TOS-358 / Totus Medicines - LARVOL DELTA

Preliminary activity of covalent PI3Ka inhibitor TOS-358 + fulvestrant in HR+HER2- BC (ESMO-BC 2026) - P1 | "TOS-358, a covalent pan-mutant oral inhibitor of PI3Kα has class leading safety and can be safely combined with fulvestrant at standard dose. Clinically meaningful tumor control is demonstrated with a CBR of 67%. Doublet data suggests potential for optimal combination with CDK4/6i for long term tolerability."

Breast Cancer • HER2 Positive Breast Cancer • CDK4 • ER • HER-2 • PIK3CA

Phase I results PI3Ka inhibitor TOS-358 (ESMO-TAT 2026) - P1 | "TOS-358, a covalent small molecule inhibitor of PI3Ka, has class leading safety + clinically meaningful tumor control + 40% tumor control >24 wks. Class leading safety + durable tumor control suggest a potential for being the optimal combination partner with CDK4/6i for long term tolerability. Development is ongoing."

P1 data • Endometrial Adenocarcinoma • Endometrial Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CDK4 • ER • HER-2 • PIK3CA

TOS-358-001: A Study to Evaluate the Safety and Tolerability of TOS-358 in Adults With HR+ Breast Cancer and Other Select Solid Tumors (clinicaltrials.gov) - P1 | N=241 | Recruiting | Sponsor: Totus Medicines | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Bladder Cancer • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HER-2 • PIK3CA

A Study to Evaluate the Safety and Tolerability of TOS-358 in Adults With Select Solid Tumors (clinicaltrials.gov) - P1 | N=241 | Recruiting | Sponsor: Totus Medicines

Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • HER-2 • PIK3CA

TOS-358-001: A Study to Evaluate the Safety and Tolerability of TOS-358 in Women With HR+ HER2- Breast Cancer (clinicaltrials.gov) - P1 | N=241 | Recruiting | Sponsor: Totus Medicines | N=175 ➔ 241

Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

TOS-358-001: A Study to Evaluate the Safety and Tolerability of TOS-358 in Women With HR+ HER2- Breast Cancer (clinicaltrials.gov) - P1 | N=175 | Recruiting | Sponsor: Totus Medicines | N=100 ➔ 175

Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

TOS-358-001: A Study to Evaluate the Safety and Tolerability of TOS-358 in Women With HR+ HER2- Breast Cancer (clinicaltrials.gov) - P1 | N=241 | Recruiting | Sponsor: Totus Medicines | Trial completion date: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Dec 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Totus Medicines Presents Early Phase 1b Clinical Data Demonstrating 100% Disease Control Rate and Class-Leading Safety for TOS-358 + Fulvestrant Doublet Therapy in HR+/HER2- Breast Cancer at ESMO Breast Cancer Annual Congress 2026 (The Manila Times) - "Key efficacy and durability findings include: 100% Disease Control Rate (DCR) in women treated with TOS-358 + Fulvestrant; 89% Clinical Benefit Rate (CBR) in women, including patients who had received prior PI3K/AKT/mTOR (PAM)-directed therapy and patients in the 4th line and beyond; Responses continued to deepen over time, including conversions from stable disease (SD) to partial responses (PR), consistent with TOS-358’s near-total inhibition of PI3Ka signaling; 60% of patients on TOS-358 + Fulvestrant remained on therapy beyond 24 weeks, with an additional 20% of patients ongoing at less than 24 weeks on trial; median time on therapy exceeds 24 weeks for the overall Phase 1 population."

P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Totus Medicines to Present Interim Phase 1b Clinical Data for TOS-358 + Fulvestrant Doublet Therapy in HR+/HER- Breast Cancer Patients at ESMO Breast Cancer Annual Congress 2026 (The Manila Times) - "Data will include efficacy, durability and safety findings in heavily pretreated patients with PI3Ka-mutant, HR+/HER- breast cancer."

