Therapeutics

FRM-0334

Overview

Name: FRM-0334
Synonyms: EVP-0334
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Discontinued)
Company: FORUM Pharmaceuticals Inc.

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

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031
FORUM Pharmaceuticals Inc. NCT02149160
N=30

Last Updated: 06 Oct 2021

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References

News Citations

  1. Progranulin-Boosting Drug Moves into Phase 2 for Frontotemporal Dementia
  2. DC: Developing But Debatable—Deacetylase Inhibitors for CNS Disease?

Alzpedia Citations

  1. Progranulin

Paper Citations

  1. . Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial. JAMA Netw Open. 2021 Sep 1;4(9):e2125584. PubMed.
  2. . Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem. 2011 May 6;286(18):16101-8. PubMed.

External Citations

  1. Xconomy news
  2. clinicaltrials.gov
  3. Patzke et al., SfN presentation abstract, 2008
  4. Leventhal et al., SfN presentation abstract, 2008
  5. Patzke et al., SfN presentation abstract, 2009
  6. Fierce Biotech news

Further Reading

Papers

  1. . The potential of epigenetic therapies in neurodegenerative diseases. Front Genet. 2014;5:220. Epub 2014 Jul 14 PubMed.
  2. . Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy. Genet Mol Biol. 2013 Sep;36(3):299-307. Epub 2013 Aug 30 PubMed.
  3. . HDAC Inhibitors--CHI's Third Annual Conference. IDrugs. 2010 Jan;13(1):13-5. PubMed.
  4. . Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging. Hippocampus. 2014 Aug;24(8):1006-16. Epub 2014 Apr 30 PubMed.