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Tolero Pharmaceuticals Presents Findings from First Clinical Studies

Salt Lake City— Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today presented data from the first clinical studies evaluating the oral investigational agents TP-1287, a cyclin-dependent kinase 9 (CDK9) inhibitor, and TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors. These results were presented in poster presentations at the American Society of Clinical Oncology (ASCO) Virtual Annual Meeting, being held May 29-31, 2020.

Preliminary findings from a Phase 1, first-in-human, dose escalation study of TP-1287 showed clinical activity and a tolerable safety profile as a monotherapy in patients with heavily pretreated, relapsed and refractory solid tumors. In the study, 44 percent (n=12 of 27) of evaluable patients remained on treatment for more than four cycles. Additionally, 48 percent (n=13 of 27) of evaluable patients experienced a best response of stable disease, and one patient experienced a partial response. TP-1287 administered at a dose of eight mg twice daily showed proof of mechanism by reducing levels of phosphorylated RNA polymerase II, a downstream target of CDK9.

The most frequently observed Grade 3 adverse events in this study included diarrhea, anemia and pain. Pending the results from the dose escalation portion of the Phase 1 trial, the study will advance into a Phase 2 expansion in patients with metastatic castrate-resistant prostate cancer to evaluate clinical activity in this setting.

Initial findings from a separate Phase 1, first-in-human, dose escalation study of TP-3654 presented at ASCO showed clinical activity and tolerability as a monotherapy in patients with heavily pretreated, relapsed and resistant solid tumors. Data from the study indicated that one-third of response-evaluable patients (33 percent, n=3 of 9) experienced stable disease for more than 16 weeks. Additionally, two-thirds of response-evaluable patients (67 percent, n=6 of 9) experienced a best response of stable disease. This study also found that patients administered TP-3654 had a reduction of BAD phosphorylation, a pro-survival downstream effector of PIM kinase activation. Further downstream biomarker data evaluating the impact of TP-3654 on the PIM kinase pathway are pending analyses.

TP-3654 was tolerated up to doses of 1440 mg once daily with no dose-limiting toxicities observed. The dose escalation portion of the study is continuing with a twice daily dosing schedule to determine the maximum tolerated dose and recommended dose for a Phase 2 study.

“We are pleased to share these clinical data on TP-1287 and TP-3654 at ASCO, to support proof of mechanism for each investigational compound. These initial findings are representative of the continued advancement of our investigational pipeline of innovative cancer therapeutics,” said David J. Bearss, Ph.D., Chief Executive Officer, Tolero Pharmaceuticals, and Chief Scientific Officer and Global Head of Research, Global Oncology. “We are continuing to progress these clinical programs as we build our understanding of the potential of TP-1287 and TP-3654 in various tumor types.”

Below are the details for the presentations:

Abstract TitleDetailsAuthor
A Phase I, First-in-human, Open-label, Dose escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP 1287 Administered Daily to Patients with Advanced Solid TumorsAbstract# 3611May 29, 20208 a.m. ETPoster PresentationBen George, M.D., Medical College of Wisconsin
A Phase I, First-in-Human, Open-Label, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-3654 Administered Daily for 28 Days to Patients with Advanced Solid TumorsAbstract# 3586May 29, 20208 a.m. ETPoster PresentationIgnacio Garrido-Laguna, M.D., Huntsman Cancer Institute

About TP-1287

TP-1287 is an investigational oral cyclin-dependent kinase 9 (CDK9) inhibitor under evaluation in a Phase 1 study in patients with advanced solid tumors (NCT03604783). TP-1287 has shown favorable oral bioavailability in preclinical models.

About TP-3654

TP-3654 is an investigational second-generation selective PIM kinase inhibitor under evaluation in a Phase 1 study in patients with myelofibrosis (NCT04176198), led by Boston Biomedical, Inc., as well as a Phase 1 study in patients with advanced solid tumors (NCT03715504), led by Tolero Pharmaceuticals, Inc.

About CDK9 Inhibition and MCL-1

MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins. In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells. MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment. The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).  Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly. Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.

About PIM Kinase

PIM kinases are major effectors of JAK/STAT proliferative signaling downstream of multiple growth factors and cytokines. PIM is overexpressed in cancers and it may enhance the ability of fibroblasts to differentiate into myofibroblasts.

About Tolero Pharmaceuticals, Inc.

Tolero Pharmaceuticals is a clinical-stage biopharmaceutical company researching and developing treatments to improve and extend the lives of patients with hematological and oncological diseases. Tolero has a diverse pipeline that targets important biological drivers of blood disorders to treat leukemias, anemia, and solid tumors, as well as targets of drug resistance and transcriptional control.

Tolero Pharmaceuticals is based in the United States and is an indirect, wholly owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., a pharmaceutical company based in Japan. Tolero works closely with its parent company, Sumitomo Dainippon Pharma, and Boston Biomedical, Inc., also a wholly owned subsidiary, to advance a pipeline of innovative oncology treatments. The organizations apply their expertise and collaborate to achieve a common objective – expediting the discovery, development and commercialization of novel treatment options.

Additional information about the company and its product pipeline can be found at www.toleropharma.com.

Tolero Pharmaceuticals Forward-Looking Statements

This press release contains “forward-looking statements,” as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. The forward-looking statements in this press release are based on management’s assumptions and beliefs in light of information presently available, and involve both known and unknown risks and uncertainties, which could cause actual outcomes to differ materially from current expectations. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice.