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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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October 5, 2005

Human Genome Science Hits the Wall

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Posted by Derek

You remember 1999 and 2000, don't you? The internet stocks got a lot of attention, but there were plenty of biotech wonders on NASDAQ, too. The genomics wave was cresting at the same time as several other technologies, and people were just caught up in the excitement of it all. Dozens of wonder cures were going to come spewing out of the human genome, and this glowing future belonged to the young and the fast. That's basically the only way to explain how Human Genome Sciences hit the prices it did.

The genome hype collapsed at roughly the same time as the early Internet hype, by one of those little jokes of history, and HGSI had to go out and earn a living. They've been trying to turn themselves into a good old biotech company, but their most advanced clinical prospect just hit a major air pocket. Somewhere around fifty per cent of the stock's remaining value evaporated when they announced that their therapy for lupus missed its Phase II endpoints.

They were going after a target protein called beta-lymphocyte stimulator, or BLyS. It's required for the survival of that variety of white blood cell, and if you cause mice to overexpress it, their revved-up beta lymphocytes give them an autoimmune disease rather similar to lupus. Humans with lupus often show elevated BLyS levels, too, making it one of the prime candidates for a new therapy.

Well, so much for theory. HGSI's LymphoStat B antibody neutralizes BLyS, all right, but that doesn't seem to be enough to slow down lupus. The treatment failed to lessen lupus symptoms or reduce the number of acute attacks. The company says that they did see some trends toward symptomatic relief, but it's clear that they were hoping for a lot more than that. They're talking about plowing ahead into Phase III, but Glaxo SmithKline (who would be paying for a lot of that) is sounding more cautious about the idea, as well they should.

So, what role does BLyS play? One theory has been that it's the main causative agent, but that's now been shot down. Another idea was the a certain level of BLyS was necessary for the autoimmune condition to take hold, but that it wasn't a player in the actual mechanism. (Recall that not all lupus patients show elevated BLyS levels). I don't know what shape that idea is in, because if it's true, then the patients who have just barely enough BLyS to support the disease state should have responded, and it doesn't sound like they saw that, either.

No, while the understanding of lupus (and other autoimmune diseases) has advanced because of this trial, it's done so in the toughest way possible. The old theories are in bad shape, and we don't seem to have much to replace them with. Here's hoping that there's something in HGSI's clinical data that might show where to go next. At the rate that they're going through cash, though, they might see this promised land and not be able to enter it. . .

Comments (4) + TrackBacks (2) | Category: Business and Markets


COMMENTS

1. Anonymous on October 6, 2005 1:05 AM writes...

Could be the other way round - BLys might be necessary for the condition to take hold, but once it's under way it becomes self-sustaining. It makes a kind of intuitive sense to me at least - the adaptive immune system *exists* to remember antigens and perpetuate responses, so that part of the process is likely to be multiply redundant. It's in the initial generation (and failure to tolerise/destroy) self-reacting cells that the key problem lies.

If the above is right, it's a major pain in the ass from a treatment point of view, because the conditions themselves are less likely to be treatable. You'd have to have a good predictor of who's likely to get lupus so you can give prophylactic measures.

Permalink to Comment

2. shhiggins on October 10, 2005 7:47 AM writes...

I think this points out the hazards inherent to the kind of business model that genomics as commercial enterprise has been forced into: pick a likely candidate without a complete understanding of function then pour huge sums into developing a single drug for it. If you pick wrong, as in this case, you are completely screwed. At the end of the day the body of knowledge is substantially improved but from a business standpoint the guys who write the checks put away their pens while talented scientists hit the unemployment line. Seems to me a better use of all that money could have been spent on learning more about the multiple factors that contribute to the disease.


A bit of a shame, actually.

Permalink to Comment

3. GATC on October 11, 2005 9:23 AM writes...

First off, for those in the industry, Human Genome Sciences is referred to as HGS, not HGSI; and second, we have only begun to harvest the fruits of the human genome project. Just as most workers in the field predicted in the beginning, getting the sequence assembled was the easy part. Learning how to analyze this mass of data will take decades!! Getting pharmaceuticals to market based on this analysis will most likely be a side show for the foreseeable future (a lot like trying to figure out what all of that dark matter is doing in the universe). Consider that we still have lists of bacterial genes of unknown function (FUN genes) numbering in the 2-300 range. Bacterial genomes are several fold less complex than a mammalian genome. And of course this does not even begin to consider the structural DNA (often referred to as junk DNA in mammalian circles but obviously there for a purpose).

Like most of BigPharma, I would imagine that HGS, through their early collaboration with SmithKlineBeecham (now GSK), went for the low hanging fruit first. You can bet the farm that LymphoStat-B is only the beginning. Lupus is a complex disease with multiple etiologies. For comparison purposes, just consider all of the difficulties over the past decade or so trying to get a decent treatment for sepsis. Where are the drugs for that indication? Trying to modulate something as complex as a systemic immune response with interconnected regulatory circuits and feedback mechanisms will most likely make combination therapies the norm rather than the exception.

Permalink to Comment

4. Derek Lowe on October 11, 2005 10:38 AM writes...

HGSI is their stock ticker symbol. Where I am in the industry, we never refer to Human Genome Sciences much at all any more, so (since I linked to their stock chart) I stuck with the NASDAQ ticker.


Your analysis of the complexity of the problem is, I think, completely correct, and you're right that it's going to take a long, long time to sort out the useful stuff from genomics. But that sure wasn't the prevailing point of view when people signed all those huge deals a few years ago. Back then, the gold rush was on, and if you didn't stake your claim fast, you were going to be left behind.

As for betting the farm, I'm sure that someone will take another crack at lupus. But this was the low-lying fruit in that area, as far as I can see, and it may be someone else's farm that gets put on the line next time. How many of these can HGS(I) absorb?

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