Last update 19 Jun 2024
TransCon TLR7/8 Agonist(Ascendis Pharma)
Last update 19 Jun 2024
Overview
Basic Info
Drug Type Small molecule drug |
Synonyms- |
Target |
Mechanism TLR7 agonists(Toll like receptor 7 agonists), TLR8 agonists(Toll like receptor 8 agonists) |
Therapeutic Areas |
Active Indication |
Inactive Indication |
Originator Organization |
Active Organization |
Inactive Organization |
Drug Highest PhasePhase 2 |
First Approval Date- |
Regulation- |
Related
3
Clinical Trials associated with TransCon TLR7/8 Agonist(Ascendis Pharma)BelieveIT-201: Phase 2, Randomized Open-labeled Trial of TransCon (TC) TLR7/8 Agonist in Combination With Pembrolizumab or With TC IL-2 β/γ, or Pembrolizumab Alone as Neoadjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma
The purpose of this trial is to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, TransCon IL-2 β/γ, and pembrolizumab given prior to curative intent surgery in treatment of participants with newly diagnosed Stage III/IVA resectable locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). After surgery, participants will receive local standard-of-care treatment and will be followed for safety, efficacy, and survival for up to 2 years.
This trial contains a safety run-in to evaluate the safety and tolerability of the two treatment arms: Arm A (TransCon TLR7/8 Agonist plus pembrolizumab) and Arm B (TransCon TLR7/8 Agonist plus TransCon IL-2 β/γ). The safety run-in will be followed by the randomized Phase 2, open-label part of the trial comparing the safety, efficacy and survival of treatment Arm A or Arm B compared to treatment Arm C (pembrolizumab monotherapy).
This trial contains a safety run-in to evaluate the safety and tolerability of the two treatment arms: Arm A (TransCon TLR7/8 Agonist plus pembrolizumab) and Arm B (TransCon TLR7/8 Agonist plus TransCon IL-2 β/γ). The safety run-in will be followed by the randomized Phase 2, open-label part of the trial comparing the safety, efficacy and survival of treatment Arm A or Arm B compared to treatment Arm C (pembrolizumab monotherapy).
Start Date29 Sep 2023 |
Sponsor / Collaborator |
IL Believe: A Phase 1/2, Open-label, Dose Escalation and Dose Expansion Study to Investigate the Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab, Standard of Care Chemotherapy, or TransCon TLR7/8 Agonist, or in Combination With Pembrolizumab and Standard of Care Chemotherapy, in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies
TransCon IL-2 β/γ is an investigational drug being developed for treatment of locally advanced or metastatic solid tumors. This is a first-in-human, open-label, Phase 1/2, dose escalation and dose expansion study of TransCon IL-2 β/γ as monotherapy or in combination therapy in adult participants with advanced or metastatic solid tumors. Given the unique PK profile enabled by the TransCon technology, TransCon IL-2 β/γ presents the opportunity to enhance the therapeutic index of current IL-2 therapy.
Start Date11 Jan 2022 |
Sponsor / Collaborator |
Phase 1/2, Open-label, Dose Escalation and Dose Expansion Study of TransCon TLR7/8 Agonist Alone or in Combination With Pembrolizumab in Participants With Locally Advanced or Metastatic Solid Tumor Malignancies
TransCon TLR7/8 Agonist is an investigational drug being developed for treatment of locally advanced or metastatic solid tumors. This Phase 1/2 study will evaluate TransCon TLR7/8 Agonist as monotherapy or in combination with pembrolizumab in dose escalation and dose expansion. Participants will receive intratumoral (IT) injection of TransCon TLR7/8 Agonist every cycle. The primary objectives are to evaluate safety and tolerability, and define the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab.
