Daré Bioscience, Inc. (DARE) Earnings Call Transcript & Summary

Good afternoon. My name is Emma, and I will be your conference operator today. At this time, I would like to welcome everyone to the Daré Bioscience webinar to discuss data from the exploratory Phase IIb RESPOND study of Sildenafil Cream. [Operator Instructions] Thank you. Sabrina Martucci Johnson, Chief Executive Officer of Daré Bioscience. I turn the call over to you.

Great. Thank you so much, and thank you for those of you who are listening in to the webinar today. If you follow Daré, you know we are a company focused solely on women's health with a broad asset of portfolios in our -- assets in our portfolio across a variety of indications. So we are very, very thrilled today to be hosting this KOL discussion and data review of the Phase IIb RESPOND study results of Sildenafil Cream. So without further ado, we're very much looking forward to digging in Obviously, the presentation today will contain and does contain forward-looking statements. So I do you to review the forward-looking statement so I do encourage you to review that forward looking statement disclaimer in full. And as I mentioned upfront, we are going to focus today on the discussion around Sildenafil Cream. But as I also noted, as a company, we are very broadly focused in women's health across contraception, vaginal health, sexual health, fertility, menopause as well with a number of programs at various stages of development, including one product that's FDA approved through which we have a commercial collaboration with Organon as well as products in or going into Phase III, a few of them, including our hormone-free contraceptive and our hormone therapy, vaginal ring technologies and then our vaginal -- hormone-free vaginal atrophy treatment preparing to go into Phase II. But as I mentioned, today's call is specifically about our Sildenafil Cream program. And I am very honored to have joining with us today our featured presenters. They are 2 of the most renowned, quite frankly, leaders in women's sexual health. They both have focused extensively in their careers in the study of women's sexual health. I think I'm correct in saying I think they're also maybe the only 2 people that can be honored enough to say that they have been the past President of both the North American Menopause Society as well as the International Society for the Study of Women's Sexual Health. So they will really be taking us through both the background of the conditions that we are interested in with sildenafil as well as the data from the Phase IIb RESPOND study. And so in terms of -- and I should have mentioned their names, let me go back a slide, that's obviously Dr. Sheryl Kingsberg and Dr. James Simon. So as I mentioned, we're going to focus today's discussion on Sildenafil Cream. And this is our novel cream formulation of sildenafil that's the active ingredient in Viagra for those of you who know it, that we have been studying specifically in terms of its ability to improve arousal in women. And so in terms of background on sildenafil before I turn it over to our 2 guest speakers today, I wanted to give you a little bit of perspective on what Sildenafil Cream is. So this is a topical formulation. This is a cream formulation, as I mentioned, has the same active ingredient that is in Viagra. It's been designed for topical administration so that women can use it on demand, applied locally to the general arousal -- to the general area, right, where she needs that arousal response and to really minimize any of the systemic exposure and therefore systemic effects that one could have with oral sildenafil. Arousal disorder is a physiologic condition, right? It's characterized as Sheryl is going to go into in great detail in terms of that ability to attain or maintain a general arousal response, there are currently no FDA-approved treatments. And of the various types of female sexual dysfunction, right? It's the most analogous erectile dysfunction in men. And so our hypothesis has been, given the similarities between ED and arousal in women, sildenafil, that active ingredient that's in Viagra, may improve general arousal response and the overall sexual experience for women, similar to what it does in men. And that was really the purpose of us evaluating the product in the Phase IIb RESPOND exploratory study. So in terms of the agenda today, I'm going to provide a very brief overview of the regulatory landscape. It's very important to understand that because it provides some context into what we actually studied in the Phase IIb trial. Dr. Kingsberg will then provide an overview of the diagnosis and treatment, the unmet need, the market opportunity for a treatment like this. Dr. Kingsberg also served as the sort of head of our centralized clinical interviewing as part of our Phase IIb study. So she also provides a very unique perspective of having overseen that for our Phase IIb study of the women who are involved in the study. And then Dr. Simon, one of the investigators in the study will review the key findings from the study. And then I'll close with overview of what those results mean in terms of next steps and then certainly open it up to questions as well. So as I mentioned upfront, there are no products currently approved for the treatment of arousal in women. There are products approved for women for other aspects of sexual dysfunction, but nothing that is approved specifically to treat that arousal disorder in women. But the FDA does have a draft guidance document that does provide some guidelines for sponsors that are interested, like Daré in developing something for women. The guidance document is actually designed to provide guidance on not just arousal, but also conditions that can include low sexual interest, desire, as well as arousal as well as combinations of lack of interest and arousal disorder in women or arousal on its own. And there are some guidelines. And as I said, these really gave us insight as to how to run our Phase IIb trial. But importantly, the kind of information we needed to collect, so we are prepared for a Phase III program and specifically generated the data that would support the design of a Phase III program. So FDA recommends a placebo run-in period, and Dr. Simon will talk about how we incorporated that in this trial. For a Phase III program, they recommend that it's at least 24 weeks of double-blind treatment. And the reason for that is that they want to see persistence while on the treatment. So something we wanted to make sure we understand clearly in the Phase IIb was persistence of response to our product. And similarly, for a drug that's intended to be used as needed, which our cream formulation is, -- very important to make sure in the trial that we were studying when is the drug likely to exert its effect? Answers to these questions are very important as we think about then that forward-looking discussion with the FDA around the Phase III program, right -- to design the program such that we have a clear understanding and recommendation on time interval following drug administration for assessing efficacy, appropriate recall periods and you'll hear us talk about those for the patient-reported outcomes. FDA also encourages the sponsors to make sure we have a well-defined patient population. So part of why we wanted Dr. Kingsberg to help us oversee and run the clinical interview process with every single subject in the Phase IIb trial is so that we could really clearly identify the patient population we were studying and understand the nuances in the patient population. We also wanted to make sure that we had well-defined and reliable patient-reported outcome instruments in the Phase IIb because that becomes critical for Phase III. So the Phase IIb study served as an opportunity for us to -- as a follow-on to a content validity study that we conducted before the Phase IIb, incorporate a variety of not only primary and secondary, but exploratory end points and the Phase IIb study serves as the validation study for those endpoints so that everything we've looked at in the Phase IIb becomes an appropriate end point to consider for Phase III. Similarly, as the sponsor considers Phase III, the FDA recommends outcome measures, including satisfying sexual events, so choosing from this menu, sexual interest, sexual arousal, level of distress. So as you'll hear Dr. Simon talk about the endpoints, you'll see that we included a number of these and very happy to have shown improvement on a number of these in the Phase IIb because similarly, that gives us some possibilities as we go into Phase III and then making sure we understand what's clinically meaningful. And so in the Phase IIb study, we won't talk about this today, but part of the study was to actually conduct exit interviews with a number of subjects to ascertain that so that all of that can go into our thinking for Phase II -- for the Phase III after the Phase IIb that we completed. So with that, I am now going to turn it over to Dr. Kingsberg, who as promised, is going to provide some perspective on the background of arousal disorder in women, the unmet need and the market opportunity for something like this. So Dr. Kingsberg.

