One of the less appealing ways that companies have tried to fill their drug portfolios over the years has been to look through their current drugs in search of one with a main active metabolite. That altered structure then becomes a clinical candidate for the next generation. I’ve said bad things before about Clarinex (desloratadine), son of Claritin (loratadine), the most famous example of this practice. That “des” prefix tells you that the newer drug is just the older one minus some part of its structure, in this case, minus a carbamate group that the liver clips off anyway. Even non-chemists can see the change, looking at the top parts of the structures in those Wikipedia articles.
Now comes Pristiq (desvenlafaxine), spawn of Effexor (you guessed it, venlafaxine). This one's also a simple metabolic change, OH from O-methyl. Wyeth has done very well with Effexor over the last few years, and they’re not ready to give up on that market share once it goes off patent this year. The timing of this new drug is, as they say, no coincidence. The Carlat Psychiatry Blog, not a place to go to find lots of warm feelings for the drug industry, has its “Top Five Reasons to Forget About Pristiq”. From the way things look, I have to agree with them; at the moment it’s hard to see much need for the stuff.
But there’s a good point made there by an investigator on the clinical trials, Dr. Michael Liebowitz of Columbia. He, quite reasonably, is waiting for the market to settle whether the drug is of any use or not: “If it is useful, then it will make money for the company, and if it is not, it won’t.” Update: there's more from Liebowitz on this topic, and on follow-on CNS drugs in general.
Exactly. I’m very much in favor of letting drugs stand or fall on their merits, if any. My first guess is that Pristiq is not much of an addition to the pharmacopeia – and if it isn’t, Wyeth deserves to lose the money they’ve put into it, since that, frankly, would have been the presumption from very early in the drug’s development. They took this drug forward at their own risk, and should profit or lose by it accordingly.
One thing I’ll say for the company, though: they actually seem to be running a head-to-head study between the two drugs. That’s good to see, and it’ll be quite interesting to see what case Wyeth can make, if any, after the data come in. At least they’re not just banging on tin cans and shouting “Now with the great taste of fish!” or something. Interestingly, as a comment on the Carlat blog points out, the company has already published data on one unimpressive trial with Pristiq, and I have to thank them for doing that, too. If there was ever a head-to-head efficacy study run between Claritin and Clarinex, I definitely missed it – I’m willing to be corrected, of course, but I’m pretty sure that there never was one).
So one-and-a-half cheers for Wyeth. I wish, in most cases, that companies would avoid the metabolite-drug idea. Alternatively, I wish that everyone’s drug pipeline was well stocked enough that such follow-ups didn’t look financially appealing. But if you’re going to have them, taking an honest look at their benefits is the only way to go.
1. Daniel Carlat, M.D. on March 19, 2008 8:16 AM writes...
I appreciate your thoughtful post on this issue. A couple of comments:
Permalink to Comment1. Dr. Liebowitz felt I had taken his quote out of context and I published his rebuttal in a subsequent post on my blog.
2. Aside from the head-to-head trial you mentioned, I have seen the abstract of a Pristiq vs. Effexor vs. placebo trial from the 2007 APA meeting. Oddly, the only results reported involved successful and well-tolerated switches of patients from Effexor to Pristiq (the second phase of the study). The fact that the comparative efficacy data were not mentioned leads me to suspect that they were not favorable for Pristiq. OK, so call me a cynic!
2. Gaudisso on March 19, 2008 4:49 PM writes...
By now this maneuver by drug companies seems pretty transparent, but at least desvenlafaxine is a NCE and not some extended release formulation (Ambien CR), repackaged formulation (Soma 250 mg), micronized version (Antara), transdermal formulation (Exelon patch) or combinations (Caduet) of previously established medications. Aside from nanotechnology, novel membrane delivery systems and biologics what other drug delivery technologies can pharmaceutical companies avail themselves of in the future? Hopefully desvenlafaxine is just a small interim step until SNDRIs or triple uptake inhibitors (serotonin, norepinephrine and dopamine) reach the market.
http://www.ingentaconnect.com/content/apl/eid/2007/00000016/00000009/art00006
Permalink to Comment3. Anonymous on March 19, 2008 4:56 PM writes...
