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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: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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August 21, 2008

RNAi: Bubble or Not?

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Posted by Derek

Many readers will well remember when Merck bought the RNA-interference company Sirna in 2006. They paid over a billion dollars for them, and made the whole RNA area an even bigger field for speculation than it was already.

Another big player in that field is Alnylam, who have been making deals all over the place. Many shareholders have been waiting for someone to buy ALNY for a similarly hefty premium, but the wait has been long (and all those agreements make such an acqusition harder and harder to realize).

As that post (and this one, and this one from 2004)) should make clear, I've been a bit cooler on the prospects for RNA therapies. I think the current RNA field is full of extremely interesting things, wonderful discoveries, fascinating research tools which could lead to all sorts of things - but I don't necessarily think it's full of new drugs per se. Nucleic acid-based therapies are just nightmarish to administer, and unless a real breakthrough in doing that appears, I think that (as drugs) they're always going to have their ankles tied together.

Well, Jonas Alsenas at Leerink Swann agrees, and he's not afraid to say so. According to Mike Huckman at CNBC, the firm initiated coverage of Alnylam with Alsenas saying that he thought the stock should be trading at about half its current value, and that he didn't see them developing any products for many years, if ever. And he went on to this statement, which I don't think anyone in the industry can deny:

The pharmaceutical industry is often swept by new technology fads. They are caused by sincere enthusiasm, fears of being left behind, and desperation to fill chronically depleted development pipelines, in our view.

I'm sure that the ALNY investors are not going to take this well, but hey, the truth hurts. For now, I continue to agree that modern RNA techniques are extraordinary research tools - but not drugs, not in almost every case.

Comments (34) + TrackBacks (0) | Category: Business and Markets


COMMENTS

1. JP on August 21, 2008 9:14 AM writes...

Couldn't agree more...I'm always amazed how quickly the industry gets in a fever pitch about the next "revolutionary" technology that will "change the industry". Color me skeptical on this one as well...

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2. Tom on August 21, 2008 9:31 AM writes...

My guess is that you missed the train my friend. Same as Jonas Alsenas at Leerink Swann, and a whole lot of other disbelievers. I have been in ALNY since the IPO and it has been a extremely pleasant ride -more than 500 %. Well I have news for you - you better believe it - MRK, PFE, NVS, Takeda, Roche, GSK, BMY are ahead of you in their recognition of RNAi.

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3. JP on August 21, 2008 9:44 AM writes...

To Tom-

I don't think the author disputes the point that the Street and various players are heavily interested in RNAi, driving up valuations and making for some nice paydays for you (apparently) and others. The point is simply that will any new therapies really come out of this vein of research outside of some new opthamalogical agents? Derek and others (including myself) are simply skeptical. That is all.

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4. Mark on August 21, 2008 9:45 AM writes...

Derek, You say, "Nucleic acid-based therapies are just nightmarish to administer, and unless a real breakthrough in doing that appears, I think that (as drugs) they're always going to have their ankles tied together."

ISIS has overcome the systemic delivery issue and has created Mipomersen, which has already demonstrated dramatic effectiveness in lowering all atherogenic lipids. That drug is now in Phase III. The drug is a nucleic acid-based therapy. This fact contradicts your opinion above.

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5. ANON on August 21, 2008 11:25 AM writes...

Mark, Derek says "not in ALMOST any case"

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6. Anonymous on August 21, 2008 11:49 AM writes...

>>4
According to http://www.isispharm.com/product_pipeline.html , *subcutaneously injectable* mipomersen is in the works. Regular SC injection sounds unpleasant (maybe not nightmarish, but worse than oral).

Are you long ISIS and working from press releases or something?

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7. Mark on August 21, 2008 11:59 AM writes...

Anon, Not quite. He says not in "almost every case".

Still, that does not address the question above. Isis has a delivery system and drug chemistry which can deliver countless drugs designed to match messenger RNA sequences.

If Isis has the ability to manufacture a drug which would inhibit almost every human mRNA, that would almost completely contradict Derek's contention.

