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DARE: Upcoming Milestones Inc FDA Feedback on Topical Sildenafil FSAD Program

09/19/2018
By Brian Marckx, CFA

NASDAQ:DARE

READ THE FULL DARE RESEARCH REPORT

Q2 / Pipeline Update
Daré (NASDAQ:DARE) continues to not only move their various development programs forward, but also continues to add promising candidates to their high-potential women’s health-focused pipeline. Relative to the former, DARE provided development updates during recent presentations at two of the most highly anticipated annual small-cap conferences; Canaccord Genuity’s Annual Growth Conference (August 9th) in Boston and H.C. Wainwright’s Annual Global Investment Conference (September 6th) in NYC. Relative to the latter, DARE’s most recent pipeline addition, CatSper, a potential first-in-kind contraceptive for both men and women, was announced in mid-July. We cover DARE’s pipeline-related updates below.

The Q2 10-Q was filed in early August. As anticipated, operating expenses climbed from the previous quarter, reflecting personnel additions, Ovaprene development-related costs, expenses related to the (May) acquisition of Pear Tree Pharmaceuticals and an increase in licensing fees related to Juniper’s intravaginal ring technology (which DARE secured in April).

Cash balance was a healthy $12.5M at Q2 quarter-end and the balance sheet remains debt-free. Cash balance should further benefit from ~$1.7M that remains under the NIH grant related to development of Ovaprene. Securing non-dilutive funding, such as this recent award, is an ongoing goal for DARE. Given that their focus on developing novel contraceptives aligns with the goals of foundations and certain government initiatives aimed at reducing unwanted pregnancies through increasing the use of birth control (which includes providing new contraceptive options), we anticipate further success in securing non-dilutive funds.

DARE Adds Novel Preclinical Contraceptive Candidate for Men and Women
In mid-July DARE announced an asset transfer agreement with Hydra Biosciences for their CatSper ion channel intellectual property. Ion channels are membrane proteins that allow for the flow of ions, and therefore the transmission of information, into cells. Backed by some of the largest global life sciences-focused venture capital funds, Hydra’s main focus is the Transient Receptor Potential (TRP) ion channel and the development of drugs for diseases that may respond to modulation of the TRP channel.

While CatSper, or Cation Channel of Sperm, is distantly related to TRP, it is unique to sperm. The CatSper channel is essential for male fertility, controlling entry of calcium (Ca2+) into the sperm cells, which is necessary for hyperactivation (i.e. swimming) to occur. Significant preclinical work has already been done that indicates CatSper may be a viable target for contraception. The CatSper family consists of four members, CatSper1 through CatSper 4, all of which are required for fertility. CatSper 1 and 2 have been established as critical for hyperactivity and motility while CatSper 3 and 4 are believed to play a role in the acrosome reaction (i.e. a process as the sperm approaches the egg). Studies on mice have shown that disruption of one or more of these channels resulted in immotile sperm but did not affect sperm production.

A drug that could temporarily block or disable CatSper could serve as a novel contraceptive option and could, at least theoretically, be taken by men and women. And, given that CatSper is unique only to sperm presents the possibility that a highly CatSper-targeted therapy could be virtually side-effect free.

The novelty of the target, non-hormonal nature and the potential that a CatSper-targeted contraceptive could be side-effect free and used by both men and women would put it in a class of its own. It also lends itself to increasing contraceptive use and, therefore, fits perfectly within the mandates of the NIH, the Bill & Melinda Gates Foundation, FHI 360 and other agencies and organizations which have provided funding for the development of novel modes of contraception which can help to reduce the rates of unintended pregnancies.

Ovaprene update
Ovaprene is DARE’s lead development program with a post-coital trial (PCT) ongoing and currently anticipated to have topline data in Q2 2019. (For reference, the clinicaltrials.org posting is here: NCT03598088). As a reminder, DARE plans to use results (assuming positive) of this trial to petition FDA for IDE approval of a pivotal randomized controlled study. Importantly, current anticipated timelines are unchanged (i.e. not delayed) from prior expectations.

