Innovative Clinical Programs Targeting the Tumor Microenvironment to Improve Outcomes in Underserved Cancers - German Equity Forum Fall Conference ...
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Innovative Clinical Programs Targeting the Tumor Microenvironment to Improve Outcomes in Underserved Cancers German Equity Forum Fall Conference Sept 2018
Forward-Looking Statements The information and opinions contained in this presentation and any other information discussed at this presentation are provided as at the date of this presentation and are therefore of a preliminary nature, have not been independently verified and may be subject to updating, revision, amendment or change without notice and in some cases has not been audited or reviewed by the Company’s auditors. This presentation is selective in nature and does not purport to contain all information that may be required to evaluate the Company and/or its securities. Neither the Company nor any other person is under any obligation to update or keep current the information contained in this presentation or to correct any inaccuracies in any such information which may become apparent or to provide you with any additional information. No reliance may or should be placed for any purpose whatsoever on the information contained in this presentation, or any other information discussed verbally, or on its completeness, accuracy or fairness. None of the Company, its investment banking representatives, or any of their respective directors, officers, employees, direct or indirect shareholders, agents, affiliates, advisors or any other person accept any responsibility whatsoever for the contents of this presentation, and no representation or warranty, express or implied, is made by any such person in relation to the contents of this presentation. Certain information in this presentation is based on management estimates. Such estimates have been made in good faith and represent the current beliefs of applicable members of management. Those management members believe that such estimates are founded on reasonable grounds. However, by their nature, estimates may not be correct or complete. Accordingly, no representation or warranty (express or implied) is given that such estimates are correct or complete. Where this presentation quotes any information or statistics from any external source, it should not be interpreted that the Company has adopted or endorsed such information or statistics as being accurate. This presentation contains forward- looking statements. These statements reflect the Company’s current knowledge and its expectations and projections about future events and may be identified by the context of such statements or words such as “anticipate,” “believe”, “estimate”, “expect”, “intend”, “plan”, “project”, “target”, “may”, “will”, “would”, “could”, “might” or “should” or similar terminology. By their nature, forward-looking statements are subject to a number of risks and uncertainties, many of which are beyond the Company’s control that could cause the Company’s actual results and performance to differ materially from any expected future results or performance expressed or implied by any forward-looking statements. The Company undertakes no obligation publicly to release the results of any revisions to any forward-looking statements in this presentation that may occur due to any change in its expectations or to reflect events or circumstances after the date of this presentation. 2
NOXXON: High-value Clinical Assets from De-risked RNA Platform
▪ NOXXON has translated a validated RNA-based platform into two clinical-stage drug
candidates addressing critical molecular pathways to treat solid tumors
▪ NOX-A12: Targeting the adaptive immune system through the chemokine CXCL12, key
player in the tumor micro-environment (TME)
- Established safety and efficacy data in hand, top-line results expected in 2018 on Phase 1/2
PD-1 (Keytruda) combo trial in metastatic colorectal and pancreatic cancer, collaboration with
Merck & Co./MSD
- Company primed to start transformative glioblastoma (GBM) trial
▪ NOX-E36: Complementary MoA targeting the innate immune system through the
chemokine CCL2 and highly-related CCL7, 8 and 13 involved in recruitment of immuno-
suppressive tumor associated macrophages (TAMs)
- Established safety and activity, plus data showing monotherapeutic potential
▪ Driven leadership team committed to moving the assets toward success
▪ Significant commercial potential underscores immediate investment opportunity
3 1. Venture Valuation AG Report
Thinking Outside the Cancer Cell – Noxxon Spiegelmers Tackle TME
“Although chemokines and their receptors were originally identified as mediators of inflammatory
diseases, it is being increasingly recognized that they serve as critical communication bridges between
tumor cells and stromal cells to create a permissive microenvironment for tumor growth and
metastasis.” – F. Guo et al. Oncogene 2016
▪ Noxxon’s proprietary compounds target core chemokines modulating the tumor
microenvironment (TME) which has been confirmed as a key contributor to tumor growth
and survival (”address the soil not just the weed“)
▪ Altering the TME presents a core approach to break tumor survival mechanisms and enable
real therapeutic impact from standard of care
▪ Modified RNA approach creates stable, injectable oligonucleotides, resistant to nuclease
degradation that directly bind and neutralize protein targets
▪ Potential of RNA-based cancer therapy approaches is now accepted: the science and
medical practice has caught up to Noxxon’s vision
4
Assets Target High-value Indications to Improve Standard of Care
NOX-A12 - anti-CXCL12/SDF-1
COMBINE WITH Near-term Milestones
SOLID TUMORS:
PANCREATIC/COLORECTAL CANCERS
BREAK TUMOR Topline (mono): Sept-18
IMMUNOTHERAPY Status : Ongoing Phase 1/2 in
PROTECTION1 combination with Keytruda® (anti-PD-1)
Topline (combo): end-18
Additional potential in NSCLC PD-1 failures
SOLID TUMORS:
GLIOBLASTOMA (orphan drug status)
Orphan
ABLATION/ Glioblastoma trial
Status BLOCK TUMOR REPAIR3 Status: Phase 1/2 planned 1st line, Temodar
US & EU RADIATION financing &
resistant inoperable patients
initiation
Additional potential in pediatric brain tumors
NOX-E36 - anti-CCL2/MCP-1 and related chemokines
SOLID TUMORS: Pancreatic
Status: Phase 1 & 2a completed in non-oncology
BREAK TUMOR IMMUNOTHERAPY &
indications
PROTECTION4 CHEMOTHERAPY Planned study in pancreatic cancer patients as
monotherapy and in multiple combinations
5 1. Feig, C. et al. PNAS 110.50 (2013): 20212-20217; Fearon, D. Cancer Immunol Research 2.187 (2014): 187-193; Poznansky, M., 4.
