Background

FRM-0334 is a histone deacetylase (HDAC) inhibitor. HDACs are key enzymes in the epigenetic regulation of gene function. By removing acetyl groups from histone proteins in chromatin, HDACs compress the chromatin and in this way repress gene expression. The rationale behind HDAC inhibition is based on evidence that decreased transcription of certain genes represents an underlying pathophysiological mechanism in several neurological disorders, including frontotemporal dementia, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis.

In particular, HDAC inhibition appears to increase expression of progranulin (Cenik et al., 2011). Haploinsufficiency of the progranulin gene is a genetic cause of familial frontotemporal dementia, and levels of progranulin protein are reduced in the blood of patients with several neurodegenerative diseases. Progranulin is a secreted growth factor, and increasing its expression via HDAC inhibition is thought to be neuroprotective.

At the 2008 Society for Neuroscience conference, EVP-0334 was reported to selectively inhibit a subset of class I and II human HDACs with nanomolar IC50 values and good brain penetrance. In mice, oral administration was reported not only to increase acetylation of histones 2A, 3, and 4 in brain with a minimal effective dose of 10 mg/kg, but also to improve cognitive performance in novel object recognition and the Morris water maze at that same dose. This presentation also noted the safety of this compound when given for two weeks at 10 times the effective dose (Patzke et al., SfN presentation abstract, 2008; Leventhal et al., SfN presentation abstract, 2008; see Dec 2008 conference news).

At the 2009 Society for Neuroscience conference, EnVivo Pharmaceuticals scientists presented data in rats. In this model, too, the compound was reported to penetrate into the brain, increase acetylation of several histones there, and at the same doses improve memory as measured by performance in two different paradigms (Patzke et al., SfN presentation abstract, 2009).

In 2014, EnVivo changed its name to Forum Pharmaceuticals (Fierce Biotech news).

Findings

In Phase 1 evaluation, 70 healthy volunteers received daily oral doses of up to 400 mg FRM-0334 for two weeks. No severe adverse events were reported at any dose (Nov 2014 conference news).

In October 2014, Forum Pharmaceuticals began a Phase 2 study of FRM-0334 in 27 patients with prodromal to moderate frontotemporal dementia who carry an FTD-causing mutation in the progranulin gene. The trial compared a four-week course of a once-daily capsule of 300 or 500 mg FRM-0334 to placebo on safety and pharmacodynamic outcomes. Measures included change in plasma and CSF progranulin concentration, as well as changes in the plasma and CSF concentration of FRM-0034 and its metabolites. According to published results, the drug was well-tolerated but changed neither plasma nor CSF progranulin, or exploratory pharmacodynamic measures including CSF biomarkers, dementia ratings, and FDG-PET (Ljubenkov et al., 2021). Both doses produced similar plasma drug concentrations, which were likely insufficient to affect histone acetylation.

In June 2016, the company shut down (Xconomy news).

See clinicaltrials.gov.

Clinical Trial Timeline