The PCT is a single-arm, 25-participant trial assessing the ability of Ovaprene to prevent sperm from penetrating the cervical mucus. Secondary measure is the change in ferrous gluconate (i.e. Ovaprene’s spermiostasis agent) in the cervicovaginal fluid from pre to post-coital. Inclusion criteria requires participants to have previous had tubal sterilization.

Each participant will be followed over the course of five menstrual cycles and cervical mucus will be evaluated as follows; baseline at cycle 1 with use of no contraception, cycle 2 with use of Caya diaphragm, and cycles 3 through 5 with use of Ovaprene. The purpose of the Caya diaphragm (in cycle 2) is just to validate that the study conditions do not influence results as compared to what would be expected in the real world. ‘Success’ of effectiveness, which will be defined as finding five or fewer sperm per high-powered field in the cervical mucus, means that DARE would expect to move immediately towards an IDE package for approval to conduct a pivotal study.

Pivotal study, as envisioned today, is expected to include ~250 participants with evaluation over 6 months. Primary endpoint would be pregnancy probability as well as safety. Secondaries are likely to include user-type feedback such as ease of use, fit, comfort, etc. So, assuming success on efficacy and in hitting their timelines in the PCT, a pivotal study is still realistic to commence in 2020/2021. If all goes well, an FDA PMA filing could happen in 2021/2022 and it is possible that Ovaprene could launch in the U.S. by sometime in 2022/2023. All these timelines are unchanged from our previous estimates.

Topical Sildenafil
Topical Sildenafil (TS) is DARE’s deputy-lead program, rights to which they licensed in February. DARE plans to develop TS for Female Sexual Arousal Disorder (FSAD), a condition characterized by the inability to attain and/or maintain sufficient physical sexual arousal and also characterized by stress. While FSAD is estimated to affect approximately 13M women in the U.S., no products currently exist that are indicated to treat the condition. While FDA does recognize FSAD as a distinct condition, the agency has never explicitly defined the specific symptoms or physiological traits of what constitutes FSAD. But, that’s mostly because an FSAD pivotal study has not yet been successful.

The safety and tolerability profile of sildenafil, which is the active ingredient in Viagra (pill), has been well-established in men. Unlike Viagra, Topical Sildenafil is a cream and designed for local administration. This is expected to provide much more targeted therapeutic effect on the genitalia and mitigate the risk profile as compared to oral Viagra. Topical Sildenafil has already been evaluated in a phase 1 (n=21) and phase 2b study (n=31), which
demonstrated that it was well tolerated and resulted in increased blood flow to the vaginal tissue in both pre- and
post-menopausal women. IP includes six issued U.S. patents related to topical delivery. Given sildenafil’s (i.e.
Viagra’s) known safety profile, a 505(b)(2) FDA NDA pathway may apply.

DARE indicated that initial discussions with FDA, mostly focused on defining FSAD in the context of clinically meaningful endpoints, have been fruitful. Given the current ambiguity of what defines “FSAD”, and the sizeable boneyard from failed attempts by others at designing a ‘female Viagra’, we are glad to see that DARE is taking a very pragmatic approach – as anything else could be a sizeable mistake and waste of time and money. And while there is no precedent for what an appropriately-designed FSAD clinical study would like, FDA’s Draft Guidance for Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment, published in October 2016, provides at least a starting point to work from.

We also think it is important to keep in mind that while there remains ambiguity in terms of how to define and measure clinically meaningful “arousal”, that the lack of complete clarity is not FDA’s intention – in fact, we think recent history shows that FDA’s goal is to facilitate industry’s development of novel drugs to treat women’s sexual function disorders – and part of that is working with companies like DARE to design feasible clinical trials (including defining and measuring endpoints). We think this is a critical point and is one of the reasons why we are spending so much time on this topic.

Sexual arousal and desire are more complicated in women: with men, an erection is correlated to arousal and arousal is correlated to desire to have sex – which means defining ‘arousal’ and ‘desire’ (and the connection between the two) in men is straightforward, as is designing clinical trials for novel ED drugs. With women, the connection between desire and arousal, appears to be more complicated – which complicates (or, at least increases the challenge of) designing female sexual dysfunction related clinical trials.

Pfizer (PFE) hoped to show that oral sildenafil (Viagra) would be effective at increasing women’s sexual arousal and desire to have sex as it has done so successfully in men. While studies showed that it was effective at increasing physiological arousal (i.e. genital stimulation, blood flow/clitoral engorgement) (Caruso et al., Erkan et al., Laan et al., Berman et al) in women, that was not significantly correlated to an increase in their (psychological) desire for sex. Following “inconclusive results” from several large scale, placebo-controlled studies with over 3,000 women, PFE subsequently dropped their female Viagra program.

Sildenafil increased arousal but trial design was flawed: Interestingly, PFE’s thesis that oral Viagra could increase women’s sexual arousal actually appears to have merit. We think that where Pfizer may have failed was in trial design, which appears to have been influenced by the assumption that arousal correlates to desire. Instead of focusing only (or mostly) on ‘arousal’, it appears they used a variety of female sexual dysfunction endpoints. There are only two PFE sildenafil FSD-related studies still listed on clinicaltrials.gov. The largest of which (n=267) is an open label study which used the Sexual Quality of Life-Female (SQOL-F) questionnaire as a substantial basis for the outcome measures. SQOL-F, an 18-item self-reported outcome instrument designed by Pfizer, focuses on measuring ‘sexual confidence’, ‘emotional well-being’ and ‘relationship issues’ – clearly not indicative of an arousal focus.

Our thesis that failure in proper clinical trial design as a result of incorrectly assuming correlation between arousal and desire seems particularly plausible given that at that time, there was virtually no reliable evidence for basing FSD-related clinical trial decisions. If PFE had focused solely on ‘arousal’ and in designing an appropriate clinical program around efficacy on FSAD, efficacy may have been much more favorable.

DSM: FDA considers guidance from the Diagnostic and Statistical Manual of Mental Disorders (DSM) in their industry guidance related to clinical trials for women with disorders related to sexual desire and/or sexual arousal. DSM, published by the American Psychiatric Association, is periodically updated. DSM-IV (published 1994, revised 2000) categorized FSAD and hypoactive sexual desire disorder (HSDD) as separate conditions. Under DSM-IV;

• FSAD is defined as “persistent or recurrent inability to attain or maintain until completion of the sexual activity an adequate lubrication-swelling response to sexual excitement, the disturbance causes marked distress or interpersonal difficulty and is not better accounted for by another Axis I disorder (except another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition”

• HSDD is defined as “persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity, the disturbance causes marked distress or interpersonal difficulty and is not better accounted for by another Axis I disorder (except another Sexual Dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition”

DSM-V was published in 2013 and modified the characterization of arousal and desire disorders – stating that they could not be reliably distinguished and, therefore, combined FSAD and HSDD into a new category called Female Sexual Interest/Arousal Disorder (FSIAD). FSIAD is defined as;

• lack of, or significantly reduced, sexual interest/arousal, as manifested by at least three of the following; absent/reduced interest in sexual activity, absent/reduced sexual/erotic thoughts or fantasies, no/reduced initiation of sexual activity, and typically unreceptive to a partner’s attempts to initiate, absent/reduced sexual excitement/pleasure during sexual activity in almost all or all sexual encounters, absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues, absent/reduced genital or non-genital sensations during sexual activity in almost all or all sexual encounters
     ◦ these symptoms must have persisted for a minimum of 6 months
     ◦ these symptoms must cause clinically significant distress
     ◦ these symptoms must not be better explained by a non-sexual mental disorder, consequence of relationship distress or other significant stressors and not attributable to substances or medication

