About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Live-Blogging A Conference: Trouble? | Main | Quick Blogroll Update »

June 8, 2009

Rolofylline Hits the Skids

Email This Entry

Posted by Derek

There is no good way to spin a Phase III failure. By then you've made it past the main reasons for a drug to wipe out (PK and total mechanistic failure). A breakdown at this stage is a more subtle affair (well, except for the money involved, which is not subtle at all). For example, a drug might show efficacy in a carefully constructed Phase II trial, but can't perform under the wider (and more realistic) conditions of Phase III.

That's what appears to have happened to Merck's MK-7418 (rolofylline, formerly KW-3902). This adenosine A1 antagonist, which Merck picked up by buying NovaCardia a couple of years ago, was being developed for acute heart failure. That's a tough indication, and this isn't going to improve that reputation. (This Forbes piece has a tour of the pile of discards that this area has become over the years. Rolofylline looked as if it might work in Phase II, but (from what I can tell from the press releases) missed every endpoint in Phase III.

On a chemical note, rolofylline is a rather odd-looking molecule. You don't see many noradamantanes hanging off of drug structures. I'm sure this wasn't the reason for the compound's failure (after all, it made it through Phase I and Phase II), but it's sure not something I have on my list of structural fragments to try.

Comments (14) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials


1. Anonymous on June 8, 2009 7:35 AM writes...

Once again this raises the question of the ability of the Research Head at Merck is capable of making good decisions (or if his team is capable of making a good decision). Unlike some companies who can't make it a decision, it appears that this crew cannot make a good decision. Perhaps I am forgetting something, but with the exception of Januvia, has anything been approved since they took over? Januvia, as I recall, was already set in motion before he took over.

It raises a question of Board oversight. If Merck is a "research driven company", presumably the Board owns that strategy. If the research has continually made bad decisions (failures are part of the game), then is the Board's responsibility or the CEO's responsibility?

Permalink to Comment

2. darwin on June 8, 2009 7:54 AM writes...

I'm with #1. The number of PIII dropouts seem disproportionate in comparison to other companies, and it seems they were involved with a $300m fiasco PIII several years ago with a BMS agreement that took a nose dive shortly afterwards. Amazing these high dollar decisions seem to fly under the radar with little accountability, considering the remaining 65,000 employees are stuck pocketing soup crackers at Denny's while at conferences in order to stay under their diminishing per diem.

Permalink to Comment

3. cookingwithsolvents on June 8, 2009 8:07 AM writes...

That IS a weird-looking molecule. . .

Permalink to Comment

4. Jonadab the Unsightly One on June 8, 2009 8:55 AM writes...

> There is no good way to spin a Phase III failure.

Sure there is:

"In view of our absolute commitment to the medical field, to quality, and above all to consumer safety, we cannot in good conscience continue to pursue FailedCandidate any longer. We had hopes for this molecule, but BigDrugCo will not bring a drug to market that we believe may be ineffective or unsafe. We will go back to the drawing board, because we are determined to produce drugs that are safe and effective."

Permalink to Comment

5. RB Woodweird on June 8, 2009 9:00 AM writes...

Perhaps naming your compound a varient of ROTFLMAO is not such a good idea?

Permalink to Comment

6. Annie on June 8, 2009 9:44 AM writes...

Have they ever licensed a succesful drug candidate or external deal under this research leader?

Permalink to Comment

7. CMCguy on June 8, 2009 10:14 AM writes...

Granted the noradamantane seems "unusual" but overall the molecule appears well compliant with "Rule of 5" and one assumes (hopes?) there was SAR work that suggested the benefit of such a "bulky grease ball" in that position. Better IMO than sticking biphenyls out there which seem to be everywhere. The thing about admantanes and similar structures is have to consider in 3D both for that portion as well as how it restricts/places the rest of the molecule. It can make it tough choice when a group that may not be aesthetically pleasing seems to be crucial to activity.

In terms of placing "blame" as #1 & #2 do, its too quick to jump on the Head of Merck Research. Derek points out the area is difficult and enough promise in Phase II to push forward into "wider (and more realistic) conditions of Phase III". This implies (to me) perhaps a poor Phase III Trial design but its easy to be a Monday morning quarterback. Agree needs be postmortem to determine if specific "bad decisions" where responsible, and more so if may reflect a "poor environment" for conducting development work or if indeed one of those unfortunate 4/5 (PHMRA) Failed Clinical compounds that do not succeed.

Permalink to Comment

8. NH_chem on June 8, 2009 10:33 AM writes...

While this looks weird, it is right up the alley of many adenosine antagonists. Take a look at compounds at Biogen, Adenosine Therapeutics (now Clinical Data), CVT, and others. That structure is very common in the adenosine world.

Permalink to Comment

9. David P on June 8, 2009 10:47 AM writes...

It is a strange-looking molecule with a strange name too, but it is not so outrageous and they must have compared with other structures. Generally, big companies are pretty conservative about what they let go forward, so they must have had data to support that decision.

I think it is pretty cool to find that cage that fits neatly in the desired pocket. The molecule will be conformationally restricted by that, which can enhance activity.

As for a positive spin, that is a good try, Jonadab, but an awfully expensive bit of PR. :)

Permalink to Comment

10. gallagher on June 8, 2009 3:14 PM writes...

Not knowing a great deal about Merck. How big a blow is this to Merck? Is it likely to have an adverse impact on jobs in the near to medium future?

Permalink to Comment

11. Anonymous on June 8, 2009 8:18 PM writes...

As a ex-Merck employee and knowing the past this does not come as a surprise. People who worked very hard to make things happen for "Merck" day in and day out have been shown the door, and the one they retained at the top never worked! If you work in one way or in other capacity you know what is genuinely out there and learn from it, if mistakes are made. The more they fail higher they climb on the mangement ladder! That is pretty much the truth (Drs. Kim, Hutchison, Metters and the clown Turner). Not long ago the last named was boasting to go big time for licensing and such. Rolofylline, if all all worked out well would have garnered $200 million or so around 2012. Not much money but the fall out from this will impact Merck negatively.

Permalink to Comment

12. Still Scared of Dinosuars on June 8, 2009 9:23 PM writes...

Not sure where all the numbers are coming from, but:
1) $300 million for a failed trial can be pretty cheap in comparison to what it usually costs to by buy a company with a drug ready to go into Phase 3...maybe...but
2) $300 million seems, ya know, pretty expensive for a drugs that "would have garnered $200 million or so around 2012". Just sayin'...

Drugs fail for a lot of reasons in Phase 3, some of them even legitimate, but the first question I always ask is, "Did the sponsor amend the protocol to increase enrollment?" My back of the briefs guess is that when that happends a trial is 3x as likely to fail as compared to trials that don't have to beg for patients. Prove me wrong.

Permalink to Comment

13. Zak on June 9, 2009 5:01 PM writes...

I interpreted for a lot of meetings between NovaCardia and the original owners of that compound. What a shame it didn't make it; everybody had such high hopes.

Permalink to Comment

14. Anonymous on June 19, 2012 5:18 AM writes...

Why? Because Tata Harper's amazing organic face moisturizer will set you back a whopping $100, and the natural and organic body washes, lotions, and makeup lining "Whole Paycheck's" beauty aisles are also pretty pricey.

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry