KAPITALMARKNADSPRESENTATION
23 MARS 2015
MICHAEL OREDSSON, VD
STABIL BAS OCH BETYDANDE UPPSIDA
Bioinvent…
…har en
teknologiplattform som
redan skapat stort värde
…har tre produkter på väg
in i klinisk fas I/II
…har fokus på
immunonkologi och
erbjuder signifikant
mervärde för patienter
och partners
↪ från prekliniskt till kliniskt bolag under 2015
↪ kraftig hävstång i värdeskapandet
↪ optimerar värde genom mjuk finansiering i tidig
klinisk fas
AFFÄRSSTRATEGI
Bevara värdet i kliniska nyckelprojekt
– Cancer Research UK genomför fas I/II-studie för BI-1206 och tillför
BioInvent > 60 MSEK i värde
– Fördelaktig finansieringsmodell i fas II-studie för BI-505 genom samarbete med
University of Pennsylvania
– BioInvent behåller värdet i båda projekten inför fas IIb
– TB-403 går direkt in i effektsökande barncancerstudie i ultraorphan-indikation
Skapa värde i F.I.R.S.T.™ genom Treg/TAM-samarbeten med Big Pharma/Big Biotech
– BioInvent tillförs licensintäkter, resurser och kompetens
– Genererar mångfald av antikroppar/targets/applikationer och ger möjlighet till
bibehållet värde för BioInvent
Fokus på USA
– BioInvent är mycket aktivt i USA: vår forskning håller hög klass och väcker stort
intresse hos ledande aktörer
AGENDA
1.Immunonkologi – framtidens cancerterapi
2.Bioinvents verktyg för nya cancerterapier
3.Egna läkemedelsprojekt
4.Prekliniska projekt
5.Affärsmodell
6.Nyemission
7.Bioinvent – på rätt plats vid rätt tidpunkt
IMMUNONKOLOGI – FRAMTIDENS BEHANDLING AV CANCER
ASCO 78
CHICAGO
MAJ 2014
5
KLINISKA
PRÖVNINGAR
>1
MILJARD USD
(YERVOY)
ANTIKROPPSLÄKEMEDEL HJÄLPER IMMUNFÖRSVARET ATT
DÖDA CANCERCELLER
YER
VOY
Immunsystemet är
kroppens mest kraftfulla
och effektiva verktyg för
att känna igen och
bekämpa cancer.
Monoklonala
antikroppar fäster på
målceller och hjälper
immunförsvaret att
döda cancerceller.
Immuno-onkologiska
antikroppsläkemedel
har redan nått
marknaden, men
behovet av ytterligare
terapier är enormt.
Antikroppsläkemedel
har dubbelt så hög
chans att nå
marknaden jämfört
med traditionella
substanser
(small molecules).
BEHANDLING AV CANCER
KIRURGI
STRÅLBEHANDLING
CELLGIFTER
UNDERSTÖDJANDE
BEHANDLING
IMMUNONKOLOGI
BIOINVENTS VERKTYG
FÖR NYA CANCERTERAPIER
BIOINVENT HITTAR RÄTT ANTIKROPPAR
F.I.R.S.T.™
Agnas med celler från patienter
n-CoDeR®
- BioInvents bibliotek med
20-30 miljarder antikroppar
–BioInvents verktyg
för att hitta rätt
antikropp
F.I.R.S.T® – BIOINVENTS UNIKA METOD ATT HITTA RÄTT
ANTIKROPP
friska
celler
sjuka
celler
1. Antikroppsbiblioteket screenas
mot sjuka och friska
celler
2. Vi identifierar de
antikroppar som
binder till sjuka
celler
3. Dessa
antikroppar testas
in vitro för att se
vilka som som ger
den bästa effekten
4. De bästa
antikropparna väljs
ut och produceras i
större mängd inför
fortsatta tester
5. Dessa antikroppar testas
i BioInvents
sjukdomsrelaterade
djurmodeller
2015 – ETT TRANSFORMERANDE ÅR
TRE PRODUKTER I KLINISK FAS I/II
