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Bart De Strooper of KU Leuven, Belgium, made such an attempt. He struck a nerve, and a probing discussion ensued on Alzforum. In a Leading Edge Essay in the November 6 Cell, De Strooper claimed that the field at large had insufficiently dissected why the semagacestat IDENTITY Phase 3 trial failed. He charged that the field jumped to a simplistic conclusion in abandoning γ-secretase as a target. Specifically, De Strooper argued that the biphasic pharmacology of semagacestat seen in Phase 2 predicted that the dosing regimen chosen for Phase 3 might be counterproductive. The drug caused peaks of complete inhibition alternating with full enzyme activity, rather than a more desirable partial but chronic inhibition, and the once-daily dosing driven by safety concerns worsened this oscillating pattern.
In particular, understanding these scientific questions will enable the field to potentially advance drugs that target γ-secretase in a more informed approach. Related approaches such as γ-secretase modulators, APP-selective GSIs, and GSIs with alternative PK/PD profiles are highly promising and should be fully pursued as potential drugs for AD.
Kolb EA, Gorlick R, Keir ST, Maris JM, Lock R, Carol H, Kurmasheva RT, Reynolds CP, Kang MH, Wu J, Houghton PJ, Smith MA.Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling. Pediatr Blood Cancer. 2012 May;58(5):815-8. Epub 2011 Aug 16 PubMed.
γ-secretase should not be abandoned as a pharmacological target. However, there is more data in favor of activating γ-secretase than inhibiting it. Bart's team themselves have shown in beautiful studies that most PSEN1 mutations lead to a less effective γ-secretase (Chávez-Gutiérrez et al., 2012). It manages to produce Aβ1-42 and 1-40 from APP, but less so the shorter Aβ1-37/38/39 isoforms that may be protective and inhibit Aβ1-42 oligomerization/fibrillization. We have shown similar results for the PSEN1 A431E mutation (Portelius et al., 2010). A GSA or GSM that boosts cleavages at Gly37, Gly38 and Val39 should be a good candidate to reduce the risk of cerebral β-amyloidosis. We clearly have more to learn about the action of GSIs.
Discontinuation of Semagacestat development was a reasonable decision based on the trial results. But this does not indicate that the amyloid hypothesis is incorrect, nor does it lessen the need for basic and clinical investigation of γ-secretase, which remains among the most plausible therapeutic targets.
1. The rationale for targeting γ-secretase is to decrease the generation of Aβ and reduce the Aβ burden mainly in the brain, where it is deposited as amyloid plaques and also accumulates in synaptotoxic soluble oligomers that are in a complex equilibrium with the plaques. From the Phase 1-3 trials, CSF measures of Aβ were never shown to be significantly reduced, suggesting that semagacestat did not have the desired impact on the steady-state levels of Aβ in the CNS (Siemers et al., 2005; Siemers et al., 2007; Siemers et al., 2006; Doody et al., 2013; Fleisher et al., 2008). Bateman and colleagues (Bateman et al., 2009) were able to show an acute reduction in newly generated Aβ by a single dose of semagacestat, however, its effect on the overall steady-state levels of Aβ is more difficult to conclude.
There are still quite a few benefits that targeting γ-secretase could provide over β-secretase. First, γ-secretase can be modulated, as opposed to inhibited, to reduce the relative levels of Aβ42. By shifting γ-secretase processing to favor shorter Aβ isoforms, the generation of soluble intracellular domains of many important substrates such as Notch will not be affected, and this should lessen side effects in humans. Alternatively, selective γ-inhibitors that specifically target APP as opposed to other γ-substrates can be developed; currently, some γ-inhibitors are relatively Notch-sparing. In addition, since γ-secretase is an intramembrane protease, inhibitors and modulators that target this enzyme tend to be cell-penetrant and thus may allow for better BBB permeability.
However, before we can further develop novel approaches to target γ-secretase safely and effectively, more needs to be learned about the basic physiology of the γ-secretase complex and substrate processing.
Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ.Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch Neurol. 2008 Aug;65(8):1031-8. PubMed.
