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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: derekb.lowe@gmail.com Twitter: Dereklowe

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August 31, 2012

Eli Lilly's Drumbeat of Bad News

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Posted by Derek

Eli Lilly has been getting shelled with bad news recently. There was the not-that-encouraging-at-all failure of its Alzheimer's antibody solanezumab to meet any of its clinical endpoints. But that's the good news, since that (at least according to the company) it showed some signs of something in some patients.

We can't say that about pomaglumetad methionil (LY2140023), their metabotropic glutamate receptor ligand for schizophrenia, which is being halted. The first large trial of the compound failed to meet its endpoint, and an interim analysis showed that the drug was unlikely to have a chance of making its endpoints in the second trial. It will now disappear, as will the money spent on it so far. (The first drug project I ever worked on was a backup for an antipsychotic with a novel mechanism, which also failed to do a damned thing in the clinic, and which experience perhaps gave me some of the ideas I have now about drug research).

This compound is an oral prodrug of LY404039, which has a rather unusual structure. The New York Times did a story about the drug's development a few years ago, which honestly makes rather sad reading in light of the current news. It was once thought to have great promise. Note the cynical statement in that last link about how it really doesn't matter if the compound works or not - but you know what? It did matter in the end. This was the first compound of its type, an attempt at a real innovation through a new mechanism to treat mental illness, just the sort of thing that some people will tell you that the drug industry never gets around to doing.

And just to round things off, Lilly announced the results of a head-to-head trial of its anticoagulant drug Effient versus (now generic) Plavix in acute coronary syndrome. This is the sort of trial that critics of the drug industry keep saying never gets run, by the way. But this one was, because Plavix is the thing to beat in that field - and Effient didn't beat it, although there might have been an edge in long-term followup.

Anticoagulants are a tough field - there are a lot of patients, a lot of money to be made, and a lot of room (in theory) for improvement over the existing agents. But just beating heparin is hard enough, without the additional challenge of beating cheap Plavix. It's a large enough patient population, though, that more than one drug is needed because of different responses.

There have been a lot of critics of Lilly's research strategy over the years, and a lot of shareholders have been (and are) yelling for the CEO's head. But from where I sit, it looks like the company has been taking a lot of good shots. They've had a big push in Alzheimer's, for example. Their gamma-secretase inhibitor, which failed in terrible fashion, was a first of its kind. Someone had to be the first to try this mechanism out; it's been a goal of Alzheimer's research for over twenty years now. Solanezumab was a tougher call, given the difficulties that Elan (and Wyeth/Pfizer, J&J, and so on) have had with that approach over the years. But immunology is a black box, different antibodies do different things in different people, and Lilly's not the only company trying the same thing. And they've been doggedly pursuing beta-secretase as well. These, like them or not, are still some of the best ideas that anyone has for Alzheimer's therapy. And any kind of win in that area would be a huge event - I think that Lilly deserves credit for having the nerve to go after such a tough area, because I can tell you that I've been avoiding it ever since I worked on it in the 1990s.

But what would I have spent the money on instead? It's not like there are any low-risk ideas crowding each other for attention. Lilly's portfolio is not a crazy or stupid one - it's not all wild ideas, but it's not all full of attempts to play it safe, either. It looks like the sort of thing any big (and highly competent) drug research organization could have ended up with. The odds are still very much against any drug making it through the clinic, which means that having three (or four, or five) in a row go bad on you is not an unusual event at all. Just a horribly unprofitable one.

Comments (26) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History | The Central Nervous System


COMMENTS

1. Anonymous on August 31, 2012 8:23 AM writes...

A very balanced and interesting summary Derek, thanks. It is unfortunate, but Lilly (and AZ IMO) are in deep, deep trouble

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2. Curious Wavefunction on August 31, 2012 8:26 AM writes...

“I haven't failed, I've found 10,000 ways that don't work” - Thomas Edison

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3. Daniel Haszard on August 31, 2012 8:57 AM writes...