BIOINVENTS FOKUSERAR PÅ CANCER
F.I.R.S.T™ LÄKEMEDELSPROJEKT
STATUS
DISCOVERY
RESEARCH
FAS I
FAS II
BI-505 (Multipelt Myelom)
BI-1206 (NHL)
START H2 2015
TB-403 (Medulloblastom)
START H2 2015
Treg (Regulatoriska T-celler)
TAM (TumörAssocierade Makrofager)
12
FAS III
BI-505 – MULTIPELT MYELOM
LIVSHOTANDE
BLODCANCER MED
UPPREPADE ÅTERFALL
ANGREPPSPUNKT:
ICAM-1 SOM PÅVERKAR
IMMUNSYSTEMETS
MAKROFAGER
SYNERGI MED
REVLIMID/VELCADE
GOD SÄKERHET OCH DJUP
RESPONS KAN
HINDRA/FÖRDRÖJA
ÅTERFALL
START AV FAS IIA I
STAMCELLSTRANSPLANTERADE
PATIENTER
REVLIMID/VELCADE
8 MDR
USD
(2014)
DRABBAR
200 000
PATIENTER
ÅRLIGEN
BI–505 KAN STIMULERA MAKROFAGER ATT RENSA UPP LÅGA HALTER AV
MYELOMCELLER MED MÅL ATT FÖRHINDRA ELLER FÖRDRÖJA ÅTERFALL
BEHANDLING AV MUTIPELT MYELOM MED
TOXISKA ”SLEDGEHAMMER” LÄKEMEDEL
BI-505 STIMULERAR MAKROFAGER
ATT ”ÄTA UPP” MYELOMCELLER
Cancer
Cancer
-cell
Friska
celler
Cancer
-cell
Friska
celler
Cancer Friska
-cell celler
Cancer
Cancer
MAKROFAG
Cancer
Cancer
Cancer
Cancer
BI-1206 – NON-HODGKINS LYMFOM/KRONISK LYMFATISK LEUKEMI
LIVSHOTANDE
BLODCANCER
MABTHERA
ANGREPPSPUNKT:
CD32B
•
•
•
REDUCERAR
RESISTENSPROBLEM
POTENTIERAR
MARKNADSLEDANDE
LÄKEMEDEL
HAR EGEN CELLDÖDANDE
EFFEKT MOT CANCER
FINANSIERING AV OCH
SAMARBETE MED CRUK
START AV FAS I/II
H2 2015
6,6 MDR
USD
2013 (NHL)
POTENTIAL ÄVEN INOM
ANDRA SEGMENT
(TEX CD38)
NHL DRABBAR
>12 000
PATIENTER
ÅRLIGEN
TB-403 – MEDULLOBLASTOM/NEUROBLASTOM
LIVSHOTANDE CANCER
SOM DRABBAR BARN
ANGREPPSPUNKT:
PIGF
MÖJLIG
BREAKTHROUGH
THERAPY DESIGNATION
SAMARBETE MED
THROMBOGENICS
START AV FAS I/II
H2 2015
UTMÄRKT
SÄKERHETSPROFIL
I TIDIGARE
KLINISKA
PRÖVNINGAR
NY KUNSKAP
OM
VERKNINGSMEKANISMEN
BIOINVENTS PARTNERS
6
Globala
läkemedelsbolag
som partners
4 4
Pågående
Fas I-studier
Pågående
prekliniska studier
…och ett flertal
projekt i discoveryfas
150
Mkr i intäkter 2012-2014
BIOINVENTS PREKLINISKA PROJEKT
REGULATORISKA T-CELLER (T-REGS) – SÅ FUNGERAR DET
REGULATORISKA T-CELLER
CD4
BIOINVENTS
ANTIKROPPAR
CD25
-
KROPPENS IMMUNFÖRSVAR
dödar cancerceller
motverkar infektioner
FOXP3
autoimmuna
sjukdomar
+
+
Cancer
-cell
Cancer
-cell
Cancer
-cell
Cancer
-cell
ANTIKROPPAR MOT T-REGS KAN BLI NÄSTA STORA
GENOMBROTT I BEHANDLING AV CANCER
Immunogenic intensification
Checkpoint inhibitor alone
BIOINVENTS AFFÄRSMODELL
BIOINVENTS AFFÄRSMODELL
F.I.R.S.T.™
-BioInvents verktyg för
att hitta rätt antikropp
n-CoDeR®
- BioInvents bibliotek
med 20 - 30 miljarder
antikroppar
EGNA
LÄKEMEDELSPROJEKT
BETALANDE KUNDER
F.I.R.S.T. ™
n-CoDeR®
FOKUS 2015
KLINISK PROGRESS
OCH PARTNERAVTAL
F.I.R.S.T.™
-BioInvents verktyg för
att hitta rätt antikropp
EGNA
LÄKEMEDELSPROJEKT
BETALANDE KUNDER
n-CoDeR®
- BioInvents bibliotek
med 20 - 30 miljarder
antikroppar
F.I.R.S.T. ™
n-CoDeR®
INTENSIFIERAD
MARKNADSFÖRING
FORTSATTA
INTÄKTER
FINANSIELL ÖVERSIKT
Jan-dec
2014
47
-73
Jan-dec
2013
82
-71
-32
-105
-30
-101
Övriga rörelseintäkter & kostnader
Rörelseresultat