P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Totus Medicines…announced that updated Phase 1 clinical data from its ongoing study of TOS-358, a next-generation covalent PI3Ka inhibitor, will be presented in an oral session at the European Society for Medical Oncology (ESMO) Targeted Anticancer Therapies (TAT) Congress (GlobeNewswire) - "Oral presentation to highlight updated Phase 1 monotherapy safety and efficacy data for TOS-358, a covalent PI3Ka inhibitor. Data will include efficacy and safety in heavily pretreated patients with PI3Ka-mutant breast cancer, endometrial adenocarcinoma, and HNSCC."

P1 data • Breast Cancer • Endometrial Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Squamous Cell Carcinoma of Head and Neck

Totus Medicines Announces Successful Completion of a Phase 1 Dose-Escalation Study and Initiation of an Expansion Trial Evaluating TOS-358, a Covalent PI3Ka Selective Therapy for the Treatment of Select Solid Tumors and Appoints Zelanna Goldberg as Chief Medical Officer (GlobeNewswire) - P1 | N=241 | NCT05683418 | Sponsor: Totus Medicines | "Successfully completed a Phase 1 dose-escalation study...Initiating an expansion trial in breast, endometrial, urothelial and head and neck cancers at 5 & 8 mg BID....'The Phase 1 study results to date have demonstrated 95% saturating target engagement of PI3Ka in patients, initial clinical activity with an unconfirmed complete response and no grade 3/4 toxicities at several low dose levels. Importantly, several patients dosed are now progression-free for over 6 months.'"

P1 data • Trial status • Breast Cancer • Endometrial Cancer • Head and Neck Cancer • Urothelial Cancer

Initial results from the phase I, first-in-human study of the covalent, PI3Kα inhibitor TOS-358 in patients with solid tumors, expressing PI3Kα mutations or amplifications (ESMO 2024) - P1 | "Phase 1a data support covalent inhibition of PI3Kα using TOS-358 as a promising therapeutic that can achieve anti-tumor effects at low doses with minimal toxicity. A phase 1b study evaluating the combination of TOS-358 and fulvestrant in HER2- breast cancer pts and TOS-358 monotherapy in bladder cancer pts is planned to initiate in 2H of 2024."

Clinical • P1 data • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • HER-2 • PIK3CA

Totus Medicines Announces Strategic Multi-Target Research Collaboration with Lilly (GlobeNewswire) - "Totus Medicines...announced today it has entered into a multi-target research collaboration with Eli Lilly and Company to discover small molecule drug candidates against undisclosed targets...Under the terms of the agreement, Totus Medicines will use its proprietary OmniDEL platform to generate high-quality covalent compounds against Lilly targets. Subsequently, Lilly and Totus will have options to exclusively pursue preclinical and clinical development and commercialization of compounds identified from the collaboration and receive milestone payments....'This collaboration validates our strategy of using our platform to generate drug candidates for partners as well as our own pipeline, which consists of a covalent PI3Kα inhibitor in Phase 1 and an AKT covalent inhibitor in preclinical development.'"

Licensing / partnership • Oncology • Solid Tumor

A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors (AACR 2023) - P1 | "Enrolment to the study commences in US with European sites planned to open later in 2023. Clinical trial information: NCT05683418."

Clinical • Bladder Cancer • Breast Cancer • Esophageal Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA

TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models (AACR 2023) - "Furthermore, we elucidate that previous reversible PI3Kα inhibitors lead to dramatic hyperglycemia due to their potent inhibition of multiple PI3K isoforms at effective concentrations of the molecules in a cellular setting. This data reveals that highly specific and potent covalent inhibition of PI3Kα leads to dramatically superior efficacy and an improved safety profile."

Preclinical • Oncology • Solid Tumor • PIK3CA

Inhibition of wild-type PI3Kα signaling is required for durable efficacy in PI3Kα mutant cancer cells due to robust re-activation of wild-type PI3Kα signaling (AACR 2023) - "Covalent molecules (namely TOS-358) achieved complete inhibition of pathway signaling in this format. Overall, this reveals the need to achieve sustained inhibition of both PI3Kα mutant and wild type signaling to achieve durable efficacy in PI3Kα mutant tumors."

