tigilanol tiglate (EBC-46) / Qbiotics - LARVOL DELTA

A Clinical Study to Investigate the Efficacy of Tigilanol Tiglate Directly in Head and Neck Cancer (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: QBiotics Group Limited | N=37 ➔ 20

Enrollment change • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Intratumoural tigilanol tiglate in the multicentre treatment of equine sarcoids and cutaneous melanomas. (PubMed, Equine Vet J) - "The observed therapeutic efficacy of TT supports clinical use as well as early interventions in horses. Successful use necessitates knowledge of the drug's mode of action and management of associated local site responses."

Journal • Cutaneous Melanoma • Melanoma • Oncology • Skin Cancer • Solid Tumor

QB46C-H07: A Clinical Study to Investigate the Efficacy of Intratumoral Tigilanol Tiglate in Soft Tissue Sarcoma (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: QBiotics Group Limited | N=10 ➔ 40 | Trial completion date: Mar 2025 ➔ Feb 2027 | Trial primary completion date: Sep 2024 ➔ Oct 2026

Enrollment change • Trial completion date • Trial primary completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Synthesis and preclinical evaluation of tigilanol tiglate analogs as latency-reversing agents for the eradication of HIV. (PubMed, Sci Adv) - "Enabled by our previously reported scalable synthesis of EBC-46, we report herein the systematic design, synthesis, and evaluation of EBC-46 analogs, including those inaccessible from the natural source and their PKC affinities, ability to translocate PKC, nuclear factor κB activity, and efficacy in reversing HIV latency in Jurkat-Latency cells. Leading analogs show exceptional PKC affinities, isoform selectivities, and functional activities, serving as promising candidates for therapeutic applications."

Journal • Preclinical • Cardiovascular • Human Immunodeficiency Virus • Infectious Disease • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Intratumoural tigilanol tiglate induces immunogenic cell death and a localised immune response in HNSCC [WITHDRAWN] (ESMO-IO 2024) - No abstract available

Immunogenic cell death • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck

Epoxytiglianes induce keratinocyte wound healing responses via classical protein kinase C activation to promote skin re-epithelialization. (PubMed, Biochem Pharmacol) - "The prototype epoxytigliane, EBC-46 (tigilanol tiglate), is a potent anti-cancer agent in clinical development for local treatment of a range of human and animal tumors...PKC-βI/-βII isoform inhibition by enzastaurin (1 μM), significantly inhibited HaCaT proliferation and wound repopulation responses induced by both epoxytiglianes, especially at 1.51-151 nM. PKC-α inhibitor, Ro 31-8220 mesylate (10 nM), exerted lesser inhibitory effects on HaCaT responses...Phospho-PKC (p-PKC) studies confirmed that epoxytiglianes transiently activated classical PKC isoforms (p-PKCα, p-PKC-βI/-βII, p-PKCγ) in a dose- and time-dependent manner. By identifying how epoxytiglianes stimulate classical PKCs to facilitate keratinocyte healing responses and re-epithelialization, these findings support further epoxytigliane development as topical therapeutics for clinical situations involving impaired re-epithelialization, such as non-healing wounds in skin."

Journal • Oncology • CCNB1 • CDKN1A • KRT17 • MMP1 • MMP10 • MMP7 • PRKCB

AN OPEN LABEL PHASE IIA STUDY EVALUATING THE PRELIMINARY EFFICACY OF INTRATUMORAL TIGILANOL TIGLATE TT) IN ADVANCED AND/OR METASTATIC SOFT TISSUE SARCOMA STS, NCT05755113) (CTOS 2024) - P2 | "Intratumoural TT appears safe for patients with STS. Efficacy in ablating injected tumours was observed across numerous histologic types, exceeding the primary endpoint for a promising response. The tolerability and promising response rate warrant further investigation of TT in patients with STS either alone or in combination with other agents."

Clinical • Metastases • P2a data • Angiosarcoma • Fibrosarcoma • Leiomyosarcoma • Oncology • Osteosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Response to tigilanol tiglate in dogs with mast cell tumors. (PubMed, J Vet Intern Med) - "Tigilanol tiglate is an effective local treatment option for mast cell tumors in dogs with a predictable clinical course and response. Because of the unique mode of action and clinical course, client education and careful case selection is necessary before electing tigilanol tiglate for local treatment."

