Biomarker projects

Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949

Stalder, A.K., et al., Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949. Br J Clin Pharmacol, 2017. 83(3): p. 476–486 https://doi.org/10.1111/bcp.13149.

ACT-389949, a first-in-class FPR2/ALX agonist, was evaluated in Phase I trials for its safety, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy subjects. The drug demonstrated a favorable safety profile with no severe adverse events, though transient decreases in white blood cells (neutrophils/monocytes) were observed 1–2 hours post-dose. PK analysis revealed a mean terminal half-life of ~29 hours and dose-dependent accumulation, supporting less-than-proportional exposure increases at higher doses.

Biomarker studies highlighted target engagement via FPR2/ALX receptor internalization in monocytes/neutrophils, which was dose-dependent and long-lasting (≥20 mg). However, cytokine profiling showed only a transient pro-inflammatory response (e.g., TNF-α, IL-6 spikes) after the first dose, with no sustained effect upon repeated dosing. A lipopolysaccharide (LPS) challenge model at steady state revealed no reduction in neutrophil recruitment, suggesting receptor desensitization.

Key findings:

1. Mechanistic validation: Receptor internalization confirmed FPR2/ALX engagement.

2. Transient efficacy: Initial cytokine activation was not maintained, likely due to rapid desensitization.

3. Clinical limitations: Despite target engagement, the lack of durable anti-inflammatory effects in challenge models questions therapeutic potential.

These biomarker-driven insights underscore the importance of early-phase mechanistic studies to identify pitfalls like desensitization. While ACT-389949 was safe, its inability to sustain anti-inflammatory activity highlights challenges in developing FPR2/ALX agonists for chronic inflammatory diseases.

Serotonin biosynthesis as a predictive marker of serotonin pharmacodynamics and disease induced dysregulation

Welford, R.W.D., et al., Serotonin biosynthesis as a predictive marker of serotonin pharmacodynamics and disease-induced dysregulation. Scientific Reports, 2016. 6(April): p. 1–10 https://doi.org/10.1038/srep30059.

This study by Welford et al. (2016) introduces a novel, sensitive method for measuring serotonin (5-HT) biosynthesis in vivo, using stable isotope-labeled tryptophan (h-Trp) and mass spectrometry. Serotonin, synthesized from dietary tryptophan, plays critical roles in vascular, gastrointestinal, and immune functions, and its dysregulation is implicated in diseases such as lung fibrosis, carcinoid syndrome, and obesity.

Key Findings:

• Innovative Biomarker Approach: By administering h-Trp to rats and tracking its conversion to labeled serotonin (h-5-HT), researchers could directly measure new serotonin synthesis in blood and tissues, providing a rapid and accurate pharmacodynamic readout.

• Pharmacological Validation: The method robustly quantified the inhibition of serotonin synthesis by known tryptophan hydroxylase (TPH) inhibitors (L-para-chlorophenylalanine and telotristat etiprate) within hours, allowing for efficient in vivo screening of potential drugs targeting peripheral serotonin production.

• Disease Application: In a rat model of bleomycin-induced lung fibrosis, increased 5-HT synthesis in the lung was detected before changes in total serotonin levels, making it an early biomarker of disease-induced dysregulation. This early rise in 5-HT synthesis correlated with upregulation of Tph1 gene expression and preceded the accumulation of total serotonin and fibrotic markers.

• Advantages Over Traditional Measures: Traditional serotonin measurements reflect slow, steady-state changes due to serotonin’s long half-life, but this isotope-tracer method provides a dynamic, real-time snapshot of biosynthetic activity. It also reduces the need for animal sacrifice and enables medium-throughput drug screening.

• Clinical Implications: The approach could be adapted for human studies to monitor serotonin biosynthesis, optimize dosing of TPH inhibitors, and better understand serotonin’s role in disease progression and treatment response.

Conclusion:
This work demonstrates that stable isotope-labeled tryptophan tracing is a powerful tool for real-time monitoring of serotonin biosynthesis. It enables early detection of disease-related changes, supports rapid pharmacodynamic assessment of new therapies, and offers significant advantages for both research and clinical applications in conditions where serotonin dysregulation plays a key role.

