I Can’t Remember If I Blogged About Alzheimer’s Recently

Posted by Jeff Berk, BOLT International;


This is the time of year where we really can’t understand why they pay the local Phoenix TV weathermen.  I mean, “meteorologists”.  Seriously, though, how hard is it to predict “100 and sunny” in May, “105 and sunny” in June, “110 and sunny” in July and, well hey, can you guess what comes next for August?  Anyway…  Today’s cactus has the brash and bold name: turbinicarpus pseudomacrochele v krainzianus minimus.  The best way to picture just how small it is, full grown, is to look at the grains of gravel.  I kind of like these little fellows.  I’ve stepped on a couple.  Smoosh.


So back to Alzheimer’s disease.  We are just starting up a new panel.  Which BTW, brings me to snidely addressing a question I got from one of the South Asian information outsourcing firms who hits our blog every day.  S/he asks me why we’re always posting old stuff in this blog.  Well, dude/dudette, we share our new stuff with our clients;  our PAYING clients.  You’re welcome to be one of THOSE aaaaanytime you want to be.  So NOW, back to Alzheimer’s.  Here are a couple of thoughts from BOLT’s Alzheimer’s Disease Thought Leader panel on the products in development that they felt had the possibility of offering the most medical benefit in the next few years…



Preferred Product Classes


  • In the 2010 survey, passive immunization scored directionally higher than g-secretase inhibition as the preferred mechanism of choice.  This result is consistent with our 2009 survey.  Note that at the time that the 2010 survey had been conducted, the skin cancer problem with semagacest had not torpedoed that MAb.  As for approval of bapineuzumab, our Panel consensus is that it will get approved with restricted labeling: “removal of plaques in ApoE4 positive patients”.  We expect a lot of off-label use. Follow up g-secretase inhibitors (e.g. BMS-708163) appear to be more selective for APP vs. notch, but we note that there are about 40 substrates for APP, so we expect there to be systemic toxicity with these drugs as well.  Our Panel really likes the “boldness” that BMS showed in recruiting an MCI cohort for the BMS-708163 pivotal Ph-III program.  Most thought leaders feel that trying to remove plaque at the AD stage is too-little-too-late.



  • Active immunotherapy rated higher in 2010 than it did in 2009.  The reasons we attribute to this are a general sense that a vaccine will be affordable for healthcare payers, the titers seen with Novartis’ CAD-106 hint that the strategy might work, and alternative strategies based on tau or b-secretase inhibition, while still very interesting, are turning out to be harder to execute than planned.  not much confidence that the “best” b-secretase inhibitor has been advanced into the clinical pipeline yet.  It has been difficult to find, but the target is well worth pursuing.  As for a favorite vaccine, our Panel had no comment.  There just is no evidence base at this time to suggest that one is more efficacious than another.



  • The choice of active vs. passive immunotherapy will demand compromising on benefits.  An active approach is going to be more affordable, and thus can be incorporated into public health systems without breaking the bank.  Considering that in the US alone there will be  millions of patients on such a therapy, typical costs of biologicals simply won’t fly.  On the other hand, a passive approach is going to be more reversible, and thus will provide an added measure of safety.  The split response of our Panel reflects the difficulty that they had in balancing these benefits and drawbacks.



  • The 2nd tier of products were tau and BACE inhibitors, and neuroprotectants/nerve growth.  There are no credible BACE inhibitors in the clinic.  Lilly is reportedly close to having a clinical candidate.   Tau inhibition is also a great concept, but once again there is a dearth of good clinical candidates.  A dark horse tau inhibitor is Ariad’s mTOR inhibitor ridaforolimus.  In terms of neuroprotectant / nerve growth strategies, two may be relevant.  SIRT-1 (GlaxoSmithKline) agonists are in late stage trials for metabolic disorders, but none of the compounds adequately cross the blood brain barrier.  Then, Ceregene’s gene therapy to deliver nerve growth factor is in early trials.



  • Abeta aggregation inhibitors, metal chelators and angiotensin II receptor blockers (ARBs) each had minor support on our survey.  We were surprised by how little interest our Panel had in drugs that were primarily going to deliver symptomatic benefit without altering the underlying disease.



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