Last week, an FDA advisory committee met to discuss the benefits and risks of flibanserin, a drug intended to restore a woman’s sexual desire. The panel voted 18-6 that the FDA approve the drug with an active risk evaluation and mitigation strategy (REMS) to ensure that the drug is prescribed appropriately and potential side effects monitored closely. The agency’s final decision will occur on or before August 18, 2015.
The drug is not a women’s version of Viagra, the Pfizer drug approved in 1998 that increases penile bloodflow in men with erectile dysfunction. Instead, flibanserin acts selectively on brain receptors to restore to women what they consider their previously normal level of sexual desire.
So, flibanserin isn’t really a “sex pill” as portrayed by some in the media, but rather a restorative. A good analogy is that people don’t take antidepressants to experience a euphoric, elevated mood. They just want to return to a normal mood response. In fact, an antidepressant won’t elevate mood in a person without depression.
Flibanserin has been designed and studied for pre-menopausal women with hypoactive sexual desire disorder (HSDD) defined most simply for women who are in a stable monogamous relationship, used to have sexual fantasies and a normal desire for sex, have lost that desire and it has been missing for a long time, and are experiencing distress and interpersonal difficulties as a result. HSDD is classified by the FDA as an of unmet medical need.
A good analogy is that people don’t take antidepressants to experience a euphoric, elevated mood. They just want to return to a normal mood response. In fact, an antidepressant won’t elevate mood in a person without depression.
I belabor the details because the drug has been criticized by others, including yours truly, for having a modest or minimal effect on sexual desire. But I fully recognize that as a man, I may have an incomplete understanding of the impact the drug will have in the lives of individual women. Hence, I have sought expert opinions in women’s health over the last two weeks to fully appreciate the scope of this unmet medical need and the drug’s benefits relative to its side effect profile.
In this article, I wanted to expand on flibanserin’s efficacy with a deeper dive into the data and discussions with caregivers.
‘Modest’ does not mean ‘minimal’
In a 45-minute discussion earlier this week, Cindy Whitehead, CEO of Sprout Pharmaceuticals, told me that the drug’s ‘modest’ effect, one that has been repeatedly shown to be statistically-significant using FDA-required tools, is being misread as ‘minimal.’
Whitehead couldn’t be more clear on the purpose of this drug and its performance in the clinical trials.
“‘Modest’ was the goal of treatment,” said Whitehead. “You don’t want to take a patient with HSDD and catapult them to hypersexuality. In fact, we looked at that in clinical trials because that would be an undesirable effect. So we are moving them back in a range that is their ‘normal.’”
Satisfying sexual experiences are not the only meaningful endpoint
Most public discussion has focused on the conclusion that flibanserin increases a woman’s sexually satisfying experiences by one per month over placebo. In part, that’s the easiest way to summarize the 306-page briefing document Sprout released for last week’s FDA hearing, and I even used it in my articles.
Whitehead says that representation obscures the context in which those increases occurred. In the most recent of three pivotal randomized, double-blind, placebo-controlled trials, women taking flibanserin in a single nighttime dose went from an average of 2.5 sexually satisfying events per month to 5.0 per month. In contrast, women in the placebo group went from 2.7 at baseline to 3.5.
So what the data show is an increase of 2.5 events per month, of which only 0.8 could be credited to placebo.
Consider if we reported instead that women doubled their number of satisfying sexual experiences (from 2.5 to 5.0) and their increase was triple that seen with placebo (increase of 0.8 vs. 2.5). That would also be true. And perhaps the perception of efficacy might be far more positive.
Perhaps we in media aren’t giving enough credit to a woman and her healthcare provider to make a decision on the significance of those results in her particular situation.
What’s not open to selective interpretation is the very fact that across the three studies, with up to five measures of efficacy, flibanserin showed in every case an improvement over placebo. As I’ve said before, that’s impressive. The confounding factor is that placebo responses are high in these types of trials, not just with flibanserin but with any drug that acts on the central nervous system.
A review by Andrea Bradford at M.D. Anderson shows that some aspects of female sexual dysfunction trial design already enhance the placebo effect, such as the interaction with clinicians who are experts in sexual medicine and comfortable with conversations like this and the trial requirement that you at least try to initiate a sexual experience once a week.
