Therapeutics

PRI-002

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Overview

Name: PRI-002
Synonyms: Contraloid, contraloid acetate, RD2
Chemical Name: all D-ptlhthnrrrrr
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Priavoid GmbH

Background

This 12-residue, enantiomeric peptide is designed to interfere with oligomerization of Aβ42 by binding to, and stabilizing, Aβ42 monomers. PRI-002 comprises D-amino acids, the optical isomers of natural L forms. D-peptides are favored for protein drugs, because they can be taken by mouth, resist protease degradation in the stomach and metabolic degradation, and are less immunogenic than natural peptides. They cross the blood-brain barrier. 

PRI-002 was identified by the Willbold lab in Düsseldorf, using mirror image phage display to select all-D peptides that bind Aβ42 (Wiesehan et al, 2003). The original hits were optimized for their ability to slow fibril formation and destabilize toxic oligomers (Aug 2009 conference news; Brener et al., 2015; Zhang et al., 2019). PRI-002 (also called RD2) was capable of disaggregating Aβ oligomers extracted from brain tissue of people who had Alzheimer’s disease (May 2022 news).

The lab has published preclinical studies on PRI-002. In mice, the peptide, when given orally, reaches nearly the same concentrations in brain as in blood (Leithold et al, 2016). The peptide appeared effective in three mouse models of Alzheimer’s. In APPSL mice, it improved performance in the Morris water maze after six weeks of treatment (Kutzsche et al., 2017). It similarly enhanced cognition in young or old APP/PS1 mice (van Groen et al., 2017; Schemmert et al., 2018). In the TBA2.1 mouse model of pyroglutamate-Aβ-induced motor neuron neurodegeneration, mice who ate PRI-002 jelly for 12 weeks showed partial improvement of their motor deficit (Schemmert et al., 2019).

At the 2020 CTAD conference, Willbold presented data on aging beagles, a model of spontaneous AD. Dogs that were older than 10, and cognitively impaired, were fed 3 or 30 mg/kg PRI-002 or placebo daily for three months. Treated dogs reportedly improved their accuracy on a test of short-term memory compared to placebo, and the memory benefit of the higher dose was retained during a two-month post-treatment washout. In the subsequent publication of this work, the investigators also reported a decrease in CSF tau oligomers after treatment at the higher dose (Kutzsche et al., 2023). Aβ oligomers were unchanged.

An 18F-labeled analog of PRI-002 was investigated as a potential PET probe for soluble Aβ oligomers, but it failed to discriminate between wild-type and APP/PS1 mice with amyloidosis (Willuweit et al., 2023).

Findings

In 2017, Willbold and others founded Priavoid GmbH, which in 2018 and 2019 conducted a Phase 1 single-ascending-dose study and a second, multiple-ascending-dose study to evaluate the safety of PRI-002 in 64 healthy men in Germany. According to published results, single doses up to 320 mg and multiple doses of 320 mg for up to four weeks produced no drug-related adverse events (Kutzsche et al., 2020). The drug showed favorable pharmacokinetics, and accumulated with repeated administration, reaching steady state after one to two weeks of dosing.

In December 2020, Priavoid began a Phase 1 trial in 20 people with mild cognitive impairment due to Alzheimer’s disease. Participants received a single 300 mg dose daily for 28 days, or matching placebo. Outcomes were safety, including adverse events, laboratory values, and electrocardiograms. The study also measured pharmacokinetics, changes in CSF, plasma and fecal biomarkers of tau, Aβ, and neurofilament light chain, and exploratory cognitive measures. Conducted in Berlin, the trial ended in January 2022. According to a poster presentation at the 2022 AAIC, the drug was safe, with no serious adverse events noted in the trial. No change was seen in CSF biomarkers, but treated patients performed better than those on placebo on an exploratory endpoint related to memory, the CERAD word list. According to additional data  presented at the 2023 CTAD conference, the improvement in CERAD was significant one month after treatment ended (news). It was observed in all participants who got drug, and half who got placebo.

At CTAD, the company reported that a Phase 2 trial is planned to begin in early 2024. In the study, at least 270 participants with MCI or mild AD will be randomized to daily doses of 300 mg or 600 mg PRI-002, or placebo, for one to two years. The primary efficacy endpoint is change in CDR-SB. Funded by SPRIN-D, the German Federal Agency of Disruptive Innovation, the study is planned to run at 40 sites in seven European countries. It does not yet appear in a trial registry.

