Background

JNJ-40346527 is an oral, selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase (for details, see on MedChemExpress). CSF-1R ligands promote survival, proliferation, and differentiation of macrophages and microglia; they also spur the growth of some cancers.

In Alzheimer’s disease, activation and proinflammatory cytokine release by microglia are essential mediators of pathology. This has spurred interest in drugs targeting microglial receptors.

JNJ-40346527 was tested in mouse models of prion disease and tauopathy (Mancuso et al., 2019). In the prion mice, the drug entered the brain and inhibited proliferation of microglia. In transgenic mice expressing human P30-1L tau, JNJ-40346527 blocked microglia proliferation and the production of the cytokines IL1β and TNFα. It reduced tau phosphorylation and neurodegeneration in the spinal cord, improved motor skills, and normalized the gene expression profile of microglia.

Findings

In November 2020, Janssen and the University of Oxford began a Phase 1 trial in people with mild cognitive impairment. The biomarker-based study will evaluate if JNJ-40346527 treatment changes CSF-1R signaling and microglia status. Three U.K. sites will enroll 54 participants with a Clinical Dementia Rating of 0.5 and randomize them 2:1 to receive 300 mg JNJ-40346527 twice daily or placebo for two weeks. Primary outcome is change in the concentration of CSF-1R ligands in cerebrospinal fluid. Secondary measures include unspecified biomarkers in CSF and plasma, CSF levels of microglia-derived extracellular vesicles and cells, CSF and plasma JNJ-40346527 levels, and safety assessments.

Depending on the results after two weeks of treatment, the trial will continue into a second randomized phase, at a dose to be determined. The trial will end in December 2021.

JNJ-40346527 was originally evaluated in cancer, arthritis, and inflammatory bowel disease, and has been tested extensively in people. It proved ineffective in Phase 2 trials for rheumatoid arthritis (Genovese et al., 2015) and Hodgkin’s lymphoma (von Tresckow et al., 2015).

In October 2019, JNJ-40346527 was reported to have been safe and well-tolerated but to have fallen short of primary endpoint in a trial for Crohn’s disease (press release, FierceBiotech story). Trials are ongoing in prostate cancer and acute myeloid leukemia.

For details on JNJ-40346527 trials, see clinicaltrials.gov.