Cindy Whitehead, CEO of Raleigh-based Sprout Pharmaceuticals, is flanked by women leadership of their 25-person organization. Credit: Sprout Pharmaceuticals
But even with that strong suggestive element, flibanserin outperformed placebo in all three pivotal trials. Whitehead says that across the three pivotal trials, “Between 46 and 60 percent of women judged their effect to be meaningful. That’s remarkable, but that says that 40 percent of women are not going to be helped by flibanserin. We are not going to help all women.”
Another consideration is that these average numbers don’t adequately reflect the magnitude of individual responders to the drug.
When the SSE data are picked apart, as shown in the company’s presentation at the FDA hearing, the results are more meaningful if considered on an individual basis. About 25 percent of women experienced an increase of four or more satisfying experiences per month (vs. about 15 percent in the placebo group). That means they went from about 2.5 to 6.5 or more. And again, in every single case – one more, two more, three more – the drug was significantly better than placebo.
So if you’re a woman who responds to the drug, that response could be considerably greater than average.
Significant sexual events are downstream of distress over desire
“The SSEs were identified as objective measures long ago when these trials were first designed with the help of FDA to come up with endpoints because it’s something you can count. But they really are a much more downstream effect of desire,” says Sheryl Kingsberg, PhD, chief of behavioral medicine in the obstetrics and gynecology at University Hospitals of Case Medical Center and a full professor of psychiatry, obstetrics and gynecology at Case Western Reserve Medical School. Kingsberg received compensation as a Sprout consultant. An author of over 70 peer-reviewed publications on women’s health, Kingsberg presented the overview and impact of HSDD at last week’s FDA hearing.
I asked her to distinguish the difference between the SSEs and the other self-reported measures of desire and distress.
Kingsberg explained, “What we’re really looking at in hypoactive sexual disorder is to increase desire. Women will have sexual events for a variety of reasons and they will rate them as satisfying for a variety of reasons. In the neurobiological model of desire, what’s missing is the motivation and reward processing – avolition, just as we see in depression. So if you put her in bed and she has a sexual event and she’s aroused and has an orgasm, she will rate that as satisfying. But what’s missing is going to be the motivation to do it again.”
The two other measures in the trial were the desire domain of the female sexual function index (FSFI-Desire) and distress (FSDS-R), one of the diagnostic criteria for HSDD. Kingsberg said that distress isn’t really anxiety but rather a feeling of sadness and inadequacy around being bothered that ‘it’s gone and they want it back.’
As with SSEs, the increase in the magnitude of difference between placebo and flibanserin also progressively increased as measures of sexual desire became more stringent. Similar the reduction in emotional distress decreased at a greater magnitude relative to placebo as stringency increased.
The combination of the primary, co-primary, and secondary measures all showed significance over placebo – all the endpoints required by the FDA. Whitehead stressed that included in these endpoints were measures of self-reported, clinical meaningfulness.
Flibanserin is the most extensively studied drug in women
Moreover, the inclusion criteria allowed for the sort of variability observed in the general population: 87 percent white and about 11 percent of the subjects being African-American; 46 percent normal weight and 53 percent overweight or obese; average age of 36 with a range from 19 to 54; and psychotherapy permitted as long as it wasn’t initiated less than 12 weeks before the trial started. That’s another major consideration of the FDA and its advisory panels: How closely does the clinical trial population reflect anticipated, real-life users of the drug?
I used to teach my pharmacy students at the University of Colorado that drug companies are only required to test their drugs in about 1,500 or 2,000 people. The FDA requires that at least 1,500 be exposed to the drug, 300 to 600 for six months or more, and 100 for at least a year. Sprout has tested flibanserin in just shy of 8,000 women, with a total study number of over 11,000.
“In a day and age where we talk about including women in clinical trials and studying drugs in female rodent model, it’s disheartening that it’s lost that flibanserin has been looked at for and in women. It is one of the largest new drug applications, ever, for women. This is in a field that, up until now, the standard of care has been repurposing male drugs.”
