Innovative Clinical Programs Targeting the Tumor Microenvironment to Improve Therapeutic Outcomes in Underserved Solid Tumors - February 2021 ...
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Innovative Clinical Programs Targeting the Tumor Microenvironment to Improve Therapeutic Outcomes in Underserved Solid Tumors February 2021
Forward-looking Statements
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circumstances after the date of this presentation.
2
NOXXON’s Unique Phase II Program Targeting CXCL12
Synergizes on Top of IO and Non-IO Standards of Care
NOXXON is a clinical-stage biotechnology company focused on improving
cancer treatments
Two tumor microenvironment (TME) targeting cancer drug candidates:
Phase II program NOX-A12 & NOX-E36
NOX-A12 provides good optionality and de-risking across multiple
tumor types and combination therapies
NOX-A12 + Immunotherapy combination in metastatic microsatellite-
stable pancreas cancer
NOX-A12 + Radiotherapy in 1st line brain cancer (glioblastoma)
NOX-E36 targets tumor associated macrophages and myeloid
suppressor cells in solid tumors
Strong IP position with patent families covering NOX-A12 & NOX-E36
Committed team with clinical, regulatory and business development experience
3
Experienced Biopharma Team
Dr. Aram Mangasarian Dr. Jarl Ulf Jungnelius Dr. Don deBethizy
CEO Senior Medical Advisor Board Member, Finance/M&A Lead
▪ 20 years biotech experience in EU, ▪ Oncologist with 25+ years clinical and ▪ Chairman of Albumedix & Saniona
transformed NOXXON into a lean research experience in large pharma and ▪ Board member of arGEN-X NV, Newron
oncology-focused company listed on academic organizations Pharma SPA, Proterris
Euronext Growth ▪ CEO at Isofol Medical ▪ Formerly CEO of Santaris Pharma
▪ Headed Business Development at Novexel ▪ Leadership positions at Celgene, Pfizer, (sale to Roche), Chairman of Rigontec
- €150m licensing deal with Forest Labs on Takeda and Eli Lilly & Company (sale to Merck & Co./MSD), Chairman
avibactam; company bought by ▪ Significant role in the approval of multiple Contera Pharma ApS, Serendex A/S
AstraZeneca for $505m successful oncology drugs including ▪ Co-founder and former CEO of Targacept
▪ Ran Business Development at ExonHit Abraxane®, Gemzar®, Alimta® and
Therapeutics; closed $30m discovery and Revlimid®
development alliance with Allergan
▪ Bertram Köhler ▪ Dr. Maurizio PetitBon ▪ Dr. Don deBethizy ▪ Dr. Oscar Izeboud
Formerly
Supervisory
Board
4
Scientific Advisory Board (SAB)
Jose Saro, MD E. Gabriela Chiorean, MD Eileen M. O’Reilly, MD Thomas Seufferlein, MD Daniel D. Von Hoff, MD
Chair of the SAB
Director, Gastrointestinal Attending Physician, Professor of Distinguished Professor
Senior Medical Director Oncology Program at Member, Memorial Gastroenterology and and Executive Vice
at AstraZeneca UW/Seattle Cancer Care Sloan Kettering Cancer Vice Dean for Research President, Molecular
Alliance Center at the Medical Faculty of Medicine
Professor of Medicine, the University of Ulm Translational Genomics
Weill Cornell Medical Research Institute
College (TGEN)
5
NOXXON’s Strong Value Proposition:
Clinical-Stage Immuno-Oncology Company with a Unique
Mechanism of Action on the TME in Solid Tumors
Pipeline Assets Complement Existing Anti-Cancer Therapies
to Enhance their Therapeutic Efficacy
Combination/ Indication Preclinical Phase 1 Phase 1/2 Phase 2
Scientific
