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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: Twitter: Dereklowe

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November 24, 2008

Two Drugs in One? Maybe Not.

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Posted by Derek

Since I was talking about Nitromed on Friday, let me mention another attempt to combine two known drugs into a new therapy. Another Cambridge company whose front doors I walk by once in a while is CombinatoRx. If they'd had that name back in the early 1990s, you'd have assumed that they did combinatorial chemistry, but their plan is to take approved drugs and find greater-than-the-sum-of-their-parts combinations to approve as a single pill.

That's not easy. It's hard enough figuring out just how single drugs behave in the real world, and any physician will tell you all about what fun it is to deal with drug interactions. Finding beneficial drug interactions, especially unknown ones, is a real uphill climb. But CombinatoRx thought they had one in the mixture of low-dose prednisolone and dipyridamole.

Prednisolone is a well-known corticosteroid which is used to suppress inflammation and the immunen response. Dipyridamole is a multi-mechanism drug that increases the free concentration of adenosine, and it's been used to inhibit clotting and lower pulmonary hypertension. Blood pressure problems are common with prednisolone, and the company believed that the prednisolone dose could be taken down to non-side-effect levels in the presence of the other drug. So they formulated a combination pill (Synavive, CRx-102) to test this out in osteoarthritis patients. The stakes were high - here's a writeup from before the results came out last month.

Things did not work out. The Phase IIb study definitively missed its endpoints. Not only did Synavive not compare to prednisolone alone, it didn't reach statistical significance versus the placebo group, either. The stock dropped 72% the next day, and the company has now announced layoffs that total 65% of its workforce.

What I have to wonder, though, is how things would have worked out in the long run even if the trial had succeeded. As Nitromed's experience shows, it's a hard business convincing insurers to pay a premium for two generic drugs just because they're now available in one pill. I know that CombinatoRx was making much out of their proprietary formulation, no doubt anticipating such objections. But I wonder if a company in this space would have to actually run a head-to-head against the two-generic-pill dosing regimen to really convince people that it had something to offer. And that would take nerves of steel, for sure. . .

Comments (12) + TrackBacks (0) | Category: Business and Markets | Clinical Trials


1. c on November 24, 2008 2:01 PM writes...

Terrible business model.

Payers are only likely to pay for compliance where there is a clear medical or cost benefit, baring in mind that this cost benefit needs to exceed the lost copayment associated with the fixed dose combination.

Additionally, physicians dislike fixed dose combinations because it reduces their ability to titrate doses.

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2. Sanders on November 24, 2008 3:26 PM writes...

I think Derek's audience has been outsourced.

They forgot to include a provision which requires them to read english.

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3. c on November 24, 2008 5:04 PM writes...

Sanders, what do you believe I didn't understand?

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4. The Pharmacoepidemiologist on November 25, 2008 8:35 AM writes...

Actually, it isn't just physicians who don't like fixed dose combo products--FDA isn't a big fan, either. Remember Panalba? I'm surprised Derek hasn't written on it a number of times by now. Worth taking a look at the social responsibility articles on

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5. Hap on November 25, 2008 12:42 PM writes...

Dr. Lowe's been popular enough for a while to actually have trolls - however, he seems to get the unfunny and bitter trolls now rather than the racist and vaguely funny trolls of yore (well, a couple of years ago).

Times change, I guess.

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6. Mike on November 25, 2008 11:15 PM writes...

Hap, I thought you were a troll?

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7. mitch on November 26, 2008 2:10 AM writes...

Hap is not a troll.

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8. Petros on November 26, 2008 5:48 AM writes...

Advair does pretty nicely and that is a fixed growth combo as is Symbicort.

Sales last year of $7 bn and $1.6 bn respectively, the latter almost all outside the US

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9. Hap on November 26, 2008 11:19 AM writes...

I don't have that much substantive to say about drug research or business (because my first-hand experience in drug research is nil and my second-hand experience is from here and C+E News) and my chemistry experience is mostly second-hand, but I try not to troll (because it's stupid and if I actually get something out of reading a blog, the least I can do is not muck up the works). I'm not able to dispassionately view myself enough to prove I'm not a troll, though.

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10. Derek Lowe on November 26, 2008 11:24 AM writes...

Hap, if you're a troll, I'm a mongoose. With a Carmen Miranda fruit hat on.

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11. Hap on November 26, 2008 5:50 PM writes...

Is there anything in the either the mechanism for asthma treatment or the method of delivery (annoying to carry two inhalers, timing problems, etc.) that makes the combinations (Advair/Symbicort) better than both of the individual drugs? There might be something there that doesn't hold for other diseases - that the timing of the doses or the convenience or something else makes the combo much better than the individual drugs.

Maybe they could show that the profiles of their formulation are distinct from those of the generics taken simultaneously and separately (though they would also need evidence that the differences actually mean something). Get around paying for new drug research and safety studies, and pay for it by having to show that your combination is better (and significantly so) than the generics taken separately - nothing comes for free.

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12. The Pharmacoepidemiologist on November 26, 2008 7:43 PM writes...

The only advantages to a combination product over the individual components is the ease of administration (one shot, one pill, one drink, one puff, etc) and the lower cost of only one "thing"--a co-pay attaches to only the combination, not the individual entity, and the cost for the combination might also be less than the sum of the individual components. Otherwise, there isn't an advantage and there's the disadvantage that everything is set, ie, can not be changed. Convenience, like it or not, is a big reason why some things get done in our society. However, convenience doesn't persuade FDA much. Witness Orzel, an oral version of 5-FU Bristol-Myers Squibb tried to bring to market about a decade ago. AdCom voted 9-0 to favor approval. FDA never let it go on the market. Convenient? You bet. But superior to what was out there from a biological perspective? FDA didn't think so.

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