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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 3, 2013

Merck's Drug Development in The New Yorker

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Posted by Derek

The New Yorker has an article about Merck's discovery and development of suvorexant, their orexin inhibitor for insomnia. It also goes into the (not completely reassuring) history of zolpidem (known under the brand name of Ambien), which is the main (and generic) competitor for any new sleep drug.

The piece is pretty accurate about drug research, I have to say:

John Renger, the Merck neuroscientist, has a homemade, mocked-up advertisement for suvorexant pinned to the wall outside his ground-floor office, on a Merck campus in West Point, Pennsylvania. A woman in a darkened room looks unhappily at an alarm clock. It’s 4 a.m. The ad reads, “Restoring Balance.”

The shelves of Renger’s office are filled with small glass trophies. At Merck, these are handed out when chemicals in drug development hit various points on the path to market: they’re celebrations in the face of likely failure. Renger showed me one. Engraved “MK-4305 PCC 2006,” it commemorated the day, seven years ago, when a promising compound was honored with an MK code; it had been cleared for testing on humans. Two years later, MK-4305 became suvorexant. If suvorexant reaches pharmacies, it will have been renamed again—perhaps with three soothing syllables (Valium, Halcion, Ambien).

“We fail so often, even the milestones count for us,” Renger said, laughing. “Think of the number of people who work in the industry. How many get to develop a drug that goes all the way? Probably fewer than ten per cent.”

I well recall when my last company closed up shop - people in one wing were taking those things and lining them up out on a window shelf in the hallway, trying to see how far they could make them reach. Admittedly, they bulked out the lineup with Employee Recognition Awards and Extra Teamwork awards, but there were plenty of oddly shaped clear resin thingies out there, too.

The article also has a good short history of orexin drug development, and it happens just the way I remember it - first, a potential obesity therapy, then sleep disorders (after it was discovered that a strain of narcoleptic dogs lacked functional orexin receptors).

Mignot recently recalled a videoconference that he had with Merck scientists in 1999, a day or two before he published a paper on narcoleptic dogs. (He has never worked for Merck, but at that point he was contemplating a commercial partnership.) When he shared his results, it created an instant commotion, as if he’d “put a foot into an ants’ nest.” Not long afterward, Mignot and his team reported that narcoleptic humans lacked not orexin receptors, like dogs, but orexin itself. In narcoleptic humans, the cells that produce orexin have been destroyed, probably because of an autoimmune response.

Orexin seemed to be essential for fending off sleep, and this changed how one might think of sleep. We know why we eat, drink, and breathe—to keep the internal state of the body adjusted. But sleep is a scientific puzzle. It may enable next-day activity, but that doesn’t explain why rats deprived of sleep don’t just tire; they die, within a couple of weeks. Orexin seemed to turn notions of sleep and arousal upside down. If orexin turns on a light in the brain, then perhaps one could think of dark as the brain’s natural state. “What is sleep?” might be a less profitable question than “What is awake?”

There's also a lot of good coverage of the drug's passage through the FDA, particularly the hearing where the agency and Merck argued about the dose. (The FDA was inclined towards a lower 10-mg tablet, but Merck feared that this wouldn't be enough to be effective in enough patients, and had no desire to launch a drug that would get the reputation of not doing very much).

few weeks later, the F.D.A. wrote to Merck. The letter encouraged the company to revise its application, making ten milligrams the drug’s starting dose. Merck could also include doses of fifteen and twenty milligrams, for people who tried the starting dose and found it unhelpful. This summer, Rick Derrickson designed a ten-milligram tablet: small, round, and green. Several hundred of these tablets now sit on shelves, in rooms set at various temperatures and humidity levels; the tablets are regularly inspected for signs of disintegration.

The F.D.A.’s decision left Merck facing an unusual challenge. In the Phase II trial, this dose of suvorexant had helped to turn off the orexin system in the brains of insomniacs, and it had extended sleep, but its impact didn’t register with users. It worked, but who would notice? Still, suvorexant had a good story—the brain was being targeted in a genuinely innovative way—and pharmaceutical companies are very skilled at selling stories.

Merck has told investors that it intends to seek approval for the new doses next year. I recently asked John Renger how everyday insomniacs would respond to ten milligrams of suvorexant. He responded, “This is a great question.”

