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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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In the Pipeline

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November 19, 2008

Novartis and Reality

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Posted by Derek

I know that it’s not necessarily fair to drag out old press releases, but let’s do it anyway. Many readers will remember a few years back when Novartis was making its big research move into Cambridge, renovating the old Necco candy building and hiring like mad. (We’ll pause for a bit of somber nostalgia at the memory of a large drug company actually hiring hordes of scientists).

While that was going on, there was a lot of talk about the way their research site was going to be run. Under its new research head, Mark Fishman, Novartis would "reinvent the way drugs are discovered" (I quote from an August 2003 article from the Boston Globe, behind their subscriber wall now, which irritated me quite a bit at the time). There was a lot of talk about Gleevec, and how this was going to be some sort of model for the future of drug discovery in the organization. (I could never quite follow that one, but I was willing to give them the benefit of the doubt). The whole thing would be a "research operation vastly different from traditional pharmaceutical research", to quote another old Globe article (May 2002).

Well, some years on now, the obvious question is: did any of this happen? Novartis as a company is doing fairly well, particularly in comparison to some of its peers. And they haven’t had any massive layoffs, to my knowledge, which puts them ahead of the game these days. So overall, the company has been successful: but is the Cambridge site the sort of place it was supposed to be, according to the original PR?

My impression is that it isn’t, at least not to the extent that we were all hearing about back then. I know a number of people who work there, and from the outside, at least, it seems to be pretty much like any other large drug research operation, albeit with less elbow room than usual in some of the labs and offices (a deliberate decision, apparently). I hear the usual talk and the usual complaints. Nothing that goes on over there strikes me as very different from other outfits of that size.

And there’s nothing wrong with that. This isn't a slap at Novartis, at Mark Fishman, or at anyone over there - it's a very good research organization. But I do wonder where all that transformational talk went. Is it still a work in progress (which seems to be the official viewpoint)? Did the organization try to change things, and fail? Was there even a clear idea of what this change was to consist of? Was there a decision made at some point that since things seemed to be going reasonably well, that the company should just leave the site to develop as it was? Or was all that talk at the beginning nothing more than, well, talk? I wondered about this at the time, and I suppose I'm still wondering now. . .

Comments (24) + TrackBacks (0) | Category: Drug Industry History


COMMENTS

1. fred on November 19, 2008 9:32 AM writes...

They score some points simply for doing LESS poorly than GSK and PFE.

The industry is doing all kinds of crazy, stupid things right now out of desparation, due to the FDA'a aversion to 1) new drugs 2) any drug that causes any slight side effect in one out of 10 million patients. Companies are overinvesting in biologicals and SIRNA, and pissing away bigger bucks in China than they blew on combo 10 years ago, with less chance of success.

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2. CMC guy on November 19, 2008 10:42 AM writes...

Maybe Novartis is going to do things differently than old Pharma as will focus on Biologics:

http://www.bloomberg.com/apps/news?pid=20601085&sid=aNMavFUvxRz4&refer=europe

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3. Jose on November 19, 2008 11:05 AM writes...

If any pharma ever really figures out a way to "reinvent the way drugs are discovered," I'll bet it won't be trumpeted in a press release, but in patent offices with an army of lawyers in tow.

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4. Anonymous on November 19, 2008 11:28 AM writes...

Hmm - let's go to record of the Cambridge lab, as quoted in the "official viewpoint" which links to a Boston Globe article from October 20, 2008. Three compounds are quoted to provide evidence for the "success" of the Cambridge experiment: LCA-696, LCI-699, and LBH-589. I arbitrarily gave a "biological novelty grade" since, to my knowledge, "novelty of chemistry" wasn't a metric for Novartis.

A Google search on those code numbers shows that they are, respectively, a combination AII Receptor Antagonist - NEP inhibitor; an aldosterone synthase inhibitor, and a HDAC inhibitor similar to SAHA/vorinostat/Zolinza.

Let's consider the novelty of each of those.

Combination AII Antag/NEP inhibitor: Proof of principle confirmed in (massively expensive) Phase 3 trials by the ACE-NEP inhibitor omapatrilat by BMS in or around 2001 (sorry - didn't check actual date). Concept put forward around 1995 of prolonging angiotensin's effect by preventing it's degradation. Only ongoing trial in clinicaltrials.gov is versus an AII Antag alone. Why not against an AII + diuretic, which has already been proven to be superior to AII alone, and are available generically? BIOLOGICAL NOVELTY GRADE = D (not quite a me-too, but...)

