new therapeutic option to the 17 million individuals in the U.S., who suffer from MDD. The current antidepressant therapies have significant limitations in terms of efficacy, and they can take up to 4 to 6 weeks to show any effect. Up to 65% of patients do not respond to their frontline antidepressant treatment and up to 40% of patients take combination therapy. Furthermore, there are only three FDA-approved adjunctive treatment…

Sure. Thank you, Sergio, and good afternoon, everyone. Today, we issued a press release announcing our business and financial results for the 3 months and 12 months ended December 31, 2021, which I will now review. For the fourth quarter ended December 31, 2021, total research and development expense was approximately $25.3 million, as compared to $14.9 million for the comparable period of 2020. The increase was primarily related to an increase in costs associated with the execution of a broader clinical program for REL-1017. Research and development expense for the most recently completed fourth quarter included a noncash charge of $1.5 million related to stock-based compensation expense. We also ended the fourth quarter of 2021 with a prepaid R&D expense balance of $8.6 million related to advanced payments to our CRO. Total general and administrative expense for the fourth quarter ended December 31, 2021, was approximately $8.9 million as compared to $6 million for the comparable period of 2020. The increase was primarily due to the increase in personnel costs, stock-based compensation and consulting services. The noncash charge related to stock-based compensation expense included in general and administrative expense totaled approximately $6.6 million in the most recently completed fourth quarter. For the fourth quarter ended December 31, 2021, we recorded a net loss of approximately $34.4 million or $1.80 per basic and diluted share compared to a net loss of $20.8 million or $1.30 per basic and diluted share for the comparable period of 2020. For the year ended December 31, 2021, total research and development expense was approximately $90.6 million as compared to $36 million for the comparable period of 2020. The increase was primarily related to an increase in costs associated with the execution of a broader clinical program for REL-1017. Research and development expense for the…

[Operator Instructions] Our first question comes from Andrew Tsai with Jefferies.

Okay. Thanks, everyone, and good afternoon. Just curious on the DMC safety community disclosure, which is routine. I’m curious if there were any kind of AEs of special interest that they were looking for. I mean, can you confirm if they were looking for withdrawals, the dependence, addiction, and so forth, were they looked at in this blinded review? Thank you.

Thank you, Andrew. I was sure you would have kicked it off. The committee is totally independent. So, they only communicate to us if there is anything that would be any worried in terms of safety that includes anything. And I do believe includes withdrawal symptoms or anything that would be out of the normal course out of the ordinary. We haven’t heard anything. We’ve got just a very, very simple and brief communications that the trial can continue as planned. That was it. So, there was nothing that would be of any worry. But to be honest, Andrew, we have seen -- and you have seen a lot of data over the last few years, and there’s been no signal that safety -- it would be of any real big worry. I mean, we’re always worried about everything, but safety is probably not what we are worried the most. I hope I answered your question.

Of course, that’s great color. And then, I’ll try to ask this one is just I’m wondering if you can give us a flavor of what we can expect to see in the top line release in mid-2022 for RELIANCE III? Presumably, we’ll see day 7, day 28 efficacy, AE rates. Will we see curves? Will we see response rates, remission rates and so forth? Have you thought about what you plan to disclose? Thanks.

Well, yes, look, we will disclose everything that we will receive from the statistical group that runs the statistical analysis, with a caveat that clearly we want to leave details for the presentation publications. But in terms of top line, we usually -- we receive the primary and secondary endpoints. I don’t know if we will receive the curves or not. We tend to be very quick. We don’t want to hold the data for too long inside the Company. So, whenever we have something that is material, we tend to do it very, very quickly in a day or two. So, it’s a way to tell you that it depends on what we receive from the statistical group, definitely primarily and secondary endpoint.

Our next question comes from Andrea Tan with Goldman Sachs.

Maybe sticking on with the monotherapy study, Sergio. Just curious if you could help frame expectations ahead of this study? And what you’ve seen specifically from your prior studies that gives you confidence in REL-1017, demonstrating a benefit here as a monotherapy? And then, I have a follow-up. Thanks.

