The foundation of research for Bimiralisib’s oral formulations currently in clinical development.

Introduction

The development of effective therapies for metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has been challenging: current standard therapies for metastatic HNSCC are either very toxic or have low response rates, and are thus not beneficial to all patients.

PIQUR Therapeutics AG lead compound, bimiralisib, has shown encouraging clinical activity and a manageable safety profile in phase I/IIa studies in patients with solid tumors and lymphomas. These results support the current phase II, proof-of-concept, study evaluating the efficacy and safety of oral bimiralisib in patients with recurrent or metastatic HNSCC harboring NOTCH1 Loss of Function (N1LoF) mutations.

Compound Discovery

The phosphoinositide 3-kinase/mechanistic target of rapamycin (PI3K/mTOR) signaling pathway plays an important role in cell survival and cell growth. Aberrant activation of the pathway is commonly observed in many human cancers and neurodegenerative diseases. Therefore, molecules that specifically block these signaling pathways represent an important development in targeted anticancer therapies.

There are a number of PI3K and mTOR inhibitors approved for clinical use, but no dual PI3K/mTOR inhibitor has been approved to date.

PIQUR Therapeutics AG set out to develop a compound with PI3K/mTOR dual activity. The rationale being that simultaneous inhibition of PI3K and mTOR, rather than one or the other, could potentially block tumor growth more efficiently. PIQUR’s lead compound bimiralisib is a balanced dual pan-PI3K/mTOR inhibitor, which has previously demonstrated anticancer activity in a number of pre-clinical models.

HNSCC

The most frequently altered signaling pathway in Head and Neck Squamous Cell Carcinoma (HNSCC) is the PI3K/mTOR pathway, although the disease has shown only modest clinical response rates to PI3K/mTOR inhibitors. Strategies guiding the selection of patients for these compounds has also remained elusive.

HNSCC is also driven largely by the loss of non-targetable tumor suppressor genes, dominated by NOTCH1, which is mutated in 18% of HNSCC. However, there is currently no biomarker-driven therapy targeting this aberration.

Recent pre-clinical studies have shown that dual PI3K/mTOR inhibition (by bimiralisib and other PI3K inhibitors) causes cell death in HNSCC with NOTCH1 Loss of Function mutations (N1LoF), the first time therapeutic vulnerability has been established for HNSCC with N1LoF mutations to any class of drug (Sambandam et al 2019). Importantly, bimiralisib showed remarkable efficacy in a heavily pre-treated patient with metastatic HNSCC whose cancer harbored N1LoF mutations. Data from this patient were presented at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Jointly, these pre-clinical and clinical data have led to bimiralisib’s evaluation as the first biomarker-driven targeted therapy for HNSCC. The current study enrols patients with refractory and/or metastatic HNSCC based on the mutational status of their disease to assess the response to treatment with bimiralisib. 

PIQUR Therapeutics AG has filed a patent application to protect its intellectual property underlying this targeted treatment approach.

Toxicology

Preclinical Studies

PIQUR Therapeutics AG successfully completed preclinical profiling and the Good Laboratory Practice (GLP) toxicology studies with their most advanced compound.

Phase IIa Clinical Studies

Oral bimiralisib has shown encouraging clinical activity and acceptable safety profiles (comparable to same class drugs) in phase I/IIa studies in solid tumours and lymphomas. This compelling data supported the initiation of a phase IIa study to evaluate the efficacy and safety of bimiralisib in patients with recurrent or metastatic HNSCC harbouring NOTCH1 loss of function (LoF) mutations. This study is currently ongoing at the MD Anderson Cancer Center in Texas, US.

From Lab to Clinic

PIQUR Therapeutics AG is working in collaboration with the MD Anderson Cancer Center to advance bimiralisib’s development for the clinical benefit of patients with indications of high unmet clinical need. Findings from the phase II study are likely to have implications beyond HNSCC (Sambandam et al 2019) as N1LoF mutations are common in other squamous cell carcinomas, including lung (8%) and esophageal (21%).

Discussion

The future of cancer medicine hinges on how biotech taps into the knowledge of both the human genome and mutations in tumor DNA to expand the library of targetable biomarkers in order to continue developing precision-targeted therapies for more patients. Delivering personalized cancer therapy with reduced toxicity and improved patient outcomes remains therefore of high priority.

PIQUR Therapeutics AG is developing targeted oncology and dermatology medicines that meet a high medical need for therapies that prolong patients’ survival and improve their quality of life.

Bimiralisib is a balanced dual pan-PI3K/mTOR inhibitor, which has demonstrated anticancer activity in a number of preclinical and clinical studies. Bimiralisib promises a therapeutic potential in a wide range of oncology and medical dermatological diseases compared to competitor compounds.