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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 non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (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, 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 relapsed or refractory CD32b-positive Non-Hodgkin Lymphoma (NHL). The targeted populations are patients with Mantle Cell Lymphoma, Follicular Lymphoma, and Marginal Zone Lymphoma. The trial is being 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 applications relating to the use of antibodies against CD-32b, such as BI-1206, in combination with other antibodies, such as rituximab, for the treatment of cancer or inflammatory diseases in certain patient groups have been filed in nine large markets, including the US. To date, patents have been granted by the European Patent Office as well as in Japan and Australia. The granted patents Patent protection has also been applied for the treatment of cancer patients who not respond to previous antibody therapy, and applications have been filed in eight large markets.

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Haematological cancer

Non-Hodgkin lymphoma (NHL) is an umbrella term for a group of cancers affecting the body’s lymphocytes, including B-cell cancer. Chronic cell lymphoma (CLL) is an incurable cancer that affects B-cells. Both NHL and CLL patients are normally treated with combinations of cytotoxic drugs, targeted therapies, such as Bruton’s tyrosine kinase inhibitors (e.g. Ibrutinib (Imbruvika®, Janssen; Imbruvica, AbbVie), and monoclonal antibodies targeting CD20 (e.g. rituximab (Rituxan®), Mabthera®, Roche). Over 600,000 patients globally are affected annually by NHL and CLL. Sales of rituximab are in excess of $7 billion per annum.

Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a slow progressing B-cell haematological malignancy that affects developing B lymphocytes. CLL cells have less immunogenic activity compared to normal lymphocytes. Over time, they overcrowd the bone marrow, making less room for healthy white blood cells, red blood cells, and platelets. This can lead to infection, anaemia, and bleeding related issues. In CLL, most of the cancer cells are found in the blood stream and bone marrow, but the lymph nodes and spleen can also be involved. CLL is the most common form of leukaemia in adults. According to the American Cancer Society, an estimated 20,110 people in the US will be diagnosed with the disease in 2017, and 4,660 will die from it. It is estimated that an additional 20,350 patients are diagnosed annually in the EU. Because of the chronic nature of CLL, many patients live with the disease for years without symptoms. Given all CLL patients are believed to express CD32b, all of them could potentially benefit from treatment with BI-1206.

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma is the most common form of lymphoma, and can affect both B cells and T cells. The disease begins in the lymphocytes, which are a form of white blood cells found in the lymphatic system, but are often present in organs outside of the lymph nodes at the time of diagnosis. Roughly 85% of NHL cases occur in B-cells, with the other 15% affecting T-cells. According to the American Cancer Society, an estimated 72,240 people in the US will be diagnosed with NHL in 2017 with an estimated additional 79,700 patients diagnosed annually in the EU. Front-line treatment typically consists of rituximab based regimens and approximately 50% of patients will become resistant to this treatment.

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 second 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

THR-317 is being evaluated in a Phase II trial in patients with diabetic macular edema (DME). 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 to significantly improve on the efficacy of currently available checkpoint inhibitor therapies for the treatment of patients with cancer. These novel antibodies may also activate anti-cancer immunity in currently non-responding patients and cancer types.

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

These are:

  • cancer-associated regulatory T cells (T-regs) and
  • tumour-associated myeloid-derived suppressor cells

BioInvent’s deep knowledge of antibody biology, innate and adaptive tumour immunology, and the translational F.I.R.S.T™ platform provides a highly differentiated and unique strategy to developing drugs with new mechanisms of action.

BioInvent’s approach has been validated through a strategic immuno-oncology research collaboration with Pfizer in December 2016 to discover antibodies to tumour-associated myeloid cells.

Tregs

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

T-regs can substantially inhibit various immune responses enabling tumour cells to escape detection. BioInvent is currently developing antibodies to modulate specific currently undetermined T-reg targets and functions as well as for known targets such as OX-40 and 4-1BB.

BioInvent is currently working to expand the pool of antibodies and targets that have been shown to be associated with T-reg specificity and T-reg depleting activity.

BioInvent is working in cooperation with Cancer Research Technology and the University of Southampton in the UK to develop new immunotherapeutic cancer drugs based on antibodies that target OX-40 and 4-1BB, two known co-receptors that help activate T cells, to produce long-lasting anti-tumour immune responses.

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 will leverage 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.

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.

Pfizer has paid BioInvent an upfront payment of $3 million when the agreement was signed and is committed to paying $1 million in research funding during 2017. Pfizer has also made a $6 million equity investment in new shares of BioInvent when the agreement was signed.

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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® (trastuzumab, Roche) and Avastin® (bevacizumab, Roche). The combined sales of these drugs  amounted to around USD 21 billion in 2016. In the next five years the patent protection for Rituxan/Mabthera® and Herceptin® will expire at the same time as new, improved combination therapies are expected to reach the market.