Association of Baseline and Pharmacodynamic Biomarkers With Outcomes in Patients Treated With the PD-1 Inhibitor Budigalimab

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

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Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22041615 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1615

Author(s):

Maurits F. J. M. Vissers ◽

Jules A. A. C. Heuberger ◽

Geert Jan Groeneveld

Keyword(s):

Clinical Trials ◽

Failure Rate ◽

Neurodegenerative Disorders ◽

Early Phase ◽

Proof Of Concept ◽

Mesh Terms ◽

Disease Modifying ◽

Early Phase Clinical Trials ◽

Pharmacodynamic Biomarkers ◽

Response Biomarkers

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date.

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Targeted Mass Spectrometry Enables Quantification of Novel Pharmacodynamic Biomarkers of ATM Kinase Inhibition

Cancers ◽

10.3390/cancers13153843 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3843

Author(s):

Jeffrey R. Whiteaker ◽

Tao Wang ◽

Lei Zhao ◽

Regine M. Schoenherr ◽

Jacob J. Kennedy ◽

...

Keyword(s):

Dna Damage ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Limit Of Quantification ◽

Peripheral Blood Mononuclear ◽

Atm Kinase ◽

Support Mechanism ◽

Radiation Induced ◽

Pharmacodynamic Biomarkers ◽

Preclinical And Clinical Studies

The ATM serine/threonine kinase (HGNC: ATM) is involved in initiation of repair of DNA double-stranded breaks, and ATM inhibitors are currently being tested as anti-cancer agents in clinical trials, where pharmacodynamic (PD) assays are crucial to help guide dose and scheduling and support mechanism of action studies. To identify and quantify PD biomarkers of ATM inhibition, we developed and analytically validated a 51-plex assay (DDR-2) quantifying protein expression and DNA damage-responsive phosphorylation. The median lower limit of quantification was 1.28 fmol, the linear range was over 3 orders of magnitude, the median inter-assay variability was 11% CV, and 86% of peptides were stable for storage prior to analysis. Use of the assay was demonstrated to quantify signaling following ionizing radiation-induced DNA damage in both immortalized lymphoblast cell lines and primary human peripheral blood mononuclear cells, identifying PD biomarkers for ATM inhibition to support preclinical and clinical studies.

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Systematic Review of Biomarkers To Monitor Therapeutic Response in Leishmaniasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04298-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 1-14 ◽

Cited By ~ 31

Author(s):

Anke E. Kip ◽

Manica Balasegaram ◽

Jos H. Beijnen ◽

Jan H. M. Schellens ◽

Peter J. de Vries ◽

...

Keyword(s):

Systematic Review ◽

Therapeutic Response ◽

Parasite Burden ◽

New Drugs ◽

Future Research ◽

Kala Azar ◽

Pharmacodynamic Markers ◽

Pharmacodynamic Biomarkers ◽

Antigenic Targets

ABSTRACTRecently, there has been a renewed interest in the development of new drugs for the treatment of leishmaniasis. This has spurred the need for pharmacodynamic markers to monitor and compare therapies specifically for visceral leishmaniasis, in which the primary recrudescence of parasites is a particularly long-term event that remains difficult to predict. We performed a systematic review of studies evaluating biomarkers in human patients with visceral, cutaneous, and post-kala-azar dermal leishmaniasis, which yielded a total of 170 studies in which 53 potential pharmacodynamic biomarkers were identified. In conclusion, the large majority of these biomarkers constituted universal indirect markers of activation and subsequent waning of cellular immunity and therefore lacked specificity. Macrophage-related markers demonstrate favorable sensitivity and times to normalcy, but more evidence is required to establish a link between these markers and clinical outcome. Most promising are the markers directly related to the parasite burden, but future effort should be focused on optimization of molecular or antigenic targets to increase the sensitivity of these markers. In general, future research should focus on the longitudinal evaluation of the pharmacodynamic biomarkers during treatment, with an emphasis on the correlation of studied biomarkers and clinical parameters.

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Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-13-0494 ◽

2013 ◽

Vol 13 (2) ◽

pp. 540-552 ◽

Cited By ~ 10

Author(s):

Elaine Mai ◽

Zhong Zheng ◽

Youjun Chen ◽

Jing Peng ◽

Christophe Severin ◽

...

