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 potential clinical indication for FRM-0334 is the treatment of a subset of
inherited frontotemporal dementia (FTD) that is due to mutations in the
granulin (GRN) gene (FTD-GRN). FTD-GRN is part of the heterogenous
frontotemporal lobar degeneration (FTLD) syndrome. The various disease entities
of the FTLD syndrome have an early onset (<65 years) and account for 5 to 10%
of all dementia and 10 to 20% of early onset dementia (Eriksen and Mackenzie,
2008).
In general, FTD is characterized by changes in personality, cognition (eg,
language impairment and executive dysfunction), and behavior (eg,
disinhibition, apathy, and compulsivity) (van Swieten and Heutink, 2008).
Common FTLD syndromes include: behavioral variant FTD, semantic dementia,
progressive apraxia of speech, agrammatic aphasia, progressive supranuclear
palsy syndrome, cortico-basal syndrome, amyotrophic lateral sclerosis with
dementia, FTD with motor neuron disease, and other less common syndromes. In
particular, the clinical phenotype of FTD-GRN is highly variable. The clinical
phenotype is usually a combination of behavioral abnormalities and language
disturbances that is most often a form of primary progressive aphasia. Mild
Parkinsonism is common, but motor neuron disease is notably rare. Marked
variation in the disease course and clinical features are common, not only
between families with different mutations, but also within individual families.
This degree of clinical variability makes it difficult to predict which cases
of familial FTD will turn out to have a GRN mutation (Mackenzie, 2007).
Approximately 10 to 50% of FTD cases are inherited in an autosomal dominant
fashion, with mutations in several genes causing pathogenesis (Eriksen and
Mackenzie, 2008; Gass et al, 2012). These include mutations in the genes
encoding microtubule-associated protein tau, progranulin (PGRN), valosin
containing protein, charged multivesicular body protein 2B, transactive
response deoxyribonucleic acid (DNA) binding protein 43 (TDP-43), and fused in
sarcoma, and most recently in the repeat expansion of the chromosome 9 open
reading frame 72 gene (C9Orf72) (Dobson-Stone et al, 2012).
Neuropathologically, the FTLD syndrome can be divided into 2 major groups that
have a clear correlation with their genetic background, including those with
tau-positive inclusions and those with ubiquitin- and TDP-43-positive
inclusions. Recently, mutations in GRN on chromosome 17q21 were found to cause
an FTLD variant with ubiquitin- and TDP-43-positive inclusions (Cruts et al,
2006; Baker et al, 2006; Gass et al, 2012). Seventy pathogenic GRN mutations in
over 230 families have been described for FTD-GRN to date. These mutations
include frameshift, splice-site, and nonsense mutations that are predicted to
produce a premature stop codon. The mutations result in haploinsufficiency and
a greater than 50% reduction in expression of PGRN in plasma (Ghidoni et al,
2012). At present, there are no drugs available to treat GRN haploinsufficiency
and the resulting neurodegeneration and dementia of FTD-GRN.
In the adult brain, GRN messenger ribonucleic acid (mRNA) and PGRN
immunoreactivity are located in certain neuronal populations (eg, pyramidal
cells of cortex and hippocampus and cerebellar Purkinje cells) and in microglia
(Eriksen and Mackenzie, 2008). In neuroinflammatory and neurodegenerative
diseases, microglia appear to produce and secrete the majority of PGRN, which
is taken up from the extracellular space by neurons (Sun and Eriksen, 2011). In
FTD-GRN, GRN haploinsufficiency and decreased PGRN levels may result in an
exaggerated neuroinflammatory response and/or loss of neurotrophic activities,
leading to neurodegeneration.
A suggested approach for the treatment of FTD-GRN caused by GRN
haploinsufficiency has been to increase PGRN levels. The histone deacetylase
(HDAC) inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) increased GRN
mRNA transcription and PGRN levels (Cenik et al, 2011). While SAHA increased
PGRN levels, it has limited central nervous system (CNS) penetration.
In the cell nucleus, DNA is tightly wound around proteins called histones, and
this DNA/histone association is called chromatin (de Ruijter et al, 2003). Gene
transcription depends on how tightly histones and DNA are associated; a looser
association promotes gene transcription. Acetylation of histones results in a
looser association of histone with DNA and therefore increases gene
transcription. Addition of an acetyl group onto histones is catalyzed by a
family of enzymes called histone acetyl transferases (HATs). Removal of acetyl
groups from histones, with subsequent decreases in gene transcription, is
catalyzed by a family of enzymes called HDACs. Thus inhibition of HDACs will
result in retention of acetyl groups on histones, thereby maintaining a loose
association between histone and DNA and increasing gene transcription. Although
histone deacetylation is the best understood function of HDACs, other proteins
in the cell can be deacetylated (Spange et al, 2009).
Furthermore, several lines of evidence indicate that HDACi may be useful for
the treatment of memory loss in patients with dementia (Tully et al, 2003;
Sweatt, 2007; Abel and Zukin, 2008; Fischer et al, 2010). In a transgenic mouse
model that displays substantial atrophy in brain regions involved in cognition
and memory, such as the hippocampus and cerebral cortex, HDACi restored memory
function tested in associative learning and spatial learning memory tasks
(Fischer et al, 2007). These results implicate HDACi as potential treatments
for cognitive disorders that arise from neurodegeneration (Sweatt, 2007).
In conclusion, the effects of SAHA on GRN mRNA and PGRN levels suggest that a
brain penetrant HDACi may be useful for treating FTD-GRN. FRM-0334 is a brain
penetrant HDACi and has shown the potential to elevate GRN mRNA and PGRN levels
in a variety of in vitro and in vivo models relevant to FTD-GRN due to GRN
haploinsufficiency and to enhance cognition in animal models. Addressing the
GRN haploinsufficiency associated with GRN mutations by increasing PGRN
expression may offer a method to potentially treat these patients.