Well, thank you, Sabrina. It is really a pleasure to participate in this webinar today. I could and actually usually do, talk about female sexuality all day long. And today, we really want to focus on female sexual arousal disorder. But I think to set the stage, I think it's helpful to really conceptualize female sexual dysfunction as comprised of 4 categories in sexual dysfunction in women. We want to include loss of desire, loss of or lack of genital arousal. The inability to reach orgasm, and pain with sexual activity. I think it's helpful to categorize them separately like that. Now the condition of interest here that the topical sildenafil will treat is female sexual arousal disorder or FSAD. I happen to prefer the DSM-IV diagnosis of FSAD over the DSM-5 classification system that uses FSIAD or female sexual interest and arousal disorder, and I'll tell you why. And in the Q&A, feel free to ask any questions about DSM-IV, or DSM-5 and the fact is that women can meet the criteria for FSIAD, but here's why I think it's helpful to keep the DSM-IV. Although there is often overlap of conditions, such that someone with problems with arousal may not surprisingly lose desire for sex or may have a downstream difficulty with orgasm or without sufficient lubrication experience painless sexual activity. The fact is that separating arousal from desire as a diagnosis provides for a better targeted approach to the condition driving those overlapping problems. FSAD is characterized by the inability to attain or maintain sufficient genital arousal during sexual activity and has to cause a woman distress to meet the criteria for the diagnosis. Distress is key to making a diagnosis. I just want to make -- I could say that a million times, distress. The symptoms of FSAD are primarily muted pleasurable sensation or decreased genital sensitivity, decreased lubrication and decreased blood flow to the genital tissue that inhibits the typical engorgement or swelling of the genital tissues, which then ties back to that loss of sensation. Now in contrast, loss of sexual interest or the DSM-IV condition called hypoactive sexual desire disorder or HSDD is characterized as a lack of or absence of desire for sexual activity, the appetite, your anticipation of. So HSDD is a problem of no interest that causes distress that is women want to want. They want their desire back. Women with FSAD have or had desire, but despite wanting to have sexual activity they've lost the ability to experience genital arousal, the loss of lubrication, engorgement and pleasurable sensation. So as I've said before, having loss of pleasurable sensation can obviously lead to a loss of desire. But it's the temporal issue here. It's the loss of arousal that leads to a loss of desire. In contrast with HSDD, it's the lack of interest that then can lead to a lack of arousal. If you're not interested, your body doesn't respond very well. And this is why the separation of those 2 disorders is better. Think about how you would direct treatment based on which is the primary problem, arousal or desire. Can I have the next slide. I can't see if you forwarded it but that was ...

That's okay.

Okay. So you can consider FSAD as -- actually, as Sabrina said earlier, you really can consider FSAD to be analogous to erectile dysfunction in males. And as you might imagine, males who cannot gain and keep erections, often, it's due to having decreased blood flow to their genitals and poor sensation. And this for men can lead to a loss of desire and difficulty reaching orgasm. So the treatment for both ED and FSAD is focused on the genitals and the PDE-5 inhibitors have been shown quite effective in treating male ED. So it makes perfect sense to use a PDE-5 inhibitor in females and in this case, we're able to use it locally instead of an oral systemic treatment. Now hopefully, we're going to the next slide, maybe. Okay. I've lost my slide for a second. I have to get it back. Okay. So well, I've lost it again. Sorry. We're looking at...

Either you can talk about it with that. It's the patient's experience, right? What is the patient experience?

Okay. So in the patient experience, and I really want to get it back -- hold on, I'm sorry that I screwed it up. Because I wanted to show the -- I've lost it all together, hold on. So in our patient experience, what we noticed is that women will experience the distress of not having the sensation. So like men, you can imagine, when men can't get and keep an erection, they often feel guilty. They feel inadequate. They really lose everything that they thought was appropriate for being a sexual partner. And so they feel guilty, they often avoid sexual activity. And I'm still trying to find it -- sorry, really. Okay, hold on. So when they report their symptoms and what we saw in the trial, is that they will report lack of genital wetness or lubrication. They have -- they can tell that there's lack of engorgement. There isn't that sort of pressure in their genitals, and they really -- it leads to a lack of desire for intimacy given their lack of arousal or sensations. They really are motivated to have that arousal. It is so distressing for them. They -- it's not just about mild bother. These women are completely dissatisfied with their sex life. Can you imagine -- and again, it's analogous to man that without having sensation, here, wants to want, you have that desire, but your body isn't responding. And so they worry about sex, they feel inadequate, and they really are embarrassed, and they often feel like there's nothing that can be done. We know and not to go to the market research then, that about 33% of women -- and this was done by SST before moving forward with the trial, you have to see what the market is. 33% of U.S. women between the ages of 21 to 60, and that's about 20 million women will experience symptoms of low or no sexual arousal. Now when we think about distress, remember that is the key to a diagnosis. That equates to about 10 million women. About 50% of these women had reported that they were distressed, and they were actively seeking treatment or wanted to find some treatment. It's very hard to find. And so what we know though is that it is a completely unmet need, and I don't know if we're on the next slide. But we know that it's a completely unmet need. There are no FDA-approved treatments. We have several PDE-5 inhibitors approved for males that have been available for decades, and we have nothing that is FDA approved for women. So if you think this is sort of a mild unmet need, these women are suffering. They have -- they are searching and they're -- trust me, there are plenty of suspiciously marketed unproven treatments out there that women are spending millions to find treatments for, but we have no sort of double-blind, placebo-controlled trials to show that these treatments are anything better than placebo. So this is a completely unmet need. Women deserve these treatments for female sexual arousal disorder. It is a very different treatment landscape than for desire, which is a central problem, FSAD, that's a genital arousal problem, is really meant for genital arousal. And so with that, and I apologize for screwing up the slides. So I hope I didn't go out of order. But I'm going to turn it over to Dr. Simon. And hopefully, he will -- when we're done with his review of the study, which was fascinating to interview these hundreds of women, we can come back to the question and answer, and I'm turning it over to Dr. Simon now.

