Probiodrug announces encouraging results of the
Phase 2a SAPHIR Study
HALLE (SAALE), Germany, 11 June 2017 -
Probiodrug AG (Euronext Amsterdam: PBD), a biopharmaceutical
company developing novel therapeutic solutions to treat Alzheimer's
disease (AD), today announced first line results of its Phase 2a
SAPHIR study in early AD patients.
The
SAPHIR study is the first clinical trial to investigate the
Glutaminylcyclase (QC) inhibitor PQ912 in patients with early AD
over a treatment period of 12 weeks. The highest dose of 800mg bid
PQ912 used in the Phase 1 multiple dose study and showing a very
high target occupancy was compared to placebo to identify early
efficacy and safety signals to optimally plan future long-term dose
ranging studies.
The
primary objective of the SAPHIR study was to investigate the safety
and the tolerability of PQ912. Secondary objectives were to assess
early effects of PQ912 on the exploratory endpoints NTB, EEG,
cerebro-spinal fluid (CSF) biomarkers related to the QC-inhibition
(mechanism of action) and to the AD pathology.
Methodology: The SAPHIR study is a
double-blind, placebo controlled randomised study carried out in 7
European countries at 21 study sites in treatment naïve patients
with early AD disease. The statistical analysis of the endpoints
was based on two-sided tests with a significance level of alpha
0.05 and not corrected for multiplicity. Results presented in this
press release are for the Intention to treat (ITT) population based
on a 'complete case' analysis.
Results: A total of 120 patients were
randomised in the SAPHIR study, 60 to the placebo arm and 60 to
PQ912 arm. Treatment arms were well balanced with respect to age,
gender, disease severity and APOE4 status. The mean MMSE
(Mini-Mental State Examination) score at baseline was 25.5 (min-max
21-30).
Safety and tolerability results (primary
objective): There were no statistically significant differences
of PQ912 vs placebo between the number of patients experiencing an
adverse event (PQ912 n=49, placebo n=45) or the number of patients
with a serious adverse event (PQ912 n=8; placebo n=5). Patients in
the treatment arm did show a significantly higher discontinuation
rate due to SAE or grade 3 adverse events compared to patients in
the placebo arm (PQ912 n=6; placebo n=0, p=0.027) and the total
number of patients non-adherent to randomised treatment for any
reason was higher in the treatment arm (PQ912 n=26; placebo n= 2;
p<0.01). Skin and gastrointestinal organ system related adverse
events were observed in a higher frequency in the PQ912 arm
compared to placebo and occurred in the majority in the first half
of the treatment period. Dose reductions prescribed by the
investigator were identical in the treatment and the placebo arm
(both n=5).
Results of the secondary exploratory
endpoints:
Molecular biomarkers in the CSF: CSF
analyses showed a highly significant QC inhibition (p=0.001),
corresponding to a calculated target occupancy of 92% (median),
which was achieved in patients with last drug intake within 24
hours before CSF sampling. A decrease in pGlu-Abeta oligomers in
the CSF was observed in the treatment arm whereas pGlu-Abeta
oligomers increased in the placebo arm. This directional
change demonstrates, together with the significant QC-enzyme
inhibition, a strong and robust target engagement.
There
was a strong trend for reduction in the level of neurogranin, a
marker of synaptic dysfunction in the ITT population in the
treatment arm compared to placebo (p=0.1), which became significant
if 3 patients starting prohibited concomitant medication during the
study were excluded (p=0.046, a 5% absolute reduction of baseline
in neurogranin observed in the treatment arm). There was also
a strong trend in the mean reduction of YKL 40, a biomarker of
inflammation, in the PQ912 arm compared to placebo (p= 0.07, 5%
absolute reduction of baseline-level in the treatment arm).
EEG: The analysis of the EEG power spectra
showed a significant reduction of theta power in the PQ912 arm
compared to placebo (p=0.002). Slow wave theta activity is reported
to increase with the onset and progression of AD. Further analysis
of functional connectivity and EEG network parameters is
pending.
Neuropsychological test battery (NTB):
Patients in the placebo arm showed overall a stable performance
with no or marginal change between baseline and week 12.
Performance on the 'One Card Back Test', an assessment of
working memory showed a statistically significant effect in favour
of PQ912 (p=0.05, Cohen's d = 0.24) while the 'Detection Test' an
assessment of attention, also showed a meaningful improvement under
PQ912 (Cohen's d=0.20) although not sufficient to reach statistical
significance. Performance on the five other cognitive
assessments, as well as on their aggregate scores, were not
influenced by treatment with PQ912 for 12 weeks (Cohen`s d <
0.2).
Additional analysis comprising all endpoints, further CSF biomarker
and subpopulations will continue during the next several months and
the full results of the SAPHIR study are intended to be reported at
scientific congresses and published in scientific journals.