Aldosterone synthase inhibitor: Searching RAAS (Renin-angiotensin-aldosterone-system) in PubMed shows first mention in 1965, searching for "aldosterone blood pressure" shows first mention in German in 1955, first mention of an aldosterone antagonist lowering blood pressure in 1958. First GENERIC aldosterone antagonist approval in 1999, concomitant with RALES study in HF patients (BP effects shown previously, but memory fails me as to when). BIOLOGICAL NOVELTY GRADE = D (not quite a me-too, but...)

Non-specific HDAC Inhibitor: 'Nuff said. BIOLOGICAL NOVELTY GRADE = F. If it distinguishes from Zolinza, it will be by 'chemistry luck' , not biological insight.

OVERALL GRADE FOR CITED COMPOUNDS: D, D, F

GPA = 0.67 = F

Comments?


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5. T on November 19, 2008 11:54 AM writes...

Zero point two. Fat, drunk and stupid is no way to go through life, son. Mr. Hoover, president of Delta house? One point six; four C's and an F. A fine example you set! Daniel Simpson Day HAS no grade point average. All courses incomplete. Mr. Blu - MR. BLUTARSKY - ZERO POINT ZERO.

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6. Ty on November 19, 2008 11:58 AM writes...

I think it will take longer than 10 years for cultural changes to begin to metrically influence the productivity. Can't say much about the productivity yet, but those who are open to the Fishman's vision are generally upbeat (read; it's not everybody, mind you). When most of the employees are proud of where the company is going, I think it's a good sign.

Gleevec is not just one of the more successfully discovered/developed drugs. It originally targeted a specific, genetically defined (mutation) subgroup of CML patients (read; Pfizer would never have launched the drug). First successful kinase inhibitor, probably the first 'genomic medicine'. And luck conspired to make it a blockbuster later, but it's not really the point. The point is, we go after diseases of smaller, preferably well defined patient population, which expedites development, and see if we can extend it to the more general mass post PoC (proof of concept). In a way, it's opposite to what drug discovery/development used to be (or what others do), where a large-market disease is defined first and people scramble to place bets on certain targets to modulate the disease. It means zero influence from marketing people on research at Novartis and therefore little (or no) top-down dictation on the projects.

Of course that's the ideal and we are not, like, isolated in an island. All the things that happen anywhere happen at Novartis, too. Changes have to be slow. Reversible reaction is the most energy efficient process. Abrupt, irreversible changes are bound to backfire and generate a lot of waste in the form of heat. You learn that in the elementary physics.

RE #4, I commend your homework, but those are offspring of East Hanover/Summit days. That's why they are already in the mid stage clinical trial. Give us a break, will ya?

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7. yukawa on November 19, 2008 12:31 PM writes...

as an aside, imho gleevec is not a good model system for future genomic medicine. it gets bandied about in this way - but the bcr-abl 'mutation' underlying these CMLs is actually a fusion protein that doesn't exist otherwise; i.e. not really a simple 'mutation' in the classical sense. how many other diseases are traced to a translocation and production of a completely novel protein that usually doesn't exist? i can't think of any big ones (but i admit i'm slightly ignorant.) most of the neoplastic diseases i can think of are believed to be heavily driven by a number of point mutations, or perhaps loss-of-function deletions. worse, recent cancer genome atlas results show that the aside from a handful of prevalent mutations in the usual suspects like p53, ras, p16, many mutations are rare and spread across network.

so perhaps it's better to look at the more common, 'canonical' neoplastic diseases and their genospecific treatments: NSCLC patients who benefit from Iressa, HER2+ breast cancer patients who benefit from Herceptin, etc (any others?). then the view is more sobering. while gleevec is successful in CML with bcr-abl > 80% 5 years from time of treatment, with other drugs like iressa, herceptin, time to progression is extended only on the order of months. these are more complicated obviously, unlike bcr-abl, the critical 'weak points' of these cancers don't lie in one aberrant gene product.

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8. Derek Lowe on November 19, 2008 12:33 PM writes...

Ty, thanks for the view from the inside. I agree that these are slow processes - in fact, I think that one of our biggest problems in the industry is that everything has such a long lead time.

