Probiodrug AG
reports First Quarter 2018 Business Update
HALLE (SAALE),
Germany, 15 May 2018 - Probiodrug AG (Euronext Amsterdam: PBD),
a clinical stage biopharmaceutical company developing novel
therapeutic solutions to treat Alzheimer's disease (AD), today
announces its first quarter business update for the period ending
31 March 2018, in the form of an interim management
report.
The interim management report for
the first quarter 2018 is available to download on the company
website
(http://www.probiodrug.de/investors/reports-and-presentations/).
OPERATIONAL
HIGHLIGHTS
-
Presentation of inhibition of
Glutaminyl Cyclase as a new treatment concept for
Alzheimer's Disease at the 255th ACS National
Meeting & Exposition in New Orleans, USA
-
Expenditures and corresponding
liquidity position (31 March 2018, EUR 9.3 million) in line with
management expectations
-
On 3 April 2018 (post period end)
detailed study design of PQ912 Phase 2b core program outlined
during full year 2017 financial results presentation
-
On 23 April 2018 (post period end)
Probiodrug announced the appointment of Dr Ulrich Dauer as Chief
Executive Officer effective 1 May 2018; Dr Konrad Glund and Dr
Hendrik Liebers left the executive team effective 30 April 2018 and
continue to support in advisory roles
Commenting on the
results, Dr Ulrich Dauer, Chief Executive Officer of Probiodrug,
said:
"This is an exciting time ahead for Probiodrug. We are very pleased
by the promising results of our Phase 2a SAPHIR trial and focused
on taking our lead drug candidate PQ912, towards Phase 2b, i.e.
clinical proof of concept.
"We are also encouraged by the
newest FDA and EMA draft guidance for early AD trials as published
in February 2018. The development strategy of the Phase 2b core
program has built in this draft guidance for which
our European study is in the setup phase, and the US study is
in an advanced stage of planning. We firmly believe that our novel
therapeutic approach to a disease modifying treatment for AD bears
the potential to make a true difference for patients suffering from
this devastating disease."
OPERATIONAL
REVIEW
Pipeline
update
Probiodrug's therapeutic approach targets pyroglutamate-Abeta
(pGlu-Abeta, also called N3pG Abeta) as a therapeutic strategy
to fight Alzheimer's disease (AD). This modified Abeta is
considered to be linked with disease initiation and progression by
seeding the formation of soluble neurotoxic amyloid oligomers.
Probiodrug is developing proprietary product candidates to target
toxic pGlu-Abeta via two modes of action: by (i) inhibiting the
production of pGlu-Abeta; and (ii) clearing existing pGlu-Abeta
from the brain.
Probiodrug's innovative approach
is based on the development of specific inhibitors for the enzyme
Glutaminyl Cyclase (QC), which is instrumental in the formation of
pGlu-Abeta. In addition, the company is developing a monoclonal
antibody targeting pGlu-Abeta to enhance its clearance.
To date, Probiodrug's pipeline
consists of two small molecule inhibitors of the QC-enzyme, PQ912
and PQ1565, and a monoclonal antibody, PBD-C06, targeting
pGlu-Abeta.
PQ912
Encouraging Phase 2a
data
In June 2017 Probiodrug communicated positive pharmacodynamic and
efficacy results of PQ912 in the Phase 2a SAPHIR Study. The
randomized, double-blind multi-center study enrolled 120 patients
with early stage Alzheimer's disease, surpassing the 110 patients
planned in the study protocol. The study was led by internationally
renowned experts in AD in seven European countries at 21
sites, with the Alzheimer Center, VU Medical Center (VUmc),
Amsterdam, NL being the lead center.
The SAPHIR study was the first
clinical trial to investigate PQ912 in patients with early AD over
a treatment period of 12 weeks. The primary endpoint of the trial
was the safety and tolerability of PQ912 compared with placebo over
a three-month treatment period. Additionally, a set of exploratory
read-outs comprising cognitive tests, functional assessments by EEG
and functional MRI and new molecular biomarkers in CSF were used to
evaluate the compound's effect on the pathology of AD, in
particular the effect on synaptic impairment, an early pathological
change in the early stages of AD.
