On July 21, 2021 NOXXON Pharma N.V. (Paris:ALNOX) (Euronext Growth Paris: ALNOX), a biotechnology company focused on improving cancer treatments by targeting the tumor microenvironment (TME), reported entering into its second clinical collaboration agreement with MSD (Merck & Co., Inc., Kenilworth, N.J. USA), to collaborate in the upcoming Phase 2 clinical trial of NOXXON’s NOX-A12 in combination with MSD’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), as second-line therapy in pancreatic cancer (Press release, NOXXON, JUL 21, 2021, View Source [SID1234585027]).

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This Phase 2 study will evaluate the safety and efficacy of NOX-A12, NOXXON’s anti-CXCL12 agent, in combination with KEYTRUDA and two different chemotherapy regimens in patients with microsatellite stable pancreatic cancer. The vast majority of pancreatic cancer patients have microsatellite stable tumors which are resistant to checkpoint inhibitor monotherapy. The study will enroll up to 70 patients and will contain an interim go/no-go in each arm in addition to usual safety and efficacy endpoints. MSD will provide pembrolizumab and expert advice for the study protocol, while NOXXON will sponsor the trial that will be conducted in clinical centers in the US and Europe.

The study will include two treatment arms to determine the most efficacious treatment combination to move forward into a registrational trial:

Arm 1: NOX-A12 + pembrolizumab + gemcitabine + nab-paclitaxel

Arm 2: NOX-A12 + pembrolizumab + nano-liposomal irinotecan + 5-fluorouracil + leucovorin

Dr. Jarl Ulf Jungnelius, Senior Medical Advisor at NOXXON, commented: "Checkpoint inhibitors have rapidly become first-line treatment options for many cancer types but have failed to demonstrate benefits in microsatellite stable pancreatic cancer as monotherapy or in combination with standard of care chemotherapy. We believe that tackling the microenvironment is a promising approach to deliver in pancreatic cancer the clinical benefits demonstrated by anti-PD-1 therapy in other tumor types."

Aram Mangasarian, CEO of NOXXON commented: "We are excited to continue our successful collaboration with MSD, a key global player in the immuno-oncology space. We expect this upcoming Phase 2 to confirm the excellent safety and more clearly define the clinical benefits that NOX-A12 can provide in combination with KEYTRUDA to patients suffering from highly aggressive cancers, such as pancreatic cancer."

About NOX-A12

NOXXON’s lead compound NOX-A12 is a highly selective inhibitor of CXCL12, a critical tumor microenvironment chemokine that shields the tumor from the immune system and promotes vasculogenesis, significantly reducing cancer treatment efficacy and promoting tumor growth. NOX-A12 acts by two potential mechanisms of action:

Reducing the CXCL12 shield around the tumor, leading to an improved access of immune effector cells like T lymphocytes to the tumor;
Blocking tumor blood vessel rebuilding by vasculogenesis post radiotherapy.
NOX-A12 is currently developed in second-line pancreatic cancer in combination with Keytruda and in glioblastoma in combination with radiotherapy.

About KEYTRUDA

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

On July 21, 2021 Eureka Therapeutics, Inc., a clinical-stage biotechnology company developing novel T cell therapies to treat solid tumors, reported the initiation of a Phase I/II clinical trial of ECT204, a GPC3 targeting ARTEMIS T-cell therapy for the treatment of hepatocellular carcinoma (HCC), the predominant type of liver cancer. The Phase I portion of the ARYA-3 study is now open for enrollment (Press release, Eureka Therapeutics, JUL 21, 2021, View Source [SID1234585026]).

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Glypican 3 (GPC3) is a promising target for HCC therapies and is found in more than 70% of HCC cells. The GPC3 protein is also expressed in other solid tumors including ovarian and lung cancer. During the ECT204 ARYA-3 investigational study, a patient’s T cells will be collected, engineered to express Eureka’s proprietary ARTEMIS cell receptors targeting GPC3, and infused back into the patient’s body to target and kill GPC3-expressing cancer cells.

The ARYA-3 trial is being run in parallel with Eureka’s ongoing ET140203 ARYA-1 trial. With ET140203, the ARTEMIS receptor targets an alpha fetoprotein (AFP)-peptide/HLA-A2 complex found on liver cancer cells using a TCR-mimic antibody. With ECT204, since the antibody directly recognizes GPC3 and does not require the patient to be HLA-A2 positive, the therapy is potentially available to a larger liver cancer patient population.