By now this maneuver by drug companies seems pretty transparent, but at least desvenlafaxine is a NCE and not some extended release formulation (Ambien CR), repackaged formulation (Soma 250 mg), micronized version (Antara), transdermal formulation (Exelon patch) or combinations (Caduet) of previously established medications. Aside from nanotechnology, novel membrane delivery systems and biologics what other drug delivery technologies can pharmaceutical companies avail themselves of in the future? Hopefully desvenlafaxine is just a small interim step until SNDRIs or triple uptake inhibitors (serotonin, norepinephrine and dopamine) reach the market.
http://www.ingentaconnect.com/content/apl/eid/2007/00000016/00000009/art00006
Permalink to Comment4. David Young on March 19, 2008 5:53 PM writes...
This sort of thing just happened in oncology, if you have noticed.
The FDA just approved LEVOleucovorin as a rescue medicine for those children with osteosarcoma who receive high dose methotrexate as part of their treatment. For years, the racemic mixture known as Leucovorin was given intravenously or orally as rescue medicine. I am unaware of the study results that compelled the FDA to consider the levo isomer as a better rescue medicine. I understand that the dextro version is inactive.
Funny, didn't Lederle do studies on Levoleucovorin back in the late 80's and then abandon further developing the drug?
I hate to ask how much more expensive LEVOleucovorin will be in contrast to plain generic leucovorin, or what will compell us to use it in the kids where plain leucovorin seems to rescue them okay. And will there be a reason for us adult oncologists who use Leucovorin with Fluorouracil for colon cancer? I understand that Spectrum will like an indication for LEVOleucovorin in colon cancer, where there must be at least 10 times the use if not closer to 100 times the use.
And if so, this must be a big blow to Adventrix pharmaceuticals since they are trying to position COFACTOR as a superior drug to Leucovorin.
Permalink to Comment5. Martin Cross on March 19, 2008 9:56 PM writes...
Why is it that patent examiners don't find these metabolites to be obvious?
Permalink to Comment6. James Lawlor on March 19, 2008 11:29 PM writes...
Do you think that these kinds of compounds offer any advantage for patients with liver disfunction who perhaps may not process the original drug as efficiently or who may need to minimize stress on the liver? Or do you think they could perhaps have less risk of hepatic side effects?
Or is this just going to become another patent tactic similar to a racemic switch? (But possibly even less useful?)
Permalink to Comment7. drtapper on March 20, 2008 6:10 AM writes...
Also, don't forget one problem in drug discovery is finding one drug that fits all. If the liver enzyme responsible is polymorphic, giving the metabolite may show some advantage in safety margin and efficacy. Isn't this what happened to Seldane?
Permalink to Comment8. Gaudisso on March 20, 2008 6:15 AM writes...
In defense of pro-drugs (not necessarily "post"-drugs like (desloratadine), some common reasons companies produce pro-drugs is for masking of the amino groups and to improve stability to enhance drug performance and pharmacokinetics.
http://www.mdpi.org/molecules/papers/13030519.pdf
Of course, just because you can create a NCE doesn't necessarily confer improved clinical utility on the product, but it may.
Permalink to Comment9. MTK on March 20, 2008 7:36 AM writes...
Martin C.,
The patents may not be for the compound itself, but perhaps a new formulation. In many instances the drug and the pro-drug are patented at the same time, but the pro-drug may be chosen as the actual API for a number of reasons. Then someone comes up with a new formulation which allows for the drug to be used.
I honestly don't have a problem with any of this as long as there is a real clinical benefit. The problem with many of these, and what Derek is saying, is not that they lack innovation or imagination, but that they lack innovation AND they're no better.
Permalink to Comment10. ed on March 25, 2008 5:35 PM writes...
Active metabolites aren't only useful when the activating enzymes are polymorphic; not everyone has normal liver function. Of course those are about the only reasons and I can't see how even taken together that would justify the R&D expense -- surely the numbers that actually benefit from an active metabolite drug vs. the parent justify orphan drug status instead.
Of course, as one of the 10% of Caucasians who are non-codeine metabolizers, I am grateful for the availability of descodeine in the marketplace, even if it came first in this case.
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