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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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July 11, 2013

The Last PPAR Compound?

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Posted by Derek

Roche has announced that they're halting trials of aleglitazar, a long-running investigational drug in their diabetes portfolio. I'm noting this because I think that this might be the absolute last of the PPAR ligands to fail in the clinic. And boy howdy, has it been a long list. Merck, Lilly, Kyorin, Bristol-Myers Squibb, Novo Nordisk, GlaxoSmithKline, and Bayer are just the companies I know right off the top of my head that have had clinical failures in this area, and I'm sure that there are plenty more. Some of those companies (GSK, for sure) have had multiple clinical candidates go down, so the damage is even worse than it appears.

That why I nominated this class in the Clinical Futility Awards earlier this summer. Three PPAR compounds actually made it to market, but the record has not been happy there, either. Troglitazone was pulled early, Avandia (rosiglitazone) has (after a strong start) been famously troubled, and Actos (pioglitazone) has its problems, too.

The thing is, no one knows about all this, unless they follow biomedical research in some detail. Uncounted billions have been washed through the grates; years and years of work involving thousands of people has come to nothing. The opportunity costs, in retrospect, are staggering. So much time, effort, and money could have been spent on something else, but there was no way to know that without spending it all. There never really is.

I return to this theme around here every so often, because I think it's an important one. The general public hears about the drugs that we get approved, because we make a big deal out of them. But the failures, for the most part, are no louder than the leaves falling from the trees. They pass unnoticed. Most people never knew about them at all, and the people who did know would rather move on to something else. But if you don't realize how many of these failures there are, and how much they cost, you can get a completely mistaken view of drug discovery. Sure, look at the fruit on the branches, on those rare occasions when some appears. But spare a glance at that expensive layer of leaves on the ground.

Comments (31) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Drug Development


COMMENTS

1. Gaspode on July 11, 2013 7:27 AM writes...

Not the last. As far as I know KD3010 and MBX-8025 are still in the game, but little is known about them other than being delta Agonists like GW501516.

Permalink to Comment

2. lcollia on July 11, 2013 7:57 AM writes...

Clearly we have to know about these failures in order to have a better view/opinion of the DD wolrd.
But, how to have a clear view of the compounds in the clinical and to have a clear view of the failed compounds?

Permalink to Comment

3. Chemjobber on July 11, 2013 8:14 AM writes...

So at what point did it become clear (like it sort of is now) that PPAR ligands don't do well in the clinic? And why did folks (Roche?) still charge ahead?

Permalink to Comment

4. exGlaxoid on July 11, 2013 8:28 AM writes...

Don't forget the PPAR alpha compounds that made it to market as well: clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate.

The sad part is that once we better understand what these drugs do and their pathways, we may find that buried among the dead PPAR compounds are some very useful pieces of information that might lead to better treatments in the future.

I worked on these compounds for several years, and while they did not pan out so far, the work was done well, and much of it published, so at least there is something in the knowledge base to show for it. I have seen other programs that went for years which have never seen the light of day, and will likely be repeated elsewhere for naught.

But for futility, I would also point to HDL raising drugs and oral/inhaled insulin mimics. Scientists have tried to make an oral insulin for 50+ years with little sucsess as of yet (at least that I am aware of.)

Permalink to Comment

5. exGlaxoid on July 11, 2013 9:20 AM writes...

Don't forget the PPAR alpha compounds that made it to market as well: clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate.

The sad part is that once we better understand what these drugs do and their pathways, we may find that buried among the dead PPAR compounds are some very useful pieces of information that might lead to better treatments in the future.

I worked on these compounds for several years, and while they did not pan out so far, the work was done well, and much of it published, so at least there is something in the knowledge base to show for it. I have seen other programs that went for years which have never seen the light of day, and will likely be repeated elsewhere for naught.

But for futility, I would also point to HDL raising drugs and oral/inhaled insulin mimics. Scientists have tried to make an oral insulin for 50+ years with little success as of yet (at least that I am aware of.)

Permalink to Comment

6. Boghog on July 11, 2013 9:24 AM writes...

There may be one last hope for PPAR-gamma targeted drugs:

PPAR-gamma ligands that selectively block Cdk5-mediated phosphorylation (PMID: 21892191)

But with all the failures, it is hard to see this approach gaining much traction, even with the novel MoA.

Permalink to Comment

7. petros on July 11, 2013 9:25 AM writes...

