Breakthrough Clinical Results
Myrio Therapeutics announced that the FDA approved its Investigational New Drug (IND) application for PHOX2B PC-CAR T, a chimeric antigen receptor (CAR-T) therapy for neuroblastoma. Developed in collaboration with a leading children's hospital, this therapy targets the PHOX2B protein, a functionally relevant and highly specific protein identified in neuroblastoma cells. The therapy's unique approach, detailed in a Nature publication, involves a binder capable of recognizing the PHOX2B peptide across multiple HLA-allotypes, potentially broadening patient access. A Phase 1 clinical trial is set to begin mid-year 2025, aiming to address the unmet need for effective treatments for high-risk neuroblastoma, which has low response rates and significant toxicities with current options.
Key Highlights
- FDA approves IND application for Myrio's PHOX2B PC-CAR T therapy.
- The therapy targets PHOX2B protein, specific to neuroblastoma cells.
- Unique binder recognizes PHOX2B peptide across multiple HLA-allotypes.
- Phase 1 clinical trial to begin mid-year 2025.
Incidence and Prevalence
Global Neuroblastoma Incidence and Prevalence: Latest Estimates
Several studies utilizing the Global Burden of Disease (GBD) database provide insights into the incidence and prevalence of neuroblastoma. It's crucial to note that neuroblastoma primarily affects young children, and thus, prevalence in older populations is minimal. The available data focuses on incidence trends and overall disease burden rather than point prevalence estimates.
2021 Estimates:
- Incidence: One study reports a global incidence of 5,560 cases (95% UI, 3734.21-7560.03) in children aged 0-14 in 2021. This translates to an incidence rate of 0.28 (95% UI, 0.19-0.38) per 100,000 individuals. Another study focusing on all ages reports increasing incidence from 1990 to 2021, with a higher burden in low SDI regions.
Trends and Projections:
- Increasing Incidence: Multiple studies concur that neuroblastoma incidence has generally increased globally from 1990 to 2021, particularly in low- and middle-SDI regions (South Asia, sub-Saharan Africa, Central Asia). This increase is attributed to factors such as improved diagnostics and reporting. High-SDI regions (North America, Western Europe) show a decreasing or stable trend due to advanced medical care and earlier diagnosis.
- Projected Increase: A Bayesian Age-Period-Cohort (BAPC) model predicts a continued increase in global incidence, mortality, and DALYs related to neuroblastoma until 2035.
Regional and Demographic Variations:
- SDI Disparities: The burden of neuroblastoma is disproportionately high in low-SDI regions with limited medical resources. This highlights the urgent need for targeted interventions and resource allocation in these areas.
- Age: Children under 5 years of age are primarily affected, with incidence rates peaking in children aged 2-4 years.
- Sex: Incidence is slightly higher in males than in females.
Data Limitations:
It's important to acknowledge that the GBD data relies on estimations and modeling, and there might be variations in data quality across different countries and regions. Precise prevalence data for neuroblastoma is generally not reported due to the disease's nature and focus on incidence and mortality in pediatric populations. Future research should focus on refining epidemiological data collection and improving early diagnosis and treatment strategies, especially in resource-constrained settings.
Mechanism of Action
The provided text discusses drugs active against neuroblastoma cell lines in vitro, including some FDA-approved drugs not currently used to treat neuroblastoma. However, it does not detail the three most common mechanisms of action among these drugs.
The text mentions a "wide spectrum of diverse mechanisms" including:
- Mitotic inhibition: Drugs interfering with cell division.
- Topoisomerase inhibition: Drugs targeting enzymes essential for DNA replication.
- Targeting various biological pathways: This is a broad category encompassing drugs affecting specific signaling pathways within cells.
- Unknown mechanisms: For some active compounds, the precise mechanism of action against neuroblastoma remains unknown.
The passage also notes that the majority of these active compounds induced caspase 3/7, suggesting involvement in apoptosis (programmed cell death).
One specific example is provided: Cucurbitacin I inhibits neuroblastoma cell growth by inhibiting the STAT3 pathway, a signaling pathway involved in cell growth and survival.
It is crucial to understand that in vitro activity does not guarantee clinical efficacy. Further research, including in vivo studies and clinical trials, is necessary to determine the true potential of these drugs for treating neuroblastoma and to establish their most common mechanisms of action in a clinical setting.
Drug used in other indications
The provided text focuses on the use of PHOX2B as a diagnostic marker and a target for CAR T-cell therapy in neuroblastoma. It does not mention any clinical trials investigating PHOX2B PC-CAR T for indications other than neuroblastoma.
While the text discusses the role of PHOX2B in other conditions like Hirschsprung disease and congenital central hypoventilation syndrome, it doesn't mention using PHOX2B PC-CAR T-cell therapy for these conditions. The focus remains on neuroblastoma, highlighting PHOX2B as a promising target due to its specificity and role in tumor development. The text also mentions the potential of peptide-centric CARs to target intracellular oncoproteins and overcome HLA restrictions, broadening the applicability of this therapy.
Therefore, based on the provided information, no clinical trials of PHOX2B PC-CAR T are mentioned for indications other than neuroblastoma.