Whitehead and her husband, Bob, who is currently Sprout’s executive vice chairman, had led Slate Pharmaceuticals through FDA approval of the first long-acting testosterone preparation for men with low testosterone, Testopel, now sold by Endo Pharmaceuticals. The current iteration of the 25-person company is so-named as it “sprouted” from the sale of Slate.
“Part of our enthusiasm in making the decision to sell off the business with one of the men’s sexual health drugs and pursue flibanserin was that here we have something with spectacular scientific understanding and a mechanism that’s going along with that understanding, as opposed to the less artful version of ‘It works in men. Let’s see if it works in women,’” says Whitehead.
Flibanserin acts in the brain to modulate serotonin responses in the prefrontal cortex of the brain that connects to limbic pleasure centers, ultimately disinhibiting norepinephrine and dopamine pathways that mediate how we processing rewarding activities. Functional MRI studies published in Neuroscience and conducted by academic researchers with no ties to Sprout are consistent with lower activity in these pathways.
Drug interactions and side effects
In fact, the more one looks at the data and FDA’s complete response letter, the company has done everything the FDA has asked, even when those requests were above and beyond those for other drugs that act on the brain.
The studies of the drug’s metabolism are an excellent example of Sprout’s efforts. About 85 percent of a flibanserin dose is handled by a drug metabolizing enzyme called CYP3A4. We know very well that some drugs inhibit the action of CYP3A4, such as antifungal drugs like fluconazole, and that almost half of all drugs are handled by that enzyme. Not just flibanserin. Half of all drugs. The company still did the work to show that flibanserin blood levels increase substantially (up to seven times) with any of these inhibitors. So if it’s approved, flibanserin will carry warnings for it not to be taken with those antifungals and warnings will be triggered when the drugs might be prescribed by two different doctors. And, moreover, those antifungals already carry the warning that they not be used with a long list of other drugs metabolized by the same enzyme.
But that’s not all Sprout did. They addressed pharmacogenomics of a secondary drug metabolizing enzyme. The remaining 15 percent of a flibanserin dose is handled by related enzymes called CYP2C9 and CYP2C19. Of the 50 changes, or polymorphisms, that occur in those enzymes across the population, some reduce their efficiency and, in turn, might have been expected to increase flibanserin blood levels in individuals that would be called slow-metabolizers. Whitehead said that the company had to screen 1,800 volunteers just to even find 25 slow-metabolizers to do the study. And after all that, there was no statistical change in flibanserin metabolism, probably because most of it is handled by the other enzyme, CYP3A4.
The primary side effects have also been exhaustively examined. Dizziness, sleepiness, and fatigue occurred at a rate of 9 to 11 percent, as compared with placebo rates of 2 to 3 percent. Placed into appropriate context, many other CNS drugs cause the same degree of these side effects, or greater: Wellbutrin, Paxil, Cymbalta, Zoloft, Prozac, Celexa. Some of these, like Wellbutrin, cause dizziness and somnolence at a rate of over 20 percent. And all of these effects are intensified by alcohol, for every one of these drugs. So flibanserin poses no unusual effects and can be managed by appropriate warnings.
The hemodynamic side effects, such as hypotension and syncope, treated very seriously by the company and the FDA advisory committee. Whitehead says they are comforted by how infrequent the reaction is. Six patients experienced these effects in the Phase 3 trials, or 0.4 percent. The rate in the placebo group was 0.3%.
“When you look other products being used off-label, like testosterone and Wellbutrin, their incidence of hypotension and syncope and hypotension are much higher than that seen in flibanserin. I say that only in the context of a conversation that seems to have caught a little bit of fire but departs from a comparator or frame of reference,” says Whitehead. “Flibanserin has risks, as does any other drug.”
We also know that these effects are intensified by antifungal drugs that inhibit CYP3A4 as well as alcohol in the range of two to four drinks ingested within 10 minutes. What this means in a post-approval population is exactly why the risk management and mitigation strategy suggested by Sprout will include health care practitioner education to counsel patients to be on the lookout for such effects.
‘Not approving this drug carries more risks’
When considering these side effects and their frequency, an important point is that they’ve been studied in detail and the FDA has the original data on each subject to examine exhaustively. A case could be made that the current situation, without flibanserin available is far more serious, where patients are taking homeopathic and herbal supplements or off-label compounded of prescription hormones.