There are, naturally, a few shots at the drug industry throughout the article. But it's not like our industry doesn't deserve a few now and then. Overall, it's a good writeup, I'd say, and gets across the later stages of drug development pretty well. The earlier stages are glossed over a bit, by comparison. If the New Yorker would like for me to tell them about those parts sometime, I'm game.

Comments (28) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | The Central Nervous System


1. NodrugsNoJobs on December 3, 2013 10:07 AM writes...

So they are going to use a dose of 10 mg which Merck concluded was not effective from their phase 2 study, did not study in their phase 3 and start the majority of patients on that. I don't think i could have predicted that, though my Magic 8 ball said "maybe"

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2. watcher on December 3, 2013 12:22 PM writes...

Well, I hope it works more naturally than does Ambien, which can have some very bizarre effects such as sleepwalking, losing one's carry-on items in airports when making lay-overs.....I've seen both happen to colleagues.

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3. Curious Wavefunction on December 3, 2013 12:37 PM writes...

"Drug development accelerated in 1985, when a company pharmacist, preparing a batch of syrup for the first human trial, accidentally swallowed a teaspoonful of the drug. He immediately fell asleep."

The good old days.

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4. Lyle Langley on December 3, 2013 12:42 PM writes...

@2, watcher...

Can you explain what you mean by "more naturally?"..."I hope it works more naturally than does Ambien..."

@3, CW...

I found that to second sentence to be so theatrical...the pharmacist took a spoonful and immediately fell asleep? Really?!? Just right there at the bench, fell over onto the floor asleep?

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5. ScientistSailor on December 3, 2013 12:49 PM writes...

@2 Watcher...
I had an Ambien 'incident' after an overnight flight, I didn't forget my bag, but after getting off the plane, and leaving the gate, I queued up to back through security. A TSA agent was nice enough to notice and asked me what was up, and direct me to the train to the terminal...

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6. watcher on December 3, 2013 12:51 PM writes...

1) no behavioral effects that are not otherwise experienced (eg sleepwalking) by the person
2) better retention of events when on the forgetting things, events, like Ambien can cause
3) and most important, much better "restful" sleep cycle.

Many people I know have unpleasant experiences with Ambien, as it really works as a hypnoric, not an inducer of a normal sleep experience. If you have not had such experienced, good for you, but these do happen, and more frequently than I'm sure is admitted by the company.

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7. Lyle Langley on December 3, 2013 1:09 PM writes...

Probably better to say "hope it works with less side effects than Ambien" rather than using the term "naturally", but, to each his/her own.

Of course side effects do happen, they happen in in a small population (sometimes larger) when taking ANY drug.

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8. Chris Croy on December 3, 2013 1:14 PM writes...

@4: I assume by "naturally" they mean it just makes people very tired and want to go to sleep vs ambien's tendency to put people into hypnotic zombie states where they do incredibly bizarre and inexplicable things that they have no memory of. For example, deciding to get up, take a shower, shave their entire groin, and then mow the lawn while naked at 2 in the morning. The ambien walrus cannot be explained, only obeyed.

As for 'immediately' - It's a bit theatrical but fairly believable. If someone accidentally took a swig of a highly concentrated solution of ambien, they would definitely pass out (or at least black out) within 15 minutes.

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9. Chemjobber on December 3, 2013 1:46 PM writes...

Linked in my handle is Kyle Finchsigmate's experiences with Ambien; truly hilarious and frightening, all at the same time.

Thank God I'm perennially sleep-deprived (?) and need way less than the recommended 15 minutes to fall asleep.

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10. Merckie on December 3, 2013 2:05 PM writes...

Merck oversold the pill even to their own people. They drank their own cool aid, as usual. They downplayed all the side effects that came with the pill, like drowsiness the next morning, etc. And now they are paying the price. Someone needs to wake up this dinosaur and I am not sure if Roger Perlmutter is going to do it, especially that he entrusted all the characters who were part of the problem to begin with to turn the ship around. The 20% cuts were mostly at the scientist jobs that barely had anything to do with the disastrous strategies Merck adopted, like the six sigma crap.