FDA Recognizes FSAD, HSDD and FSIAD: FDA did significant work in compiling their industry guidance for female sexual dysfunction – which we think speaks to the agency’s motivation to facilitate drug development for female sexual dysfunction. Following publishing of DSM-V, FDA held separate patient-focused public meetings and an industry-focused meeting with the respective goals of hearing “perspectives from women with female sexual dysfunction (FSD) on their condition and on currently available therapies” and “to discuss several scientific challenges associated with drug development, including diagnostic criteria, endpoints, and patient-reported outcome instruments.” Results of these meetings (and related public workshops) highlighted the need for effective pharmaceutical therapies to treat female sexual dysfunction and were used to compile FDA’s Industry Guidance to help facilitate development of new drugs that specifically address FSIAD, HSDD and FSAD.

Results were also used for the basis of FDA’s decision to not combine FSAD and HSDD into a single disorder of FSIAD (as DSM-V had), but to instead recognize all three (i.e. FSAD, HSDD and FSIAD) as potential targeted primary indications. FDA specifically notes that FSAD and HSDD should remain characterized as distinct disorders given that the DSM revision (combining HSDD and FSAD into FSIAD) “have not been universally accepted by the scientific community” (including the International Society for the Study of Women’s Sexual Health).

Given significant disagreement regarding the change from various groups, including International Society for the Study of Women’s Sexual Health (ISSWSH), FDA chose to not adopt DSM-V definition and instead continues to recognize (i.e. as of their 2016 Draft Guidance) ‘desire’ and ‘arousal’ as separate and distinct conditions.

2016 Draft Guidance: Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment
Guidance for Industry DRAFT GUIDANCE. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Published October 2016. The purpose of the Draft Guidance is to aid sponsors in developing drugs for FSD-related indications, specifically FSIAD, HSDD and FSAD.

The Guidance document is 12 pages long and can be found here. As is the case with all of FDA’s topical industry draft guidance, it is non-binding and while providing recommendations, allows sponsors to use an alternative approach as long as it “satisfies the requirements of the applicable statues and regulations.” It is also not ‘finalized’ – meaning (or at least implying) that FDA believes that there is more to learn about FSD-related diagnosis and how best to evaluate the safety and efficacy of therapies targeting these conditions.

While FDA’s Guidance provides recommendations, it does not provide specific direction on choosing, constructing and validating patient-reported outcomes (PROs), nor does it offer a template for clinical trial design. Key points include that, “It is essential that sponsors use well-defined and reliable PRO instruments” and “For any PRO instrument proposed as a key study endpoint to support labeling claims, the sponsor should provide supportive information for FDA review (e.g., a copy of the assessment, the instrument’s conceptual framework and scoring, evidence of the instrument’s content validity and other measurement properties including reliability, construct validity, and ability to detect change).”

FSFI: While a validated PRO for ‘low arousal’ does not exist, FDA’s Guidance suggests that the arousal domain of the Female Sexual Function Index (FSFI) may be a good place to start. It also suggests that, if used, FSFI-arousal should be supplemented by additional validated ‘low arousal’ measures. FSFI is a 19-question PRO that a clinical trial participant completes monthly. Questions relate to six domains (desire, arousal, lubrication, orgasm, satisfaction and pain) as a measure for overall sexual function. It has a history of use as a primary endpoint in both drug (see Addyi, below) and device studies (including as the primary endpoint in Viveve Medical’s ongoing U.S. pivotal phase 3 study for ‘improvement in sexual function’).

It is important that whatever DARE uses for a primary endpoint, that it is clinically meaningful and validated. We note that two studies are widely cited as validation for FSFI in female arousal, desire and orgasmic disorders;

Rosen, R, et al. administered it to 128 subjects with FSAD (and a similar number of age-matched controls) and concluded that the “results support the reliability and psychometric (as well as clinical) validity of the Female Sexual Function Index (FSFI) in the assessment of key dimensions of female sexual function in clinical and nonclinical samples.” Additionally, individual domain scores as well as the total FSFI score “showed good ability to differentiate between FSAD and non-FSAD subjects.” The study was published in 2000 in the Journal of Sex & Marital Therapy.