While this was discussed somewhat at the FDA hearing, I had been chatting on Twitter with Lisa Larkin, MD. She was amenable to talking in more than 140 characters at a time to share her clinical experiences on patients with HSDD who are currently without access to anything with a well-quantified safety and efficacy profile. Larkin, an associate professor of obstetrics and gynecology is also director of the University of Cincinnati’s Women’s Center. She also testified at last week’s FDA hearing but has not received any funding from the company.
Her motivation is that she has a high-volume academic practice where we sees women routinely with HSDD, often dealing with problems of self-medication with herbs and supplements managing patient misadventuring with implantable testosterone products from compounding pharmacies. Dr. Larkin also takes issue with those who oppose the drug based on the faulty belief that HSDD is a disorder made up by pharma.
To those who propose that only a behavioral approach is necessary, Dr. Larkin says, “Of course, I recognize that sexual dysfunction is a multifactorial problem and a large number of women can benefit from therapy, treatment of their depression, marital issues, have past issues of sexual abuse. And, clearly, this drug is not for that.”
Larkin adds, “Where I really take issue is where people aren’t actively writing prescriptions like I am lack a very good sense of side effect profiling. And to say that it’s all made up by pharma is frankly a disservice to women.”
“But this biggest point that I didn’t have time to get to at the FDA was that not approving this drug puts women at more risk because what I see in practice day in and day out is people doing flukey, unregulated, untested supplements, compounded stuff, looking for answers going to these anti-aging centers.”
Relative to these other approaches, Dr. Larkin says that doctors can make assessments based on known and well-quantified risks. “With any approved drug, the risks are identified in the package insert and prescribing information and we as clinicians have data that can tell us alcohol is a bad thing, that there are specific drug interactions. With all of these other things and compounded drugs being used off label, it’s really not a safer alternative.”
The most dramatic cases Larkin faces are with women given implantable testosterone pellets. She has had multiple patients who’ve gone to anti-aging clinics with testosterone levels “in the thousands” – a normal level in men is 800 to 1,100 nanograms per deciliter. Women present as edgy, agitated, and aggressive, and yes, their hot flashes go away and their libido briefly improves. But in three to six months they come in with clitoromegaly, where the clitoris grows to more closely resemble a penis, acne, hair loss, and feel unwell.
Another type of risky patient she just saw was a premenopausal woman with hormone-dependent, breast cancer who was getting testosterone pellets and came to her for hormone replacement therapy. As testosterone gets converted to estrogen, that already increases the risk for breast cancer recurrence. The best she can do in such a case right now is to recommend a topical estrogen preparation. But hormonal approaches can only do so much and Larkin has little else to offer her patients. Flibanserin would be another important tool that she could use safely in many of her patients.
The wisdom of Even the Score
Dr. Larkin has been a supporter of the Even the Score campaign to urge the FDA and Congress to recognize HSDD and “even the score’ by approving flibanserin. It’s been criticized by opponents as just a pharma-funded public relations campaign – Whitehead says that ‘patient advocacy’ is more appropriate.
Larkin says she had some unease about the perception but the whole reason it was mobilized by a spectrum of women’s groups and drug companies that included Sprout was that, “We were being neglected. I think we needed the campaign to raise awareness and I support having done the campaign because the end result is really what I believe we need.”
The most prevalent messaging from the Even the Score campaign was that the agency has been exhibiting gender bias in approving 26 medicines for sexually-related disorders in men and zero or few for women.
In working with regulators on drugs for both genders, Whitehead has a related but distinct perspective. “I believe that there is a condition bias on HSDD that’s a factor of a lot of things. I think we have deeply-held beliefs around women and sexuality and we do see here a different risk tolerance in terms of decision-making between men and healthcare provider versus women and healthcare provider.”
“The sheer abundance of data we have generated on safety – and we’re proud of how robust our data is – that informs a lot. We feel firmly that we have characterized the benefit as well as the risks of flibanserin, says Whitehead.