Yes. Well, good afternoon, Andrea, and thanks for your question. So, the -- what we kind of -- can be applied to the monotherapy is clearly the lack of any potential for abuse that we have seen and the safety, that’s pretty common to all the studies. What we don’t have is any -- based on efficacy as a monotherapy. We do have very strong efficacy data for the adjunctive therapy, but not as a monotherapy. So, that’s what really -- it would be the most interesting data point. And there is not much else that we can apply or infer in the -- from Phase 2 into the monotherapy data. We can kind of, I don’t know, speculate that patients that failed 1 or 2 or 3 previously antidepressants, they are not completely different from patients that have not failed any previous antidepressant. So, we don’t see a major difference between the two patient populations. But yes, we’d be very anxious to see this efficacy results as a monotherapy as well.

Got it. And then, is there anything that can be inferred or will there be any read-through from the monotherapy results for the adjunctive pivotal studies here?

Well, that’s a very difficult question to answer. But, if the study is successful as a monotherapy, then we could infer -- just because we already have data as an adjunctive treatment positive, so we can infer that probably there is some indication of efficacy in -- across all the patient population for all the adjunctive and monotherapy population. If it doesn’t go the way that we hope and we believe, then it’s -- it gets more speculative, right? Let’s say, it fails as monotherapy, but we have positive Phase 2 as an adjunctive. So, I would say -- I tend to say that if this study in monotherapy is not positive, I would not read through much into the adjunctive. And I want to go a little bit more in detail. What we don’t know if there is any role of the inadequate response to the underlying antidepressant therapy as an adjunct. We don’t know if there is any synergistic effect between a non-effective SSRI or SNRI and NMDA channel blocker. That’s what we will learn from the monotherapy and the adjunctive therapy trial. There’s a lot of speculation. So, we want to see the data, and then we can be more accurate and realistic.

Got it. And then, maybe just one last question. Just given that you are looking to include data from RELIANCE-OLS in your filing package, could you just remind us on the time frame there for the amount of follow-up and when you think you might have a completion for that portion?

Well, we have a rolling NDA. So, we will start to file the models like the preclinical and the CMC well in advance than when we have the clinical data. The goal is to -- it takes about six months realistically. It’s a big site potentially for two indications and there’s a new chemical entity. So it’s a big NDA. And so, we calculate six months as a fair time to do it correctly. And you know what happened when they don’t do it correctly. That’s not a situation that we want to find ourselves. So, if everything goes according to the plan, we should be able to complete the NDA by mid-2023.

Our next question comes from Joon Lee with Truist Securities.

Hi. Thanks for taking our questions. And congrats on all the progress. So, now that you have completed two successful human abuse potential studies, has your outlook changed on possibly looking towards ex-U.S. opportunities in regions where they have maybe stricter substance abuse laws? I believe China may have been one of them? And do you have any plans to enter the U.S. -- enter the EU at some point? And I have a follow-up.

Thank you, Joon. It’s a bit too early. And look, we are extremely busy and committed to the U.S. Phase 3 program. In terms of areas where there is more sensitivity to like a substance abuse or Japan is the one that is the most sensitive. Europe, we had a few interactions with the EMA, with the European FDA. And there was no specific mention or specific interest in the abuse potential of the drug. With that said, they were preliminary conversations. So, I don’t know if it was the right time for the regulators to go deeper in these aspects. So, we will do something. We will look into that, but a little bit later on. We really would like the Phase 2 program correctly and to do it right. That’s the real focus.

Great. And then, in addition to the Phase 2a data that you published in American Journal of Psychiatry, you also published data showing rapid rise in BDNF after -- in human subjects dosed with oxymethadone. So, can you elaborate on the significance of that? And what do you plan to do with that information? Are you following that up with any other studies?

Yes. That’s a great question. Well, what we have done already, we have used these data. They were -- this new data and to strengthen the IP. So, we put the BDNF data and the neuroplastic effect in a patent filed in 2018 that is under review. And the clear indication is that mechanistically, an NMDA channel blocker, they are very different from anything that is like SSRIs and rightly traditional mechanism of action. And it would indicate clearly that scientific and mechanistically, there is a neuroplastic effect. We did an increase in functionality and increase in the proliferation of dendrite connection between nerve cells, and that happened very quickly. And this BDNF brain-derived neurotrophic factor is a growth factor. So there should be some correlation between the BDNF increase and the neuroplastic effect. Just to be clear, Joon, the FDA does not consider BDNF as a surrogate for clinical efficacy in depression. So, we won’t use it with the FDA say increase the BDNF and there is efficacy. That’s not going to fly. But clearly, for IP, it’s very interesting. It’s been confirmed by the extended and sustained effect of the drug after the therapy is stopped. So, at least for one week after interruption of the treatment, you still see a very nice and prolonged and sustained antidepressant effect. So, the clinical result, they match very, very clearly, the scientific and mechanistic expectation. So, we will continue eventually for other indications to try to understand better and to leverage this potential for neuroplastic effect of the drug, very important data, very important data.