3,4
-55
0,5
-19
Finansnetto
0,9
1,1
Resultat efter skatt
-54
-18
46
65
MSEK
Nettoomsättning
FoU
Försäljning- & administrationskostnader
Livkida medel
24
FULLT GARANTERAD FÖRETRÄDESEMISSION OM CIRKA 75
MSEK
•
Emissionen är säkerställd upp till 100 procent, inkluderande
teckningsåtaganden (i vissa fall utöver tidigare pro rata-andel) från
välrenommerade life science-investerare såsom Healthcare Equity L/S,
Vixco Capital AB/Mats Thorén och East Bay AB (Peter Thelin family office)
•
Management och nyckelpersoner har lämnat teckningsåtaganden
•
Slutliga emissionsvillkor meddelas senast den 17 april 2015
•
Teckningsperiod mellan 28 april – 13 maj 2015
•
Emissionslikviden stärker BioInvents finansiella ställning och säkerställer
kapitalbehov under kommande 12-18 månader
25
SAMMANFATTNING AV NYHETSFLÖDET
BI-1206
BI-505
FAS I/II-STUDIE
MED FULL
FINANSIERING AV
CRUK
FAS IIA-STUDIE I
SAMARBETE MED
UNIVERSITY OF
PENNSYLVANIA
TB-403
FAS I/II-STUDIE I
PEDIATRISK
CANCER
TACK
NEXT GENERATION ANTIBODIES IN IMMUNO ONCOLOGY
Björn Frendéus, PhD, CSO
Anna Wickenberg, PhD, VP Clinical Development
BioInvent International AB
Capital market presentation
23 March 2015, Stockholm, Sweden
AGENDA
The importance of F.I.R.S.T discovery of antibodies and targets
BI-1206 – antibody targeting CD32b with significant potential for B cell cancer
BI-505 – ICAM-1 antibody to overcome MRD in Multiple Myeloma
TB-403 – antibody targeting the PlGF/Nrp1 pathway in childhood cancer
Next generation mAb targeting Tregs and TAMs for cancer therapy
29
THE DYNAMIC BIOLOGY OF ANTIBODIES
Type II
B1
Type I
Rituximab
Ab mechanism-of-action
1F5
Tumor cell death (%)
Programmed cell death
In vivo therapeutic activity
Complement Cell lysis
Cragg & Glennie
•Three CD20 antibody clones (Rituximab, 1F5, B1) on same backbone (Fc)
•Similar affinities (Kd = 3-8 nM)
Cragg & Glennie 2004
32
CDC
ANTIBODY BIOLOGY DETERMINES CLINICAL EFFICACY
Media Release
Basel, 24 July 2013
Roche's obinutuzumab (GA101) delayed disease progression longer than
MabThera/Rituxan in people with one of the most common forms of blood cancer
Phase III CLL11 study showed GA101 plus chlorambucil, a chemotherapy, was superior
to MabThera/Rituxan plus chlorambucil in helping people with previously untreated
chronic lymphocytic leukemia live longer without their disease worsening
About obinutuzumab (GA101)
GA101 is the first investigational type II, glycoengineered medicine designed to attack
cells that have a certain marker (CD20) on their surface. It attacks targeted cells both
directly and together with the body’s immune system. GA101 is currently being
investigated in a large clinical program, including multiple head-to-head phase III
studies versus MabThera/Rituxan in indolent non-Hodgkin lymphoma (NHL) and
diffuse large B-cell lymphoma (DLBCL).
In the U.S., GA101 is being developed and will be commercialized in collaboration
with Biogen Idec.
