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Clinical pipeline

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

BioInvent’s lead drug candidate BI-1206 is a fully human antibody targeting CD32b, an immunosuppressive protein that is expressed in some patients with B-cell cancers. Research has shown that the expression of CD32b could lead to the development of resistance to rituximab, the current standard of care treatment of B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). As a result, BI-1206 is being developed as a drug candidate in combination with rituximab in B-cell cancers.

The first clinical study (Phase I/II) with BI-1206 is currently ongoing in patients with NHL and CLL who are resistant to rituximab. The initial safety and dose readouts from this study are expected in the first half of 2018. The study is financed and executed by Cancer Research UK (CRUK), Cancer Research Technology (CRT) and Leukaemia & Lymphoma Research (LLR).

In Q3 2017, BioInvent announced plans to expand the therapeutic potential of BI-1206 with an additional Phase I/IIa clinical study in combination with rituximab. The study is planned to include approximately twenty patients with indolent B-cell Non-Hodgkin Lymphoma (NHL) that is relapsed or refractory to rituximab. The targeted sub-indications are patients with Mantle Cell Lymphoma, Follicular Lymphoma, and Marginal Zone Lymphoma. The trial is planned to start in H1 2018. It will be an open-label, single arm study, and the last patient is expected to finish the trial before the end of 2019.

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 nine large markets, including the USA. So far patents have been granted by the European Patent Office as well as in Japan and Australia. 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.

TB-403 in paediatric brain tumours

- development in collaboration with Oncurious, subsidiary of ThromboGenics

TB-403 is a humanised antibody directed against the PlGF protein, which is believed to inhibit its signaling via the Nrp-1 receptor. PlGF is expressed in certain paediatric cancers including medulloblastoma, Ewing’s sarcoma, neuroblastoma and alveolar rhabdomyosarcoma.

TB-403 is currently in a Phase I/II study for the treatment of patients with medulloblastoma in cooperation with a US based pediatric oncology network, Beat Childhood Cancer. The study progresses and the third dose level is ongoing.

TB-403 has received Orphan Drug Designation for medulloblastoma from the European Medicines Agency.

TB-403 is being developed in collaboration with Oncurious, a subsidiary of ThromboGenics. In July 2017, BioInvent’s ownership in TB-403 increased from 40 to 50 percent following renegotiation of the longstanding collaboration agreement signed in 2004. BioInvent continues to contribute 50 percent of the development costs.

Patent protection
Patents for TB-403 and similar antibodies have been granted in Europe, the US, Japan and several additional countries, and patent applications are pending in further countries. Patents covering use of antibodies against PIGF, for example for the purpose of treating or preventing cancer, have also been granted, including in the US.

THR-317 in diabetic macular edema

- under development by ThromboGenics

In April 2018 BioInvent’s partner ThromboGenics announced initial data from a Phase l/ll, single-masked, multicentre study to evaluate the safety and efficacy of two dose levels of THR-317 for the treatment of diabetic macular edema. ThromboGenics reported initial data for the anti-VEGF treatment naive group (n=40) up to Day 90; 30 days after the last intravitreal (IVT) anti-PlGF administration. The primary focus of this study was safety outcomes. THR-317 was safe and well tolerated. No dose-limiting toxicities or relevant safety events were reported at either dose level.

In July 2017 the cooperation agreement from 2004 was renegotiated. Under the amended arrangement, ThromboGenics gains full and exclusive ownership of THR-317 for development and commercialization in all non-oncology indications. ThromboGenics will continue to carry all costs for the development of THR-317 in non-oncology indications, and BioInvent is entitled to five percent of the project’s economic value.

Patent protection
Patents for the antibody have been granted in Europe, the US, Japan and several additional countries, and patent applications are pending in further countries.

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 act to significantly improve efficacy of currently available checkpoint inhibitor therapies and/or activate anti-cancer immunity in currently non-responding patients and cancer types.

BioInvent is developing antibodies to overcome the effects of two key cells that suppress the immune system in the tumour micro-environment. These are:

  • cancer-associated regulatory T cells (Tregs) and
  • tumour-associated myeloid cells

 

Tregs

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

Tregs can substantially inhibit various immune responses, enabling tumour 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.

