RESEARCH & DEVELOPMENT

BioMed Valley Discoveries engages in research and development projects with intent to address unmet clinical needs across a variety of diseases and therapy modalities.

In our first decade, we have investigated research and development opportunities across a number of disease states, including a variety of compounds and mechanisms in the areas of oncology and immuno-oncology. These projects have included multiple mechanistic approaches:

  • Bacterial destruction of tumors from the inside out
  • Small molecules that target pathways critical to cancer cell growth, proliferation, and survival
  • Antibodies and antibody-drug conjugates that target and attack unique components of the cancer microenvironment

Our focus on critical unmet patient needs continues to drive our future research. Although our current programs focus on the development of therapies in the areas of oncology and immuno-oncology, we consider research and development opportunities across a number of disease states, modalities, and mechanisms.

We seek to work with innovative partners and collaborators to find creative solutions to drug development challenges. We also consider in-licensing opportunities and out-licensing partnerships.

CURRENT PROGRAMS

Our current therapeutic development programs represent a multi-faceted approach to eradication of tumors through direct targeting of cancer cells as well as components of the tumor microenvironment.

CNV-NT: Clostridium novyi-NT — Tumor-fighting Bacteria

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 Clostridium novyi-NT (C. novyi-NT, or CNV-NT), a tumor-fighting bacteria that is injected into tumors to kill the cancer from the inside out. Preclinical research has shown that CNV-NT 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). In one preclinical research study, tumor tissue was destroyed and did not return during the follow-up period in about 30% of animals treated with CNV-NT. 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 have advanced CNV-NT to Phase I clinical trials to investigate the effects of CNV-NT in patients with inoperable tumors. These trials will evaluate the safety of CNV-NT and determine the appropriate dose to use as single or combination therapy. 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:

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

CNV-NT Trials

BVD-523: A Targeted Inhibitor of the MAPK Pathway

Source: In-licensed from large biotechnology company
Stage: Phase I/IIa

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 BVD-523 (ulixertinib), 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 (BVD-523) 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 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 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 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

BVD-523 Trials

BVD-723: A PI3K-gamma Specific Inhibitor

Source: In-licensed from large biotechnology company
Stage: Pre-IND

The emerging field of immunotherapy, which boosts the natural defenses of an individual’s immune system, has great promise across a variety of disease types. Immune cells use a series of checkpoints to help regulate the immune response. Cancer cells often interfere with these checkpoints and reduce the ability of the immune system to recognize and destroy the cancer cells. Immune checkpoint inhibitors are a type of immunotherapy that can counteract a cancer’s evasiveness and help boost an immune response to the disease.

Dozens of immune checkpoint inhibitors (including anti-PD-1/PD-L1 and anti-CTLA4) have entered preclinical and clinical efforts with multiple approved therapies on the market. However, these efforts have highlighted the challenge of overcoming the effects of certain immune cells that can infiltrate the tumor and blunt the response to checkpoint inhibitors.

The PI3 kinase (PI3K) family of enzymes contributes to signal transduction in different immune cells. The PI3K-gamma(γ) isoform is key to myeloid function and infiltration within the tumor microenvironment. Inhibition of this specific isoform has been demonstrated to lead to a pro-inflammatory tumor microenvironment and help direct tumor destruction even in settings of checkpoint inhibitor resistance due to resident immunosuppressive cells in the tumor.

BioMed Valley Discoveries is developing BVD-723, a novel, selective PI3Kγ small molecule inhibitor which demonstrates anti-cancer activity when used alone and in combination with checkpoint inhibitors in syngeneic mouse models of cancer.

Presentations and literature on BVD-723:

2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Abstract | Poster

CD276-ADC: Dual-compartment Targeting for Cancer Ablation

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. Based on this, BioMed Valley Discoveries is exploring the use of a CD276 antibody-drug conjugate (ADC) as a therapeutic agent 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-directed ADCs armed with different toxic payloads were able to destroy CD276-positive cancer cells with or without destruction of the associated blood supply depending on the nature of the toxin associated with it. Since CD276 overexpression is associated with many different tumor types, this approach could impact a large variety of disease states.

Presentations and literature on CD276:

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

CLINICAL TRIALS

BioMed Valley Discoveries’ clinical programs are associated with the following open studies:

CNV-NT Clinical Trials

Safety Study of Intratumoral Injection of Clostridium Novyi-NT Spores to Treat Patients With Solid Tumors That Have Not Responded to Standard Therapies
Condition: Solid Tumor Malignancies
Status: This study is ongoing, but not recruiting participants
More information

CNV-NT Program

BVD-523 Clinical Trials

BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer
Condition: Pancreatic Cancer
Status: Recruiting participants
More information

Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies
Condition: Advanced Solid Tumors
Status: This study is ongoing, but not recruiting participants
More information

Absorption, Metabolism and Excretion (AME) of Single Dose Radiolabeled BVD-523 in Volunteers
Condition: Healthy
Status: This study has been completed
More information

Phase 1/2 Study of the ERK1/2 Inhibitor BVD-523 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndromes
Conditions: Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Status: This study has been completed
More information

BVD-523 Program

HIGHLIGHTS

Our experience to date has enabled us to perform a wide variety of preclinical studies and complex phase I and II clinical trials across many disease models and modalities looking at both safety and efficacy endpoints.

We perform GMP drug substance and drug product manufacturing as well as distribution for clinical investigations. Our approach allows us to develop strong, efficient programs and partnerships with top physicians and clinical sites in the US.

Key accomplishments include:

2017

Completion of ulixertinib/BVD-523 Phase 1/2a trial in patients with advanced malignancies

2015

Fast Track status granted for ulixertinib/BVD-523

2014

Publication of CNV-NT first patient trial results

2013

Orphan Drug Designation granted for ulixertinib/BVD-523

2013

Initiation of ulixertinib/BVD-523 human clinical trials

2013

Initiation of CNV-NT human clinical trials

COMMITMENT TO PATIENTS

The needs of patients motivate us daily. Science and empirical evidence drive our research and development process toward improving patient care and quality of life. Our goal is to develop distinctive therapies that represent major advances in patient care.

In early-stage development, we provide an opportunity for patients to participate in clinical trials to help advance understanding of diseases and potential treatments. We seek input and guidance from patient organizations to help develop clinical trial protocols that meet patient needs, while providing valid scientific information.