scientist in laboratory

Vancouver-based clinical-stage biopharmaceutical company Bold Therapeutics has initiated a research collaboration with scientists from the University of Ottawa to explore the potential of their investigational drug BOLD-100, a first-in-class anti-resistance therapeutic ruthenium-based small molecule drug, as a novel antiviral agent and the potential of the investigational agent in the treatment of patients diagnosed with COVID19.

Pancreatic cancer represents a significant unmet therapeutic need. Adding BOLD-100 to the Standard-Of-Care of Gemcitabine (Gemzar®; Eli Lilly) in the treatment of patients with pancreatic cancer shows a statistically significant extension of both median and overall survival in preclinical pancreatic cancer models.

Earlier this year the company received clearance from Health Canada to initiate a Phase Ib trial of BOLD-100 in combination with FOLFOX (a combination of leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin) for the treatment of gastric, pancreatic, colorectal and bile duct (cholangiocarcinoma) cancers. [1]

BOLD-100 is a sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] formulated as a sterile lyophilized powder for intravenous infusion. The drug selectively inhibits stress-induced upregulation of Glucose Regulated Protein 78 (GRP78; required for the tumor to proliferate and invade normal tissue) which results in drug resistance, survival, and proliferation of tumor cells.

Increased levels of GRP78 are associated with drug resistance and increased cell survival. [2]

Preclinical development
A previously completed Phase I monotherapy study of BOLD-100 (N=46) demonstrated that the drug was well-tolerated with a manageable safety profile including minimal hematological activity.

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“Based on compelling preclinical efficacy in combination with a wide range of anti-cancer agents, we are excited about the prospects of BOLD-100 in combination with FOLFOX,” noted Jim Pankovich, Executive Vice President of Bold Therapeutics Clinical Development.

The drug appears to significantly enhance the activity of a wide range of other anti-cancer therapies by disabling a critical and previously untargeted resistance, survival and proliferation pathway common across cancers.

Bold’s development efforts focus on some of the most challenging cancer indications where existing therapies are largely ineffective, resulting in a significant unmet medical need.

“The combination of exciting preclinical data in a range of challenging solid tumor models, including gastric, pancreatic, triple-negative breast, and lung cancers, as well an encouraging safety profile seen in early clinical trials, supports the continued clinical development of BOLD-100,” Pankovich added.

“I am hopeful that these results translate into improved outcomes for patients, significantly advancing the treatment of these devastating diseases,” he concluded.


Beyond cancer: COVID19
But, being an inhibitor stress-induced upregulation of GRP78, BOLD-100 also appears beneficial beyond the treatment of patients with cancer.

GRP78 is a common receptor for viral recognition of host cells as a potential binding site for COVID19.

A study published by Ibrahim et al in Journal of Infection, investigated the sequence and structural alignments of the coronavirus. Protein-protein docking was performed to test the four regions of the Spike protein (S) that fit tightly in the GRP78 Substrate Binding Domain β (SBDβ).

According to the researchers, the docking pose revealed the involvement of the SBDβ of GRP78 and the receptor-binding domain of the S protein in recognition of the host cell receptor. In addition, published literature suggests that inhibiting or blocking GPR78 can reduce viral loads or viral replication in both Japanese Encephalitis Virus and Dengue Virus, while inhibiting GRP78 expression with either epigallocatechin gallate (EGCG) or siRNA decreased viral transcript production in models of Ebola.

In a new study scientists from the University of Ottawa are to explore the potential of Bold Therapeutics’ investigational drug BOLD-100.

Mark Bazett, Ph.D., Director, Preclinical Development

“We will be using our lentiviral-based infection system, derived from HIV, equipped with the SARS-CoV-2 (COVID-19) spike, to study the impact of BOLD-100 on viral entry,” explained Marc-André Langlois, Ph.D, Professor of Medicine and Canada Research Chair in Molecular Virology and Intrinsic Immunity, Department of Biochemistry, Microbiology and Immunology (BMI) at the Faculty of Medicine, the University of Ottawa in Canada.

“There is an urgent need for novel antiviral agents effective against COVID-19 and related pathogens, and we look forward to advancing our understanding of the role that GRP78 plays in viral entry.”

“We look forward to collaborating with Langlois’ team at the University of Ottawa,” added Mark Bazett, Ph.D., Director of Preclinical Development at Bold Therapeutics.

“In the interim, we continue to seek other potential collaborators who could also help generate additional data, particularly related to viral replication,” Bazett added.

Ongoing development
“In 2019, the Bold Therapeutics team built a strong foundation for rapid growth and development, including raising capital, engaging with potential development partners, completing cGMP manufacturing of BOLD-100, establishing collaborations with leading academic institutions to further elucidate the mechanism of action of BOLD-100, and finalizing a protocol that should efficiently determine the safety and preliminary efficacy in the treatment of GI cancers,” said E. Russell McAllister, Chief Executive Officer.

“I look forward to an exciting, data-driven 2020, with preliminary results from our pioneering Phase 1b trial expected by year-end.”

Earlier this year, Bold Therapeutics confirmed that the company currently has ample cGMP clinical product available and an open IND / CTA in the United States and Canada, respectively, allowing for potentially rapid clinical development.e

[1] Gifford JB, Hill R. GRP78 Influences Chemoresistance and Prognosis in Cancer. Curr Drug Targets. 2018;19(6):701–708. doi:10.2174/1389450118666170615100918
[2] Chiou JF, Tai CJ, Huang MT, et al. Glucose-regulated protein 78 is a novel contributor to acquisition of resistance to sorafenib in hepatocellular carcinoma. Ann Surg Oncol. 2010;17(2):603–612. doi:10.1245/s10434-009-0718-8
[3] Ibrahim IM, Abdelmalek DH, Elshahat ME, Elfiky AA. COVID-19 spike-host cell receptor GRP78 binding site prediction [published online ahead of print, 2020 Mar 10]. J Infect. 2020;80(5):554–562. doi:10.1016/j.jinf.2020.02.026 [Article]

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