"We look forward to working with City of Hope on our ARYA-1 and ARYA-3 clinical trials," said Dr. Cheng Liu, President and CEO of Eureka Therapeutics. "ECT204 and ET140203 ARTEMIS T cells were engineered with our proprietary tumor infiltration and controlled cytokine release technologies that we believe can improve on the performance of engineered T cell therapies in solid tumors. Effective treatment for HCC is a highly unmet medical need, and we are committed to bringing our therapies to patients faster."

"We are excited to provide City of Hope patients with both GPC3 and AFP targeted therapy options to treat HCC," said Dr. Daneng Li, Program Lead of the Hepatobiliary Tumor Program and principal investigator of the trial at City of Hope, a comprehensive cancer center near Los Angeles. "Engineered T-cell therapy is a novel approach, and it has the potential to transform how solid tumors will be treated in the future."

The ARYA-3 study is an open-label, dose escalation, multi-center, Phase I/II clinical trial of ECT204 ARTEMIS T cell therapy to initially assess the safety and determine the recommended phase II dose (RP2D) in adult patients with advanced GPC3-positive HCC. Additional information about Eureka’s Phase I/II study may be found at ClinicalTrials.gov, using Identifier NCT: NCT04864054.

Patients, caregivers, and healthcare professionals interested in Eureka’s clinical trials and technology can find more information by visiting eurekaconnectme.com.

Liver cancer is the fourth leading cause of cancer death worldwide, accounting for an estimated 782,000 deaths in 2018. About 43,000 new cases, and 30,000 deaths from liver cancer are expected to occur in the U.S. in 2020. The rate of liver cancer diagnosis has more than tripled since 1980, according to the American Cancer Society. Patients with advanced HCC have a poor prognosis and limited treatment options.

On July 21, 2021 Vedanta Biosciences, Inc., a leading clinical-stage microbiome company developing a new category of oral therapies using defined bacterial consortia manufactured from clonal cell banks, reported the closing of a $68 million Series D financing and provided a pipeline update (Press release, Vedanta Biosciences, JUL 21, 2021, View Source [SID1234585025]).

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The Series D financing was led by affiliates of Magnetar Capital. Other participants in the financing were new and existing investors including Verition Fund Management, Fosun Health Capital, co-founder PureTech Health, Rock Springs Capital, Skyviews Life Science, JSR Corporation, SymBiosis LLC, Shumway Capital, Health for Life Capital (Seventure Partners), and other institutional investors. The round also includes a $25 million investment from Pfizer as part of the Pfizer Breakthrough Growth Initiative, which was announced in January 2021.

Vedanta plans to use the proceeds to advance its pipeline of defined bacterial consortia, including progressing VE303 into a Phase 3 clinical trial in patients at high risk for recurrent CDI, initiating a Phase 2 clinical trial of VE202 in mild to moderate ulcerative colitis, and continuing to advance programs in additional indications.

"We are delighted to welcome the new investors in our Series D round and are grateful to our existing shareholders and partners for their continued support," said Bernat Olle, Ph.D., Co-founder and Chief Executive Officer of Vedanta Biosciences. "Since our last funding round, we have made significant progress advancing defined bacterial consortia as a new modality for infectious and immune-mediated diseases. This most recent financing, together with the support we receive from BARDA for our CDI program, will enable us to advance mid- and late-stage programs in CDI and IBD, as well as support early exploratory clinical studies in additional indications."

"Drugs based on defined bacterial consortia are a promising new therapeutic modality with the potential to transform medicine, and Vedanta is the leader in this category, with a state-of-the-art discovery platform, field-leading GMP manufacturing capabilities, and an advanced pipeline," said Ted Koutouzis, MD, Managing Director of Fiscus Venture and Reimagined Ventures, affiliates of Magnetar. "We are proud to support the company’s efforts."

Vedanta’s Pipeline

Vedanta Biosciences is developing a potential new category of oral therapies based on rationally defined consortia of bacteria derived from the human microbiome. All of the Company’s pipeline programs are wholly owned.

