TLY012 / D&D Pharmatech - LARVOL DELTA

DND Pharmatech Completes KRW 226.5 Billion Convertible Bond Payment, Reflecting Expectations for DD01 (The Asia Business Daily) - "The market views this fundraising as reflecting expectations for the results of the Phase 2 clinical trial of DD01, the company’s lead pipeline for MASH (Metabolic Dysfunction-Associated Steatohepatitis) treatment, as well as the potential for future technology transfer...The company plans to use the secured funds to expand clinical trials and R&D for its follow-up pipeline, including the fibrosis treatment candidate TLY012. TLY012 aims to enter clinical trials as early as the beginning of next year."

Financing • New trial • Fibrosis • Metabolic Dysfunction-Associated Steatohepatitis

Reduced severity of radiation esophagitis in mice following 2 weeks of ONC212 treatment [WITHDRAWN] (AACR 2025) - "Our results provide a strategy with an orally bioavailable drug for treatment of severe esophagitis that is caused by therapeutic radiotherapy involving the esophagus. Additional directions for future research include studies of other TRAIL pathway agonists such as TRAIL itself, TLY012, or other imipridones including ONC201 or ONC206 effects on severity of radiation esophagitis."

Preclinical • Breast Cancer • Esophageal Cancer • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • CCL2 • CCL22 • CCL3 • CXCL12 • EGF • IGF1 • IL16

Post-exposure suppression of radiation pneumonitis suggests non-redundant independent effects of TGF-beta and TRAIL/DR5 (AACR 2024) - "While some rescue from radiation pneumonitis was observed via GLPG0187, it was to a lesser extent compared to treatment of WT and TRAIL-/- C57Bl/6 mice with TLY012. Future directions include investigating the synergistic effects between TLY012 and GLPG0187 in suppressing radiation pneumonitis and decreasing fibrotic response to radiation."

Oncology • Thoracic Cancer • TGFB1

PIM inhibition increases membrane expression of TNFRSF10B(DR5) and combination with recombinant human TRAIL synergizes to reduce renal cell carcinoma cell viability (AACR 2025) - "To investigate synergism between PIM inhibitors and recombinant human TRAIL (rhTRAIL), RCC cell lines were treated with increasing concentrations of SGI-1776 or TP-3654 and rhTRAIL (TLY012) for 24 hours and assessed for viability via Cell Titer Glo assay. These results reveal novel therapeutic strategies for the treatment of RCC, highlighting PIM kinases as targets to potentiate TRAIL induced apoptosis. Current studies are ongoing to understand the mechanism of PIM kinase involvement in DR5 regulation and sensitivity to TRAIL in RCC."

Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Oncology • Renal Cell Carcinoma • Solid Tumor • PIM1 • TNFRSF10B

D&D Pharmatech pursues direct perpetual CB issuance without underwriter (Chosun Biz) - "D&D Pharmatech seeks private investors for 80 billion won perpetual CBs after underwriting talks fail...D&D Pharmatech chose this perpetual CB issuance to raise funds for new drug development. The company is currently conducting a phase 2 clinical trial in the U.S. for DD01, a metabolic dysfunction-associated steatohepatitis (MASH) treatment that is also known as an obesity drug, and the need for funding has grown ahead of plans to advance clinical development of the anti-fibrosis treatment TLY012."

Financing • Fibrosis • Metabolic Dysfunction-Associated Steatohepatitis

D&D Pharmatech's 'TLY012', "Confirmed Possibility of Alleviating Side Effects of Radiation Cancer Treatment" (HIT News) - "D&D Pharmatech announced on the 28th that its currently under development fibrosis treatment candidate 'TLY012' has shown the effect of alleviating chronic side effects such as pneumonia and fibrosis caused by radiation therapy...The study was conducted jointly with the D&D Pharmatech research team, and the results were published in the Journal of Clinical Investigation (Impact factor 13.3 as of 2023), an academic journal of the American Society for Clinical Investigation....The company explained that in preclinical studies, TLY012 was shown to reduce pneumonia, increased alveolar wall thickness, and decreased oxygen saturation that occur after radiation exposure. The company also emphasized that it was confirmed to have the effect of protecting against long-term lung damage after radiation exposure, as well as reducing dermatitis, esophagitis, and fibrosis, and increasing survival rates."

Preclinical • Pancreatic Ductal Adenocarcinoma

TRAIL receptor agonist TLY012 in combination with PD-1 inhibition promotes tumor regression in an immune-competent mouse model of pancreatic ductal adenocarcinoma. (PubMed, Am J Cancer Res) - "In summary, the combination of anti-PD-1 and TLY012 prevented the growth of PDAC in an immunocompetent mouse model while increasing tumor-infiltrating CD8+ T cells, decreasing circulating T-regulatory cells and altering plasma cytokine expression of CCL5, interferon-gamma, and IL-3 to promote proinflammatory, antitumor effects. Combining TLY012 and anti-mouse PD-1 modifies immune cell and cytokine levels to induce a more proinflammatory immune environment that contributes to decreased PDAC tumor growth."

