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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

« The Examiner Finally Snaps | Main | Ah, It's Fine. Just Send the Darn Thing Out Already. »

January 25, 2006

If It's Not One Thing. . .

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Posted by Derek

I'm starting to wonder how we're going to get many drugs even as far as the clinic these days. I don't think I'm alone in feeling that it's just one thing after another.

Modern mass spectrometry techniques can find all sorts of interesting metabolites for your compounds after they've been dosed in animals. If you look hard enough, you're likely to find some structures that you don't want (epoxides, quinone precursors, and other potentially toxic beasts). In the old days, we'd never have seen them, but now we get a chance to worry about them.

There's always our good friend the Ames test to make you hold your breath. It's true that not every Ames positive compound is going to be a mutagen in humans, but it's also true that no one is going to develop one because they happen to feel lucky, either.

Anyone who doesn't hold their breath when their drug candidate goes into two-week rat testing hasn't been in the business long enough. Even if the rodents act normally during the whole thing, you can't breath normally again until the tissues are examined by the histopathologists, Perfectly reasonable-looking rats can be hiding amazing things at the microscopic level.

And for the last few years we've had to worry about QT prolongation. That's a cardiac side effect that can lead to very serious trouble - sometimes. And we have some ways to check for it early in development, which work - sometimes. The list of drugs that came to the market before we realized all this is rather impressive.

All this is why I wonder when I read about small startup companies with three or four compounds in clinical trials. Have they really jumped through all the hoops that a big company has the resources for? And if not, how much worse off are they for it?

Comments (15) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. John Johnson on January 25, 2006 10:11 PM writes...

I do not envy employees of small startups. They live on the dangerous side, and you can hear it in their voices. They sometimes give me the most challenging statistical problems, too, in the form how to reduce sample size without compromising ability to show a significant result on a clinically relevant treatment difference.

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2. dlib on January 26, 2006 2:34 AM writes...

Sadly what you say is true enough. Mass Spec on a raw potato and a cooked potato ( cooking increases the carcinogenicity ) might prevent that from being approved too. Peanut butter...

In a normal life span the mutagens/carcinogens we're continuously exposed to are in the noise of the hazards of our day-to-day lives. Remember the biggest risk factor for cancer is age.

dlib

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3. Kay on January 26, 2006 6:37 AM writes...

Small companies cannot skip anything that's important because we all have the same regulator. The vast difference in NME/dollar between small and large must be a people and paper-shuffling problem.

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4. NJBiologist on January 26, 2006 7:34 AM writes...

I wince when some of my friends call their companies' preclinical tox departments "where promising compounds go to die." But with all of the potential toxicities a drug company can be sued for, I'm not sure this isn't a completely rational response.

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5. qetzal on January 26, 2006 9:50 AM writes...

Derek asked:

"All this is why I wonder when I read about small startup companies with three or four compounds in clinical trials. Have they really jumped through all the hoops that a big company has the resources for?"

As one who has spent his career to date in small companies, my experience is no, they usually haven't. However, my experience is with biologicals &/or new delivery technologies for known drugs. Obviously, the tox questions for such products are different.

I like small biotech, but I would have the same concerns as Derek if I worked for a small company trying to develop NCEs. I very much doubt such companies screen their NCEs as thoroughly for tox issues as a big pharma.

I think a common mindset is to do the tox that's essential to get into Phase 1, and delay the rest until ~ Phase 2. By then, one hopes the clinical data is promising, and justifies spending the additional money. That's also consistent with the typical assumption that there will be a big pharma partner before phase 3, who will 'handle that stuff.'

But how much risk will big pharma take on a Phase 2 compound that hasn't passed all the tox screens they would have insisted on in-house? What does a small biotech do if a tox study run in parallel with Phase 2 raises an issue?

I don't know, since I've never worked for a small company focused on NCEs. I hope this post gets some comments from people who have.

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6. Milo on January 26, 2006 12:09 PM writes...

"In the old days, we'd never have seen them, but now we get a chance to worry about them."

Based on this statement, one could say that the "requirement" of having a drug with "high therapeutic value" (I am sure there is a better phrase for that...) and low/no side effects is a large part of the problem. I guess people want drugs that have no adverse effect at all. I am not sure how realistic this is, but it seems to be what the consumer wants.

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7. Jim Hu on January 26, 2006 3:29 PM writes...

Shouldn't there be a market niche for companies to contract just to do the tox part? I know that there are companies that contract out just to consult on how to navigate the FDA paperwork, one of our former PhDs worked for one.

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8. Derek Lowe on January 26, 2006 3:40 PM writes...