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11. Esteban on December 3, 2013 2:26 PM writes...

@Merckie: Triple post due to Ambien use? Just kidding, most people learn the hard way about this "feature" of the comments section.

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12. Esteban on December 3, 2013 2:28 PM writes...

And it's already cleaned up! Oh well...

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13. Lyle Langley on December 3, 2013 3:03 PM writes...

@6 and 8...

Not to belabor the point, but, again, these events you describe for Ambien are side-effects from a drug, therefore, the hope is that suvorexant has less (or more mild) side-effects. The "naturally" is a bit misleading as most drugs are there to correct an "imbalance" in the system - or add/subtract to the system.

I do like your use of the term "tendency" meaning that this is the norm; when it clearly is not.

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14. watcher on December 3, 2013 7:17 PM writes...

#8: I don't know why you are trying to put your terms or wording into my postings. That really is rude.

The infirmary of the company where I worked used to give it out when first approved to staff who frequently travelled internationally. After a while, they stopped due to the frequent feedback of the odd events and feelings the drug caused. They did not want to carry extra liability from using the drug for staff, even though it was not this company's drug.

The "zombie state" events caused by Ambien are well documented by many people. Several people I know, a number have commented here. Many people have such effects and cannot take the drub more than once. Almost certainly, many people who had a full script for the drug through most of it away after one or two "odd" instances.

Yes, these are certainly "side effects", but trying to smooth over the nature of the experiences by wordsmithing is really not needed here, unless you are one of the people who were associated with the drug in R&D or the magic or "Merck marketing".

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15. watcher on December 3, 2013 7:21 PM writes...

apology to #8. last post was meant for # 4, 7,, 13 all one and the same.

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16. Anonymous on December 4, 2013 3:07 AM writes...

@13 : the fact that Ambien's issues are "side-effects" of its hypnotic mecanism does not mean that a new drug can't induced a more normal sleep.

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17. Lyle Langley on December 4, 2013 9:07 AM writes...


Okay, one more time... The only "wordsmithing" going on here is from you and your "natural" sleep state. All drugs have side-effects, whether it be Ambien, Suvorexant, Tylenol, etc. Drugs will always have side-effects and trying to use terms like "naturally" will not mask them. I also like how peoples such as yourself make it sound like everyone that takes a drug experiences the worst of the worst side effects. Yes, Ambien can have horrible side effects; however, it has been prescribed millions of times and these are a small percentage, not what you are explaining.

What should be said - and yes, I will put words in your mouth when you misuse them - is that Suvorexant will hopefully provide a restful evening with less side effects (and there will be side effects) than previously prescribed sleep drugs. It has nothing to do with "natural" experience. I'm done now, but please, keep on.

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18. Anon tired of pharma crap on December 4, 2013 9:47 AM writes...

#17 Lyle - I agree with this post. Ambien has neen on the market for a while. The risk/benefit profile is well known. Compared to the number of prescriptions filled, the side effects are miniscule. Yes, all drugs have side effects. The issue here is that there is a new agent, with an unknown side effect profile in the broader population. Who knows what will happen when Suvorexent is marketed? Will some patients take a triple dose if they cannot fall asleep within an hour (I suspect a lot of the Ambien effects are due to overdosing). The FDA made the right call here.

Typical Merck arrogance at work - if a H2H study was done with Ambien and Suvorexant showed superiority in safety, I think the FDA would have approved it. Really doubt this would happen now, and even if this is the case, competitors would get on the market with the relevant comparator data long before Merck would. Goodbye to a potentially great asset!

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19. watcher on December 4, 2013 9:50 AM writes...

17: Say what you want for youself, but don't try to project what is in someone else's mind or whatever may their intention. You simply can't and don't know, no matter how much you want to interject your own words.

I'm done with this silly debate; it's become a total waste of my time by now.

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20. David P on December 4, 2013 12:33 PM writes...

GSK and Actelion were codeveloping an Orexin drug (Almorexant) and that was dropped, which didn't bode well for the Merck drug, but it really looked like it would have at least a better side effect profile than the existing meds, which has to be a good thing.

GSK had another drug candidate in the pipeline but I haven't read anything about it in ages.

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21. sleepyhead on December 4, 2013 2:37 PM writes...