Plasma Lysosphingomyelin Demonstrates Great potential as a Diagnostic Biomarker for Niemann-Pick Disease Type C in a retrospective Study

Welford, R.W.D., et al., Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study. PloS one, 2014. 9(12): p. e114669–e114669 https://doi.org/10.1371/journal.pone.0114669.

Niemann-Pick disease type C (NP-C) is a rare, fatal neurovisceral lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes, leading to cholesterol and sphingolipid accumulation. Diagnosis is challenging due to heterogeneous symptoms and reliance on invasive methods like the filipin test. This study identifies plasma lysosphingomyelin (SPC) as a highly sensitive and specific biomarker for NP-C.

Key Findings:

1. Biomarker Validation:

   • SPC and glucosylsphingosine (GlcSph) were measured via a validated LC-MS/MS assay in 57 NP-C patients and 70 controls.

   • SPC levels were 2.8-fold higher in NP-C patients vs. controls, with minimal overlap (median: 19.0 nM vs. 6.8 nM).

   • GlcSph levels were modestly elevated (1.4-fold), but less discriminatory.

2. Diagnostic Accuracy:

   • SPC showed near-perfect diagnostic performance (AUC = 0.999) for miglustat-naïve patients aged 2–50 years. A cutoff of 11 nM SPC achieved 100% sensitivity and 97% specificity.

   • GlcSph had lower utility (AUC = 0.776).

3. Stability & Practicality:

   • SPC and GlcSph are stable in plasma under routine handling (room temperature, freeze-thaw cycles) and detectable in dried blood spots.

   • The assay is robust, scalable, and compatible with clinical workflows.

4. Clinical Relevance:

   • SPC elevation is independent of age (except in patients >50 years) and unaffected by miglustat therapy.

   • Combining SPC with oxysterols (e.g., cholestan-triol) may enhance diagnostic confidence.

Implications:

SPC offers a non-invasive, reliable diagnostic tool for NP-C, potentially replacing the filipin test. Its use could accelerate diagnosis, enabling earlier treatment and improving patient outcomes. The assay also has utility for monitoring therapeutic responses and screening at-risk populations.

Traditional and Digital Biomarkers: Two Worlds Apart?

This article explores the evolving landscape of biomarkers in healthcare, focusing on the distinctions and synergies between traditional and digital biomarkers. Traditional biomarkers-such as blood pressure, cholesterol, or molecular markers-are well-established in clinical research and practice, providing objective, often snapshot-based measurements that guide diagnosis, prognosis, and therapy monitoring. Their development and validation are rigorous, involving multiple stakeholders and regulatory oversight.

Babrak, Lmar M., et al., Traditional and Digital Biomarkers: Two Worlds Apart? Digital Biomarkers, 2019: p. 92–102 https://doi.org/10.1159/000502000.

With the rise of digital devices and health apps, digital biomarkers have emerged as a new class: objective, quantifiable physiological or behavioral data collected via portable, wearable, or implantable technologies. Digital biomarkers enable continuous, real-world, and often non-invasive monitoring, offering richer and more granular health data than traditional methods. They are particularly valuable in fields like neurology and psychiatry, where objective and remote measurement is challenging.

The article highlights key similarities-both types aim to inform health status and treatment-and differences: digital biomarkers generate massive, complex datasets and require advanced analytics, but can be less invasive and more scalable. However, challenges remain, including semantic ambiguity, lack of standardization, data privacy concerns, and regulatory hurdles. The authors call for harmonized terminology and regulatory pathways to accelerate the clinical adoption of digital biomarkers.

Classification is proposed:

• "Approved" digital biomarkers improve or accelerate established clinical practices (e.g., digital heart rate monitoring).

• "Original" biomarkers offer new measurements for known outcomes or established measurements for new outcomes.

• "Novel" biomarkers introduce entirely new measurements and outcomes.

Conclusion:
Digital biomarkers have the potential to transform precision medicine by enabling continuous, individualized health monitoring and supporting early diagnosis and better disease management. To realize their promise, the field must address challenges in standardization, validation, and regulation, ensuring that both traditional and digital biomarkers can work together to advance healthcare.