And while you're surely right about these drugs being legacies (as in #5 above, "Legacies usually get asked to pledge automatically, right?), they're being used by Novartis management as evidence that the Cambridge way is working.

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9. Anonymous on November 19, 2008 2:28 PM writes...

An interview with Bayer CEO Werner Wenning just came out in Spiegel mag, and he explains how well capitalism actually works, and how his company management always takes a wise long-term view (as opposed to the banking industry):

http://www.spiegel.de/international/business/0,1518,591282,00.html

Managers rather are rather good at weaving tripe and poop into a whip, then cracking it proudly in front of their audience.

Permalink to Comment

10. Ben on November 19, 2008 4:02 PM writes...

I suppose I'm a bit astonished that you bought into Fishman's hype. But even beyond my standard skepticism at "changing the way we do business" statements, I feel strongly that one should be especially skeptical when they try to model a drug discovery process off of any single successful drug if only because each target, each process, each PK profile, each chemistry is entirely different.

If anything, the Gleevec story is hardly consistent with a repeatable formula -- e.g. chasing a rare disease, ignoring faulty SAR, the fusion protein happens to adopt two conformations, etc. Your thoughts?

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11. Dlib on November 19, 2008 4:10 PM writes...

"reinvent the way drugs are discovered"...What are the differentiators amongst the different Pharma companies??? The quote seems to imply something about science. It is folly to think there are any real differentiators in the science between the companies. The instruments / kits / access to scientific observables are identical. The only possible difference is the ingenuity of using those tool sets differently.

That leaves more process and organizational differentiators as the key ( perhaps ones that allow or reward ingenuity ).

IMHO... you guys ( myself included ;-) don't know what observables or combination of observables are required to reinvent the science of drug discovery ( to be more predictable / deterministic ). Pictures...kinetics...expression profiles...on and on.

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12. Anonymous on November 19, 2008 4:43 PM writes...

Dear #6:

#4 here...(All vaguely reminiscent of "The Prisoner", no? http://www.sixofone.org.uk/). I am sorry if you took umbrage at my quoting the facts. In fact it wasn't 'homework' but rather 'recall'...a legacy of being old. I have no axe to grind here. I was simply reacting to the statement of apparent erroneous fact in that esteemed piece of pulp fiction, the Boston Globe, that cited evidence for the success of the new model. "Three of the experimental drugs, which still have internal code names and were discovered in Cambridge, are being tested in humans: LCZ-696 and LCI-699 are in mid-stage clinical trials for hypertension. And LBH-589 is in early trials for two types of cancer, multiple myeloma and advanced solid tumors."

I apologize for not knowing that those were, in fact, NOT discovered at Cambridge as quoted but rather at East Hanover.

However, it thus begs the question to be asked: Is this the best evidence that can be cited for success of the new model?

If the average time from concept to approval is 10 - 13 years, a number that is often quoted, and from concept to IND filing is 5 - 7 years then I would suggest two consequences:

1. About 1/2 the time is spent in post-IND development. Therefore in 6 years, there should be some evidence of approvals resulting from a reinvention of the drug discovery process. Of course, if all those molecules began their lives in the old paradigm, then perhaps there was no ability to change their fate in the 1/2 life cycle that has occurred.

2. 6 or so years in, there should be evidence of molecules form the new paradigm. It is not my fault that the data submitted as proof, fail to provide such proof. It behooves Novartis to provide such data, if they wish me to agree with their conclusion. It's somewhat akin to Novartis assuming that I am only reading the discussion to their paper, as opposed to looking at the results section.

Please, understand, I have NO axe to grind with Novartis. I do not even work in the industry. I am, quite simply, an old-time pharmacologist who drew my own conclusions from the data submitted.

Signed

#4

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13. drug_hunter on November 19, 2008 6:12 PM writes...

To continue the "prisoner" theme, for much of what I know about Novartis, my only answer can be, "that would be telling..."

But here is what I can say. There are some extremely smart people at Novartis. There are some risk-takers and some people with real vision. There are people who understand all the minutae of what it takes to make a drug. All good. But of course, there is an amazing culture clash going on between Cambridge and Basel; and it is very hard to hire only top-notch people when you are hiring so quickly; and they suffer all the usual inefficiencies of any large multinational organization. So there are nagging operational challenges that I think have hindered what Novartis is attempting to do. Bottom line: the jury is still out, and I wouldn't rule out that in fact Novartis will be Top Dog in 2020.