Yes. And then if I could follow up with one quick question. When you do complete enrollment in the monotherapy study, would you disclose completion of enrollment?

Yes, we probably will. Usually -- companies usually do, and we don’t want to be different from anybody else in this aspect. And so, we probably will do. A few weeks. Yes, a few weeks. The statistician usually will take very wide range of timing when they lock the database and when they provide the top line, they usually tell us like 2 to 4 weeks that is for statistician is a narrow range. For us, a little bit less narrow. But so you assume that when we complete enrollment and probably around the months, we will have the top line data.

Our next question comes from Yatin Suneja with Guggenheim.

A couple of questions for me. Can you talk about what you might [Technical Difficulty].

Sorry. Yatin, you broke up.

Can you just talk about the discontinuation rate, what you might have assumed in the study and how it might be trending? How is the conversion from randomized to the open label?

Yes, we can. I don’t know how specific I should be before Maged shuts me down. But the dropout rate is significantly -- not statistically, right, but it’s very much lower than what we assumed. We look at historical and we discuss with the CRO that has a lot of experience in running the depression studies. And we assume mid-double digits, so around 15% in the statistical plan to be sure that we reach a number of patients that is -- that can be evaluated, it is high enough -- for the power of the study. And what we have seen so far across the board, it’s much lower than that. I would say, is low to mid-single digits. So, according to the CRO, that’s not been seen before in depression study. Now, I’d like to be always directed and open. What we can read through that is like safety, compliance, tolerability. It should not -- doesn’t look to be an issue. I would not make the big step on reading anything into efficacy, because half of the patients are taking placebo. In terms of rollover, that’s also a number that the -- it’s a very good number. So, about 3 out of 4 patients, they accept and are happy to continue from the 28 days to roll over into the long-term safety. That’s much higher than the average for this kind of stuff.

That’s helpful.

Safety, tolerability and acceptance and compliance, they look very good.

Got it. Got it. Very helpful. Then one more question. So I think one of the pushbacks are -- the things that we generally discuss with investor is the performance of the placebo arm in Phase 2. So, can you just talk about how much cushion we might have in the Phase 3 studies, how you might be controlling it? Any reason to believe that the monotherapy placebo rate might be different than the adjunctive one? Just give us some comfort and color around it.

No, I can give you -- can share what is -- what we discuss on a daily basis. We are fully aware that placebo effect is -- and that is strictly related with the quality of the patient population, meaning the patient should be a depressed patient that -- to enter the study. And the -- for the Phase 2, I do remember the delta from baseline to day 7 for the placebo was around 8 or 9 points. That’s a little bit a bit lower than what has been seen historically, slightly lower. But there is one point. The study was 7 days on placebo. Placebo effects tend to increase over time. So, 7 days to have a placebo delta from baseline of 8, 9 points at day 7 is not unusual. It’s actually even on the high side. We have seen placebo effect of 4, 5, 6 points in other studies at day 7. So, there is really nothing unusual there. It is something unusual -- is slightly higher. That was also expected, because in clinic studies, they tend to have a higher placebo effect than outpatient studies. So, the second part of your question, what we are doing to try to minimize as much as possible the placebo effect. But, there is no magic, no secret that can be -- that we use, that nobody else has used, but we try to put together all the experience. And Dr. Fava is the principal investigator, has published a lot about the potential for placebo effect. And so, he is kind of an expert on, I would say, on trying to control as much as possible, unusual placebo response. With that said, there is a tidbits here and there, like there is a statement that the patient is reading…

[Operator Instructions] Our next question comes from Jay Olson with Oppenheimer.

Could you remind us how the human abuse study results compare to Spravato? And would the human abuse data appear in the FDA-approved label, so they could be used for promotional purposes?

