Earlier this year, when an FDA panel recommended the approval of the drug Flibanserin, the makers of a competing drug, Bremelanotide, were at the hearing. “We were probably one of the louder cheers,” said Steve Wills, CFO and COO of Palatin, the Cranbury-based pharmaceutical company that is developing Bremelanotide. Wills, along with Carl Spana, CEO of the firm at 4 Cedar Brook Drive, saw their rival’s success as vindication of the seriousness of the disorder they are both intended to treat: female sexual interest/arousal disorder (FSIAD.)

“There were 205 public speakers at the hearing. Some were professionals, and the majority were patients,” Wills said. “The passion that these women had would bring tears to your eyes. As of now, they have no treatment option whatsoever.”

By recommending approval of the drug, the panel had determined its potential benefits outweighed its risks. Industry observers say a panel recommendation is a good indication that the drug will ultimately be approved for sale.

Palatin is engaged in a large, phase 3 clinical trial of Bremalanotide, a shot delivered by auto-injector to the thigh or abdomen, that is used “on demand” to increase libido for about an hour afterwards. If all goes as planned, the product will be sold under a yet-to-be-determined trade name by 2018. The drug may also come in patch form later on, for women who are turned off by the injector. Flibanserin, made by Raleigh, North Carolina-based Sprout Pharmaceuticals, is a pill that must be taken every day to maintain its effectiveness.

But what exactly are these drugs treating?

As defined by the FDA, Female Sexual Interest/Arousal Disorder covers several different previously defined disorders, including hypoactive sexual arousal disorder, female sexual arousal disorder, orgasm disorder, and sexual pain; severe enough to cause distress. Men who suffer similar problems in their own sexual functioning can restore their vigor with Viagra, Levitra, or Cialis — all multibillion dollar drugs — but there are no FDA-approved drugs for women. (For that matter, the male drugs target erectile dysfunction, but are not aimed at improving desire.)

The development of a “little pink pill” counterpart to the little blue pill has been fraught with controversy. The FDA rejected Flibanserin in 2010 over safety concerns and sent it back for evaluation once again in 2013, approving it only after more risk management studies. The quest for a “female Viagra” has also suffered from the problem of defining the exact nature of FSIAD, and measuring whether the any given treatment has been successful. Viagra and Cialis are for treatment of erectile dysfunction. They act on the circulatory system, and cause increased blood flow, which allows for an erection.

Determining female sexual arousal is a much more complex question, especially because no biological cause for low female libido has been identified. In addition to measuring a physical indicator — vaginal blood flow — the studies of Flibanserin and Bremelanotide have surveyed women about how many satisfying sexual encounters they had after taking the drug. In a 2014 study of 327 premenopausal women, the women surveyed who took Bremelanotide reported they were more frequently and easily aroused for longer and had more frequent orgasms compared to a control group that took a placebo. The subjects reported a 50 percent increase in the number of “satisfying sexual events.”

Sheryl Kingsberg, a psychologist and sexologist at the University Hospital of Cleveland, ran the Phase II trial. “The challenge several years ago was finding validated tools to measure what is a subjective quality, which is female sexual desire. We now have validated tools to do that,” Kingsberg said. She said the “female sexual desire subscale” is a survey to do that, and that “sexually satisfying events” is a subsequent event and a useful though imperfect measure. “It’s sort of a surrogate marker for desire because our interpretation was that if you had more desire, you would have more events. But men and women choose to be sexual for many reasons, not just desires, which is why it’s not the best measure.”

The complex and amorphous nature of studying women’s sex drives versus counting erections has caused critics to question whether the proposed libido drugs are truly helping.

In an opinion article published in the Los Angeles Times in 2014, Ellen Laan, a sexologist and researcher for the Kinsey Institute, and Leonore Tiefer, a professor of psychology at NYU, argued that sexual problems in most women were related to what was going on in the bedroom, not what was going on in women’s bodies. “No diagnostic test has identified any biological cause — brain, hormone, genital blood flow — for most women’s sexual problems. On the contrary, abundant evidence shows that low sexual desire in women typically reflects a difference in desire between two partners. It is unethical and unscientific to attribute a couple’s discrepancy in desire to the woman’s biological deficit,” they wrote.

