Oncology | Biosplice

Cancer is one of the most important health problems facing the world. It is the second leading cause of death and most costly illness in the United States.¹

Biosplice’s goal in oncology is to broadly impact cancer therapy through pharmacological modulation of corrupted proteomes at the level of RNA-recoding.

Our scientific platform is rooted in the biological systems that govern alternative splicing (AS). Endowing the human genome with enormous protein coding potential, AS can also commonly be “highjacked” by cancers to enable their growth, survival, dissemination throughout the body, and evasion of current standard-of-care therapies. Biosplice has designed small molecules that inhibit CLK/DYRK family kinases to selectively disrupt alternative splicing in a manner that is tuned to disease and tissue context. This can be lethal to cancer cells that rely on dysregulation of AS for survival, and lead to reversal of drug tolerance mechanisms, and loss of oncogene pathway activation.

A monumental challenge facing durable cancer therapy is the extreme mechanistic diversity and adaptive capacity of tumors within and among cancer patients. For any given drug, benefit is increasingly limited by the subtype of disease and by rapid emergence of drug resistance. Our goal is to deliver broadly active and durable therapy by exploiting AS as a common cancer vulnerability within the ocean of confounding diversity.

References

American Cancer Society. Cancer Facts &Figures 2021. Atlanta: American Cancer Society; 2021.

Cirtuvivint (SM08502)

Overview Mechanism of Action

Overview

Biosplice has developed a suite of small molecule inhibitors of the CDC2-like kinase (CLK) and dual-specificity tyrosine regulated kinase (DYRK) family. These kinases, relatively unexplored for drug development, govern the efficiency and specificity of alternative RNA splicing by directly phosphorylating serine/arginine-rich splicing factors (SRSFs) and thereby influencing pre-mRNA splice junction selection.

The program’s lead clinical asset is cirtuvivint (SM08502), a first-in-class pan-CLK inhibitor which has completed dose-escalation in Phase 1 with subject enrichment ongoing in specific solid-tumor types.

Mechanism of Action

Dysregulation of alternative pre-mRNA splicing has been identified as a common mechanistic driver of tumor initiation, disease progression, and emergence of therapy resistance. An iterative screening and design optimization campaign developed cirtuvivint (SM08502), a potent pan-inhibitor of CLK/DYRK kinases which are known to regulate alternative splicing.

By inhibiting CLK and DYRK activity, cirtuvivint can control the activity states of these proteins, without halting the majority of constitutive spliceosome activity. Upon cirtuvivint exposure, tumor-selective changes in alternative splicing events are observed, with minimal changes in healthy cells and tissues. Drug-dependent reduction in aberrant splicing activity leads to reduced expression of oncogenic proteins and reduced activity of key tumorigenic regulatory systems.

Expanded Access

Biosplice is committed to developing safe and effective medical solutions to help patients. Biosplice may, in the future, provide access to its investigational drug products for expanded access, sometimes called “compassionate use,” if and when there is sufficient scientific evidence to support an expectation of net benefit to the specific patient and where such use would not unduly jeopardize the investigational product’s potential to benefit a larger patient population.

Biosplice is not offering expanded access for any investigational drug product at this time.

Publications

Alternative Splicing Regulation as a Novel Therapeutic Target in Soft Tissue Sarcoma

American Society of Clinical Oncology (ASCO) | June 02 - 06, 2023

Ultra-selective DYRK1A inhibitors as a new therapeutic approach for the treatment of hematological malignancies

AACR 2023 | April 14 - 19, 2023

Cancer Cell, | January 09, 2023

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia

Cancer Cell. doi:10.1016/j.ccell.2022.12.002

Eric Wang, Jose Mario Bello Pineda, Won Jun Kim, Sisi Chen, Jessie Bourcier, Maximilian Stahl, Simon J. Hogg, Jan Phillipp Bewersdorf, Cuijuan Han, Michael E. Singer, Daniel Cui, Caroline E. Erickson, Steven M. Tittley, Alexander V. Penson, Katherine Knorr, Robert F. Stanley, Jahan Rahman, Gnana Krishnamoorthy, James A. Fagin, Emily Creger, Elizabeth McMillan, Chi-Ching Mak, Matthew Jarvis, Carine Bossard, Darrin M. Beaupre, Robert K. Bradley, and Omar Abdel-Wahab.

