Inhibition of the β-secretase enzyme, which starts the process of snipping APP into Aβ, has long been seen as one of the most promising therapeutic options for Alzheimer disease. But as almost 10 years of unsuccessful efforts show, β-secretase (BACE1) inhibition has been a tough nut to crack. However, there is some progress in this area now. In a paper in the August 18 Journal of Neuroscience, scientists led by Hiroaki Fukumoto at Takeda Pharmaceutical Company in Osaka, Japan, in collaboration with Takeshi Iwatsubo at the University of Tokyo, report that a non-peptidic BACE inhibitor with moderate potency significantly lowers Aβ levels in vivo in a mouse model of AD. This compound is one of a new wave of BACE inhibitors that often have less potency than previous candidates, but penetrate the brain and are effective in vivo. Several companies are testing similar compounds, with most being in the preclinical phase and a few making it to Phase 1 trials. Although none of the new candidates has yet broken through as a viable therapy, these results are showing that effective BACE inhibition may be possible and is being actively pursued in many quarters.

“In the early days of BACE1 inhibitor development by the pharmaceutical industry, many candidate inhibitors were peptide-based, were poorly absorbed when taken orally, and did not cross the blood-brain barrier well,” said Iwatsubo. These early candidates were optimized for high potency in vitro, but due to their lack of brain penetrance, they showed little activity in vivo. These failures led to new strategies, with many pharmaceutical companies now making next-generation compounds that are generally distinguished by lipophilic structures often made up of multiple phenyl rings.

To find such a candidate, Fukumoto and colleagues at Takeda used a cellular assay to screen for small compounds that reduced the secretion of Aβ Several years ago they discovered a promising non-peptidic, lipophilic compound they named TAK-070. In a culture of mouse neuroblastoma cells overexpressing human APP with the Swedish mutation, a concentration of 3 μM TAK-070 suppressed the secretion of Aβ by about 25 percent, a modest reduction compared to many BACE1 inhibitors. TAK-070 also increased the production of the secreted form of APP produced by α-secretase cleavage (sAPPα), which is considered neuroprotective, by about 90 percent.

Fukumoto and colleagues next investigated the mechanisms of BACE1 inhibition, using a cell-free assay to show that TAK-070 directly inhibits BACE1. The kinetics of the experiment indicated that TAK-070 was not competing with BACE1 substrates for the active site of the enzyme, as classic peptidic inhibitors do. Instead, TAK-070 appears to bind a region of about 10 amino acids in the membrane-spanning portion of BACE1, as the authors showed by surface plasmon resonance assay using truncated forms of the secretase. This demonstrates that molecules do not have to target the BACE1 catalytic site for successful inhibition, Iwatsubo said. He added that the mechanism by which TAK-070 inhibits BACE1 is still unknown.

Finally, Fukumoto and colleagues tested TAK-070 in an AD mouse model (Tg2576). Starting at seven months of age, just before amyloid plaque formation begins, the mice were fed 8.2 mg/kg per day for six months, a regime they tolerated without noticeable adverse effects. Soluble Aβ decreased about 25 percent, similar to the in vitro effectiveness of TAK-070, while sAPPα increased about 22 percent in the brains of these mice. Insoluble Aβ in these mouse brains also decreased about 30 percent, but intriguingly, the number of amyloid plaques was reduced by 60 percent after six months of treatment. The authors also looked at the effects of one to two weeks of oral TAK-070 (1 or 3 mg/Kg) treatment in young AD mice just starting to show cognitive deficits. In the Y-maze and Morris water maze tests of spatial memory, TAK-070-treated mice recovered memory to close to wild-type levels, while treated mice fully recovered novel object recognition.

The fact that TAK-070 achieves the same potency in vitro and in vivo is unexpected, Iwatsubo said, and suggests that the molecule penetrates the blood-brain barrier and cell membranes easily, at least in mice. It is also noteworthy that a partial reduction in Aβ, along with enhancement of sAPPα, was effective enough to substantially reduce amyloid plaques over chronic treatment, and to significantly improve cognition with short-term treatment, providing hope that even BACE inhibitors with modest in vivo activity could provide real therapeutic benefits. It is not clear if Takeda plans to continue development of this particular compound, which was listed as being in Phase 1 clinical trials in 2005 (see Jacobsen et al., 2005). In the pharmaceutical industry in general, companies frequently start publishing compounds in the public scientific literature after they have been discontinued internally, and active development has shifted to newer compounds.

TAK-070 is one of many similar compounds under development industry-wide, as presentations by several pharmaceutical companies at the International Conference on Alzheimer’s Disease (ICAD) 2010 made clear. The same themes are emerging across the industry: Companies are starting to develop molecules with reasonable in-vivo activity, and are now facing the next set of challenges, including drug safety and meaningful clinical outcomes.

One example of a drug scuttled by a safety issue came from the research team led by Patrick May at Eli Lilly in Indianapolis. At ICAD 2010, they presented data on a BACE inhibitor dubbed LY2811376, that in dogs reduced Aβ in CSF by 70 percent up to nine hours after dosing. In Phase 1 human trials, LY2811376 was well tolerated and reduced plasma Aβ in a dose-dependent manner. May said that Lilly’s research team was very pleased with the pharmacodynamics of the molecule. However, during the Phase 1 study, “we obtained some additional non-clinical toxicology data that was of sufficient import that we terminated development of this molecule,” said May. Nonetheless, his team regards LY2811376 as a breakthrough molecule that showed, contrary to some industry fears, that “BACE is a druggable target.” May added that Lilly remains committed to pursuing BACE inhibitors as a therapeutic approach to AD, based in large part upon the LY2811376 trial, which the company regards as a proof-of-concept study. Coauthor James Audia at Lilly said that LY2811376 “also went against the conventional wisdom that BACE inhibitors have to be exquisitely potent in vitro in order to translate into in vivo models.”