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8. Mark M on August 21, 2008 12:28 PM writes...

I know that intranasal administration was examined (briefly) by Nastech for RNAi but now the firm has exited nasal delivery altogether as a reformed business (MDRNA).

Method of administration is a serious issue to VC, many of whom think every new API should be able to be pounded out into a pill exhibiting RT stability. And if cant be, then your molecule is gargage. If the disease is serious enough and there is nothing else out there, patients usually will not mind paying for a daily injection (sure, SC is better than IV)

Formulation issues aside, equally serious issues of off target effects, manufacturing/COGs, and clinical relevance of hitting these biological target in this unproven way are all reasons for concern for RNAi-based therapeutics. I think the long and torturous road ISIS has been on has helped pave the way somewhat wrt mfg.

Tom's comments above highlight the fundamental difference that exists between investors who care solely about return and those involved in discovery of new molecules whose desire is to see a new medicine actually approved for human use. For Tom, ALNY is already a success despite no approved product.

Tom you may wish to cash in soon before the reality of entering uncharted waters in the clinic affects your gains.


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9. DevicesRus on August 21, 2008 12:38 PM writes...

Since 3 of the top selling drugs, all with sales >$4B per year are biologics needing needles or some other delivery, I think the world knows how to handle these kinds of molecules. I worry though that the RNAi and other nucleic acid based drugs have the delivery needs of proteins with the off target effects of small molecules.

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10. sick of you on August 21, 2008 1:05 PM writes...

Hopefully you will get the axe in the upcoming layoffs and you won't be posting this idiotic blog anymore

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11. Mark M on August 21, 2008 1:14 PM writes...

"Hopefully you will get the axe in the upcoming vertex layoffs and you won't be posting this idiotic blog anymore"

Every time Derek posts anything that is critical of a technology or a firm in particular, these whackos come out of the woodwork. This guy reminds me of the Dendreon investor who blamed Derek for his "loosing" $50k.

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12. Derek Lowe on August 21, 2008 1:37 PM writes...

As you can tell from the post, I'd also agree that if you've made 5-fold on ALNY, it's time to take the money and run. The clinic, as Mark M notes, is a very different world, and fraught with all kinds of uncertainty. The first few systemic RNAi drugs are going to be nail-biters, indeed.

I agree that ISIS has done an awful lot of hard work trying to make nucleic-acid based drugs viable. I had stock in them for a while myself, and I wish them well. But several other promising programs of theirs have not panned out, as everyone knows, and I'll wait until they get through the FDA before pounding them on the back. If they do have a generally applicable platform for antisense drugs, though, they will presumably coin money with it. I doubt that they do, but I won't be sad if I'm wrong about that.

And as for Sick, I don't think you've thought this through - if I get laid off, I'll have *more* time to post on the blog. . .right? I've edited your comment to remove the name of my employer, BTW - it's not the biggest secret in the world, but my blogging isn't connected to them.

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13. Hap on August 21, 2008 1:43 PM writes...

...and everytime the loons overinvested in some small company come out, I worry about my 503(c), because these people actually have money and participate in the stock market. I also worry about how deep the similarities in logic run between them and the people running larger stock funds.

On the other hand, I'm sure than Ayn Rand fans will get a laugh from them (money won't stay with people unable to earn it - stupid people with money will eventually be stupid people without money). That should be worth something.

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14. Skeptic on August 21, 2008 1:45 PM writes...

"I think the current RNA field is full of extremely interesting things, wonderful discoveries, fascinating research tools which could lead to all sorts of things..."

Then why don't you blog about that instead of wasting ink on the toilet paper machines that inhabit the public stock exchanges?

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15. SciChick on August 21, 2008 6:07 PM writes...

