Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 2)
Company: FORUM Pharmaceuticals Inc.
FRM-0334 is a histone deacetylase (HDAC) inhibitor. HDACs are imporatant 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, 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 10mg/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 2008; Leventhal et al., SfN 2008; see Dec 2008 conference story).
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 2009).
According to the company website, Phase 1 evaluation has been completed (see Forum Pharmaceuticals website).
In December 2014, Forum Pharmaceuticals will begin a Phase 2 study of FRM-0334 in an estimated 30 patients with prodromal to moderate frontotemporal dementia who carry an FTD-causing mutation in the progranulin gene. The trial will compare a four-week course of a once-daily capsule of a low dose and a high dose of FRM-0334 on safety and pharmacodynamic outcomes. Measures include change in plasma and CSF progranulin concentration, as well as changes in the plasma and CSF concentration of FRM-0034 and its metabolites. The study is set to run through fall 2016. See clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|FORUM Pharmaceuticals Inc.||NCT02149160||
- Cenik B, Sephton CF, Dewey CM, Xian X, Wei S, Yu K, Niu W, Coppola G, Coughlin SE, Lee SE, Dries DR, Almeida S, Geschwind DH, Gao FB, Miller BL, Farese RV, Posner BA, Yu G, Herz J. 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.
- Coppedè F. The potential of epigenetic therapies in neurodegenerative diseases. Front Genet. 2014;5:220. Epub 2014 Jul 14 PubMed.
- Mohseni J, Zabidi-Hussin ZA, Sasongko TH. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy. Genet Mol Biol. 2013 Sep;36(3):299-307. Epub 2013 Aug 30 PubMed.
- Rosato RR. HDAC Inhibitors--CHI's Third Annual Conference. IDrugs. 2010 Jan;13(1):13-5. PubMed.
- Castellano JF, Fletcher BR, Patzke H, Long JM, Sewal A, Kim DH, Kelley-Bell B, Rapp PR. 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.