In response to such criticism, Palatin’s Spana says women deserve to have a pharmaceutical option available. “I think that these women clearly have an issue and they are distressed by that issue,” he says. “They are capable of making an informed decision with their partner and their healthcare provider as to what type of therapy they want to have. Our goal is to provide a choice for them. They do not have a choice, and they deserve one.”

He also said that even if arousal is psychological in nature, a pharmaceutical treatment could still be a valid option, and that many psychological disorders are treated with drugs. He said the majority of women do not respond to sex therapy or other forms of behavioral therapy, which he views as evidence of a physiological cause of some kind.

Kingsberg, who has worked in the field of female sexual health for 24 years, says it has been an uphill battle to get research funded for treating FSIAD. “It’s clearly a huge unmet medical need,” she says, and pointed out that FSIAD is on the FDA’s list of top 20 conditions with unmet medical needs.

Kingsberg also said there were many women who did not respond to sex therapy, and that there was strong evidence for there being a physical cause for FSD. “I would look at it the same way we conceptualize depression,” she said. “It’s nice to have more than one option out there. There are some patients who respond really well to psychotherapy, and some who only respond to antidepressants, and some who do well with a combination.”

According to some surveys, about 11 percent of women were “distressed” about a sexual functioning problem, meaning that they might meet diagnostic criteria for FSD.

“These women are not responding normally to sexual cues,” Spana says. “Her partner approaches her, touches her, maybe takes her out to dinner, the kids aren’t going to be home. Normally the person will have some responses to that: increased desire, increased arousal. But many of these women don’t have that interest in engaging in a sexual encounter. What Bremelanotide does is to help restore a normal response to sexual cues and allow her to have a normal sexual encounter with the partner, and alleviate distress.”

In October of 2014, the FDA held a “voice of the patient” hearing where about 80 women who had been diagnosed with FSIAD said what it was like to have the disorder. “In a beautiful place with the man I love, my body was like a shell with nothing inside,” one woman said. “I knew I wanted to have sex, but I had no desire. I refrained,” said another.

In some cases, the lack of desire had a profound effect on the lives and relationships of the women. One woman said she avoided intimacy at all costs. “I found myself avoiding any situations where a sexual experience may occur … going to bed after my husband fell asleep or jumping out of bed in the morning before he got up just so he wouldn’t try to initiate sex. I even found myself avoiding simple hugs and kisses.” Some women said FSIAD had contributed to divorces or the dissolution of relationships. Others said it affected their self esteem or experienced shame, stigma, and embarrassment.

Both Flibanserin and Bremelanotide work directly on the brain. Flibanserin regulates neurotransmitters. Bremelanotide increases activity in the hypothalamus, a region of the brain involved in arousal and desire. Because peptides work directly on the desire mechanisms of the brain, they are being investigated as a means of controlling cravings for food and tobacco.

The use of Bremelanotide as a treatment for female sexual desire began in the 1990s at the University of Arizona, where researchers were trying to develop a drug that would prevent skin cancer by increasing pigmentation in the skin. By using certain peptides, molecules that would cause the skin to release pigments and change skin tone, they hoped to create a protective effect that would block damaging UV rays. Essentially, it was intended to be a tanning drug. But the researchers noticed that college men taking the drug were getting “spontaneous erectile activity.”

The company Rho-Med was founded to take advantage of this discovery by developing Bremelanotide as a treatment for low libido, and that’s when Spana stepped in.

Spana grew up in Westchester County, New York, where his father was a mailman and his mother was a housewife. “I was always interested in being a scientist,” he said. Spana studied biochemistry at Rutgers, earning a bachelor’s degree, and got a doctorate in molecular biology at Johns Hopkins.

The typical career path would have been to pursue a professorship, but Spana was more interested in technology commercialization. He worked at Bristol Myers-Squibb for three years before joining a merchant bank investing in early stage biotechnology companies. Albuquerque-based Rho-Med caught the bank’s attention, and it sent Spana in to be on the board of directors. In 1996 the company was re-structured and Palatin was founded with Spana as chief technical officer, to develop several kinds of peptide-based drugs.

Around 2000 Spana became CEO and the company moved to Cranbury with about 100 employees. The company continued to research Bremelanotide as a treatment for erectile dysfunction while researching some other drugs. The company’s first commercial product was NeutroSpec, an imaging agent for detecting appendicitis, approved by the FDA in 2004. Disaster struck the following year when two patients died and several others had life-threatening incidents after off-label uses of NeutroSpec. Palatin voluntarily pulled it from the market.