Scientists led by Matthew Kennedy at Merck Research Labs in Kenilworth, New Jersey, also presented data at the 2010 ICAD on a novel class of low-molecular-weight iminoheterocyclic aspartic protease inhibitors, which are non-peptidic, orally available, and penetrate the blood-brain barrier (see Zhu et al., 2010 and Wang et al., 2010). When tested on AD model mice (TgCRND8) for up to 24 weeks, one of the compounds, SCH 785532, reduced cortical Aβ levels by about one-third, delayed the maturation of plaques, and also moderately improved cognitive performance. “SCH 785532 is an early prototype inhibitor with modest brain activity,” Kennedy wrote in an e-mail to ARF, but a related compound, SCH 1359113, “is more potent both in vitro and in vivo. SCH 1359113 reduces cortical Aβ levels after only a few doses,” he wrote. Kennedy noted that Merck currently has a compound in Phase 1 clinical trials, and plans to report on the progress of its BACE1 inhibitor program at major meetings over the next several months.

The biotechnology company CoMentis, headquartered in San Francisco, California, also has a BACE inhibitor, CTS-21166. Phase 1 clinical trials suggest it penetrates the brain and reduces plasma Aβ levels (see ARF related news story). There have been no recent updates on this inhibitor, however, and CoMentis declined to comment for this article.

Phil Iredale at Pfizer said the company is committing significant resources toward finding an effective BACE inhibitor. Pfizer presented preclinical data at ICAD 2010 as well, demonstrating that a compound they developed by rational drug design lowers brain Aβ levels by 40 to 60 percent in wild-type mice, although it is less potent in AD model mice. “The data are very encouraging,” Iredale said. For the whole pharmaceutical industry, Iredale said, BACE inhibition “has been a very difficult target to tackle. It’s only been in the last year or so that there has been evidence of successful molecules that look like they might actually have drug-like properties.” Iredale said that industry programs are still in the early phases of finding a feasible BACE therapy, and one of the biggest future challenges will be to bridge the gap between a simple readout of Aβ levels, and meaningful clinical improvement of AD symptoms. “I think there’s still a long road to go,” Iredale said, “but there is a lot of excitement because of the advances that have recently been shown.”

Marwan Sabbagh of Banner Sun Health Research Institute in Sun City, Arizona, presented a different approach to BACE1 inhibition at this year’s ICAD. A team led by Yong Shen at Banner Health had previously found that disrupting tumor necrosis factor (TNF) signaling by deleting the TNF receptor reduces Aβ production and amyloid plaques in AD mice through the inhibition of BACE1 (see He et al., 2007). Because the immunomodulatory drug thalidomide is known to inhibit TNF signaling, Shen and colleagues tested thalidomide’s effects in mice, and confirmed that it reduced Aβ levels and plaque numbers. Banner Health is now preparing a Phase 2 clinical trial led by Shen and Sabbagh to test the effectiveness of thalidomide at lowering Aβ, sAPPβ, and BACE1 levels in plasma and CSF, Sabbagh said. They were able to skip a Phase 1 trial, he said, because thalidomide is already an FDA-approved drug, and its safety and side effects, which include severe fetal malformations when taken by pregnant women, are known. These tragic side effects in the late 1950s and early 1960s banished thalidomide from the physician’s toolbox until research into its effects on treatment-resistant multiple myeloma resurrected the drug for use under tight restrictions. The most significant side effect of thalidomide in adults is considered to be peripheral neuropathy (see Ochonisky et al., 1994). Because of this concern, Sabbagh said, their study will perform nerve conduction tests on participants, and anyone who develops neuropathy will be withdrawn from the trial. The Phase 2 trial is expected to start by the end of August, and will enroll 45 people with mild to moderate AD, who will take 400 mg/day thalidomide for 24 weeks. In this initial trial, Sabbagh said, the researchers will primarily evaluate effects on AD biomarkers, rather than on clinical changes in the disease.—Madolyn Bowman Rogers


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News Citations

  1. Keystone Drug News: CoMentis BACE Inhibitor Debuts

Paper Citations

  1. . Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease. NeuroRx. 2005 Oct;2(4):612-26. PubMed.
  2. . Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I--inhibitor design and validation. J Med Chem. 2010 Feb 11;53(3):951-65. PubMed.
  3. . Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors. J Med Chem. 2010 Feb 11;53(3):942-50. PubMed.
  4. . Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol. 2007 Aug 27;178(5):829-41. PubMed.
  5. . Thalidomide neuropathy incidence and clinico-electrophysiologic findings in 42 patients. Arch Dermatol. 1994 Jan;130(1):66-9. PubMed.

Other Citations

  1. Tg2576

External Citations

  1. Phase 1 human trials
  2. CTS-21166
  3. Phase 1 clinical trials
  4. thalidomide
  5. Phase 2 clinical trial

Further Reading


  1. . Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16. PubMed.

Primary Papers

  1. . A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease. J Neurosci. 2010 Aug 18;30(33):11157-66. PubMed.