CHF 5074


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Name: CHF 5074
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Mild Cognitive Impairment, Alzheimer's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Alzheimer's Disease (Inactive)
Company: CereSpir™ Incorporated, Chiesi Pharmaceuticals Inc.


This compound was initially reported as a γ-secretase modulator but is now portrayed as acting on multiple targets, particularly microglia. Long-term use of NSAIDs confers some protection against incident Alzheimer’s, and a widely noted finding that certain NSAIDs lower Aβ42 production independent of their action on the Cox enzymes prompted widespread research into NSAID derivatives of similar function (see Weggen et al., 2001). From 2007–2011, CHF5074 was being reported as a γ-secretase modulator that affected Aβ- and other amyloid-related outcomes. Subsequent preclinical studies proposed other mechanisms of action, such as restoring neurogenesis, reorganizing the astrocytic cytoskeleton, reducing tau, rescuing synaptic plasticity, or acting on microglia to counteract inflammation (see Nov 2012 conference storySivilia et al., 2013).


Phase 1 clinical trials consisted of three studies in 144 healthy young men to establish pharmacology and initial safety data. CH 5074 was reported to be safe and tolerable in these subjects; one notable side effect was mild diarrhea.

In 2011, a first multicenter Phase 2 trial compared doses of 200, 400, and 600 mg/day, primarily to determine the maximum tolerated dose at 12 weeks. Participants were 96 patients with amnestic or nonamnestic mild cognitive impairment (MCI); no amyloid or tau biomarkers were used for inclusion. CH 5074 pharmacology was similar to Phase 1; some patients withdrew due to diarrhea. An anti-inflammatory benefit measured as reduction in CSF CD40 and TNF-α concentration, as well as a trend toward improved executive function, were reported for carriers of the ApoE4 risk allele but not noncarriers (see Ross et al., 2013).

This trial went into a 24-week extension study to determine longer-term tolerability, and 51 participants then enrolled into a second extension. reports this second extension will continue to 48 weeks, a CereSpir™ media release claims 90 weeks. CereSpir™ was founded to complete the clinical development of CHF 5074 and market it.

A second, two-year Phase 2 trial was to have started in 2012 to compare two undisclosed doses of CH 5074 and placebo for their effect on brain volume and other outcomes in a population of people with amnestic MCI who were genetically enriched for AD risk by being ApoE4 carriers. This trial was withdrawn from prior to enrollment, reportedly to be placed on hold to await the outcome of licensing negotiations (see Nov 2012 news story, Aug 2013 conference story).

Clinical Trial Timeline

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
Chiesi Pharmaceuticals Inc. NCT01421056
Chiesi Pharmaceuticals Inc. NCT01602393

Last Updated: 13 Nov 2013


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News Citations

  1. CTAD: ApoE Carriers Sought for Trial of NSAID Derivative
  2. Clinical Trials Roundup: Four Hits, No Home Runs

Paper Citations

  1. . CHF5074 Reduces Biomarkers of Neuroinflammation in Patients with Mild Cognitive Impairment: A 12-Week, Double-Blind, Placebo-Controlled Study. Curr Alzheimer Res. 2013 Aug 2; PubMed.
  2. . Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice. BMC Neurosci. 2013;14:44. PubMed.

External Citations

  1. media release
  2. Weggen et al., 2001

Further Reading


  1. . CHF5074 restores visual memory ability and pre-synaptic cortical acetylcholine release in pre-plaque Tg2576 mice. J Neurochem. 2013 Mar;124(5):613-20. PubMed.
  2. . The γ-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice. J Alzheimers Dis. 2011;24(4):799-816. PubMed.
  3. . The γ-secretase modulator CHF5074 reduces the accumulation of native hyperphosphorylated tau in a transgenic mouse model of Alzheimer's disease. J Mol Neurosci. 2011 Sep;45(1):22-31. PubMed.
  4. . Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives. J Alzheimers Dis. 2010;22(4):1135-55. PubMed.
  5. . CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. 2010;20(1):159-73. PubMed.
  6. . CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br J Pharmacol. 2009 Mar;156(6):982-93. PubMed.