A Randomized, double blind, placebo-controlled, parallel-group study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple oral doses of CNP520 in healthy elderly subjects

One of the main pathological features of Alzheimer*s disease (AD) is the
presence of amyloid plaques in the brain cortex. These plaques are constituted
of aggregated fibrils of amyloid-β (Aβ) peptides that derive from the amyloid
precursor protein (APP) (Masters and Beyreuther 2006). The amyloid cascade
hypothesis states that deposition of Aβ is an early event in the pathogenesis
of AD and may ultimately lead to neurodegeneration and dementia of the
Alzheimer type (Hardy and Selkoe 2002). Potential disease-modifying strategies
target decreasing Aβ generation from APP. Such strategies include inhibition of
beta-site-APP cleaving enzyme-1 (BACE-1) that catalyzes the processing of APP
and
formation of Aβ. CNP520 is a potent inhibitor of BACE-1 with 3-fold selectivity
over BACE-2 and no relevant off-target activity. Theoretical safety risks have
been identified in BACE-KO mice or reported for other BACE inhibitors. These
are believed to be due to BACE-2-mediated or off-target effects (e.g.
retinopathy, hair discoloration). None of these findings has been identified in
the completed toxicology studies with CNP520 up to 13 week duration. There have
been no clinical studies completed. The first-in-human (FIH) study is ongoing.
It is a randomized, double-blind, placebo-controlled, single and multiple
ascending oral dose study to assess the safety, tolerability, pharmacokinetics
(PK) and pharmacodynamics (PD) of
CNP520 in healthy adult and elderly subjects.

Primary objective:

To determine the safety and tolerability of multiple, once-daily oral doses of
CNP520 over 13 weeks in healthy elderly subjects
Safety: ECG, vital signs and laboratory data; assessment of cognitive function;
dermatological assessment and visual
field/acuity testing Tolerability: Adverse event data

Secondary objective:

To assess the change from baseline of CSF Aβ concentrations (Aβ1-38; Aβ1-40;
Aβ1-42) in healthy elderly subjects over 13 weeks
treatment with CNP520 as compared to placebo. Concentrations of Aβ 1-38, Aβ
1-40 and Aβ 1-42 in CSF over 13 weeks.
To determine the CNP520 plasma PK and CSF concentrations of once daily oral
doses of CNP520 over 13 weeks in healthy elderly
subjects.
Plasma PK parameters: Day 1: Cmax, Tmax, AUClast and if possible T1/2, AUCinf,
Vz/F and CL/F
Day 91: Cmax,ss, Tmax,ss, AUClast,ss, AUCtau,ss, T1/2, Vz/F, CLss/F and Racc.
Population PK analysis: PK results from current study will be pooled with other
studies.
CNP520 concentrations in CSF

Exploratory objectives:

To quantify additional PD biomarkers of the amyloid cascade in CSF including
sAPPα, sAPPβ and other Aβ isoforms.
Concentrations of additional PD biomarkers in CSF.
To quantify Aβ1-40 in plasma and potentially additional PD biomarkers of the
amyloid cascade in plasma.
Concentrations of Aβ1 -40 in plasma and potentially additional PD biomarkers in
plasma.
To perform exploratory genotyping to examine impact of genetic
variants/polymorphisms on safety, PK and/or PD of CNP520.
Genotype of targets that may modulate safety, PK and/or PD (e.g.
drug-metabolizing enzymes, receptors etc.).

This is a non-confirmatory study that is planned to be conducted at multiple
sites worldwide. This randomized, double-blind, placebo-controlled, study, has
a parallel-group design. Once-daily oral doses of CNP520 will be given over 13
weeks duration to healthy elderly
subjects aged 60 to 80 years.

The study will consist of an up to 28-day screening period, a 2 day baseline
period including a cerebrospinal fluid sample collection, and 13 week treatment
period followed by a Study Completion evaluation approximately 4 weeks after
the last drug administration.
Approximately 125 subjects will be randomized to five treatment groups:
* CNP520 2 mg o.d.,
* CNP520 10 mg o.d.,
* CNP520 35 mg o.d.
* CNP520 85mg o.d.
* Placebo
The randomization ratio will be 1:1:1:1:1. Hence, there will be approximately
25 subjects enrolled per treatment group and approximately 20 completers per
treatment groups are expected.

Safety assessments will include physical examinations, ECGs, vital signs,
standard clinical laboratory evaluations (hematology, blood chemistry,
urinalysis), Neurological examination, Cognitive assessments, C-SSRS,
ophtalmological assessments (Visual Field Test and Best corrected Visual
acuity), dermatological assessment, adverse event and serious adverse event
monitoring.
Refer to the Assessment schedule for further details of safety, pharmacodynamic
and PK assessments.
For dosing days when the subject does not have a scheduled visit, the subject
will take the drug and a diary (drug administration, AEs, Conmeds) will be
completed by the subject.
Dosing must occur in the morning (Assessment schedule).
Subjects will also be contacted by the site by phone at regular intervals to
obtain information regarding safety and tolerability as well as compliance with
study requirements including drug administration. In case of relevant safety
aspects identified during any of the 2 week outpatient periods, unscheduled
visits may be set up per investigator judgment.
In order to evaluate compliance of drug intake, subjects may be randomly called
for 2 or more unscheduled visits during the 13 weeks treatment period, where
additional unscheduled PK blood samples will be drawn. The investigator will be
responsible for scheduling these visits.
Study Completion evaluation will be performed approximately 4 weeks (+/- 4
days) after the last drug administration.

The most frequent adverse events associated with LPs include mild to moderate
procedural headache and catheter site pain. Other adverse events such as
infection, bleeding or spinal cord trauma are rare or very rare.

There have been no commonly reported adverse events identified in the First in
Human study that would require any specific treatment. Most commonly reported
AEs that were suspected to be drug-related were nervous system disorders
(mainly headache and dizziness).
Symptomatic treatment of these or other adverse events should be applied as
appropriate. In case of any QT prolongation by >60 ms compared to baseline the
following applies for subjects concerned:
If absolute QTcF < 500 msec:
* Maintain dosing
* Intensify individual ECG monitoring
If QTcF > 500 msec
* Suspend dosing (see Section 7.1)
* Apply continuous ECG monitoring subject and initiate consultation by a
cardiologist to decide on need for hospitalization. Obtain unscheduled safety
lab assessment primarily to quantify electrolytes.