Perfect. Thank you Sheryl.

Thanks, Sheryl. So this is just the title slide that says exploratory Phase IIb RESPOND study, and I'm going to take you through the overview of the trial design and the key findings to date. Can I have the next slide, please.

Yes. Hope that you are seeing it?

No. Can you hit next, please? I'd like Slide 16, please.

Yes. It should be on it.

There we go. So we're good, Sabrina. So -- on this slide, this is an overview. So this is, as Dr. Kingsberg noted, an exploratory study classified as Phase IIb to evaluate a particular formulation of Sildenafil Cream versus placebo over 12 weeks of double-blind dosing and this is followed by a -- following a nondrug and placebo run-in, which I'll spend a few minutes talking about as this is incredibly important in all trials where there is a high placebo response. It isn't to say that Sildenafil Cream in this trial is a placebo, but in trials in sexual medicine, the average placebo effect across all domains is typically in the 60-plus percent. So in order to reduce that placebo response, we have a unique trial design, which I'll take you through in just a minute. There were co-primary endpoints. These are patient-reported outcomes, which have their own strengths and weaknesses, so-called PROs. And in this case, they were improvement in localized genital sensation of arousal also known as the arousal sensation domain of the sexual function questionnaire and reduction in sexually related distress specifically focused on female sexual arousal disorder. Secondary endpoint for the trial was measured change in the number of satisfactory sexual events or SSEs. And then there were some exploratory endpoints in this IIb RESPOND trial. And they included efficacy at different time points and an exploratory endpoint to see whether the diary responses within 24 hours of an actual sexual event corresponded to or were correlated with a 28-day recall assessment as very few study subjects in any sexual event-related trial like to record their data right after an event and there is incredible fatigue on the response of subjects when they have to record it multiple times within 24 hours of an event. Can I have the next slide, please.

Yes. So I just advanced it. Takes a minute.

So this is a study design graphic that shows how this Phase IIb RESPOND study was performed first and importantly, over 10,000 women applied to enroll in the trial, giving you in the audience some sense of just how significant a problem sexual function is in women and how much unmet need there is. Those 10,000 who applied to enroll were screened, a subset of them were enrolled. And in the trial, they underwent a no drug run-in for 4 weeks and then a single-blind run-in for another 4 weeks. These 2 run-in periods are commonplace these days to reduce dropouts and to reduce individuals who have a placebo effect and to reduce the ultimate placebo related impact of just being in a trial or just interacting with study staff. The patient screening included phone screening, histories and physical exams and then a centralized clinical interview screening to fully characterize the symptoms and whether there were comorbidities and what those comorbidities were. If there are questions about the central clinical interviews, I will direct you to focus those for Dr. Kingsberg, who has significant experience in this trial and others in that process. Uniquely in this study, partners were enrolled and that was largely to acquire any safety data of the potential interaction of the test article or vehicle on the partners as they had sexual activity together. And the subjects completed these electronic diary assessments both postcoital or post sexual events as well as for the 28-day recall questionnaire in a 4-week time frame. Next slide, please. So in the next slide, we'll be looking at the participant distribution or disposition in the trial. In the first column, you have the analysis set in question. Next column is the group that were randomized to sildenafil, then placebo, and then the total is in the final column, and you can see that the study subjects, whether you're looking at those randomized, those that entered the double-blind phase, those that completed treatment those that were included in the intent-to-treat analysis, safety analysis, et cetera, were, by and large, equally proportioned to sildenafil and placebo with as one might expect a few more dropouts in the placebo group than in the active treatment group, which is common in all trials where there is no benefit to the placebo compared to the active. I don't want to emphasize the differences here. I want to focus your attention on the similarities in all of the data sets that we'll be describing. Can I have the next slide, please. So as opposed to participant distribution, the next slide will look at the female adverse event rates and those two were quite similar across groups. I just went back. There we go. So in the trials of this nature, you want a significant number of captured emergent adverse events. Here, in the first row, called TEAE. You want a high percentage because it tells you that your study team is adequately questioning the subjects for any adverse event. And here, you see about 30% of subjects in both the sildenafil and placebo group had an adverse event. Now an adverse event doesn't mean it's related in any way to the investigational product, it could be a headache. It could be the flu. It could be COVID during this trial captured as an adverse event. You want that first row to have a significant number of adverse events. And in the typical trial, those percentages would not be 30%, they'd be 50% or 60%, emphasizing that this group of study subjects were largely healthy and without underlying illnesses, et cetera, even during the treatment period. Then the next row is treatment-related adverse events, and those are approximately equal between the 2 treatment groups at about 14% and then here's where you want very few in number, then the next row is treatment-emergent adverse events leading to discontinuation of the investigational product. And in each of the 2 treatment groups, you have about 2% of each and a total of 2%, which says that the effect of the vehicle is equal in this case to the effect of the active treatment, about 2%, which is very reassuring for the active treatment product containing sildenafil and shows very few adverse events even relating to the vehicle here labeled placebo. And then we had 3 subjects -- or excuse me, 2 subjects, 2%, where the treatment led to discontinuation of the IP, a very low amount overall. Then underneath this, we have the number of sexual acts with investigational products during the double-blind dosing period, and this is very similar to both groups, although larger as we would hope in the sildenafil group, but does speak to the fact that this study sample were sexually active and enough sexual activity for us to draw some conclusions in the treatment effects And may I have the next slide which should be a summary of the common female treatment-emergent adverse events? So this is Slide 20, a summary of those most common female treatment-emergent adverse events. As I mentioned, COVID shows up right and shining on the top of the infections and infestations group. The other endpoints are illustrated for you here. They include vaginal infections, bacterial vaginosis, urinary tract infections, et cetera, with no big differences between the active treatment groups and the placebo. And then the issues that I would look toward as an investigator as to whether there were application site reactions or application site problems. And there are some with both the sildenafil and the carrier placebo, but they are not different, suggesting that the addition of sildenafil to the carrier vehicle did not increase or change the female reported adverse events. Importantly, there was no vaginal -- vulvovaginal discomfort and [Audio Gap] You can see that the active product has very good tolerability based on these endpoints. May I have the next slide, please. The male partner treatment-emergent adverse events. There's -- any adverse events, we want to capture those in the same way that I mentioned before. There were very few adverse events, only 1 leading to discontinuation of IP in the sildenafil group unrelated to the placebo group. And under a summary of the most common male partner treatment emergent adverse events in the bottom panel of this slide, you see very few events and literally no differences between the sildenafil group and the placebo group with extremely small numbers in the table altogether. And they are largely unrelated to the vehicle or the sildenafil namely the 2 most common being COVID infection and sinusitis. Next, please. So now we're focused on the highlights in the outcomes or the benefits of the treatment versus placebo rather than the adverse events. And here is shown the highlights of the responses. The positive findings from this exploratory Phase IIb trial support continued development of sildenafil in a randomized Phase III trial of a design to be discussed with the agency and agreed to with them as was stated, we have no prior treatments that are FDA approved in this therapeutic class. And so Daré is forging new horizons here. But the Sildenafil Cream did show in this small Phase IIb trial, meaningful improvements in the co-primary endpoints of arousal sensation on the sexual function questionnaire. And even though this endpoint did not achieve statistical significance, and improvements in the secondary endpoints that were prespecified and focus on the sexual experience, including sexual satisfaction, arousal, lubrication, achievement and pleasure of orgasm. And interestingly, given Dr. Kingsberg's dichotomy between HSDD on desire and our focus here on a genital response, there was also an improvement in the sexual experience as it related to sexual desire. And we'll talk about that in the next slide. Next, so these are the highlights of those outcomes. There were more satisfying sexual events with Sildenafil Cream as a proportion compared to the placebo cream, 68.6% and 74.1% at 4 and 8 weeks, respectively. Compared to the placebo of 47.9% and 67.9% at those 2 time points and that were -- those were statistically significant with a P-value of 0.04. There was improvement in overall impression of change compared to -- from sildenafil compared to placebo, 44% to 49% of subjects on active treatment compared to 37% and 44% of subjects on the placebo and those were statistically significant changes. There was an improvement in the arousal lubrication endpoints, which just barely missed statistical significance with a p-value of 0.059. There was an improvement in the achievement of pleasure with orgasm, again, just missing statistical significance with a p-value of 0.066. And improvement, as I mentioned, quite a surprise in this central aspect of sexual function of sexual desire, which was statistically significant from baseline to week 8 with a p-value of 0.02. So I think that the next slide, please, Slide 24. I'm going to turn it over to you, Sabrina for, I believe, Slide 24 and let you -- let our audience know just how we interpret these key findings.

Yes. Thank you, Dr. Simon, and thank you also, Dr. Kingsberg and you'll obviously both be here for the Q&A. So to summarize what Dr. Simon just took you through. And really, this is to set up and give you some perspective for the next steps, which I'll go over in the next slide, right? So as you heard Dr. Simon outlined response was noted in multiple domains, right, a physical arousal as well as interest. So in those data that Dr. Simon highlighted what you saw were improvement in multiple facets, right, of the sexual experience and particularly areas that can be part of that sexual dysfunction experience that Dr. Kingsberg outlined. So we saw improvements in arousal lubrication, which is a very physical aspect of arousal response, improvement in orgasm, as well as improvement in desire. And Dr. Simon also noted when going through some of the demographic data of the trial that -- the fact that there were actually more sexual events in the Sildenafil Cream group than they were in placebo group, which certainly makes sense in the context of these findings. As Dr. Simon also noted, in terms of when did we see the maximum separation from placebo. When was that response demonstrated in the Sildenafil Cream group as opposed to placebo. And what, as Dr. Simon outlined, what you saw in the Sildenafil Cream group, and he highlighted this in the context of desire, but this was seen also with the arousal lubrication and orgasm is at that maximum separation from placebo was demonstrated within 8 weeks post randomization. So in some cases, as early as 4 weeks post randomization. So for those assessments where improvement was noted following Sildenafil Cream that improvement was achieved by week 8, and it was maintained through the end of the study, so through week 12. And this is really important in the context of the FDA guidance document, right? This demonstrates persistence while on treatment. Whereas in the placebo group, there were no such trends observed and no such improvements, right, achieved at the 8-week mark. The other thing that Dr. Simon highlighted, which is very relevant for the program going forward with the concordance between the findings on that arousal diary, which as he noted, can cause a lot of patient fatigue gets administered every -- within 24 hours of the sex act, so not always the funnest thing to have to complete. That was formerly compared in this study to a 28-day recall period. To provide support for endpoints that reduce patient burden as the 28-day recall does. So fortunately, that is what we saw that the arousal diary in 28 -- recall responses were similar between groups and that really provides support for the less burdens on longer recall period. So what does all of this mean in terms of next steps? So I want to highlight a few things before we open it up for the Q&A. So in terms of next steps, as you can probably guess. The activities are very focused on getting in front of the FDA for an end of Phase II meeting so that we can really solidify the Phase III program with the FDA. And to do that, there is an important activity that is underway, and that's related to what's called the psychometric analysis of the Phase IIb study data set, so that's really an analysis that allows us to put together the full report on the validation of all these end points, it allows us to further refine the measures and the endpoints that we saw in the completed study and really package them up for use in a Phase III pivotal study. So that is underway as long -- as well as the other preparations, right, for an end of Phase II meeting with the FDA where all of these results will be discussed with the FDA. But importantly, the proposed Phase III program can be discussed with the FDA. So what are some of the considerations for the Phase III program for discussion with the FDA? And I want to tell you right now, we don't have the answers to all of these today, but I want to highlight the type of things we're looking at and why this data set that we've generated is exciting to have this data set in the context of this. So one is the indication in patient population. So as you heard from Dr. Kingsberg and Dr. Simon, the women in this study had to have arousal problems as their primary complaint. Their primary problem with their lack of physical arousal. What we saw in the study is that we showed improvement on sexual interest as well as arousal and orgasm, so that does provide an opening to consider both of the DSM diagnostic criteria that include arousal DSM-IV, which cause arousal out as its own stand-alone only arousal complaint syndication as well as a diagnosis in DSM-5, which is arousal along with interest disorder. And so we do have that opportunity, and we'll need to consider, right, which is the potential indication to pursue. The FDA encourages sponsors to conduct the trials in a well-defined patient population. We did this in the Phase IIb that we really will have a good understanding of who that patient was that responded well. And that we can take forward to the FDA as we propose our go-forward program, specifically in this context of arousal disorder or interest arousal disorder. Primary endpoints the FDA and the guidance document gives that menu from which a sponsor can select in terms of looking at satisfactory sexual -- satisfying sexual events, sexual interest, or desire, sexual arousal, which, in our case, we really like talking out within the context of arousal lubrication, which is very easy for women to understand as well as orgasm and then also sexual distress, which we like looking at in the context of the patient global impression of change of concern. So we have multiple domains that were improved in the Phase IIb, very specific to this menu from the FDA. And that really gives us an opportunity to design the Phase III endpoint in a way that makes sense, specifically for our product that had such a broad impact on sexual dysfunction. And we've got some choices that we're going to need to make through the data analysis that is ongoing right now in terms of whether we recommend responder analyses or co-primaries versus what's primary versus secondary. So that's part of a lot of the analyses and the psychometric analysis of the database that's going on right now. And then finally, we also have to give some consideration and recommendation to the FDA in terms of the duration of the study and the efficacy assessment timing, so as we talked about, we saw a really nice separation as early as 4 and certainly within 8 weeks post randomization. And then that nice persistent response through week 12. So this really does give us some opportunity of thinking about and proposing to the FDA as requested through their guidance document of when we measure -- when we're looking for that efficacy improvement compared to our product, which is on demand. So that gives us a lot of flexibility and timing. We can push for an earlier time point because it is an on-demand product versus requiring long-term administration before one would expect to see an effect. And then importantly, we were able to demonstrate that the 28-day recall, which is less burdensome was just as correlated nicely as a 24-hour recall, so that we can make a case to rely on the less burdensome longer recall period for the subjects. So those discussions with the FDA around these findings are going to determine the efficacy endpoint assessment timing and the Phase III duration. But we have a lot of great data from the study to support that. And then finally, I just want to highlight that this is a 505(b)(2) pathway program. So it is the same active that is in Viagra. So it is a brand-new indication, so that does mean that 2 Phase III studies would be expected to be required, but we are able to rely on a lot of the systemic safety information from the male Viagra program. So with that, let me open it up for any questions.

