Therapeutics

Semagacestat

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Overview

Name: Semagacestat
Synonyms: LY450139 Dihydrate , hydroxylvaleryl monobenzocaprolactam
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Eli Lilly & Co.
Approved for: None

Background

Semagacestat is a γ-secretase inhibitor that reduces Aβ40 and 42 production and secretion by the γ-secretase enzyme complex. The rationale is that reducing the formation of Aβ from its substrate APP targets an upstream event in the amyloid cascade and represents a direct test of the amyloid hypothesis. In preclinical animal studies, semagacestat reduced both soluble Aβ and amyloid plaque burden.

Findings

Semagacestat is the first γ-secretase inhibitor to have been taken into Phase 3 clinical trials. Phase 1 evaluated, in 27 healthy volunteers, three doses of semagacestat for its ability to lower the rate of Aβ synthesis in the CSF. It reported dose-dependent reduction (Bateman et al., 2009). This trial used a new radiolabeling technique to measure production and turnover rates of newly generated proteins in the CSF. Called SILT, it has since become more widely used in CNS drug development (Bateman et al., 2007).

In Phase 2, an initial trial in 70 people with mild to moderate Alzheimer's disease tested 30 mg for one week followed by 40 mg for five weeks (Siemers et al., 2006). A second trial gave 60 mg of semagacestat for two weeks, then 100  mg for another 12 weeks to  51 Alzheimer's patients. On the primary outcome of safety and tolerability, this trial showed a greater number of skin-related side effects in the treatment group, for example rash and lightening hair color. It also showed a significant reduction of plasma  levels, but not in CSF  levels. On secondary efficacy endpoints of cognition and function, this study showed no difference between semagacestat and placebo. A time course showed a biphasic response to semagacestat called "overshoot." Following the inhibitory phase, plasma Aβ exceeded baseline levels and remained elevated at all doses throughout most of a 24-hour post-dose period (Fleisher et al., 2008; Siemers et al., 2007).

Lilly started two pivotal Phase 3 trials, IDENTITY-1 and IDENTITY-2, intending to assess a total of 3,036 patients on up to 21 months of treatment. IDENTITY-1 compared 100 and 140 mg/day of semagacestat to placebo for their ability to improve cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and function as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) in patients with Alzheimer's disease in 24 countries around the world. IDENTITY-2 tested 60 mg/day against the same outcome measures but contained more secondary endpoints and substudy assessments. Both trials were to run until 2012, but were halted in 2011 because of both an increased risk of skin cancer and infections and lack of efficacy. Notably, both cognition and function not only did not improve but worsened in all three treatment groups  (Doody et al., 2013). Lilly terminated development of semagacestat.

Possible explanations for semagacestat's failure center around the compound's broad-based inhibition of all γ-secretase's 40-plus substrates, particularly Notch. This is is thought to have been detrimental to both safety and pharmacology (see conference story). In addition, a toxic function for an intermediate product of APP processing called b-CTF, whose concentration rises with semagacestat treatment, has been proposed  (see conference story). At a systems level, disruption of hippocampal network function has been reported (Hajos et al., 2013).

Insight gained from semagacestat development has stimulated the search for APP-versus-Notch selective inhibitors and for γ-secretase modulators.  Semagacestat continues to be used in research. For clinical trials of semagacestat, see clinicaltrials.gov.

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References

Paper Citations

  1. . A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009 Jul;66(1):48-54. PubMed.
  2. . Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates. J Am Soc Mass Spectrom. 2007 Jun;18(6):997-1006. PubMed.
  3. . Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology. 2006 Feb 28;66(4):602-4. PubMed.
  4. . 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.
  5. . Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol. 2007 Nov-Dec;30(6):317-25. PubMed.
  6. . A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50. PubMed.

Other Citations

  1. conference story

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50. PubMed.
  2. . Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol. 2007 Nov-Dec;30(6):317-25. PubMed.
  3. . 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.
  4. . Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology. 2006 Feb 28;66(4):602-4. PubMed.
  5. . Exacerbation of psoriatic skin lesions in a patient with Alzheimer disease receiving gamma-secretase inhibitor. J Am Acad Dermatol. 2013 Feb;68(2):e46-8. PubMed.
  6. . ACS chemical neuroscience molecule spotlight on semagacestat (LY450139). ACS Chem Neurosci. 2010 Aug 18;1(8):533-4. PubMed.
  7. . Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans. Drug Metab Dispos. 2010 Apr;38(4):554-65. Epub 2010 Jan 14 PubMed.
  8. . Requirement of Notch activation during regeneration of the intestinal epithelia. Am J Physiol Gastrointest Liver Physiol. 2009 Jan;296(1):G23-35. Epub 2008 Nov 20 PubMed.
  9. . Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin. 2014 Oct;30(10):2021-32. Epub 2014 Jul 14 PubMed.