Ketan Desai

Myriad Options on Alzheimers Disease

You make good points User19367. I note that you are not too optimistic on Flurizan, but are on the company, sentiments I share. Where we differ if whether the street is pricing in failure or success for Flurizan. If the trial is positive, and the stock pops up $10, I will still be able to cover my shorts and come out ahead. If they break the company up, I will certainly buy the diagnostic business.

Myriad Options on Alzheimers Disease

To Ksaales:

There are so many holes in your repertoire, I don't know where to start.

1. When you provide data, provide the primary data. The link you provided DOES NOT show Flurizan has no effect on Cox.

2. As your ref states, RF is converted to SF in the human body - even if to a small extent. And SF is a Cox inhibitor.

3. You make the common mistake in assuming that the only mode of action of NSAIDS is Cox inhibition. Not so. For example, read Immunology Today, Volume 19, Issue 4, 1 April 1998, Pages 169-172
Inhibition of leukocyte adhesion: an alternative mechanism of action for anti-inflammatory drugs. And from your own article:

Inhibition of the two isoforms of cyclooxygenase (COX1 and COX2) is the primary (but not only) pharmacological action of NSAIDs that results in their anti-inflammatory properties (38). Some NSAIDs activate the peroxisome proliferator γ nuclear transcription factor; this activation may have anti-inflammatory consequences relevant to AD (39, 40).

So, your whole contention of no Cox means no anti-inflammatory activity holds no water. SHOW ME A REPORT THAT DEMONSTRATES THAT FLURIZAN HAS NO ANTI-INFLAMMATORY ACTIVITY IN ALL INFLAMMATORY MODELS, NOT JUST COX.

4. Even the article you cite says: Our recent finding that ibuprofen, indomethacin, and sulindac lowered Aβ42 production independently of their effects on COX suggests that this property could contribute to their apparent protective efficacy in AD (15). See my previous comment on Ibuprofen, which did not show efficacy in a clinical study. So, Ibuprofen lowered Aβ42 production, but did not show efficacy in clinical trials. And you expect different results from Flurizan?

5. From your own citation: R-flurbiprofen is also reported to inhibit NF-κB. Inhibition of NF-κB has been postulated to reduce the inflammatory response in AD (45). AND YOU SAY FLURIZAN HAS NO ANTI-INFLAMMATORY ACTIVITY? DO YOU KNOW ANYTHING ABOUT INFLAMMATION?

6. The data will be out soon - we will see who is right.

Goodbye.

Myriad Options on Alzheimers Disease

To Ksaales:

So Flurizan does not claim to have any anti-inflammatory properties? Do a google search on Flubiprofen, which is what Flurizan is. To use your own language, ignoring facts........

www.pharmacology2000.c...

Myriad Options on Alzheimers Disease

To Ksaales:

Gamma secretase is not the only MOA of NSAIDS in AD (see below from an article published in NEJM). That is why I stand by my statement that "this study gives hints on the possible outcome".

The neuropathologic features of Alzheimer's disease include the accumulation of microglia around plaques, a local cytokine-mediated acute-phase response, and activation of the complement cascade (1,2). This inflammatory response may damage neurons and exacerbate the pathologic processes underlying the disease (3). Nonsteroidal antiinflammatory drugs (NSAIDs) may influence this inflammatory response by inhibiting cyclooxygenase-1 and cyclooxygenase-2 and by activating the peroxisome proliferator (PPAR) nuclear transcription factor (4,5,6). In addition, cyclooxygenase-mediate... oxidation is important in the calcium-dependent glutamate-signaling pathway that involves N-methyl-D-aspartate. In this way, NSAIDs may be able to protect neurons directly by reducing cellular responses to glutamate (7).

1. Aisen PS. Inflammation and Alzheimer's disease: mechanisms and therapeutic strategies. Gerontology 1997;43:143-149.
2. Aisen PS. Inflammation and Alzheimer disease. Mol Chem Neuropathol 1996;28:83-88.
3. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195-218.
4. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997;272:3406-3410.
5. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391:79-82.
6. Leveugle B, Fillit H. Proteoglycans and the acute-phase response in Alzheimer's disease brain. Mol Neurobiol 1994;9:25-32.
7. Breitner JC. Inflammatory processes and antiinflammatory drugs in Alzheimer's disease: a current appraisal. Neurobiol Aging 1996;17:789-794.

Myriad Options on Alzheimers Disease

To Mudphud (I guess that is an acronym for MD PhD):

Your point about naproxen and celecoxib and their ineffectiveness in mouse models is true. However, as you point out in the part of the article that you pasted, ibuprofen does lower Aβ42. But ibuprofen, as cited by the authors of the ADAPT study, was not effective in a trial (Goodwin JS, Regan M. Cognitive dysfunction associated with naproxen and ibuprofen in the elderly. Arthritis Rheum. 1982;25(8):1013-1015).

Other studies have also shown ineffectiveness of NSAIDS (Karplus TM, Saag KG. Nonsteroidal anti-inflammatory drugs and cognitive function: do they have a beneficial or deleterious effect? Drug Saf. 1998;19(6):427-433).

To be fair, I must also point out that some studies have shown a beneficial effect (Rozzini R, Ferrucci L, Losonczy K; et al. Protective effect of chronic NSAID use on cognitive decline in older persons. J Am Geriatr Soc. 1996;44(9):1025-1029.)

However - from a commercial point of view, and therefore from a stock point of view, two things remain:

1. What is the effect of Flurizan? The phase II data was less than stellar, and I make it very clear in my article that the ADAPT study is not identical but gives hints.
2. If other anti-inflammatories have the same effect as Flurizan, why would anyone take Flurizan when cheap generics would have the same effect?

So that other readers can make their own minds, I'm pasting a link to the cited article:

archneur.ama-assn.org/...

Esperion Spin-Off: Does It Signal the Start of a New R&D Era?

Good analysis. I would go further and say that Big Pharma may change so that each company becomes a holding company. Each therapeutic area could be spun off into a separate company. There are plusses and minuses to this. The advantage is that an individual therapeutic area does not feel it is being held down by another, or is getting a step-motherly treatment. The disadvantages are that cross-functional learning and applications will be lost, as will flexibility in terms of human resources, scale, etc.