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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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December 4, 2012

Merck Presses Ahead on Alzheimer's:

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Posted by Derek

One Alzheimer's compound recently died off in the clinic - Bristol-Myers Squibb's avagacestat, a gamma-secretase inhibitor, has been pulled from trials. The compound "did not establish a profile that supported advancement" to Phase III, says the company. Gamma-secretase has been a troubled area for some time, highlighted by the complete failure of Lilly's semagacestat. I wondered, when that one cratered, what they were thinking at BMS, and now we know.

But Merck is getting all the attention in Alzheimer's today. They've announced that their beta-secretase inhibitor, MK-8931, is moving into Phase III, and the headlines are. . .well, they're mostly just not realistic. "Hope for Alzheimer's", "Merck Becomes Bigger Alzheimer's Player", and so on. My two (least) favorites are "Merck Races to Beat Lilly Debut" and "Effective Alzheimer's Drug May Be Just Three Years Away." Let me throw the bucket of cold water here: that first headline is extremely unlikely, and the second one is insane.

As I've said here several times, I don't think that there's going to be any big Lilly debut into Alzheimer's therapy with their lead antibody candidate, solanezumab. (And if there is, we might regret it). The company does have a beta-secretase (BACE) inhibitor, but that's not what these folks are talking about. And looking at Merck's compound, you really have to wonder if there's ever going to be one there, either. I like Fierce Biotech's headline a lot better: "Merck Ignores Red Flags and Throws Dice on PhII/III Alzheimer's Gamble". That, unfortunately, is a more realistic appraisal.

It's interesting, though, that Merck is testing this approach in a patient population that includes patients with moderate cases. After solanezumab and bapineuzumab appears to have hit that target without any clear signal that they had improved symptoms for patients with more fully developed cases, there has been a growing move to shift R&D into earlier-stage patients, whose brains have not already been seriously damaged by the disease. Merck is likely to face growing skepticism that it can succeed with the amyloid hypothesis when tackling the same population that hasn't delivered positive data.

And BACE has been a rough place to work in over the years. The literature is littered with oddities, since finding a potent compound that will also be selective and get into the brain has been extremely difficult. I actually applaud Merck for having the nerve to try this, but it really is a big roll of the dice, and there's no use pretending otherwise. I wish that the headlines would get that across, as part of a campaign for a more realistic idea of what drug discovery is actually like.

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. anchor on December 4, 2012 1:46 PM writes...

Derck: ...it's like running a marathon. You know you are not going to win, but still want to complete! We are talking about pride! Otherwise appropriate headline @ fierce biotech.

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2. G2 on December 4, 2012 2:20 PM writes...

Is the structure of MK-8931 already disclosed?

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3. bank on December 4, 2012 2:30 PM writes...

Two points. First, does anyone have an idea when the trial results will be announced, so we can short MRK and make money without being done for insider trading?

Second point, the inclusion of patients with mild cognitive impairment is sensible from the point of view of preventing severe Alzheimer's, however that population doesn't always go on to develop the full-blown disease: "About 16% of subjects diagnosed with MCI reverted back to normal or near-normal cognition approximately 1 year later."[1] So having a few "successes" in that category is to be expected by chance alone.

[1] Reversion from mild cognitive impairment to normal or near-normal cognition: Risk factors and prognosis.
Koepsell TD, Monsell SE.
Neurology. 2012 Oct 9;79(15):1591-8. PMID:23019264

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4. Lyle Langley on December 4, 2012 3:52 PM writes...

To the best of my knowledge, the structure of MK-8931 has not been disclosed. At the Spring ACS meeting last year (San Diego) there was a symposium on AD and the structure was hand written on a slide from someone not within Merck. I couldn't see the structure well and I forgot who's presentation had it. The preliminary data is quite impressive...for what it's worth...and in this area, probably not much.

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5. Anonymous on December 4, 2012 3:57 PM writes...

stem cell therapy should be seriously considered and accelerated for AD and other degenerative diseases

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6. Jumbo on December 4, 2012 7:02 PM writes...

Yes, BACE has presented a lot of challenges. Combining potency, selectivity, bioavailability has made it take a lot longer to get to the clinic than many envisioned 10 yr ago. But I take issue with the judgement that failure with Abeta clearing mAbs makes the choice of moderate AD patients unwise. In an initial efficacy trial, why wouldn't you try in those patients? I realize the bar is higher, but since when do clinical failures (testing other MoAs) persuade one to be so much more cautious in studies? Nothing ventured, nothing gained, I say. Not that I am predicting this mechanism will be the hoped-for breakthrough.

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7. Squib on December 4, 2012 9:43 PM writes...

@6, I completely agree. As long as you explicitly state at the beginning of the study that you will isolate the groups for separate statistical analysis if efficacy is only shown in one group, what is there to lose?

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8. Anonymous on December 5, 2012 3:59 AM writes...

#3 - There are many causes of MCI, not just Alzheimer's. However, with biomarker measures (CSF, PET, MRI) you can detect MCI patients in whom Alzheimer's is the root cause. These are the patients enrolled in MCI due to Alzheimer's studies and these patients do not revert back to normal cognition.

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9. Matt on December 5, 2012 7:06 AM writes...

I agree with #6 Jumbo and #7 Squib.

I think it is invalid to assume we've done this experiment before, when this drug has an utterly different method of action from the antibody approach. Comparison with other BACE trials is relevant, but as Jumbo points out, meeting potency / selectivity / bioavailability has been tough, so it's possible candidates have made very different trade-offs.

