BOLD-100 Development Pipeline

The Untapped Potential of Metallotherapeutics:
Novel Mechanisms-of-Action and Broad Versatility

Metallotherapeutics, or metal-based small molecule therapeutics, are unquestionably some of the most effective anticancer agents available. Despite significant advances in biologic and gene therapies, cisplatin, carboplatin and oxaliplatin continue to be included in the WHO Model List of Essential Medicines, and even today a majority of cancer patients receive a metallotherapeutic at some point in the course of their treatment.

Cisplatin, or (SP-4-2)-diamminedichloridoplatinum(II), arguably the first metallotherapeutic, remains one of the most potent and widely used anticancer drugs, with proven utility in the treatment of testicular, ovarian, head and neck, bladder, lung, and cervical cancer, as well as melanoma and lymphomas. Cisplatin has a multimodal mechanism-of-action, with its primary mechanism involving generation of DNA lesions by interacting with purine bases on DNA followed by activation of several signal transduction pathways which finally lead to apoptosis. Unlike targeted therapies, which are easily evaded through pathway redundancy and resistance mechanisms, this multimodal mechanism-of-action gives cisplatin unmatched breadth of utility across indications and combinations.

Like cisplatin, Bold Therapeutics' BOLD-100 also has a unique multimodal mechanism-of-action whose therapeutic potential is becoming increasingly evident. Like cisplatin, BOLD-100 causes DNA damage and cell cycle arrest -- but it also alters the unfolded protein response (UPR) through selective GRP78 inhibition, a mechanism that appears difficult to evade and particularly effective against heavily mutated or resistant cancer cell lines. As a result, extensive preclinical and, more recently, clinical data suggests that BOLD-100 could enhance the effectiveness of a wide range of existing cancer therapies and significantly improve patient outcomes. BOLD-100 has already received Orphan Drug Designations (ODDs) in gastric and pancreatic cancer and expects to receive a Breakthrough Therapy Designation (BTD) in colorectal cancer and potentially other gastrointestinal cancer indications in the near future.

Realizing the untapped potential of metallotherapeutics and leveraging unparalleled development and manufacturing expertise in metallotherapeutics, Bold Therapeutics is focused on discovering and developing the next generation of metallotherapeutics with novel mechanisms-of-action, broad therapeutic potential, high potency, and low systemic toxicity.

Clinical Investigations

BOLD-100 is the most clinically advanced ruthenium-based therapeutic in development. BOLD-100 is currently being studied in a global Phase 2 trial with 6 sites in Canada, 2 in the U.S., 1 in Ireland, and 5 in South Korea, in combination with FOLFOX for the treatment of advanced gastrointestinal (bile duct, colon, gastric, and pancreatic) cancers (NCT04421820).

In February 2022, BOLD-100 completed a Phase 1b clinical trial in combination with FOLFOX for the treatment of advanced gastrointestinal (gastric, pancreatic, colon and bile duct) cancers. The Phase 1b data indicated that (1) BOLD-100 can be safely combined with FOLFOX chemotherapy at a dose of 625 mg / m2 (the highest dose level tested), with no new Grade 3 or 4 treatment-emergent adverse events; and (2) patients can safely remain on treatment for an extended number of treatment cycles. ASCO 2022 poster can be viewed here.

In April 2023, efficacy data from the Phase 2 study in advanced colorectal cancer was presented at AACR 2023, showing a clinically significant remarkable improvement over standard of care. In patients in the 3rd line and beyond advanced colorectal cancer group (n=17), the results showed a positive median Progression-Free Survival (PFS) of 4.7 months, Overall Survival (OS) of 9.8 months, and Overall Response Rate (ORR) of 13%. These results compare favorably to Standard of Care data (median PFS: 2.0 months; median OS: 7.1 months, ORR: 1.5%). AACR 2023 poster can be viewed here

BOLD-100 has received Orphan Drug Designations (ODDs) from the FDA in both gastric and pancreatic cancers. Results in gastric and bile duct cancer are expected to be presented at upcoming scientific conferences, and Bold Therapeutics expects to initiate Phase 3 trials in multiple indications in the near future.

