Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study
Abstract Introduction Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative dise...
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Adis, Springer Healthcare
2024-12-01
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| Series: | Neurology and Therapy |
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| Online Access: | https://doi.org/10.1007/s40120-024-00691-w |
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| author | Annette Janus Daniël Dumas Juliette Le Douce Sébastien Marie Giuseppe Pasculli Pauline Bambury Sighild Lemarchant Philip Kremer Yann Godfrin |
| author_facet | Annette Janus Daniël Dumas Juliette Le Douce Sébastien Marie Giuseppe Pasculli Pauline Bambury Sighild Lemarchant Philip Kremer Yann Godfrin |
| author_sort | Annette Janus |
| collection | DOAJ |
| description | Abstract Introduction Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative diseases (NDD). The cyclized peptide NX210c is a thrombospondin type 1 repeat analogue derived from subcommissural organ-spondin. It exerts beneficial effects in animal models of NDD owing to its effects on neurons and endothelial cells. NX210c demonstrated a good safety profile in a single ascending dose phase 1a clinical study. The present multiple ascending dose phase 1b study was performed to evaluate the tolerability and pharmacological effects of repeated doses of NX210c in healthy elderly (age: > 55 years) volunteers. Methods This was a randomized, placebo-controlled, double-blind study (EudraCT No. 2022-002868-76), investigating safety/tolerability, pharmacokinetics, and pharmacodynamics (including blood and cerebrospinal fluid biomarkers). Participants received 5 or 10 mg/kg NX210c or placebo (10-min infusion) thrice weekly for 4 weeks in an ascending dose fashion. Follow-up was conducted 2 weeks after last dosing. Results The investigation included 29 participants. No serious adverse events were recorded and all adverse events were mild. Dedicated central nervous system testing did not reveal neurotoxicity. Biomarker evaluation showed a statistically significant reduction in blood claudin-5 and a trend toward reduction of blood homocysteine. In silico data modelling revealed salient pharmacokinetic-pharmacodynamic relationships, including reduction of claudin-5, neurofilament light chain, and SPARC-like protein 1 release, and degradation of homocysteine. Conclusion Multiple doses of NX210c exhibited a good safety profile, showed non-cumulative pharmacokinetics, and exerted pharmacodynamic effects on biomarkers linked to BBB integrity. The effects of NX210c on claudin-5 and biomarkers influencing BBB integrity—and the overarching brain protection it offers—provide a novel therapeutic strategy targeting an underlying driver of neurodegenerative conditions for which disease-modifying treatments are limited or not available. |
| format | Article |
| id | doaj-art-76c288f6a5934d4eba96cc1520a6d1bf |
| institution | Kabale University |
| issn | 2193-8253 2193-6536 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Adis, Springer Healthcare |
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| series | Neurology and Therapy |
| spelling | doaj-art-76c288f6a5934d4eba96cc1520a6d1bf2025-01-26T12:58:32ZengAdis, Springer HealthcareNeurology and Therapy2193-82532193-65362024-12-0114135737710.1007/s40120-024-00691-wSafety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose StudyAnnette Janus0Daniël Dumas1Juliette Le Douce2Sébastien Marie3Giuseppe Pasculli4Pauline Bambury5Sighild Lemarchant6Philip Kremer7Yann Godfrin8Axoltis PharmaCentre for Human Drug Research (CHDR)Axoltis PharmaAxoltis PharmaInSilicoTrials TechnologiesInSilicoTrials TechnologiesAxoltis PharmaCentre for Human Drug Research (CHDR)Axoltis PharmaAbstract Introduction Blood-brain barrier (BBB) integrity is fundamental to brain homeostasis, enabling control of substance exchange and safeguarding neurons against harmful toxins, pathogens, and immune cells that lead to dysregulation and inflammation involved in ageing and neurodegenerative diseases (NDD). The cyclized peptide NX210c is a thrombospondin type 1 repeat analogue derived from subcommissural organ-spondin. It exerts beneficial effects in animal models of NDD owing to its effects on neurons and endothelial cells. NX210c demonstrated a good safety profile in a single ascending dose phase 1a clinical study. The present multiple ascending dose phase 1b study was performed to evaluate the tolerability and pharmacological effects of repeated doses of NX210c in healthy elderly (age: > 55 years) volunteers. Methods This was a randomized, placebo-controlled, double-blind study (EudraCT No. 2022-002868-76), investigating safety/tolerability, pharmacokinetics, and pharmacodynamics (including blood and cerebrospinal fluid biomarkers). Participants received 5 or 10 mg/kg NX210c or placebo (10-min infusion) thrice weekly for 4 weeks in an ascending dose fashion. Follow-up was conducted 2 weeks after last dosing. Results The investigation included 29 participants. No serious adverse events were recorded and all adverse events were mild. Dedicated central nervous system testing did not reveal neurotoxicity. Biomarker evaluation showed a statistically significant reduction in blood claudin-5 and a trend toward reduction of blood homocysteine. In silico data modelling revealed salient pharmacokinetic-pharmacodynamic relationships, including reduction of claudin-5, neurofilament light chain, and SPARC-like protein 1 release, and degradation of homocysteine. Conclusion Multiple doses of NX210c exhibited a good safety profile, showed non-cumulative pharmacokinetics, and exerted pharmacodynamic effects on biomarkers linked to BBB integrity. The effects of NX210c on claudin-5 and biomarkers influencing BBB integrity—and the overarching brain protection it offers—provide a novel therapeutic strategy targeting an underlying driver of neurodegenerative conditions for which disease-modifying treatments are limited or not available.https://doi.org/10.1007/s40120-024-00691-wNX210c peptideSubcommissural organ-spondinNeurodegenerative diseaseBlood-brain barrierClaudin-5Homocysteine |
| spellingShingle | Annette Janus Daniël Dumas Juliette Le Douce Sébastien Marie Giuseppe Pasculli Pauline Bambury Sighild Lemarchant Philip Kremer Yann Godfrin Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study Neurology and Therapy NX210c peptide Subcommissural organ-spondin Neurodegenerative disease Blood-brain barrier Claudin-5 Homocysteine |
| title | Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study |
| title_full | Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study |
| title_fullStr | Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study |
| title_full_unstemmed | Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study |
| title_short | Safety, Tolerability and Pharmacokinetic-Pharmacodynamic Relationship of NX210c Peptide in Healthy Elderly Volunteers: Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study |
| title_sort | safety tolerability and pharmacokinetic pharmacodynamic relationship of nx210c peptide in healthy elderly volunteers randomized placebo controlled double blind multiple ascending dose study |
| topic | NX210c peptide Subcommissural organ-spondin Neurodegenerative disease Blood-brain barrier Claudin-5 Homocysteine |
| url | https://doi.org/10.1007/s40120-024-00691-w |
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