Meston, CM extended FSFI validation with women diagnosed with female orgasm disorder (FOD) and HSDD. Results showed that each of the FSFI domains as well as the total FSFI score differentiated (significantly) between HSDD subjects (n=44) and controls as well as FOD subjects (n=71) and controls. The authors concluded that the “ability of FSFI to differentiate between clinical and nonclinical groups of women lends support for the discriminant validity of the FSFI among these groups [i.e. those diagnosed with HSDD and FOD] of women”. The study was published in 2003 in the Journal of Sex & Marital Therapy

The ‘arousal’ domain consists of FSFI questions three through six and asks the respondent to rate their feelings of arousal in the context of frequency, level, confidence and satisfaction:


View Exhibit I - FSFI-arousal

FDA encourages use of co-primaries and secondaries…
FDA encourages the use of co-primary and secondary endpoints to further support demonstration of treatment benefit. FSFI-arousal is presumably an option for DARE as a primary or secondary endpoint, although their September investor presentation indicates their first choice for primaries may be a ‘genital sensation’ measure and ‘distress’. FSFI (i.e. the full 19-item questionnaire) may also be under consideration (as a secondary). Others potentially under consideration, we think, could be PROs related to ‘satisfying sexual events’ (SSEs), a short-recall period (e.g. daily) arousal diary, lubrication and associated distress.

However, FDA’s Draft Guidance is less than clear in certain areas as it relates to endpoints. For example, while it states that change in the number SSEs can be used as a primary endpoint in FSD trials (for indications such as low desire, interest and/or arousal), a few paragraphs later they suggest against use of SSE as a primary as; DSM does not include it as a definition for low interest, desire and/or arousal and comments from the October 2014 public meetings recommended against its use as a primary.

As such and coupled with the lack of industry-wide acceptance of SSEs as a valid proxy for desire or arousal (along with its controversy as an endpoint in Addyi trials- see below), we don’t expect it to be on DARE’s short list of primary endpoints (although, perhaps as a secondary). In fact, DARE’s September 2018 investor presentation indicates that they proposed to FDA to not include SSE as a primary and that the agency was receptive.

We do think a short-recall arousal diary, lubrication and distress could be viable coprimaries and/or secondaries. FDA’s Draft Guidance recommends using a short-recall measure, especially for drugs dosed daily or on an as-needed basis (as Topical Sildenafil is being designed) – while we are not aware of a validated short-term/daily arousal measure, we think it is likely to be addressed with FDA.

It seems clear that FDA embraces the DSM-IV definition of FSAD – which hinges the inability to maintain adequate lubrication as a response to sexual excitement and which causes marked distress and which cannot be better explained by other causes. DARE indicated that they are interested in a ‘genital sensation’ related measure (which could encompass lubrication) as a primary – although we do not yet know specifics.

As it relates to ‘lubrication’, we think one possibility is the FSFI-lubrication domain (below), which consists of four questions (#s 7 – 9) related to lubrication in the context of; frequency, ability to achieve, frequency in maintaining and ability to maintain.


View Exhibit II - FSFI-lubrication

As it relates to ‘distress’, FDA’s Guidance provides little direction as to an appropriate PRO for distress associated with low arousal. The Female Sexual Function Index (FSDS), a validated 12-question PRO, was designed to measure sexually-related personal distress in women. It was subsequently modified, adding a 13th question; bothered by low sexual desire, to customize it specifically for distress associated with low desire. This modified (and validated) version, FSDS-R, is cited in FDA’s Draft Guidance as potentially useful for ‘desire’ related programs and was used as a secondary endpoint in all three of Addyi’s phase 3 FDA trials (for HSDD). It also received (largely) strong support from panelists during the October 2014 industry-focused workshops as an appropriate measure of distress associated with HSDD.

