pioneering the next genera3on of redirected t cell engaging … · 2020. 2. 20. · bites...
TRANSCRIPT
1CONFIDENTIAL
Q1 2020
Pioneering the Next Genera3on of
Redirected T Cell Engaging Therapeu3cs in Immuno-Oncology
2
Agenda
• Corporate Overview: Leader in T Cell Engaging Therapy in Solid Tumors
• The Opportunity: T Cell Engaging Therapy in Solid Tumors – Game Changing
• The Maverick Solution: COBRA™ Therapeutic Platform
• COBRATM Platform Validation: Lead Candidate MVC-101
• Path to Treating Patients: Clinical Strategy & Indications of Interest
• Single Focus on Developing T Cell Engaging Therapies: COBRA™ Pipeline
mavericktx.com
CORPORATE OVERVIEW
4
Maverick TherapeuEcs IntroducEon
• Immuno-Oncology company launched in 2017
• Our Mission: Become the Leader in T Cell Engaging Therapy in Solid Tumors
COBRA™: A novel condiEonally acEve T cell engager
designed to safely target solid tumors with highly
specific and potent acEvity
5
Partnerships
Focus
Strategic Validation
$125M of Committed Funding
ValidaEon of approach,
scienEfic plaJorm and
programs by key industry
leaders
Develop proprietary,
best-in-class, T cell-engaging
antibody therapeutics
5 year drug development
project based on the promise
of early-stage research
6
Leadership Team
mavericktx.com
T Cell Therapy in Solid Tumors = Game Changing Opportunity
THE OPPORTUNITY
8
The Promise of Bispecific T Cell Engagers
BiTEs significantly enhance immune response to tumors rela3ve to an3body dependent cellular cytotoxicity (ADCC)
blinatumomab
rituximab100,000 fold
Dreier, et al. (2002), Int. J. Cancer, 100: 690–697
2012: Amgen acquires Micromet for $1.2 billion
2014: FDA grants accelerated approval of blinatumomab (Blincyto®) for the treatment of adult patients
with relapsed or refractory ALL
Sp
eci
fic
Cy
toto
xic
ity
[%
]
Antibody Concentration [ng/ml]
• BiTEs are a class of bispecific an3bodies (bsAbs) used for cancer treatment
• They are a fusion between tumor-targe3ng and T cell engaging recombinant an3body fragments
9
The Challenge of bsAbs Beyond Hematological Cancers
• bsAbs redirect T cells to cell surface targets, regardless of whether expressed on the tumor or on healthy 3ssues
• Blinatumomab transiently depletes normal B
cells in hemo-onc patients, which can be
tolerated
• Damage to normal tissues by bsAbs results in
significant toxicity and limits patient response
by lowering the dose that can be safely
administered
The COBRA™ design can manage the limitations of less specific bsAb targets, by taking
advantage of the tumor’s unique proteolytic microenvironment for T cell activation
Normal Tissue Tumor Tissue
T cell
B-cell counts of 20 patients treated with blinatumomab
B-cell Depletion (to ≤1/ μl)
Klinger, et al. (2012), Blood, 119:6226-6233
10
I/O Landscape: Enormous Unmet Need in Solid Tumors
Hematological Cancers Solid Tumor Cancers
Cancer Types Lymphoma, leukemia, myeloma
Breast, lung, prostate, colorectal,
melanoma, uterine & ovarian, kidney &
renal, head & neck, pancreas, others
Therapies
• Bispecific T cell engagers
(blinatumomab)
• CAR-T (tisagenlecleucel,
axicabtagene ciloleucel)
• Checkpoint Inhibitors (nivolumab,
pembrolizumab, ipilimumab)
Average Overall
Response Rates40 – 93%** 0.5 – 24%**
# of new cases* 174,000 = ~10% of all cancers 1,561,000 = ~90% of all cancers
* American Cancer Society, 2018
** Based on efficacy data in prescribing information for each therapy listed
There are 900% as many solid tumor cancers as there are hematological cancers
mavericktx.com
COBRA™: A Novel Conditionally Active Bispecific Antibody
THE MAVERICK SOLUTION
12
COBRA™ = Conditional Bispecific Redirected ActivationαEGFR sdAb inacEve VLαCD3 VH αEGFR sdAb inactive VHαCD3 VL αHSA sdAb
Protease
Cleavable Linker8 a.a. 8 a.a.
