Futsing Around in Pharma

As I fumble to string words together to explain what happened to futsernol, a heavy sense of futility sits on my gray-haired chest. I’ve cared about the drug—no, about what it could have done for millions of suffering people—for too many years not to care. There’s not a damn thing I can do about it, but I can’t seem to let it go, either. 

Maybe you too will be bitter once you’ve read this story. Maybe that’s why I’m writing, to tick you off.  

Futsernol—let’s call it FUTS—looked great in rats for treating depression. A loveable little Italian bench scientist named Carlo Crespi was its creator, shaping it to do this and that to various receptors in the brain. When praised about it, he’d only turn his head a little, smile shyly, and stroke his stubby black beard. But it was genius stuff. 

It came into my hands for clinical development from Carlo. We both worked for Eurenne Pharmaceuticals, a giant Swiss firm. Eurenne treated us in its US arm like unruly stepchildren, correcting us quarterly as over-indulged, over-spending, and bullheaded. We’d learn to take their firm hand Or Else. Over my first three years at Eurenne, almost half of our clinical people took the Or Else route. They apparently missed having a chance to actually use their heads.  My project manager from Basle, Achso Lindgren, used to say, “Management assumes you lose 50% of your IQ points when you go to work for Eurenne.” He said it with a sardonic smile. But he meant it.           

In the clinic, FUTS didn’t look so great.  Some patients got over their depression, but almost as many got well on placebo.  My favorite psychiatrist, crusty old Jay Cromwell out in La Jolla, told me “It starts out great but just poops out”—proving once again that antidepressants either take a month to start working, trying the patience of patients and their families alike, or work from the start but run out of gas before the six-week visit, the usual finish line in clinical trials.

But Eurenne’s top management, led by the imperious Dr. Baeglund, a little martinet whose perpetual calm seemed linked to his status as a statistician as well as an MD, refused to stop whipping a dead horse. Bland smile fixed in place, he closed our segment of the quarterly meeting in Basle telling the FUTS project leader, “Try again, and get the doses right this time, won’t you?” 

It was worth a shot. The world was full of antidepressant users, but most of them felt de-sexed by the drugs. I liked drugs like FUTS, drugs that retooled just one or two cylinders of the serotonin “engines” in the brain. I had more than the benefit of reading about research, too; I took a day a week to run a clinic for depressed patients. I’d explain how a run-of-the-mill antidepressant could take a month to work, and what the side effects would be. As often as not, guys like Ben S, struggling to pay attention to his work as a tax accountant because depression was sapping his strength and attention, would say, “No, thanks. Things are bad enough with my wife.” Or women like Molly L would find they had become so turned off about sex that they were considering divorce. Or, once in a while, they’d storm into my office like Jane G, demanding something else because, on a drug I’d prescribed, she had been horrified to find herself peeing on her partner during sex. 

So, I begged Marketing to let us add a measure of sexual function to the last set of FUTS trials. It wouldn’t beat the positive comparator, Plarzel, for depressive symptoms, but it ought to beat Plarzel for sexual symptoms and thus gain new life.

It took us another year and a half, but the late-phase II trials showed that FUTS flopped—again—on depression scales, didn’t even beat placebo, but for sexual symptoms, it beat Plarzel and placebo. On a brief little self-rated scale of sexual problems, FUTS looked good for sexual desire, even if it didn’t seem to do much for arousal or orgasm. 

Dr. Baeglund, almost frowning on seeing the study results, gave up on developing FUTS for depression. But it didn’t take much arm-twisting by the project head before he okayed two trials to see if FUTS could conquer sexual problems. 

FUTS was no freak to me. Its shift from development as an antidepressant to a drug for sexual desire (technically, Hypoactive Sexual Desire Disorder, HSDD) started for me a decade earlier. I developed direct-acting serotonergic agents for depression for Crystal Croiers and Quid from 1989 through ‘91. It was a relief from the usual dilemma of improving patients’ moods while robbing them of their sex lives. CCQ had a whole family of drugs that worked on serotonin receptors in the brain. The drugs were cultivated as serotonin 1a-receptor agonists. Old pro Jack Fagan said “1A is where the action is,” in 1986 after the first study he had done with one of those drugs, Trukerone. 

And he should know. Fagan had made a big name for himself in St. Louis as an academic psychiatrist in the early 1970s, when the Diagnostic and Statistical Manual of Mental Disorders was full of hoary old names for disorders—and hoary old ideas of where the problems originated—but not a word of description of what they really meant. Fagan chucked out every school of psychiatry that worshipped psychoanalysis and the unconscious and took a know-nothing position about what causes mental illness. He pulled descriptions from the published literature. He adopted a “Chinese menu” approach, becoming the first twentieth-century psychiatrist to differentiate disorders by symptoms instead of the trauma that supposedly led to mental disease. Fagan’s criteria for depression, schizophrenia, and a few other related mental disorders came out in 1972.  