Company-Sponsored Programs

VE303 for the Prevention of Recurrence in High-risk Patients with Clostridioides difficile (CDI) Infection

VE303 consists of 8 clonal human commensal bacterial strains selected for their ability to provide colonization resistance to C. difficile.
In a Phase 1 healthy-volunteer study, VE303 showed rapid, durable, and dose-dependent colonization and accelerated gut microbiota restoration after a course of antibiotics.
Vedanta is currently evaluating VE303 in a Phase 2 clinical trial in patients at high risk of recurrent CDI and will report results from this trial in Q3 2021.
In 2020, Vedanta was awarded up to $76.9 million of federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, under Contract No. 75A50120C00177, to partially fund the development of VE303. This was the first-ever grant from BARDA in the microbiome field.
The Company expects to complete the build-out of its Phase 3 and commercial launch cGMP manufacturing facility for supply of VE303 by the end of 2021.
The company plans to initiate a Phase 3 trial in mid-2022.
VE202 for the Treatment of Inflammatory Bowel Disease (IBD)

VE202 consists of 16 clonal human commensal bacterial strains selected for their ability to induce regulatory T cells in the gut mucosa, decolonize pro-inflammatory organisms, and strengthen the epithelial barrier.
In June 2021, Vedanta presented positive Phase 1 topline data of VE202 in healthy volunteers at the International Human Microbiome Consortium Congress. VE202 was generally safe and well tolerated at all doses and demonstrated durable and dose-dependent colonization.
Vedanta plans to initiate a Phase 2 clinical trial of VE202 in patients with mild to moderate ulcerative colitis in the second half of 2021.
VE202 is being developed in part through funding provided by the Pfizer Breakthrough Growth Initiative.
VE800 for the Treatment of Advanced and Metastatic Tumors

VE800 consists of 11 clonal human commensal bacterial strains selected for their ability to induce CD8+ T cells, potentiate anti-tumor activity, and enhance the effects of checkpoint inhibitors.
The Company is nearing completion of Stage 1 of an open-label Phase 1 study to evaluate the safety and initial clinical activity of VE800 in combination with Bristol Myers Squibb’s Opdivo (nivolumab) in 54 patients across select types of advanced or metastatic cancers.
This trial is being done under a collaboration and supply agreement with Bristol Myers Squibb.
To date, VE800 has demonstrated an acceptable safety and tolerability profile, though the observed response rates did not meet the prespecified criteria to expand into the next stage of the study. Vedanta is analyzing blood, stool, and tumor samples from patients in whom response or disease control was observed, to profile patient subtypes that might benefit from microbiome manipulation. The company plans to present the results at a future medical conference.
The Company will continue work to identify cancer settings and patient populations that might benefit from microbiome manipulation with its defined bacterial consortia.
Preclinical Programs

VE707 is a preclinical program for the prevention of infection by several problematic Gram-negative Enterobacteriaceae, which are some of the most common hospital-acquired pathogens. Vedanta has received funding from Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) of up to $7.4 million, plus up to $3.5 million more if certain milestones are met, to advance VE707. The company expects to select a development candidate in H2 2021.
Investigator-Sponsored Studies

VE416 in Peanut Allergy

VE416 consists of 7 bacterial strains of the Clostridia class, which were selected based on the ability to induce immune tolerance in the gut.
A Phase 1/2, investigator-sponsored clinical study is underway at Massachusetts General Hospital, exploring use of VE416 both as a monotherapy and in combination with an oral peanut immunotherapy over the course of several months.
Topline data from the Phase 1/2 clinical trial is expected to be reported in 2022, subject to investigator timelines.
VE303 in Hepatic Encephalopathy

A new Phase 2 investigator-sponsored trial evaluating VE303 in patients with hepatic encephalopathy (HE) was recently initiated by the University of Michigan Hospitals-Michigan Medicine. The randomized, double-blind, placebo-controlled trial is planned to enroll up to 18 adult patients with a confirmed diagnosis of cirrhosis and history of at least one episode of overt HE.
FJS Consultants Limited acted as a placement agent for Vedanta’s investors in China. BARDA is the Biomedical Advanced Research and Development Authority, part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services.

On July 21, 2021 Turnstone Biologics Corp., a clinical-stage biotechnology company pioneering the development of cancer immunotherapies, reported the successful completion of an $80 million Series D financing co-led by PFM Health Sciences and Point72 (Press release, Turnstone Biologics, JUL 21, 2021, View Source [SID1234585024]). Additional new investors Eventide Asset Management, Surveyor Capital (a Citadel company), Ridgeback Capital Investments, Takeda Ventures Inc., CaaS Capital, JM Family Enterprises, Inc., Northleaf Capital Partners, 404 Bio and an undisclosed investor were joined by existing investors Versant Ventures, OrbiMed, F-Prime Capital, Sectoral Asset Management, Sixty Degree Capital, Brace Pharma Capital and Teralys Capital.