IMHO RNAi certainly has a tremendous amount of potential as therapeutics, and I am glad that major pharmas are investing heavily on it. Otherwise, what academic lab would have the resources to develop antisense oligos into drugs? The major obstacle with antisense drugs is certainly not the synthesis of the oligos - rather, it's the delivery, stability, safety, PK, etc etc. that many people have pointed out. Development on these aspects is only possible in industry, unless the good old NIH is going to have some kind of special program on it. Academic research just doesn't cut it without the necessary corroboration by clinical evaluation. Mark Davis at Caltech Chem. Eng. is the only group in the US that I am aware of who has developed delivery vehicles and evaluated them beyond simple cell-based assay. I think Davis has started a company based on his technology, not surprisingly.

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16. 2cents on August 21, 2008 9:03 PM writes...

FYI, Mipomersen which is in phase 3 trials, is a second generation antisense oligonucleotide. The ASO is stabilized by converting the backbone phosphodiester linkages to phosphorothioate linkages (replace O with S). The oligo has 10 DNA residues flanked on either end with 4-5 methoxyethyl sugar modified nucleoside residues. These improve affinity to target mRNA, further stabilize the ASO toward enzymatic degradation and also reduce non-specific interactions with cellular proteins. The ASO is administered (200 mg once a week) via a sc injection with no formulation or delivery agents. The ASO accumulates in liver tissue where it has a half-life of approx 30 days. It is by far the most potent cholesterol (and other atherogenic lipids) lowering agent in human trials and has shown >75% LDL reduction in humans at high doses (400 mg).

Derek, too bad you sold the stock, it is up almost 300 to 400% from four years ago! Nucleic acid therapeutics is becoming a reality and it is only a matter of time before there will be some oligos on the market making money.

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17. Pony fodder on August 21, 2008 11:47 PM writes...

Abbot cutting.

http://www.forbes.com/feeds/ap/2008/08/21/ap5347771.html

Only 1000 jobs. Please hire more MBAs to show how profits come from cuts. This is how a snide, underhanded MBA gets his year end bonus. FIRE everyone, outsource, the stock goes up and HE AND HE ALONE lives happily ever after. If you really think the company is better off, think again

repeat- THIS IS HOW AN MBA GETS HIS DAUGHTER A GOLD PLATED PONY AT YEAR'S END. EXPECT MORE CUTS TO COME FOR MORE PONIES!

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18. UK Chemist on August 22, 2008 5:59 AM writes...

It looks like some people in the US don't like skeptics.If things turn bad Derrick you should come to the UK, we love'em.

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19. alt on August 22, 2008 7:32 AM writes...

Derek,
I'm a frequent reader of your blog and mostly enjoy your perspective, and I'm aware of your longstanding skepticism of RNAi (although I don't share it).

However, you do yourself no favors when you make comments like "the truth hurts".

We won't know the ultimate truth until RNAi therapeutics are either on the market or they aren't. Of course, at that time the stock market valuations of the companies involved (such as Alnylam) will be either much higher or much lower than they are now. Those that are invested now are betting that RNAi will work well enough toward at least a few targets to drive the market capitalization higher. It only takes a handful of drugs that prove effective toward previously undruggable targets to yield a multi-billion dollar market cap. I believe that is what the majority of Anylam shareholders are waiting for - not for a quick buyout as you claim.

The fact that Alsenas came out with a bearish note doesn't make you right anymore than the fact that most of the analysts being bullish with price targets of $40-ish makes you wrong.

As far as the note, did you read it or just the summary that came out on the wires? After reading the entire note, I was struck by the bias in what should have been an objective analysis. It appeas to me that Alsenas has an agenda, although I don't claim to know what it is.

Comments like Alnylam is "supposedly validating" have no place in an objective analysis, and I would take issue with many of his conclusions - for instance he says that because a number of Alnylam's top executives have prior work experience at Millenium (which acquired Velcade rather than developing it internally) that Alnylam is destined to abandon RNAi and acquire some other technology.

That makes about as much sense as claiming that since a number of Alnylam's top executives have prior work at Biogen Idec (which is also true) that Alnylam is destined to have a market cap in excess of $15 billion.

