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AACR ANNUAL MEETING 2018: NANOBIOTIX PRESENTED PRECLINICAL DATA SHOWING
NBTXR3 NANOPARTICLES CAN ACTIVATE THE cGAS-STING PATHWAY

On April 17, 2018 NANOBIOTIX (Euronext: NANO – ISIN: FR0011341205), a late clinical-stage nanomedicine company pioneering new approaches to the local treatment of cancer, reported that preclinical data evaluating the activation of the cGAS-STING pathway by NBTXR3 has been presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago, Illinois (April 14-18, 2018) (Press release, Nanobiotix, APR 17, View Source [SID1234525489]).

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NBTXR3 is a first-in-class product designed to destroy, when activated by radiotherapy, tumors and metastasis
through physical cell death and to induce immunogenic cell death leading to specific activation of the immune
system.
Establishing how NBTXR3, activated by radiotherapy, impacts and primes the immune response against tumor
cells is central to Nanobiotix’s immuno-oncology program. Recently, the cGAS-STING pathway has emerged as
the key component of the anti-tumor immune response, along with immunogenic cell death. Therefore,
evaluation of the impact of NBTXR3 on this conserved signaling cascade is essential.

Dr Elsa Borghi, CMO, commented, "cGAS-STING activation is of fundamental importance in establishing an
adaptive anti-tumor immune response. These encouraging preliminary results suggest that NBTXR3 activated by
radiotherapy could increase the activation of this pathway, compared to radiotherapy alone."
"Activation of the cGAS-STING pathway by NBTXR3 nanoparticles exposed to radiotherapy"
J. Marill, N. Mohamed Anesary, A. Darmon, P. Zhang and S. Paris.
Poster number #4571
In this poster, Nanobiotix presents data showing a dose-dependent increase in cGAS-STING pathway activation
with NBTXR3 activated by radiotherapy through both in vitro and in vivo analyses.
In vitro analyses show a significant increase in luciferase activity (reflecting the transcriptional activity of IRF) was
observed in HCT116-DUAL cells treated with NBTXR3 plus RT, compared to radiotherapy alone. Further,
NBTXR3 activated by radiotherapy triggers an increased generation of micronuclei (involved cGAS-STING
response) compared to radiotherapy alone.
In vivo, NBTXR3 activated by radiotherapy leads to a greater production of IFN-b and overexpression of its gene,
compared to radiotherapy alone.
Previous work has demonstrated that NBTXR3 activated by radiotherapy increased cancer cell killing efficiency
along with Immunogenic Cell Death (ICD), compared to radiotherapy alone. Here, in vitro data generated from
HCT116-DUAL and in vivo data from CT26 tumors further demonstrate that NBTXR3 activated by radiotherapy
is able to trigger a stronger activation of the cGAS-STING pathway, compared to radiotherapy alone, even in
combination with the STING agonist 2’,3’-cGAMP. Moreover, NBTXR3 can maximize the effect of 2’,3’-cGAMP,
the natural agonist of STING, when activated by the radiotherapy.
These observations support the rationale for using NBTXR3 with radiation therapy in combination with
immunotherapeutic agents and/or STING agonist to transform tumors into an in-situ cancer vaccine.
These results, obtained in human and mouse colorectal cancer cells models, could have a very positive impact
on the anti-tumoral immune response, potentially transforming non-responding tumors into responding, i.e.
turning them from "cold" to "hot".
NBTXR3 positioning in IO
Many IO combination strategies focus on ‘priming’ the tumor, which is now becoming a prerequisite of turning
a "cold" tumor into a "hot" tumor.
Compared to other modalities that could be used for priming the tumor, NBTXR3 could have a number of
advantages: the physical and universal mode of action that could be used widely across oncology, a one-time
local injection and good fit within existing medical practice already used as a basis for cancer treatment, as well
as a very good chronic safety profile and well-established manufacturing process.
Published preclinical and clinical data indicate that NBTXR3 could play a key role in oncology and could become
a backbone in immuno-oncology.
Nanobiotix’s immuno-oncology combination program opens the door to new developments, potential new
indications, and important value creation opportunities.
***
About American Association for Cancer Research (AACR) (Free AACR Whitepaper) www.aacr.org
The AACR (Free AACR Whitepaper) Annual Meeting is one of the main international oncology events highlighting the best cancer science and medicine
from institutions all over the world. The American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago,
Illinois (April 14-18, 2018).
About NBTXR3
NBTXR3 is a first-in-class product designed to destroy, when activated by radiotherapy, tumors and metastasis through
physical cell death and to immunogenic cell death leading to specific activation of the immune system.
NBTXR3 has a high degree of biocompatibility, requires one single administration before the whole radiotherapy treatment
and has the ability to fit into current worldwide standards of radiation care.
NBTXR3 is being evaluated in head and neck cancer (locally advanced squamous cell carcinoma of the oral cavity or
oropharynx), and the trial targets frail and elderly patients who have advanced cancer with very limited therapeutic options.
The Phase I/II trial has already delivered very promising results regarding the local control of the tumors and a potential
metastatic control through in situ vaccination.
Nanobiotix is running an Immuno-Oncology program with NBTXR3 that includes several studies. In the U.S., the Company
received the FDA’s approval to launch a clinical study of NBTXR3 activated by radiotherapy in combination with anti-PD1
antibodies in lung, and head and neck cancer patients (head and neck squamous cell carcinoma and non-small cell lung
cancer). This trial aims to expand the potential of NBTXR3, including using it to treat recurrent or metastatic disease.
The first market authorization process (CE Marking) is ongoing in Europe in the soft tissue sarcoma indication.
The other ongoing studies are treating patients with liver cancers (hepatocellular carcinoma and liver metastasis), locally
advanced or unresectable rectal cancer in combination with chemotherapy, head and neck cancer in combination with
concurrent chemotherapy, and prostate adenocarcinoma.