“If you can do that, and look at precedent after precedent of other products that are out there and the ability of there to be shared decision-making between patient and provider, I do scratch my head at what the opposition thinks in terms of their firmly held belief that this shouldn’t be turned over to women.”
For more health and pharmaceutical news and commentary, follow me on Twitter @DavidKroll, or here at Forbes.com.
The drug is not a women’s version of Viagra, the Pfizer drug approved in 1998 that increases penile bloodflow in men with erectile dysfunction. Instead, flibanserin acts selectively on brain receptors to restore to women what they consider their previously normal level of sexual desire.
So, flibanserin isn’t really a “sex pill” as portrayed by some in the media, but rather a restorative. A good analogy is that people don’t take antidepressants to experience a euphoric, elevated mood. They just want to return to a normal mood response. In fact, an antidepressant won’t elevate mood in a person without depression.
Flibanserin has been designed and studied for pre-menopausal women with hypoactive sexual desire disorder (HSDD) defined most simply for women who are in a stable monogamous relationship, used to have sexual fantasies and a normal desire for sex, have lost that desire and it has been missing for a long time, and are experiencing distress and interpersonal difficulties as a result. HSDD is classified by the FDA as an of unmet medical need.
A good analogy is that people don’t take antidepressants to experience a euphoric, elevated mood. They just want to return to a normal mood response. In fact, an antidepressant won’t elevate mood in a person without depression.
I belabor the details because the drug has been criticized by others, including yours truly, for having a modest or minimal effect on sexual desire. But I fully recognize that as a man, I may have an incomplete understanding of the impact the drug will have in the lives of individual women. Hence, I have sought expert opinions in women’s health over the last two weeks to fully appreciate the scope of this unmet medical need and the drug’s benefits relative to its side effect profile.
In this article, I wanted to expand on flibanserin’s efficacy with a deeper dive into the data and discussions with caregivers.
‘Modest’ does not mean ‘minimal’
In a 45-minute discussion earlier this week, Cindy Whitehead, CEO of Sprout Pharmaceuticals, told me that the drug’s ‘modest’ effect, one that has been repeatedly shown to be statistically-significant using FDA-required tools, is being misread as ‘minimal.’
Whitehead couldn’t be more clear on the purpose of this drug and its performance in the clinical trials.
“‘Modest’ was the goal of treatment,” said Whitehead. “You don’t want to take a patient with HSDD and catapult them to hypersexuality. In fact, we looked at that in clinical trials because that would be an undesirable effect. So we are moving them back in a range that is their ‘normal.’”
Satisfying sexual experiences are not the only meaningful endpoint
Most public discussion has focused on the conclusion that flibanserin increases a woman’s sexually satisfying experiences by one per month over placebo. In part, that’s the easiest way to summarize the 306-page briefing document Sprout released for last week’s FDA hearing, and I even used it in my articles.
Whitehead says that representation obscures the context in which those increases occurred. In the most recent of three pivotal randomized, double-blind, placebo-controlled trials, women taking flibanserin in a single nighttime dose went from an average of 2.5 sexually satisfying events per month to 5.0 per month. In contrast, women in the placebo group went from 2.7 at baseline to 3.5.
So what the data show is an increase of 2.5 events per month, of which only 0.8 could be credited to placebo.
Consider if we reported instead that women doubled their number of satisfying sexual experiences (from 2.5 to 5.0) and their increase was triple that seen with placebo (increase of 0.8 vs. 2.5). That would also be true. And perhaps the perception of efficacy might be far more positive.
Perhaps we in media aren’t giving enough credit to a woman and her healthcare provider to make a decision on the significance of those results in her particular situation.
What’s not open to selective interpretation is the very fact that across the three studies, with up to five measures of efficacy, flibanserin showed in every case an improvement over placebo. As I’ve said before, that’s impressive. The confounding factor is that placebo responses are high in these types of trials, not just with flibanserin but with any drug that acts on the central nervous system.
A review by Andrea Bradford at M.D. Anderson shows that some aspects of female sexual dysfunction trial design already enhance the placebo effect, such as the interaction with clinicians who are experts in sexual medicine and comfortable with conversations like this and the trial requirement that you at least try to initiate a sexual experience once a week.
But even with that strong suggestive element, flibanserin outperformed placebo in all three pivotal trials. Whitehead says that across the three pivotal trials, “Between 46 and 60 percent of women judged their effect to be meaningful. That’s remarkable, but that says that 40 percent of women are not going to be helped by flibanserin. We are not going to help all women.”
Another consideration is that these average numbers don’t adequately reflect the magnitude of individual responders to the drug.
When the SSE data are picked apart, as shown in the company’s presentation at the FDA hearing, the results are more meaningful if considered on an individual basis. About 25 percent of women experienced an increase of four or more satisfying experiences per month (vs. about 15 percent in the placebo group). That means they went from about 2.5 to 6.5 or more. And again, in every single case – one more, two more, three more – the drug was significantly better than placebo.
So if you’re a woman who responds to the drug, that response could be considerably greater than average.
Significant sexual events are downstream of distress over desire
“The SSEs were identified as objective measures long ago when these trials were first designed with the help of FDA to come up with endpoints because it’s something you can count. But they really are a much more downstream effect of desire,” says Sheryl Kingsberg, PhD, chief of behavioral medicine in the obstetrics and gynecology at University Hospitals of Case Medical Center and a full professor of psychiatry, obstetrics and gynecology at Case Western Reserve Medical School. Kingsberg received compensation as a Sprout consultant. An author of over 70 peer-reviewed publications on women’s health, Kingsberg presented the overview and impact of HSDD at last week’s FDA hearing.
I asked her to distinguish the difference between the SSEs and the other self-reported measures of desire and distress.
Kingsberg explained, “What we’re really looking at in hypoactive sexual disorder is to increase desire. Women will have sexual events for a variety of reasons and they will rate them as satisfying for a variety of reasons. In the neurobiological model of desire, what’s missing is the motivation and reward processing – avolition, just as we see in depression. So if you put her in bed and she has a sexual event and she’s aroused and has an orgasm, she will rate that as satisfying. But what’s missing is going to be the motivation to do it again.”
The two other measures in the trial were the desire domain of the female sexual function index (FSFI-Desire) and distress (FSDS-R), one of the diagnostic criteria for HSDD. Kingsberg said that distress isn’t really anxiety but rather a feeling of sadness and inadequacy around being bothered that ‘it’s gone and they want it back.’
As with SSEs, the increase in the magnitude of difference between placebo and flibanserin also progressively increased as measures of sexual desire became more stringent. Similar the reduction in emotional distress decreased at a greater magnitude relative to placebo as stringency increased.
The combination of the primary, co-primary, and secondary measures all showed significance over placebo – all the endpoints required by the FDA. Whitehead stressed that included in these endpoints were measures of self-reported, clinical meaningfulness.
Flibanserin is the most extensively studied drug in women
Moreover, the inclusion criteria allowed for the sort of variability observed in the general population: 87 percent white and about 11 percent of the subjects being African-American; 46 percent normal weight and 53 percent overweight or obese; average age of 36 with a range from 19 to 54; and psychotherapy permitted as long as it wasn’t initiated less than 12 weeks before the trial started. That’s another major consideration of the FDA and its advisory panels: How closely does the clinical trial population reflect anticipated, real-life users of the drug?
I used to teach my pharmacy students at the University of Colorado that drug companies are only required to test their drugs in about 1,500 or 2,000 people. The FDA requires that at least 1,500 be exposed to the drug, 300 to 600 for six months or more, and 100 for at least a year. Sprout has tested flibanserin in just shy of 8,000 women, with a total study number of over 11,000.
“In a day and age where we talk about including women in clinical trials and studying drugs in female rodent model, it’s disheartening that it’s lost that flibanserin has been looked at for and in women. It is one of the largest new drug applications, ever, for women. This is in a field that, up until now, the standard of care has been repurposing male drugs.”
Whitehead and her husband, Bob, who is currently Sprout’s executive vice chairman, had led Slate Pharmaceuticals through FDA approval of the first long-acting testosterone preparation for men with low testosterone, Testopel, now sold by Endo Pharmaceuticals. The current iteration of the 25-person company is so-named as it “sprouted” from the sale of Slate.
