- Phase 2 Clinical Trial for Frontotemporal Dementia with GRN Mutation, an Ultra-orphan Disease, Planned to Begin in Fourth Quarter of 2014 -
WATERTOWN, Mass. – October 28, 2014 – FORUM Pharmaceuticals Inc. (previously known as EnVivo Pharmaceuticals, Inc.), a biopharmaceutical company singularly focused on the development and delivery of innovative medicines to treat serious brain diseases, today announced results from FRM-0334 research studies at the 9th International Conference on Frontotemporal Dementias. FRM-0334 is a small molecule designed to specifically treat the effects of a genetic variation of frontotemporal dementia (FTD) associated with a granulin deficiency (FTD-GRN). FTD-GRN is a rare, early-onset and rapidly progressive neurodegenerative brain disorder that can affect behavior, cognition, language and motor skills, due to a reduction in the progranulin protein. Five studies were presented, featuring investigative data on FRM-0334 pharmacology, screening and identification of additional progranulin modulators, pathways to increase progranulin release, potential biomarker selection and therapeutic approaches to treating the disease.
“As part of FORUM’s mission to develop therapies for serious brain diseases, we are investigating FRM-0334 for the treatment of granulin-associated FTD, a rare genetic disease that strikes many patients in the prime of life, progresses rapidly and is ultimately fatal,” said Deborah Dunsire, M.D., President and Chief Executive Officer of FORUM Pharmaceuticals. “No therapies currently exist to address the immense needs of FTD patients and families, and FORUM is excited to share results from these promising FRM-0334 studies with leaders and experts in the research community at the 9th International Conference on Frontotemporal Dementias. As an earlier-stage candidate in our robust product pipeline, FRM-0334 complements FORUM’s Phase 3 encenicline development program for Alzheimer’s disease and schizophrenia. We plan to initiate a Phase 2 clinical trial for FRM-0334 later this year.”
“Patients with granulin-associated FTD have missense mutation in one of the two copies of the GRN gene, which results in significantly less granulin protein. It is believed that this loss of the granulin protein is detrimental to neuronal survival over the course of the disease,” said Gerhard Koenig, Ph.D., Senior Vice President, Research and Chief Scientific Officer at FORUM. “FRM-0334 is a histone deacetylase (HDAC) inhibitor that enhances gene transcription of the healthy GRN gene copy and may have the promise to positively affect neuronal survival for patients with FTD-GRN. The studies presented at the conference detailed our research in the pharmacology of FRM-0334.”
In the oral presentation, “The clinical stage HDAC inhibitor FRM-0334 induces progranulin in rodent brain and in FTLD-GRN patient-derived lymphoblasts,”
Holger Patzke, Ph.D., Senior Director, Biology, at FORUM, described the company’s development of highly brain penetrant HDAC inhibitors to epigenetically target brain function. Pharmacology results from lead compound FRM-0334 demonstrated increased granulin expression in normal animals and up to five-fold increased granulin expression in cultured rat nerve cells and in cell lines derived from patients carrying the granulin mutations.
Additional presentations at the conference focused on screening and identification of novel progranulin modulators and pathways to increase progranulin release, potential biomarker selection and potential therapeutic approaches to treating FTD-GRN. The poster, “A phenotypic screen of a mouse microglial cell line reveals novel mechanisms to modulate levels of progranulin,” described the role of phenotypic screening and methods of mapping and validation studies in the identification of progranulin modulators. The study, “Depletion of cellular cholesterol levels results in increased progranulin secretion and altered progranulin glycosylation,” detailed how cellular cholesterol depletion may provide a pathway for progranulin induction, thereby potentially offering a novel therapeutic approach for FTD-GRN. Another potential therapeutic approach to treating FTD-GRN was described in, “Anti-inflammatory transforming growth factor ß signaling increase microglial progranulin levels,” which demonstrated data supporting the hypothesis that progranulin may have a role in regulating CNS inflammation. The study, “Assessment of variability of progranulin concentrations in human cerebrospinal fluid (CSF),” characterized the longitudinal levels of PGRN in CSF in subjects 45-65 years of age, supporting future development of clinical biomarkers and calculation of clinical trial size estimates.
Full content of all abstracts presented at the 9th International Conference on Frontotemporal Dementias abstracts may be found at: http://www.ajnd.us/files/FTD_2014_9th_International_Conference_on_Frontotemporal_Dementias_Abstracts_Vancouver.pdf
About FRM-0334
FORUM Pharmaceuticals is developing FRM-0334, an orally available, small molecule inhibitor of histone deacetylase enzymes (HDAC), for the potential treatment of patients with frontotemporal dementia (FTD) associated with genetic mutation of the granulin (GRN) gene, known as FTD-GRN. Neurodegeneration arising in this disease is associated with low production of the precursor protein progranulin that results from the gene mutation. FRM-0334 functions by regulating HDAC enzymes, which in turn results in increased expression of the granulin gene and the progranulin protein. Because of its ability to inhibit HDAC enzymes, FRM-0334 may have therapeutic potential to reverse the metabolic consequences of the genetic defect that causes granulin-associated FTD.
FORUM has completed a Phase 1 clinical study of FRM-0334 in healthy subjects in Europe, where it was found to be well tolerated at all doses. The Company plans to initiate Phase 2a clinical trials to evaluate safety, tolerability and pharmacodynamics of FRM-0334 in the United States and Western Europe by the end of 2014.
About Frontotemporal Dementia (FTD)
Frontotemporal dementia (FTD), part of the frontotemporal lobar degeneration (FTLD) syndrome, is a rare but rapidly progressing degenerative syndrome having several subtypes, and is characterized by changes in personality, cognition, language and behavior. FTD has an early onset, often occurring in people 50 to 60 years of age, and is usually fatal in less than 10 years from its onset. FTD affects an estimated 50,000 to 60,000 in the United States and an estimated 15 to 22 people per 100,000 worldwide.
A specific subtype of FTD, FTD-GRN, results from genetic missense mutations in the granulin (GRN) gene that lead to less progranulin protein, believed to play an important role in neuron survival. In FTD-GRN, neuronal degeneration occurs in the context of abnormal accumulations of a specific protein that builds up within neurons. This form of FTD affects an estimated 3 to 15 people per 100,000 people and accounts for 5 to 10 percent of all cases of FTD.
About FORUM Pharmaceuticals Inc.
FORUM Pharmaceuticals Inc. and its subsidiaries (“FORUM Pharmaceuticals” or “FORUM”) are dedicated to developing groundbreaking medicines in support of all those who are affected by or caring for people with serious brain disease, to help them live fuller, more enriching lives. The Company’s robust and diverse pipeline is focused on discovering and developing new treatments for important neurodegenerative diseases that explore novel mechanisms of action to potentially alter the progression of brain disease and provide improvement in cognitive and overall function. FORUM’s lead compound, encenicline (EVP-6124), is currently being evaluated in separate ongoing Phase 3 clinical trial programs: COGNITIV SZ, which looks to improve cognitive impairment in patients with schizophrenia, and COGNITIV AD, which aims to improve cognition in patients with Alzheimer’s disease. The Company is also developing genetically-targeted therapies, including FRM-0334 for the potential treatment of frontotemporal dementia. Privately owned, FORUM Pharmaceuticals is based in Watertown, Mass. For more information about FORUM, visit www.forumpharma.com.
FORUM Pharmaceuticals and the FORUM octagon logo are trademarks of FORUM Pharmaceuticals Inc.
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