[Operator Instructions] Your first question will come from the line of Catherine Novack with Jones Research.

My first is for both Dr. Simon and Dr. Kingsberg. I'm curious if you can just discuss FSAD from a clinician's perspective, how is it typically recognized in the clinical setting? What relevant information do you gather from the patient? What are the hallmarks of the disease that allow you to rule out conditions with similar symptoms. And then following on that, how would this change if there were an FDA-approved treatment for FSAD? And then I have a follow-up question.

So I'm happy to weigh in initially. And in the absence of relationship issues, comorbidities and medical problems. And that's a big start. Patients complain as Dr. Kingsberg suggested of being in the mood or having desire for sexual activity, but just never responding in the context of a loving partner, they don't respond with getting wet and/or feeling pleasure, they don't feel tingling or throbbing of the vulvar and clitoral area and they just don't have a positive interaction because they may have secondary to dryness and absence of those arousal responses, they may have pain, dryness leads to pain. So this is easy to disentangle with simple questions in the office and not typically something that requires a lot of blood work or dynamic testing or anything else. Does -- Sheryl, do you want to add anything?

Sure. Well, I'd like to talk myself right out of a job, but it really doesn't take a sexual medicine expert to be able to diagnose FSAD because I think that should be one of the questions. Can a generalist be able to diagnose it without having to go into great detail. They only have maybe 10-minute visit. So women will come in. I certainly encourage every clinician to ask about sexual concerns as part of their general history. But if a woman is distressed, she would be more than happy to jump in and say I'm having sexual concerns. The key to teasing out the diagnosis really is, which is the primary symptom. And women are very clear, and I interviewed hundreds of them, whether -- which came first, because that is always frightening to people well, how do I know whether it's an orgasm or arousal or desire problem, women will know, and they can tell you I have lost sensation. And as a result, I really don't want to have sex anymore or it hurts when I have sex, and that gives you the FSAD diagnosis. To your point of, are there other medical conditions that could confound this maybe, but it's the same that's true with ED. There are many reasons why men develop ED from other medical conditions. And while the old diagnosis says you need to -- if it's not -- if it's better explained by another medical condition, it's not the diagnosis. In this case, the genital problem may still respond to the sildenafil. So it's -- in that case, it will be an empirical approach with very -- the safety is very high. And to Dr. Simon's point about ruling out other psychosocial issues, women are smart, and they can tell you whether their lack of arousal is due to a poor relationship or a bad lover versus the fact that their sensation has been muted or their lubrication has changed.

Let me also add for a nonclinical audience that even though we try from a social aspect not to compare women and men, they're different, their parts are different, et cetera. We don't want to objectify men and women. But the answer is, from a sexual response point of view, the thinking about desire versus thinking about erections in men or thinking about desire for sex in women and then thinking separately about arousal, which, in this case, we can say lubrication, tingling, throbbing, pleasurable vulvar and vaginal and clitoral swelling, these are very analogous responses even though the physical parts are different. And I do think that in a nonclinical group, thinking of them more as being the same than different, is quite helpful.

That's very helpful and then I had a question a little bit on patient population. I know you haven't made any specific announcements about this. But are there medical issues that you would explicitly exclude from pivotal study that might confound the efficacy results?

So maybe I'll make a comment and then Dr. Simon and Dr. Kingsberg can definitely weigh in. But from a regulatory perspective, when you're running a trial like this, there are expectations about certain right exclusionary -- inclusionary and exclusionary provisions, right, around the patients. And so this study was designed with sort of obvious ones in place around other medical conditions that could confound findings, requirements around how long the women had to have -- had arousal problems, right, it not being just situational. So we would expect those similar kinds of constraints and considerations as we think about going forward. But I do want to highlight one of the things that or a couple of things actually that we did in this trial that are likely not relevant in the Phase III program, and then I'll definitely turn it over to Dr. Simon, Dr. Kingsberg is we, as Dr. Simon talked about, we enrolled the partners and I should highlight the partner, we focused on the male partner adverse event, frankly, because there were many more male partners in the study. But from a partner perspective, we wanted to demonstrate that the product was safe for the partners so that we don't have to enroll the partners going forward. So we are obviously thrilled with having had a lot of sexual events, right, over 2,000 sexual events in the study and having such a low rate of adverse events, not only for her, but for the partners in the program is helpful. So going forward, that's not a consideration. But a lot of the other standard medical exclusionary criteria, we would expect to be similar. But I don't know, Dr. Simon and Kingsberg, anything else you want to highlight on that?