Keyword(s):

Monoclonal Antibody ◽

Pharmacodynamic Biomarkers

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Pharmacodynamic biomarkers and differential effects of TNF ‐ and GM ‐ CSF ‐targeting biologics in rheumatoid arthritis

International Journal of Rheumatic Diseases ◽

10.1111/1756-185x.13395 ◽

2018 ◽

Vol 22 (4) ◽

pp. 646-653 ◽

Cited By ~ 7

Author(s):

Xiang Guo ◽

Shiliang Wang ◽

Alex Godwood ◽

David Close ◽

Patricia C. Ryan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Differential Effects ◽

Gm Csf ◽

Pharmacodynamic Biomarkers

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Metabolomics combined with pattern recognition and bioinformatics analysis methods for the development of pharmacodynamic biomarkers on liver fibrosis

Molecular BioSystems ◽

10.1039/c7mb00093f ◽

2017 ◽

Vol 13 (8) ◽

pp. 1575-1583 ◽

Cited By ~ 4

Author(s):

Junwei Fang ◽

Liping Wang ◽

Yang Wang ◽

Mingfeng Qiu ◽

Yongyu Zhang

Keyword(s):

Pattern Recognition ◽

Network Analysis ◽

Liver Fibrosis ◽

Bioinformatics Analysis ◽

Analysis Methods ◽

Pharmacodynamic Biomarkers

Metabolomics combined with pattern recognition and network analysis maybe an attractive strategy for the pharmacodynamics biomarkers development on liver fibrosis.

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Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses

Antibiotics ◽

10.3390/antibiotics10111368 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1368

Author(s):

Manjunath P. Pai ◽

Ryan L. Crass

Keyword(s):

Drug Exposure ◽

Current Approach ◽

Dose Selection ◽

Underlying Assumption ◽

Exposure Response ◽

Liver And Kidney ◽

Trial Endpoints ◽

Pharmacodynamic Biomarkers ◽

Antibiotic Efficacy ◽

Efficacy Studies

Antibiotic efficacy determination in clinical trials often relies on non-inferiority designs because they afford smaller study sample sizes. These efficacy studies tend to exclude patients within specific populations or include too few patients to discern potential differences in their clinical outcomes. As a result, dosing guidance in patients with abnormal liver and kidney function, age across the lifespan, and other specific populations relies on drug exposure-matching. The underlying assumption for exposure-matching is that the disease course and the response to the antibiotic are similar in patients with and without the specific condition. While this may not be the case, clinical efficacy studies are underpowered to ensure this is true. The current paper provides an integrative review of the current approach to dose selection in specific populations. We review existing clinical trial endpoints that could be measured on a more continuous rather than a discrete scale to better inform exposure–response relationships. The inclusion of newer systemic biomarkers of efficacy can help overcome the current limitations. We use a modeling and simulation exercise to illustrate how an efficacy biomarker can inform dose selection better. Studies that inform response-matching rather than exposure-matching only are needed to improve dose selection in specific populations.

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Development of pharmacodynamic biomarkers for ATR inhibitors

Molecular Oncology ◽

10.1016/j.molonc.2014.09.012 ◽

2014 ◽

Vol 9 (2) ◽

pp. 463-472 ◽

Cited By ~ 13

Author(s):

Tao Chen ◽

Fiona K. Middleton ◽

Susanna Falcon ◽

Philip M. Reaper ◽

John R. Pollard ◽

...

Keyword(s):

Pharmacodynamic Biomarkers

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STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2105390118 ◽

2021 ◽

Vol 118 (36) ◽

pp. e2105390118 ◽

Cited By ~ 1

Author(s):

Keke Liang ◽

Evan R. Abt ◽

Thuc M. Le ◽

Arthur Cho ◽

Amanda M. Dann ◽

...

Keyword(s):

Pet Imaging ◽

Cell Metabolism ◽

Nucleotide Metabolism ◽

Type I Interferons ◽

Ductal Adenocarcinoma ◽

Type I ◽

Flt Pet ◽

Positron Emission ◽

Pharmacodynamic Biomarkers

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling–induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling–dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist–based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

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