Remember-Zyprexa Diabetes connection conflict of interest.

Eli Lilly made $67 billion to date,paid $1.4 billion in criminal fines.
Thousands got diabetes as Zyprexa side effect and have to take Lilly insulin to treat the diabetes that was caused by their Zyprexa.
Eli Lilly Zyprexa can ruin your Pancreas and make you a type 2 diabetic in just a few months of use.I took it 1996-2000 and now am a diabetic for it.
'Atypical' antipsychotic Zyprexa is the worst offender of them all.Google-Haszard Zyprexa - got a page up.
-Daniel Haszard

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4. anon2 on August 31, 2012 9:04 AM writes...

With so many recent similar examples, how is it that stock holders, CEOs, corporate boards gleefully support and willingly commit additional funds to R&D? What evidence is there that simply taking more shots on goal will provide improved success toward achieving phase 3 primary endpoints?

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5. Calvin on August 31, 2012 9:24 AM writes...

@4 anon2

Giving up and investing elsewhere is an option but I'm not sure you'll find much support for that round here. And it won't take long before the wider public understand what the implications of giving up are and they won't like it either.

My own view is that Lilly is way ahead of AZ in that it has been very focussed in certain areas and has been very hypothesis driven. AZ have gone with a scattergun shot on goal appraoch with a randomness that is frankly bizarre. AZ are toast. They don't even have any P3 results to talk about. Lilly have a pipeline of sensible compounds testing out rational hypotheses. They only need one home run, but I agree they are running out of innings.

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6. drug_hunter on August 31, 2012 10:30 AM writes...

One chemist's view from 800 miles east of Indianapolis: Completely agree that Lilly deserves a great deal of credit for taking some high-risk but reasonable bets that -- if they had paid off -- would have been of true medical importance. I hope that Lilly's management keeps going in this direction -- it will pay off eventually!

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7. Bernard Munos on August 31, 2012 11:28 AM writes...

I think Lilly deserves credit, and should be commended for being bold. This is what real innovation is about. But it should be faulted for taking drug candidates into advanced clinical development despite the lack of credible evidence that they were doing any good. Having compounds fail in phase III for lack of efficacy and/or safety is evidence that the bar has been set too low.

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8. bbooooooya on August 31, 2012 11:53 AM writes...

re #5, " And it won't take long before the wider public understand what the implications of giving up are and they won't like it either."

That's the issue: it WILL take years before the wider public understands the implications.

I'm not even sure I agree wholly that the public won't like it: I don't think they'll care. I hope a cure for Alzheimer's is found, and that better treatments for cancer emerge, but will anyone notice if they don't, or will it be status quo? What if no one finds a better drug for restless leg syndrome or gastroesophogeal reflux disorder?

#6, "it will pay off eventually". A priori, there is no reason that should be a true statement.

#7, " Having compounds fail in phase III for lack of efficacy and/or safety is evidence that the bar has been set too low". Oh, so companies should only take drugs to phase 3 that they know will work? Makes sense, and jibes with some great consultant reports I've read suggesting that projects that don't work be killed sooner. I think that's correct, but I'd love to know how the brain trust at McKinsey or BCG thinks they can know a study's outcome before it begins (and then rightsize it!). Tea leaves? Palm reading? I agree that there are cases where phase 3 studies begin despite failed phase 2 studies (which is moronic, looking at you ELN.....), but a lot of phase 3 studies fail after successful phase 2 studies.

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9. barry on August 31, 2012 12:57 PM writes...

I do respect Lilly for pushing forward in some really tough problems. But I can't get over that structure. Is pomaglumetad methionil the most hydrophilic candidate ever put forward for a CNS disorder (barring lithium)?

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10. CL on August 31, 2012 1:29 PM writes...

#9 It's kind of funny how you can see the glutamate substructure built into this molecule. I didn't expect that anybody would actually try to compete with glutamate for its binding site, when there's also an allosteric site to go after.