“Part of our enthusiasm in making the decision to sell off the business with one of the men’s sexual health drugs and pursue flibanserin was that here we have something with spectacular scientific understanding and a mechanism that’s going along with that understanding, as opposed to the less artful version of ‘It works in men. Let’s see if it works in women,’” says Whitehead.
Flibanserin acts in the brain to modulate serotonin responses in the prefrontal cortex of the brain that connects to limbic pleasure centers, ultimately disinhibiting norepinephrine and dopamine pathways that mediate how we processing rewarding activities. Functional MRI studies published in Neuroscience and conducted by academic researchers with no ties to Sprout are consistent with lower activity in these pathways.
Drug interactions and side effects
In fact, the more one looks at the data and FDA’s complete response letter, the company has done everything the FDA has asked, even when those requests were above and beyond those for other drugs that act on the brain.
The studies of the drug’s metabolism are an excellent example of Sprout’s efforts. About 85 percent of a flibanserin dose is handled by a drug metabolizing enzyme called CYP3A4. We know very well that some drugs inhibit the action of CYP3A4, such as antifungal drugs like fluconazole, and that almost half of all drugs are handled by that enzyme. Not just flibanserin. Half of all drugs. The company still did the work to show that flibanserin blood levels increase substantially (up to seven times) with any of these inhibitors. So if it’s approved, flibanserin will carry warnings for it not to be taken with those antifungals and warnings will be triggered when the drugs might be prescribed by two different doctors. And, moreover, those antifungals already carry the warning that they not be used with a long list of other drugs metabolized by the same enzyme.
But that’s not all Sprout did. They addressed pharmacogenomics of a secondary drug metabolizing enzyme. The remaining 15 percent of a flibanserin dose is handled by related enzymes called CYP2C9 and CYP2C19. Of the 50 changes, or polymorphisms, that occur in those enzymes across the population, some reduce their efficiency and, in turn, might have been expected to increase flibanserin blood levels in individuals that would be called slow-metabolizers. Whitehead said that the company had to screen 1,800 volunteers just to even find 25 slow-metabolizers to do the study. And after all that, there was no statistical change in flibanserin metabolism, probably because most of it is handled by the other enzyme, CYP3A4.
The primary side effects have also been exhaustively examined. Dizziness, sleepiness, and fatigue occurred at a rate of 9 to 11 percent, as compared with placebo rates of 2 to 3 percent. Placed into appropriate context, many other CNS drugs cause the same degree of these side effects, or greater: Wellbutrin, Paxil, Cymbalta, Zoloft, Prozac, Celexa. Some of these, like Wellbutrin, cause dizziness and somnolence at a rate of over 20 percent. And all of these effects are intensified by alcohol, for every one of these drugs. So flibanserin poses no unusual effects and can be managed by appropriate warnings.
The hemodynamic side effects, such as hypotension and syncope, treated very seriously by the company and the FDA advisory committee. Whitehead says they are comforted by how infrequent the reaction is. Six patients experienced these effects in the Phase 3 trials, or 0.4 percent. The rate in the placebo group was 0.3%.
“When you look other products being used off-label, like testosterone and Wellbutrin, their incidence of hypotension and syncope and hypotension are much higher than that seen in flibanserin. I say that only in the context of a conversation that seems to have caught a little bit of fire but departs from a comparator or frame of reference,” says Whitehead. “Flibanserin has risks, as does any other drug.”
We also know that these effects are intensified by antifungal drugs that inhibit CYP3A4 as well as alcohol in the range of two to four drinks ingested within 10 minutes. What this means in a post-approval population is exactly why the risk management and mitigation strategy suggested by Sprout will include health care practitioner education to counsel patients to be on the lookout for such effects.
‘Not approving this drug carries more risks’
When considering these side effects and their frequency, an important point is that they’ve been studied in detail and the FDA has the original data on each subject to examine exhaustively. A case could be made that the current situation, without flibanserin available is far more serious, where patients are taking homeopathic and herbal supplements or off-label compounded of prescription hormones.
