bimiralisib (PQR309) / Torqur - LARVOL DELTA

Quantitative Analysis of Bimiralisib in Dried Blood Spots of Mouse Blood Using a Validated LC-MS/MS Method: An Application to Pharmacokinetic Study. (PubMed, Biomed Chromatogr) - "Under optimized conditions, the retention times for bimiralisib and the internal standard (IS, Nilotinib) were approximately 1.14 and 1.27 min, respectively, with a total run time of 2.00 min per injection. All validation parameters met the required acceptance criteria, and hematocrit levels had no impact on bimiralisib concentrations in DBS. The validated method was utilized to determine intravenous and oral pharmacokinetic parameters by quantifying bimiralisib in mouse blood, with results correlated to pharmacokinetic data from mice plasma."

Journal • PK/PD data • Preclinical • Oncology

A randomized phase 2 proof-of-concept study to evaluate the efficacy and safety of topical bimiralisib application in patients suffering from actinic keratosis on the face and/or scalp and/or back of hands over a 2 and 4-week treatment period (AAD 2025) - "Bimiralisib gel 2% demonstrated efficacy in the treatment of AK, with a favorable safety profile supporting further clinical investigation. An analysis of all patients in this ongoing study will be available for poster presentation."

Clinical • P2 data • Actinic Keratosis • Dermatology • Non-melanoma Skin Cancer • Oncology • Pruritus • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

Torqur AG Presents Interim Phase 2 Clinical Trial Results at American Academy of Dermatology (AAD) 2025 Annual Meeting (Businesswire) - P2 | N=20 | NCT06319794 | "Bimiralisib topical gel (2%) demonstrated strong efficacy with 60% of patients who completed the initial treatment and follow up visit showing either complete or partial clearance of their lesions. Notably, 70% in the 4-week treatment group (Arm B, 17 patients) and 50% in the 2-week treatment group (Arm A, 18 patients) showed significant improvement, reinforcing its potential as an effective targeted therapy for Actinic keratosis....The safety profile indicates that bimiralisib topical gel (2%) was well tolerated, with treatment-related adverse events primarily being mild (Grade 1) and resolving quickly after treatment completion....The Phase 2 trial is enrolling patients across two renowned dermatology centers in Switzerland...with full results expected in June 2025."

P2 data • Actinic Keratosis • Oncology

Study on the Safety and Efficacy of Bimiralisib Gel in Participants Suffering From Actinic Keratosis (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: TORQUR | Not yet recruiting ➔ Recruiting

Enrollment open • Actinic Keratosis • Dermatology

The small nucleolar RNA SNORD46 and SNORD72 have tumor suppressor activity in diffuse large B cell lymphoma (AACR 2024) - "Here, we characterized SNORD46 and SNORD72, the two snoRNAs most upregulated cells after YK-4-279 and TK-216 and mapped to the 1p34.1 locus recurrently lost in DLBCL.Methods...Furthermore, the snoRNAs were upregulated in four ABCs and four GCB DLBCLs cell lines exposed to the PI3K/mTOR inhibitor bimiralisib. Bioinformatic analysis indicated the possible binding of SNORD46 and especially of SNORD74 to BCR signaling molecules (SYK, LYN, BTK, PI3Kδ, IRAK4, IRAK1, CARD11), RNA helicases (RHA, DDX21, DDX5) and essential DLBCL proteins (BCL6, IRF4).Conclusions. SNORD46 and SNORD74 exert tumor suppressor activity in DLBCL cells, possibly as negative regulators of the BCR signaling."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • CARD11 • DDX21 • DDX5 • ETS1 • FLI1 • IRAK4 • IRF4 • LYN • PIK3CD • SYK

PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3β and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma. (PubMed, Cell Death Dis) - "Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3β and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC."

Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • HSPD1

PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3β and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma (Nature, Cell Death Dis) - "More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3β and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition."

Preclinical • Nasopharyngeal Carcinoma

PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3β and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma (Nature, Cell Death Dis) - "More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3β and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition."

Preclinical • Nasopharyngeal Carcinoma

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. (PubMed, Cancers (Basel)) - "Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations."

Journal • Metastases • P1 data • Diabetes • Fatigue • Oncology • Solid Tumor • Squamous Cell Carcinoma

Study on the Safety and Efficacy of Bimiralisib Gel in Participants Suffering From Actinic Keratosis (clinicaltrials.gov) - P2 | N=40 | Not yet recruiting | Sponsor: TORQUR

New P2 trial • Actinic Keratosis • Dermatology

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors (Multidisciplinary Digital Publishing Institute) - P1 | N=70 | NCT02483858 | Sponsor: PIQUR Therapeutics AG | "The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B....There was one partial response in a head and neck squamous cancer patient with a NOTCH1^T1997M mutation."