Philip Scheltens, Director of the Alzheimer Center
VU University Medical Center Amsterdam, and Principal Investigator
of the SAPHIR study commented: The population studied was
very representative of patients with early AD. The primary
objective of the SAPHIR study was safety and tolerance. Although
differences between treatment arms were observed we are confident
that the drug is safe and well tolerated in the AD population. We
set out to detect small signals on the various sensitive secondary
exploratory outcome measures in a relatively short time frame and
were happy to see very strong target engagement, significant
effects on a working memory task and EEG theta power and
encouraging results in the right direction on synaptic and
inflammatory CSF markers. These results point to a direct effect on
pGlu-Abeta with beneficial effects on synaptic function, even in
such a short treatment period.
Inge Lues, Chief Development Officer at Probiodrug
commented: We are very positively encouraged by the
outcome of the SAPHIR trial and look forward to the results of
further analyses. The results observed support our hypothesis of
pGlu-Abeta being synaptotoxic. The SAPHIR study was designed to
guide the future development of PQ912 in AD. In this first
in-patient study, we used a high dose achieving about 90% QC
occupancy to meet two goals: to get a first picture of frequency
and types of safety and tolerability events and at the same time to
test for early signals of efficacy in a relatively short treatment
period of 12 weeks.
The
results will guide the design of future studies of PQ912 and
support the use of lower doses of PQ912 still reaching relevant
target occupancy of the QC enzyme, as well as the option to
introduce a titration phase for the 800 mg bid dose. We are
encouraged by having observed early indicators of response to PQ912
in the CSF, the EEG and the NTB. The results we have today in our
hand are tremendously useful to deliver a tailored future
development program.
CONFERENCE CALL
Probiodrug will host a conference call open to the public Monday,
June 12th, at 15:00
Central European Summer Time (CEST). The conference will be held in
English. To participate in the conference call, please call one of
the following numbers ten minutes prior to commencement:
Please
dial one of the following access numbers,
then enter the PIN Code: 17625824#
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A
Question and Answer session will follow the presentation of
results.
###
For more information, please contact:
Probiodrug
Dr Konrad Glund, CEO
Email: contact@probiodrug.de
Hume Brophy
Conor Griffin, Alexander Protsenko, Jonothan Blackbourn
Tel: +44 (0) 20 7862 6381
Email: probiodrug@humebrophy.com
The Trout Group
Tricia Truehart
Tel: +1 (646) 378-2953
Email: ttruehart@troutgroup.com
MC
Services AG
Anne Hennecke, Caroline Bergmann
Tel: +49 (0) 211 529 252 20
Email: probiodrug@mc-services.eu
Notes to Editors:
About Probiodrug AG
Headquartered in Halle (Saale), Germany, Probiodrug AG (Euronext
Amsterdam: PBD) is a biopharmaceutical company focused on the
development of new therapeutic products for the treatment of
Alzheimer's disease.
Founded
in 1997, the company successfully developed a novel therapeutic
concept for diabetes - the DP4 inhibitors - which provided the
basis for a novel class of antidiabetics - the gliptins. Its core
capabilities are based on its long-standing expertise in the
elucidation of the structure and function of enzymes involved in
the modification of proteins and peptides, which play a central
role in pathological conditions.
Today
Probiodrug's aim is to become a leading company in the development
of Alzheimer's disease treatments and to thereby provide a better
life for Alzheimer's disease patients. It has identified a new
therapeutic concept linked to disease initiation and progression.
The development approaches are targeting pyroglutamate-Abeta
(pGlu-Abeta) as a therapeutic strategy to fight Alzheimer's
disease. The Company has medical use and composition of matter
patents related to the inhibition of Glutaminyl Cyclase (QC) and
anti-pGlu-Abeta- specific monoclonal antibodies, providing it, in
the Company's view, with a leading position in this field of
research.
Probiodrug's lead product candidate, PQ912, is a highly specific
and potent inhibitor of Glutaminyl Cyclase (QC), which has shown
therapeutic effects in Alzheimer's animal models. PQ912 was
evaluated in a Phase 2a study, the SAPHIR trial. In a preceding
Phase 1 study with healthy young and elderly volunteers, PQ912 has
shown to be safe and well tolerated and also revealed high
QC-inhibition.
www.probiodrug.de
About Alzheimer's disease
Alzheimer's disease is a neurological disorder, which is the most
common form of dementia, and ultimately leads to death. Because
Alzheimer's disease cannot be cured and is degenerative, the
affected patients must increasingly rely on others for assistance.
Today, 47 million people live with dementia worldwide, and this
number is projected to treble to more than 131 million by 2050, as
populations age. Dementia also has a huge economic impact.
Alzheimer's has an estimated, global societal cost of US$ 818
billion, and it will become a trillion dollar disease by 2018.
(World Alzheimer Report 2016).
Forward Looking Statements
Information set forth in this press release
contains forward-looking statements, which involve a number of
risks and uncertainties. The forward-looking statements contained
herein represent the judgment of Probiodrug AG as of the date of
this press release. Such forward-looking statements are neither
promises nor guarantees, but are subject to a variety of risks and
uncertainties, many of which are beyond our control, and which
could cause actual results to differ materially from those
contemplated in these forward-looking statements. We expressly
disclaim any obligation or undertaking to release publicly any
updates or revisions to any such statements to reflect any change
in our expectations or any change in events, conditions or
circumstances on which any such statement is based.