After more than a decade in development, Freya Pharma Solutions plans to advance an oral tablet dubbed Lybrido into Phase III trials to treat female sexual interest/arousal disorder (FSIAD).

On September 28, the company announced that it received scientific advice from the EMA on the upcoming Phase III trial, which will be followed by additional studies in Europe and the US.

The company is aiming to enrol the first patient in the ALETTA Phase III trial in Q1 or Q2 of 2023, says Dr. Jan van der Mooren, Freya’s chief medical officer (CMO). The company plans to submit a request for advice from the FDA at the end of this year or the start of 2023, he adds. Although the subsequent study is not even in the planning stage, it would likely be in the US, says van der Mooren.

In 2015, the FDA approved Sprout Pharmaceuticals’s Addyi, also known under the generic name flibanserin, for use by pre-menopausal women with hypoactive sexual desire disorder (HSDD). In 2019, the agency authorized the use of Vyleesi, an injectable form of bremelanotide, for the same condition. There are no approved treatments in the EU.

HSDD is associated with a loss of sexual desire and stimulation. In the same sphere, female sexual arousal disorder (FSAD) describes a condition where individuals encountered difficulties with maintaining vaginal lubrication. Since the publication of the fifth Diagnostic and Statistical Manual of Mental Disorders in 2013, both conditions are grouped under the term FSIAD, which includes reduced arousal and interest.

Despite the recognized need and demand for options to treat female sexual dysfunction, several safety and access issues associated with the use of available options. Moreover, despite the buzz generated when Addyi was launched in 2015, only one other drug has since been marketed.

“Look at how many options there are for men and look at how many approved options there are for women. To say two is fine and enough does a disservice to women,” states Sheryl Kingsberg, PhD, Chief of the Division of Behavioral Medicine at the University Hospitals Cleveland.

Studying female sexual interest disorder

In December 2021, Amsterdam-based Freya acquired Lybrido, a tablet consisting of testosterone and sildenafil, and Lybridos, a combination of testosterone and buspirone, from the Dutch biotech Emotional Brain. The upcoming Phase III trial is evaluating Lybrido. For now, Freya is focused on Lybrido and the future development of Lybridos will be determined later, says van der Mooren.

These two combinations serve different purposes. While Lybrido could be for women who have issues maintaining desire and arousal, Lybridos is intended for by those who do not feel pleasure. The compound combination is nothing new, as sildenafil is used as a treatment for erectile dysfunction, commonly known under the name Viagra, says Dr. Itzhak Ben-Zion, head of the Sexual Health Clinic at Soroka University Medical Centre in Beer-Sheva, Israel.

According to Kingsberg, the combination featured in Lybridos would be more appropriate to treat HSDD in women who have high sexual inhibition. Lybrido would be more suitable for women fitting the overall definition of FSIAD and experiencing difficulties with arousal and desire, she notes.

Defining these disorders comes with its own share of debate. FSIAD is not a biologically validated diagnosis, which is confusing and inaccurate, says Dr. James Simon, clinical professor at George Washington University School of Medicine in Washington DC.  Dr. Susan Davis, director of Monash University ’s Women’s Health Research Program in Australia, says that FSIAD as a diagnosis is not evidence-based. What’s more, the World Health Organization did not include it in its 11th revision of the International Classification of Diseases (ICD-11) in 2019, she notes.

The FDA has accepted that sponsors can submit applications for the indication of FSIAD, but they can also still have an indication for HSDD and FSAD, says Kingsberg. Whether companies should apply for a combined diagnosis or a separate one is a question in the field, she says. Meeting the criteria of an FSIAD diagnosis can be more challenging for the Freya compounds, explains Kingsberg, citing the FDA’s draft guidance on target populations in FSIAD. There, the agency suggested that sponsors carry out their trials in well-defined trial populations for FSIAD where subjects with this condition should only be included if the drug targets both desire and arousal.

Van der Mooren says that the EMA supports the FSIAD diagnosis. The upcoming study will investigate desire, distress, and arousal as the key endpoints in pre-menopausal women with FSIAD, states van der Mooren. The female sexual function index (FSFI) questionnaire will be used to measure the change in desire over 24 weeks, he adds.

Moreover, any potential use of Lybrido or Lybridos would also come with a screening test that will determine which of these drugs will benefit the patient, says Simon.

Emotional Brain worked on these two tablets for much of the past decade. One Phase II trial was completed back in 2013, as per ClinicalTrials.gov. Later, however, the company did not have the financial capacity to further develop the compounds, van der Mooren confirms. Freya has raised sufficient money to start the Phase III program and will now focus on the most relevant activities, he says.

A one-size-fits-all approach

While Addyi and Vyleesi were the first treatments to arrive on the market, Kingsberg says they do not work for all women, and they both work differently. While Addyi is taken once daily and shows results after several weeks, Vyleesi is an injectable treatment that can be used as little as 45 minutes before intercourse.

But these treatments have their own limits. According to Simon, both treatments only work in about 50% to 60% of patients, and Kingsberg agreed. To some women, the use of an injectable is not attractive, says Kingsberg.

For Addyi, the drug’s original approval came with a boxed warning against alcohol consumption over risks of blood pressure. This changed in 2019, and women are now advised to stop drinking alcohol at least two hours before using Addyi or skip the bedtime dose. In 2021, the drug faced further scrutiny over its safety profile after a high number of adverse events, like dizziness, tiredness, and nausea, among others, were reported to the FDA.

Overall, side effects serve as a more significant barrier in this condition than elsewhere because the condition is not life-threatening, says Ben-Zion.

In contrast, Freya is projecting its compounds as on-demand options that do not have warrant warnings for interactions with alcohol. But Davis, says that an on-demand option could be of interest to only some women, rather than the majority. Using a one-size-fits-all approach in this particular condition does not work, says Kingsberg. Some women may want an on-demand option, while others may want a daily pill, she explains. Moreover, some women may find certain side effects like sleepiness, seen with other alternatives, beneficial, adds Kingsberg and Simon.

Neither Addyi nor Vyleesi is approved by the EMA. This means that Freya is particularly targeting the European market and aims to target that first, says Van der Mooren, adding that the US would follow.

Stigma slows research and development

All this development comes in the backdrop of a wider sense of stigma against the use of pharmacologic options for female sexual function, says Kingsberg. Awareness of female sexual function is limited along with the options to treat it. This sense of stigma also harms any research and development, she notes.

Some women are also wary of using pharmacologic options when addressing sexual dysfunction, says Kingsberg. While some find help in psychotherapy, others seek pharmacologic options and a combined approach often works synergistically, she adds.

Additionally, it is difficult to get either available treatment prescribed, says Kingsberg. Women either need to use online pharmacies or deal with “prior authorisations” with insurers in order to get their prescription reimbursed, which makes access harder, she adds. The combination of stigma and access barriers harms potential uptake, despite the interest of those experiencing such conditions.

“A sexual dysfunction is not a disease. It is a condition. And women deserve all approaches for this condition,” says Kingsberg.