P1 data • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Recent biological applications of heterocyclic hybrids containing s-triazine scaffold. (PubMed, RSC Adv) - "s-Triazine possesses an auspicious status in the field of drug discovery and development owing to its presence in many naturally occurring compounds as well as commercially available drugs like enasidenib, gedatolisib, bimiralisib, atrazine, indaziflam, and triaziflam. These s-triazine-based heterocyclic hybrids have been reported to show enhanced biological activities in recent years. Therefore, it is important to summarize and highlight recent examples of these hybrids which is imperative to attract the attention of the drug development community."

Journal • Review • Oncology

Concurrent inactivation of PI3K and PLK1 is synergistic and overcomes acquired resistance to PI3K inhibitors in NOTCH1MUT HNSCC (AACR 2023) - "We further tested the PLK1-specific inhibitor onvansertib (0-100nM) combined with pan-PI3K inhibitor copanlisib (0-200nM) or dual inhibitor bimiralisib (0-1μM). We will further validate this combination in vivo to determine the effect of combined PI3K and PLK1 inhibition on tumor growth and survival. These novel findings may lead to the development of a better therapeutic approach for NOTCH1MUT HNSCC and for patients who develop acquired resistance to targeted therapies."

Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5 • AURKB • CASP3 • NOTCH1 • PLK1

Oral dual PI3K/mTOR inhibitor bimiralisib demonstrates tolerability and a signal of activity in head and neck squamous cell cancer with NOTCH1 loss-of-function mutation (AACR-NCI-EORTC 2019) - P2; "Conclusion Bimiralisib was well tolerated and RP2D of 140 mg given orally twice weekly on Days 1 and 2 was selected for further studies. In agreement with our preclinical models, there was an encouraging activity in a SCCHN patient with NOTCH1 LoF mutation and this observation is now being validated in a proof-of-concept phase 2 study (NCT03740100)."

Rationale for Combining the BCL2 Inhibitor Venetoclax with the PI3K Inhibitor Bimiralisib in the Treatment of IDH2- and FLT3-Mutated Acute Myeloid Leukemia. (PubMed, Int J Mol Sci) - "In this study, the BCL-XL inhibitor A1331852, MCL1-inhibitor S63845, dual PI3K-mTOR inhibitor bimiralisib (PQR309), BMI-1 inhibitor unesbulin (PTC596), MEK-inhibitor trametinib (GSK1120212), and STAT3 inhibitor C-188-9 were assessed as single agents and in combination with venetoclax, for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. For the venetoclax and bimiralisib combination treatment, responders were enriched for IDH2 and FLT3 mutations, whereas non-responders were associated with PTPN11 mutations. The combination of PI3K/mTOR dual pathway inhibition with bimiralisib and BCL2 inhibition with venetoclax has emerged as a candidate treatment in IDH2- and FLT3-mutated AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2L1 • FLT3 • IDH2 • PTPN11

Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer. (PubMed, Oncologist) - P2 | "Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100)."

IO biomarker • Journal • Diabetes • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • NOTCH1

SPR965, a PI3K/mTORC1/C2 inhibitor for treatment of chordoma (AACR 2022) - "SPR965 was more active at 1uM than PI3K/mTOR inhibitors VS-5584, Bimiralisib, PF-04691502, WYE-687, Dactolisib, and Voxtalisib in the Kinase Chemogenomic Set. In SF8894 PDX model SPR965 was more efficacious as it produced similar tumor growth inhibition at 12- and 17-fold lower dose than Buparlisib (PI3K) and Palbociclib (CDK4/6) respectively, both these compounds are in phase 2 clinical trials. In CF459 PDX model SPR965 exhibited dose-dependent tumor growth inhibition, and at 10mg/kg profoundly slowed tumor growth compared to Palbociclib. Studies are underway to elucidate potential mechanisms of SPR965 sensitivity."

Late-breaking abstract • Chordoma • Oncology

Novel patient-derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma. (PubMed, J Pathol) - "Using high-throughput screening of 157 inhibitors targeting the PI3K/AKT/mTOR pathways in vitro, we identified a dozen inhibitors (such as BEZ235, LY2090314, and AZD8055) with significant growth-suppressive effects...Furthermore, we demonstrated two orally bioavailable inhibitors AZD8055 and PQR309 suppressed NF2-associated schwannoma growth both in vitro and in vivo...Furthermore, we demonstrated two orally bioavailable inhibitors AZD8055 and PQR309 suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies."