Having watched the trials and tribulations of this class, especially the PPAR gamma and dual agonists, I had been surprised that Roche kept plugging away with aleglitazar. The FDA's additional toxicology requirements for this class of drugs was sufficient to kill off a number of development compounds

Permalink to Comment

8. petros on July 11, 2013 9:58 AM writes...

Re Gaspode's comment

Kalypsys KD3010 looks long gone, the company's website is a single page only referring to one drug in development for allergic rhinitis.

MBX-8025, discarded by J&J, looks to be the last survivor from 20 compounds in development in 2010!

Permalink to Comment

9. barry on July 12, 2013 2:59 PM writes...

"...but there was no way to know that without spending it all" may not be strictly correct. there's a lot of Big Pharma activity justified just because the competitor is working on it, rather than because the biological rationale is sound.
Once it was determined that the toxicity is mechanism based, the target should have been scratched. As you say, the opportunity cost runs into the billions. So show that the tox. is the same with two (potent, selective) cmpds of different structural series, and that the tox. is gone with inactive cmpds. in these lead series, then kill the target. We can do that for mere $millions, not $billions.

Permalink to Comment

10. watcher on July 12, 2013 3:16 PM writes...

#4: Yes,, but one needs to acknowledge that these older drugs were all weaker on the targets while the most recent generation of compunds were at least 100 to 1000 fold more potent. Also, because of the greater potency, these newer ones tended to have cross reactivity with multiple PPARs. In my organization, folks would advertise that they had a potent selective molecule at 1nM or even more potent, and say they had 10 to 100 fold selectivity. Yet, in all their deceitful glory they neglected to remind many in the organization who did not know the details that such lower levels of potency would, itself, likely have demonstrable activity at typical in vivo concentrations. Basic biochemical principles at work!

Permalink to Comment

11. Boghog on July 12, 2013 3:42 PM writes...

@Barry and watcher:

Many of the more recent attempts were "balanced" or "pan" PPAR agonists that by design activated two or more PPAR subtypes. Even if a several structurally diverse subtype selective PPAR agonists display toxicity implying mechanism based toxicity, a "balanced" ligand in theory could escape that toxicity (think COX inhibitors).

Permalink to Comment

12. kristall36 on July 12, 2013 7:12 PM writes...

INT131 (InteKrin) is a partial modulator of PPARg, and seems alive.

Permalink to Comment

13. kristall36 on July 12, 2013 7:13 PM writes...

INT131 (InteKrin) is a partial modulator of PPARg, and seems alive.

Permalink to Comment

14. watcher on July 13, 2013 9:19 PM writes...

to 11: I don't understand your point---they still didn't avoid toxicity.

Permalink to Comment

15. Boghog on July 14, 2013 7:55 AM writes...

to 14: In the case of PPAR agonists, mechanism based toxicity by definition means toxicity resulting from changes in the expression of PPAR regulated genes. Furthermore the different PPAR subtypes regulate a partially overlapping set of genes. Regulation of some of the PPAR-gamma genes apparently cause toxicity by perturbing metabolism in such a way that is toxic to the liver. In theory regulation of other genes by another PPAR subtype might counter act that toxicity. Hence the right balance of activation of the three PPAR subtypes could in theory be therapeutic while avoiding the toxicity (analogous to non-selective COX inhibitors which are cardio-protective vs. selective COX2 inhibitors which have adverse cardiovascular effects). In practice finding the right balance between the three PPAR subtypes may be very difficult or impossible to achieve.

A more promising approach, as I already mentioned in 6 above, are PPAR-gamma ligands that selectively block Cdk5-mediated phosphorylation (PMID: 21892191) while having no effect on PPAR-gamma regulation gene expression. These types of ligands should be completely free of the mechanism based liver toxicity mentioned above.

Permalink to Comment

16. observer on July 14, 2013 9:49 AM writes...

Aileron was founded on counterintuitive observations that polar molecules like peptides would just waltz through the hydrophobic/hydrophilic cell membrane if one would just add a hydrophobic staple (many examples of hydrophilic stapling by side chain lactams had been published over years) to them. Verdine stated something like "now all intracellular targets can be addressed."

The Phase one molecule has nothing to do with this, of course. It seems to be just a carbon version of the by now common lactam analog of a class B GPCR ligand, in this case growth hormone- releasing hormone (corrected). Thus extracellular GPCR binding site. No one seems to go below the hype to state that this is in no way a validation of the founding technology re intracellular targets. Good practical idea to save something, but of little apparent novelty or value to science.

