A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating, Phase 2a Safety, Tolerability, and Pharmacodynamic Study of Two Doses of an Histone Deacetylase Inhibitor (FRM-0334) in Subjects With Prodromal to Moderate Frontotemporal Dementia With Granulin Mutation

The purposes of this study are to investigate the safety, tolerability, and pharmacodynamics of FRM-0334 in subjects with prodromal to moderate frontotemporal dementia with granulin mutation.

Start Date01 Oct 2014

Sponsor / Collaborator

FORUM Pharmaceuticals, Inc.

100 Clinical Results associated with EVP-0334

100 Translational Medicine associated with EVP-0334

100 Patents (Medical) associated with EVP-0334

Literatures (Medical) associated with EVP-0334

01 Jan 2010·IDrugs : the investigational drugs journal

HDAC Inhibitors--CHI's Third Annual Conference.

Article

Author: Rosato, Roberto R

The HDAC Inhibitors meeting, held in Boston, included topics covering new therapeutic developments in the field of HDAC inhibitors. This conference report highlights selected presentations on HDAC inhibitors for the treatment of cancer, inflammation, and neurodegenerative and other CNS diseases. Investigational drugs discussed include several compounds under evaluation by Karus Therapeutics Ltd, OCID-4681 (Orchid Research Laboratories Ltd) and EVP-0334 (EnVivo Pharmaceuticals Inc).

JAMA Network OpenQ1 · MEDICINE

A Randomized Clinical Trial

Q1 · MEDICINE

ArticleOA

Author: Vandenberghe, Rik ; Koenig, Gerhard ; McGinnis, Scott M. ; Hannequin, Didier ; Marek, Ken ; Wisniewski, Gary ; Haynes, Beth Ann ; Koestler, Mary ; Rojas, Julio C. ; Onofrj, Marco ; Le Ber, Isabelle ; Mummery, Catherine J. ; Riordan, Henry J. ; Auriacombe, Sophie ; Pasquier, Florence ; Edwards, Lauren ; Borroni, Barbara ; Ljubenkov, Peter A. ; Iaccarino, Leonardo ; Goodman, Ira J. ; Boxer, Adam L. ; Boeve, Bradley F. ; van Swieten, John C. ; Grossman, Murray ; La Joie, Renaud ; Hesterman, Jacob ; Moebius, Hans ; Frisoni, Giovanni B. ; Harris, Baruch ; Hilt, Dana ; Patzke, Holger

ImportanceHistone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations.ObjectiveTo characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency.Design, Setting, and ParticipantsIn this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021.InterventionsDaily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days.Main Outcomes and MeasuresPrimary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]).ResultsA total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2 to -2.2 × 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 × 10-5 SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4 to -5.6 × 10-5; P < .001), and high CSF t-tau (-7.2 × 10-4 SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3 to -9.5 × 10-5; P = .03).Conclusions and RelevanceIn this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible.Trial RegistrationClinicalTrials.gov Identifier: NCT02149160.

News (Medical) associated with EVP-0334

11 May 2010

·www.biospace.com

EnVivo Pharmaceuticals, Inc. Initiates Phase IIb Alzheimer's Disease Trial For EVP-6124

WATERTOWN, Mass., May 11 /PRNewswire/ -- EnVivo Pharmaceuticals today announced the initiation and dosing of patients in a Phase IIb study of its EVP-6124 compound, a selective alpha-7 nicotinic agonist in patients with mild to moderate Alzheimer's disease. The multi-center, dose ranging, placebo controlled, six-month study taking place in the U.S. and Europe is designed to determine the safety and efficacy of EVP-6124 in producing procognitive effects and improving the clinical condition of Alzheimer's disease patients. "Patients with Alzheimer's disease have a number of symptomatic therapies available to them. However, the effects of the available medications are modest. Even if significant progress is made in slowing disease progression, more effective therapies that sustainably improve the cognition of the patients are clearly needed," said Kees Been, EnVivo president and CEO. "There is growing consensus that alpha-7 nicotinic agonists can potentially improve the cognitive function in Alzheimer's disease patients as evidenced by the number of large pharmaceutical companies advancing similar drugs through development. The potential upside for patients is considerable and we look forward to completing our Alzheimer's disease study by the middle of next year." The Phase IIb study will enroll mild to moderate Alzheimer's disease patients who will be randomized to three separate doses of EVP-6124 or placebo over six months. Efficacy will primarily be determined by the ADAS-Cog scale, a commonly used and accepted measure of cognition in patients with Alzheimer's disease. Secondary assessments will include other cognitive and clinical measures. EVP-6124 also is being tested in patients with schizophrenia in a separate Phase IIb study that started in late 2009. Two previous studies with EVP-6124 in Alzheimer's disease patients demonstrated that it was well tolerated and produced significant effects on a variety of cognitive measures of brain function such as attention, memory and executive function (complex thinking tasks). EVP-6124 had procognitive effects in two separate clinical trials: one study conducted in Alzheimer's disease patients already treated with Acetyl Choline Esterase Inhibitors (AChEI) and one in Alzheimer's disease patients not on AChEI therapy (naive patients). EVP-6124 is a selective agonist for the alpha-7 subtype of the nicotinic acetylcholine receptor and is being developed by EnVivo for potential cognitive enhancement in both schizophrenia and Alzheimer's patients. It has been shown to have excellent CNS penetration, oral bioavailability, pharmacokinetics and metabolic profile. About EnVivo Pharmaceuticals EnVivo Pharmaceuticals, located in Watertown, Mass., is a biopharmaceutical company dedicated to discovering and developing small molecule therapeutics for disorders of the central nervous system, with a current focus on Alzheimer's disease, cognitive disorders and schizophrenia. The company's lead product is an alpha-7 nicotinic acetylcholine receptor agonist and has been tested in Phase IIa clinical trials for cognition disorders in Alzheimer's disease and schizophrenia. The company's other programs include an epigenetics program based on Histone Deacetylase inhibition (HDACi) with EVP-0334 as the lead molecule for cognition in Alzheimer's disease which has completed Phase I studies, and several preclinical programs such as a Gamma Secretase Modulator (for Alzheimer's disease) and a PDE10 inhibitor program (for schizophrenia). For more information about EnVivo, visit . SOURCE EnVivo Pharmaceuticals

Small molecular drug

100 Deals associated with EVP-0334

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Dementia	Phase 2	US	Mirati Therapeutics, Inc.	-
Dementia	Phase 2	GB	Mirati Therapeutics, Inc.	-
Dementia	Phase 2	BE	Mirati Therapeutics, Inc.	-
Dementia	Phase 2	NL	Mirati Therapeutics, Inc.	-
Dementia	Phase 2	IT	Mirati Therapeutics, Inc.	-
Frontotemporal Dementia	Phase 2	-	FORUM Pharmaceuticals, Inc.	-
Frontotemporal Dementia	Phase 2	-	FORUM Pharmaceuticals, Inc.	-
Parkinson Disease	Phase 2	US	FORUM Pharmaceuticals, Inc.	-
Alzheimer Disease	Preclinical	US	EnVivo Pharmaceuticals	-
Dementia	Preclinical	FR	Mirati Therapeutics, Inc.	-

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