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14. Steve on November 19, 2008 6:47 PM writes...

I distinctly remember being laughed at by my supervisor (GK) at Novartis when I spoke of how my efforts within the group were akin to what I would have done in a "startup" environment. He told me, "Novartis will never be like a startup" I left that place in disgust, what a load of BS. I wrote an email to Fishman telling him what was going on and I wound up in a little room with my supervisor and an HR rep yelling at me saying I did it all in an effort to garner severance pay from them. I wish I never set foot in the place, it was truly a disheartening experience that I hope to never repeat again.

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15. Jose on November 19, 2008 7:05 PM writes...

The parallels are eerie....

Number Two: "We want information, information, information..."

Prisoner: "You won't get it."

Number Two: "By hook or by crook, WE WILL."

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16. John on November 20, 2008 12:03 AM writes...

I'm not sure why mr. Lowe should be considered an authority on 'what it takes' to develop any drug. His constant mantra of 'outsource to China', makes one believe he is a mechanist who equivocates a chemist with a tinker toy machine. Can the so called free markets solve every problem, or ARE THEY THE PROBLEM?

If every chemist in the USA is unemployed due to free trade, will he still be hypnotized by the catch phrases of libertarian society?

When Dr. Lowe grows up and realized the world is made of people, not markets, perhaps drug development will improve. I feel deeply saddened by this blogger's attempts to further undermine chemist's tenuous grip on a sustainable living.

-I for one am taking my leave of this site.

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17. Snoop Dog on November 20, 2008 8:58 AM writes...

Oh, Novartis has had big cuts. They have been cutting jobs right and left. IT has been totally dismantled and outsourced to India and Argentina. Finance is going the same direction.

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18. Toluene on November 20, 2008 9:42 AM writes...

This is standard speak for pharma R&D executives. No one gets ahead saying "I am going to do things just like the guy before". All new VPs of R&D at my former company tried something new--with the same result--we should have stuck with the traditional methods. Systems Biology, Innovation Projects, Compound Factories, Receptor Modulators, Hiring Academics to run Applied Research--ALL FAILED. As for the employees, if we did not drink the Cool Aid and support the new mantra, we were considered outcasts.

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19. Steve on November 20, 2008 9:45 AM writes...

"Novartis praises reorganisation of its Research:

Novartis has said that the reorganisation of its R&D team in recent years has given it a larger and
more promising pipeline of drugs in development, with fewer medicines failing during human trials.
During the presentation of its pipeline in Cambridge, Massachusetts, head of Research Mark Fishman
said that Novartis is well on the way to bringing more innovative drugs to the market. The group said
that it had 139 clinical development projects in its pipeline, including 88 new chemical entities, or 40%
more than in 2005. Novartis added that it had 14 biological drugs in clinical testing in 2007. It also
pointed out that 80% of compounds that successfully passed the proof of concept stage in 2006-07
have entered into phase II/III, a 60% increase compared with 2003-05.

The Wall Street Journal Europe 20/11/08"

Permalink to Comment

20. Christiane on November 20, 2008 1:55 PM writes...

Derek,

Back in 2005, NIBR invited me to come up and look around and talk with Marc Fishman and his people. Does this mean their whole push into translational medicine wasn't as successful as they claim it has been? Or that with just about all companies claiming to do translational medicine, what Novartis was doing is no longer unique?

Here's the article I wrote back then; unfortunately, most of it is locked. But feel free to e-mail me and I'll send it to you.

http://www.pharmalive.com/magazines/randd/view.cfm?articleID=2362

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21. someone who knows on November 24, 2008 1:20 AM writes...

Never trust the Swiss....

I have been researching Gleevec for quite some time on and off, mostly because of all the hoopla.

The IRIS data was very over stated, lately it seems no one can replicate it in the real world setting. This speaks to what some of the others who have posted here noted. In fact, the BCR ABL oncogene is a good target but not the best target. The genomic instability caused by the disease means that there are multiple pathways that must be hit. Someone here is calling Gleevec the first genomic drug - please give us all a break! It certainly is not...It does not, will not, and can never cure the disease.

