Addyi REMS-A Shanda

I seem to be on an Addyi kick lately. I got an email today about the Risk Evaluation and Mitigation Strategy (REMS) for Addyi, the newly approved medication for Hypoactive Sexual Desire Disorder.

There was a lot of fuss about this REMS, because Addyi is known to cause hypotension and syncope particularly alcohol is consumed. So the FDA created a REMS that involved special training and official certification for prescribers of Addyi (as well as pharmacies dispensing Addyi).

I mentioned in a previous post that I didn't want to do the training. I assumed it would be something along the lines of the 8 hour training required to prescribe Buprenorphine, and I didn't want to put that kind of effort into it. More importantly, I don't think the drug works, and I thought it would be easier to tell a patient I'm not certified to prescribe Addyi, than to have a long discussion about why it's not a good idea for her to take Addyi. Yeah, okay, that's a copout. I also didn't want to support this Shanda* of the FDA and Sprout (the company that makes Addyi).

*Shanda is Yiddish for something shameful or scandalous. I think Yiddish has much better words than English for expressing exasperation and outrage. Also sounds. An appropriate one here would be, Feh.

Buuuut...I got curious after I got the email. So I checked it out. What's involved is:

1. Read the Addyi Prescribing Information

2. Complete the Addyi REMS Program Prescriber and Pharmacy Training

3. Complete the Addyi REMS Program Knowledge Assessment

4. Enroll by completing the Addyi REMS Program Prescriber Enrollment Form


I want to go out of sequence for this next bit. I'll start with the Knowledge Assessment. Here it is:

Please note, this is not a section of the Knowledge Assessment. This is it. The whole shebang. I didn't need special training to answer this one.

And the training? It took me less time than reading through this post. The main point of it seems to be the Patient-Provider Agreement Form. This needs to be signed by both prescriber and patient, and states that the prescriber has counseled the patient, and the patient understands the counseling.

It's kind of brilliant. The FDA is covered for approving Addyi by the existence of  this special "training". Sprout is covered for producing and selling a dangerous drug that doesn't work by putting the burden of counseling the patient on the prescriber. And by covered, I mean legally.

This is what's required of the prescriber:

There might have been something useful in the "training" if it included recommendations for assessing a patient's ability to abstain from alcohol, or suggestions about how to encourage a patient not to drink while taking Addyi. But that would place some liability on Sprout or the FDA. So they didn't do it.

I am definitely not gong to enroll as a prescriber.

Addyi-dendum

Maker of Addyi, ‘Female Viagra’ Drug, Being Sold to Valeant for $1 Billion

Wow! That was fast! On Tuesday, the FDA approves Addyi to treat Hypoactive Sexual Desire disorder (HSDD) in women. And on thursday, the maker of Addyi, Sprout pharmaceuticals, is sold to Valeant for $1 billion.

According to the NY Times article (link above), about $100 million has been invested in Sprout since its formation in 2011. And now it gets $1 billion. Nice.

Let's look at the sequence of events here:

Boehringer Ingelheim develops flibanserin as an antidepressant, but it doesn't work.

They notice that it increases sexual desire, so they test it for that, but the FDA rejects it in 2010, and they give up on it.

Meanwhile, Slate Pharmaceuticals, run by a couple named the Whiteheads, is selling an implantable testosterone product for men. In 2010, Slate receives a warning from the FDA for making exaggerated claims about this drug.

The Whiteheads learn about flibanserin, sell Slate, and form Sprout to acquire it.

Sprout conducts 2 studies that fail to show an increase in sexual desire, change the outcome measure, keep getting rejected by the FDA, then create Even the Score to put political pressure on the FDA to approve flibanserin on the grounds that if they don't, they are guilty of gender bias.

On Tuesday, the FDA caves to this pressure and approves flibanserin, brand name Addyi.

