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Clinical pipeline

BI-1206 in Non-Hodgkin lymphoma
and chronic lymphocytic leukemia

In April 2020, BioInvent provided a preliminary insight into progress of its Phase I/IIa trial of BI-1206 in combination with rituximab for the treatment of Non-Hodgkin Lymphoma (NHL). In the Phase I part of the trial, three separate early signs of activity have been observed across different subtypes of NHL, even though the doses of BI-1206 are still suboptimal. In particular, a patient in the 70mg cohort has achieved a complete response. The patient is reported to be in “a very good general condition and without any signs of toxicity”. In the 30mg cohort, one patient with follicular lymphoma (FL) remained on treatment for the full maintenance period of one year, and another patient with mantle cell lymphoma (MCL) showed complete depletion of circulating MCL cells. The dose escalation process continues as planned.

As reported earlier, target-mediated drug disposition has not yet been overcome, and thus, the optimal dose has not yet been reached. Notwithstanding, pharmacodynamic analysis at the current doses showed depletion of peripheral B cells, including circulating mantle cell lymphoma cells during the first week of therapy.

Early results from the Phase I open label study in indolent non-Hodgkin lymphoma are expected in H2 2020.

Background
BI-1206 is a high-affinity monoclonal antibody that selectivity bind to FcγRIIB (CD32B), the only inhibitory member of the FcγR family. FcγRIIB is overexpressed in several forms of NHL and overexpression has been associated with poor prognosis in difficult-to-treat forms of NHL, such as mantle cell lymphoma. By blocking FcγRIIB, BI-1206 is expected to recover and enhance the activity of rituximab or other anti-CD20 monoclonal antibodies in the treatment of these diseases. The combination of the two drugs could provide a new and important option for patients suffering from NHL, and represents a substantial commercial opportunity.

In September 2018 BioInvent started a dose escalation, consecutive-cohort, open-label phase I/IIa study of BI-1206. The study will recruit approximately 30 patients across sites in the EU and the U.S. The trial is evaluating BioInvent’s proprietary antibody BI-1206 in combination with rituximab in patients with indolent relapsed or refractory Fc NHL. The targeted subindications are mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma. The study will explore BI-1206’s safety and tolerability, and seek to determine a recommended phase ll dose (RP2D) when given in combination with rituximab. Expression of biomarkers will be assessed to explore a potential correlation with clinical activity.

This study is run in parallel with the ongoing Phase I/IIa study of BI-1206 in patients with CLL and NHL conducted in the UK by Cancer Research UK. The study is testing single agent activity. Given the overlap with BioInvent’s own Phase I/IIa trial of BI-1206 in combination with rituximab in Non-Hodgkin Lymphoma (NHL), and the fact that standard of care for patients with chronic lymphocytic leukemia (CLL) has dramatically evolved over the last few years, recruitment in the UK study has become increasingly challenging in particular since CRUK can only carry out trials in the UK. For these reasons we have agreed to limit the CRUK study to monotherapy, which is almost completed. This will result in a more complementary work and more efficient use of resources.

In January 2019 the U.S. Food and Drug Administration granted orphan designation for BI-1206 for the treatment of mantle cell lymphoma.

In November 2019 BioInvent had a poster presentation with preclinical data on BI-1206 at the annual American Society of Hematology (ASH) meeting in Orlando. The abstract highlighted a preclinical study of BI-1206 in an ibrutinib-venetoclax dual resistant PDX (patient derived xenograft) model derived from a mantle cell lymphoma (MCL) patient. Single agent BI-1206 had potent anti-MCL activity in the FcγRIIb-expressing MCL PDX model. FcγRIIb was further shown to be highly expressed in 20/20 primary patient MCL samples examined. Along with previously published data demonstrating an important role for FcγRIIB in resistance to rituximab-based cancer immunotherapy, and BI-1206 in boosting rituximab efficacy and overcoming rituximab-resistance, these data indicate the high potential of BI-1206 to address a significant unmet need in MCL and B-cell malignancies.

BI-1206 in combination with pembrolizumab in solid tumors

In July 2019 BioInvent received authorization from the FDA to proceed for an IND application for a Phase I/IIa clinical trial of BI-1206 in combination with KEYTRUDA® (pembrolizumab) for the treatment of solid tumors. The first patient was enrolled in June 2020.

The objective of this trial is to explore the safety and tolerability profile of the combination of BI-1206 with KEYTRUDA®, to characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile and to determine the recommended dose of BI-1206 when combined with KEYTRUDA®. It will be conducted in several sites across the US and Europe and will assess potential signs of antitumoral activity, as well as exploring the expression of potential immunological markers that might be associated, and eventually predict clinical responses.

The Phase I/IIa trial is divided into part A, a dose escalation of BI-1206 in combination with the standard dose of KEYTRUDA, and part B, which will explore the activity of the combination treatment in patients with advanced lung cancer, melanoma and other types of malignancies. Patients will be refractory to or have progressed on previous treatments with anti-PD1/PDL1 targeting agents. Early results from the Phase I open label study is expected in H2 2021.

BioInvent entered in December 2019 into a clinical trial collaboration and supply agreement with Merck, to evaluate the combination of BioInvent’s BI-1206, one of its proprietary anti-FcγRllB antibodies and Merck’s anti-PD-1 therapy, KEYTRUDA® (pembrolizumab) in a Phase l/lla clinical trial for patients with solid tumors. The agreement helps BioInvent to expand BI-1206 clinical development to solid tumors in combination with one of the most successful immuno-oncology drugs.

Background
The program is based on BioInvent’s preclinical data demonstrating the ability of BI-1206 to address an important mechanism of resistance to PD1 inhibition, providing a way to enhance anti-tumor immune responses in patients with solid tumors. The Phase I/IIa clinical trial will evaluate the drug combination in patients with advanced solid tumors, who have been previously treated with anti-PD1 or anti-PD-L1 antibodies, and is a multicenter, dose-finding, consecutive-cohort, open-label trial. The Phase I/IIa trial is planned to be carried out in the U.S. and the EU.

Patent protection
Patent projection for the use of antibodies against CD32b, such as BI-1206 in combination with other antibodies, such as rituximab, in the treatment of cancer or inflammatory diseases in certain patient groups has been applied for in eight large markets, including the USA. So far patents have been granted by the European Patent Office as well as in Japan and Australia. The European patent is valid in 24 countries. Corresponding applications are pending in another five countries. Patent protection has also been sought in eight large markets for the treatment of cancer patients who are no longer responding to previous antibody therapy.

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Haematological cancer

Non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) is an umbrella term for a group of cancers that develop in the body’s lymphatic system. Examples of sub-indications are patients with Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL). Examples of subindications are patients with Mantle Cell Lymphoma, Follicular Lymphoma, and Marginal Zone Lymphoma. Aggressive lymphomas are usually treated with combinations of various chemotherapeutic agents and monoclonal anti-bodies such as rituximab (Rituxan®, Mabthera®, Roche). Low-grade lymphomas have a better prognosis and treatment is often only initiated once a patient has disease symptoms.

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is an incurable lymphoma disease that normally affects older people. The course of the disease is often slow and patients are usually treated with chemotherapy, often combined with monoclonal antibodies.

Pre-clinical pipeline

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Novel mechanisms for antibody-mediated immune modulation

BioInvent’s preclinical research is focused on developing novel immuno-modulatory antibodies for cancer therapy. Such antibodies may significantly improve efficacy of currently available checkpoint inhibitor therapies and/or activate anti-cancer immunity in currently non-responding patients and cancer types.

 

TAMs

Strategic collaboration with Pfizer - developing antibodies that act on tumour-associated myeloid cells

In partnership with Pfizer Inc. since December 2016, BioInvent works to identify novel oncology targets and therapeutic antibodies that may either reverse the immunosuppressive activity of tumor-associated myeloid cells or reduce the number of tumor-associated myeloid cells in the tumor.

BioInvent announced in July 2019 selection of the first target and in December 2019 the second target discovered by BioInvent’s proprietary F.I.R.S.T™ technology platform under the collaboration with Pfizer Inc. The selection of targets triggered two payments from Pfizer to BioInvent of $0.3 million. Under the terms of the 2016 agreement, potential selection and development of antibodies directed against this target, as well as potential selection of further targets and development of antibodies directed at them, would allow BioInvent to be eligible for further milestone payments.

In July 2020 BioInvent announced that the research term under its collaboration and license agreement with Pfizer had been further extended until the end of 2020. The purpose of the research extension is to permit the companies to further identify and characterize new targets and antibodies binding to these targets.

BioInvent is eligible for potential future development milestones in excess of $500 million (assuming five antibodies are developed through to commercialization). The Company could also receive up to double digit royalties related to product sales. In exchange, Pfizer will have the right to develop and commercialize any antibodies generated from this agreement.

BioInvent received an upfront payment of $3 million when the agreement was signed in December 2016, and research funding has been received during 2017, 2018 and 2019. Pfizer also made a $6 million equity investment in new shares of BioInvent when the agreement was signed.

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Tregs

Developing antibodies that act on regulatory T cells (Tregs) via novel or validated targets

Tregs can substantially inhibit various immune responses, enabling tumor cells to escape detection. BioInvent is utilizing its F.I.R.S.T™ platform to identify and characterize monoclonal antibodies to cancer-associated Treg targets in a function-first, target-agnostic, manner. The company is also pursuing differentiated antibodies to known targets through novel mechanisms and pathways.