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11. dichotomous on August 31, 2012 1:40 PM writes...

@#8 - your argument on Phase 3 would be more compelling if half of the Phase 3 failures weren't for safety and efficacy reasons. If Phase 2 studies don't give insight into efficacy, safety, and/or dose, what is the value of a Phase 2 study?

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12. Bernard Munos on August 31, 2012 2:29 PM writes...

To bbooooooya (#8)

You read me correctly. Only drug candidates that are backed up by COMPELLING evidence that they are safe and efficacious should advance into phase III. It is the ethically appropriate and economically sensible thing to do. I cannot speak for McKinsey or BCG as I do not follow their work. The fact that failure rates in phase III have declined from 80% to 50%, and in submission from 90% to 60%, suggests there has been a lowering of the standards of performance across the industry. My recommendation is not about knowing "a study's outcome before it begins", but being very demanding before blowing hundreds of millions of dollars on compounds whose efficacy and safety data are less than convincing. If the combined failure rate for phase III and submission is 70% (higher than for phase II), we've got a problem.

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13. Hap on August 31, 2012 2:42 PM writes...

4: Because you can't get drugs any other way. If you don't think you can get them at all, then it's time for investors to get their money back and let people find someone who can.

8: I'd be pretty sure the public won't like it - antibiotic resistance (if it became more widespread, which would be likely given the lack of new antibiotics) would take us back to 1935. If people going into a hospital have a significant chance of never leaving it, all of the people soon to be old and to be pondering frequent Russian roulette draws might change their minds. In a society with fewer children, the possibility of losing significant numbers of them to cuts or dirt might also change minds.

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14. anon2 on August 31, 2012 3:42 PM writes...

#8: Indeed, money and resources are needed to find new drugs. Lots. Increasingly, more and more for the types of diseases that are not well treated today by medication. Let me state that I am not against funding. And there always will be folks willing to take high risk for potential high reward. There also are people who are addicted to gambling and can bankrupt themselves in casinos. I'm afraid this will be the outcome for many companies when looking at Pharma's successes on big gamble phase 3 studies. Kudos to Lilly for trying, assuming that these were indeed good choice assets to progress. But in my experiences of over 30 years, not all compounds having progressed to Phase 2 or 3 were good choices from the get go. And then, tying this to other topics in this forum, last week showed strong support for taking funds used for stock buy-backs to be put into additional R&D funding instead. Why should stock holders accespt more "shots on goal" when the approach simply does not provide better odds of success? Yes, many who read and comment in this forum WANT things to be different, WANT to think that the clock can be reversed, WANT to blame someone for the industry's woes, WANT an easy solution to getting more jobs back. Sorry folks. Welcome to today's reality, not yesterday's rosy retrospective

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15. Hap on August 31, 2012 4:19 PM writes...

If you know of ways to get drugs with decreased R+D, I imagine there are lots of pharma CEOs and VC people who would love to hear from you. Unfortunately, you can't get drugs without discovering them (or overpaying for someone else to do so), and you can't discover them without R+D.

What's worse is that cutting R+D isn't going to help - the losses are in clinical trials. You need better information going into trials (so that you don't go into them if you shouldn't) and management unwilling to disregard negative data for short-term goals. I guess if you don't have candidates, you don't have bad ones, but you don't have good ones, either. Remarkably enough, that scheme isn't going to make any money, either. You need better data, not less of it.

If you've decided that it's time to start dying (a phrase that may become apt in the absence of effective drugs) instead of living, then stock buybacks don't seem to benefit a whole lot of people. There's still a lot of money locked up in an organnization committed to failure that could be used by investors to do something useful. Instead, you've got a Ponzi scheme in quicksand trying to find the slowest psychopath. Why do I think that won't work well?

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16. anon2 on August 31, 2012 4:29 PM writes...

#15: Welcome to yesterday.

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17. Hap on August 31, 2012 4:34 PM writes...

Yes, I love dying of whooping cough, syphilis, and smallpox. Yesterday is so fun. Whee!

