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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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March 19, 2008

Now Your Liver Doesn't Have to Make It For You

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Posted by Derek

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.

Comments (15) + TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | The Central Nervous System | Why Everyone Loves Us


COMMENTS

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:
1. 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!

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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

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3. 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

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4. 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.

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5. Martin Cross on March 19, 2008 9:56 PM writes...

Why is it that patent examiners don't find these metabolites to be obvious?

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6. 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?)

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7. 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?

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8. 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.

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9. 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.

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10. 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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11. Dan on July 23, 2008 11:01 PM writes...

The Potential Fallacies Associated With Me-Too Medications

“But corruption is neither need based nor greed based. It’s simply opportunity based.” -----Billy Tauzin, president and C.E.O. of PhRMA, the pharmaceutical industry’s most powerful lobbying group, as Mr. Tauzin stated in Boston recently.
It has been said by others that the pharmaceutical industry should not have government regulation or interference from our government at all because that would drastically limit if not eliminate innovation as well as our health care choices and options, both from the perspective of the doctor and the patient, so the public has been told often by others. Also what has been stated by this industry that their internal controls prevent wrongdoing? So, according to some, the public’s health would be limited and possibly harmed without the copious innovation of this industry. As with other issues we face as citizens, this is another attempt by these others to apparently install fabricated fear in our minds- void of any proof or reason, and is a fallacy.
As it has turned out, the pharmaceutical industry’s lack of innovation in particular has happened and they have appeared to do this on their own, overall, those innovators and lifesavers.
Over the past several years, those few meds created and FDA approved with true therapeutic advantages happened by discovery with government involvement in over half of these meds with clear clinical advantages for certain patients. Conversely, of the new chemical entities approved lately and developed by drug companies, over 50 percent of these have microscopic therapeutic advantage for patients, so I understand upon information and belief. This inefficient drug development by the pharmaceutical industry has created what is now the dominant development strategy of drug companies, and this strategy is known as the intentional development of what are phrased, ‘me too’ drugs.
These drugs essentially are small molecular variations of the original molecule in a particular class of medications. In other words, they tweak the original molecule in order to obtain patent rights for their now new drug project. This me too objective of drug companies now accounts, I believe, for about 80 percent of the research budgets of drug companies. And because the FDA only requires a potential med to be superior to a placebo in their mandatory clinical trials, usually these me too meds are approved- regardless of their necessity for others, or the need for such drugs.
And me too drugs are selected by the drug company for their potential blockbuster status as well as the speculated growth of a particular market, which means making over 1 billion dollars a year on such a drug, at least. For example, statin drugs, for high cholesterol patients, is a multi- billion dollar market. As a result, there are several statin meds now available for use by doctors to prescribe to their patients. Yet, arguably, me too drugs are all essentially very similar in regards to safety, efficacy, and cost, regardless of the class referred to so often saturated with me too meds, with few exceptions. The differences overall are minor once again with most me too drugs, overall. As aggressive marketers, the makers of these meds are suspected of doing a bit of publication planning, it is suspected, to falsely claim superiority of their newly approved me too drug over all the other drugs in a particular class both during and after the creation of these me too meds. Also, other classes of meds with several me too drugs may include SSRI anti-depressant drugs, as well as those meds for hypertension. There may be a dozen drugs in a particular class of medications that are all essentially the same in regards to their treatment abilities for patients with such disease states that they treat.
Now, there may be cases where a patient tolerates one drug in a class over another for unknown reasons, so in these few cases, some me too drugs occasionally are beneficial for patients for some reason or another, but should absolutely not be a primary objective of the drug companies to create them as often as they do. Instead, true innovation and discovery should be the focus of pharmaceutical companies, and it does not appear to be the focus of the pharmaceutical industry, presently. It appears that, thanks to the Bayh-Dole Act of 1980, they license molecules from those in the academic world, and then proceed with development of another’s creation they claim as their own.
Further vexing is that competition in the pharmaceutical industry amazingly does not and has not been of any financial benefit for the consumer, as competition normally does create. This fact is greatly demonstrated with other industries and is the apex of business operations. This pharmaceutical industry model is an exception, and the reason for this remains an unknown, as far as the etiology of being deprived of this costly environment of drug spending, yet it can be speculated that the me too drug makers claim uniqueness of their me too drug, which is rather deceptive.
This progressive marketing paradigm of the pharmaceutical industry, such as the creation of me too meds solely for their own profit, clearly illustrates their focus on these issues over true research and science, so it seems. Innovation, along with ethics, use to define this pharmaceutical industry. Sadly, it seems this is not the case today, which ultimately and potentially deprives potential treatment methods potentially for the public health if the objectives were focused on their true purpose. Yet hopefully, such historical qualities of drug companies will return some time, in time.
“Most people are other people. Their thoughts are someone else’s opinions, their lives a mimicry, their passions a quotation.” --- Oscar Wilde
Dan Abshear
Author’s note: What has been written was based on information and belief.