NOX-A12 + Immunotherapy Collaborator
Pancreatic Cancer 2021
NOX-A12 + Radiotherapy
Brain cancer / Glioblastoma 2022
Orphan Drug Status US & EU
NOX-A12 Preclinical
Evaluation
Undisclosed Indication Market >€1b Top-10 Pharma
NOX-E36 Combinations
2021
Solid Tumors
Supportive clinical data from non-oncology Phase 2
Trial completed Trial ongoing
7
All timelines subject to financing and patient recruitment
NOXXON’s Unique Approach:
Modulating Tumor Microenvironment Chemokines
to Improve Standard of Care Therapies
Role of CXCL12 Chemokine Axis in Cancer
NOX-A12 Inhibition Provides Strong Differentiation
Roles CXCL12 / CXCR4 / CXCR7 Axis
MIGRATING CELLS (Immune, Tumor, Endothelial)
• Establishment of tumor-promoting
microenvironment CXCR4 CXCR7
RECEPTORS
• Stimulation of tumor growth
• Recruitment of endothelial progenitor cells Receptor interaction (specific)
(growth support, tumor vascularization)
CXCL12 Concentration
• Adhesion
CXCL12 Anchoring (non-specific)
• Chemotherapy resistance
• Spreading / metastasis
STROMAL OR TUMOR CELL SURFACES
NOX-A12 binding of the chemokine CXCL12:
Blocking only CXCR4 is not sufficient for adequate
1) blocks receptor interaction with both
control of the TME and may be counter-productive
CXCL12 receptors (4 and 7) and down-stream
in certain cancer therapy contexts
signaling
2) neutralizes anchor domain detaching
chemokine & destroying the location
information of the chemokine concentration
gradient
9
Based on information from Guo et al., 2015, Walters, M.J. et al., Br J Cancer. 2014, Würth, R. et al., Front Cell Neurosci, 2014; Guo, J-Ch. et al.,
Oncotarget, Advance publications, 2016; Miao, Z. et al., PNAS, 2007; Yun, H-J. et al., Oncol Lett, 2015; C. Jiang (2020) Mol. Med. ReportsThe TME is the Key to Solid Tumors
Unique multimodal MoA of NOX-A12 enables infiltration of anti-cancer immune
cells into the TME, prevents entry of immunosuppressive cells, and blocks repair of
damaged tumors
4
NOX-A12
NOX-E36
↑ Trafficking & infiltration
5 of immune effector cells
↓ Suppressive myeloid
cells to tumors
6
NOX-A12
↓ Neovascularization of
damaged tumors by bone-
marrow-derived cells
7
10
Adapted from Chen & Mellman 2013, Immunity 39:1The Checkpoint Eligibility & Response Gap:
NOX-A12 Targets More Responders With Better Responses
TME-Targeting Drugs
like NOX-A12 and
NOX-E36 have
potential to push these
curves upwards
11 JAMA Network Open. 2019;2(5):e192535. doi:10.1001/jamanetworkopen.2019.2535NOXXON at the Forefront of Chemokine Development for Cancer with
Limited Direct Competition in Brain & Pancreatic Cancer
CXCL12, CXCR4, CXCR7 Pipeline Phase 2
Phase 1/2 Pancreatic Cancer
by Indication (n=49)
Preclinical
CXCR4 CXCR7
chemokine receptor receptor
NOX-A12 Motixafortide
NOXXON --
BioLineRx
Plerixafor
Sanofi
Mavorixafor
X4 Pharma
Brain Cancer
CXCR4 CXCR7
chemokine receptor receptor
NOX-A12 Plerixafor --
NOXXON IIT L. Recht
X4P-002
X4 Pharma
Includes assets in active development worldwide from preclinical phase to registration.
Source: Biomedtracker by Informa Pharma Intelligence, NOXXON Pharma analysis, November 2020
12NOX-A12 + Radiotherapy in Glioblastoma
Glioblastoma is a Devastating Orphan Brain Cancer where the
TME Plays Significant Role
NOX-A12 is one of the few agents that offers the potential to address the major unmet need in
Glioblastoma of significantly increasing survival, via its synergy with RT and effects in the
hypoxic tumor microenvironment.