Launch of the Anti-Cancer Agent / a Humanized Anti-PD-L1 Monoclonal Antibody â€œTECENTRIQ®â€

On April 17, 2018 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it has launched atezolizumab, a recombinant humanized anti-PD-L1 monoclonal antibody, (brand name, "TECENTRIQ Intravenous Infusion 1200 mg;" hereafter, "TECENTRIQ") for the treatment of "unresectable advanced or recurrent non-small cell lung cancer (NSCLC) today (Press release, Chugai, APR 17, 2018, View Source [SID1234525488]). TECENTRIQ received a manufacturing and marketing approval on January 19, 2018 and was listed on the National Health Insurance (NHI) reimbursement price list today.

"Cancer immunotherapy is expected to be a breakthrough therapy which may significantly change cancer treatment. As our mission is to deliver innovative therapeutic drugs to patients, it is a great pleasure for us to finally being able to launch TECENTRIQ," said Chugai’s President & CEO, Tatsuro Kosaka. "We will continue our research and development activities in multiple cancer types and combination therapies to realize sustained therapeutic effects and improvement of survival rate, as well as cure in more patients with cancer."

TECENTRIQ is an immune checkpoint inhibitor targeting PD-L1 (Programmed Death-Ligand 1) which is a protein expressed on tumor cells and tumor-infiltrating immune cells. PD-L1 blocks T-cell activity by binding with PD-1 and B7.1 receptors on T-cell surface. By inhibiting PD-L1, TECENTRIQ may enable the activation of T-cells and boost immune response against cancer cells.

In Japan, the annual prevalence of lung cancer is estimated to be approximately 128,700 in 2017 (male: 86,700, female: 42,000). The annual mortality of lung cancer, the leading cause of cancer deaths (the second leading cause in women) in Japan, is approximately 78,000 (male: 55,600, female: 22,400; predicted figure for 2017).*

As a top company in the field of oncology in Japan, Chugai firmly believes that the launch of TECENTRIQ in Japan as a new therapeutic option for the treatment of "unresectable advanced or recurrent NSCLC," will allow us to further contribute to treat patients and promote appropriate use of drugs.

Pharma Sales Drive J&Jâ€™s First Quarter

On April 17, 2018 Johnson & Johnson reported a strong first quarter with $20 billion in sales that was fueled by significant growth in its pharmaceuticals business (Press release, BioSpace, APR 17, 2018, View Source [SID1234525487]).