COBRA™ Construct Design and Predicted Folding
Inactivated VH & VL domains pair
with αCD3 VH & VL domains
min2.5 5 7.5 10 12.5 15 17.5 20 22.5
mAU
0
100
200
300
400
500
600
700
DAD1 A, Sig=280,2 Ref=off (JK180703 SEC lot 803 2018-07-03 11-14-55\005-P1-A5-Pro186 lot PL-0803.D)
14
.69
8
17
.00
4
15.7
41
Monomer = 97.5%
AnalyEcal Size Exclusion Chromatography
Predicted COBRA™ Folding
EGFR/MMP9 = MVC-101 = Maverick COBRA™ Program 1
Protein A and Prepara3ve SEC purifica3on
13
MVC-101 Ac3ve Dimer
αCD3 agonist (dimer of αCD3 VH and VL )
Binds EGFR
Binds CD3
MVC-101 Cleavage Products
αCD3
VH and VL
inactive
VH and VL
Binds EGFR
Impaired CD3 binding Binds serum albumin
+
MVC-101
Cleaved MVC-101 Dimerizes to Form the Active Molecule
Binds EGFR
Impaired CD3 binding
Binds serum albumin
14
CharacterizaEon of COBRA™ Binding
sdAb(monovalent EGFR binding)
MVC-101(bivalent EGFR binding)
Active MVC-101(tetravalent EGFR binding)
αEGFR KD (nM)
αEGFRKD (nM)
αCD3 KD (nM)
αHSAKD (nM)
αEGFRKD (nM)
αCD3 KD (nM)
Human 2.7 0.12 nb 11.3 <0.01 1.7
Cyno 6.3 0.14 nb 10.8 <0.01 2.4
Mouse nb* nb nb 106.3 nb nb
*nb = no binding
Binding kinetics to EGFR, serum albumin and CD3ε were assessed via the Octet system
15
COBRA™ Mechanism of AcEon
= MVC-101; = cMVC-101; = inactivating domain; = adMVC-101
Cell Surface
Target Antigen=
Watch our mechanism of action video here:
https://www.mavericktx.com/technology/#our-science
mavericktx.com
MVC-101: In Vivo Efficacy Data
COBRA™ PLATFORM VALIDATION
17
Activated MVC-101 Demonstrates Potent In Vitro Activity
HT29 Tumor Cells
E:T 10:1
48 hours
0.001
0.01
0.1 1 10100
1000
0.0
0.5
1.0
T cell Killing Assay
Concentration (pM)
Tu
mo
r ce
lls
- R
LU
MVC-NCL
MVC-101
MVC-101 Pre-Cleaved
200X
(Non-cleavable)
18
0 5 10 15 20 25 30 35 40 45
0
500
1000
1500
2000
SCC25
Days post initial dose
0 5 10 15 20 25 30 35
0
500
1000
1500
2000
LoVo
Days post initial dose
Tu
mo
r V
olu
me
(m
m3)
MVC-NCL - 100 µg/kg
MVC-101 - 100 µg/kg
MVC-101 - 20 µg/kg
MVC-101 - 4 µg/kg
0 5 10 15 20 25 30 35
0
500
1000
1500
2000
HT29
Days post initial dose
MVC-101 Regresses Established Solid Tumors in Mice
Dosed every 3 days for 7 doses total
Cell Lines:
8,774 EGFR/cell 33,218 EGFR/cell 239,344 EGFR/cell
19
0 24 48 72 96 120 144 1680.1
1
10
100
1000
10000
Time (Hours)
Pla
sm
a C
on
c (
ng
/mL
)
Pre-Cleaved MVC-101 - 100 µg/kg
MVC-101 - 100 µg/kg
MVC-NCL - 100 µg/kg
PK in non-tumor bearing mice
Cleaved MVC-101 Clears More Rapidly Than Intact MVC-101
MVC-101
MVC-NCL
MVC-101
Pre-Cleaved
0 5 10 15 20 25 30 35
0
500
1000
1500
2000
LoVo
Days post dose initiation
Tu
mo
r V
olu
me
(m
m3)
MVC-NCL - 100 µg/kg
MVC-101 - 100 µg/kg
Pre-Cleaved MVC-101 - 100 µg/kg
20
Bio
log
ica
l Re
spo
nse
Le
vel
Log (exposure)
Preclinical Results Predict Increased Therapeutic Window
Efficacious
Dose
Maximum
Tolerated
Dose
MVC-101 exposures at efficacious doses relative to tolerated doses predicts