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"Turnstone is developing next-generation medicines in two of the most clinically validated fields of immunotherapy for solid tumors," said Sammy Farah, Ph.D., MBA, President and CEO at Turnstone. "This oversubscribed financing will allow us to advance our vision to benefit millions of cancer patients underserved by current treatment options. We are delighted to welcome PFM Health Sciences, Point72 and additional new investors to Turnstone, and we are grateful for the steadfast support of our existing syndicate."

Proceeds from the financing will be used to advance Turnstone’s pipeline of programs from its oncolytic virus and TIL therapy platforms. Turnstone’s lead oncolytic virus candidate, RIVAL-01/TAK-605, is currently in the dose escalation stage of a Phase 1/2a clinical study in solid tumors conducted in collaboration with Takeda Pharmaceutical Company Limited ("Takeda"). The product is derived from the Company’s proprietary vaccinia virus platform that has been engineered for enhanced immune-stimulation and tumor cell selectivity, large transgene carrying capacity for local expression of encoded therapeutics, and with flexibility for both intratumoral and intravenous delivery.

Turnstone’s lead TIL therapy candidate, TIDAL-01, is expected to enter clinical development by early next year. The program builds on clinically validated treatment protocols while enriching for the most relevant T-cells for tumor eradication, preserving broad antigen diversity, and minimizing time to treatment for patients, with the ultimate goal of extending the benefit of TIL therapy across a wider range of solid tumor types.

Concurrent with the financing, Santhosh Palani, Ph.D., CFA, Partner at PFM Health Sciences, will join the Company’s Board of Directors. "The addition of the TIL therapy platform to Turnstone’s existing viral immunotherapy creates a significant strategic advantage for the Company," said Dr. Palani. "Turnstone’s TIL programs represent the most direct approach to advance the field as there is strong clinical evidence that selection of tumor reactive T-cells can drive better patient outcomes. The enhanced benefit and curative potential that Turnstone can uniquely bring by combining viral immunotherapy with TILs to solve challenges associated with solid tumors, drives yet another layer of excitement."

On July 21, 2021 Merus N.V. (Nasdaq: MRUS), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported the novel mechanism of action (MOA) of MCLA-145, the Company’s clinical stage Biclonics T-cell agonist (Press release, Merus, JUL 21, 2021, View Source [SID1234585023]). MCLA-145 binds with high affinity and specificity to PD-L1 and CD137. The unique immunostimulatory mechanism of action of MCLA-145 was published in Nature Communications on June 21, 2021, titled "A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context dependent T cell costimulation and checkpoint blockade."

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"Our recent Nature Communications publication is another example of the power and potential of our unique Biclonics platform technology allowing for high throughput functional screening to discover novel Biclonics —human, common light chain, IgG antibodies in the bispecific format—that can unlock innovative biology," said Cecile Geuijen, Chief Scientific Officer. "Preclinically, MCLA-145 has been observed to potently activate immune effector cells, only in the context of the tumor microenvironment, and can simultaneously block inhibitory signals in the same immune cell population."

MCLA-145 was identified by screening hundreds of bispecific IgG antibodies for immune activation via PD-L1 engagement among other characteristics. MCLA-145 was shown to potently activate T cells even in the presence of suppressive conditions. Furthermore, MCLA-145 was shown to enhance T cell priming and to promote long-term T cell immunity. These in vitro findings were translated to in vivo experiments where MCLA-145 anti-tumor activity was superior to the current standard immune checkpoint inhibitor comparators and linked to recruitment and intratumor expansion of CD8+ T cells.

MCLA-145 is currently being evaluated in a phase 1 open-label, multicenter dose escalation study, including a planned safety dose expansion phase, in patients with solid tumors. MCLA-145 is the first drug candidate co-developed under Merus’ global collaboration and license agreement with Incyte, which permits the development and commercialization of up to 11 bispecific and monospecific antibodies from our Biclonics platform. Merus retains full rights to develop and commercialize MCLA-145, if approved, in the United States; and Incyte holds full rights to develop and commercialize MCLA-145 outside the United States.

About MCLA-145
Discovered through an unbiased functional screening of multiple immunomodulatory target combinations, MCLA-145 is a Biclonics T-cell agonist that binds with high affinity and specificity to human PD-L1 and CD137 in preclinical models. The unique immunostimulatory profile of MCLA-145 derives from the potential to potently activate immune effector cells in the context of the tumor microenvironment while simultaneously blocking inhibitory signals in the same immune cell population.