Journal • Oncology

An open label phase IIa study evaluating the preliminary efficacy of intratumoural tigilanol tiglate (TT) in advanced and/or metastatic soft tissue sarcoma (STS) (ESMO 2024) - P2 | "Intratumoural TT appears safe for patients with STS. Efficacy in ablating injected tumours was observed across different histologic types. The primary endpoint for a promising response was met within the first 5 evaluable patients."

Clinical • Metastases • P2a data • Angiosarcoma • Fibrosarcoma • Leiomyosarcoma • Oncology • Osteosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

A Clinical Study to Investigate the Efficacy of Intratumoral Tigilanol Tiglate in Soft Tissue Sarcoma (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: QBiotics Group Limited | Phase classification: P2a ➔ P2

Metastases • Phase classification • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Tigilanol Tiglate-Induced Changes in Secretome Profiles Alter C-Met Phosphorylation and Cell Surface Protein Expression in H357 Head and Neck Cancer Cells. (PubMed, Cells) - "This was accompanied by rapid cleavage of the cellular junction adhesion protein Nectin-1 and the nerve growth factor receptor NGFRp75/TNFR16. These findings, that TT is a novel negative regulator of protumorigenic c-MET and NGFRp75/TNFR16 signalling, as well as regulating Nectin-1-mediated cell adhesion, further contribute to our understanding of the mode of action and efficacy of TT in the treatment of solid tumours."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • MET • NECTIN1 • NGFR • SDC1

Immunogenic oncolysis by tigilanol tiglate. (PubMed, Oncoimmunology) - "A recent study revealed the capacity of this pyroptosis inducer to elicit hallmarks of immunogenic cell death. In addition, intratumoral injection of tigilanol tiglate can sensitize subcutaneous cancers to subsequent immune checkpoint inhibitors targeting CTLA-4 alone or in combination with PD-1."

Journal • Oncology • PD-1

Tigilanol tiglate is an oncolytic small molecule that induces immunogenic cell death and enhances the response of both target and non-injected tumors to immune checkpoint blockade. (PubMed, J Immunother Cancer) - "These data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy."

Checkpoint block • Checkpoint inhibition • Immunogenic cell death • Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CALR • CTLA4 • GSDME • HMGB1

Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents. (PubMed, J Am Chem Soc) - "Fifth, further oxidation to the most densely oxygenated acerifolin A (23) and tigilanol tiglate (24) was realized through organizing a 3D shape of the B-ring. Assessment of the HIV latency-reversing activities of the 12 tiglianes revealed seven tiglianes (14-17 and 22-24) with 20- to 300-fold improved efficacy compared with prostratin (12), a representative latency-reversing agent. Therefore, the robust synthetic routes to a variety of tiglianes with promising activities devised in this study provide opportunities for advancing HIV eradication strategies."

Journal • Human Immunodeficiency Virus • Infectious Disease

QBiotics gains FDA orphan drug designation for cancer treatment (Investing.com) - "QBiotics Group Ltd has achieved a significant regulatory milestone as its pioneering intratumoural oncology asset, tigilanol tiglate, receives Orphan Drug Designation (ODD) from the United States Food and Drug Administration (FDA) for the treatment of soft tissue sarcoma."

Orphan drug • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Orphan Designation: Treatment of Soft Tissue Sarcoma (FDA) - Date Designated: 02/08/2024

Orphan drug • Soft Tissue Sarcoma

Novel Skeletal Rearrangements of the Tigliane Diterpenoid Core. (PubMed, J Nat Prod) - "To investigate the role of the secondary 5-hydroxy group in the activity of the anticancer drug tigilanol tiglate (2b) (Stelfonta), oxidation of this epoxytigliane diterpenoid from the Australian rainforest plant Fontainea picrosperma was attempted...On the other hand, a series of remarkable skeletal rearrangements associated with the presence of a 5-keto group were discovered during its synthesis, including a dismutative ring expansion of ring A and a mechanistically unprecedented dyotropic substituent swap around the C-4/C-10 bond. Taken together, these observations highlight the propensity of the α-hydroxy-β-diketone system to trigger complex skeletal rearrangements and pave the way to new areas of the natural products chemical space."

