Programs

Source: In-licensed from Johns Hopkins University
Stage: Phase I

As tumors continue to grow, regions within the tumors become starved of nutrients and oxygen (hypoxic), and start to grow more slowly, lie dormant, or die (become necrotic). Hypoxic, slow-growing, and necrotic tumor cells are often resistant to radiation therapy and chemotherapy, however, this is an ideal environment for anaerobic bacteria that thrive in low oxygen conditions.

Based on this biology, BioMed Valley Discoveries is studying a new way to combat cancer—one that exploits the unusual conditions inside the tumor using CNV-NT (BVD-550), a tumor-fighting bacteria that is injected into tumors to kill the cancer from the inside out. Preclinical research has shown that CNV-NT (BVD-550), can destroy cancer cells in low-oxygen areas of tumors while leaving well-oxygenated tissue unharmed. The tumor-fighting bacteria can then be controlled using commonly available antibiotics.

While this approach to cancer treatment may sound unconventional, there is a long history of scientific study behind it. In the 1890s, physician William B. Coley observed that some cancer patients who underwent surgery and developed a bacterial infection afterward became completely cured of their tumors. Then, in the 1950s and 1960s, researchers tried using an anaerobic bacterium, Clostridium butyricum (C. butyricum), to fight cancer. Although C. butyricum destroyed large portions of tumors, scientists at the time could not adequately control the adverse effects of the bacteria or the toxins produced by the bacteria. As a result, the use of anaerobic bacteria to treat tumors was put on hold while radiation and chemotherapy emerged as standard treatments.

More recently, Bert Vogelstein’s laboratory at Johns Hopkins University returned to the study of bacteria as a possible cancer treatment using a strain of Clostridium novyi from which a lethal toxin was removed (C. novyi-NT/BVD-550). In one preclinical research study, tumor tissue was destroyed and did not return during the follow-up period in about 30% of animals treated. In addition to destroying tumor cells, the bacteria have been shown to provoke the animal’s immune system to attack cancer cells.

Building on these promising results, we advanced CNV-NT (BVD-550) to Phase I clinical trials to investigate the effects in patients with inoperable tumors. These trials established a recommended Phase II dose that is now being used in combination with pembrolizumab (NCT03435952). While many years of challenging work remain, our hope is that this work will someday lead to a new class of therapies to combat cancer, attacking tumors from the inside out.

Presentations and literature on CNV-NT (BVD-550):

28th EORTC-NCI-AACR Symposium Abstract | Poster

13th International Congress on Targeted Anticancer Therapies Abstract | Poster

Intratumoral Injection of Clostridium novyi-NT Spores induces antitumor responses. Roberts NJ et al. Sci Transl Med. 2014;6:249ra111. Abstract

Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors.  Janku F et al. Clin Cancer Res. 2021;27(1):96-106.
Abstract

CNV-NT (BVD-550) Trials

Source: In-licensed from large biotechnology company
Stage: Phase II

The mitogen-activated protein kinase (MAPK) pathway is a major intracellular signaling mechanism that controls growth, proliferation, and survival of cells. Numerous different cancers have been associated with mutations and subsequent abnormal activation of this pathway, making the cancers highly dependent on this pathway for their survival and growth.

The extracellular signal-regulated kinase (ERK) is the terminal master kinase in the MAPK pathway. BioMed Valley Discoveries is testing whether ulixertinib (BVD-523), a novel targeted cytotoxic designed to inhibit ERK, can be used to treat cancers that harbor mutations in the MAPK signaling pathway.

A large body of clinical experience has shown successful inhibition and disease control with a variety of inhibitors of other members of the MAPK pathway upstream of ERK (BRAF and MEK). Unfortunately, these same studies have also demonstrated that patients given targeted therapies often develop tumors that are resistant to a drug that was initially effective. Because of this, understanding resistance mechanisms and selecting targeted treatment regimens that can overcome or prevent resistance in the first place represent a major opportunity for effective treatment.

Our ERK inhibitor is a potent, selective small molecule that has demonstrated impressive in vitro and in vivo preclinical efficacy, and is expected to be effective in cancer settings where MAPK pathway dependence has been demonstrated. Beyond its use as a single-agent, front-line therapy, we plan to assess whether ulixertinib (BVD-523) may be effective as part of novel combination therapy regimens, as well as in patients with specific genetic profiles that accompany acquired resistance. Because of ERK’s downstream position in the pathway we believe that its inhibition may provide durable efficacy that is less often complicated by acquired drug resistance. In summary, targeting ERK with ulixertinib (BVD-523), either alone or in combination with other drugs, should be a valuable strategy to safely treat cancers that exhibit abnormal MAPK pathway activity.

Presentations and literature on ulixertinib (BVD-523):

2017 ASCO Annual Meeting Abstract | Presentation | Press Release

2017 AACR Annual Meeting Abstract | Presentation

2015 ASCO Annual Meeting Abstract | Presentation | Related video

2015 AACR Annual Meeting Abstract | Presentation

Ulixertinib (BVD-523)

Source: Cooperative research and development agreement with National Cancer Institute
Stage: Pre-IND

The cell-surface protein CD276/B7-H3 is broadly overexpressed by a wide variety of cancer cells as well as on the tumor-infiltrating blood vessels associated with those cells. Due to this dual-compartment expression, CD276-directed ablation of both the primary tumor cell as well as the supporting tumor blood supply could prove to be an extremely effective therapeutic approach.

An additional cell-surface protein, tumor endothelial marker 8 (TEM8), is overexpressed on cancer-associated fibroblasts and endothelium and provides a separate target for the tumor microenvironment. Based on this, BioMed Valley Discoveries is exploring the use of both CD276 antibody- and TEM8 antibody-drug conjugates (ADCs) as therapeutic agents to target multiple solid tumor types.

Antibody-drug conjugates (ADCs) represent a promising anti-cancer strategy in which the antibody directs targeted, selective localization of a toxic payload. Preclinical studies have shown that CD276- and TEM8-directed ADCs armed with different toxic payloads were able to destroy cancer cells with or without destruction of the associated blood supply depending on the nature of the toxin associated with it. Since the overexpression of these tumor antigens is associated with many different tumor types, this approach could impact a large variety of disease states.

References:

Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature. Seaman S et al. Cancer Cell. 2017;31:501-515.e8. Abstract | Commentary

Tumor stroma–targeted antibody-drug conjugate triggers localized anticancer drug release Szot C et al. JCI. 2018 Abstract

Translational medicine: doing things differently. Biopharma Deal. 2021. | PDF