5.
Nywening Lancet Oncol 2016 http://dx.doi.org/10.1016/S1470-2045(16)00078-4
Steurer, M. et al. ASH 2014 642 for CLL & Ludwig, H. 2017 Leukemia for MM
Nature America 6:543 (2000): 543-548
2. Rocarro et al. Cell reports 9 (2014): 118-128; Marasca, R. & Maffei, R., Blood 123 (2014): 952-953
3. Liu, S. et al. Neuro-Oncology 16.1 (2013): 1-8; Castro, B. & Aghi, M. Neuro-Oncology 16.1 (2014): 4-6
NOX-A12 Overview
▪ NOX-A12 neutralizes the chemokine
CXCL12, a key player in the TME Inhibition of the
NOX-A12 blocks binding to both core CXCL12/CXCR4/CXCR7 axis to
receptors CXCR4 and CXCR7
CXCL12 plays an important role in tumor Break tumor protection1 Block tumor repair2
angiogenesis, tumor cell proliferation and
chemo-resistance
Levels of CXCL12 correlate with poor
prognosis in many tumor types
▪ NOX-A12 has a strong safety & CXCL12
tolerability profile & clear PK/PD profile
Tested in 116 patients in Phase 1/2
development
Indication: Solid Tumors Indication: Solid
▪ Two core programs to solidify scientific (e.g. pancreatic, colorectal Tumors
rational with ability to expand cancer, NSCLC) (e.g. glioblastoma)
MSD Keytruda combo trial in pancreatic
cancer
Glioblastoma
6 1. Feig 2013, PNAS 110:20212; Fearon 2014, Cancer Immunol Res 2:187; NOXXON data
2. Liu 2014, Neuro-Oncology 16:21
Ongoing Phase 1/2 Trial in MSS Colorectal & Pancreatic Tumors
Trial Design1
Patient Profile
Part 1 Part 2
NOX-A12 Induction NOX-A12 + Keytruda®
▪ Phase 1/2 proof-of mechanism/concept Patients with PD after 1 Tumor biopsy before 2 Patients from Part 1
trial in 2 indications : multiple prior lines of and after NOX-A12 then transitioned to
1. Colorectal cancer (MSS) therapy. treatment for 2 weeks combination
10 patients treatment of
Best response to
2. Pancreatic cancer (MSS) Primary endpoint: NOX-A12 with
previous treatment
generally PD
Changes in the tumor checkpoint inhibitor
10 patients
MSS = microsatellite stable microenvironment
Micro-satellite stable induced by NOX-A12: Endpoint:
▪ Response rate in targeted patient immune cells & Assess safety and
disease where
population to anti-PD-1 alone ~0%3 checkpoint inhibitors cytokine/chemokine efficacy of
(CPI) aren’t efficacious2 profile combination
▪ Regulatory scientific advice will be
planned when data available
Collaboration with:
Timeline3
▪ 3 Sept 2018 – Patient recruitment completed
▪ Sept 30- Oct 3 - Top-line, MoA data from Part 1 to be presented at the 4th CRI-
CIMT-EATI-AACR International Cancer lmmunotherapy Conference, NY, USA
▪ end-2018 – Top-line efficacy data for NOX-A12 + Keytruda from Part 2
7 1. Clinicaltrials.gov trial NCT03168139
2. Diaz, L. et al, 2016 J Clin Oncol 34, 2016 (suppl; abstr 3003) oral presentation at ASCO 2016
3. NOXXON Pharma NV 3 Sept 2018 Press Release
Preliminary interim data
NOX-A12 Penetrates Tumor Tissue, Neutralizes CXCL12
CXCL12
1200
CRC patients PaC patients
1000
1200 CXCL12
% change from baselines
800 1000
% change from baseline
800
600
600
400
400
200 200
0
Upper limit for
0
1 6 9 10 14 17 18 2 3 4 13 15 spontaneous fluctuation All Patients
Patient 1 6 9 10 14 17 18 2 3 4 13 15
n = 17 patients of which 12
D0 (pg/ml) 167,32 142,23 131,63 105,66 43,18 98,2 88,74 173,9 130,69 174,83 72,18 40,59 with matched biopsies
D14 (pg/ml) 1162,1 439,89 275,07 323,82 459,64 393,7 321,33 305,81 535,36 527,5 616,02 321,12
available for analysis
▪ NOX-A12 binding and neutralization of CXCL12 results in increased CXCL12 half-life.