Lack of Effective Therapies & Low Overall High Unmet Need Patient Segments:
Survival: mOS: 12-15 months,
MGMT unmethylated promoter - chemotherapy
5-year survival: ~4% ineffective
Industry Interest Significant : ~80 active trials Incomplete resection - poor prognosis &
Orphan with ~23k new cases / yr. in US + EU therapeutic responses
Glioblastoma Long-Term Survival Rates
100%
100%
80%
60%
40%
18%
20% 11%
4%
0%
Diagnosis/ 2-year 3-year 5-year
Trial Entry
14 Sources: Poon MTC, et al., Scientific Reports 2020 Vol. 10 Issue 1; Hegi ME et al. N Engl J Med 2005;352:997-1003;
Biomedtracker by Informa Pharma Intelligence & NOXXON Pharma analysis, November 2020,NOX-A12’s MOA is Relevant to GBM: Attacking Key Survival
Mechanisms Following Radiotherapy
SUPERIOR PHARMACOLOGY CD11b monocytes
Direct targeting of CXCL12
provides more complete inhibition VASCULOGENESIS
of axis than CXCR4 or CXCR7 Main driver of new vessel CXCR4 receptor
antagonists formation after radiotherapy is
driven by CXCL12 and blocked
CXCR7 receptor
Radiotherapy NOX-A12
by NOX-A12
Endothelial Cells
Tumor Attraction to
Vessel CXCL12 CXCL12
destruction chemokine
triggers
Hypoxia
HIF-1
HIF-1 triggers the two
main pathways to re-grow VEGF
blood vessels:
Vasculogenesis &
Angiogenesis.
ANGIOGENESIS
RADIOTHERAPY kills many tumor cells No survival benefit of
Plays no significant role in
and destroys blood vessels in irradiated anti-VEGF in GBM1
zone leading to lack of oxygen (hypoxia) in new vessel formation
the tumor making a more hostile following radiotherapy
environment for the tumor
Inhibition of the CXCL12/CXCR4/CXCR7 axis can block tumor vasculogenesis
15 Source: Figurea Adapted from Liu 2014, Neuro-Oncology 16:21 and Kioi 2010 J. Clin. Invest, 120:3
1. Gilbert et al., (2014) NEJM 30:8 & Chinot et al., (2014) NEJM 30:8NOX-A12 + Radiotherapy Significantly Increases Survival and
Demonstrates Complete Regression of Brain Tumors
Autochthonous brain tumor model in rats Effects of treatments
Radiotherapy
at day 0
Pregnant rats:
ENU on gestational
age day 17 - 18
Tumor
recurrence
detected only
in 1/3rd of
animals
Key features of the model
100% Complete Response
▪ Spontaneous tumor development in immuno- MRI Detection limit
competent host
▪ Diversity of tumor cell sensitivity comparable
to human situation
▪ Refractory to standard therapies
Combining NOX-A12 with radiotherapy resulted in 100% complete response (66% durable)
in a spontaneous rat model of brain cancer
16 Source: Liu 2014, Neuro-Oncology 16:21NOX-A12 + Radiotherapy: Phase I/II in 1st Line Incompletely Resected Brain
Cancer Patients – Consistent Tumor Volume Reductions seen in 1st Cohort
Imaging allows assessment of MoA (prevention of blood
vessel regrowth) and efficacy (tumor volume reduction)
Newly diagnosed brain
cancer (glioblastoma)
Incomplete surgical
resection or biopsy only Radiotherapy
MGMT promoter
unmethylated: +
chemotherapy will be
NOX-A12 Six months
ineffective, so not used
therapy
Progression-Free Survival
(PFS) is 6 months and
Overall Survival (OS) 10
months in this population1
Dose Recruitment Treatment
Cohort Treatment results
mg/week Status status
Adverse event profile seen as expected from
Last patient has
All patients radiotherapy in glioblastoma2
1 200 completed
recruited (n=3) Tumor volume reductions seen in all patients (6-
treatment
60% maximal reduction)3, durable responses
All patients Treatment
2 400 Q2-20214
recruited (n=3) ongoing
3 600 Recruiting Mid-20214
17
1. Kreth 2013, Annals of Oncology 24:3117 3. Assessed by MRI, average of two independent central readers, includes unscheduled scans
2. Cutoff date for safety database: 23-Oct-2020 cutoff 4. Timeline subject to recruitment rate and other risksNext Step in Brain Cancer: Pivotal Trial Targeting Approval
NOX-A12 + Radiotherapy in 1st line MGMT Promoter Unmethylated Patients
Target Start Target
2022 Completion
2024
Phase II Study in Newly Radiotherapy + NOX-A12
diagnosed brain cancer
Treatment until
(glioblastoma)
progression
MGMT promoter
vs. Assess: PFS, OS,
unmethylated population: other efficacy
chemotherapy known to endpoints
be ineffective1 Standard of Care
18
1. Hegi et al. (2005) NEJM 352:997NOX-A12 + Immunotherapy in Pancreatic Cancer
Pancreatic Cancer is Generally Diagnosed at Advanced Stage &
Outcomes Remain Poor
NOX-A12 is one of the few agents that offers the potential to address the major unmet need in
pancreatic cancer in terms of the TME, promoting recruitment of key immune cells.