No, I think one of the things that will always come into play will be medications that might ultimately be excluded or may indicate a more global vascular problem, those might be discussion points with the FDA in terms of designing the ultimate study population.

Yes. And then maybe some analyses, right, to allow certain things in, then maybe we might want to analyze them difference, for instance, right? We know that the SSRIs, for instance, right, can change, right? Someone's desire perspective, potentially routes and response. So there are things that we know that may also impact some of the decisions made around inclusions and exclusions.

And I'd like to jump in with another local condition. You need to think about some of our dermatologic conditions that will probably be rolled out like in sclerosis. But again, usually ruled out in these kind of trials, and this is a premenopausal population. So we're not as worried about vulvovaginal atrophy but the dermatologic conditions probably will be considered.

Yes, as they were in the Phase IIb.

Got it. And if I can just sneak in one more question. Looking at the population for the ADI pivotal trials, we see that they were enrolling women who are in monogamous heterosexual relationships. Is that something that you're continuing the study? Or are you going to see a more diverse population of relations ...

Great question. We allowed great diversity in the Phase IIb, and we look forward to continuing to allow great diversity. So in Phase IIb partner of choice or no partner. So we actually also had some women who participated in the study unpartnered and that was okay, right? They could just use the product on their own. And so -- and partner -- male or female partner was allowed, and we would foresee particularly giving these findings to be able to proceed into Phase III with a similar demographic.

Your next question comes from the line of Douglas Tsao with H.C. Wainright.

Just maybe for the 2 physicians, I'll start with the question. Just trying to understand or your perspective on the challenge been treating FSAD versus HSDD, where obviously, there have been a couple of products launched and we haven't seen as much commercial adoption as perhaps some expected or thought and I know there's been some limitations in terms of the dosing and the side effect profiles for those agents. But how do you think about the relative potential or ease of adoption of something like Sildenafil Cream in FSAD versus what we've seen with the drugs treating HSDD?

I think I'd like to go first and quickly and you leave the more substantive aspects to the question to you, but I'm happy to weigh in after. I think there are dramatic differences in acceptability of a as desired or on-demand treatment versus a systemic treatment that is either daily or that is by injection. And so I foresee many fewer barriers to using -- to be a little colloquial, a little dab of this product than having to take a pill every day or having to give yourself an injection, even if it's as easy as an auto injector for any aspect of sexual function. And I think that as it relates to HSDD, the dosage forms and the need to use for daily flibanserin, our barriers at least in terms of reminding the patient that she's got a real problem.

So from the clinician perspective, I think the adoption will be much faster and easier. I think sildenafil has been around since 1998. And so everybody knows it, everybody knows how it works. There is no question for a clinician, what's the mechanism and now that it's local, there is no concern about the systemic effects. So you've got 2 advantages. One is people know what it is, and it is now local without a systemic effect and women will know quickly whether it works for them. And I think women will be willing to try it again because it is local. And really, there are no approved treatments. And trust me, they are spending millions of dollars on other unproven treatments. And so if there is access from clinicians who are willing to prescribe it. And like I said, I think they will, I think that will be a big game changer.

And I guess for Dr. Kingsberg and Dr. Simon a follow-up. I'm just curious, when you look at the top line data, what is maybe the most surprising thing that you saw in the Sildenafil Cream data? And also maybe what's the most encouraging thing? And then I have one follow-up for Sabrina.

Well, Jim, do you want to go? Or you want me to go first?

So I've already said that what was most surprising was the impact of an arousal therapy that worked on desire. Now that is not surprising if something improves your experience, you're going to want to do it more. But using Sheryl's dichotomists discussion and description of HSDD versus FSAD and then her description of the DSM-IV versus 5 way of taxonomy. This was the biggest surprise to me that the women in this trial had better response in terms of the primary endpoints related to arousal, but that converted in them to a greater desire to have sex. That was the big surprise for me.

Well, and I'd like to say it wasn't a surprise for me because it's kind of what I said earlier, it is a downstream effect. It makes perfect sense. Now remember, these women did not have primary HSDD. They might have had secondary, but many women -- so you have a population of women who either had arousal with no other disorder or they had overlap as long as FSAD was primary. So some of these women enjoyed once their arousal was back, it makes sense that their desire would come back. And for some, they're -- with having arousal, their desire got even better. So I think that you're looking at a population where it makes perfect sense that the downstream effect would be not only better orgasm but better desire. And what is surprising to me is that we really could use as much as I prefer the DSM-IV categories in classification, you could use the FSIAD as a diagnosis, and that will be up to Daré to decide but it would -- but these women who would meet the criteria for FSIAD could certainly be included. I just think it's cleaner to look at an FSAD primary as the diagnosis.

Okay. Great. And just one question first of rigs given the richness of the data set and the need for 2 Phase III studies, I'm just curious if your thinking in terms of 2 identical Phase III studies, which obviously sort of adds a certain level of operational simplicity versus potentially having some variability in terms of the endpoints and potentially getting a richer or broader data set that could be used for labeling?