The highest dose of 800mg bid
PQ912 used in the Phase 1 multiple dose study was applied and
showed a high level of target engagement (QC inhibition),
confirming the finding in Phase 1 in elderly healthy volunteers of
more than 90%, significant improvements of one test of working
memory (one back test) and a clear trend in detection test
(attention domain). At the functional level a very significant
positive effect was found on the EEG theta power. Regarding
exploratory biomarkers in the spinal fluid, encouraging results in
the right direction on synaptic and inflammatory CSF markers were
obtained. Regarding safety overall no major safety concern
associated with PQ912 was raised. There were no significant
differences in the number of subjects with AE or SAE between active
and control arm. A significantly higher number of patients
discontinuing within first weeks of treatment with PQ912 compared
to placebo was observed; there were clinically relevant differences
in the number of patients with skin and GI effects. These events
appeared early in the study and were fully reversible. Safety and
tolerability are likely to be improved by lower dose, still showing
a high enzyme inhibition, and a slower titration regime. In summary
the study revealed a positive benefit risk ratio of PQ912 and
provides important guidance how to move forward in the development
of PQ912 as a disease-modifying drug for AD.
Detailed design of Phase 2b core program presented (post
period)
In October 2017, Probiodrug announced the initiation of the Phase
2b core program for PQ912 and detailed the strategy. The Phase 2b
core program is planned to comprise of two complementary clinical
Proof of Concept studies in Europe and the USA. The development
strategy has built in the newest FDA and EMA draft guidance for
early AD trials as published in February 2018. In April 2018
Probiodrug presented the detailed study design of the Phase 2b core
program.
The Phase 2b core program will
consist of two clinical trials, to be executed in the European
Union (EU) and the USA, respectively. The first Phase 2b study is
intended to investigate the safety and efficacy of the optimal dose
range of PQ912 in early AD patients. This trial will build on the
excellent and efficient infrastructure which was established for
the Phase 2a SAPHIR study. Moreover, it is based on the valuable
results of the SAPHIR study and has been designed with the guidance
of international KOLs in the Alzheimer's field. Prof Philip
Scheltens, MD PhD, Director of the Alzheimer Center VU University
Medical Center Amsterdam, NL will once again serve as Principal
Investigator and Chairperson for this study, which is to be
conducted in the EU. A second complementary study is currently in
the planning phase and is intended to be carried out in the USA and
will also be chaired by a highly renowned Principal
Investigator.
Combination therapies
Probiodrug is also working on potential combination therapies.
Here, new positive results with PQ912 and PBD-C06 alone and in
combination in AD animal models have been presented at the
13th International
Conference on Alzheimer's and Parkinson's Diseases
(AD/PDTM 2017),
Vienna, Austria.
Huntington's disease
Probiodrug is exploring potential second indications for its QC
inhibitors. PQ912 demonstrated beneficial effects in a preclinical
Huntington's disease (HD) model; the data of this study have been
presented at the 12th Annual HD
Therapeutics Conference of the CHDI Foundation, Malta, in
April 2017. HD is the most common inherited neurodegenerative
disorder where, due to a mutation, the poly-glutamine amino acid
sequence is expanded in a protein called huntingtin (HTT). There is
currently no disease modifying therapy for this condition. PQ912
clearly improved several signs of the disease in a well
characterized BACHD mouse model of HD. BACHD mice carry the human
gene for mutant HTT (mHTT). At six weeks old, parallel to the onset
of first behavioral changes, metabolic and neuropathological signs
of the disease become visible. The BACHD mice were treated for
18 weeks with food pellets containing PQ912. PQ912 treatment
for 18 weeks caused a significant reduction (approximately
30%) in brain mHTT levels. These lowered mHTT levels were
associated with reduced levels of the inflammation/gliosis marker
GFAP-protein, a striking normalization of the abnormal body weight
gain, the energy metabolism as well as of several mRNA levels
coding for HSPs in BACHD mice at 24 weeks of age.
PBD-C06
PBD-C06 is a monoclonal antibody, currently in preclinical stage.
PBD-C06 targets pGlu-Abeta, aiming to selectively clear the brain
of pGlu-Abeta while leaving non-toxic forms of Abeta untouched.