High unmet need in relapsed & refractory
Lack of Effective Therapies & Low Overall patient settings
Survival: mOS: ~6 months,
Pancreatic cancer stroma sequesters T-cells
preventing engagement with tumor cells -
5-year survival: ~7% (mostly resectable) many immunosuppressive cells: TAMs, MDSCs
Industry Interest Significant : ~100 active trials Agents like NOX-A12 are ideally positioned to
be combined with checkpoint inhibitory and
~75k new cases / yr. in US + EU other MoAs to improve long-term outcomes
1981-1990
1991-2000
2001-2010
20 Sources: Sun, H. (2015) Scientific Reports 4, 6747.doi:10.1038/srep06747; S. Pusceddu, M, et al. (2019) Cancers Vol. 11 Issue 4;
Seo YD, et al., (2019) Clin Cancer Res; 25(13); Biomedtracker by Informa Pharma Intelligence & NOXXON Pharma analysis, November 2020,Phase 1/2 Trial of NOX-A12 + Immunotherapy in 20 Patients with
Metastatic Colorectal (11) & Pancreatic Tumors (9)
Baseline tumor biopsy 2nd tumor biopsy
NOX-A12 NOX-A12 + Keytruda®
1 2
Patients from Part 1 then transitioned to
NOX-A12 monotherapy combination treatment
for 2 weeks of NOX-A12 with checkpoint inhibitor
until progression
Primary endpoint: Endpoint:
Changes in the tumor Assess safety and efficacy
microenvironment induced by of combination
NOX-A12: immune cells &
cytokine/chemokine profile
Clinical Trial a Scientific Collaboration with:
21Unexpectedly High Number of Patients with Long Survival for this
Heavily Pre-Treated Population
▪ Colorectal cancer patients receiving 6th line of therapy on average
▪ Pancreatic cancer patients receiving 4th line of therapy on average
22 Source: Halama et al, Final Top-Line Data: CXCL12 inhibitor NOX-A12 and pembrolizumab in microsatellite-stable, metastatic colorectal or pancreatic
cancer, ESMO Virtual Conference Poster 4103 Sept 2020NOX-A12 + Immunotherapy: Mode of Action (MoA)
▪ CXCL12 excludes effector immune cells from entering the tumor and attracts bone-
marrow derived immune-suppressive / pro-cancer cells to region of tumor
Anti-Cancer Tumor Immuno-suppressive /
Immune Response Pro-cancer
Helper T Cell
Killer T Cell
Natural Killer
Cell
CXCR4 receptor CXCL12 Chemokine
CXCR7 receptor
23
Sources: Feig 2013, PNAS 110:20212; Fearon 2014, Cancer Immunol Res 2:187; Liu 2014, Neuro-Oncology 16:21, NOXXON dataNOX-A12 + Immunotherapy: Mode of Action (MoA)
▪ NOX-A12 reduces CXCL12 “wall” around solid tumors, allowing Killer T cells to
enter, eliminates attraction of immune-suppressive / pro-cancer cells
Anti-Cancer Tumor Immuno-suppressive /
Immune Response Pro-cancer
Helper T Cell
Killer T Cell
Natural Killer
Cell
CXCR4 receptor CXCL12 Chemokine
CXCR7 receptor NOX-A12
24
Sources: Feig 2013, PNAS 110:20212; Fearon 2014, Cancer Immunol Res 2:187; Liu 2014, Neuro-Oncology 16:21, NOXXON dataNOX-A12 + Immunotherapy: Mode of Action (MoA)
▪ NOX-A12 reduces CXCL12 “wall” around solid tumors, allowing Killer T cells to
enter, eliminates attraction of immune-suppressive / pro-cancer cells
Anti-Cancer Tumor Immuno-suppressive /
Immune Response Pro-cancer
Helper T Cell
Killer T Cell
Natural Killer
Cell
CXCR4 receptor CXCL12 Chemokine
CXCR7 receptor NOX-A12
25
Sources: Feig 2013, PNAS 110:20212; Fearon 2014, Cancer Immunol Res 2:187; Liu 2014, Neuro-Oncology 16:21, NOXXON dataNOX-A12 Penetrates Tumor Tissue and Triggers Th1-Type
Anti-Tumor Immune Response
> 3-fold increase
Patient 10 was the only