Permalink to Comment

17. watcher on July 14, 2013 5:43 PM writes...

15: still to be shown viable with enough of a safety window to allow human use. A big hurdle. I would not put money into a biotech doing this work as it's almost certain to be going down into a black hole.

Permalink to Comment

18. Singh. on July 15, 2013 1:20 AM writes...

Indian authorities very recently approved a dual Dual PPAR compound called Saroglitazar by Zydus. It is indicated for diabetic dyslipidemia. Do check the website - http://lipaglyn.com/

Permalink to Comment

19. Boghog on July 15, 2013 1:23 AM writes...

17: I would agree that the "balanced" approach is highly risky since (1) the details of what is causing this mechanism based toxicity have not been worked out and (2) there is no guarantee, only blind hope, that there are other PPAR regulated mechanisms that might counteract that toxicity.

The second approach, selective blockade of Cdk5-mediated phosphorylation, is much more promising. This type of selective receptor modulation should have a very large safety window. The ligand binds to PPAR-gamma blocking phosphorylation but not trigger increased in PPAR-gamma regulated gene expression. This selectivity is a concentration independent. No matter how high the concentration of the drug used, there will be no increase PPAR-gamma regulated gene expression.

The main worry would be potential spill over effects on PPAR-alpha and -delta. However high binding selectivity between the PPAR subtypes is fairly easy to achieve.

Finally I don't understand your comment in #10: "Also, because of the greater potency, these newer ones tended to have cross reactivity with multiple PPARs." The more potent a ligand is, the more selective it tends to be. One of course would need to lower the dose of a potent, selective ligand to achieve in vivo selectivity. Or am I missing something?

Permalink to Comment

20. watcher on July 15, 2013 7:32 AM writes...

Boghog: yes you are missing something. Yes the dsoe can typically be lowered, but usually the systemic eposure levels are still high enough for the drug to have some binding to the other receptors, which can cause some of their pharmacology and side effects if any. If the potency is only 5 to 10 uM then, at typicaly in vivo exposure levels, any cross talk is less likely to manfest into severe pharmacology. You have to have seen exposures and pharmacokinetics of many compounds to appreciate the issue.

Permalink to Comment

21. Boghog on July 15, 2013 3:06 PM writes...

watcher: I do appreciate the possibility of Cmax driven side effects, especially with agonists of nuclear receptors. Relatively short exposure times can saturate these receptors, the off rates are on the order of several hours, and the effects of short exposure of NR ligands can last for days (hit and run mechanism). In these cases, a sustained release formation that reduces Cmax might help. However I am still am having trouble understanding how a less potent ligand would necessarily improve the safety window. Sure the off target side effects would be less, but wouldn't the in vivo efficacy also be less?

In direct response to 14: "I don't understand your point---they still didn't avoid toxicity."

The original question is why did drug companies continue to invest in PPAR drug candidates after mechanism based toxicity was established. My point was that mechanism based toxicity was first demonstrated in selective PPAR agonists. For a time it was thought that dual or balanced agonists might provide a better safety profile. It was only later that mechanism based toxicity was also demonstrated in the dual agonists.

Permalink to Comment

22. barry on July 16, 2013 8:36 AM writes...

re BogHog:
But Cdk-5 inhibition has toxicological consequences of its own. Your dual inhibitor is letting the tiger into the kitchen to chase out the dog. The whole PPAR-gamma project needed to be killed, not patched, billions of dollars ago.

Permalink to Comment

23. Boghog on July 16, 2013 10:46 AM writes...

re: Barry

However the Cdk-5 inhibition would be exquisitely selective. The PPAR-gamma ligand would not directly inhibit Cdk-5, only prevent Cdk-5 from phosphorylating one of its substrates, PPAR-gamma. Hence the PPAR ligand it would not interfere with phosphorylation of any other Cdk-5 substrate. Therefore this ligand should be free of toxicity due to Cdk-5 inhibition.

I am not defending the dual agonist idea, just providing one explanation that contributed to prolonging of some of these projects.

Permalink to Comment

24. Xero on July 16, 2013 12:33 PM writes...

Is Lipaglyn of the India pharma co. has some potential? Since its been launched just a month ago I dont see any news abt its use in clinic so far. If its approved worldwide then the picture will be clear related to its 'safety' and 'efficacy'.

Permalink to Comment

25. watcher on July 16, 2013 8:16 PM writes...

Boghog, you are full of hypotheses and proposals. No results. I know what I've seen with "selective", dual and pan PPARs. All were toxic in their own ways. You need to produce some results. I'm done here.

Permalink to Comment

26. Boghog on July 16, 2013 11:09 PM writes...

watcher:

It is pretty clear that the classical PPAR agonists are dead and I am not defending that approach, just providing one explanation that lead to the continuation of some of these projects. One type of ligand that you have probably not looked at are non-agonist PPAR-gamma ligands that block Cdk5-mediated phosphorylation. The results are reported in:

Nature, 2011, 4;477(7365):477-81, Antidiabetic actions of a non-agonist PPAR-gamma ligand blocking Cdk5-mediated phosphorylation (PMID: 21892191).

Also see:
Nat Rev Drug Discov. 2011 10(11):814, Diabetes: Safer PPAR-gamma-targeted drugs on the horizon? (PMID: 21997749)
Nat Rev Endocrinol. 2011 7(11):630, Diabetes: T2DM-PPAR-gamma ligands without the adverse effects? (PMID: 21946892)

Permalink to Comment

27. novice on July 17, 2013 11:42 AM writes...

Being a complete novice to this field of drug discovery and clinical trials I had a few questions and would appreciate any response:

The way I have seen things go with Sirt1 activators (GSK/Sirtris) and now with the PPAR alpha activators (which coincidentally are known to interact with each other significantly) there seems to be a lot of issues with targets which seem to be important in a number of metabolically important tissues.

1. Is choosing a target which is generally important in all tissues an issue? Or is it an issue with the small molecule that is developed for/against the target?

2. In clinical trials, are the toxicity parameters more stringent now than they were a few years ago? I mean are the outcomes more critically reviewed... eg. maybe an enzyme level increase of two fold was acceptable earlier is considered to be abnormal and unacceptable now? And this is the reason why we see so many withdrawals?

3. Are the Sirt1 activators and PPAR activators doomed?

I understand question no.3 is what everyone has been talking of, but I would still like to get more input...

Permalink to Comment

28. novice on July 17, 2013 11:43 AM writes...

Being a complete novice to this field of drug discovery and clinical trials I had a few questions and would appreciate any response:

The way I have seen things go with Sirt1 activators (GSK/Sirtris) and now with the PPAR alpha activators (which coincidentally are known to interact with each other significantly) there seems to be a lot of issues with targets which seem to be important in a number of metabolically important tissues.

1. Is choosing a target which is generally important in all tissues an issue? Or is it an issue with the small molecule that is developed for/against the target?

2. In clinical trials, are the toxicity parameters more stringent now than they were a few years ago? I mean are the outcomes more critically reviewed... eg. maybe an enzyme level increase of two fold was acceptable earlier is considered to be abnormal and unacceptable now? And this is the reason why we see so many withdrawals?

3. Are the Sirt1 activators and PPAR activators doomed?

I understand question no.3 is what everyone has been talking of, but I would still like to get more input...

Permalink to Comment

29. Boghog on July 17, 2013 3:39 PM writes...

At the risk of over staying my welcome, I will take a shot at @27/28:

Chronologically, the PPAR alpha activators came way before the Sirt1 activators.

#1: It depends on what you are trying to do. If you are trying to minimize the chances of side effects, a target with restricted tissue distribution could be a huge advantage. If you are trying to treat a systemic disease that affects many organs, a target with wide tissue distribution could be essential in achieving efficacy.

#2: All parameters are more stringent than they used to be. However lack of efficacy has proven to be more of a issue than toxicity.

#3: Jury is still out on Sirt1 activators, but the available evidence is not good. Classical PPAR agonists are dead.

Permalink to Comment

30. Boghog on July 18, 2013 3:47 PM writes...

Just to clarify the above post, the problems with PPAR agonists and Sirt1 activators are qualitatively different. PPAR agonists are efficacious but have toxicity concerns. Sirt1 activators appear to be safe, but there are doubts that they are efficacious.

Permalink to Comment

31. GrthzGd on January 23, 2014 1:27 PM writes...

Any thoughts on GFT505? The Lille/Cambridge MA drug company Genfin started a Phase 11b trial on the drug, with 150 subjects (half on placebo) last November.

Permalink to Comment

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