Start Date18 Mar 2021 |
Sponsor / Collaborator |
100 Clinical Results associated with TransCon TLR7/8 Agonist(Ascendis Pharma)
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100 Translational Medicine associated with TransCon TLR7/8 Agonist(Ascendis Pharma)
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100 Patents (Medical) associated with TransCon TLR7/8 Agonist(Ascendis Pharma)
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191
Literatures (Medical) associated with TransCon TLR7/8 Agonist(Ascendis Pharma)01 Apr 2024·Journal of colloid and interface science
In vivo visualization of tumor-associated macrophages re-education by photoacoustic/fluorescence dual-modal imaging with a metal-organic frames-based caspase-1 nanoreporter
Article
Author: Nie, Liming ; Fan, Zhijin ; Sun, Tong ; Zeng, Fanchu ; Huang, Guojia ; Jiang, Xiaoxiao ; Liang, Changhong
Tumor-associated macrophages (TAMs) are vital in the tumor microenvironment, contributing to immunosuppression and therapy tolerance. Despite their importance, the precise re-education of TAMs in vivo continues to present a formidable challenge. Moreover, the lack of real-time and efficient methods to comprehend the spatiotemporal kinetics of TAMs repolarization remains a significant hurdle, severely hampering the accurate assessment of treatment efficacy and prognosis. Herein, we designed a metal-organic frameworks (MOFs) based Caspase-1 nanoreporter (MCNR) that can deliver a TLR7/8 agonist to the TAMs and track time-sensitive Caspase-1 activity as a direct method to monitor the initiation of immune reprogramming. This nanosystem exhibits excellent TAMs targeting ability, enhanced tumor accumulation, and stimuli-responsive behavior. By inducing the reprogramming of TAMs, they were able to enhance T-cell infiltration in tumor tissue, resulting in inhibited tumor growth and improved survival in mice model. Moreover, MCNR also serves as an activatable photoacoustic and fluorescent dual-mode imaging agent through Caspase-1-mediated specific enzyme digestion. This feature enables non-invasive and real-time antitumor immune activation monitoring. Overall, our findings indicate that MCNR has the potential to be a valuable tool for tumor immune microenvironment remodeling and noninvasive quantitative detection and real-time monitoring of TAMs repolarization to immunotherapy in the early stage.
01 Mar 2024·Acta biomaterialia
Nanoparticle-integrated dissolving microneedles for the co-delivery of R848/aPD-1 to synergistically reverse the immunosuppressive microenvironment of triple-negative breast cancer
Article
Author: Wang, Jiachen ; Huang, Sicong ; Xiao, Zecong ; Wen, Ting ; Wei, Huiye ; Li, Bo ; Shuai, Xintao
Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. STATEMENT OF SIGNIFICANCE: The limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.
31 Dec 2023·Oncoimmunology
B cells require licensing by dendritic cells to serve as primary antigen-presenting cells for plasmid DNA
Article
Author: Rastogi, Ichwaku ; McNeel, Douglas G
DNA vaccines have been an attractive approach for treating cancer patients, however have demonstrated modest immunogenicity in human clinical trials. Dendritic cells (DCs) are known to cross-present DNA-encoded antigens expressed in bystander cells. However, we have previously reported that B cells, and not DCs, serve as primary antigen-presenting cells (APCs) following passive uptake of plasmid DNA. Here we sought to understand the requirements for B cells to present DNA-encoded antigens, to ultimately increase the immunogenicity of plasmid DNA vaccines. Using ovalbumin-specific OT-1 CD8+ T cells and isolated APC populations, we demonstrated that following passive uptake of plasmid DNA, B cells but not DC, can translate the encoded antigen. However, CD8 T cells were only activated by B cells when they were co-cultured with DCs. We found that a cell-cell contact is required between B cells and DCs. Using MHCI KO and re-purification studies, we demonstrated that B cells were the primary APCs and DCs serve to license this function. We further identified that the gene expression profiles of B cells that have been licensed by DCs, compared to the B cells that have not, are vastly different and have signatures similar to B cells activated with a TLR7/8 agonist. Our data demonstrate that B cells transcribe and translate antigens encoded by plasmid DNA following passive uptake, however require licensing by live DC to present antigen to CD8 T cells. Further study of the role of B cells as APCs will be important to improve the immunological efficacy of DNA vaccines.