Yes, Doug, fantastic question. So it's definitely something that we're looking at. And I'm with both Dr. Kingsberg and Dr. Simon, when I say, on the one hand, we probably should not have been surprised about desire, given the improvement we saw, right, and not only arousal lubrication and as Dr. Simon noted, that -- and both Dr. Simon and Kingsberg noted, lubrication is something that women notice right? So seeing improvement in that and in orgasm probably should not be surprised that we saw the improvement in desire as well. However, it was not anticipated. It wasn't even part of our top line data set. We weren't anticipating that we would show not only improvement but statistically significant improvement in that. And so it does allow us to think about just as the guidance document allows, right, studying a population that definitely has arousal, right, as a problem. But maybe even a broader population, right data set that the FSIAD, DSM-5, right allows one to contemplate. So I think it does open up for that. And then in the design of the trials, I mean, again, we saw this improvement. We saw the sildenafil group were on those domains where they showed improvement. It happened relatively quickly, right, within that 4 to 8 week time frame post dosing, and then it was persistent. The guidance document calls for 24-week studies, but we do think there's a possibility here, right, to have a conversation with the FDA around shorter trials. And you see that with -- in erectile dysfunction. Some studies were 3 months, right? So to your question, these are the kind of things you want to explore. I do think there's some positives to potentially, if it can be done in a favorable, right, sponsored-favorable and women-favorable way, to have 2 slightly different, right, trial designs that ultimately get us the same outcome, but really ensure that it's very clear the broad patient population that this can serve, right, and the different ways that it can serve that population that could be a great value too. So as we're doing more deep dives into these data. These are relatively new data, right? We only got the top line last month. These are relatively new data. We're doing a lot of deep dives, ad hoc analyses, planned analyses so that we can really come forth with a Phase III program that is in the Daré way as kind of thoughtful, but as time and capital efficient as possible, but gets us the labeling that we want right? We've executed on that one. We'd love to execute on that again in the context of this program, and that's what we're thinking about. The long answer to your question and couldn't answer it totally specifically, but hopefully, you have some sense of how we're trying to think creatively about we do have some nice richness in the data and the opportunities, and we want to leverage it as best we can.

Your next question comes from the line of Kumar Raja with Roth Capital.

Very helpful. My question is for Dr. Kingsberg and Dr. Simon. I just wanted to get a perspective in terms of what do you see in terms of split of FSAD patients in premenopausal versus postmenopausal? And what are your thoughts in terms of physiological response with the [indiscernible] in the postmenopausal women?

So I'm happy to jump in on this. What I would say is that all sexual dysfunctions tend to increase in prevalence up to and including the age of menopause around age 50. This includes both desire disorders and arousal and orgasmic disorders. So the prevalence goes up. And the distress after about age 55 or 60 tends to go down, whether that is a partner issue or an acceptance on the part of women in that age group, I don't think is known. But certainly, for women in menopause or in the early menopause, say, 50 to 60, these are highly prevalent issues and more prevalent than they are in younger women as was studied here. And I do not personally believe that there's a real difference except for the potential in menopausal women for pain being a comorbidity. I think the dichotomy on desire, arousal and orgasm, between pre- and postmenopausal women is largely an FDA hallucination and not a real biologic difference beyond just the pain or dryness that is a comorbidity in menopausal women and typically not a big problem until at least age 55.

Well, I certainly would agree with Dr. Simon that there is no reason to really separate out pre and postmenopausal women. And the only reason that's been done in the HSDD trials and now here is that's an FDA requirement centrally. And the only issue with the postmenopausal population may be whether or not you treat the genital urinary syndrome of menopause first or simultaneously to see if that resolves some of the problems. But otherwise, I agree with Dr. Simon. The prevalence is probably higher in postmenopausal women, but it is pretty darn high in premenopausal women. And I think both absolutely will benefit from the topical sildenafil.

Okay. Great. Sabrina, I had one question for you. You talked about shorter efficacy period. And in terms of safety, FDA request a 52-week safety. So what are your expectations there? Like if they agree for a shorter efficacy you think even the safety follow-up would be shorter?

That's certainly our hope. I mean, look, the data that Dr. Simon went through on the adverse event, I mean part of why we were so interested, obviously, in seeing those data and also collecting the data on the partners is to make sure that what we hypothesized would be true, right? We did not expect that the adverse event profile should be different between placebo and active because the levels of systemic uptake of sildenafil are quite low, right, with this dosage form. It's very localized. So that's exactly what we saw, right, not really systemic effects, localized effects that were mild and transient and as Dr. Simon outlined, really did not lead to discontinuation right, of the product. And so really have that nice safety profile across a large number of events. So our hope is that one of the reasons that sometimes you want a 24-week study is because you have to demonstrate safety, right? as well over that period of time. So -- and to be clear, that's definitely what the guidance document says. But obviously, we want to try to see if there's flexibility on that, given the scientific data that we've captured, right, which demonstrates a safety profile from the topical formulation that is just quite mild, right? The most common events were just localized reactions that were proportionally not a large group of women and same in both groups.

Your next question comes from the line of Kemp Dolliver with Brookline Capital Markets.

Great. So first question relates to the winnowing process from 10,000 people expressing interest and then who you actually enrolled. Was this a case where you saw people they saw the headlines, they got excited about the topic, hit the button and then you found along the way that many of them really didn't appreciate what they were getting into? Or were there -- how many other factors were involved in that process?

So let me give a high level, but then I'm going to turn it over to Dr. Kingsberg, who actually, as I mentioned, ran the centralized screening that we did with the clinical interviews. So -- but I'll start first to give you that high-level perspective. So definitely, you put something out there about an arousal trial, and it absolutely peaks people's interest which is great, right? It's kind of like Dr. Simon talked about. You want to see that, right? You want to see that there is enthusiasm to explore something like this further, right? So we definitely saw that. But then you -- obviously some people as they dive in and they understand what's required in the study, right, suddenly realize, "Oh, I didn't know it was going to be 5 months in duration. " So in terms of weeding people out in the early phases, the 2 things that someone may have noted instead of this isn't for me, was related to -- it's not so much the duration of the study, but that they had to be in the same relationship the whole time or no relationship. So for some women, that just wasn't an option, right? So they were not a good candidate. But the other was that in this study, which we do not anticipate in Phase III based on the safety profile we demonstrate, but this is first-in-human study of this nature where it gets to be used in a sex act predominantly with another person. We had to enroll the partners. And so for -- obviously, for some couples, that just wasn't an option right for them. But then after that point, it really came down to the medical screening. So as Dr. Kingsberg and Simon both talked about, there were certainly medical conditions, comorbid conditions, comorbid vaginal pain conditions or other things like that, that made someone no longer candidate for the study. But then once they made it through all that, they went through a clinical interview process. And for this study, in particular, we really wanted to make sure we, in the clinical interview knew everything we could about her arousal problems and what else is going on in her life and if there were any anything that we felt couldn't be captured and documented well, she may not be a great candidate for the study. So maybe Dr. Kingsberg, if you don't mind just giving a little overview of that clinical interview process.