We are not aware of a validated PRO for distress associated with low arousal. This may be a case where DARE will need to design their own PRO – which presumably might include using FSDS as a guide and modifying it so as to be suitable for measuring arousal related distress (similar to how FSDS was modified for HSDD).


View Exhibit III - FSDS-R (validated for 'desire')

Addyi’s experience provides insight and may prove beneficial to DARE: While FDA has little experience with FSFI-arousal, they do have some experience with FSFI-desire as it served as an endpoint in Addyi’s (Flibanserin) U.S. phase 3 studies. Flibanserin was initially developed as an SSRI but after failing anti-depression trials, Boehringer Ingelheim switched to HSDD.

Addyi was evaluated in three U.S. phase 3 clinical trials for HSDD, the first two used ‘satisfying sexual events’ (SSEs) and a ‘daily desire diary’ as co-primary endpoints and FSFI-desire and FSDS-R (a distress-related PRO) as secondaries, while the third study used FSFI-desire and SSEs as co-primaries and FSDS-R as a secondary. All three studies showed statistically significant improvement in SSE’s as well as on FSFI-desire and reduction of stress (as measured by FSDS-R) but ‘desire’ as measured by the daily diary was not statistically significant in either of the two studies in which it was included.

While Addyi was eventually approved in August 2015 for the treatment of HSDD, questionable efficacy and safety concerns resulted in it being a commercial flop (generating revenue of just ~$55M in 2016 and $80M in 2017). Much of the questions relative to efficacy appeared to relate to questions about the validity of the studies’ endpoints – including criticism that the number of SSEs is not a reliable proxy for determining ‘desire’.

Addyi was a disappointment for Boehringer Ingelheim and Sprout (Sprout acquired rights following Boehringer’s initial attempt at an HSDD indication which an FDA panel voted 10-1 against on efficacy and 11-0 against on safety) but also likely served as somewhat of an embarrassment, and learning experience, for FDA. It may have also been a catalyst towards publishing of their revised guidance (in 2016). Important to note is that FDA draft guidance for FSD-related studies during much of the time of Addyi’s development for HSDD was relatively scant – in fact FDA’s 2000 FSD Draft Guidance, which provided little in the way of actual ‘guidance’ of validated PROs, was withdrawn in 2010.

The reason for our discussion about Addyi is because we think it illustrates the potential complexity of designing an appropriate FSD-related study and the potential for poor outcomes of failing to do so. FDA’s FSD-related guidance at that time was significantly lacking, which may have contributed to Addyi’s ultimate commercial failure. We also find it interesting that FDA eventually approved Addyi despite the advisory panels’ near-unanimous vote against doing so in 2010 and lack of much additional evidence of efficacy and safety supporting Sprout’s refilling of the NDA in 2013.

Public pressure to approve a drug that could address low sexual desire in women (similar to what Viagra had done for men), as well as potentially, motivation within FDA to do the same, may have played a part. Either way, we think the high-profile failure of what was expected to be the first ‘female Viagra’ may have been a real motivating moment for FDA in building a better framework for the evaluation of novel FSD drugs and in having a proactive approach towards working with sponsors in trial design and endpoint selection. So, Addyi’s failure may be an indirect benefit to DARE.

Considerations:
Others have attempted FSD-related (i.e. HSDD, FSAD) U.S. clinical programs and most have failed. Addyi is the only drug to be approved for an FSD indication but it is largely viewed as a commercial failure. Vivus’ FSAD program for their alprostadil (Alista) is an example of another failure. Alprostadil injection is FDA approved for ED but, alprostadil (cream) failed to demonstrate efficacy in a phase 2 study in FSAD with a primary endpoint of female sexual encounter profile (FSEP). Apricus, similarly attempted and failed at a U.S. FSAD indication for alprostadil cream (under Femprox name).