Journal • Preclinical • Brain Cancer • Fibrosis • Genetic Disorders • Neurofibromatosis • Oncology • Rare Diseases • Solid Tumor • NF2

Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial. (PubMed, Cancers (Basel)) - "In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs."

Journal • P1 data • Cutaneous T-cell Lymphoma • Dermatology • Mycosis Fungoides • Oncology

Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation. (PubMed, Cold Spring Harb Mol Case Stud) - "Dual PI3K/mTOR (LY3023414, bimiralisib) and AKT inhibitors (ipatasertib, afuresertib) induced dose-dependent reductions in cell growth. However, mTOR-selective inhibitors (everolimus, rapamycin) alone did not exert cytotoxic effects. The MEK1/2 inhibitor trametinib did not impact proliferation even at the highest doses tested. Our data suggest that molecularly targeted strategies may be effective in PI3K/AKT/mTOR-activated ssRMS. Taken together, these data highlight the importance of utilizing patient-derived models to assess molecularly targetable treatments and their potential as future treatment options."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • GNAS • PIK3CA • PTEN

Single-arm Study With Bimiralisib in Patients With HNSCC Harboring NOTCH1 Loss of Function Mutations (clinicaltrials.gov) - P2; N=8; Terminated; Sponsor: M.D. Anderson Cancer Center; Completed ➔ Terminated; The trial was closed because the sponsor became insolvent.

Clinical • Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MRI

A Phase II Study to Assess the Safety and Efficacy of the Dual mTORC1/2 and PI3K Inhibitor Bimiralisib (PQR309) in Relapsed, Refractory Lymphoma. (PubMed, Hemasphere) - "Per protocol, hyperglycemia required treatment with oral antihyperglycemic agents in 28% and with insulin in 14%. At 60 mg or 80 mg continuous dosing, bimiralisib showed modest efficacy with significant toxicity in heavily pretreated patients with various histological subtypes of lymphoma."

Clinical • Journal • P2 data • Diabetes • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia

Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines. (PubMed, Cells) - "mtp53 silence enhanced PQR309-inhibited cell viability, spheroid formation, and the expressions of p-Akt, c-Myc, and CDK6. This is the first study to reveal the novel finding of the PI3K/mTOR dual inhibitor in lowering cell viability by abolishing the PI3K/Akt/mTOR/c-Myc/mtp53 positive feedback loop in endometrial cancer cell lines."

Journal • Preclinical • Endometrial Cancer • Oncology • Solid Tumor • CDK6 • KRAS • MYC • PIK3CA • PIK3R1 • PTEN • TP53

[VIRTUAL] Single-arm study of bimiralisib in head and neck squamous cell carcinoma (HNSCC) patients (pts) harboring NOTCH1 loss of function (LOF) mutations. (ASCO 2020) - P2 | "In the second stage, IHC and WES may be performed on pre- and post- treatment (day 15 and progression) tissue to examine pharmacodynamics and mechanisms of resistance. Research Funding: PIQUR"

Clinical • IO Biomarker • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • NOTCH1 • PIK3CA

[VIRTUAL] New drugs for low grade lymphoproliferative diseases (EHOC 2020) - "For symptomatic patients or for those with high tumor burden, initial treatment is usually chemoimmunotherapy with an anti-CD20 monoclonal antibody (mo-Ab), most commonly Rituximab or Obinutuzumab plus an alkylator, such as bendamustine or chlorambucil and/or a pourine analog, such as fludarabine or cladribine...Newer anti-CD20 mo-Abs, such as Ublituximab appear equally effective, but have not yet been tested comparatively with the previous ones. Radioconjugates such as 90Y-ibritumomab tiuxetan and 131I-tositumomab are no more in broad use due to unpredicted myelotoxicity. The newer 90Y-epratuzumab tetratexan appears safe as consolidation following R-CHOP in DLBCL patients. Polatuzumab vedotin, Pinatuzumab vedotin and Tafasitamab targeting CD19 have mainly been used, combined with an anti-CD20 mo-Ab to treat RR-DLBCL with success, which render them candidates for indolent lymphomas also...Acalabrutinib, already approved for CLL/SLL and MCL, is now being tested for other..."

IO biomarker • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hepatology • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CRBN • EZH2 • SYK