And today, Valeant announces that it is acquiring Sprout for $1 billion cash plus a share of future profits:

Sprout is passionate about women's sexual health and has focused solely on the delivery of a treatment option for the unmet need of premenopausal women with acquired, generalized Hypoactive Sexual Desire Disorder (HSDD)

I'm sure Sprout is as passionate about women's sexual health as Slate was about men's sexual health.

Exactly as passionate.

Addyi

Addyi.

That's the proposed trade name of Flibanserin, the new "female viagra" drug that's making headlines because the FDA has not approved it, but agreed to call a panel to review their decision.

No idea how to pronounce, "Addyi."

There are all kinds of controversies here. The group, Even the Score, is complaining that the FDA is guilty of gender bias. They're funded, in part, by Sprout Pharmaceuticals, the company that makes flibanserin. The FDA claims they just don't think the benefits outweigh the risks, and they seem to have agreed to the review panel because of political pressure. Other women's advocacy groups, like Our Bodies Ourselves, are opposed to the drug, for the same reasons as the FDA. There are questions about the diagnosis of Hypoactive Sexual Desire Disorder, for which the drug is being developed.

All sorts of difficulties. And who knows the answers? I certainly don't. So let's look at the drug (FDA report of June 4, 2015).

Flibanserin was originally developed by Boeringer Ingelheim, as an antidepressant. Then Boeringer Ingelheim switched to evaluating it as a treatment for low sexual desire in women. I don't know how that switch came about. In 2012, Sprout Pharmaceuticals acquired flibanserin.

The FDA is now on its third review cycle for flibanserin. In the first review cycle there was a unanimous, 11 to 0 vote not to approve the drug:

The FDA agreed that the NDA could not be approved and issued a Complete Response letter in
2010, citing the following deficiencies:

*Lack of substantial evidence of efficacy because the phase 3 trials did not show a
  statistically significant change from baseline for one of the pre-specified co-primary
  efficacy endpoints.

*Overly restrictive entry criteria for the phase 3 trials, precluding a full assessment of
  efficacy and safety in the target population.

*The need for a DDI study to characterize the effects of a moderate CYP3A4 inducer and
  a moderate CYP3A4 inhibitor on flibanserin pharmacokinetics. The letter also asked the
  Applicant to submit results from a meta-analysis of phase 1 pharmacokinetic and safety
  data in women who concomitantly received flibanserin with an oral contraceptive (a
  weak CYP3A4 inhibitor).

*The need to complete the ongoing 12-week trial assessing the concomitant use of
  flibanserin with selective serotonin or norepinephrine reuptake inhibitors, with particular
  attention to possible exacerbation of depression.

*The need for a study assessing the effects of co-administered flibanserin and alcohol on
  tolerability, blood pressure and orthostatic vital signs.

*The need for a study assessing the effects of supra-therapeutic doses of flibanserin on
  orthostatic vital signs and risk of syncope in healthy premenopausal women.

*The need for an assessment of the risk of accidental injury with root cause analyses.

*The need for an assessment of the potential for human abuse because of central nervous
  system effects. 

The first study in premenopausal women ended in 2008. The primary outcome measures were changes from baseline in frequency of satisfying sexual events (SSE) and changes in desire, both measured by electronic diary entries kept by study subjects. The secondary outcome measure was change in distress associated with reduced sexual desire, assessed by diary entries and by using response to Question 13 in the Female Sexual Distress Scale-Revised (FSDS-R), which is, "How often do you feel bothered by low sexual desire," rated on a scale of 0-4.

There was no statistically significant difference in the measure of desire. The company blamed this result on "diary fatigue", and proposed using two questions from the desire domain of the
Female Sexual Function Index (FSFI-desire, which uses a 28-day recall period) to
assess changes in desire. I'm pretty sure the two questions are, "How often did you feel sexual desire," and, "How would you rate your level of sexual desire," in the past 4 weeks, on a 1-5 scale.

In other words, they wanted to change the primary outcome measure after the study was complete.