So actually, one of the only fringe benefits or silver lining COVID is telehealth. And so we were able to do these centralized visits face-to-face using Zoom. And we really were able to spend 20 to 30 minutes interviewing these women, and I had created a structured interview but women were very forthcoming and very candid with describing their symptoms. And in terms of the who we excluded, I'd say 80% by the time they got to us, the vast majority had been excluded for other medical reasons or your medications. But within our interviews, it really came down to some women, it was clear, had relationship issues when they were excluded and for others, their -- it was a primary orgasmic disorder or they had lifelong arousal disorder, and this was an acquired condition. I should have clarified that FSAD has -- it's either generalized or situational. And so women had to have generalized that was. It's not just due to one particular partner or activity. It's generalized to all sexual situations and it needed to be acquired, that is women needed to have an experience and know what they consider normal arousal was for at least 2 years of their prior life if they were going to be in the trial. So some women were excluded because they had lifelong and others were excluded if their primary diagnosis really was hypoactive sexual desire disorder and their downstream effect was no arousal or many heads, for example, lifelong orgasmic disorder and/or, again, the primary issue was pain. So it was very fascinating to see how women presented, but that is how we've excluded them, and we whittled it down to the 200 in the trial.

Yes. And I think the good news of all of that is some of the places, the things that were kind of gating right, in this study for some women for their participation. As I mentioned, the most significant was the male partner, right? And it wasn't actually -- if they had a female partner that tended to not be a problem. It was the male partner needing to formally enroll in this study. And it wasn't a problem per say, it just took extra work on our part to provide the site and the patients with educational materials, right? And also, in that point, this hasn't been studied before. I mean, honestly, now if we had to do it again, I don't think it'd be a big problem because you'd have as part of the consent, the Phase IIb findings of what might be experienced. But for this first study, we didn't obviously have that. So we couldn't point to that. And as Sheryl noted, we went to -- Dr. Kingsberg noted, we went to a lot of effort in the clinical interview to really characterize each woman who did participate in the study and also thoughtfully -- not only thoughtfully exclude people but also thoughtfully try to include people that might have some of these other conditions, right? She had primary arousal disorder but had -- was complaining about her interest or desire as well so that we could have a data set that allowed us to kind of understand the nuances between the patient groups, all of whom had arousal problem.

The next question is for some context because the trial was not powered for efficacy, but you do have some P-values in here on some of the measures. So does that caveat of powering applied to all the data you've presented? Or were some of the -- are some of these actually adequately powered?

Right. And I should be really clear on that, because I don't want to have any of those points unnecessarily cause confusion. This is the first trial of its kind. So one has no idea what -- when we designed this trial, there weren't other studies of arousal specifically in women that we could point to for our powering assumptions for our effect size assumptions to know what a clinically meaningful improvement might be. And as you may recall, so we had to make some assumptions, which obviously we did. And then based on an interim, a blinded interim look to just understand like that statistician was guided to let us know, like does it make sense to stop the site or should we continue enrolling because the whole point of this study is to figure out and put forward to the FDA a plan for Phase III. And frankly, we don't need statistical significance on anything to do that, right? You just needed to understand what is the clinically meaningful improvement, what endpoints demonstrate separation, right? Can we use a 28-day recall all the things we've been talking about. And so we stopped it with the 99 subjects per arm. And so as you can see, like on desire, we did hit statistical significance. 99 is sufficient power per arm to hit significant on that endpoint. And for other endpoints, you need a little bit more, right, than 99 per arm. And so we wanted to make sure that people understand and understood at front, this trial was not designed with the expectation that if you don't hit a 0.05, it's not a success. It was designed to tell us where do we see improvement? When do we see improvement, right? What are the outcome measures that women who have an exposure to Sildenafil Cream, which we know from other studies that we've done increases the blood flow, right? What are the best tools? What are the best questions right, to capture that. What does she notice, right? So again, hindsight's 2020, but not really surprising that actually arousal lubrication of all the types of questions we asked stands out, right, as Dr. Simon actually highlighted, right? That's what women notice. They noticed lubrication. They noticed whether they had an orgasm or not, right? And fantastic to know that they noticed that they had more desire and that, that translated into more sexual events. So that's a long way of saying, yes, I mean, what this study now allows us to do is know for every single one of these end points what is the end to ensure, right, what is the effect size. And therefore, what's our end, right, to get the confidence interval we want to achieve the power, right adequate power for the study. So now we know that.

Right and my last question relates to the timetable for next steps. Given that you're still conducting analyses, is there any reason that you might push out your timetable for an end of Phase II meeting because you want to do another dive into some other pieces of information? Or do you feel like you have a very good handle on the data you want to generate for FDA?

Yes. Great question. So we definitely want to do this right, right? You only get to have an end of Phase II meeting, you get that first end of Phase II meeting experience, right, one, so we want to make sure that we take the time to do that appropriately, and this is a very rich data set. Having said that, we have plans and time lines to work as aggressively as we can to get through all the data, which we are not all the way through, to get through all the data in detail, these other analyses we want to do because of the exciting findings we've seen, right, that just prompts more analyses, and we're not done with the psychometric work, which is a requirement, in a report this requirement. For that end of Phase II meeting and for the endpoints to be used in Phase III. But we are prepared to move, and we are moving fast and aggressively. This is -- these are very exciting findings, and we want to move as fast as we possibly can to get in front of the FDA with the caveat being, obviously, there's a process, right, to making a meeting request. There's a process to a briefing book and the timing of that. And obviously, there's certain reports -- formal reports that have to be a part of that for that to be an efficient meeting. So we're working as fast as we can. And I do look forward to giving a more concrete update on that timing, once we have that timing confirmed, which does involve the FDA as well, obviously.

This concludes our questions for now. I turn the call back over to Sabrina.

Great. Well, thank you, everyone, for your participation today. Thank you, and particulate to Dr. Kingsberg and Dr. Simon for leading the discussions today and sharing your expertise around sexual health and female sexual health specific to the discussion today. So sincerely thank you on behalf of Daré to both of you, thanks everyone on the call and very much look forward to keeping people updated about these programs and moving forward. And hopefully bringing something forward to women that they have not yet had and very much deserved as men have had for the past almost 30 years. So thank you all.

Thank you for attending. You may now disconnect.