▪ Increased total CXCL12 levels signaling neutralization seen in all patients
▪ Clear tissue immune response profiles seen in patients with largest increases
8
Preliminary interim data
NOX-A12 Monotherapy Can Trigger Signatures Consistent with
Immuno-Stimulatory, Cytotoxic / Th1 Type Response
Tissue responders
15 (PaC)
14 (CRC)
13 (PaC)
4 (PaC)
1 (CRC)
Patient Number (indication)
6 (CRC)
17 (CRC)
3 (PaC)
IFN-
IL-2
2 (PaC) immuno-stimulatory TNF-
/ Th1 signature
Tissue non-responders
CXCL9/M IG
CXCL10/IP-10
10 (CRC)
IL-1
9 (CRC) immuno-suppressive
/ myeloid signature IL-1
IL-6 n = 17 patients of which 12
18 (CRC) with matched biopsies
available for analysis
-100 -50 0 50 100 150 200 250
% change from baseline
9
NOX-A12 – Attacking Glioblastoma by Blocking Key Survival Mechanisms
“Recently, we have learned that
glioblastomas efficiently recover
after radiotherapy through
recruiting mononuclear cells from
the bone marrow, which then induce
new vessels and hogtie immune cells CXCL12
that could fight the tumor. Through
inhibiting the CXCL12 axis, the main
communication signal of the tumor
to these cells, NOX-A12 could make
a significant impact in this most
aggressive form of cancer, breaking
its survival mechanisms.”- Frank A.
Giordano, Vice Chair & Associate
Professor, Radiation Oncology, University
Medical Center Mannheim
10NOX-A12 Significantly Increases Survival and Demonstrates Complete
Regression of Brain Tumors
Autochtonous brain tumor model in rats
Pregnant rats:
ENU on gestational
age day 17 - 18
(10 mg/kg - 10 wks)
(10 mg/kg - 10 wks)
Key features:
▪ Spontaneous brain tumor development in
Tumor
immuno-competent host recurrence
▪ High clinical (translational) relevance due to detected only
similar tumor cell diversity in 2 out of 6
animals
▪ Very refractory to standard treatment
▪ In the 2nd study, MRI was used and only rats with
identifiable tumors were sorted into the groups
Orphan drug status obtained for NOX-A12 + radiotherapy in US & EU
11 Source: Liu S-C et al., Neuro Oncol. 2014 Jan;16(1):21-8External Clinical Validation for CXCL12 Axis Interference in
Glioblastoma: Reported at ASCO 2018
▪ Phase I/II study assessing the impact of CXCR4 blockade (PI: Lawrence D.