Even if γ-secretase ultimately proves to be a bad drug target, I believe an unbiased research approach would lead to unexpected good targets for AD. I predict that even these good targets would somehow connect to γ-secretase activity. However, I am confident that the knowledge acquired in the discovery process would point to ways and means for severing that connection. As an illustration, if I were to look for inhibitors of Notch, I would start a detailed analysis of the naturally produced dominant-negative molecules that are likely to produce fewer side effects. If I were to look for a better way to deliver γ-secretase inhibitor to humans, I would start by identifying the peaks and troughs of Notch activities and explore the effect of drug delivery at peak or trough times depending on the effect desired (note that ultradian oscillation of Notch activity is reported in vertebrates and known to be important for somitogenesis).
Semagecestat and LessonsAs several contributors already mentioned, target engagement is critically important in initial proof-of-mechanism studies in early drug development. For semagacestat, it seems that target engagement was achieved at the higher doses but the issue was that compound exposure only covered target engagement for 12 hours (Bateman et al., 2009). We can only speculate that Lilly might have had additional data which increased their confidence that Aβ was significantly reduced over 24 hours. As others have pointed out, the chosen dose in Phase 3 was lower and probably did not result in sufficient exposure to lower Aβ for a long enough period of time. One important lesson from this experience is that any trial going forward needs to assure that the targeted reduction of the biomarker of interest (Aβ total, Aβ42, etc.) is achieved over the whole course of the day, not just 12 hours.
Our field will be given only a few more reasonable chances to show some clinical success in testing the amyloid hypothesis. Some might argue that one more antibody failure combined with lack of efficacy of the ongoing BACEi trials will cause a shutdown of most, if not all, investment in targets aimed at amyloid reduction. This is why we believe that an intervention with a GSM in pre-symptomatic FAD patients has the best scientific rationale and, with the right molecule, the highest probability of success. GSMs deserve priority in our mind over new, more substrate-specific GSIs in that hypothesis testing scenario.
In summary, we agree that the pharmaceutical industry should be persuaded to sustain its interest in many types of Aβ or amyloid targeting therapies, including γ-secretase inhibitors. While we now know that the γ-secretase complex consists of four subunits (presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx 1) encoded by four different genes (PSEN, NCT, PEN2, and APH1) (De Strooper, 2003), even the relationship between presenilin and γ-secretase was found after development of semagacestat had begun. In our view, taken together, the data would suggest that the cognitive worsening seen in the IDENTITY trial was most likely due to inhibition of cleavage of a γ-secretase substrate other than APP. Thus, perhaps through targeting (or not targeting) one particular subunit of γ-secretase, selective inhibition of APP cleavage could be achieved, or γ-secretase modulation could obviate the cognitive worsening seen in IDENTITY. During the past decade, much has been learned about the γ-secretase complex, and much has been learned from the clinical results obtained from trials using semagacestat and other similar γ-secretase inhibitors. The field can build on these learnings and continue to work toward finding safe and effective treatments for AD that target the γ-secretase complex.
Karran E, Hardy J.A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol. 2014 Aug;76(2):185-205. Epub 2014 Jul 2 PubMed.
Bart de Strooper conducted a comprehensive analysis of clinical studies of Semagacestat based on published data and made a convincing argument that the failed clinical trial does not disqualify γ-secretase as a target for AD drug development. We should focus on lessons learned from failed clinical trials and develop a better understanding of γ-secretase structure and function under physiological and pathophysiological conditions, which would provide a molecular basis for development of effective and safe γ-secretase-based therapy for AD treatment. The most surprising outcome of the clinical trial of Semagacestat was the worsening of memory in patients (Doody et al., 2013). The other major adverse effect of the trial was the increased risk of skin cancer, which likely resulted from inhibition of Notch signaling by Semagacestat (Xia et al., 2001; Nicolas et al., 2003). While the Notch-associated side effects are somewhat better understood, the mechanism of cognitive decline is elusive. It may be informative to compare clinical studies of the γ-secretase inhibitor Avagacestat (Coric et al., 2012). 153554b96e
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