Journal • Oncology

A PILOT PHASE II STUDY TO EVALUATE THE SMALL MOLECULE TIGILANOL TIGLATE IN PATIENTS WITH ADVANCED SOFT TISSUE SARCOMA: CLINICAL TRIAL IN PROGRESS (CTOS 2023) - P2a | "Not applicable"

Clinical • Metastases • P2 data • Angiosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Tigilanol Tiglate is a small molecule oncolytic that induces immunogenic cell death and promotes immune cell infiltration into human tumors (SITC 2023) - P2a, P2b | "Conclusions These data indicate that TT is an oncolytic small molecule with the potential to ablate target tumours and enhance immunotherapy combinations through promoting immune cell infiltration. TT is currently undergoing Phase II trials in head and neck cancer (NCT05234437) and soft tissue sarcoma (NCT05755113)."

Immune cell • Immunogenic cell death • Head and Neck Cancer • Oncology • Sarcoma • Skin Cancer • Soft Tissue Sarcoma • Solid Tumor • CALR • CD8 • GSDME • HMGB1

Defining in vitro topical antimicrobial and antibiofilm activity of epoxy-tigliane structures against oral pathogens. (PubMed, J Oral Microbiol) - "In vitro antimicrobial activity of EBC structures (EBC-46, EBC-1013 and EBC-147) against Streptococcus mutans, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis in minimum inhibitory concentration, growth curve and permeabilization assays were determined...Furthermore, biofilm disruption assays on titanium discs induced significant biofilm disruption in S. mutans and P. gingivalis (p < 0.05). EBC-1013 is a safe, semi-synthetic, compound, demonstrating clear antimicrobial biofilm disruption potential in peri-implantitis."

Journal • Preclinical • Immune Modulation • Infectious Disease

QBIOTICS TO PRESENT AT SACHS 9TH ANNUAL IMMUNO-ONCOLOGY INNOVATION FORUM AND THE BIO INTERNATIONAL CONVENTION (PRNewswire) - "The presentations will include recent phase I safety and efficacy data with Tigilanol tiglate (TT) in cancer patients and details of two ongoing phase II studies in later stage patients with Head and Neck cancer and Soft Tissue Sarcoma, being treated with TT."

P1 data • P2 data • Head and Neck Cancer • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

A Clinical Study to Investigate the Efficacy of Intratumoral Tigilanol Tiglate in Soft Tissue Sarcoma (clinicaltrials.gov) - P2a | N=10 | Recruiting | Sponsor: QBiotics Group Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

QB46C-H04: A Trial of Intratumoural Tigilanol Tiglate in Adult Participants With Stage IIIB to IV M1c Melanoma (clinicaltrials.gov) - P2b | N=1 | Terminated | Sponsor: QBiotics Group Limited | N=40 ➔ 1 | Trial completion date: Sep 2027 ➔ Jul 2022 | Recruiting ➔ Terminated | Trial primary completion date: Feb 2027 ➔ Jul 2022; Insufficient Patient Recruitment Rates

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Melanoma • Oncology • Solid Tumor

A Trial of Tigilanol Tiglate in Combination With Pembrolizumab in Stage IIIB to IV M1c-melanoma (clinicaltrials.gov) - P1/2 | N=3 | Terminated | Sponsor: QBiotics Group Limited | N=22 ➔ 3 | Trial completion date: Sep 2024 ➔ Jul 2022 | Recruiting ➔ Terminated | Trial primary completion date: Jul 2023 ➔ Jul 2022; Insufficient Patient Recruitment Rates

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Melanoma • Oncology • Solid Tumor • BRAF

Tigilanol tiglate is a naturally occurring small molecule oncolytic that effectively ablates tumors via intratumoural injection and can enhance response to immune checkpoint blockade (SITC 2022) - P1/2, P2b | "Background Tigilanol Tiglate (TT) is a novel small molecule under development for local treatment of solid tumours via intratumoral (I.T.) injection. TT is currently undergoing Phase I/II trials in head and neck cancers (ACTRN12619001407189), soft tissue sarcomas, Stage III melanoma in-transit ( NCT05234437 ) and non-resectable Stage IIIB to IV M1c melanoma (TT/pembrolizumab combination: NCT04834973 ). 5"

Checkpoint inhibition • Head and Neck Cancer • Melanoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CALR • HMGB1