patient with favorable
baseline T-cells numbers
at tumor invasive margin
Increased neutralization of CXCL12 by NOX-A12 correlates with immune activation and clinical benefit
26 Source: Halama et al, Final Top-Line Data: CXCL12 inhibitor NOX-A12 and pembrolizumab in microsatellite-stable, metastatic colorectal or pancreatic
cancer, ESMO Virtual Conference Poster 4103 Sept 2020Overall Survival Longer Than Expected for this Heavily
Pre-Treated Population
Expected survival
Colorectal cancer
patients receiving
on average their
6th line of therapy
Pancreatic cancer
patients receiving
on average their 4th
line of therapy
Responses to
immunotherapy can
take 3-6 months to
observe and many
advanced patients
don’t have that time
Of the five stable disease patients (25% of the study population)
three survived for more than a year
27 Source: Halama et al, Final Top-Line Data: CXCL12 inhibitor NOX-A12 and pembrolizumab in microsatellite-stable, metastatic colorectal or pancreatic
cancer, ESMO Virtual Conference Poster 4103 Sept 2020Positioning NOX-A12 to become part of the standard of care
NOX-A12 + Immunotherapy in 2nd Line Pancreas Cancer
Target Start Target
Comparison of two combinations will define the winning
H2-2021 Completion
combination to be taken into a pivotal trial
H2-2023
Phase II Study in 2nd line Arm 1 : NOX-A12 + anti-PD-1 + Gemzar/Abraxane
Pancreas Cancer
Treatment until
Patients
progression
Microsatellite Stable
vs. Assess: DCR, PFS,
Patients where anti-PD-1 OS, other efficacy
monotherapy ineffective endpoints
Arm 2 : NOX-A12 + anti-PD-1 + Onivyde/5FU/LV
28 Timelines subject to regulatory and manufacturing timelines and appropriate financing / partnershipMultiple Value Inflection Points in 2021 and Beyond
▪ NOX-A12 + immunotherapy 2nd Line Pancreas Cancer trial to begin H2 2021 – final
overall survival data from Phase 1/2 combined with safety profile of combination with
checkpoint antibody in metastatic, microsatellite-stable colorectal and pancreatic cancer
warrant further clinical development
▪ NOX-A12 + radiotherapy: trial in 1st line brain cancer ongoing
→ 1st cohort top-line data target shows tumor volume reduction in all patients
→ 2nd cohort fully recruited, top-line data target Q2-2021
→ 3rd cohort top-line data target mid-2021
– Expansion cohort planned: initiation 2021
– Pivotal Trial Initiation planned 2022
▪ Top-10 Pharma conducting preclinical evaluation on NOX-A12 for undisclosed additional
indication
29NOXXON: Corporate Profile & Financials
▪ NOXXON Pharma N.V. is a Dutch management holding company listed on Euronext Growth Paris
(ALNOX) and located in Berlin, Germany
▪ NOXXON Pharma AG is the operational subsidiary from which all clinical development is carried out
and where all intellectual property is held
▪ ~ 15 employees, headquarters in Berlin, Germany
▪ Cash & equivalents: €10.7 million (30 June 2020), €9.9 million gross raised thereafter and additional
~€12.8 million nominal capacity (5 Feb 2020) still available via the Atlas Convertible Bond vehicle
Financials and Shareholding structure
Public listing 28 September 2016
ISIN Code NL0012044762
Ticker ALNOX
Euronext Growth Paris
Market
(ex-Alternext)
Market Cap ~ €28 M (25/01/2021)
Shares outstanding 61,455,532 (25/01/2021)
*All percentages as per June 2020 (rounded to one decimal place)
30Thank you
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