I could continue, but I won't. I'd be curious though, if you did read the note if there was anything you disagreed with, or found to be an illogical conclusion, or if you accepted it as valid in its entirety.

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20. Petros on August 22, 2008 7:44 AM writes...

Derek does seemed to have touched a nerve with some people but Isis provide reasoanble justification for his comments.

Founded in 1989, and with much hype along the way, it has managed to get one product to market- Vitravene for CMV retinitis, and currently has just one in phase III. Isis has yet to break even.

It's fairly symptomatic of companies founded on new technology. A lucky few get snapped up for megabucks by big pharma before the brown doodah hits the fan and their bubble bursts, many go down the pan, while survival has often required a change of business startgey- look at the genomics and proteomics companies. A few manage to carry on

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21. JC on August 22, 2008 4:33 PM writes...

Reminds me of the solid-phase craze of the 90's.

During which I made 10,000 ureas, sulfonamides & amides on resin (none of which went anywhere)

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22. 2cents on August 22, 2008 10:19 PM writes...

Small molecule chemists tend to be rather myopic (probably the reason for the current lack of productivity in the pharmaceutical industry). RNAi right now maybe a fad like combi chem once was. But comparing the two is just plain stupid.

Combichem was like a bunch of monkeys typing randomly and hoping for a best seller.

RNAi as a field is tremendously exciting and may potentially expand the frontiers of biology and medicine. Obviously, there are great challenges facing the field but if you have read any of the recent literature by Alnylum and others, the results are fascinating.

I dont recall any leads derived from combichem programs providing any meaningful pharmacological results in rodents or in non-human primates which were published in Nature. Maybe some stupid papers in JACS published by people who made thousands of ureas and sulfonamides just because they could.

I hope that RNAi will deliver on the promise it has, but drug development is tricky business and success (as defined by drugs making money) is hard to come by. So one will have to wait and see how things go.

But to compare combichem with RNAi reflects a complete lack of understanding of the science behind the two technologies and maybe an indication of the commenters lack of scientific acumen.

I would encourage the "small insoluble heterocycle" crowd to brush up on their oligonucleotide chemistry because you just might end up looking for a job at a RNAi company in the near future.

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23. Pfizerbull on August 22, 2008 11:00 PM writes...

Derek

I also read your blog regularly and enjoy it. You have your opinions, I have mine. I am also in the industry.

Unfortunately I guess you personify Big Pharmas poor productivity.

How can you (as you have stated here on this blog) work your entire career in the pharmaceutical industry without ever having been involved in the development of a drug on the market. Doesn't this make you think something is wrong.

Doesn't this say something about the current approach to drug discovery and indeed perhaps the weight your opinion on a new transformative technology should hold.

My guess is that this is one reason you have an issue with RNAi therapeutics (I quote, , but hey, the truth hurts).

What truth is that? So far all the preclinical work out of Alnylam is near perfect and what could be hoped for in such a short time (the PNAS paper last week for example).

I am not sure where your bias is coming from but for one, synthetic chemists are unlikely to be hired in their 1000s to make useless compounds that never make it to market when RNAi therapeutics start taking off. We will need a few operators of robot oligo machines.

Please open your eyes to the possibilities.

Everything can be framed in a negative way.

In some ways I take this brutal reaction of some to a new technology as a contrarian indicator that "something significant is up".

Do yourself a favor and buy a few ALNY shares to hedge your position. Even the strongest believers in the efficient market theory purchased a few shares of Berkshire Hathaway to hedge their bets and got rich doing so.

Pfizerbull

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24. milkshake on August 23, 2008 10:06 AM writes...

Pfizerbull, it is obvious that you are not a medicinal chemist, and that you are not very informed about how the medchem development process actually works - and I would strongly encourage you not to invest any money (yours, or yours clients) into the biotech and pharma.