25
News (Medical) associated with TransCon TLR7/8 Agonist(Ascendis Pharma)03 Jun 2024
- 40% of efficacy-evaluable patients (2 out of 5) in the initial cohort of patients with anti-PD-1 refractory melanoma treated with TransCon IL-2 β/γ in combination with TransCon TLR7/8 Agonist exhibited confirmed clinical responses with no new safety signals
- 45% of efficacy-evaluable patients (5 out of 11) whose disease progressed on check-point inhibitors exhibited confirmed clinical responses when treated with TransCon IL-2 β/γ as monotherapy or in combination treatment
COPENHAGEN, Denmark, June 03, 2024 (GLOBE NEWSWIRE) -- Ascendis Pharma, Inc. (Nasdaq: ASND) reported new and updated results from its ongoing Phase 1/2 IL-Believe Trial of TransCon IL-2 β⁄γ in a poster presentation at ASCO 2024, the annual meeting of the American Society of Clinical Oncology being held in Chicago May 31–June 4, 2024. Data included the first presentation of Phase 2 dose expansion Cohort 4 (TransCon IL-2 β⁄γ in combination with TransCon TLR7/8 Agonist) in post anti-PD-1 melanoma and new analyses of patients from dose escalation cohorts with prior disease progression on checkpoint inhibitors, along with biomarker studies correlating cytotoxic immune cell expansion and clinical benefit.
As of the April 16, 2024 data cutoff, confirmed clinical responses were observed in 40% (two out of five) of efficacy-evaluable patients from Cohort 4, suggesting potential synergy of Ascendis Pharma’s two novel immunotherapy agents.
Of efficacy-evaluable patients with prior disease progression on checkpoint inhibitors to date in the IL-Believe Trial, confirmed clinical responses (per RECIST v1.1) were observed in 45% (five out of eleven) administered TransCon IL-2 β/γ doses ≥80 μg/kg every 3 weeks, suggesting clinical benefit in treatment-resistant settings.
Monotherapy (n=4): 1 confirmed partial response (PR) in colorectal cancer
Combination with pembrolizumab (n=2): 1 confirmed complete response and 1 confirmed PR in small-cell lung cancer
Combination with TransCon TLR7/8 Agonist (n=5): 2 confirmed PRs in melanoma
Biomarker analysis demonstrated comparable, cytotoxic immune expansion between TransCon IL-2 β/γ monotherapy and combination therapy with pembrolizumab, indicating that administration of TransCon IL-2 β⁄γ expands cytotoxic lymphocytes and elevates levels of cytokines and chemokines in the blood without the corresponding expansion of Tregs or eosinophils (markers of toxicity). A statistically significant correlation of clinical benefit with both CD8+ T cell expansion and activation was observed, directly linking this pharmacodynamic effect to clinical activity.
In this trial, TransCon IL-2 β⁄γ alone or in combination with pembrolizumab or TransCon TLR7/8 Agonist was generally well tolerated with no new safety signals.
“We are very encouraged by the clinical response and safety pro TransCon IL-2 β⁄γ and are pleased to see it working as designed to recruit and amplify the body’s immune response with sustained immune activation without a corresponding increase in markers of toxicity,” said Stina Singel, M.D., Ph.D., Ascendis Pharma’s Executive Vice President and Head of Clinical Development, Oncology. “These new data in a heavily pre-treated population who progressed on or did not benefit from prior checkpoint inhibitors support TransCon IL-2 β⁄γ as the first biased IL-2 cytokine therapy to show not only monotherapy activity in a convenient outpatient setting every 3 weeks but also a direct correlation between clinical benefit and expansion of CD8+ T cells. We look forward to additional data readouts expected later this year from larger, indication-specific cohorts.”