In the mid-2000s, Palatin was developing Bremelanotide as a nasal spray. “It was quite effective,” Spana said. However, there was a problem with how some patients absorbed the drug. Most people would uptake about 15 percent of the drug when it was administered by nasal spray, but a handful of people absorbed 100 percent of it, and suffered more side effects than the normal population. “It turned out we needed to have the format of the drug with more consistent delivery,” Spana said. “It wasn’t orally bioavailable, so we moved to a subcutaneous format.”

The company also received some feedback from the FDA about using it as an erectile dysfunction treatment. Because there were already good ED treatments on the market, the agency would hold Bremelanotide to a higher standard of safety and efficacy than it would if no other treatment existed.

In 2008 the company changed the target gender of Bremelanotide. “We made the strategic shift to female sexual dysfunction for a more direct regulatory path,” he said. “We thought the market needed it.”

The company now has about 20 employees and has received more than $300 million in funding from investors. If Bremelanotide is approved, the company will not create its own marketing department to sell it, but will likely partner with another firm, so no large expansion is on the horizon.

Bremelanotide has held two phases of clinical trials and is now recruiting subjects for the third and final phase, marketed as “Reconnect,” which will involve about 1,000 subjects. It is also researching other peptides to treat cardiovascular and pulmonary disease, obesity, and diabetes.

If both Bremelanotide and Flibanserin are approved, they will be marketed towards the same customers. Palatin estimates the potential market size is about 2 million people, based on surveys that showed 11 percent of women had sexual problems and were distressed about them. Palatin predicted $1.3 billion in annual sales by 2020.

“This market will be a large market, and it will require multiple treatment options,” Spana said.

Wills pointed out that the market for Viagra was $1.5 billion before Cialis hit the market, after which point it grew to $2.5 billion. Bremelanotide does enjoy a few advantages over its competitor, including its on-demand usage. Also, unlike Flibanserin, Bremelanotide has no known interactions with alcohol — a bonus, since people have been known to combine sex and alcohol.

The subcutaneous delivery is a potential downside, though Wills says the design of the auto-injector device minimizes the pain involved. It’s a pen-sized cylinder with a button on the end. The patient presses it against her thigh or abdomen, presses the button, and holds it in place for two seconds while a spring-loaded needle inside the cylinder automatically injects the medicine and is withdrawn.

Some potential customers are not waiting for the regulators to make up their mind. Bremelanotide, sold as PT141, can be bought on websites, “for research purposes only” and there are Youtube videos showing how to mix and inject the drug.

Kingsberg cautioned against using the gray market version of Bremelanotide. “It’s frightening that people are so desperate to treat this unmet medical need that they’re buying this unproven, unsafe drug. It’s certainly not what Palatin produces, and I have no idea what’s in it. One of the things I’ve complained about for a long time is that women not being allowed an FDA-approved treatment is not benign, because women and men are so desperate to treat this, they will search out ads on the Internet and in the back of magazines. There are unscrupulous people who would try to dupe women into taking unproven and potentially unsafe treatments.”

Wills says a treatment for women with low libido is long overdue. He said some of the test subjects they interviewed became emotional when talking about the effect the drug had on their lives. “It was incredible just how much better they felt about themselves and their relationships, and just across the board.”

Kingsberg said she was heartened by the progress towards the market of Bremelanotide and Flibanserin. “For me, it’s validating and actually very moving, because for so long, it’s been frustrating for me to watch my clients struggle to try to work around the fact that they have no biological urge,” she said. “Desire is a biologic urge to want. It’s not just in the moment. It’s the anticipation, and it’s the reward processing. you can have an orgasm, for example. You can have a satisfying event, but whether you want it again in the future is more about what your desire is. To see women have that restored is quite powerful, and they’re very happy with the impact the drugs have had.”

Kingsberg said the test subjects mostly had had normal sexual desire at one point, but had lost it somewhere along the way. They wanted to restore themselves to their normal baselines, not go “from 0 to 60,” she said. “The criticism for both Bremelanotide and Flibanserin was that the effect is modest, and I think that’s because people who call this modest do not understand what women are looking for.”

Palatin Technologies Inc. (PTN), 4B Cedar Brook Drive, Cranbury 08512; 609-495-2200; fax, 609-495-2201. Carl Spana, CEO. www.palatin.com.

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