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18. Howie on September 1, 2012 8:51 AM writes...

@Hap-you make a distinction between R&D and clinical studies. I don ' t follow. Aren't clinical studies part of development? For that matter, aren't clinical studies part of research?

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19. anon2 on September 1, 2012 12:20 PM writes...

Yes Howie, and as understood in such a statement, a huge conbribution to the overall cost. Phase 2 data does not necessarily provide overwhelming confidence for pharmacological sucess (and safety) in Phase 3. And that's one of the key, primary overriding rub in today's world of R&D investment, and as it then reflects on the decreasing number of jobs throughout the R & D cycle (target ID, early discovery, preclinical, through ALL of clinical development).

There indeed have been grand successes that were driven from within Pharma, including of the most recent great examples with successful HIV treatments which have extended life and transformed areas of treatment for the better. But like in the stock market, past does not provide any guarantee or necessarily a lot of confidence that the future will hold equivalent history and success as the past. And, when looking in ones foggy rear view mirror, it's important to remember not everything has always demonstrated to be of positive value to humankind---VIOX, Avandia, original use of Thalidomide, LSD, and many more.

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20. neuroscientist on September 1, 2012 6:23 PM writes...

Derek,

Please delete Daniel Haszard's account and stop letting him post here. He seems to spend his entire day mining the internet for Lilly-related articles.

A quick look at his bat shit crazy website makes it clear he was prescribed olanzapine for more than just PTSD.

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21. Nathan_NZ on September 2, 2012 4:38 PM writes...

I've been following the work on pomaglumetad methionil (LY2140023) over the last few years as I was working on similar compounds during my PhD. It's sad to see it fail again as I was rather excited to see something different - an amino acid of all things - making it to clinical trials these days. I hope this isn't the end of exploring new targets with compounds containing multiple stereocentres.

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22. neurosympathy on September 3, 2012 11:21 AM writes...

@20 I suspect you're hitting send from a suburb of the Circle City, or perhaps from an office with a mailstop that starts with the letters "MC." So tell me, is "bat shit crazy" now standard parlance in LRL, or are you just a random insensitive jackass pretending to understand neuroscience?

Lilly's corporate ethics are a matter of public record. Their current trajectory almost makes me believe in Karma.

So here's a tip. When you encounter someone who may have a mental illness, you've basically got two options. 1. offer them support. 2. Stay out of the way of people who will. You're not helping by engaging this person, particularly in such an insulting and dismissive way.

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23. MIMD on September 3, 2012 2:03 PM writes...

Maybe to improve their research strategy Lilly needs to be I referred to me as person who specializes in pharmaceutical based research who wanted to reach out to I to see if you maybe able to recommend anyone that could qualify for the below position.

link

(No, no typos here.)

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24. TX Raven on September 4, 2012 5:55 AM writes...

@21:
Do you know (or anyone else) if they demonstrated target engagement in the clinic with pomaglumetad methionil?
Thank you.

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25. Hap on September 4, 2012 9:07 AM writes...

18: A previous post here said that funding is split between discovery research (finding a target and a compound to hit that target, early (nonhuman) testing) and clinical trials (testing in people - is it toxic? does it work (better than what's out there)? does it have any other problems we didn't find before? is our target appropriate for the disease?) about 1:2 - a lot of money is spent finding compounds and targets, but far more is spent seeing if those drugs work in people. Since there are far fewer compounds in later stage trials than early ones or research, the cost per clinical trial (per drug) for trials is pretty large relative to discovery.

The consequence is that if you want to make drug discovery profitable, one likely path is to find good drugs more quickly and get rid of bad drugs earlier (before they get to the expensive trials). This probably requires more and better stage early research (or research into better models and testing methods) - hence cutting early stage research and outsourcing it could be not only ineffective but counterproductive.

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26. Hap on September 4, 2012 4:31 PM writes...

This is the comment from which the figure (2:1 clinical:R+D spending) was drawn.

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