2.1 Primary Objectives
• Evaluate the safety and tolerability of 2 fixed doses of FRM-0334 (300 and
500 mg daily in 2 sequential periods) over 28 days in subjects with prodromal
to moderate FTD-GRN
• Assess the PD effects of FRM-0334 on the change from baseline in plasma
concentrations of PGRN after 28 days
2.2 Secondary Objectives
• Assess the PD effects of FRM-0334 on the change from baseline in CSF
concentrations of PGRN after 28 days
• Characterize the plasma and CSF concentrations of FRM-0334 and metabolites
following once daily dosing after 28 days
• Characterize the intra- and inter-individual variability in plasma and CSF
concentrations of PGRN
2.3 Exploratory Objectives
• Assess the effects of FRM-0334 after 28 days on the change from baseline in
function using the Frontotemporal Dementia Clinical Dementia Rating Sum of
Boxes (FTD-CDR-SB) scale and the Alzheimer*s Disease Cooperative Study -
Clinical Global Impression of Change (ADCS-CGIC) scale, and activities of daily
living using the Frontotemporal Dementia Rating Scale (FRS) in subjects
requiring a support person
• Assess the PD effects of FRM-0334 after 28 days on the change from baseline
in plasma concentrations of PGRN mRNA and the CSF concentrations of total tau
(t-tau), tau phosphorylated at threonine 181 (p-tau181), 42 amino acid form of
β-amyloid (Aβ42), neurofilament light chain (NF-L) and additional CSF
biomarkers (eg, TDP-43), as technically feasible, and regional cerebral glucose
metabolism using 18F-FDG-PET

This is a randomized, double-blind, placebo-controlled, dose-escalating, Phase
2a study to evaluate the safety, tolerability, PD, and PK of FRM-0334 for 28
days in subjects with prodromal to moderate FTD-GRN. For this study, the
condition of *prodromal* does not require any clinically visible or measurable
symptoms, but only the presence of the genetic mutation FTD-GRN. Subjects will
receive FRM-0334 or placebo during 2 sequential periods (Group 1: 300 mg or
placebo; Group 2: 500 mg or placebo [identical number of subjects per period]).
After all subjects in Group 1 (300 mg [n=12] or placebo [n=3]) have been
randomized and completed (or discontinued) double-blind treatment, safety,
tolerability, and any available PK data will be reviewed in a blinded fashion.
Randomization of subjects into Group 2 (500 mg [n=12] or placebo [n=3]) will
begin only after the 28-day, double-blind safety, tolerability, and available
PK data for Group 1 (300 mg or placebo) are deemed acceptable by the Medical
Monitor and the Sponsor. Blinded safety, tolerability, and PK data for the 500
mg cohort will be reviewed on an ongoing basis. Enrollment will be competitive.
Recruitment will be terminated after randomization of 30 subjects.

Once daily oral dosing of 300 or 500 mg FRM-0334 as a white, opaque, size No.
1, hard gelatin capsule for 28 days, supplied as a 100 mg capsule that will be
size- and color-matched to the placebo capsule. As a reference standard, once
daily oral dosing of placebo for 28 days, supplied as a capsule that will be
identical in appearance to the 100 mg FRM-0334 capsule.

Risks Associated With FRM-0334
There is a risk of side effects (unwanted effects or health problems) from
taking FRM 0334. Some of these risks may be serious or even life-threatening.
If you take FRM-0334 and suffer lasting or serious side effects, it might
affect your private medical insurance coverage.

Some effects are headache, muscle pain, diarrhea, and flatulence. Two subjects
treated in a prior study of FRM-0334 had mild elevations of liver function
tests which required further monitoring but no medical treatment and there was
no liver damage

There is a risk of side effects (unwanted effects or health problems) from
taking FRM*0334.
There has been 1 study with FRM-0334; 87 people have taken at least one dose of
the FRM-0334. The most common side effects of FRM-0334 during this study were:
headache, muscle pain, diarrhea, and gas. Two subjects in the study had
increases in certain blood tests that measure how the liver functions. These
changes were mild and required further monitoring but did not require treatment
and there was no liver damage.