DARE’s goals will need to focus on ‘arousal’ – including a clinically relevant definition, how to measure it, how to identify the appropriate trial population and making sure it is delineated from ‘desire’. They will also need to have agreement with FDA. Learning from the mistakes of other FSD-related programs, including those of PFE, Sprout/Boehringer and Vivus, and working with a receptive and motivated FDA means DARE could be starting from a much more favorable position than others that have attempted an FSD clinical program. A lot of questions remain unanswered, however.

While FDA recognizes female low sexual arousal as distinct from ‘desire’, there is lack of agreement that the two can be distinguished. DSM-IV defined female low arousal separately from female low desire but DSM as-updated (in 2013) modified the characterization of arousal and desire disorders – stating that they could not be reliably distinguished and, therefore, combined FSAD and HSDD into a new category, FSIAD. There is also disagreement as to the validity of specific FSD-related symptoms. For example, given lack of expert consensus that lubrication correlates to arousal, ‘lubrication’ was absent in DSM-V as symptomatic of FSIAD despite being included in the ‘arousal’ definition in DSM-IV.

Given ambiguity over whether clinical FSAD even exists and if it does, uncertainty about how to properly define it, means DARE faces challenges not typical of most (non-FSD) drug developers. “Correctly’ defining symptomatic female low sexual arousal and using that to successfully identify an appropriate FSAD target population (including, potentially delineating from comorbid arousal-desire) will be critical for DARE to be successful in demonstrating efficacy of Topical Sildenafil in FSAD.

Eligibility and inclusion/exclusion criteria are considerations in identifying the appropriate target population. Sprout used what some claimed was too restrictive inclusion/exclusion enrollment criteria in order to cherry-pick a population that would respond to Addyi. Specifically, that one of their pivotal phase 3 trials was restricted to only women that were; pre-menopausal, in stable heterosexual relationships, without existing psychiatric or other medical conditions and absent use of medications. Eligibility criteria were less strict in Sprout’s other phase 3 trials.

FDA’s Draft Guidance addresses eligibility – while noting that exclusion criteria should be limited to ensure the trial population is representative of women that would likely use the drug, also recommending that eligibility be confined only to those most likely to respond to the drug. The only specifics on this topic in the Draft Guidance is that trial subjects should have a history of low arousal and associated distress, sexually active and in stable relationships. It further recommends including subjects with a broad range of severity of sexual dysfunction (with associated distress) and considering including both pre and post-menopausal women in the same trial or in separate trials (DARE recently noted that they expect Topical Sildenafil’s target population to include both pre and post-menopausal women). Further, exclusion/inclusion criteria can be modified in subsequent phase 3 trials so as to evaluate the drug in a less restrictive patient population.

Safety has been a topic of some concern with oral sildenafil for ED (as well as for Addyi for female HSDD). FDA inherently has a higher safety hurdle for drugs that treat non-life threatening conditions, particularly those with daily or on-demand dosing. While generally considered safe, Viagra has been associated with certain cardiovascular and other risks, such as hearing and vision loss. Unlike Viagra, Topical Sildenafil is a cream and designed for local administration. This is expected to provide much more targeted therapeutic effect on the genitalia and potentially mitigate the risk profile as compared to oral Viagra.

Timelines…
Management noted in their recent presentations that they have been in contact with FDA in order to get clarity on many of the topics we have covered – including defining and measuring ‘arousal’ and identifying the most appropriate endpoints and PROs. DARE’s current timeline is to complete a content validity study – essentially a market research study which, along with further consultation with FDA (a type C meeting with FDA is anticipated later this year), will be used to further refine design of their phase 2b clinical study. So, while a lot of important questions remain, if all goes well, many of those could be answered by year-end. We think agreement with FDA on design of phase 2b clinical trial protocol would me a major milestone and, potentially, a value inflection point. As such, we will be eager to hear any additional feedback from FDA.

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