TAMs

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

In December 2016, BioInvent announced that it has entered into a cancer immunotherapy research collaboration and license agreement with Pfizer Inc. to develop antibodies targeting tumour-associated myeloid cells. BioInvent leverages its expertise to identify novel oncology targets and therapeutic antibodies that inhibit cancer growth either by reversing the immunosuppressive activity of tumour-associated myeloid cells or by reducing the number of tumour-associated myeloid cells in the tumour. The collaboration is progressing well – a pool of antibodies has been generated, that will now be characterized for functional activity.

Under the terms of the agreement BioInvent could be eligible for potential future development milestones in excess of $0.5 billion (assuming five antibodies are developed through to commercialisation). The company could also receive up to double digit royalties related to product sales. In return Pfizer will have the right to develop and commercialise any antibodies generated from this agreement.

BioInvent received an upfront payment of $3 million when the agreement was signed in December 2016, and $1 million in research funding has been received during 2017. Pfizer also made a $6 million equity investment in new shares of BioInvent when the agreement was signed.

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Anti-CTLA-4/Oncolytic virus

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

BioInvent and Transgene collaborate to co-develop oncolytic virus (OV) candidates encoding a validated anti-CTLA-4 antibody sequence - potentially with additional transgenes - capable of treating multiple solid tumours.

Transgene is contributing both its OV design and engineering expertise, as well as its proprietary Vaccinia viruses. These oncolytic viruses are designed to directly and selectively destroy cancer cells by intracellular replication of the virus in the cancer cell (oncolysis). Oncolysis is important as it induces an immune response against tumours. In addition, the replication of the virus allows the expression of the genes carried by the oncolytic viral genome, including therapeutic “weapons” e.g. an immune modulatory anti-CTLA-4 antibody that boost immune responses against the tumour.

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.T.TM platforms. A lead anti-CTLA-4 antibody will be selected for encoding within the viral vectors. The local expression of such therapeutic antibodies delivered into the cancer cell is expected to augment the anti-cancer effects of viral oncolysis, by efficiently modulating the tumour micro-environment and increasing the immunogenicity of the tumour.

The research and development costs, as well as revenues and royalties from candidates generated from the collaboration, will be shared 50:50.

Encoding BioInvent’s anti-CTLA-4 antibody sequence in Transgene’s vaccinia virus backbone promises to optimize the efficacy of this potent checkpoint inhibitor, while reducing the side effects seen when it is given systemically. The relevance of this concept is underscored by our recent publication in Cancer Cell on the mechanism-of-action of clinically validated anti-CTLA-4 antibody ipilimumab (Vargas et al Cancer Cell, 2018 https://doi.org/10.1016/j.ccell.2018.02.010). The finding that FcR-dependent mechanisms are associated with responses to ipilimumab in human subjects, suggests that Treg deletion contributes to the clinical activity of ipilimumab, and supports the notion that tumor targeted delivery of Treg deleting anti-CTLA-4 antibodies, e.g. through antibody-encoding oncolytic viruses, may be a tractable strategy to optimise anti-CTLA-4 based efficacy and tolerability. There is also the potential for this novel OV product to be significantly more effective than the combination of single agents. Transgene has generated preclinical proof-of-concept data showing that an oncolytic vaccinia virus encoded with a checkpoint inhibitor resulted in better overall survival than the corresponding combination of separate single agents.

About antibodies

Antibodies are nature’s own defence molecules. They are highly selective and very well-tolerated in their human form.

The antibody-based drug segment is one of the fastest growing segments in the global pharmaceutical market. Three of the world's top-selling antibody-based drugs are Rituxan/Mabthera® (rituximab, Roche), Herceptin® (rastuzumab, Roche) and Avastin® (bevacizumab, Roche). The combined sales of these drugs  amounted to around USD 22 billion in 2017. In the next five years the patent protection for several of the best-selling drugs will expire at the same time as new, improved combination therapies are expected to reach the market.