The productivity problems of big pharma are caused by bad management and corporate irresponsibility that gets hidden for many years, the feedback between stupid action and its consequences can take a decade to because the research-to-profit development cycle is extremely slow. Self-confident overpaid business people that are good at fooling the investors and maniplating the stock price for a shot-term gain in this situation can carve out good living for themself, ruining the research productivity in the process, and tracking the consequences back to the original bad decisions many years back is nearly impossible, how one can see what could have been made but never was as the research was "transferred' to another site and let to die.
Or the company decides to quit doing medchem research altogether (like Celera) and just needs their people to complete their projects to certain stage so that it could sell them to highest bidder, and then fire all research staff.

Pfizer has developed a particularly nasty reputation - I think one of their last original drugs was Viagra (an accident and discovered not in US but in Sandwich) and long before that, a good one was Fluconazole. But most of what they have they just bought dearly, from other companies, and they overpaid dearly for lots of it - using their stockholders money.

Corporate megalomania is the prime vehicle of the business-folk management self-aggrandisment.

Paul Janssen has been publically warning his fellow pharma execs more than two decades ago, repeating to them that their management management style was deluded and that their current profitable times would end-up in tears, and they laughed at him and said he was too old-fashioned and out of touch with the dynamic management theory.

So many good projects die for completely non-scientific reasons (mergers, for example), and rationale behind the projects and it directions could change many times, the management decides that that the project has no real profit potential (Lipitor project almost got killed that way, and it was actually the back-up series pursued only because there was a patent conflict with the more promising series) or the underlying biology does not work. All kinds of nasty tox effects can show later on in long term animal studies, or things have no efficacy in clinic.

But the worst problem is when your project is taken away from you and killed for no good reasons (like the PI fell out of favor, or there is a competing project at another company site and those people want to do their series and have a bigger political influence). When one lives through this experience several times, it is hard not to become cynic and filled with despair

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25. Cellbio on August 23, 2008 12:30 PM writes...

Wow, from a post skeptical about the next great thing, some can see into Derek's heart and know the true cause of declining productivity! Why not take it at face value, a skeptical opinion. I share this skepticism. I am not a med chemist, I must be a myopic biotech veteran that is also part of the problem with declining drug approval rates.

I do think RNAi will work in a few places, and liver targets may be one, but being skeptical of the oversold promise is a reasonable viewpoint.

For those that are critical of big pharma productivity, where is the "other" approach that is working better? I'd love to know. Here's a thought...Productivity is declining because a fair chunck of tractable biology has been explored in the prior decades. We have made progress in certain areas (RA for instance) and this makes new entrants face tougher hurdles for regulatory and commercial success.

I do think that if something like RNAi, or antisense, or gene therapy, enables us to attack intracellular targets with the specificity of biologics, then a new era begins. However, the magnitude of the promise does not diminish the challenges that lie ahead. The promise does fuel investment, and perhaps a bubble of enthusiasm, but this is nothing new. For those of us that have been around, we have seen this all before in the form of genomics, proteomics, expression arrays, systems biology, anti-sense, gene therapy etc. RNAi does seem all too familiar, and yes we need the believers to keep pushing hard. Maybe us skeptics will be wrong some day.

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26. David on August 23, 2008 5:56 PM writes...

Derek,

Isis, Genta and Gilead Sciences were 3 early stage antisense companies that largely created the technology used these days for making nucleic acids longer than a trimer. I should also credit Marv Caruthers and Bob Letsinger for the solid phase synthesis methods that allowed these companies to tackle complex biolical problems using chemically modified nucleic acid oligonucleotides. The scarcity of marketed drug products based on oligonucleotides testifies to the difficulties encountered along the way. Isis was a tour de force med chemistry machine for many years as it pumped out thousands of chemically modified oligonucleotides in a search for efficacious drugs based on this technology platform. The current generation of modified oligos is much simpler and more subtle in design than the preceding generation for a reason. Life demands it!

In any case, understanding the mechanism(s) for successful delivery to the cytoplasm of a highly hydrophilic and unstable siRNA will be a very important milestone in pharmaceutical chemistry and may revolutionize delivery of many other essentially inactive leads due to cellular barriers.