Thank you, Jay. Good afternoon. Well, the first question, how the comparison with ketamine of REL-1017 compared with Spravato, they are totally different. Esketamine, it is a low-dose ketamine. The isomer of racemic ketamine, but works exactly the same as racemic ketamine according to all the literature. So, the J&J run the study, because probably was asked by the FDA, but clearly, the expectation was not that esketamine is less potentially usable than racemic ketamine. It’s exactly what happened. You have seen the data of REL-1017. I don’t know how many zeros after the period in terms of p value compared to ketamine. So, the data are completely different. And if the abuse data -- the non-abuse data or the lack of abuse -- meaningful abuse potential data for REL-1017 will be on the label can be used promotional, well, the straight answer is that the FDA will decide. We won’t emphasize much about the lack of abuse potential of REL-1017 as a promotional tool. Its efficacy, rapid acting, sustained efficacy, they are a lot more powerful. With this data, I mean I don’t think anybody would think that there is any risk of abuse. So, at time of potential approval, it probably -- people assume -- won’t be the focus of the attention of the clinician. So personally, if you asked me directly, maybe some centers that mimic what the FDA has already published in -- in ‘19 that the isomer lacked abuse potential and rest of respiratory depression, that’s what I could speculate that could be in the label by mimicking the FDA statement.

Okay, great. And maybe as a follow-up, can you talk about any findings from your market research, as you test the REL-1017 profile with prescribers, as you plan for your commercial launch? And especially, if you have any feedback from payors in the U.S.? And then, if you are considering a partner ex-U.S.?

Yes. So, we did -- it’s never too early to discuss with the payors. So we keep everybody that is in the chain as updated as possible. From my experience, the payors really consider seriously to get into a conversation when they have Phase 3 data. Before data from their perspective, they will say show me the data, then we can discuss. Like really top-down and -- the monotherapy, it’s a bit more challenging in terms of reimbursement and depending on the price, because the frontline therapy that is currently proposed supported by the payors is generic SSRI. They work a little bit and they are relatively safe, and they’re extremely inexpensive. So, that’s a little bit of a hard, though, to overcome in monotherapy. Adjunctive, there is no antidepressant approved. So that would be a great. It’s going to be very difficult to have an adjunctive treatment where there’s no competition in terms of antidepressant. And that works fast. And hopefully, we don’t believe it will be priced at the esketamine range, so would be potentially affordable by a mass market patient population. So, that one, we don’t believe it’s going to be a major challenge to get reimbursement and as -- I don’t know how to call it, but as a frontline adjunctive treatment. With that said, going back for a second to monotherapy. If you -- the data in Phase 3 will be any close to the Phase 2 data that we have seen in monotherapy, meaning the monotherapy will mimic somewhat the adjunctive Phase 2 data, it’s going to be difficult for the payors, not to reimburse the drug that works much faster. There is pharmacoeconomic data, too, right, that if you can get out or improve your depression status quicker, you are more productive. That’s more European, but I do believe the U.S. also focused on these aspects, too, right? And so the pharmacoeconomic. If you can improve and go to work a lot faster than if you take an SSRI, that’s probably a lot more value than to save some reimbursement or some payors money, using -- starting with an SSRI. So, if you have a rapid acting and sustained efficacy drug, it’s going to be difficult not to reimburse it, even as a monotherapy. The key will be clinical data.

Okay, great. And any plans to find an ex-U.S. commercial partner?

Well, the -- as always, in this kind of like situation pre-Phase 3 data, there’s always some conversation here and there, but we don’t believe that nothing will happen. We are too close to Phase 3 data. Nobody will sign an agreement or paying like the adequate price a few months before Phase 3 data. So, straight answer is not before, not before Phase 3 data. We don’t expect anything to happen outside the U.S. before Phase 3 data. We also would like to retain the global rights. That is -- there is a value in having the global rights.

There are no further questions at this time. I’d like to turn the call back over to Sergio Traversa for any final remarks.

Thank you. Thank you, operator. Well, thank you very much, everyone, on the call for the interest -- the time and the interest in our program. And I would like to thank also the Relmada team for the effort and the energy they put in this program, and the clinicians and the patients that really are helping to complete this ambitious, but realistic program to offer patients a good or better solution to treat depression. With that said, I wish everyone a wonderful rest of the day. Thank you.

This concludes today’s conference. You may disconnect your lines at this time. Thank you for your participation.