I am not convinced about having to find early-stage AD patients. For the antibody approach (eg bapineuzumab), the logic goes like this: "it hasn't produced clinical benefit in any population we studied, so it must then work in this other population we didn't study." It does not seem likely to me, if solanezumab failed to arrest the progress of AD at moderate stage, it would somehow work to arrest the progress at an early stage. It's possible, if pre-AD MCI reaches a threshold where a completely different mechanism kicks in (tau disorder, for example), but less likely.

I think it reasonable to expect successful AD drugs will produce clinical results for early, moderate, and possibly even late-stage AD. Not reversing the course of the disease, but dramatically slowing its progression. Tau and inflammation being the wildcards on how much the progression can be slowed.

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10. newnickname on December 5, 2012 8:47 AM writes...

Drug discovery, in general, is dominated by so-called "thought leaders" and I think the targeting of gamma-secretase was one on the ideas embraced and promoted by some important Boston based thought leaders. If you questioned the theory or suggested alternative targets, you were pretty much unfundable (and unemployable!).

I can't think of the driving force (thought leaders) behind beta-secretase. I'll have to look it up later unless followers here can help me out. Thank you.

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11. petros on December 5, 2012 10:12 AM writes...

Interesting gamble by Merck. Is this the last throw of the "great" SGP pipeline that was talked up when SGP "acquired" Merck?

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12. cdsouthan on December 5, 2012 12:53 PM writes...

The complete silence from CoMentis on CTS-21166 (also a blinded structure mapping) suggest this fell by the wayside at PI, but it would be important for the BACE1 inhibitor field and Merck to know why

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13. bank on December 5, 2012 2:53 PM writes...

@newnickname

The theory behind beta-secretase (BACE) is similar to that behind gamma-secretase, in that inhibiting BACE will result in less Abeta being produced, and less Abeta would mean less Alzheimer's.

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14. Matt on December 5, 2012 6:30 PM writes...

@newnickname:

See this blog entry

where a natural mutation that inhibits the BACE1 clipping of APP was associated with lower rates of AD, and indeed even stronger cognitive scores than the healthy geriatric population.

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15. newnickname on December 6, 2012 1:22 PM writes...

@13 and 14: Thank you. Dennis Selkoe (Harvard) definitely led the band and beat the drum for gamma-secretase. He also leads the beta brigade or is there someone else?

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16. Lane Simonian on December 9, 2012 10:29 PM writes...

Researchers and pharmaceutical companies are getting confused because two pathways intersect. Phospholipase C activity leads to the release of BACE and to y-secretase activity which leads to the formation of amyloid plaques (phospholipase C activity also leads to the release of acetylcholinesterases). The pathway that leads to Alzheimer's disease is phospholipase C--protein kinase C--MAPK (p38 and perhaps JNK)-- tumor necrosis alpha--NFkB translocation (inducible nitric oxide) and NADPH oxidase activation (superoxide anions). Inucible nitric oxide combines with superoxide anions to form peroxynitrites which oxidize critical receptors in the brain including those involved in short-term memory (muscarinic acetylcholine), mood (serotonin and opiod), sleep (melatonin), alertness (dopamine), smell (oflactory), and brain growth (adrenergic). Peroxynitrites also nitrate NMDA receptors leading to the influx of calcium and efflux of glutamate which kill brain cells.

Amyloid plaques increase the formation of peroxynitrites, but peroxynitrites sustain their own formation through the oxidation of MAP kinase(s). You can slightly slow down early the formation of peroxynitrites and thus slightly slow down Alzheimer's disease by removing amyloid plaques or by inhibiting the enzymes that result in the formation of amyloid plaques, but you can only delay the onset of the disease and its early progression by inhibiting phospholipase C and you can only partially reverse Alzheimer's by scavenging peroxynitrites and by repairing part of their damage.

One observer on other sites has suggested that the compound being developed by Merck is similar to curcumin. If this is true, it makes perfect sense as curcumin inhibits phospholipase C gamma, the translocation of NFkB, and the activation of NADPH oxidase. Curcumin also scavenges peroxynitrites and repairs part of their damage. The international site for MERCK (MERCK Millipore) lists several peroxynitrite scavengers developed by the company and several diseases linked to peroxynitrites (but not Alzheimer's disease). The danger for MERCK, however, in developing peroxynitrite scavengers to treat Alzheimer's disease is that one of its drugs Fosamax is likely involved in the formation of peroxynitrites. Fosamax inhibits the same pathway (phosphatidylinositol-3/AKT kinase) as three genes tied to Alzheimer's disease: TREM2 deficiencies, presenilin gene mutations, and the APOE4 gene. Moreover, peroxynitrites not only kill cells involved in taking minerals out of bones (osteoclasts), they also kill cells involved in bone formation (osteoblasts), heart cells and brain cells. Indeed, all the negative side effects of Fosamax are tied to peroxynitrite formation: irregular femur breaks, jaw osteonecrosis, atrial fibrilation, esophagitis, esophogeal cancer, and perhaps most ironic of all Alzeimer's disease. So if Merck truly is developing a peroxynitrite scavenger to treat Alzheimer's disease, it has to be mindful of its potential contribution to the disease via Fosamax.

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17. Lane Simonian on December 12, 2012 3:21 PM writes...

An important correction: Merck and Merck Millipore are different companies.

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