I think it is important to take stock of Pharma success stories as well as examining the past failures before attempting to describe a sector as over-invested. It certainly took a very long time for monoclonals to generate the revenues they make today. It wasn't an easy path nor was the the avaerage med chemist on board for the ride either.

Perhaps it just isn't the type of problem that a traditional medicinal chemist can wrap his head around. Either way, the public benefits from the research as it gets captured in journals along the way. Big Pharma is investing precisely becuase they see a day when the small molecule target is mostly mined out and not such a productive activity for a large enterprise.

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27. CMC guy on August 23, 2008 11:38 PM writes...

#26 David states "Perhaps it just isn't the type of problem that a traditional medicinal chemist can wrap his head around." Although it is true classically trained synthesis people have a natural prejudice towards small molecules I think its wrong to suggest chemists in phrama industry are not open to/aware of other approaches. As Cellbio points out there is heavy skepticism from such new technologies and waiting see if actually work. Part of this is the obvious great over hyping of the science that frequently takes place, frankly often to promote investment capital, when still at bench level research. Isis has been mentioned and is a prime example as "antisense" was going to be the future of new drugs. Almost 20 years later only 1 "product" approved. I agree Isis has stuck with it and has done solid science (because concept is a good idea), resolving some big issues, and they do seem to have promising stuff that may be effective but still remains an unproven source of medicines.

Another similar part is that there have been so many paradigm shifts or other "improved" ways to discover drugs in the past 20 years that have not lead to big break throughs anticipated. Computer Aided Design, Antisense, Biologics, Peptides or peptidometics, Combichem-HTS, and other techniques all were supposed to replace traditional med chem. It seems each has added something and a few still maturing (like antisense) however not as much as promised so still appears to be room for large contributions from older approaches. More and more of that foundation is being lost/outsourced so the new technologies better bear fruit or will have no new drugs to talk about.

Milkshake is correct IMO that lack of productivity tied more to management than science. Blockbusteritis has probably killed more projects than potency or tox results. Emphasis on Lifestyle drugs vs treating diseases has derailed mission and limited areas of exploration. Mergers too have undercut many potential candidates when the knowledge or champions associated with a program do survive the integration. I also think incomplete organizations (most Biotechs) who do not understand the whole process are inclined to make mistakes that could be avoided. Can't blame FDA directly per se yet the Reg burdens have gotten harder and seem to be growing because of political pressures. I don't feel science has all the answers but it must be a core element to any drug program and we have gotten away from it.

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28. 2cents on August 24, 2008 12:16 AM writes...

I can understand the dilemma small molecule chemists must face these days. It has become really hard to find small molecules that fit the block-buster paradigm. At the same time there is pressure from newer technologies like RNAi. The skepticism is understandable.

I think it is easy to just blame management for the current malaise but the truth remains that the low hanging fruit in small molecule discovery is all but gone. You cant blame management to outsource some of the work to cut costs and offload risk.

I also find the comparsions to Isis interesting. Here is a company with a market cap of 20 compounds in development. On the other hand is Pfizer which spends 7 billion a year on R&D and has not discovered anything in the last 10 years or more. Maybe its the management, maybe its all the ivy league trained chemists that work at Pfizer, who knows. But the truth remains, the golden era of small molecule drug discovery is pretty much over. So quit whining and get to work, its not going to get any easier.

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29. Human Being on August 24, 2008 11:49 PM writes...

CHEMISTS are-hated by industry, hated by executives, hated by politicians, hated by students, and now...hated by biologists and RNA dabblers?


O.K time to set up the suicide booths. Single file, 25 cents a pop. No cheating with cyanide if the knives don't take you down fast enough.

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30. processchemist on August 25, 2008 11:04 AM writes...

@CMC

Am I wrong in seeing a parallel with the "new technology storms" in the process-manufacturing field? I remember statements like:
- No chiral technologies, no party (nowadays I see very few chiral leads)
- No biocatalisys, no future
- Batch processing will be wiped out by microreactors
- If you don't get industrial solid phase peptide technology, you're going nowhere

Permalink to Comment

31. CMC guy on August 25, 2008 12:02 PM writes...

processchemist yes I have encountered those "revolutionary" paths for process/manufacturing (along with several others concepts) however because our area usually gets less attention see less dramatic trends than the faddishness that seems to hit discovery/med chem side periodically.

