BRAINco Biopharma Multiple sclerosis Drug Discovery project brochure. Licensing opportunity. Folleto descriptivo del proyecto de búsqueda y desarrollo de fármacos en Esclerosis Múltiple. Oportunidad de licencia.

1. LICE
ENSIN OPP
NG PORTU
UNITY
Y
New treatment for Multip Scler
ple rosis
Phosphodiester
rase 7 (PD
DE7) inhi
ibitors for the trea
atment of
f
Multip Sclero (MS)
ple osis
Advanta
A ages:
Ne small m
ew molecules with selec
ctive PDE activity
E7 y.
Mo
olecules a active in two well est
are e o tablished MS anim
mal
mo
odels.
Th
hey show Neuro
w oprotectiv
ve and Anti-In nflammatory
roperties, answering the main MS clini needs.
pr g n ical
When oral administered, compoun
W lly nds´ leve found in
els
br plasma sup
rain and p pport their biological activity
y.
Hyp
pothesis
PDEs are enzymes th regulate intracellula levels of
hat ar f
cAMP AM
MP
yclic adeno
cy osine monoophosphate (cAMP) and cyclic c
gu
uanosine m monophosphaate (cGMP). PDE7 enzymes
7 s PDE7
sp
pecifically co
ontrol cAMP levels.
P
cAMP pla key role in neuro
ays es onal functioons, such ass
ne
euronal survi ival, growth cone responnses, neurite outgrowth,
e ,
as well as in neuroprotect tion and neu
uroinflamma ation.
PDE7
PDE7 is e
expressed in immune and pro-inf
n flammatory
y inhibitors
ce as well a in brain.
ells, as
Anti‐
‐Inflammat
tion
Up-regulati of PDE
ion E7A and PDDE7B protein has been
ns n
Neu
uroprotection
ammation i a Parkin
ssociated to neuroinfla
as o in nson disease e
Neeurogenesi
is
moodel. In this mode el, PDE7 inhibitors protected d
omaninergic neurons an avoided m
do c nd microglial act
tivation after
r
dif
fferent insult
ts.
The
T control of cAMP l levels by PD specifi inhibitor represen a new th
DE7 fic rs nts herapeutic approach f
for
the trea
atment of neuroinflam
mmatory associated di
iseases, suc as MS.
ch

2.
Devel
lopmen Stage Candidate Id
nt e: dentification
BAC
CKGROUN
ND
The m goal of this project is the gener
main f ration, select
tion and dev
velopment of low molecu weight, orally availa
f ular able,
selec inhibitors for the treatme of MS. In addition to an anti-infl
ctive PDE7 in r ent n o activity, neuroprotective and
flammatory a
neurogenic propeerties are als pursued.
so
BRAAINco molecu have be specifically designed to interact with PDE7. The design a synthesi of more th a
ules een d w and is han
hund
dred compoun belongin to differen chemical f
nds ng nt families has led to the sel
l lection of two PDE7 inhibitors.
o
IMBCCo020 and IMBCo010 are the m most advance compoun out of several mol
ed nds lecules selec
cted for fur
rther
devel
lopment. A b
brief descript
tion of the da obtained with these tw compoun is present below.
ata wo nds ted
BIO
OCHEMICA AND C
AL CELL BASE ASSAY
ED YS
Enzy
ymatic activity:
IM
MBCo020 an IMBCo010 showed an in vitro PD inhibitio activity in the nanomo range (I
nd n DE7 on olar IC50).
N significant effect was found on oth PDEs.
No her
In
ncubation of different M relevant c types (ne
f MS cell euroblastoma and macro
a ophages cell lines, as well as rat prim
mary
as
strocytes) with BRAINco compounds resulted in an increase of cAMP lev (Fig.1).
o s vels
Neur
roprotection and Neuro
n ogenesis:
BRAINco co ompounds p protected M relevant cell types (macropha
MS s ages, astroc
cytes and microglia) f
m from
Li
ipopolysacch
haride (LPS) induced da
) amage (Fig.2).
Se
elected comp ced erentiation of postnatal oligodendrocy precursors and neuro
pounds induc the diffe o yte ospheres (Fig
g.3).
CNPase
*B ence PDE7 inhibi
BRL50481: refere itor
β-Tub
TH
Fig
gure 1. cAM MP production inn Figure 2. Neurop
e protection in Figure 3. Neurosphere differentiati
e ion analysed by
moouse macrophag cell line.
ge mouse macrophages, measured by
e , immunocy ytochemistry (C
CNPase: oligod
dendrocyte marrker,
nitrite production.
e β-Tub: neu
uronal marker a TH: dopami
and inergic marker)
).

