On April 9, 2021 Interim data from a first-in-human trial evaluating the safety, therapeutic activity and maximum tolerable dose of THOR-707 (SAR444245), a highly differentiated not-alpha interleukin-2 (IL-2) candidate, as a monotherapy and in combination with anti-PD-1, reported that it will be presented Saturday, April 10 as a late-breaking poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Sanofi, APR 9, 2021, View Source [SID1234577771]). The Saturday late-breaking poster session will include additional updated data.

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Interim safety, anti-tumor activity and biomarker data further validate the not-alpha IL-2 profile seen preclinically. In both the combination and monotherapy settings, initial activity was observed, with three confirmed partial responses, which includes patients who have received prior anti-PD-1 therapeutics.

"THOR-707 has a potentially best-in-class profile and reinforces the promise of our Synthorin technology platform to overcome difficult targets with precision biology," said John Reed, M.D. Ph.D., Global Head of Research & Development, Sanofi. "The activity observed both as single agent and with an anti-PD-1 further strengthens our belief that as a unique not-alpha IL-2, THOR-707 could become a backbone of future immuno-oncology therapies. We will continue to explore the molecule’s potential for best-in-disease combinations."

THOR-707 is a precisely PEGylated version of IL-2, where the PEG chain is attached to a novel amino acid inserted at a location on IL-2 that prevents it from engaging the alpha-receptor and binding to immune receptors that cause drug toxicities (IL-2R-alpha, CD25). The engineered IL-2 retains near-native binding to the beta-gamma receptors that selectively expand tumor-killing T effector cells and Natural Killer (NK) cells without the alpha-mediated immunosuppressive effects of regulatory T cells or eosinophil-mediated vascular leak syndrome.

Interim results indicate a similar pattern where CD8+ T cells and NK cells increased after the first dose of THOR-707 and sustained throughout the entire cycle , with a dose escalating effect; this effect was enhanced when combined with KEYTRUDA (pembrolizumab). No significant increases in CD4+ regulatory T cells or eosinophils were observed, indicative of not-alpha IL-2 receptor selectivity.

No dose-limiting toxicities were observed for THOR-707 at reported doses, up to 24 μg/kg as monotherapy and 16 μg/kg in combination. The most common treatment emergent adverse events (TEAEs) following the first dose included flu-like symptoms, fever, vomiting/nausea and chills. Symptoms were transient and resolved with standard supportive care. Among G3-4 related toxicities was a transient decrease in lymphocyte count, which preceded T cell expansion.

No eosinophilia or vascular leak syndrome was reported at any doses tested. IL-5 levels remained at or below the lowest level of detection, suggesting a rationale for the lack of IL-5 associated toxicity observed during treatment.

"Novel approaches, such as not-alpha IL-2, seek to activate this powerful immune pathway while mitigating current challenges with dosing and safety to potentially expand the patient population who could benefit from treatment," said Filip Janku, M.D. Ph.D., Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. "Preclinically, THOR-707 appeared to activate an anti-tumor immune response without an increased risk of alpha-mediated toxicities, such as eosinophilia or vascular leak syndrome. While early, the interim clinical data at AACR (Free AACR Whitepaper) align very closely to what we saw in preclinical research and suggest further study of this not-alpha IL-2 molecule is warranted, both alone and in combination with a synergistic treatment such as anti-PD-1."

THOR-707 dose escalation has progressed beyond projected monotherapy RP2D of 24 μg/kg Q3W to 32 μg/kg Q3W to further characterize the upper bounds of the dose range.

In addition to testing THOR-707 in combination with KEYTRUDA, Sanofi is planning to evaluate the activity of this novel biologic in combination with other anti-PD-1 antibodies, including Libtayo1, (cemiplimab) anti-CD38 antibody Sarclisa (isatuximab) and anti-EGFR.

Editor’s Note: Sanofi previously entered into an agreement with Merck & Co. Inc., Kenilworth, NJ, USA (known as MSD outside the U.S. and Canada) to conduct a Phase 2 trial evaluating THOR-707 combined with or in sequenced administration with KEYTRUDA.

About THOR-707 (SAR444245)

THOR-707 is a precisely PEGylated engineered version of IL-2 with an increased half-life being investigated for the treatment of many types of malignancies. Additionally, pharmacology is being assessed to determine if THOR-707 may allow for less frequent dosing. In pre-clinical experiments, THOR-707 exhibited the ability to induce the expansion of CD8+T-cells suggesting potential for anti-tumor effects both as single agent as well as in combination with an anti-PD-1 monoclonal antibody. THOR-707 is not approved by any regulatory authority.

THOR-707 is the first molecule from the Synthorin technology platform. Synthorins are novel proteins built on Sanofi’s unique Expanded Genetic Alphabet platform, which allows scientists to fill important gaps in protein therapeutics by vastly expanding the variety of building blocks available to bioengineers. Used on its own or in combination with other Sanofi technologies, the Expanded Genetic Alphabet platform is enabling the company’s scientists and bioengineers to develop novel biologics for cancer and other diseases.

On April 9, 2021 Sanofi reported the successful completion of its acquisition of Kymab Group Ltd., adding KY1005 to its pipeline, a fully human monoclonal antibody targeting key immune system regulator OX40L (Press release, Sanofi, APR 9, 2021, View Source [SID1234577770]). The acquisition continues to build on Sanofi’s leading presence in immunology aligned with the company’s strategy to pursue best-in-class treatments in defined areas.

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Kymab’s pipeline also includes the oncology asset KY1044, an ICOS agonist monoclonal antibody, currently in early Phase1/2 development as monotherapy and in combination with an anti-PD-L1.

On April 9, 2021 Evotec SE (Frankfurt Stock Exchange: EVT, MDAX/TecDAX, ISIN: DE0005664809) reported the most advanced asset arising from their joint venture with Exscientia has entered human clinical trials (Press release, Evotec, APR 9, 2021, View Source;announcements/press-releases/p/evotec-and-exscientia-announce-start-of-human-clinical-trials-of-novel-immuno-oncology-drug-6045 [SID1234577769]). The A2a receptor antagonist, which is in development for adult patients with advanced solid tumours, was co-invented and developed between Exscientia and Evotec, including application of Exscientia’s next generation 3-D evolutionary AI-design platform, Centaur Chemist. The drug candidate has potential for best-in-class characteristics, with high selectivity for the target receptor, bringing together potential benefits of reduced systemic side effects as well as minimal brain exposure to avoid potential undesired centrally-mediated side effects.

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Tumour cells produce high levels of adenosine, a molecule that helps them escape immune system detection by binding to the A2a receptor on cancer-fighting T-cells, reducing T-cell ability to eliminate disease. Therefore, this highly selective A2a receptor antagonist is being investigated for its ability to prevent adenosine from binding to the T-cell receptor and potentially promote anti-tumour T-cell activity.

Dr Craig Johnstone, Chief Operating Officer of Evotec, commented: "We highly value our ongoing partnership with Exscientia, which has been highly collaborative and productive in every respect. We are therefore delighted to announce the start of clinical development of our co-owned A2a antagonist with Exscientia in the hope that the fruits of our collaboration can bring potential benefits to patients in the future."

Prof. Andrew Hopkins, CEO and founder of Exscientia, said: "We set ambitious therapeutic objectives for this project, especially high selectivity for the A2a receptor and central nervous system (CNS) sparing properties, in order to reduce the likelihood of potential side effects. Even with these challenging objectives, we were able to discover our candidate molecule within 8 months of project initiation."

Exscientia will lead further clinical development of the molecule and Evotec will retain co-ownership rights throughout clinical development.

