Cox-2's Die Hard: With a Vengeance

When Vioxx was first pulled off the market, I suggested that this would lead to what I termed a "Me-Too Drug Domino Effect" in which other drugs in the COX-2 class would also be at risk (see original Pharma Marketing News Op Ed piece: Vioxx Withdrawal and the "Me-Too Drug Domino Effect").

No sooner had I said this than bad news about cardiovascular effects of Bextra came out. Shortly afterward, of course, Celebrex was put under a cloud followed by naproxen. This is the classic Me-To Drug Domino Effect -- drugs in the same class will be suspect until proven innocent (naproxen especially may be a wrongfully accused victim).

[See the PHARMA-MKTING discussion thread on the Celebrex issue: Celebrex Problems -- What Should Pfizer Do?]

BTW, the Me-Too Drug Domino Effect can also be positive. This happens after the first blockbuster in the class comes out and gives the Me Too drugs a boost in sales right off the bat (perhaps this low hanging fruit inducement is why it is so difficult NOT to develop Me Too drugs).

Will Celebrex Crash and Burn?
At the end of this post I make a prediction about Celebrex based upon a unique analysis. But first, let's see what the "experts" say.

Before a recent study revealed that Celebrex may also have negative CV side effects, Pharma Marketing News hosted a survey to access why Pfizer would risk testing Celebrex's ability to protect the heart (see the full text article with survey results: Will COX-2 Inhibitors Crash and Burn?).

At the time of the survey (Oct-Nov 2004) the negative clinical trial results regarding Celebrex were not publicly known. Surprisingly, a higher percentage of pharma company respondents than non-pharma respondents thought that, yes, Celebrex would crash and burn (25% vs. 15%, respectively). No marketing agency/consultant respondents thought so. Clearly, the marketing people are drinking their own Kool-Aid.

The Molecule's the Thing
Pfizer has said that Celebrex is "different" than Vioxx. Some clinical data are different and Celebrex does have a different chemical composition (combination of atoms). However, if you look at the molecular structures (arrangement of atoms in 3-D space) of Vioxx, Celebrex, naproxen and Mobic, you will see some are more different than others (click to see graphics).

Vioxx Molecular Structure
Celebrex Molecular Structure
Bextra Molecular Structure
Naproxen Molecular Structure

I studied biochemistry and specialized in building molecular models for X-ray crystallographers studying how drugs interact with proteins. So I know a bit about how inhibition of enzymes -- like the COX-2 enzyme -- works.

It is the shape (molecular structure or 3-D arrangement of atoms) of inhibitor molecules (e.g., drugs) that is critical. Drug inhibitors work by fitting into a crevice of the enzyme usually designed for its natural target molecule. This lock-and-key 3-D fit prevents the normal molecule from entering the active site of the enzyme. (If you want to learn more about this sort of thing, take a look at an NIH brochure: The Structures of Life.)

My Prediction: Celebrex Will Crash and Burn
While Vioxx and Celebrex (and Bextra) indeed do have different chemical compositions, their 3-dimensional molecular structures are very similar. This makes sense: drug patents are issued based on differences in chemical composition, not 3-D structure or even mechanism of action. Therefore, to produce a patentable Me-Too molecule, drug companies strive to keep the 3-D structure similar to the original molecule (thereby preserving its "fit" in the active area of the enzyme) while changing the peripheral, unimportant atoms hanging off the molecule (thereby making the chemical composition different and the molecule patentable).

If you rotate the molecular structure images (or molecular models) of Vioxx, Bextra, and Celebrex just right, you can practically superimpose one upon the other except for the odd atom bits hanging off.

Naproxen and Mobic, on the other hand, have completely different 3-D molecular structures, a fact not lost upon physicians who already have gone back to prescribing Mobic, which has been on the market much longer than Vioxx or Celebrex.

I predict, therefore, that Celebrex (and Bextra) will crash and burn and be pulled off the market or voluntarily withdrawn by Pfizer. Moreover, I predict that naproxen and Mobic will be vindicated and become the leading pain killers of choice to replace Celebrex and Vioxx.