PBD-C06 has been successfully humanized and also de-immunized to
avoid detection by the patient's endogenous immune system. For the
first time for an anti-pGlu-Abeta approach, PBD-C06 has not only
shown the ability to reduce Abeta/plaques but also to significantly
improve cognitive deficits in aged Alzheimer's mice. Moreover, no
evidence was found of increased microhemorrhages after treatment
with PBD-C06.
PBD-C06 revealed a unique binding
mode, published in the Journal of Biological Chemistry (Piechotta et al., J. Biol. Chem. 2017 292:12713).
PQ1565
PQ1565 is a QC-inhibitor, currently in preclinical stage. The
product candidate has shown attractive drug-like properties in
preclinical studies. The compound is ready for regulatory
toxicology studies.
Operational
Update
Probiodrug gave a presentation entitled "Inhibition of glutaminyl cyclase as a new concept for the
treatment of Alzheimer's disease: PQ912, the first-in-class
QC-inhibitor in clinical development for AD" at the
255th National
Meeting & Exposition of the American Chemical Society (ACS),
New Orleans, USA in March 2018.
The presentation highlighted
Probiodrug's first-in-class small molecule QC-Inhibitor PQ912,
selected for development due to a good drug-like profile and a
comprehensive preclinical proof of concept data package showed an
excellent dose-dependent brain penetration and target engagement in
man and an attractive therapeutic window. The first 3-month trial
in early AD patients provided a set of positive pharmacodynamic and
efficacy results which all support the underlying concept of
QC-Inhibition reducing the seeding of highly synaptotoxic oligomers
and providing guidance for the outline of the next Phase 2b study
(see Pipeline Update above).
CORPORATE
REVIEW
Financials
The first quarter of 2018 was characterized by EUR 1,026k research
and development expenses, significantly lower than in the first
quarter of 2017 (EUR 2,268k). The higher costs in the first quarter
2017 resulted from the Phase 2a study (SAPHIR) of PQ912, which was
completed in the second quarter 2017. General and administrative
expenses amounted to EUR 513k and were at the same level as in the
first quarter of 2017 (EUR 507k). In the first quarter 2018
the Company has not generated any revenues, also in line with the
corporate planning. Correspondingly, the comprehensive loss of the
reporting period was EUR 1,511k, compared to EUR 2,798k in the
first quarter of 2017.
All results are in line with
management expectations.
Probiodrug held EUR 9.3 million in
cash and cash equivalents as of 31 March 2018.
POST PERIOD
UPDATE
Probiodrug
Appoints Dr Ulrich Dauer as Chief Executive Officer
On 23 April 2018, Probiodrug announced the appointment of Dr Ulrich
Dauer to the position of Chief Executive Officer effective 1 May
2018. He teams up with long-serving Chief Development Officer
Dr Inge Lues who has borne key responsibility for development of
Probiodrug's pipeline. Dr Konrad Glund, CEO and co-founder of the
company, retired effective 30 April 2018. CFO Dr Hendrik
Liebers, by mutual agreement, resigned from the Management Board
effective 30 April 2018. Dr Glund and Dr Liebers continue to
support Probiodrug in advisory roles.
Detailed study design of Phase 2b
core program of PQ912 presented on 3 April 2018, during full year
2017 financial results
The overarching Phase 2b development program will comprise two
trials, one in Europe and one in the USA. The trials will be
complementary having a set of key elements of the design in common
(such as patient population, inclusion criteria etc.) but will
include several differences such as treatment duration, additional
endpoints and difference in futility/interim analyses.
The clinical efficacy endpoints
will be sensitive measures of cognition and of activities of daily
living. Both studies will include dose titration and/or several
doses for efficacy and safety and are suitable to provide Proof of
Concept. The trials are designed according to the latest
regulatory guidelines by the FDA (draft) and the European EMA (both
February 2018). Probiodrug is pursuing a step-wise clinical
development approach with a current focus on clinical Proof of
Concept, which contrasts with a frequently used strategy for
other programs, jumping from Phase 1b/ to Phase 3 based
only on biomarkers effects - to increase time to market
but accepting a risk of late stage failure.
The European study is in the setup phase whereas the US study is in
advanced planning status.