I quote the FDA report (p.11):

The Division advised that failure to meet one of the two co-primary efficacy
endpoints did not constitute an acceptable reason to alter a pre-specified and
agreed-upon endpoint. Furthermore, the Division and the Study Endpoints and
Label Development (SEALD) team had already shared with the Applicant
concerns regarding limitations of FSFI-desire instrument, regarding 1) recall bias
due to the use of a 28-day recall period, and 2) content validity of the two
questions. 


In the second review cycle, in 2013, the FDA cited:

*Numerically small treatment differences compared to placebo, which do not clearly
  outweigh the safety concerns.

*Concerns with content validity of the FSFI sexual desire domain, used as the co-primary
  efficacy endpoint in the new phase 3 trial, and used as a secondary endpoint in the two
  prior phase 3 trials.

*Concerns about how healthcare providers would identify appropriate candidates for
  flibanserin, taking into account the change in DSM diagnostic criteria.

*A clinically significant interaction with alcohol causing syncope and hypotension.

*Increased exposures to flibanserin with moderate and strong CYP3A4 inhibitors, causing
  clinically significant hypotension in some cases.

*Events of central nervous system depression (e.g., somnolence), some of which appear
  temporally associated with accidental injury. 


The FDA made several requests for additional data and analysis, if the drug was to be reconsidered.

In December, 2013, Sprout submitted a dispute resolution request, and asked that flibanserin be approved without additional data or analyses. This was denied in February, 2014.

And thus began Sprout's campaign to pressure the FDA into reassessing by invoking gender bias.

I apologize for my cynicism, but I suspect a political and social media campaign is cheaper and faster than additional research, especially when there is little expectation that additional research will improve the drug's prospects for approval.

What is flibanserin? It's a 5HT1A agonist and 5HT2A antagonist. It also binds moderately to 5HT2B & C, and dopamine D4. Its mechanism of action in HSDD is unknown.

There are significant interactions with fluconazole (7-fold increase) and ketoconazole (4.6-fold increase), and serious risks of hypotension and syncope, especially with concomitant alcohol use. Flibanserin is not a PRN drug, so interactions with alcohol are unavoidable, unless one completely avoids alcohol, which is unlikely in a general population.

Some alcohol-related data:

The exclusion criteria in the flibanserin studies are important to consider. One was a recent history (6 months) of major depression or history of a suicide attempt, or current suicidal ideation. Another was decreased sexual desire due to medication. So the studies could not assess decreased sexual desire due to depression, medication, or other psychiatric illnesses (another exclusion criterion). The generalizability of the results is therefore questionable.


But the bottom line is, does it work? If it does, then maybe women who are willing to risk the adverse events should be offered the drug. There are women who participated in the trials who feel they were helped by the drug, and are disappointed not to have access to it.

This is the FDA's efficacy conclusion (p.33):


The three pivotal trials conducted in North America of flibanserin 100 mg qhs showed a
statistically significant difference between flibanserin and placebo on the endpoints of SSEs,
FSFI-desire score (but not daily desire measured by an eDiary) and FSDS-R Q13 distress score.
These findings and the magnitude of the treatment effects are consistent across the three trials.
However, the treatment differences are numerically small. The FDA is seeking expert advice
from a multidisciplinary advisory committee panel as to whether these observed effects outweigh
...safety concerns... 

To clarify, the first two trials used the eDiary as the primary outcome measure for desire, the condition flibanserin is intended to treat, with no statistically significant results. The third trial switched to FSFI-desire score as the primary outcome measure for desire.

And the overall results(p. 5):

*From a median baseline of about 2-3 SSEs per month, flibanserin resulted in a median
  placebo-corrected increase of about 0.5-1.0 SSEs per month.

*From a mean baseline of about 1.8-1.9 on the FSFI desire score, flibanserin resulted in a
  placebo-corrected mean increase of 0.3-0.4 (the FSFI desire score range is 1.2-6.0).

*From a mean baseline of 3.2-3.4 on the distress score, flibanserin resulted in a placebocorrected
  mean improvement of 0.3-0.4 (on a scale of 0-4). 


We'll just have to wait and see.