an increased therapeutic window compared to standard T cell engagers
Standard T Cell Engagers
21
Bio
log
ica
l Re
spo
nse
Le
vel
Log (exposure)
Preclinical Results Predict Increased Therapeutic Window
Efficacious
Dose
Maximum
Tolerated
Dose
Increased
Therapeutic
Window
MVC-101 exposures at efficacious doses relative to tolerated doses predicts
an increased therapeutic window compared to standard T cell engagers
COBRA™ MVC-101
22
Clinical Strategy & Indications
PATH TO TREATING PATIENTS
CONFIDENTIAL 23CONFIDENTIAL
MABEL
Bio
log
ica
l Re
spo
nse
Le
vel
Log (exposure)
COBRA Safety Mechanisms Enable Increased FIH Dose
• FDA requires MABEL* starting dose for standard bispecific T cell engagers
• COBRA safety features & robust pre-clinical safety package combined with
an ex-US strategy allow Maverick to maximize FIH dose
COBRA™ MVC-101
“... [We] would, in principle, accept
the proposed approach based on
the HNSTD, provided that the
Sponsor is confident that the
calculated starEng dose should not
be sub-efficacious in the proposed
pa3ent popula3on”
Star3ng ra
nge based
on feedback
*MABEL = minimum anticipated biological effect level
CONFIDENTIAL 24CONFIDENTIAL
Clinical Development Strategy
Transition to select
indications and 3+3
design prior to
expansion
1+3 design for
ini3al steps
X μg/kg
X μg/kg
X μg/kgNon-Small Cell
Lung Cancer
N = 15-20
X μg/kg
Colorectal Cancer
N = 15-20X μg/kg
Head & NeckSCC
N = 15-20
• U3lize ex-US regulatory feedback
to maximize star3ng dose
• Dose Escala3on run in Australia
• Begin US IND filing once sufficient
safety data has been collected
• Dose Expansion run in AUS and US
X μg/kg
CONFIDENTIAL 25CONFIDENTIAL
PaEent PopulaEons of Interest
Head and Neck
Squamous Cell
Carcinoma (HNSCC)
Colorectal Cancer
(CRC)
Non-Small Cell Lung
Cancer (NSCLC)
EGFR Expression
Consistency
High (97%)
constitutively
expressed for all
subtypes1
Constant for both
KRAS mutant and
wildtype2
Most consistent
within EGFR mutant
subtype3
Standard of Care
Efficacy* Bar –
Objective Response
Rate (ORR)
pembrolizumab4
16%
regorafenib5
1%
docetaxel6
15%
*Based on MVC-101 target clinical posi3oning
1. Zimmerman M, et al. (2006), Radiat Oncol, 10.1186/1748-717X-1-11
2. Callisia C, et al. (2015), Journal of Gastrointestinal Oncol, 6(6):660-667
3. Mascaux C, et al. (2011), Clin Cancer Res, 24:7796-807
4. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
5. http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf
6. http://uspl.lilly.com/cyramza/cyramza.html
CONFIDENTIAL 26CONFIDENTIAL
• 98% EGFR positive by IHC
• PD-1 combination: Potential path
to first line for COBRATM
Induc-onTherapy:
1st Line:
Surgery ±
Radiation
Platinum Chemo
+ Radiation
Resectable Unresectable
Anti-PD1
HNSCC Initial
Presentation
Recurrent Unresectable Locally
Advanced or Metasta3c Disease
2nd LineOr Later:
30%
1. World Health Organization
2. National Cancer Institute
3. Australian Institute of Health and Welfare
4. Cetuximab + platinum + fluorouracil
40%
Metastatic
60% 30% 10%
AnE-PD1 moving to
inducEon therapy
EXTREME4
EXTREME42nd Line:
90% 10%
MVC-101
AnE-PD1
16% ORR
Path to Early Line: Head and Neck SCC (HNSCC)
MVC-101+
Worldwide1 US2 AUS3
New Cases per Year 700,000 50,000 5,200
Deaths per Year 380,000 10,000 1,200
CONFIDENTIAL 27CONFIDENTIAL
• 83% EGFR posi3ve by IHC
“More than 90% of pa?ents with
metasta?c colorectal cancer will
require second-line treatment.”7
1st Line:
2nd/ (3rd) Line:
Ras Mut (30-50%) Ras WT (25-30%) BRAF Mut
Chemo4 + Bev5 Chemo4 +
An3-EGFR6
Chemo4 +
Bev5Regorafenib
MSI-H
Molecular testing
3rd LineOr Later:
Limited Patient
Population
Path to Early Line: Colorectal Cancer (CRC)
MVC-101
Regorafenib MVC-101
4th LineOr Later:
MVC-101
1 % ORR
Unresectable
Metastatic CRC
42%38%
42%
Worldwide1 US2 AUS3
New Cases per Year 1,800,000 145,000 16,400
Deaths per Year 861,000 51,000 5,600
1. World Health Organization
2. National Cancer Institute
3. Australian Institute of Health and Welfare
4. 5-FU + Oxaliplatin + Irinotecan given concurrently (FOLFOXIRI) or sequentially
(irinotecan monotherapy 2nd) 5. Bevacizumab
6. Cetuximab or panitumumab
7. Tanios Bekaii-Saab (2018) Clinical Advances in Hematology & Oncology 16 (9) Supp 18
CONFIDENTIAL 28
COBRA™ Pipeline
SINGLE FOCUS ON DEVELOPING
T CELL ENGAGING THERAPIES
CONFIDENTIAL 29CONFIDENTIAL
COBRA™ PlaJorm Pipeline
30
Maverick Achievements
ü We have designed a conditionally active, highly potent T cell engaging
platform
ü In vitro assays demonstrate protease mediated linker cleavage increases
potency of T cell-mediated killing up to 200-fold
ü Regression of established solid tumors in xenograft-bearing mice is
dependent on tumor mediated activation
ü Half-life extended MVC-101 has a more rapid clearance rate post
proteolytic activation
ü Exploratory tox study validates COBRA mechanism of action and
establishes meaningful therapeutic index
ü First-in-class programs with best-in-class design
31
Maverick Highlights
UNMET MEDICAL NEEDThe COBRA™ pla{orm is designed to safely target a broad range of solid tumors with
highly specific and potent ac3vity while limi3ng on-target toxici3es in normal 3ssues
TECHNOLOGYProprietary, best-in-class, T cell-engaging antibody therapeutics that are selectively
activated by the tumor microenvironment
INTELLECTUAL PROPERTYPatents issued for T cell engaging and half-life extension domains; multiple patents filed
for conditionally active formats
PEOPLEMaverick is led by a team of leading experts in protein engineering, immunotherapy
and T cell therapeutic research and development
FUNDING/MILESTONES$125M of commi}ed funding through 2021, providing the runway for clinical proof of
concept in pa3ents
32CONFIDENTIAL
Thank You