My two cents worth on Suvorexant:
1) The FDA rejected their own expert panel's recommendation to approve the drug. Highly unusual.
2) A couple FDA senior staffers (who were for sure involved in decision to reject panel's recommendation) apparently have it in for insomnia meds. Why? I have no idea. Ever notice why you never see commercials anymore (FDA basically banned them), why after 15 years on market did they suddenly put out press release to recommend cutting dose size of Ambien? One particular FDA gentleman, Dr. Farkus, goes around giving speeches on the evils of insomnia medication (easily searchable). Should an active government employee be doing that? Can he remain truly objective?
3) The entire transcript of the NDA meeting is available on FDA website and from laymen's perspective the safety looked quite decent to me.
Like a prior poster pointed out, all medications are going to have some impact on someone in the study. Can you imagine if aspirin was a new drug seeking approval? I digress. Anyway, the safety data looked better than Ambien and again given the millions of prescriptions for that drug, when used as directed pose no problems for a hugely vast majority of people.
4) The onset to sleep and ability to stay asleep evidence looked very compelling for Suvorexant. So the drug clearly works.
5) Lastly, did the FDA for even one second ever consider how dangerous it is for people to be driving after getting a bad night's sleep because they are suffering from insomnia??? I don't have the stats but, I'm sure there are multitudes of more accidents/deaths caused by sleep deprived drivers than any caused by somewhat "somnolent" drivers who have taken Ambien (let alone this new drug Suvorexant).
I hope Merck sticks with this groundbreaking medication and the FDA weighs the benefits/risks and approves it at some point. Better late than never.

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22. SteggyW on December 6, 2013 9:49 AM writes...

I am curious that among the many comments on Ambien and 'Dose', no one has mentioned the fact that there is a form of low dose Zolpidem available - Intermezzo (by Purdue Pharma). The dosage is 3mg Zolpidem for man and 1.5 mg for woman. "Intermezzo is the First and Only Prescription Sleep Aid Approved for Use As Needed for the Treatment of Insomnia When a Middle-of-the-Night Awakening is Followed by Difficulty Returning to Sleep and the Patient has at Least Four Hours of Bedtime Remaining Before the Planned Time of Waking". Personal experience is that Intermezzo works and you wake up feeling having a naturally good sleep. As far as I can tell the downside of Intermezzo is as a band name drug it's a bit expansive.

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23. sleepyhead on December 6, 2013 2:14 PM writes...

RE: Intermezzo.
My opinion: This is the company that is largely responsible for bringing an overbearing focus on safety of Ambien/zolpidem, and all insomnia meds including Suvorexant, from the FDA (for the relatively small percent of people who suffer adverse reactions, which gets inordinate tons of media publicity) relative to the efficacy argument for the millions of people suffering from insomnia and all that stems from that condition.
I really find it hard to believe there would have been 40 million prescriptions filled last year for Ambien/zoplidem if the drug didn't work.
Anyway, back to this Intermezzo. This company, Purdue Pharma, are of course infamous for being the makers of the greatly abused Oxycodone (Now THAT has serious abuse potential along with thousands of overdoses, compared with hardly any with zoipodem. I read in the New Yorker article the Madoffs tried to commit suicide by overdosing on Ambien but, then they just woke up the next morning.)
So anyway, Ambien goes off patent and this Purdue company comes up with this ridiculous idea to offer a brand name drug called Intermezzo which is just zolpidem in much smaller doses that you take sublingually. Why? Obviously so they can charge brand name prices for it.
Oh c'mon! What B.S.! It's just as easy to just break a zolpidem tablet in half or quarters and put that under your tongue instead. It works just as well.
To get this Intermezzo approved they had to do safety tests, primarily driving tests, and lo and behold some people showed they couldn't drive as well after taking this newly rejiggered zolpidem, especially if taken in the middle of the night which was the whole shtick behind it, and not taking it the night before, such as with Ambien. These safety tests prompted the FDA to relook at Ambien and made them extra cautious (some would say overly cautious) on ALL insomnia medications, including Suvorexant. That's my theory anyway. Thanks a lot Purdue Pharma.

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24. SteggyW on December 6, 2013 9:02 PM writes...

