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San Diego: Merck Reports BACE Inhibition in Primates

Series - Society for Neuroscience Annual Meeting 2007:

The 37th annual conference of the Society for Neuroscience offered morsels of news on β-secretase-1 (BACE1), the enzyme that carries hope for a next generation of little white pills to treat Alzheimer disease. The effort to exploit Robert Vassar and Martin Citron’s discovery 8 years ago (Vassar et al., 1999) of this APP scissor for drug development has hit technical snags over the years. Even so, the general sense is that by now, a handful of pharmaceutical and biotech companies have compounds that are currently being optimized and at least a couple—one by CoMentis and possibly one by Takeda—have entered initial human tests. Whatever clinical data exist are unpublished, but in the meantime, read our brief summary of two preclinical developments reported last month in San Diego.

Adam Simon of Merck in West Point, Pennsylvania, presented a poster on his company’s study of a new, still-unnamed aminopyridine-oxadiazole inhibitor. First author Sethu Sankaranarayanan and colleagues tested its ability to lower Aβ40 and 42 in body fluids by infusing it intravenously into a so-called “cisterna magna-ported” rhesus monkey model (previously described in an ARF related news story). In this model, an in-dwelling catheter in the monkey’s cisterna magna at the base of the neck enables scientists to take repeated small samples of cerebrospinal fluid (CSF) to assess in real time how a drug affects a given set of readouts. Using six monkeys, the scientists infused two different doses of the BACE inhibitor for 4 hours, and for each experiment took samples before, during, and after the infusion. They measured a dose- and time-dependent reduction of up to 40 percent of Aβ40 and 42 in CSF, as well as a 60 percent reduction of Aβ40 in plasma. (When asked about plasma Aβ42, Simon said that it has been seen to change before, but the assay data do not meet the group’s technical standards so they don’t show them.) This is significant because one difficulty with developing BACE inhibitors had been that the relationship between inactivating the enzyme and the resulting drop of Aβ is not linear; for example, genetic halving of BACE in heterozygous knockout mice achieved only a modest reduction of Aβ concentration.

In the Merck study, CSF levels of the BACE1 cleavage product sAPPβ decreased by 10 percent. Theoretically, a reduction in BACE1 activity would leave APP available to sheddases and predict a corresponding increase in α cleavage. In practice, CSF sAPPα levels merely trended upwards in a non-dose-dependent fashion, indicating that there are layers of biological complexity that the scientists don’t understand yet, Simon said.

The Merck team began addressing concerns that BACE1 inhibition might cause demyelinating side effects, which had been implicit in the discovery last year that neuregulin-1 is a physiological BACE1 substrate during myelination early in life (Willem et al., 2006; Hu et al., 2006). Sankaranarayanan and colleagues first confirmed these findings using BACE1 knockout mice developed in Philip Wong’s laboratory. Then they infused Merck-3, a different, potent experimental BACE1 inhibitor (which is not suitable for human drug development because it does not enter the brain well; see Stachel et al., 2004) for a week into the brain ventricle of adult mice expressing wild-type human APP off a yeast artificial chromosome (see also ARF related news story). The inhibitor blocked BACE1, but levels of neuregulin-1, and various markers of myelination, did not change. This leads the Merck team to conclude, for now, that neuregulin-1 cleavage by BACE is important primarily during development and may not pose a problem in aged people. Careful studies looking for interactions of BACE inhibition with white matter changes in people or old mice have not been conducted.

The inhibitor presented here is better than previous ones in that it enters the brain and does not get extruded again by the efflux pump P-glycoprotein, as had earlier compounds by Merck, Wyeth, and other companies. However, in the process of “hiding” a BACE inhibitor from this pump, potency can diminish (see Moore et al., 2007). The inhibitor on the SfN poster is a different one from the ones discussed in this paper. Yet other scientists noted that the doses given to the monkeys were fairly high, and that its structure did not appear to suggest ideal drug properties. Large pharmaceutical companies frequently present data on projects that are behind their internal cutting edge, or on compounds that are not the real McCoy they are developing clinically. When asked about inhibitors in trials, Simon intoned the standard “Sorry, can’t confirm or deny.”

One thing this new Merck inhibitor cannot do is to be orally available, i.e., effective when swallowed. (Pharma companies much prefer pills to infusions. Merck collaborates with Sunesis to develop orally available BACE1 inhibitors.) On that front, researchers at Wyeth in Princeton, New Jersey, presented new data. Their BACE1 inhibitor WAY-258131 is a small molecule that, when fed to Tg2576 mice either once or repeatedly, decreased plasma and brain Aβ. When added to food for 3 months to 6-month-old PSAPP transgenic mice, WAY-258131 reduced their brain plaque load, first author David Riddell and colleagues reported on a poster. They also showed that the compound was able to reverse memory deficits in young, plaque-free transgenic mice, but not in old mice, invoking again the question of whether a secretase inhibitor can be enough once AD is established (see ARF related SfN 2005 story) For an open-access, up-to-date, and well-written review of all things BACE, see Cole and Vassar, 2007.—Gabrielle Strobel.

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References

News Citations

  1. Madrid: γ-secretase Dimers, A New Model, A Drug in Clinic
  2. Madrid: BACE News Roundup, Part 2
  3. SfN: How to Dispose of Plaques? Closing Spigot Won’t Do; Enzymes Nibble

Paper Citations

  1. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999 Oct 22;286(5440):735-41. PubMed.
  2. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, Destrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.
  3. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006 Dec;9(12):1520-5. Epub 2006 Nov 12 PubMed.
  4. Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi S, Simon AJ, Kuo L, Vacca JP. Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). J Med Chem. 2004 Dec 16;47(26):6447-50. PubMed.
  5. Moore KP, Zhu H, Rajapakse HA, McGaughey GB, Colussi D, Price EA, Sankaranarayanan S, Simon AJ, Pudvah NT, Hochman JH, Allison T, Munshi SK, Graham SL, Vacca JP, Nantermet PG. Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg Med Chem Lett. 2007 Nov 1;17(21):5831-5. PubMed.
  6. Cole SL, Vassar R. The Alzheimer's disease beta-secretase enzyme, BACE1. Mol Neurodegener. 2007;2:22. PubMed.

External Citations

  1. CoMentis
  2. Sunesis

Further Reading

Primary Papers

  1. Sankaranarayanan S, Price EA, Wu G, Crouthamel MC, Shi XP, Tugusheva K, Tyler KX, Kahana J, Ellis J, Jin L, Steele T, Stachel S, Coburn C, Simon AJ. In vivo beta-secretase 1 inhibition leads to brain Abeta lowering and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1. J Pharmacol Exp Ther. 2008 Mar;324(3):957-69. PubMed.

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