His idea was, if you could tell one mental disorder from another by its symptoms, then you could test a treatment in a group of patients with the same symptoms, measure change in those symptoms with the treatment, and maybe that would lead to progress in treating mental disorders.  

This might sound stupidly obvious, but it wasn’t at the time. It led to breakthrough drugs for mental illness. Even before Fagan came out with his criteria, Nathan Kline in New York got spectacular results borrowing an ancient Indian herb containing reserpine to treat hospitalized patients with schizophrenic symptoms. Almost immediately after this led to winning the American version of the Nobel prize in 1957, he borrowed another drug, iproniazid, from the tuberculosis ward because it perked up infected patients—and got spectacular improvement in patients with depressive symptoms because drugs like iproniazid, monoamine oxidase inhibitors (MAOI), treat virtually any kind of depression, mild or severe, agitated or catatonic.

But no MAOI is benign. Humans like foods and beverages containing tyramine, which is concentrated in cheeses and wines. Tyramine elevates blood pressure. With an MAOI onboard, people can’t metabolize tyramine. A cheese-and-wine party can bring disaster—headaches for starters, strokes as finishers. Safer antidepressants had to be found. 

At CCQ, we worked on that. CCQ’s serotonin 1a agonists with 2a antagonist properties had no sexual side effects, even though they weren't that great for severe depression. Also, a few tantalizing reports came in of people with sexual excitement, even spontaneous orgasms. 

CCQ was about to downsize psychiatric research, so I started job-hunting while monitoring the first controlled clinical trial of one of the CCQ antidepressants for sexual dysfunction in depressed patients. The study design was terrible. It required patients with sexual problems while on a standard antidepressant (an SSRI) to go off it and risk recurrence of depression, restart it until getting full-blown sexual dysfunction again, and then get randomized to the CCQ drug or (again!) to SSRI. No surprise: enrollment was poor. But eventually, by 1995, the trial was a success. A patient could get over his or her depression without losing their sex drive.

Eurenne hired me as a seasoned hand to develop futsernol (FUTS) as an antidepressant. Immediately, I could see that FUTS was a lot like CCQ’s sexually advantageous drugs. Unfortunately, Ethos's idea for differentiating FUTS from the pack of antidepressants was to prove a fast onset of action. That approach failed because evaluating patients every few days made the placebo effect skyrocket, masking possibly better effects of futsernol.

When Dr. Baeglund demanded that last round of depression trials in 1999, I discovered a new, very brief sexual function scale that was self-rated and minimally intrusive on a clinic visit. This scale, the Arizona Sexual Experiences Scale or ASEX, had not been validated to show loss of sexual desire; it was only a general screener for sexual dysfunction. 

But studying sexual function was in its infancy. No wonder Ethos’s marketing group feared adding the ASEX to the depression trials. But we lucked out; FUTS beat Plarzel and placebo on the ASEX, especially on the scale’s “sex drive” item.

Coincidentally, a national survey published in JAMA was brought to our attention by expert consultants in early 2001; it showed that loss of sexual desire was the most prevalent sexual problem of US women. So, loss of sexual desire became the indication for which our project leader asked Dr. Baeglund for funds. Dr. B authorized two “proof of concept” trials. We got them running in 2002. They were nearing completion in 2003 when turnover in local leadership gave me the opportunity to become worldwide medical head for clinical development of FUTS that July.

The first person I needed to give the results was my line boss in Chicagoland, Arlan Spelling. Arlan, a feisty maverick who pined to work as a weather forecaster instead of overseeing medical research, had been adamantly opposed to running the sex trials because, he said, women would never volunteer, would never stoop to disclose such private issues. Hadn’t he asked his wife and her friends whether they would enter such a clinical trial and heard them say they were totally turned off? 

Dr. Baeglund, of course, overruled Arlan, and by November of 2003 we had the results. I will never forget how much fun it was to show Arlan the graphs. The FUTS groups’ curves looked better than placebo on almost all measures at almost all time points in both trials. Arlan’s face got redder with each page I turned. 

Two months later, I made my first trip to Basle and convinced the skeptics that FUTS had potential for improving female sexual desire. Even Dr. Baeglund accepted the good news. I knew he was won over when he stopped me in the hall afterwards and asked with a rueful smile, “Could futsernol also be developed for men?”

But men had Viagra and me-too drugs like it for Erectile Dysfunction (ED). Women had zip for sexual problems. Yet women developed distressing levels of low sexual desire more often than men got ED. And ED was a multi-billion-dollar-a-year market. 

On the other hand, it was like working on a misfiring engine without tools. There was no standard way to measure what was normal and what wasn’t, no standard diagnostic exam, no way to tell how much improvement was worthwhile, and extremely limited information about what was going wrong, if anything, in the brain. 

At an international conference on women’s sexual health, after two hours discussing all that was known about sexual desire, the panel decided we don’t know what women really want. The experts in the field—the “sexperts”, we joked—would start with a slide showing a big metal box with a welter of dials, meters, and rheostats to represent women’s sexuality vs. a flat box with one on-off switch to represent men’s. Audiences laughed—but it was not particularly true.  It turns out that you can’t get very far in sexual medicine without giving up the clichés.   

But here was FUTS making women mark on rating scales that their feelings were changing. After years of feeling turned off, they were back to noticing handsome men. Drab sparrows at their intake visits, they’d show up in the clinic after a month or two on FUTS with their lips glossed, wearing form-fitting clothes, hair and nails done up.  We didn’t have to know exactly what was going on biochemically—it was obvious that their brain was refocused on sex. 

But we did not have sensitive, accurate measures of sexual desire in women. Nor was there any scientific or regulatory roadmap on how to prove a treatment effective for sexual function in women.

  The second critical thing I found missing in the development plan, and what I pitched to Arlan, was flexible dosing. The time-tested way to develop drugs for emotional problems is to start with flexible dosing—to devote initial trials to seeing if any dose in any regimen works. Clinicians are empowered to start with a dose that was well tolerated in normal volunteers and to push the dose up to the highest that normal subjects tolerated. They are told to start dosing in the morning and at bedtime, and if that doesn’t work, to give the new drug three times a day; if it works, to back off to once a day and see if the improvement lasts. Then come placebo-controlled studies with more limited flexibility of dosing and finally, if FDA requires it, a fixed dose study to determine the minimum effective dose.

  But no, two fixed-dose proof-of-concept trials were all that the FUTS project team, or Basle, would authorize.

The third critical thing I saw missing in Basle’s plan was special safety studies. After the depression trials—and again after the proof-of-concept sex trials—it was clear that the main side effect of FUTS was drowsiness. Drowsiness may seem benign, but it is not to the FDA. The agency knows from other drugs for the brain that drowsiness may foretell fatigue, injurious falls, slowed reaction time and trouble with driving, depression, worse effects with alcohol, even suicidality. I kept telling Arlan and the rest of local management that failure to investigate drowsiness, particular if FUTS were taken with alcohol, would lead to trouble with FDA. But they refused to authorize special safety studies, said “we’ll handle it with labeling”—meaning that they would write the official instructions for use of the drug to exclude patients taking alcohol or having other issues with drowsiness.

Ayn Rand wrote, "You can avoid reality, but you cannot avoid the consequences of avoiding reality." The FUTS program failed to include an alcohol interaction study or a driving safety study. Also, the dose was raised in lockstep, could not really be adjusted for a given patient to achieve efficacy. Yet, in the similarly subjective field of antidepressants, thirty percent of trials with flexible doses fail, while sixty percent of trials with fixed doses fail. 

Yet another, fourth, problem was self-created by Eurenne: the disorder. I argued that the only women with well-known sexual problems who were already in the doctor’s office were those with depression, especially those taking SSRIs. So, we ought to target them first. Nothing doing, the Core Team said: we should treat women with a primary problem of lost sexual desire, not women who were already on some CNS drug. They said FDA wouldn’t look kindly on treating a drug side effect with another drug. What they overlooked was that depression was already being treated with a “cocktail” of drugs in a high proportion of patients—with an SSRI as the mainstay but with a sleeping pill added for insomnia and/or a stimulant to cope with the fatigue patients felt during the day.

The Core Team pointed to the JAMA survey: 32% of women had had problematic low desire. It was the by far the most frequent female sexual problem. But that didn’t mean 32% of the US female population had a primary sexual disorder. When Ethos finally did its own survey of women for sexual problems, it found that a large proportion of women with low sexual desire had it while taking an antidepressant or because of depression itself.

The focus for Phase III, the big registrational trials that would make or break FUTS, remained on the primary desire disorder, HSDD, and Eurenne stuck to a fixed dose. And ignored doing safety studies. Oh, the Core Team did respond to Marketing’s idea to give all of the dose at bedtime to take advantage of the drowsiness, and that cut dropouts for side effects drastically from almost 50% in the proof-of-concept studies.

But every one of those problems came back to bite the company. Lack of a well-validated, treatment-sensitive measure: FDA wanted a “simple daily measure” of desire, yet, in our Phase III trials, making patients fill out a diary every day raised the placebo response to a disastrously high 60-70%. Fixed dose: with no “back-down” dose available, over ten percent of the subjects given FUTS dropped out for side effects, mainly drowsiness and related issues, leading FDA and its advisory committee to vote FUTS down for safety. The focus on HSDD: after Dr. Baeglund gave up on FUTS and sold it to a start-up, which studied the safety issues mentioned above, the start-up got FUTS approved by the FDA. But in the first year of marketing, extremely few women with primary loss of sexual desire went to their doctor for it. Arlan was proven right. At the same time, the proportion of women taking an antidepressant, half of whom get sexual dysfunction, jumped to 17.7% in 2018—and, of course, those twenty million women were already seeing a doctor.

No wonder I keep grinding my teeth.