About half of the healthcare giant’s quarterly sales was driven by the company’s pharma business. In its quarterly report, the healthcare giant said pharmaceutical sales generated $9.8 billion in the first quarter. That was an increase of 19.4 percent over the same period last year. The bulk of the company’s pharma sales were made overseas, according to the data. J&J said international sales increased by 33.1 percent and domestic sales increased 9.9 percent.

The company noted that strong sales were driven by drugs such as Darzalex (daratumumab), a treatment for multiple myeloma, Tremfya (guselkumab) a treatment for moderate to severe plaque psoriasis and blood-cancer treatment Imbruvica (ibrutinib). During the first quarter J&J filed a supplemental New Drug Application for Imbruvica as a treatment for Waldenström’s macroglobulinemia.

Johnson and Johnson noted other strong-performing drugs including Zytiga (abiraterone acetate), which is used for the treatment of metastatic, castration-resistant prostate cancer. During the quarter Zytiga gained approval for an additional indication as at treatment of metastatic high-risk castration-resistant prostate cancer. Two other strong performers included inflammatory disease treatment Stelara (ustekinumab) and the anti-blood clotting drug Xarelto.

Also, during the first quarter, J&J gained approval from the U.S. Food and Drug Administration for Erleada, an oral androgen receptor inhibitor for the treatment of patients with non-metastatic castration-resistant prostate cancer.

Johnson & Johnson noted that the pharmaceutical business gained a 7.6 percent boost from the company’s 2017 $30 billion acquisition of Swiss-based Actelion, which manufactures Tracleer, a drug used to treat pulmonary arterial hypertension a form of high blood pressure in the arteries of the lungs. While J&J saw an increase in earnings from the deal, the company noted that it discontinued development of one of the drug candidates picked up in that acquisition. In its earnings report, J&J said it terminated development of cadazolid, a Phase III program for the treatment of clostridium difficile-associated diarrhea. Months after the deal was announced Actelion disclosed that cadazolid saw mixed results in two identical studies. The drug hit the mark in reducing diarrhea in patients in one study but failed to do so in a joint-study.

Alex Gorsky, chief executive officer of Johnson & Johnson, said the company’s pharmaceutical business delivered robust returns for the company.

In addition to its strong pharma showing, J&J said its medical device business saw sales of $6.8 billion for the first quarter, which represented an increase of 7.5 percent over the prior year.

Not only did J&J see strong revenues from its pharma business, Gorsky added that the company is also benefitting from a revamping of U.S. tax laws. He said the new legislation that reduced corporate tax rates in the United States will allow the company to invest more than $30 billion in research and development, as well as capital investments over the next four years. Gorsky said that investment is an increase of 15 percent over the previous four years.

Alpine Immune Sciences Announces Preclinical Data Demonstrating ALPN-202 Eliminates Tumors and Creates Persistent Tumor Resistance in a Murine Cancer Model

On April 17, 2018 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing treatments for cancer and autoimmune/inflammatory diseases, reported preclinical study results of its ALPN-202 immuno-oncology program (Press release, Alpine Immune Sciences, 17 17, 2018, View Source [SID1234525447]). ALPN-202 will be the second product candidate to come out of the company’s proprietary scientific platform following ALPN-101, which is projected for an IND filing in the fourth quarter of 2018.

ALPN-202 is designed to antagonize PD-L1 and CTLA-4 while also providing CD28 costimulation. Recent literature suggests the lack of CD28 costimulatory signaling may be a principal reason why many tumors do not respond to PD-L1 or CTLA-4 blockade. ALPN-202’s ability to agonize the costimulatory receptor CD28 potentially improves the immune system’s response to cancer.

Alpine used its proprietary scientific platform to engineer Variant Ig Domains (vIgDs) based on CD80. Single vIgD proteins were created capable of binding PD-L1, CTLA-4, and CD28. These vIgDs were then fused to an Fc backbone and used in various in vitro and in vivo studies to characterize functional activity and assess anti-tumor activity in mice implanted with human PD-L1 transduced tumors. Results showed:

ALPN-202 eliminated tumors in most mice (73% or 8/11 tumor free) compared to durvalumab, an FDA-approved anti PD-L1 antibody (18% or 2/11 tumor free), and controls (0/11 tumor free).
Importantly, those mice tumor free after receiving ALPN-202 were re-challenged with tumor and 100% of them were resistant to the newly-implanted cells without receiving additional doses of therapy, suggesting the potential for ALPN-202 to induce anti-tumor memory.
ALPN-202 elicited CD28 costimulation only in the presence of PD-L1.
Scientific Support and Rationale for ALPN-202
PD-1/PD-L1 inhibitors likely are most effective only when sufficient T cell activating signals, such as via CD28 costimulation, are present. Indeed, recent research demonstrated CD28 costimulation appears to be required for PD-1 inhibition to rescue exhausted T cells in some settings (Science 355:1423, 2017), yet the CD28 ligands CD80 and/or CD86 are often poorly expressed in tumor microenvironments. Because it provides both checkpoint blockade and CD28 costimulation, the ALPN-202 program is therefore well positioned to potentially be a more potent and broadly applicable therapeutic.

"Previously published data suggest PD-1 blockade requires CD28 costimulation to work, at least in some cancers. The preclinical data we are presenting at AACR (Free AACR Whitepaper) indicate the ALPN-202 program proteins are capable of delivering both with a single molecule," said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. "Additionally, these data demonstrate we can modulate three targets (PD-L1, CTLA-4, and CD28) with a single domain (in contrast to the need for multiple targeting domains for other therapeutic formats like bi- or tri-specific antibodies), demonstrating the potential promise of our versatile scientific platform."

"Our goal in oncology is to develop paradigm-shifting therapeutics that meaningfully improve upon existing therapies like PD-1/PD-L1 inhibitors," said Mitchell H. Gold, M.D., Executive Chairman and Chief Executive Officer of Alpine. "The preclinical data presented at AACR (Free AACR Whitepaper) show ALPN-202 antagonizes PD-1 and CTLA-4, and provides a CD28 costimulatory signal, resulting in a potent anti-tumor response. As we drive the ALPN-202 program towards the clinic in 2019, we believe we can create the next generation of immuno-oncology therapeutics with novel mechanisms of action using our proprietary scientific platform."

amcure Presents Pre-Clinical Anti-tumor and
Anti-Metastatic Effects of AMC303 at AACR

On April 17, 2018 amcure, a biopharmaceutical company developing first-in-class cancer therapeutics, reported pre-clinical results of its lead drug candidate, AMC303 (Press release, amcure,APR 17, 2018, View Source [SID1234525445]). The data showed the strong anti-tumor and anti-metastatic effects in various epithelial tumor cells by binding of AMC303 to the extracellular domain of CD44v6. The research was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in a poster entitled ‘The allosteric inhibitor of CD44v6 AMC303 blocks c-MET, Ron and VEGFR-2 dependent signaling and cellular processes’.

"The results presented in this study emphasize the importance of CD44v6 inhibition in cancer and the potential of this approach to improve the chances against this disease," said Klaus Dembowsky, MD, PhD, CEO of amcure. "Not only did we show strong anti-cancer effects for AMC303, but we gained new mechanistic insights into the role of AMC303 in inhibition of one of the key drivers of metastasis, Epithelial-Mesenchymal-Transition (EMT). We look forward to substantiating the strong preclinical data sets for AMC303 with results from our current and future clinical trials."

The CD44 family of transmembrane glycoproteins comprises several variants that are involved in many cellular processes. The isoform CD44v6 has been shown to play a major role in tumor growth and metastasis. In this study, the amcure research team has shown that blocking CD44v6, an essential coreceptor for the receptor tyrosine kinases VEGFR-2, c-MET and RON by AMC303, interferes with several key steps in tumor progression and metastasis including EMT, cell migration and invasion. This novel mode of action results in strong anti-tumor and anti-metastatic effects of AMC303.

About AMC303
amcure’s lead compound, AMC303, is being developed as a potential treatment for patients with advanced and metastatic epithelial tumors, e.g. pancreatic cancer, head and neck cancer, gastric cancer, colorectal cancer, breast cancer and lung cancer. AMC303 has a high specificity for inhibiting CD44v6, a co-receptor required for signaling through multiple cellular pathways (c-Met, VEGFR-2, RON) involved in tumor growth, angiogenesis and the development and regression of metastases.

AMC303 has demonstrated strong effects in various in vitro and in vivo assays.