BI-1808 and BI-1910 (anti-TNFR2)

Two different types of TNFR2 targeting antibodies are being developed by BioInvent – BI-1808 (a ligand blocker), and BI-1910 (an agonist).

A clinical trial application was submitted in June 2020 to begin a Phase I/IIa, first-in-human study of BI-1808, as a single agent and in combination with KEYTRUDA® (pembrolizumab) for the treatment of solid tumors or cutaneous T-cell lymphoma (CTCL). Phase I clinical trial with BI-1808 expected to start before the end of 2020

The study will explore the safety, tolerability, and potential signs of efficacy of BI-1808 as a single agent and in combination with KEYTRUDA® in patients with ovarian cancer, non-small cell lung cancer and cutaneous T cell lymphoma. It will also investigate the expression of potential immunological markers that might be associated with clinical responses. It will be conducted at several sites across Europe and the U.S. and is expected to enroll approximately 120 patients.

The Phase I stage is divided into two sections. Part A is a dose escalation of BI-1808 to assess safety, tolerability, and pharmacokinetics & pharmacodynamics, and to determine the recommended dose as a single agent for Phase II trials. It will be followed by part B, which will explore the safety, tolerability and recommended dose of BI-1808 in combination with KEYTRUDA®. Phase IIa will consist of expansion cohorts to assess signs of efficacy of BI-1808 as single agent and in combination with KEYTRUDA® in lung cancer and ovarian cancer patients. A separate cohort will explore the activity as single agent in CTCL (Sézary syndrome and mycosis fungoides).

Exciting translational data was presented at AACR Virtual Annual Meeting II in June 2020. In vivo studies show that both ligand-blocking and agonistic antibodies regress large established tumors and synergize with anti-PD-1 therapy. Further mode-of-action dissection demonstrate that while the ligand-blocking antibody depleted intratumoral Tregs, the agonist increased intratumoral CD8+ T effector cells. Both antibodies expanded tumor-specific CD8+ T cells and induced long-lasting T cell memory.

Background

BioInvent has identified tumor necrosis factor receptor 2 (TNFR2), a member of the so called TNFR superfamily (TNFRS) as a target within the Treg program.

TNFR2 is particularly upregulated on tumor-associated regulatory T cells (Tregs) and has been shown to be important for their expansion and survival. As a part of its Treg program, BioInvent identified and characterized a wide panel of TNFR2-specific antibodies, generated from its proprietary n-CoDeR® library and unique F.I.R.S.TTM discovery tool, of which BI-1808 and BI-1910 are the lead development candidates.

BT-001 - Partnership with Transgene – developing next generation oncolytic viruses expressing an anti-CTLA-4 antibody to treat solid tumors

BioInvent and Transgene announced in March 2020 that the first clinical trial application for BT-001 was submitted and that the first-in-human trial is expected to start before the end of 2020 in Europe and the US.

Promising findings was presented at AACR Virtual Annual Meeting II in June 2020. Cure rates exceeding 70% were seen in multiple mouse models, demonstrating the powerful therapeutic effect of BT-001 when used as a single agent, providing a solid basis for BT-001’s upcoming clinical development. BT-001 has multiple mechanisms of action. It has been designed to combine the killing of cancer cells (oncolysis), and the production of the anti-CTLA4 antibody and GM-CSF directly in the tumor site, while also generating an immune response against tumor cells. It was shown that the anti-CTLA-4 antibody and GM-CSF accumulate in tumors with low systemic exposure. When new tumor cells were implanted in mice that had been cured after a first BT-001 treatment, a strong tumor-specific response and long-lasting immune memory were developed by these mice. These data indicate that BT-001 has the potential to make a significant difference in the treatment of solid tumors.

Background
BioInvent and Transgene collaborate to co-develop oncolytic virus (OV) candidates encoding a validated anti-CTLA-4 antibody sequence – potentially with additional transgenes – aimed at treating solid tumors, with the potential to be significantly more effective than the combination of a virus and an antibody as single agents.

Transgene is contributing both engineering expertise, as well as its proprietary Vaccinia viruses, designed to directly and selectively destroy cancer cells by intracellular replication of the virus in the cancer cell (oncolysis). Oncolysis induces an immune response against tumors, while the “weaponized” virus allows the expression of genes carried by the viral genome, here an immune modulatory anti-CTLA-4 antibody, which will further boost immune response against the tumor.

BioInvent is providing its cancer biology and antibody expertise to the collaboration, as well as anti-CTLA-4 antibody sequences generated through its proprietary n-CoDeR®/F.I.R.S.TTM platforms.

In March 2019 BioInvent and Transgene announced an extension of their collaboration to co-develop multifunctional oncolytic viruses encoding antibodies targeting an undisclosed target, which can be used in the treatment of a broad range of solid tumors.

The research and development costs, as well as revenue and royalties from candidates generated from the collaboration, are shared 50:50.