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Clinical pipeline

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

BI-1206 is a monoclonal antibody that recognizes with high affinity and selectivity FcgRIIB (CD32B), the only inhibitory member of the FcgR family. CD32B is overexpressed by a number of NHL tumors, and overexpression has been shown to be associated with poor prognosis in difficult-to-treat forms of NHL, such as mantle cell lymphoma or follicular lymphoma. By blocking FcgRIIB, BI-1206 is expected to recover and enhance the activity of rituximab or other anti-CD20 monoclonal antibodies. The combination of the two drugs could provide a new and important option for patients suffering from NHL.

In July 2018, the FDA accepted BioInvent’s IND application for its new clinical study that will explore the activity of its proprietary monoclonal antibody BI-1206 in combination with rituximab. In May 2018 the Swedish Medical Product Agency approved the initiation of the same study.

The new clinical study is a Phase l/lla, dose escalation, consecutive-cohort, open-label study of BI1206 in combination with rituximab in patients with indolent relapsed or refractory B-cell NHL. The trial is estimated to recruit approximately 30 patients. The targeted sub-indications are mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma. The study will explore safety and tolerability, dose and regimen of BI-1206, and will determine a recommended phase II dose (RP2D) to be used in the Phase IIa part of the study. Pharmacokinetics and pharmacodynamics of BI-1206 will be investigated closely to identify the RP2D, and expression of biomarkers will be assessed to explore potential correlation with activity.

This study will 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 ongoing study is currently testing single agent activity and is open for enrollment of additional patients. In July 2018, BioInvent announced that no dose limiting toxicity had been reported.

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 developed in collaboration with Oncurious, a subsidiary of ThromboGenics. BioInvent’s ownership in TB-403 is 50 percent and contributes with 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, singlemasked, multicenter 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 doselimiting toxicities or relevant safety events were reported at either dose level. Later in April 2018 ThromboGenics initiated a Phase II study with THR-317 in combination with ranibizumab (Lucentis®, Novartis). The study will evaluate the efficacy and safety of the combination.

ThromboGenics carries 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 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 tumorassociated myeloid cells or reduce the number of tumor-associated myeloid cells in the tumor. To date, pools of antibodies have been generated and are being characterized for functional activity.

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 return 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 $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 - aimed at treating solid tumors.

Transgene is contributing both its OV design and 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 oncolytic viral genome, such as an immune modulatory anti-CTLA-4 antibody, to further boost immune response against the tumor.

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

This novel OV product has the potential 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. 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.