Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Saracatinib is an inhibitor of the Src/abl family of kinases. It was originally developed by AstraZeneca for various types of cancer, but discontinued in Phase 2 for lack of efficacy. The Discovering New Therapeutic Uses program at the National Center for Advancing Translational Sciences (NCATS) funded a grant to Stephen Strittmatter and colleagues at Yale University to explore the clinical use of saracatinib for Alzheimer's through Phase 2a. Through its Open Innovation Initiative, AstraZeneca agreed to supply the drug and matching placebo for clinical trials in Alzheimer's disease (see NIH Director's blog).
The rationale for this repurposing grew out of work on the tyrosine kinase Fyn. This member of the src kinase family is expressed in the brain and involved in signal transduction pathways underpinning synaptic plasticity. Fyn is believed to mediate Aβ toxicity. For example, it has been reported to become activated in the postsynapse in response to interactions at the postsynaptic plasma membrane between oligomeric Aβ, the prion protein, and the metabotropic glutamate receptor mGluR5. A separate line of evidence has linked Fyn to tau; reporting, for example, that Fyn phosphorylates dendritic tau, which then localizes Fyn to the postsynaptic density (Um, et al. 2012; Ittner et al., 2010; for review see Nygaard et al., 2014).
A preclinical treatment study reported that AZD0530 blocked Fyn in brain slices, and rescued synaptic depletion and spatial memory deficits in APP/PS1 mice (see Kaufman et al., 2015).
In July 2013, a Phase 1b multiple-ascending-dose study at Yale began evaluating a one-month course of 50 to 125 mg AZD0530 taken once daily by 24 people with mild to moderate Alzheimer's disease. One primary goal was to confirm the safety of a one-month course of saracatinib, as previously found in oncology trials; the other was to quantify how well the drug penetrated the blood-brain barrier. In April 2015, the drug was reported to have been "reasonably safe and well-tolerated" in this study, although one case of congestive heart failure and pneumonia on the highest dose was considered possibly related to saracatinib. The ratio of plasma to CSF drug levels was reported to be 0.4 and dose-dependent, indicating brain penetration. The 100mg and 125mg doses achieved CSF levels corresponding to brain levels that rescued memory deficits in transgenic AD mouse models (Kaufman et al., 2015). This four-week treatment regimen did not affect secondary outcome measures of cognition or behavioral function, activities of daily living, or brain activity as measured by FDG-PET (Nygaard et al., 2015).
In December 2014, a 152-patient Phase 2 study began. Called Connect, this 22-center study uses the Alzheimer's Disease Cooperative Study infrastructure to compare a 12-month course of 100 and 125 mg AZD0530 to placebo. A two-week plasma level is used to adjust dose. This trial ascertains the clinical AD diagnosis by way of amyloid imaging. Its twin primary outcome measures are cerebral glucose metabolism and safety; secondary measures include cognitive and behavioral measures, as well as imaging and fluid biomarker measures and influence of ApoE genotype on the treatment effects.
For all trials on this compound, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
- Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, Robinson SA, Gunther EC, van Dyck CH, Nygaard HB, Strittmatter SM. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol. 2015 Jun;77(6):953-71. Epub 2015 Mar 21 PubMed.
- Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, Kaufman AC, Rosenberg BJ, Sekine-Konno T, Varma P, Chen K, Koleske AJ, Reiman EM, Strittmatter SM, van Dyck CH. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):35. Epub 2015 Apr 14 PubMed.
- Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci. 2012 Sep;15(9):1227-35. Epub 2012 Jul 22 PubMed.
- Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M, Hardeman E, Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.
- Nygaard HB, van Dyck CH, Strittmatter SM. Fyn kinase inhibition as a novel therapy for Alzheimer's disease. Alzheimers Res Ther. 2014;6(1):8. Epub 2014 Feb 5 PubMed.