Recht, Stanford, CA)
▪ Population: newly diagnosed adult GBM patients
▪ Initial results (presented at ASCO 2018):
29 patients enrolled
It is safe to block the CXCL12-CXCR4 axis in GBM patients
improved response to radiation therapy
very promising survival data (estimated median overall survival was 20.7 months)
Out of field first recurrence rate of 58.8% compared to 10% in control group
▪ Study showed proof-of-concept of blocking the CXCL12-CXCR4
communication
12 Reference: http://abstracts.asco.org/214/AbstView_214_230151.htmlNOX-A12: Planned Phase 1/2 Trial 1st Line, MGMT Unmethylated,
unresectable GBM with Radiotherapy
Study population
▪ 9 patients with newly diagnosed glioblastoma multiforme (recruit in cohorts of 3, wait for
safety/efficacy signals after each triplet)
▪ Include only patients with unmethylated MGMT promoter (no activity of temozolomide –
therefore not given)
▪ Biopsy-only or partial tumor resection (to have an imaging correlate to assess for efficacy)
Primary objective and efficacy endpoints
▪ Safety of NOX-A12 in combination with radiation therapy (RT)
Secondary objectives and endpoints
▪ Major secondary endpoints: PFS-6, mPFS, or mOS
▪ pharmacokinetics and pharmacodynamics of NOX-A12 during and after administration
Timeline (assuming Sept-2018 financing of trial:
2018 2019 2020
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
PFS-6 Cohort 1 2 3
GBM Ph 1/2 dose escalation (9 P)
13NOX-E36 – A Phase 2-ready Monotherapy Oncology Drug Candidate
▪ Targeting a core tumor survival mechanism, preventing Tumor Associated Macrophage
(TAM) recruitment
- NOX-E36 binds and neutralizes CCL2 (MCP-1) and three other related chemokines1 implicated in creating immune
privilege of tumors via recruitment of tumor associated macrophages (TAMs)
- TAMs have been recognized to play a crucial role in tumor survival strategies by repressing other immune cell activity,
encouraging blood and lymph vessel development to support growing tumors, and help cancer cells metastasize to
new sites in the body
▪ De-risked program with good clinical safety profile and strong scientific rational
- NOX-E36 has demonstrated its safety, tolerability and activity on CCR2+ monocytes in Phase 1 and a non-oncology
Phase 22 in over 150 subjects
- Data from Pfizer’s CCR2 antagonist in pancreatic cancer patients suggests that even partial inhibition this axis
translates into improved efficacy3
- A rodent version of NOX-E36 prevents recruitment of TAMs, enhances cytotoxic T cell infiltration and reduces tumor
burden
▪ Providing potentially best in class pharmacology on monocyte/macrophage chemokines in
the Innate PD-1 Resistance Signature (IPRES)4
▪ Ready to move into proof-of-concept studies in cancer patients
14 1. Oberthür, D., et al. (2015). “Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2.” Nat Commun 6: 6923.
2. Menne, J. et al (2016) Nephrol Dial Transplant (2016) 0:1–9
3. Nywening Lancet Oncol 2016 http://dx.doi.org/10.1016/S1470-2045(16)00078-4
4. Xia Bu et al (2016) Learning from PD-1 Resistance: New Combination Strategies. Trends in Molecular Medicine, June 2016, Vol. 22, No. 6NOX-E36 Prevents Recruitment of TAMs, Enhances Cytotoxic T cell
Infiltration and Reduces Tumor Burden in a Pancreatic Cancer Model
Model: Syngeneic PDAC in
immunocompetent mice
A. control mNOX-E36 B. (control)
TAMs TAMs
(control)
A,B. Statistically significant decrease
in TAM infiltration in mNOX-E36 group
Reduced
control mNOX-E36 tumor volume
C. CD8+ T-cells CD8+ T-cells E.
in mice treated
after tumor
establishment
D.
C,D. Trend towards higher CD8 T cell E. Trend towards smaller tumor size in
infiltration in mNOX-E36 group established tumor group
15
Source: J. Lazarus et al. (2017) Poster PT165 A Novel CCL2 Inhibitor Reduces Tumor Associated Macrophage Infiltration in a Murine Model of Pancreatic Cancer. Society of Surgical Oncology 70th Annual Cancer SymposiumPhase 2 Data: Strong Activity of NOX-E36 on CCL2 Chemokine Axis
Exemplary patient, Day 1 Time course of monocyte count change from baseline
Normalized to baseline; arithmetic means ± SEM
Data shown from ITT group NOX-E36 n=50; Placebo n=25
150
p < 0.05 vs. placebo n.s.