3.
Development Stage: Candidate Identification
ANIMAL MODELS
Two well established MS animal models were used: the gold standard experimental autoimmune encephalomyelitis
(EAE) and the Theiler’s virus model.
Clinical Score:
Clinical scores were significantly improved in the animals treated with BRAINco molecules at the peak of the
disease (Fig.4 and 5).
Figure 4. Effect of IMBCo010 on EAE animal model. Figure 5. Effect of IMBCo020 on Theiler´s virus animal model.
Tissue analysis:
Immunohistochemical analyses of spinal cord samples from treated animals showed anti-inflammatory and
neuroprotective properties of the compounds (Fig.6 and 7).
Anti-inflammation Neuroprotection
Vehicle Vehicle
IMBCo020 IMBCo020
Figure 6. Decreased microglia reactivity (Iba-1) on the left and Figure 7. Myelin staining on the left and Neurofilament staining
decreased levels of TNF-α pro-inflammatory cytokine on the right.
(protection from axonal damage) on the right.
PHARMACOKINETICS, METABOLISM, AND SAFETY CHARACTERIZATION
Initial PK results after single oral administration showed that selected molecules were present both, in plasma
and brain, at levels supporting their biological activity.
The compounds also showed good ADME-tox and security profiles (Genotoxicity, Cardiotoxicity, Metabolism,
Off-target effects).

4.
Su
ummary
MS
M is an au utoimmune chronic inf flammatory disease of the central nervous sys
t stem, affectting the bra
ain
and
a the spin cord. Ac
nal ctive inflamm mation may determine the initial o
y e onset of the disease, fo
e ollowed by a an
irreversible neurodegen
i neration. A present, t
At there is no cure for M Current treatment strategies a
MS. s are
aimed at e
a enhancing t the quality of life o patients via modify
y of fying the d disease cou urse, treatinng
exacerbation and man
e ns naging symp ptoms. Unt recently, first line t
til therapies were long-ter injectab
rm ble
immunosuppressants, w a limit efficacy Currently new oral treatments are under developmen
i with ted y. y, d nt,
and
a the firs orally ad
st dministered drug, Fing golimod, ha been alr
as ready approoved. Neve ertheless, th
his
treatment m
t mainly target the inflam
ts mmatory com mponent of the disease
f e.
BRAINco i collabora
B is ating with a network of academ institutes in the de
mic evelopment of selectiv
ve
Phosphodiesterase 7 in
P nhibitors for the treatm
r ment of MS. Novel chem mical series have been designed b
s n by
virtual mod
v deling approoaches base on struct
ed tural inform
mation on th enzymes and Struc
he s cture Activity
Relationship analysis. Intellectua property has been generated covering th
R p al hese chemiical familie
es.
Selected com
S mpounds sh how anti-inflammatory and neurop
y protective p
properties in both, MS relevant ce
n ell
based assay and anim models. Compound are orally available, cross the blood brain barrier an
b ys mal ds n nd
show a good safety pro
s d ofile.
In
I addition, a biomark program is ongoin The objective is to identify n
, ker m ng. o non-invasive biomarke
e ers
specific to the mecha
s anism of ac
ction of BR ompounds, which cou be used for patient
RAINco co uld d
selection.
s
BRAINc Biopharma S.L
co a
Edificio 50 Parque tecnológ de Vizcaya | 48
04. gico 8160 Derio (Bilbao) . Vizcaya. Spain | T +34 94 406452 | Fax: +34 94 40 4526
Telf: 25 06
jmasse@
@brainco.es | www.brainco
o.es