While this was discussed somewhat at the FDA hearing, I had been chatting on Twitter with Lisa Larkin, MD. She was amenable to talking in more than 140 characters at a time to share her clinical experiences on patients with HSDD who are currently without access to anything with a well-quantified safety and efficacy profile. Larkin, an associate professor of obstetrics and gynecology is also director of the University of Cincinnati’s Women’s Center. She also testified at last week’s FDA hearing but has not received any funding from the company.
Her motivation is that she has a high-volume academic practice where we sees women routinely with HSDD, often dealing with problems of self-medication with herbs and supplements managing patient misadventuring with implantable testosterone products from compounding pharmacies. Dr. Larkin also takes issue with those who oppose the drug based on the faulty belief that HSDD is a disorder made up by pharma.
To those who propose that only a behavioral approach is necessary, Dr. Larkin says, “Of course, I recognize that sexual dysfunction is a multifactorial problem and a large number of women can benefit from therapy, treatment of their depression, marital issues, have past issues of sexual abuse. And, clearly, this drug is not for that.”
Larkin adds, “Where I really take issue is where people aren’t actively writing prescriptions like I am lack a very good sense of side effect profiling. And to say that it’s all made up by pharma is frankly a disservice to women.”
“But this biggest point that I didn’t have time to get to at the FDA was that not approving this drug puts women at more risk because what I see in practice day in and day out is people doing flukey, unregulated, untested supplements, compounded stuff, looking for answers going to these anti-aging centers.”
Relative to these other approaches, Dr. Larkin says that doctors can make assessments based on known and well-quantified risks. “With any approved drug, the risks are identified in the package insert and prescribing information and we as clinicians have data that can tell us alcohol is a bad thing, that there are specific drug interactions. With all of these other things and compounded drugs being used off label, it’s really not a safer alternative.”
The most dramatic cases Larkin faces are with women given implantable testosterone pellets. She has had multiple patients who’ve gone to anti-aging clinics with testosterone levels “in the thousands” – a normal level in men is 800 to 1,100 nanograms per deciliter. Women present as edgy, agitated, and aggressive, and yes, their hot flashes go away and their libido briefly improves. But in three to six months they come in with clitoromegaly, where the clitoris grows to more closely resemble a penis, acne, hair loss, and feel unwell.
Another type of risky patient she just saw was a premenopausal woman with hormone-dependent, breast cancer who was getting testosterone pellets and came to her for hormone replacement therapy. As testosterone gets converted to estrogen, that already increases the risk for breast cancer recurrence. The best she can do in such a case right now is to recommend a topical estrogen preparation. But hormonal approaches can only do so much and Larkin has little else to offer her patients. Flibanserin would be another important tool that she could use safely in many of her patients.
The wisdom of Even the Score
Dr. Larkin has been a supporter of the Even the Score campaign to urge the FDA and Congress to recognize HSDD and “even the score’ by approving flibanserin. It’s been criticized by opponents as just a pharma-funded public relations campaign – Whitehead says that ‘patient advocacy’ is more appropriate.
Larkin says she had some unease about the perception but the whole reason it was mobilized by a spectrum of women’s groups and drug companies that included Sprout was that, “We were being neglected. I think we needed the campaign to raise awareness and I support having done the campaign because the end result is really what I believe we need.”
The most prevalent messaging from the Even the Score campaign was that the agency has been exhibiting gender bias in approving 26 medicines for sexually-related disorders in men and zero or few for women.
In working with regulators on drugs for both genders, Whitehead has a related but distinct perspective. “I believe that there is a condition bias on HSDD that’s a factor of a lot of things. I think we have deeply-held beliefs around women and sexuality and we do see here a different risk tolerance in terms of decision-making between men and healthcare provider versus women and healthcare provider.”
“The sheer abundance of data we have generated on safety – and we’re proud of how robust our data is – that informs a lot. We feel firmly that we have characterized the benefit as well as the risks of flibanserin, says Whitehead.
“If you can do that, and look at precedent after precedent of other products that are out there and the ability of there to be shared decision-making between patient and provider, I do scratch my head at what the opposition thinks in terms of their firmly held belief that this shouldn’t be turned over to women.”
For more health and pharmaceutical news and commentary, follow me on Twitter @DavidKroll, or here at Forbes.com.
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