Phase 2 Clinical Trial For Progranulin-deficient FTD Announced

SAN FRANCISCO, 10/28/14 - Watertown, MA-based FORUM Pharmaceuticals announced plans to initiate a Phase 2 clinical trial of its lead compound, FRM-0334, in progranulin mutation carriers before the end of 2014. A mutation in one of the two copies of the progranulin gene that an individual carries results in abnormally low levels of progranulin protein and culminates in the development of FTD. Therefore, drugs that elevate progranulin levels by increasing gene expression from the second, unmutated copy of progranulin hold promise as potential therapeutics if they are able to restore levels in mutation carriers.

Speaking on October 25, 2014 at the 9th International Conference on Frontotemporal Dementias in Vancouver, Canada, Holger Patzke, PhD, Senior Director of Biology at FORUM, detailed FRM-0334’s pharmacology. FRM-0334 is a brain-penetrant histone deacetylase inhibitor (HDACi) that increased progranulin expression in cultured rodent neurons and, most importantly, in cell lines derived from patients carrying progranulin mutations. Phase 1 safety studies showed no toxicity or side effects.

FORUM’s clinical trial will enroll 30 individuals at multiple participating research sites across the United States and Europe. Individuals must carry a mutation in progranulin and know their mutation status. Trial participants will receive either FRM-0334 (low or high dose) or placebo for 28 days, and progranulin levels in both plasma and cerebral spinal fluid will be measured before and during the dosing regimen to determine if FRM-0334 raises progranulin protein levels.

The promise of HDAC inhibitors in elevating progranulin expression was initially demonstrated by work funded by the Bluefield Project from the labs of Drs. Joachim Herz and Gang Yu at the Universty of Texas, Southwestern Medical Center. Drs. Herz, Yu and colleagues identified SAHA, another HDACi, as a potent inducer of progranulin expression in a screen of FDA-approved compounds. SAHA is approved for use in the treament of certain cancers, but it produces significant side effects and does not penetrate the brain, thus its use was not recommended for progranulin-deficient FTD.  Building on Dr. Herz and Yu's discovery, FORUM's development of FRM-0334, which is brain penetrate and nontoxic, is a significant milestone in efforts to develop a treatment of progranulin-deficient FTD.

Click here to read FORUM’s press release.