33
33
F.I.R.S.TTM DISCOVERY
FUNCTION, RATHER THAN TARGET, DEFINED
Differential cell panning to isolate pools of antibodies
Mapping of Ab target specificities scFv/Fab
Heat map antibody binding to different Cell types (FACS)
10 000 scFv/Fab analyzed
Identification of unique clones
Syngeneic
mouse
models
DNA sequencing
High throughput
IgG production
Patient
materials
500-1000 scFv/Fab analyzed
In vitro testing (Functionality
e.g. ADCC, PCD, internalization)
~500 IgG analyzed
Target
identification
Function-first
screening
Target id.
~100 IgG analyzed
In vivo
~10 IgG
A function-led discovery platform for combined antibody and target discovery
34
F.I.R.S.TTM GENERATED PROGRAMS
Multiple Myeloma (ICAM-1, BI-505)
B cell malignancy/Lymphoproliferative Diseases (CD32b, BI-1206)
Over coming antibody drug resistance
Regulatory T cells (discovery stage)
Discovery of T-Reg modulating and depletion mAbs and targets
Tumor associated macrophages (discovery stage)
Shifting TAM toward M1 phenotype
35
35
F.I.R.S.TTM ANTI-CLL ANTIBODIES
Patient
materials
Discovery of mAb and targets with superior PCD and ADCC activity
1. Differential cell panning
TARGET
CLL cells from
10 patients
+
2. Screening of scFv
3. Identification of unique clones
550 unique clones identified, yielding ~80 unique binding patterns
NON-TARGET
PBMC +/- B cells
CLL cells
Cell binding in flow cytometry; 7000 clones
analyzed
Flow cytometry
mapping of unique
scFv against CLL
cells, normal B cells
and various cancer
cell lines
4. High throughput IgG production
PBMC
300 clones produced as IgG
36
CLINICALLY RELEVANT TARGETS AND MABS IDENTIFIED
Patient
materials
Rituximab
CD200
”best-in-class”
Rituximab
ADCC results normalized to Rituximab
37
37
BIOINVENT CANCER & IMMUNOLOGY IN VIVO MODELS
1. In vivo screening models (cell lines)
Scid/ARH-77 (sc, iv)
Scid/Daudi (sc)
Scid/Raji (sc/iv)
Lymphoma/leukaemia*
Scid/Granta (sc, iv)
Scid/Jeko (sc/iv)
Mantle Cell Lymphoma*
Scid/RPMI-8226 (sc, iv)
NOG/U266 (iv)
Scid/OPM-2 (sc)
Scid/EJM (sc)
Multiple myeloma*
Balb/c/4T1 (sc, ortho)
C57BL/6 ID8 (i.p.)
Immune modulation*
Scid/PC-3 (sc)
Scid/DU-145 (sc)
Balb/c-4T1 (orthopic)
C57BL/6 ID8 (i.p.)
Balb/c-CT26 (s.c)
C57BL/6 B16.F12 (s.c)
C57BL/6 MB49 (s.c)
2. Immunomodulation models (M1/M2, TH1/TH2)
and Target validation (PoC)
4T1 (Balb/c )*
B16-F10 (C57/Bl6)*
ID8(C57/Bl6)*
KPC, KrasP53 double TG** (Hagemann Lab) – Pancreatic Cancer
TCL1 TG mice ** (SOTON) – Chronic Lymphocytic Leukaemia
3. Identification of therapeutically optimal lead
candidate human mAb and clinically optimal
target/epitope
Nod/scid-irrad*. Chronic Lymphocytic Leukaemia (BM/Spleen)
Nod/scid-irrad*. Acute Myeloid Leukaemia (BM/Spleen)
Nod/scid-irrad*. Mantle Cell Lymphoma (BM/Spleen)
Hu-scid.*
Multiple myeloma (fully human BM)
*or NOD/scid-IL-2rg-/-
4. MoA related models, transgenes & KOs
Solid cancer models
Scid/common g chain -/- (activatory FcgR dependency)**
Scid/cd32b-/- (inhibitory FcgR dependency)**
Shi-scid-IL-2rg-/- (NK cell deficient)*
Clodronate liposome depletion (Macrophage-dependent MoA)*
Anti-asialo mAb (NK cell dependent MoA)*
42
AGENDA
The importance of F.I.R.S.T discovery of antibodies and targets
BI-1206 – antibody targeting CD32b with significant potential for B cell cancer
BI-505 – ICAM-1 antibody to overcome MRD in Multiple Myeloma
TB-403 – antibody targeting the PlGF/Nrp1 pathway in childhood cancer
Next generation mAb targeting Tregs and TAMs for cancer therapy
43
CD32B ON TARGET B-CELLS REDUCES RITUXIMAB EFFICACY
