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DARE: Ovaprene PCT Continues. TS Content Validity Study, Thermographic Study Underway

12/03/2018
By Brian Marckx, CFA

NASDAQ:DARE

READ THE FULL DARE RESEARCH REPORT

Q3 / Pipeline Update
Daré (NASDAQ:DARE) reported financial results for their third quarter and provided an operational update. Relative to the financials, operating expenses were $2.6M, or about 12% less than our estimate. We, do, however continue to expect R&D expense and opex as a whole to increase with further progression of DARE’s two lead development programs; Ovaprene and Topical Sildenafil.

Cash balance remains at healthy levels, ending Q3 at $9.5M. Cash used in operating activities was $2.8M and $7.6M ($2.5M and $8.1M, ex-changes in working capital) in the three and nine months ending 9/30/18, compared to $1.4M and $1.6M ($1.3M and $2.1M, ex-changes in working capital) in the comparable prior-year periods.

In terms of the operational update…
DARE appears to be making substantive progress on both of their lead programs as well as on earlier-stage pipeline candidates. Recent and anticipated near-term development-related milestones include;

Ovaprene
‣ Post-coital test (PCT) commenced in May. Per Q3 call, enrollment is progressing as planned
‣ Data from PCT expected 2H’19
‣ Assuming positive results (i.e. finding five or fewer sperm per high-powered field in the cervical mucus), will then file IDE to FDA seeking approval to conduct a pivotal randomized controlled study

Topical Sildenafil
‣ Type C meeting with FDA in Q3’18 regarding development program including design of Ph2b clinical trial
‣ Nov 27th: DARE announces commencement of Thermographic Feasibility Study. See our discussion below
‣ Content validity study commences, Nov. 29th press release
‣ Following completion of CVS, will request another Type C meeting with FDA for additional guidance prior to commencing at-home portion of Ph2b study

Refresher on DARE’s Two Lead Programs; Ovaprene and Topical Sildenafil

Ovaprene
A post-coital trial (PCT) is ongoing and currently anticipated to have topline data in 2H 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.

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, we believe an FDA PMA filing could happen in 2021/2022 and that it is possible Ovaprene could launch in the U.S. by sometime in 2022/2023. All these timelines are unchanged from our previous estimates.

Topical Sildenafil
DARE, which licensed rights to Topical Sildenafil (TS) in February, 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 has had several interactions with FDA focused on defining FSAD in the context of clinically meaningful endpoints and related design of their ongoing content validity study. This includes a Type C meeting with FDA in Q3’18. Another meeting is anticipated following conclusion of the content validity study in order to gain additional guidance prior to the commencement of the at-home portion of the Phase 2b study.

DARE also recently announced commencement of enrollment in a ‘thermography feasibility study’, which presumably could be used as part of the formal Phase 2b and eventual pivotal studies as an objective measure of ‘arousal.’ Per DARE’s press release describing the technique, “genital temperature, a surrogate for genital blood flow, will be captured and recorded utilizing an infrared camera capable of detecting heat patterns from blood flow in body tissues. The study consists of the screening visit (visit 1), the double-blind dosing of placebo or active cream (visits 2-3) and a safety follow-up.”

This is a particularly interesting development as it appears to address one of the ‘unknowns’ as to potential endpoints. Specifically, as it relates to a potential physiological (non-subjective) measure of ‘arousal’. It is also interesting as Pfizer, when they attempted to develop oral sildenafil for female sexual dysfunction, also incorporated a physiological, genital blood flow measure in their clinical studies. Pfizer’s studies used Doppler to measure clitoral blood flow and genital engorgement – and successfully demonstrated that oral sildenafil was effective on improving these endpoints. As we have discussed in prior recent reports, we believe Pfizer’s failings with their ‘female Viagra’ were not an ability to hit endpoints but instead related to trial design. For example, while it appears that they successfully demonstrated improvement in physiological arousal, they failed in demonstrating the connection to a (psychological) desire to have sex. Further, our thesis is that it appears they used an inappropriate patient reported outcome for measuring psychological arousal. DARE’s pragmatic approach is reassuring that they will not make similar mistakes.

Another interesting element of DARE’s press release is that it mentions that Dr. Irwin Goldstein is the principal investigator of the thermography feasibility study. Dr. Goldstein is widely recognized as a renowned expert in the field of female sexual dysfunction and led Pfizer’s sildenafil programs as well as Boehringer Ingelheim’s flibanserin development. Dr. Goldstein’s involvement with DARE suggests to us that they are in good hands.

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 big 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 have provided additional detail on this topic in prior reports.

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