Yep, there are indeed contract houses for this sort of thing, and that's often where smaller companies will turn. Here's a few of them, and I've heard of more. But they're not cheap, and I think that in many cases (as Qetzal says above) the assumption is that someone else will do it eventually.

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9. GATC on January 26, 2006 3:50 PM writes...

The limit of detection thing goes for environmental exposures as well just look at old DuPont today being ragged on by the environmental wackoos over perfluorooctanoic acid (PFOA)contamination. If one reads the press today you would be forced to conclude that this stuff is just dripping off of new Teflon cookware when in reality it is precursor feed-stock that passed human tox screens long ago and is not in the finished product at all. And what about all of those human pharmaceuticals that we hear about being detected in our waterways. Sounds to me like the next blockbuster will have to include an EPA environmental impact statement before making it to the clinic if we continue with this nonsense.

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10. Still Scared of Dinosaurs on January 26, 2006 4:22 PM writes...

"small startup companies with three or four compounds in clinical trials"
Hmmm, I think of any company with >1 drug in the clinic as fairly mature.
One reason small companies do less tox is that they go after end-stage patients with serious and life-threatening conditions where a lot of the barriers to approval are lower. Even when the regs don't specify it you can sometimes leave things more in the gray area than would be allowed in other indications. The assumption is that whatever the tox data show the drug will still be approveable because the need is so great.
The same applies to early clinical development, though I think it's more problematic. It's not uncommon for small companies to base two Phase 3 studies on one Phase 2 study. They end up with results significantly better than placebo but without a compelling rationale for the dose they propose going forward versus alternative regimens with their drug. Sometimes that ends up being the difference between a successful drug and an approved-but-disappointing drug.

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11. weirdo on January 26, 2006 10:35 PM writes...

"Small companies cannot skip anything that's important because we all have the same regulator. The vast difference in NME/dollar between small and large must be a people and paper-shuffling problem."

Sorry, Kay, but you simply don't know what you're talking about here.

Yes, there is a bare minimum that every drug needs to "meet". But it's really, really very bare. And, having seen packages from literally dozens of biotechs, it is clear that few jump through all the hoops compound development teams from large companies do. I think the reason is very simple: the bare minimum hoops are designed to make sure you don't hurt anyone in Phase I. That's not enough for big pharma -- they actually need to find a drug. And it's all those nit-picky assays and experiments -- looking for that one in a million side-effect -- that kills so many pre-clinical molecules. Quite frankly, your average biotech is going to try to sell their drug long before they'd ever get to that stage, so why run the risk of attaching a red flag to your company's flagship molecule (pun intended).

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12. Kay on January 27, 2006 6:32 AM writes...

Sorry, Weirdo, but you simply don't know what you're talking about here.

Perhaps you've not read the mid-January Guidance and final rule on eIND and on cGMP, respectively. As you read them, please underline the phrases that indicate that the industry is way too conservative in tox and is generally unproductive. Let's then compare phrase count.

Here's the rub: folks at White Oak recognize that animals don't represent outbred humans. If you bring them a strong prospect for an important medical advance, then some tox wrinkles can be ironed out.

Here is the big picture: you must get to humans to see any truth in our business. Animals are not predictive, so designing a drug for them will not have a good ROI.

Do "compound development teams from large companies" have good ROI in the recent past? Should they be viewed as models to emulate?

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13. tom bartlett on January 27, 2006 8:50 AM writes...

"That's not enough for big pharma -- they actually need to find a drug. And it's all those nit-picky assays and experiments -- looking for that one in a million side-effect -- that kills so many pre-clinical molecules."

So, you do two species 5 week tox, cytochrome induction, Ames, basic metabolite ID, Herg, QT in dog, some PK scaling studies-- what else would you specifically propose pre-IND?

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14. Still Scared of Dinosaurs on January 27, 2006 11:27 AM writes...

"the bare minimum hoops are designed to make sure you don't hurt anyone in Phase I"
And that gets you all the way through Phase 1, most of the time.
You ever see the look on somebody's face when they're showing you development time lines--with a quick jump into 12-week Phase 2 studies--and you tell them they can't do that unless they have 12-week tox beforehand? I've never been clear when the 1-1 relationship between tox and clinical trials ends, but NEVER EVER EVER assume that sufficient tox data to support the next step exists.
And the definition of "exists" is "QCed, signed off, and sent the the FDA".

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15. Derek Lowe on January 27, 2006 1:42 PM writes...

A nasty example of that was seen when Merck and Kyorin had to pull their PPAR alpha-gamma compound (KRP-297) well into phase III, because 2-year rodent tox data had come in showing a carcinogenicity risk. No, you can never breath easy.

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