THROUGH INTERNALIZATION
Lim et. al; Blood. 2011
Lee, Br J Hematol. 2014
Mantle cell lymphoma
Follicular lymphoma
45
FCGRIIB DE-SENSITIZES IMMUNE EFFECTOR CELLS AND MUTES
ANTI-CANCER MAB THERAPEUTIC ACTIVITY
wt
g -/FcgRIIb
-/-
47
BI-1206 BLOCKS RITUXIMAB INTERNALIZATION
Novel mechanism to overcome anti-body drug resistance
90
80
% internalized CD20
70
60
50
40
2h
6h
30
20
10
0
Rituximab
Rituximab +
CD32B (1:1)
Rituximab
Pat 1
Rituximab +
CD32B (1:1)
Pat 2
48
Rituximab
Rituximab +
CD32B (1:1)
Pat 3
BI-1206 ENHANCES RITUXIMAB ADCP THROUGH INHIBITION OF
CD20 INTERNALIZATION IN VITRO
Anti-CD32b significantly enhances rituximab ADCP in primary CLL
% macrophages loaded with CLL cells
70
60
rituximab + isotype control
N297Q
***
rituximab + CD32B N297Q
50
40
30
***
*
20
10
0
patient 1
patient 2
patient 3
Exprimental setup:
pre-incubation with CD32B-N297Q 3h prior to addition of rituximab and monocyte derived macrophages
49
BI-1206 HAS DIRECT CYTOTOXIC ACTIVITY IN VITRO
Anti-CD32b is more effective inducer of ADCC, PCD and ADCP compared
with rituximab in primary patient CLL cells
ADCC
PCD
50
ADCP
BI-1206 POTENTIATES RITUXIMAB B CELL DEPLETION IN
IMMUNOCOMPETENT HCD32+HCD20+MCD32B-/- MICE
51
RITUXIMAB EFFECTIVELY DEPLETES SOLITARY, BUT NOT
STROMAL-CELL ASSOCIATED, PATIENT CLL CELLS IN VIVO
Patient
materials
huCLL-scid mouse
mAb-treatment (ctrl mAb or rituximab 10 mg/kg)
Stroma (spleen)
Solitary (peritoneum)
52
THERAPEUTIC ANTI-CD38 AND ANTI-CD19 ANTIBODIES ARE ALSO
INTERNALIZED IN A CD32B-DEPENDENT MANNER
53
53
CLINICAL DEVELOPMENT OF BI-1206
56
INSIGHTFUL KOL FEEDBACK ON BI-1206 DATA PACKAGE
Unmet Needs in DLBCL
“Relapse, Refractory and failed HSCT is a
pressing unmet need as nothing keeps
patients alive longer than 6 months”
- nnn, MD, Roswell Park Cancer Center
Treatment
“If you have a mAb to overcome rituximab
resistance, then you have something great
and immediately useful and a big product
across all B-Cell malignancies. ”
- US Hem/Onc Expert
Treatment
“I can’t see rituximab going away in the near future,
the data I’ve seen from Gazyva doesn’t support
replacing rituximab, plus everybody in the world is
familiar with rituximab”
- US Lymphoma Expert
Unmet Needs in CLL
“Now obviously if you would take CD-20
therapy and further enhance that with
another antibody, I think there would be a
lot of enthusiasm for that”
- nnn, Mayo Clinic
57
14-BI-1206-1: A SIGNAL SEEKING PHASE I/IIA SAFETY STUDY WITH BI1206 AND RITUXIMAB IN PATIENTS WITH CD32B+ B CELL MALIGNANCY
• First In Man
• 4 sites in UK is planned to participate
• Coordinating PI – Prof Andrew Davies, Southampton
58
14-BI-1206-1: A SIGNAL SEEKING PHASE I/IIA SAFETY STUDY WITH BI1206 AND RITUXIMAB IN PATIENTS WITH CD32B+ B CELL MALIGNANCY
PART A
PART B
•
•
•
Establish safety and toxicity profile of
BI-1206
Determine the maximal tolerated
dose or the dose at which CD32b is
completely saturated
•
•
Establish further safety and
tolerability of BI-1206 as a single
agent and in combination with
rituximab
Document anti-tumor activity in
patients with relapsed or refractory
B-cell malignancies as a single agent
or in combination with rituximab
Indicate possible and optimal
downstream clinical development
paths
59
14-BI-1206-1: A SIGNAL SEEKING PHASE I/IIA SAFETY STUDY WITH BI1206 AND RITUXIMAB IN PATIENTS WITH CD32B+ B CELL MALIGNANCY
•
A multicenter first in man, open
label, two part, phase I/IIa study in
patients with relapsed or refractory
CD32b positive B cell malignancies.