Article

Preliminary Evidence of Clinical Activity from Phase 1 and 1b Trials of the CLK/DYRK Inhibitor Cirtuvivint (CIRT) in Subjects with Advanced Solid Tumors

European Society for Medical Oncology (ESMO) | September 09 - 13, 2022

Multigenomic characterization of context-dependent alternative splicing in normal and neoplastic cells

AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics | October 07 - 10, 2021

Evaluation of systemic pan-CLK/DYRK inhibition on organ function and tissue self-renewal

AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics | October 07 - 10, 2021

Preclinical efficacy landscape of the pan-CLK/DYRK inhibitor Cirtuvivint (SM08502)

AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics | October 07 - 10, 2021

Initial results from a Phase 1 trial of a first-in-class pan-CDC2-like kinase inhibitor (SM08502) with proof of mechanism in subjects with advanced solid tumors

American Association for Cancer Research (AACR) Annual Meeting | April 09 - 14, 2021

SM08502, a Novel, Small-Molecule CDC-like Kinase (CLK) Inhibitor, Demonstrates Strong Antitumor Effects and Wnt Pathway Inhibition in Castration-Resistant Prostate Cancer (CRPC) Models

American Association for Cancer Research (AACR) Annual Meeting | June 22 - 24, 2020

Transcriptome Analysis of TCGA Prostate Cancer Samples Identifies an Association of Poorer Survival and Aggressive Disease Biology with CDC-like Kinase (CLK) Expression and Spliceosome Regulation

American Association for Cancer Research (AACR) Annual Meeting | June 22 - 24, 2020

SM08502, a Novel, Small-Molecule CDC-like Kinase (CLK) Inhibitor, Demonstrates Strong Antitumor Effects and Wnt and Cyclin D-CDK4/6-RB Pathway Inhibition in Hormone-Receptor-Positive (HR+) Breast Cancer Models

American Association for Cancer Research (AACR) Annual Meeting | June 22 - 24, 2020

SM08502, a Novel, Small-Molecule CDC-like Kinase (CLK) Inhibitor, Demonstrates Strong Inhibition of the Wnt Signaling Pathway and Antitumor Effects as Monotherapy and in Combination with Chemotherapy in Triple-Negative Breast Cancer (TNBC) Models

San Antonio Breast Cancer Symposium (SABCS) | December 10 - 14, 2019

Cancer Letters | September 24, 2019

The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models

Cancer Letters. doi:10.1016/j.canlet.2019.09.009

Betty Y.Tam, Kevin Chiu, Heekyung Chung, Carine Bossard, John Duc Nguyen, Emily Creger, Brian W. Eastman, Chi Ching Mak, Maureen Ibanez, Abdullah Ghias, Joseph Cahiwat, Long Do, Shawn Cho, Jackie Nguyen, Vishal Deshmukh, Josh Stewart, Chiao-wen Chen, Charlene Barroga, Luis Dellamary, Sunil K. KC, Timothy J. Phalen, John Hood, Steven Cha, Yusuf Yazici

Article

SM08502, a novel, small-molecule CDC-like kinase (CLK) inhibitor, demonstrates strong inhibition of the Wnt signaling pathway and antitumor effects in diverse ovarian cancer models

American Association for Cancer Research (AACR) - Advances in Ovarian Cancer Research | September 13 - 16, 2019

Inhibition of tumor growth and post-treatment regrowth by SM08502, a novel, small-molecule CDC-like kinase (CLK) inhibitor, in combination with standard of care in pancreatic cancer models

American Association for Cancer Research (AACR) - Pancreatic Cancer Meeting | September 06 - 09, 2019

SM08502, a novel, small-molecule CDC-like kinase (CLK) inhibitor, demonstrates activity against cancer stem cell (CSC)-enriched pancreatic cancer cells and suppresses stemness in vitro

American Association for Cancer Research (AACR) - Pancreatic Cancer Meeting | September 06 - 09, 2019

SM08502, a novel, small-molecule CDC-like kinase (CLK) inhibitor, downregulates the Wnt signaling pathway and demonstrates antitumor activity in pancreatic cancer cell lines and in vivo xenograft models

American Association for Cancer Research (AACR) - Pancreatic Cancer Meeting | September 06 - 09, 2019

Effects of SM08502, a Novel, Oral, Small-Molecule Inhibitor of Wnt Pathway Signaling, on Gene Expression and Antitumor Activity in Colorectal Cancer (CRC) Models

American Society of Clinical Oncology (ASCO) | May 31 - June 04, 2019