Summary: TLX101 (formerly known as ACD-101) is a groundbreaking small molecule derived from 4-Iodophenylalanine. This radiopharmaceutical is designed for both imaging and therapeutic purposes, utilising different isotopes of iodine: 123I for SPECT imaging, 124I for PET imaging, and 131I for therapy. It specifically targets gliomas, a class of aggressive and often fatal brain tumours. The European Medicines Agency (EMA) granted orphan drug status to 123I-ACD-101 in 2006 for glioma diagnosis, and to 131I-ACD-101 for glioma therapy the same year. The FDA also granted orphan drug status to 131I-ACD-101 in 2011.
With its dual function as a cytostatic molecule and a radio-sensitiser, TLX101 enhances the biological effects of external radiation therapy (XRT). This article provides an overview of TLX101, including its mechanism of action, clinical trial progression, and potential for transforming glioma management.
Introduction to Gliomas
Gliomas represent a heterogeneous group of primary brain tumours originating from glial cells. They account for nearly 30% of all brain tumours and 80% of malignant brain tumours. Glioblastoma multiforme (GBM), classified as a WHO Grade IV glioma, is the most aggressive and common subtype, characterised by poor prognosis and limited treatment options.
Standard therapy for gliomas typically involves a combination of surgery, external radiotherapy (XRT), and chemotherapy. However, recurrence is frequent, and effective treatment options for advanced stages remain scarce. This has necessitated the development of innovative approaches like targeted radiopharmaceuticals such as TLX101.
Overview of TLX101
Chemical Structure and Properties
TLX101 is based on 4-Iodophenylalanine, a modified amino acid with selective uptake by glioma cells. The molecule can be radioactively labelled with iodine isotopes for either diagnostic imaging or therapy:
- 123I-TLX101: SPECT imaging
- 124I-TLX101: PET imaging
- 131I-TLX101: Therapeutic applications
Mechanism of Action
TLX101 exploits the tumour-selective uptake of phenylalanine through the L-type amino acid transporter 1 (LAT-1). LAT-1 is overexpressed in gliomas, facilitating preferential intratumoral accumulation of the radiopharmaceutical. This mechanism allows for effective targeting of tumour cells while sparing healthy tissues.
- Cytostatic Effects: TLX101 inhibits tumour cell proliferation.
- Radio-Sensitising Effects: It enhances the efficacy of external radiotherapy by increasing tumour radiosensitivity.
- Beta Radiation from 131I: The therapeutic isotope emits beta particles, which induce direct DNA damage in tumour cells, leading to apoptosis and tumour volume reduction.
Regulatory Milestones
Orphan Drug Designation
Orphan drug status is granted to therapies addressing rare and serious conditions with unmet medical needs. The following milestones underline the recognition of TLX101’s potential:
- 123I-ACD-101: Granted orphan drug status by the EMA in 2006 for glioma diagnosis.
- 131I-ACD-101: Granted orphan drug status by:
- The EMA in 2006 for glioma therapy.
- The FDA in 2011 for glioma therapy.
This designation facilitates expedited development, regulatory support, and market exclusivity for TLX101.
Clinical Trials of TLX101
Preclinical Studies
Preclinical investigations demonstrated that TLX101 effectively accumulates in glioma tissue across all grades (WHO Grades II–IV), independent of tumour histology. This tumour-selective uptake laid the foundation for its transition to clinical trials.
Phase I Clinical Trials
Both 123I-TLX-101 and 131I-TLX-101 entered Phase I trials to evaluate their safety, tolerability, and dosing in humans. Key outcomes include:
- Sustained tumour volume reduction with 131I-TLX-101.
- Prolonged survival of a glioblastoma patient for 3.5 years following the first treatment, with no further therapeutic options available.
International Multi-Centre Study (2018–2022)
In September 2018, a global multi-centre Phase I/II study was initiated to assess the safety, tolerability, dosing schedule, and preliminary efficacy of 131I-TLX-101 in patients with recurrent glioblastoma multiforme (GBM). This trial also investigated the molecule’s synergistic potential with external radiotherapy (XRT).
The study’s completion, expected by October 2022, will provide critical insights into TLX101’s therapeutic potential and its role in glioblastoma management.
Therapeutic Potential of TLX101
Advantages Over Existing Therapies
- Targeted Delivery: LAT-1-mediated uptake ensures high tumour specificity, minimising systemic toxicity.
- Dual Modality: The radiopharmaceutical offers both diagnostic and therapeutic capabilities.
- Enhanced Radiation Therapy: As a radio-sensitiser, TLX101 complements external radiotherapy, potentially reducing required radiation doses and sparing healthy tissues.
- Activity Across Tumour Grades: TLX101 demonstrates efficacy in both low- and high-grade gliomas.
Survival Outcomes
Preliminary data indicate that 131I-TLX-101 contributes to sustained tumour reduction and improved survival, even in advanced glioblastoma cases with limited treatment options.
Challenges and Future Directions
Challenges
- Tumour Heterogeneity: Variability in LAT-1 expression among patients may influence therapeutic efficacy.
- Radiation Safety: Handling and administration of radioactive isotopes require specialised facilities and protocols.
- Long-Term Toxicity: Comprehensive evaluation of potential long-term adverse effects is essential.
Future Directions
- Combination Therapies: Investigating TLX101 in conjunction with novel immunotherapies and chemotherapies could enhance outcomes.
- Biomarker Development: Identifying biomarkers for LAT-1 expression could enable personalised treatment strategies.
- Expanded Indications: Exploring TLX101 for other LAT-1-expressing tumours may broaden its therapeutic applications.
Conclusion
TLX101 represents a promising advancement in glioma management, combining targeted radiotherapy with imaging capabilities. Its unique mechanism of action, leveraging the LAT-1 transporter, ensures selective accumulation in gliomas, offering hope for patients with limited treatment options. With ongoing clinical trials and regulatory support, TLX101 holds the potential to revolutionise the diagnosis and therapy of gliomas, including the most aggressive forms such as glioblastoma multiforme. As research continues, this innovative radiopharmaceutical may pave the way for more effective and personalised treatments for brain tumours.
You are here: home »