TransCon IL-2 β⁄γ is an investigational long-acting prodrug with sustained release of an IL-2Rβ⁄γ-selective analog (IL-2 β⁄γ), designed to address the known limitations of interleukin-2 (IL-2) cancer immunotherapy through prolonged activation of IL-2Rβ⁄γ with low Cmax. The Phase 1/2 IL-Believe Trial is investigating the safety and tolerability of TransCon IL-2 β⁄γ alone or in combination with the checkpoint inhibitor pembrolizumab and/or chemotherapy or TransCon TLR7/8 Agonist in participants with locally advanced or metastatic solid tumors. The recommended Phase 2 dose (RP2D) for TransCon IL-2 β⁄γ in the IL-Believe trial is 120 µg/kg administered intravenously every three weeks in an outpatient setting in both the monotherapy and combination-therapy arms.
About Ascendis Pharma A/S
Ascendis Pharma is applying its innovative TransCon technology platform to build a leading, fully integrated biopharma company focused on making a meaningful difference in patients’ lives. Guided by its core values of Patients, Science, and Passion, Ascendis uses its TransCon technologies to create new and potentially best-in-class therapies. Ascendis is headquartered in Copenhagen, Denmark and has additional facilities in Europe and the United States. Please visit ascendispharma.com to learn more.
Forward-Looking Statements
This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, included in this press release regarding Ascendis’ future operations, plans and objectives of management are forward-looking statements. Examples of such statements include, but are not limited to, statements relating to (i) the potential synergy of TransCon IL-2 β⁄γ and TransCon TLR7/8 Agonist; (ii) the timing of data from indication-specific cohorts for TransCon IL-2 β⁄γ; (iii) the ability of TransCon IL-2 β⁄γ to address the known limitations of interleukin-2 (IL-2) cancer immunotherapy through prolonged activation of IL-2Rβ⁄γ; (iv) Ascendis’ ability to apply its TransCon technology platform to build a leading, fully integrated biopharma company; and (v) Ascendis’ use of its TransCon technologies to create new and potentially best-in-class therapies. Ascendis may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions, expectations and projections disclosed in the forward-looking statements. Various important factors could cause actual results or events to differ materially from the forward-looking statements that Ascendis makes, including the following: dependence on third party manufacturers, distributors and service providers for Ascendis’ products and product candidates; unforeseen safety or efficacy results in Ascendis’ development programs or on-market products; unforeseen expenses related to commercialization of any approved Ascendis products; unforeseen expenses related to Ascendis’ development programs; unforeseen selling, general and administrative expenses, other research and development expenses and Ascendis’ business generally; delays in the development of its programs related to manufacturing, regulatory requirements, speed of patient recruitment or other unforeseen delays; Ascendis’ ability to obtain additional funding, if needed, to support its business activities; the impact of international economic, political, legal, compliance, social and business factors. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to Ascendis’ business in general, see Ascendis’ Annual Report on Form 20-F filed with the U.S. Securities and Exchange Commission (SEC) on February 7, 2024 and Ascendis’ other future reports filed with, or submitted to, the SEC. Forward-looking statements do not reflect the potential impact of any future licensing, collaborations, acquisitions, mergers, dispositions, joint ventures, or investments that Ascendis may enter into or make. Ascendis does not assume any obligation to update any forward-looking statements, except as required by law.
Ascendis, Ascendis Pharma, the Ascendis Pharma logo, the company logo, and TransCon are trademarks owned by the Ascendis Pharma group. © June 2024 Ascendis Pharma A/S.
Investor Contacts:
Media Contact:
Tim Lee
Melinda Baker
Ascendis Pharma
Ascendis Pharma
+1 (650) 374-6343
+1 (650) 709-8875
tle@ascendispharma.com
media@ascendispharma.com
ir@ascendispharma.com
Patti Bank
ICR Westwicke
+1 (415) 513-1284
patti.bank@westwicke.com
Clinical ResultASCOPhase 2ImmunotherapyPhase 1
15 May 2024
Bolt Biotherapeutics is reshuffling to cut costs and extend its cash runway to the second half of 2026.
The California biotech
said
Tuesday afternoon that it is dropping its lead oncology asset, as well as staging an executive team revamp and slashing its employee count in half.
Bolt will cease development of an immune-stimulating antibody conjugate (ISAC), dubbed trastuzumab imbotolimod or BDC-1001, after the company found it was unlikely to meet a predefined success criteria. The candidate was in a Phase 1/2 trial in solid tumors, but had
lackluster results
in 2021. BDC-1001 comprises a HER2-targeting biosimilar of Herceptin conjugated with a TLR7/8 agonist.
ADCClinical ResultPhase 1
15 May 2024
Bolt Biotherapeutics announced it is slashing its workforce by about 50% and terminating development of its lead cancer drug trastuzumab imbotolimod (BDC-1001) after determining the programme would not meet predefined success criteria. The changes also include a leadership shake-up, with CEO Randall Schatzman and chief medical officer Edith Perez being moved to advisory roles, while chief financial officer Willie Quinn now steps in to lead the company.The decision to halt the Boltbody immune-stimulating antibody conjugate (ISAC) programme follows a strategic review by Bolt. Trastuzumab imbotolimod, a HER2-targeting biosimilar of Herceptin (trastuzumab) conjugated with a proprietary TLR7/8 agonist, was being evaluated as a single agent or together with Bristol Myers Squibb's Opdivo (nivolumab) in a Phase I/II study of patients with HER2-positive solid tumours, including breast, colorectal, endometrial and gastroesophageal cancers.Data from a Phase I study presented at last year's European Society for Medical Oncology (ESMO) meeting showed a response rate of 29% with trastuzumab imbotolimod at the proposed Phase II dose. One patient with salivary gland cancer achieved a complete response in the monotherapy arm, while three partial responses were observed, including one in the monotherapy arm for biliary tract cancer and two in the combination arm for colorectal and ovarian cancer.With trastuzumab imbotolimod sidelined, Bolt plans to shift resources to its next-generation ISAC pipeline, including BDC-3042, a Dectin-2 agonist antibody currently in Phase I testing across multiple solid tumours. The company also aims to deliver clinical data for BDC-4182, a next-gen ISAC targeting Claudin 18.2 that's under development in gastric and pancreatic cancers.Bolt expects the moves to extend its cash runway into the second half of 2026, which will allow it to fund its way through those two goals for BDC-3042 and BDC-4182.Meanwhile, other executive changes include Grant Yonehiro being promoted to chief operating officer, while other promotions include Dawn Colburn becoming senior vice president of clinical development and Michael Alonso named as senior vice president of research.
Phase 1Executive ChangeClinical ResultPhase 2
100 Deals associated with TransCon TLR7/8 Agonist(Ascendis Pharma)
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R&D Status
10 top R&D records. to view more data
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| Indication | Highest Phase | Country/Location | Organization | Date |
|---|---|---|---|---|
| Locally Advanced Head and Neck Squamous Cell Carcinoma | Phase 2 | - | 08 Aug 2023 | |
| Advanced Malignant Solid Neoplasm | Phase 2 | US | 18 Mar 2021 | |
| Advanced Malignant Solid Neoplasm | Phase 2 | AU | 18 Mar 2021 |
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Clinical Result
Clinical Result
Indication
Phase
Evaluation
View All Results
| Study | Phase | Population | Analyzed Enrollment | Group | Results | Evaluation | Publication Date |
|---|
Phase 1/2 | Solid tumor absolute lymphocyte counts (ALC) | cytotoxic lymphocytes (CLs) | soluble CD25 ... View more | - | TransCon IL-2 β/γ alone | sfaucqhyrc(kujvugtkgg) = One Dose Limiting Toxicity of G3 Cytokine Release Syndrome was reported at 160 µg/kg uttzrgfdku (cexyytvpdk ) | Positive | 24 May 2024 | |
TransCon IL-2 β/γ + pembrolizumab |
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