On April 9, 2021 Exscientia, a leading artificial intelligence (AI)-driven pharmatech company, reported the first AI-designed molecule for immuno-oncology to enter human clinical trials (Press release, Exscientia, APR 9, 2021, View Source [SID1234577758]). The A2a receptor antagonist, which is in development for adult patients with advanced solid tumours, was co-invented and developed through a Joint Venture between Exscientia and Evotec, including application of Exscientia’s next generation 3-D evolutionary AI-design platform as part of Centaur Chemist. The drug candidate has potential for best-in-class characteristics, with high selectivity for the target receptor, bringing together potential benefits of reduced systemic sides effects as well as minimal brain exposure to avoid undesired psychological side effects. Preclinical data related to this project will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting to be held 9-14 April, 2021.

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With this announcement, the company’s AI technologies and drug-hunting expertise are now responsible for the first two AI-designed drugs to enter Phase I testing, following on from Exscientia’s previous announcement in 2020.1

Andrew Hopkins, CEO of Exscientia said, "Immuno-oncology medicines are bringing benefit to a range of cancer patients. Our selective A2a receptor antagonist addresses a next-generation immuno-oncology strategy to empower the human immune system by reversing the effects of high adenosine concentrations. We set ambitious therapeutic objectives for this project, especially high selectivity for the A2a receptor and central nervous system (CNS) sparing properties, in order to reduce the likelihood of systemic side effects. Even with these challenging objectives, we were able to discover our candidate molecule within 8 months of project initiation."

Tumour cells produce high levels of adenosine, a molecule that helps them escape immune system detection by binding to the A2a receptor on cancer fighting T-cells, reducing T-cell ability to eliminate disease.2 Exscientia’s AI-designed A2a receptor antagonist is being investigated for its ability to prevent adenosine from binding to the T-cell receptor and potentially promote anti-tumour T-cell activity.

On April 9, 2021 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported initial promising results from a Phase I study combining intravenous (IV) oncolytic virus TG6002 and oral 5-FC in patients with advanced gastrointestinal carcinomas (Press release, Transgene, APR 9, 2021, View Source [SID1234577757]). These data provide a clinical proof of concept for Transgene’s double deleted VVcopTK-RR- patented virus backbone: after IV administration, TG6002 reached the tumor, multiplied within tumor cells, and induced the local expression of its payload (the FCU1 gene).

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These results will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual meeting taking place from April 10-15, 2021.

DATA CONFIRM THAT THE CHEMOTHERAPY AGENT 5-FU IS PRODUCED IN PATIENTS’ TUMORS AFTER INTRAVENOUS ADMINISTRATION

TG6002 is a novel oncolytic virus that has been engineered to combine multiple mechanisms of action. It has been designed to:

selectively replicate within cancer cells. This is due to the deletion of the viral genes encoding TK and RR, which reduces the virus’s ability to grow in normal cells. This selective viral replication leads to the breakdown of the infected tumor cells in a process called oncolysis,
prime an immune response against the primary tumor and metastases,
and to induce the local expression of a biologically active enzyme able to convert 5-FC into its active cytotoxic metabolite 5-FU, directly in the tumor.
The data demonstrate that high concentration and continuous production of 5-FU chemotherapy can be obtained within the tumors through the local conversion of the pro-drug 5-FC (administered orally). This mechanism of action is based on the in-tumor expression of the proprietary FCU1 gene that has been integrated within the genome of TG6002.

In this study, extensive analyses are being performed including metastasis biopsy with synchronous blood sampling, assessment of virus presence, quantification of 5-FC and 5-FU and assessment of neutralizing antibody titers.

These analyses have allowed Transgene to document TG6002’s pharmacokinetics (PK) and biodistribution, and the functioning of the FCU1 gene when given by IV administration.

Detailed results:

✔ TG6002 infects tumors after intravenous administration, remains active and effectively express FCU1 gene selectively in tumor tissue;
✔ Absence of widespread virus distribution in the body and association of FCU1 activity with high virus concentration in tumor tissue suggest that the replication of TG6002 is concentrated in tumor cells;
✔ None of the patients presented clinical signs of extra-tumoral dissemination of the virus suggesting a high tumor specificity of the viral replication;
✔ The study is continuing with escalating dosing of TG6002.