Novartis position as number one in this field is quite tenuous, Gleevec is going off patent in a few years, their second generation TKI, Nilotinib is tanking big time. The only reason why they are where they are now is the "captive audience" of the cancer patients, who are suffering immeasurably. We all must hope that the "model" of Gleevec is never used again. It is smoke and mirrors...

LBH 589 was "shelved" over toxicity issues...

They now want to try a foray into Biologics, because they have milked TKI "theory". Caused billions of dollars to be diverted from bonafide research, wasted money and lied to everyone saying they would reinvest from the sales of Gleevec. There are quite a few fat cats at Novartis. Not to mention all the doctors they "bought" off with nice trips and research money to solidify the mouse trap.

I do have an axe to grind, anyone personally caught up in it would too!

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22. Serphimo on April 15, 2009 8:36 PM writes...

Trust me, nothing new happens at Novartis.

1)It is a company where no one wants to stick their necks out. We did not have a standard compound submission requirement till 4 years after this site opened.

2) They just try to pre-emptively cover every possible accident/mishap in the labs with excessive red-tape and document filings. In the mean time venting in the labs are horrible along with no isolated lab areas so if someone sets up a stinky reaction, you have to smell it the whole day ling.

3) No support for lab equipment/IT support. All of the computer programs never work properly. There is not a day at work that anything works well. Also we use old/antiquated equipment that chemists have to maintain and take care of. So now med chemists are analytical chemists. Mind you no extra pay.

4) No process support for med chem. We have to synthesize huge quantities of material. Anytime a request is put in for scale-up the standard answer is 3 months lag time.

5) No analytical group support to help with separations of compounds. No reverse phase separation support at all and minimal chiral HPLC support. We turn in 1g compound and receive back 100mg each enantiomer that is still impure!!

6) Old walk-up LCMS machines that break down every 2 hours or so and then a huge backlog.

7) Cramped labs with no space to store solvents, so storage is extremely limited.

If this is the change Fishman brags about, then God help us all. Maybe the change is make the big bucks on shoddy support as compared to other big pharma. Someone above said it is like a startup and he could not be more true. I have seen startups with better setups!! Pay is OK, but get ready for the stress of working there. Trust me if you can find somewhere else to work, go there.

Permalink to Comment

23. I used to work there on January 15, 2010 4:01 PM writes...

It was the most stressful place I have ever worked. The people that Fishmann has recruited are managers, not scientists. They care nothing for the staff, and are self-promoting and PR-driven.

Stay away from NIBRI, or you will regret it like I did.

Permalink to Comment

24. AldenG on March 23, 2011 11:00 AM writes...

Anonymous at #4, aren't you being too harsh on the concept of an aldosterone synthase inhibitor? This is not at all the same thing as an aldosterone blocker. If it is effective, many of us with primary aldosteronism -- and that is probably 10-15% of all hypertensive patients, though it typically takes a dozen doctors before the correct diagnosis is made -- will jump at the chance to switch from eplerenone or (much worse) spironolactone. That's assuming we will be able to afford it, of course, a doubtful assumption. Today, nothing but an aldosterone blocker is effective against the progressive severe hypertension and electrolyte imbalance caused by adrenal hyperplasia or aldosteronoma. Most patients never get correctly diagnosed and never get control of their BP or sodium/potassium balance

Here's the difference between an aldosterone blocker and an aldosterone synthase inhibitor: The blocker blocks the sodium hoarding and potassium wasting in the kidneys and (to a lesser extent) sweat glands, plus some other effects in the heart and blood vessels. But it does not block all types of aldosterone receptors, particularly in the brain, mor all effects of the hormone. The level of aldosterone can easily multiply five-fold over pre-treatment levels using one of these drugs. Thus an aldosterone blocker actually exacerbates the brain fog and tinnitus normally found in sufferers of primary aldosteronism. Both problems have grown in me apace with my plasma aldosterone concentration despite normalization of BP and Na:K. If an aldosterone synthase inhibitor could work as effectively to normalize blood pressure and electrolytes, those of us waiting for it have great hope that it could also normalize brain function and hearing. I don't know if that meets some ivory-tower test for novelty, but we suffering patients would regard that not as a "me-too" drug but as a quantum leap in quality of care providing a level of relief that today is only available to the minority with one-sided dysfunction and the means to lateralize the problem and have it surgically removed..

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