Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial
Abstract Self-replicating amyloid beta (Aβ) oligomers are considered as one of the major drivers for disrupted synaptic function and plasticity, leading to impaired neuronal viability and progression of Alzheimer’s disease (AD). Here, we investigated the safety, tolerability and pharmacokinetics of...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59295-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849312961908178944 |
|---|---|
| author | Janine Kutzsche Nicoleta Carmen Cosma Gunther Kauselmann Friederike Fenski Christine Bieniek Tuyen Bujnicki Marlene Pils Oliver Bannach Dieter Willbold Oliver Peters |
| author_facet | Janine Kutzsche Nicoleta Carmen Cosma Gunther Kauselmann Friederike Fenski Christine Bieniek Tuyen Bujnicki Marlene Pils Oliver Bannach Dieter Willbold Oliver Peters |
| author_sort | Janine Kutzsche |
| collection | DOAJ |
| description | Abstract Self-replicating amyloid beta (Aβ) oligomers are considered as one of the major drivers for disrupted synaptic function and plasticity, leading to impaired neuronal viability and progression of Alzheimer’s disease (AD). Here, we investigated the safety, tolerability and pharmacokinetics of the anti-oligomeric peptide PRI-002, which was developed to disassemble toxic Aβ oligomers into non-toxic monomers. In a randomized, double-blind, single-center phase 1b trial, 20 patients aged between 50 and 80 years, with mild neurocognitive impairment (MCI) or mild dementia due to AD were recruited. Eligible patients were randomly assigned (1:1) to receive 300 mg PRI-002 once daily (q.d.) or placebo for 28 days. During treatment, study visits were performed on baseline (Day 1), Day 14, Day 28 and an additional follow-up visit on Day 56. Safety assessments were carried out at all visits to determine the primary endpoints. On Day 7 and Day 21 additional phone visits were carried out to assess concomitant meds and AEs. Primary endpoints were nature, frequency, severity, and timing of adverse and serious adverse events (AE/SAEs) and treatment discontinuation. Furthermore, standard laboratory values, electrocardiogram (ECG), electroencephalogram (EEG), magnetic resonance imaging (MRI), and vital signs were assessed. Secondary endpoints included the evaluation of pharmacokinetic characteristics of PRI-002 in plasma and the determination of cerebrospinal fluid (CSF) concentrations of PRI-002. The trial is registered in EudraCT 2020-003416-27 and clinicaltrials.gov NCT04711486 . In the study, 19 out of 20 patients were randomly assigned to PRI-002 (n = 9) or placebo (n = 10) and completed the study. One patient withdrew informed consent before randomization. All primary endpoints were met. Overall, the study drug was well tolerated. In total n = 16 AEs were reported in the verum group, while n = 27 AEs were noted in the placebo group. No SAEs were reported. No significant changes in clinical chemistry, hematology or hematoserology were detected. ECG, EEG and MRI revealed no changes and in detail no ARIA were observed. Pharmacokinetic parameters were unrelated to sex, age, and weight. Furthermore, no significant changes were detected in p-tau, t-tau, Aβ 1-40, Aβ 1-42 and Aβ oligomers in CSF. Patients receiving PRI-002 performed significantly better than those receiving placebo in the CERAD word list at Day 56 (P ≤ 0.05). In conclusion, 28 days of treatment with 300 mg q.d. PRI-002 was well tolerated in patients with MCI or mild dementia due to AD. |
| format | Article |
| id | doaj-art-5e279ddc960e41c9a6017f6d8f7ae9d3 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5e279ddc960e41c9a6017f6d8f7ae9d32025-08-20T03:52:53ZengNature PortfolioNature Communications2041-17232025-05-011611910.1038/s41467-025-59295-zOral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trialJanine Kutzsche0Nicoleta Carmen Cosma1Gunther Kauselmann2Friederike Fenski3Christine Bieniek4Tuyen Bujnicki5Marlene Pils6Oliver Bannach7Dieter Willbold8Oliver Peters9Institute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbHDepartment of Psychiatry and Neuroscience, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu BerlinInstitute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbHDepartment of Psychiatry and Neuroscience, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu BerlinDepartment of Psychiatry and Neuroscience, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu BerlinInstitute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbHattyloid GmbHattyloid GmbHInstitute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbHDepartment of Psychiatry and Neuroscience, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu BerlinAbstract Self-replicating amyloid beta (Aβ) oligomers are considered as one of the major drivers for disrupted synaptic function and plasticity, leading to impaired neuronal viability and progression of Alzheimer’s disease (AD). Here, we investigated the safety, tolerability and pharmacokinetics of the anti-oligomeric peptide PRI-002, which was developed to disassemble toxic Aβ oligomers into non-toxic monomers. In a randomized, double-blind, single-center phase 1b trial, 20 patients aged between 50 and 80 years, with mild neurocognitive impairment (MCI) or mild dementia due to AD were recruited. Eligible patients were randomly assigned (1:1) to receive 300 mg PRI-002 once daily (q.d.) or placebo for 28 days. During treatment, study visits were performed on baseline (Day 1), Day 14, Day 28 and an additional follow-up visit on Day 56. Safety assessments were carried out at all visits to determine the primary endpoints. On Day 7 and Day 21 additional phone visits were carried out to assess concomitant meds and AEs. Primary endpoints were nature, frequency, severity, and timing of adverse and serious adverse events (AE/SAEs) and treatment discontinuation. Furthermore, standard laboratory values, electrocardiogram (ECG), electroencephalogram (EEG), magnetic resonance imaging (MRI), and vital signs were assessed. Secondary endpoints included the evaluation of pharmacokinetic characteristics of PRI-002 in plasma and the determination of cerebrospinal fluid (CSF) concentrations of PRI-002. The trial is registered in EudraCT 2020-003416-27 and clinicaltrials.gov NCT04711486 . In the study, 19 out of 20 patients were randomly assigned to PRI-002 (n = 9) or placebo (n = 10) and completed the study. One patient withdrew informed consent before randomization. All primary endpoints were met. Overall, the study drug was well tolerated. In total n = 16 AEs were reported in the verum group, while n = 27 AEs were noted in the placebo group. No SAEs were reported. No significant changes in clinical chemistry, hematology or hematoserology were detected. ECG, EEG and MRI revealed no changes and in detail no ARIA were observed. Pharmacokinetic parameters were unrelated to sex, age, and weight. Furthermore, no significant changes were detected in p-tau, t-tau, Aβ 1-40, Aβ 1-42 and Aβ oligomers in CSF. Patients receiving PRI-002 performed significantly better than those receiving placebo in the CERAD word list at Day 56 (P ≤ 0.05). In conclusion, 28 days of treatment with 300 mg q.d. PRI-002 was well tolerated in patients with MCI or mild dementia due to AD.https://doi.org/10.1038/s41467-025-59295-z |
| spellingShingle | Janine Kutzsche Nicoleta Carmen Cosma Gunther Kauselmann Friederike Fenski Christine Bieniek Tuyen Bujnicki Marlene Pils Oliver Bannach Dieter Willbold Oliver Peters Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial Nature Communications |
| title | Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial |
| title_full | Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial |
| title_fullStr | Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial |
| title_full_unstemmed | Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial |
| title_short | Oral PRI-002 treatment in patients with MCI or mild AD: a randomized, double-blind phase 1b trial |
| title_sort | oral pri 002 treatment in patients with mci or mild ad a randomized double blind phase 1b trial |
| url | https://doi.org/10.1038/s41467-025-59295-z |
| work_keys_str_mv | AT janinekutzsche oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT nicoletacarmencosma oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT guntherkauselmann oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT friederikefenski oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT christinebieniek oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT tuyenbujnicki oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT marlenepils oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT oliverbannach oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT dieterwillbold oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial AT oliverpeters oralpri002treatmentinpatientswithmciormildadarandomizeddoubleblindphase1btrial |