•
Part A :
•
•
Single agent BI-1206 dose
escalation, classic 3+3 design
Part B:
•
Open, randomized, two-armed
study to investigate Single agent BI1206 at R2PD and Combination of
BI-1206 at R2PD and rituximab
•
enriched for CLL & MCL patients
(high CD32b expression)
3/24/2015
60
BUILDING EVIDENCE TO SUPPORT DEVELOPMENT OF BI-1206
THROUGH MULTIPLE PATHWAYS
Preclinical studies
Clinical Study
-
14-BI-1206-001
Safety and efficacy
signal in
combination with
rituximab
Safety and efficacy
signal as single
agent in CLL and
subtypes of NHL
Bio bank sample phenotyping
aCD38 combination in vivo
CD32b expression
on NHL subtypes
In vivo efficacy in
combination with
aCD38
Building a body of evidence and data
Multiple Ph II options emerging
62
62
MULTIPLE PH II CLINICAL DEVELOPMENT OPPORTUNITIES MAY EMERGE
Building a body of evidence and data
Multiple Ph II options emerging
Combination with
other mAbs
Single agent
aCD20
In relapsed/refractory CLL, MCL and/or NHL
PhII combo in CLL, MCL and/or NHL
relapsed/refractory and/or patients unfit for
chemotherpy
BI-1206 effect in combination with tyrosine
kinase inhibitors in CLL or MCL
aCD38
in MM; single agent and/or combination
effects with current and emerging SoC
PhII combo with in multiple myelom
activity in autoimmune disorders
63
63
AGENDA
The importance of F.I.R.S.T discovery of antibodies and targets
BI-1206 – antibody targeting CD32b with significant potential for B cell cancer
BI-505 – ICAM-1 antibody to overcome MRD in Multiple Myeloma
TB-403 – antibody targeting the PlGF/Nrp1 pathway in childhood cancer
Next generation mAb targeting Tregs and TAMs for cancer therapy
64
MINIMAL RESIDUAL DISEASE SETTING IS OPTIMAL THERAPEUTIC
USE FOR BI-505 BASED ON MODE OF ACTION
“sledgehammer”
e.g. MPV, bortesomib, revlimid
TTP
Depth
of response
Trial in smoldering
MM
Phase I
patients
sledgehammer
sledgehammer + BI-505
MRD
BI-505 MoA
1. Activates macrophages in BM compartments, which in the absence of BI-505 support
MM survival and drug-resistance, to kill off MM cells (TAM reprogramming)
2. Super induces macrophage effector cell influx into Multiple Myeloma bone marrow
3. Blocking of ICAM-1 mediated cell adhesion induced drug resistance
65
THE ”SLEDGE HAMMER” COMBINATION CONCEPT: ENHANCED
EFFICACY FOLLOWING COMBINATION OF BI-505 WITH REVLIMID
OR BORTEZOMIB
AUC, tumor growth
Survival
The combination of BI-505 and Revlimid or Velcade significantly enhances the therapeutic
effect in subcutaneous RPMI-8226 model.
Treatments were performed in a therapeutic setting and was started only once well-established tumors (3x3 mm)were formed and were
thereafter continued for 150 days. Importantly 4 out of 5 lenalidomide + BI-505 and 2 out of 5 bortezomib + BI-505 treated mice were
completely tumor free at termination. Remaining mice were terminated due to high tumor burden.
· Antibodies were administered i.p. 2 times/week and bortezomib i.v. once/week. Lenalidomide was administered p.o. 5 times/week
for two consecutive weeks followed by one week of washout and thereafter repeated. Treatment stopped at day 150.