2cents I disagree that have picked all the low hanging fruits from small molecules as think have been in the wrong orchards and have made the pickers spend more time on shiny tools that were not productive. Again I do blame mostly on management who has misdirected the industry for many years. I know it is not easy business and do welcome advances in other fields. The dilemma is that people in charge who know little abandon certain projects to chase new fangled areas that may or may not work.

I believe most of Isis compounds are in early development (preclin or phase 1) and the majority are being developed by partners. Genta had an approval failure a couple years ago so IMO antisense, although great potential, remains unproven.

Human being great comments, guess there is much jealousy out there.

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32. Pfizerbull on August 25, 2008 9:44 PM writes...

To Milkshake who says.....

it is obvious that you are not a medicinal chemist, and that you are not very informed about how the medchem development process actually works - and I would strongly encourage you not to invest any money (yours, or yours clients) into the biotech and pharma.

Indeed I am not a medicinal chemist. I am a biotech entrepreneur (pharmacologist PhD trained) who has successfully started 2 biotechs, and been involved in the development of several drugs currently in Phase III and II. Perhaps to my detriment, I also obtained the much cursed MBA degree. I see myself as a generalist scientist and suggest that part of the blame has to be laid at the feet of bench scientists who proclaim and pidgeon hole themselves to be "medicinal chemists". These false boundaries in peoples heads may be part of the problem.

I also think it is naive to blame management on the low productivity in big pharma. Innovation comes in waves and we are at the start of a new one.

Sure people are wary (genomics, metabolomics, antisense etc and all the other hyped non-producing technology).

However RNAi is well positioned to leverage off all the knowledge presented by the aforementioned.

It is wise to be skeptical, but it seems very faddish to simply write of new biotech technologies because so many others have been hyped and failed previously.

PB.

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33. processchemist on August 26, 2008 6:56 AM writes...

2cents

best wishes if you're starting another startup focused on RNAi or if you're raising funds for such a project. Maybe if you start talking about "nanostructured delivery systems for RNAi drugs" to the inverstor you'll be able to obtain the best results.

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34. Jonadab the Unsightly One on August 26, 2008 7:12 AM writes...

> If the disease is serious enough

Sure, if you're treating metastatic cancer, or AIDS, then maybe you can tell the patient to come into the hospital every forty-three and a half hours for injections under the fingernails, and some of them will actually comply. But those are special cases.

Most drugs really do need to be once-a-day or twice-a-day pills. Even well-established injection-administered drugs for which there's no real substitute have serious patient-compliance issues. It took the doctor several *years* to finally convince my dad to take insulin, and he's never been at all consistent about taking the same dose every time like he's supposed to do. (With a once-a-day pill, you just put one of the things in his pill case for each morning, and assuming he doesn't forget to take his meds too often the dose is fairly consistent. But with the injection, he draws out however much he draws out.) He's been on insulin for several years now, and his blood sugar fluctuates between 140 and 300. (The doctor would like it to be stable between 90 and 110. Haha, tell us another one, doc.) So yeah, it's a real problem, not just some foolish requirement the VCs made up to amuse themselves at your expense.

Regarding RNAi, or any new thing like that, just because it has all kinds of great potential doesn't mean the milk and honey are going to start flowing into the pocketbook tomorrow morning at 9am sharp. There are always going to be optimists who believe everything is going to become wonderful overnight, and they're stupid. And there are always going to be pessimists who don't believe anything good can ever happen, and they're generally wrong too. On the one hand, just because RNAi therapies are difficult to administer at this point doesn't mean they're not worth exploring. They could be very much worth exploring, especially in the long term. On the other hand, they're probably not going to fundamentally alter the structure of the universe by next Tuesday.

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