Clinical • Bladder Cancer • Oncology • PIK3CA

Development and validation of a pharmacodynamic (PD) assay for TOS-358, the first covalent inhibitor of PI3Kα in clinical development (AACR 2023) - "We furthermore utilized this assay to explore the turnover rate of PI3Kα across multiple diverse tumor types, mutations, and tissues. This approach enables highly sensitive target engagement analysis of TOS-358 across multiple formats."

Clinical • PK/PD data • Oncology • Solid Tumor • PIK3CA

Totus Medicines Announces First Patient Dosed in Phase 1 Trial of TOS-358 for the Treatment Of Select Solid Tumors (PRNewswire) - "Totus Medicines...announced today the dosing of the first patient in a Phase 1 clinical trial of TOS-358, the company's first-in-class covalent PI3Kα inhibitor for the treatment of numerous cancers with known PIK3CA mutations....The Phase 1 clinical trial will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TOS-358 as a single agent in 241 trial participants with select solid tumors....This study will be conducted in two parts: a dose finding portion to determine the maximum tolerated dose, and recommended phase 2 dose of TOS-358 administered orally on once a day and twice daily schedules; and a dose expansion portion to evaluate safety and tolerability in tumor-specific cohorts administered TOS-358 at the recommended phase 2 dose and schedule."

Trial status • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • Uterine Cancer

Totus Medicines Announces Presentations at the Upcoming American Association for Cancer Research (AACR) Annual Meeting (PRNewswire) - "Totus Medicines, a clinical stage biotechnology company fueled by its breakthrough Accel™ platform, announced it will be presenting four posters at the American Association for Cancer Research (AACR) Annual Meeting, regarding its lead program, TOS-358, the first highly specific, covalent PI3Kα inhibitor."

Clinical data • P1 data • Preclinical • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

A Study to Evaluate the Safety and Tolerability of TOS-358 in Adults With Select Solid Tumors (clinicaltrials.gov) - P1 | N=241 | Recruiting | Sponsor: Totus Medicines | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • HER-2 • PIK3CA

A Study to Evaluate the Safety and Tolerability of TOS-358 in Adults With Select Solid Tumors (clinicaltrials.gov) - P1 | N=241 | Not yet recruiting | Sponsor: Totus Medicines

New P1 trial • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • HER-2 • PIK3CA

Preclinical characterization of TOS-358, a potent and selective covalent inhibitor of wild-type and mutant PI3Kα with superior anticancer activity (AACR-NCI-EORTC 2022) - "Indeed, in several PDX models, TOS-358 induced tumor regressions while the clinical stage molecules Alpelisib and Inavolisib were unable to generate similar tumor regressions despite pharmacokinetic exposures comparable to, or in excess of, TOS-358. Finally, TOS-358 generated little or no glucose impact in mice and dogs at exposures that produced superior efficacy in these cancer models. Taken together, our in vitro and in vivo data reveal TOS-358 to be a potent, selective covalent inhibitor of PI3Kα with superior anticancer activity to comparator molecules."

Preclinical • Oncology • PIK3CA

Totus Medicines Announces Poster Presentation for TOS-358, the First Highly Selective Covalent Molecule Targeting PI3Kα, at the 34th EORTC-NCI-AACR Symposium in Barcelona (PRNewswire) - "Totus Medicines...announced yesterday the poster presentation for TOS-358 at the 34th EORTC-NCI-AACR Symposium (ENA 2022) held in Barcelona Oct 26-28, 2022. The poster exhibits data from the clinical development candidate TOS-358, the first highly selective covalent molecule targeting PI3Kα, which is the most mutated oncogene in cancer. Totus Medicines is set to start clinical trials of TOS-358 in early 2023."

New P1 trial • Preclinical • Oncology • Solid Tumor