RE: RE: Intermezzo.

It’s certainly not dull to read sleepyhead’s colorful writing.

First let me make a disclaimer that I have no shred of connection with Purdue Pharma (Professionally and personally).

As a part-time insomnia patient Intermezzo works for me and Ambient does not. As many have pointed out that there is an unpleasant aftereffect with Ambient, I belong to that sub-population. And it happens that I breaks pill often as I believe the less the better. Obviously this shouldn’t be applied to antibiotics as you don’t want to cultivate antibiotic-resistance. It’s not clear whether you had personal experience or it’s a quick clever idea on this “breaking a zolpidem tablet in half or quarters and put that under your tongue”. I haven’t tired the ‘quarters’ yet but I can tell that 1)it’s not easy to do a good job on breaking a small and solid tablet into Four similar sized parts and 2) it’s not the right one to put under your tongue.

It’s a bit strange to see that a product like Intermezzo would be viewed as a “ridiculous idea”. Regarding ‘taking in the middle of the night’ or ‘the night before’, apparently you simply have no idea that it's a medical fact that there are indeed two types (maybe more) of insomnia: one can’t get into sleep and another wakes up in the middle of the night and can’t fall into sleep again. You forget that “patients first”. If a medicial product serves a section of the patient population, then it’s doing a good service, plus it’s not harming anyone.

Back to Suvorexant. I am certainly looking forward to the days that I can pop a 10mg (or 15 mg) and have a good night sleep. I do think the decision not to approval 15mg, 20 mg Suvorexant does deny a good medicine to at the least the Ambient-‘intolerant’ sub-population of people having sleep problems. In this sense Sleepyhead is right in pointing out that having sleep-deprived people driving around is not a safe situation.

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25. tommy on December 8, 2013 2:07 PM writes...

We will see how the drug finally works and we can again learn from this case. A drug needs a clearly defined indication related DMPK profile. A half-life of 12 h will keep your original plasma levels (simplification) after 12 h! still at 50% of the initial conc. with all the consequences...

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26. Me on December 19, 2013 7:44 PM writes...

@10; did you also find the C&E news article on how the recent downsizing was a management blood bath? Poor reporting with faulty data on management to scientist losses.

I love the Merck coolaid, how about that survey? It is like watching the flow in and out of the circus clown car...the only difference is in each cycle some of the lesser clowns and spectators get eaten by the lions...

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27. rTMS on February 2, 2014 2:15 PM writes...

It would be interesting to see orexin antagonists with a shorter half life say, 2-4hrs max for sleep onset. This would help get orexin antagonists foot in through the door, then you could try for orexin antagonists with longer half life for sleep maintenance. This would address side effects that the FDA worries about - they probably don't want people with residual sedation driving their cars to work the next morning only to plow through an intersection killing a bunch of kids at a bus stop.

Before the next orexin antagonist candidate is even considered for Phase I: SHORTER HALF LIFE PLEASE!!!

This would seem to be common sense. Use the concept of zaleplon as a model. It is almost always out the the system when the patient wakes up the next morning. 5-ht2a is probably a better target for sleep maintenance. Heavily sedating drugs don't bode well if they are still in your system the next morning. It is a simple concept I wish advanced pharmaceutical research companies would adopt, it would save them so much wasted money and man hours researching a dead end traffic accident drug waiting to happen. I don't get why such smart people don't see the obvious common sense staring them in the face, test the half life first of sleep drugs before bothering to advance them into a more costly clinical trial.

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28. insomniac on February 3, 2014 9:54 PM writes...

As another reader pointed out, insomnia is in itself a danger. Now it's been implicated in Alzheimer's disease for cryin' out loud, because of the toxins that build up in the brain when one doesn't get enough sleep.

I've been unable to sleep beyond 3-5 hours without 2-3hrs awake and adapt to a non-segmented sleep cycle for most of my adult life. Ambien and Lunesta work, but I develop a tolerance and must take more to get the same effect. If I had an alternative I could at least reduce my reliance on z-drugs.

I just don't understand how the FDA could arrive at the conclusion that this drug was more dangerous than Ambien or Lunesta at the recommended doses..Nonetheless, I hope and pray that Merck goes forward with production at the lower dose.

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