· N=5-6 mice / group
· *=p<0,05, ** = p<0,01
73
MECHANISM OF ACTION:
BI-505 HAS MACROPHAGE DEPENDENT IN VIVO ANTI-MYELOMA ACTIVITY
Figure 6. BI-505 confers Fc-FcgR dependent
antitumor activity through macrophages
Veitonmäki et al, Cancer Cell, 2013
E) Tumor growth in macrophage or NK cell depleted SCID mice
bearing established RPMI-8226 myeloma tumors treated with
BI-505 or control antibody. ***p < 0.001.
G) Tumor growth in BI-505 or control antibody treated NK-cell
deficient NOD/Shi-scid/IL-2Rg-/- mice transplanted with RPMI8226 myeloma cells. ***p < 0.001.
76
MECHANISM-OF-ACTION:
BI-505 INDUCES MACROPHAGE INFILTRATION TO TUMOR LESIONS
BI-505 causes a significant influx of macrophages in tumors compared to
isotype control treated mice (upper panel and diagram), suggesting that
macrophages are the dominant effector cells
77
Mechanism-of-action
MACROPHAGES AND ICAM-1 ARE IMPLICATED IN MM DRUG
RESISTANCE
80
CLINICAL DEVELOPMENT OF BI-505
MULTIPLE MYELOMA
81
BI-505 CLINICAL PHASE I DOSE ESCALATING STUDY - CONCLUSIONS
BI-505 has a favorable safety profile in doses up to 20 mg/kg 2qw
At dosing 10 mg/kg, exposure levels needed for complete receptor
saturation on bone marrow MM cells was achieved
Of the 29 treated patients in dose group 6 and onwards (dose 0.09 – 20
mg/kg), 7 patients, 24 % had stable disease for at least 2 months.
16/29 patients were treated with doses below receptor saturation level
Response data is comparable to elotuzumab (aCS1) phase I single agent
therapy data
INSIGHTFUL KOL FEEDBACK ON BI-505 DATA PACKAGE
Unmet Need
“Basically resistance is the biggest concern, in
reality we have only two classes of drugs,
therefore agents that can deepen a response
that could play a meaningful role in delaying
the time to relapse”
-nnn, MD -Dana Farber
Method of Action
“If BI-505 can clean up MRD that other
treatments miss, then you’ve got something
really compelling”
-nnn, MD -University of Pennsylvania
Unmet Need
“Treatments that have a lower toxicity for
patients, as most are elderly and on the
treatments for prolonged periods of time, or
increases in PFS. Ideally treatments that can
provide both low toxicity and longer PFS”
-nnn, MD - Duke
Phase I Data
“given that it is a heavily treated population, I
wouldn’t readily dismiss the 25% stable
disease you observed in your earlier trial.”
-nnn, MD/PhD - MD Anderson
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URGENT MEDICAL NEED IN MM PATIENTS
• Patients relapse and become resistant to available therapies
Relapse
Side
effects
• Increased burden of disease and cumulative side effects with each
new treatment line – elderly patients - balance between tumor
control and managing side effects
• Treatment currently include 2 major classes:
Limited
options
Need
• Proteasome inhibitors (bortezomib, carfilzomib)
• iMID (lenalidomide, thalidomide, pomalidomid)
• Urgent need for treatments with new mechanisms of action
• Significant interest in new agents with low toxicity to deepen
response by targeting MRD
84
MINIMAL RESIDUAL DISEASE SETTING IS OPTIMAL THERAPEUTIC
USE FOR BI-505 BASED ON MODE OF ACTION
“sledgehammer”
e.g. MPV, bortesomib, revlimid
TTP
Depth
of response
Trial in smoldering
MM
Phase I
patients
sledgehammer
sledgehammer + BI-505
MRD
BI-505 MoA
1. Activates macrophages in BM compartments, which in the absence of BI-505 support
MM survival and drug-resistance, to kill off MM cells (TAM reprogramming)
2. Super induces macrophage effector cell influx into Multiple Myeloma bone marrow
3. Blocking of ICAM-1 mediated cell adhesion induced drug resistance
86
MULTIPLE MYELOMA – ROLE FOR MONOCLONAL ANTIBODIES
• Remitting and relapsing disease - ultimately incurable
• Evidence for minimal residual disease negativity predicting for PFS and OS