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Doctor holding clipboard while speaking to patient.

Mechanism of Action

BOLD-100 is an anticancer agent being developed in combination with standard-of-care therapies, to improve patient outcomes in difficult to treat cancers. Most current treatment strategies for advanced cancers are either effective in only some patient populations or have high relapse rates. BOLD-100 is designed to be used in combination with these treatments to improve patient outcomes. In preclinical studies, BOLD-100 enhances a wide range of therapies, including standard of care agents like chemotherapies and targeted agents, but also novel drugs currently in development like ATR inhibitors.

BOLD-100 has a unique, multimodal mechanism-of-action that selectively kills cancerous cells. Specifically, BOLD-100 alters the unfolded protein response (UPR) through selective GRP78 inhibition, leading to endoplasmic reticulum stress, activation of the unfolded protein response, and cellular death via apoptosis. Additionally, cancer cells utilize this pathway to become resistant to standard of care therapies - by targeting this pathway, BOLD-100 is able to overcome this resistance, improving outcomes in both sensitive and resistant cancers.

BOLD-100 also induces reactive oxygen species (ROS) which causes DNA damage and cell cycle arrest. DNA damaging agents are a mainstay of cancer therapy - by also activating this pathway, BOLD-100 can potentiate the effect of current cancer therapies, demonstrating the unique potential of combinational strategies with BOLD-100 to potentiate efficacy while overcoming resistance.

Mechanism of Action infographic

Extended Pipeline Development

Bold Therapeutics is developing a robust pipeline of novel metallotherapeutics. We have developed an innovative, best-in-class screening platform to identify metallotherapeutics with high anticancer activity and low toxicity. Leveraging the unique properties of metallotherapeutics, this screening program is specifically designed to identify compounds with novel anticancer mechanisms. Working with an extensive global network of leading academic chemists, Bold Therapeutic has access to the most innovate metallotherapeutic compounds in development. Research and development activities for pipeline expansion with BOLD-200 and BOLD-300 are ongoing while screening continues in the search for new and interesting metallotherapeutics. We encourage potential collaborators to connect with us here.

Global Development and Collaborations

Bold Therapeutics is working with a leading team of international partners, clinicians and collaborators to develop BOLD-100. We believe collaborations and partnerships are the key to scientific discovery and advancement. Connect with us if you’re interested in collaborating with us to explore the potential of BOLD-100.

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BOLD-100 and its precursor molecules’ (KP1339, NKP-1339, IT-139) clinical scientific and clinical advancements have been presented and published in dozens of peer-reviewed forums.
A full list of publications is available here.
Select papers / posters:

Spratlin JL, O’Kane G, Goodwin RA, et al. BOLD-100-001 (TRIO039): A phase 1b dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastrointestinal solid cancers: Interim safety, tolerability, and efficacy. ASCO 2022 Abstract. View

Bakewell S, Conde I, Fallah Y, et al. Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer. Cancers (Basel). 2020 Sep 16;12(9):2647. View

Neuditschko B, Legin AA, Baier D, et al. Interaction with Ribosomal Proteins Accompanies Stress Induction of the Anticancer Metallodrug BOLD-100/KP1339 in the Endoplasmic Reticulum. Angew Chem Int Ed Engl. 2021 Mar 1;60(10):5063-5068. View

Burris HA, Bakewell S, Bendell JC, et al. Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort. ESMO Open. 2017;1(6):e000154. Published 2017 Feb 23. View

Bakewell SJ, Rangel DF, Ha DP, et al. Suppression of stress induction of the 78-kilodalton glucose regulated protein (GRP78) in cancer by IT-139, an anti-tumor ruthenium small molecule inhibitor. Oncotarget. 2018;9(51):29698–29714. Published 2018 Jul 3. View

Lizardo MM, Morrow JJ, Miller TE, et al. Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression. Neoplasia. 2016;18(11):699–710. View

Heffeter P, Atil B, Kryeziu K, et al. The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo. Eur J Cancer. 2013;49(15):3366–3375. View

Gifford JB, Huang W, Zeleniak AE, et al. Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma. Mol Cancer Ther. 2016;15(5):1043–1052. View