IO biomarker • Journal • Preclinical • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pancreatitis • Scleroderma • Systemic Sclerosis • CCL5 • CD8 • IFNG

TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury. (PubMed, J Clin Invest) - "We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications."

Journal • Preclinical • Breast Cancer • Dermatitis • Dermatology • Fibrosis • Gastrointestinal Disorder • Immunology • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CCL2 • CCL22 • TLR7

[PREPRINT] TRAIL receptor agonist TLY012 in combination with PD-1 inhibition promotes tumor regression in an immune-competent mouse model of pancreatic ductal adenocarcinoma (bioRxiv) - "B-cell activating factor (BAFF), which promotes PDAC tumors, decreased to 44% of control mice with dual treatment at 7 days and remained decreased at 3 months. Long-term dual treatment showed the highest levels of proinflammatory cytokines interferon gamma (average 5.6 times control level, p=0.046), CCL5 (average 14.1 times control level, p=0.048), and interleukin-3 (IL-3, average 71.1 times control level, p=0.0053). Flow cytometry showed trends toward decreased circulating regulatory T cells, increased NK cells, and a higher proportion of CD8+ T cells within tumors in dual treatment group."

Preclinical • Preprint • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

D&D Pharmatech's fibro disease drug candidate wins patent in Australia (Korea Biomedical Review) - "D&D Pharmatech said Friday that it has completed registering new material and application patent in Australia for TLY012, a drug candidate in development for treating fibrotic diseases, such as liver cirrhosis, systemic sclerosis, and chronic pancreatitis....A company official also said, 'The new substance/use patents expire in 2040 and beyond, allowing D$D Pharmatech to maintain its proprietary technology for a longer period and strengthening its position in the global market through continued R&D and commercialization.'"

Patent • Fibrosis • Metabolic Disorders • Pancreatitis • Systemic Sclerosis

ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma. (PubMed, Am J Cancer Res) - "Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials."

Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • ATF4 • CASP3 • CASP8 • CFLAR • HER-2 • KRAS • MLH1 • PARP1 • PIK3CA • TP53 • XIAP

Therapeutic targeting of TRAIL death receptors. (PubMed, Biochem Soc Trans) - "In this review, we summarize the successes and shortcomings of first- and second-generation TRAIL pathway-based therapies, concluding with an overview of the discovery and clinical introduction of ONC201, a compound with a unique mechanism of action that represents a new generation of TRAIL pathway-based approaches. We discuss preclinical and clinical findings in different tumor types and provide a unique perspective on translational directions of the field."

Journal • Oncology

Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo. (PubMed, Cancer Biol Ther) - "Taken together, the preclinical efficacy of ONC201 and TLY012 represents a novel therapeutic option for further testing in pancreatic cancer patients. This combination showed marked efficacy in tumor cells that are both sensitive and resistant to the pro-apoptotic effects of ONC201, providing rationale to further investigate the combination of ONC201 plus TLY012 in patients with pancreatic cancer."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ATF4 • BCL2L1 • BIRC5 • CASP3 • CFLAR • TNFA • XIAP

"Congrats @AakashVJhaveri on published article: Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo #eldeirylab ⁦@BrownUCancer⁩ ⁦@BrownMedicine⁩ https://t.co/2xJMo4T1Iw" (,@weldeiry)

Preclinical • Oncology

D&D Pharmatech acquires US patent for treatment of systemic sclerosis and chronic pancreatitis [Google translation] (Medipana) - "D&D Pharmatech recently received a patent for use of 'Death Receptor Agonist for the alleviation of systemic sclerosis' and a composition for 'Death receptor agonist for the treatment of chronic pancreatitis and pain' It was announced that it had been decided to register a use patent...It is expected to further strengthen the patent portfolio of TLY012."

Patent • Systemic Sclerosis

Theraly Fibrosis granted US Orphan Drug Designation for TLY012 for systemic sclerosis (Businesswire) - "Theraly Fibrosis...today announced that the US Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to TLY012 for the treatment of systemic sclerosis."

Orphan drug • Immunology • Systemic Sclerosis

Theraly Fibrosis granted US Orphan Drug Designation for TLY012 for chronic pancreatitis (Businesswire) - "Theraly Fibrosis...today announced that the US Food and Drug Administration has granted Orphan Drug Designation (ODD) to TLY012 for the treatment of chronic pancreatitis. The company plans to initiate a phase 1/2a clinical trial in 2020....Clinical trials evaluating TLY012 for chronic pancreatitis and other fibrotic diseases are expected to begin in 2020."

New trial • Orphan drug

TLY012 fares well in mouse model as potential treatment for scleroderma (Scleroderma News) - "TLY012, a lab-made equivalent of a natural protein called TRAIL, can reverse skin fibrosis in mice with scleroderma by blocking important cells involved in the underlying mechanism of skin scarring, a research study found....Their experiments showed that myofibroblasts of SSc patients are more sensitive to TLY012 because they express higher levels of DRs compared with healthy skin cells. Thus, using TLY012 was found to prevent the formation of too many of these cells, which may provide a viable therapeutic approach for scleroderma."

Preclinical