• Aim to deepen and prolong responses in combination with existing agents
;
SLAMF7 (CS1), elotuzumab
• Phase I/II monotherapy best
response stable disease 26.5% –
comparable to BI-505 ph I
• Phase I combination with
lenalidomide and dexamethasone
82% ≥PR
• Phase III trials ongoing
CD38, eg daratumumab
• Phase I monotherapy 42% ≥PR
• Phase II combination with
lenalidomide and dexamethasone
86% ≥PR
• Phase III trials ongoing
• Deep responses but duration
unclear
BI-505 POST AUTOLOGOUS STEM CELL TRANSPLANTATION
– PHASE II SIGNAL SEEKING CLINICAL STUDY PLANNED
• investigate safety and efficacy of BI-505 in combination with maintenance
lenalidomide in multiple myeloma patients post autologous stem-cell
transplantation (ASCT)
• low tumor burden, but patients relapse eventually
• investigating if BI-505 has the potential to deepen the response post ASCT
• One-armed open study, a matching historical control cohort treated with
lenalidomide will be selected from a similar protocol
ASCT
N≈30, treated with BI-505 and
lenalidomide for 9 mo, 1 y post-ASCT
Readout:
• safety
• proportion of patients in CR
• MRD
• Macrophage PD markers
89
AGENDA
The importance of F.I.R.S.T discovery of antibodies and targets
BI-1206 – antibody targeting CD32b with significant potential for B cell cancer
BI-505 – ICAM-1 antibody to overcome MRD in Multiple Myeloma
TB-403 – antibody targeting the PlGF/Nrp1 pathway in childhood cancer
Next generation mAb targeting Tregs and TAMs for cancer therapy
102
F.I.R.S.T.™ - REGULATORY T CELLS
•
•
•
•
•
•
BioInvent has unique knowledge and access to;
Regulatory T cells including protocols to generate these cells(target cells)
Normal cytotoxic (and helper) T cells (non-target cells)
High-throughput in vitro functional assays for assessment of antibody depleting
activity against regulatory T cells (targets) and cytotoxic T cells (non-targets)
Immunocompetent in vivo models for proof-of-concept studies
Strong knowledge and experience from working with T cell and immune cell
based immunological assays for assessment of efficacy and safety (at regulatory
level)
• There is great potential for immune modulatory antibodies
• Huge market and great commercial potential for more active single or combination
antibody therapies, showing increased efficacy but also improved safety, in larger patient
populations
• F.I.R.S.T platform ideally suited to identify optimal targets and antibodies with superior
specificity and depleting activity, against regulatory T cells
110
F.I.R.S.T™ TAM
•
Tumor Associated Macrophages (TAM’s) are pro-tumorigenic, enhance tumor growth and progression, and
decrease efficacy of various anticancer therapies.
•
Macrophages are, however, plastic and can be re-educated. The aim is to generate immunomodulatory
antibodies targeting TAMs for therapy of cancer. Anti-TAM antibodies may act by several mechanisms-of-action
to relieve immune suppression and enhance antitumor activity:
•
Deplete, re-educate and/or block recruitment of TAM
•
Improve innate (MF) and adaptive (CD8 T cell) antitumor immunity
•
Aim: Using the n-CoDeR© F.I.R.S.T™ platform and primary myeloid cells isolated from tumors of M2/TH2prone, as well as M1/TH1 prone mice, a diverse pool of antibodies against clinically relevant targets will be
identified.
Anti-tumor
Pro-tumor
1.Pro-inflammatory
2.Activate anti-tumor immunity
3.Direct tumoricidal effects
1.
2.
3.
4.
M1
M2
(includes TAMs)
111
Suppress anti-tumor immunity
Pro-angiogenic
Production of tumor growth factors
Facilitate metastasis
SYNERGY BETWEEN TARGETING T REG AND TAM
+
APC
(DC or MF)
-Tumor lysis
-Antigen release
-Inflammation
-
+
1
-APC activation
-Cytokine production
-
CD4+
Th cell
-
+ +
TAM
TAM
2
T reg
cell
-
-
+
CD8+
APC
Cytotoxic T cell
+
+
+
3
+
CD8+ T cell
CD8+ T cell
activation
Tumor cell death
112
+-
CD4+
TACK