CLINICAL PROOF OF CONCEPT OF THE FEASIBILITY OF THE IV ADMINISTRATION OF TRANSGENE’S PROPRIETARY ONCOLYTIC VIRUS

To-date, the only oncolytic virus that has received regulatory approval is only approved for intra-tumoral administration, restricting its use to superficial lesions.

Transgene aims to enlarge the number of solid tumors, such as gastro-intestinal tumors, that could be addressed by an oncolytic virus, by developing oncolytics that can be administered intravenously.

The findings that will be presented at AACR (Free AACR Whitepaper) demonstrate the relevance of intravenous administration of Transgene’s next generation oncolytic viruses including TG6002.

These data also suggest that candidates derived from Transgene’s unique Invir.IO platform could also be given intravenously, extending the use of these therapies to a broad range of solid tumors.

Title of the poster: "Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas"
Authors: Kaidre Bendjama, Philippe Cassier, Victor Moreno, Bernard Doger, Emiliano Calvo, Maria De Miguel, Christiane Jungels, Philippe Erbs, Damien Carpentier, Alain Sadoun.
Abstract/Poster Number: LB179
Session: PO.IM02.11 – Vaccines
The e-poster presentation will be available on the AACR (Free AACR Whitepaper) website beginning at 8:30 am US EDT on Saturday, April 10, until Monday, June 21. The text of this abstract will be posted at 12:01 am US EDT on Friday, April 9 on the AACR (Free AACR Whitepaper) website.

About the trial (NCT03724071)
This trial is a single-arm open-label Phase I/II trial evaluating the safety and tolerability of multiple ascending doses of TG6002 administered intravenously in combination with oral 5-FC, a non-cytotoxic pro-drug that can be converted in 5-FU, its active metabolite. Based on the safety profile of TG6002, several dose levels have been added to the initial Phase I clinical protocol. At the end of this Phase I part, Phase II patients will receive the recommended dose of TG6002. The trial has safety as primary endpoint for the Phase I part and efficacy for the Phase II part. The trial also evaluates pharmacokinetic properties and biodistribution of TG6002, along with immune modulation of the tumor micro-environment. This European study will enroll up to 40 patients suffering from advanced gastrointestinal carcinomas who have failed and/or are intolerant to standard therapeutic options in the Phase I part. Patients with colon cancer and liver metastases will be enrolled in the Phase II part.

Dr. Philippe Cassier, M.D., PhD, head of the early-phase trials unit at Centre Léon Bérard (Lyon, France) is the principal investigator of the trial.

About TG6002
TG6002 has been engineered to directly kill cancer cells (oncolysis), to enable the production of a chemotherapy agent (5-FU) within the tumor, and to elicit an immune response by the body against the tumor cells. In preclinical experiments, TG6002 has been shown to induce the shrinkage of the primary tumor as well as the regression of distant metastases (Foloppe, et al., Molecular Therapy Oncolytics, View Source).

The production of 5-FU directly in the tumor aims to achieve a better anti-tumoral effect with limited chemotherapy-induced side effects.

TG6002 induces the production of 5-FU in the cancer cells it has infected, by enabling the local conversion of the pro-drug 5-FC (administered orally) into 5-FU. 5-FU is a common chemotherapy agent for patients with gastro-intestinal cancers. This mechanism of action is based on the in-tumor expression of the proprietary FCU1 gene that has been encoded in the genome of TG6002, taking advantage of the virus selective replication in the tumor cells.

When administered systemically, 5-FU is associated with side effects that can lead to treatment discontinuation. With TG6002, 5-FU is produced within the tumor where it is expected to be present at a high concentration level in contrast to the very low levels anticipated in the rest of the patient’s body.