The key design of the Phase 2b
core EU study SAPHIR 2 is built on the outcome of the Phase 2a
SAPHIR 1 study. Objectives are safety and efficacy evaluated
in two stages: stage one (3 months) will focus on safety
followed by stage 2 with efficacy as primary endpoint for a total
treatment duration of at least 9 months.
-
The target population
are patients with early AD as in SAPHIR
1; eligibility is defined by Abeta/p-Tau biomarker
cut-offs.
-
The Neuro-Psychological Test Battery (NTB) to be
used is identical to the one applied in the Phase 2a study. The
sample size of 250 patients to be randomized into the study was
calculated based on an extrapolated effect size for those tests of
the NTB, which were positively affected by PQ912 in the Saphir
trial. The progression of the extrapolated placebo group from
SAPHIR 1 was very much in line with the slope of control groups
from 4 different historical data sets provided
by Cogstate obtained from more than 300
patients.
-
The secondary endpoints will be the full NTB and
the Amsterdam Instrumental Activity of Daily Living Questionnaire,
the EEG and the synaptic marker neurogranin as well as the
inflammatory marker YLK-40, which were both reduced by PQ912 in the
SAPHIR 1 study.
-
The investigator trial network and the CRO core
team will be identical to the Phase 2a study, additional
countries and sites will be added.
In summary, the innovative design of the EU study
has a long enough treatment duration to enable predictive cognitive
read-outs and to inform about an optimal dose.
Invitation to
Probiodrug's Ordinary General Meeting of Shareholders on 21 June
2018
On 09 May 2018 Probiodrug invited its shareholders to its ordinary
general meeting of shareholders to be held on Tuesday, 21 June 2018
at 11:00 am (CEST), at the das Leonardo Royal Hotel Berlin
Alexanderplatz, Otto-Braun-Straße 90, 10249 Berlin, Germany. The
relevant documents can be found at
http://www.probiodrug.de/investors/annual-shareholders-meeting-2018/.
###
For more
information, please contact:
Probiodrug
Dr Ulrich Dauer, CEO
Email: contact@probiodrug.de
Optimum Strategic
Communications
Mary Clark, Supriya Mathur, Hollie Vile
Tel: +44 (0) 203 714 1787
Email: probiodrug@optimumcomms.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 clinical stage biopharmaceutical company
focused on the development of new therapeutic products for the
treatment of Alzheimer's disease (AD). Probiodrug has identified a
new therapeutic concept linked to disease initiation and
progression. The development approaches are targeting a key
neuro-/synaptotoxic component of the pathology, pyroglutamate-Abeta
(pGlu-Abeta) as a therapeutic strategy. Its lead product, PQ912,
has successfully completed a Phase 2a (SAPHIR) study. The company's
pipeline also includes PBD-C06, an anti-pGlu-Abeta-specific
monoclonal antibody, in preclinical development. Probiodrug has
medical use and composition of matter patents related to the
inhibition of QC and anti-pGlu-Abeta-specific monoclonal
antibodies, and has, in the Company's view, a leading position in
this field of research.
About
PQ912
PQ912, is a first in class, highly specific and potent inhibitor of
Glutaminyl Cyclase (QC), the enzyme catalyzing the formation of
synaptotoxic pGlu-Abeta. PQ912 has shown therapeutic effects in AD
animal models. A Phase-1 study in healthy young and elderly
volunteers revealed a dose dependent exposure and showed good
safety and tolerability up to the highest dose with >90%
target occupancy in the spinal fluid. In June 2017, Probiodrug
announced top-line data of the Phase-2a SAPHIR trial of PQ912 and
presented the study results at CTAD 2017. Results strongly support
(a) the hypothesis of pGlu-Abeta being synaptotoxic and (b) the
therapeutic concept pursued by Probiodrug. The study provides
important guidance how to move forward in the development of PQ912
as a disease-modifying drug for AD. Altogether, the results make
the program highly attractive for further development; the company
has initiated the preparation of a Phase 2b core program.
Founded in 1997 by Hans-Ulrich
Demuth and Konrad Glund, 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. Today, Probiodrug aims to become a leading company in the
development of AD treatments and to thereby provide a better life
for Alzheimer's disease patients.
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. Today, 47
million people live with dementia worldwide, and this number is
projected to treble to more than 131 million by 2050, as the global
population ages. 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.