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12. James O'Brien, M.D. on October 3, 2008 12:36 PM writes...

The data for Pristiq seems to suggest it is a me-too SNRI for plain vanilla depression, but based on my reading of the literature and Stahl's latest psychpharm book, I can see some advantages for pain/depression syndromes as well as post-menopausal autonomic syndromes over Effexor.

The thing is with Effexor, you have to dose pretty high to liberate NE and DA, and many pain patients are sensitive to side effects anyway. Not so with Pristiq. Then you have the CD6 metabolism issue that Pristiq nicely avoids.

Then the question really becomes how Pristiq compares with Cymbalta for pain syndromes.

I would like to see some good combination studies comparing Pristiq/Lyrica (or Neurontin) vs. Effexor/Lyrica vs. Cymbalta/Lyrica for pain patients who have MMPIs with +70 elevations on scales 1-3. Because after all, if you are going to treat, it is best to combine with an alpha 2 delta ligand if pain is a major component.

We always have to remember, as Stahl points out, the choice of antidepressant is not based upon the DSM symptoms, but for the most part, the associated symptoms.

I am definitely thinking out loud here, and I would welcome comment from Dr. Carlat and others on this.

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13. Chris on February 27, 2009 8:48 PM writes...

If at high doses effexor is an SNDRI, and pristiq's affinity is supposedly higher for all transmitters, then is it possible to use pristiq as an SNDRI?

If so, what dosage would be safe? Hepatoxicity doesn't seem to be too much of an issue if high doses of Effexor were used and pristiq bypasses the first metabolism.

Though efficacy of pristiq at 50mg surpasses that of 100mg dosages and higher, and efficacy is superior to higher doses of effexor, is there a much higher dosage that would make pristiq an SNDRI?

http://www.rcpsych.ac.uk/files/samplechapter/usedrugs5Chap.pdf

looking at table 26.1, it would seem 150mg-250mg dosages might acheive this...does anyone have any long term , high dosage studies on pristiq?

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14. dee on June 21, 2009 7:08 PM writes...

does anyone have a good estimate when SNDRIs will be on the u.s. market? how far along in the development pipline are they? are any in later stage clinical trials yet?

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15. Getheren on September 14, 2013 7:14 PM writes...

I'm not a chemist, but I spent years working in inpatient psych. One huge problem we have had in my field, for many years, is psych meds that depend on first-pass metabolism. Substance abuse is very common among the inpatient psych population, and not surprisingly, so is liver dysfunction.

Meds sometimes take hours to take effect (I have personally seen delays as long as an entire shift) when the patient's liver is so shot to hell that it slowly dribbles out active metabolite, molecule by grudging molecule. This also increases required doses, obviously, because the rate of active metabolite production creeps down toward the rate of active metabolite clearance.

Now, that's one thing if the med in question isn't particularly toxic and is a routine medication given on a specified schedule. In other situations, it's something totally other.

I'm sure that everyone here will understand that it's rather suboptimal if emergency meds given to a patient who is violently acting out take hours rather than minutes to take effect. The delay sometimes forces us to use takedowns and physical restraints, which we would exquisitely prefer not to do because of safety, ethical, and dignity concerns.

Speaking for all inpatient psych workers, we would be *ecstatic* if God (or Derek) gave us active-metabolite psych meds.

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