SEM, normalized to baseline
Relative monocyte count ±
100
Exemplary patient, Day 29
50
1 15 29 43 57 71 85 99 113
Day Emapticap
Placebo
Treatment Follow-up
Upon treatment with NOX-E36:
➢ The number of monocytes in peripheral blood decreases by 15-20% on treatment
➢ The presence of the CCL2 receptor CCR2 on the monocytes is reduced 4 to 5-fold
16
Source: Menne, J. et al (2016) Nephrol Dial Transplant 2016;32(2):307-315Turn-around Team with Strong Commitment
Dr. Aram Mangasarian - CEO Dr. Jarl Ulf Jungnelius – CMO Dr. Don deBethizy - Chairman
▪ Took over as CEO 2016, former CBO at ▪ Oncologist with more than 25 years ▪ Chairman of Albumedix, Board member
Noxxon clinical and research experience in large arGEN-X NV, Newron Pharma SPA,
▪ Headed Business Development at pharma and academic organizations Proterris
Novexel - €75m upfront licensing deal ▪ Leadership positions at Celgene, Pfizer, ▪ Formerly CEO of Santaris Pharma (sale
with Forest Labs in 2008 on avibactam; Takeda and Eli Lilly & Company to Roche), chairman of Rigontec (sale to
company bought by AstraZeneca for ▪ Significant role in the approval of Merck & Co./MSD), Chairman Contera
$505m in 2010 multiple successful oncology drugs Pharma ApS, Serendex A/S
▪ Ran Business Development at ExonHit including Abraxane®, Gemzar®, Alimta® ▪ Co-founder and former CEO of
Therapeutics; closed $30m discovery and and Revlimid® Targacept
development alliance with Allergan
Supervisory Board
Dr. Hubert Birner Dr. Maurizio Petitbon
Bertam Köhler Dr. Walter Wenniger, Independent
17NOXXON Corporate Overview and Financials
▪ Shares traded on EuroNext Growth Paris – ALNOX
▪ Market capitalization : ~€10 million market cap - Key shareholders include: TVM,
Sofinnova, Kreos, Andera (formerly Edmond de Rothschild Investment Partners),
DEWB & NGN
▪ Cash : ~ €622 K as of 31 Dec 20171, subsequent financing of €2.75 million via
convertible debt vehicles2 venture debt remaining not-yet-converted to equity
€841K3
▪ Projected cash burn : ~€350K/month (including the NOX-A12/KEYTRUDA® clinical
trial)
▪ ~ 10 employees, headquarters in Berlin, Germany
18 1. NOXXON Pharma NV Annual Report, published 30 Apr 2018
2. NOXXON Press releases 23 Jan 2018, 13 Mar 2018, 6 Jun 2018, 3 July 2018, 1 Aug 2018, 19 Aug 2018
3. NOXXON Press releases 2 May 2017, 18 July 2017Investment Opportunity
▪ Management has brought lead asset to completion of high-value proof
of concept clinical trial
▪ Company is now on the cusp of multiple value inflection events around
data read-outs over next four months
▪ Capitalization is ready for transformation out of “clean-up” phase with
significant potential around both clinical assets
▪ Short time frame to establishing pole position in addressing crucial
molecular pathways and big oncology opportunities
▪ Immediate investment would enable:
NOX-A12 efficacy read-out in ongoing CRC PaC trial – paving way to regulatory pivotal
trial
Glioblastoma clinical data by end of 2019
Termination of variable-rate investor’s existing put option1 allowing Noxxon to control
the supply of new shares
19 1. NOXXON Pharma Press Release, published 13 March 2018, and 14 Aug 2018Key Upcoming Events and Value Drivers 2018-2019
2018 2019
Aug. Sept. End-2018
NOX-A12 Completion Top-line Top-line
MSD Combo of MoA Data efficacy data
recruitment
Sept March June Dec.
NOX-A12 KOL Event GBM clinical 1st cohort 1st cohort
GBM Brain Tumor trial recruited efficacy &
Experts initiation and dosed safety readout
Equity raise
Termination
Corporate Yorkville put option,
conversion
remaining Kreos debt
Investigator
NOX-E36 NOX-E36 CMC initiated trial
pancreatic
cancer
20NOXXON Opportunity
▪ Clinically-validated and de-risked anti-cancer approach targeting the tumor micro-
environment (TME) through potent activity on the adaptive (NOX-A12) as well as innate
(NOX-E36) immune system
▪ Lead program NOX-A12 in combo with Merck & Co.’s KEYTRUDA®, company primed to
deliver top-line results on Phase 1/2 trial in 2018
▪ NOX-E36 monotherapy potential: Targeting the chemokine CCL2 as well as highly-related
CCL7, 8, and 13 involved in recruitment of immuno-suppressive tumor associated
macrophages (TAMs)
▪ Revitalized lean and focused organization, management and Supervisory Board
committed to translating these assets into value for investors
▪ Investment opportunities underway:
- Minimal investment in place to reach very near-term returns on Phase I/II trial results
- Support for GBM initiation places NOX-A12 compound on fast-track in high-value indication
21Contact Aram Mangasarian, CEO E-mail: amangasarian@noxxon.com
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