For details on PRI-002 trials, see clinicaltrials.gov.

Last Updated: 22 Nov 2023

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References

News Citations

  1. After Long Wait, Aβ Oligomer Detangler Poised for Phase 2
  2. Vienna: Can a D-Peptide Turn Tiger Into Pussycat?
  3. Oligomer Assay Finds Similar Aβ Profiles in AD and in Mice

Paper Citations

  1. Kutzsche J, Jürgens D, Willuweit A, Adermann K, Fuchs C, Simons S, Windisch M, Hümpel M, Rossberg W, Wolzt M, Willbold D. Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study. Alzheimers Dement (N Y). 2020;6(1):e12001. Epub 2020 Mar 20 PubMed.
  2. Wiesehan K, Buder K, Linke RP, Patt S, Stoldt M, Unger E, Schmitt B, Bucci E, Willbold D. Selection of D-amino-acid peptides that bind to Alzheimer's disease amyloid peptide abeta1-42 by mirror image phage display. Chembiochem. 2003 Aug 4;4(8):748-53. PubMed.
  3. Brener O, Dunkelmann T, Gremer L, van Groen T, Mirecka EA, Kadish I, Willuweit A, Kutzsche J, Jürgens D, Rudolph S, Tusche M, Bongen P, Pietruszka J, Oesterhelt F, Langen KJ, Demuth HU, Janssen A, Hoyer W, Funke SA, Nagel-Steger L, Willbold D. QIAD assay for quantitating a compound's efficacy in elimination of toxic Aβ oligomers. Sci Rep. 2015 Sep 23;5:13222. PubMed.
  4. Zhang T, Gering I, Kutzsche J, Nagel-Steger L, Willbold D. Toward the Mode of Action of the Clinical Stage All-d-Enantiomeric Peptide RD2 on Aβ42 Aggregation. ACS Chem Neurosci. 2019 Dec 18;10(12):4800-4809. Epub 2019 Nov 22 PubMed.
  5. Leithold LH, Jiang N, Post J, Ziehm T, Schartmann E, Kutzsche J, Shah NJ, Breitkreutz J, Langen KJ, Willuweit A, Willbold D. Pharmacokinetic Properties of a Novel D-Peptide Developed to be Therapeutically Active Against Toxic β-Amyloid Oligomers. Pharm Res. 2016 Feb;33(2):328-36. Epub 2015 Sep 17 PubMed.
  6. Kutzsche J, Schemmert S, Tusche M, Neddens J, Rabl R, Jürgens D, Brener O, Willuweit A, Hutter-Paier B, Willbold D. Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer's Disease. Molecules. 2017 Oct 10;22(10) PubMed.
  7. van Groen T, Schemmert S, Brener O, Gremer L, Ziehm T, Tusche M, Nagel-Steger L, Kadish I, Schartmann E, Elfgen A, Jürgens D, Willuweit A, Kutzsche J, Willbold D. The Aβ oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology. Sci Rep. 2017 Nov 24;7(1):16275. PubMed.
  8. Schemmert S, Schartmann E, Zafiu C, Kass B, Hartwig S, Lehr S, Bannach O, Langen KJ, Shah NJ, Kutzsche J, Willuweit A, Willbold D. Aβ Oligomer Elimination Restores Cognition in Transgenic Alzheimer's Mice with Full-blown Pathology. Mol Neurobiol. 2018 Jul 12; PubMed.
  9. Schemmert S, Schartmann E, Honold D, Zafiu C, Ziehm T, Langen KJ, Shah NJ, Kutzsche J, Willuweit A, Willbold D. Deceleration of the neurodegenerative phenotype in pyroglutamate-Aβ accumulating transgenic mice by oral treatment with the Aβ oligomer eliminating compound RD2. Neurobiol Dis. 2019 Apr;124:36-45. Epub 2018 Nov 2 PubMed.
  10. Kutzsche J, Schemmert S, Bujnicki T, Zafiu C, Halbgebauer S, Kraemer-Schulien V, Pils M, Blömeke L, Post J, Kulawik A, Jürgens D, Rossberg WM, Hümpel M, Bannach O, Otto M, Araujo JA, Willuweit A, Willbold D. Oral treatment with the all-d-peptide RD2 enhances cognition in aged beagle dogs - A model of sporadic Alzheimer's disease. Heliyon. 2023 Aug;9(8):e18443. Epub 2023 Jul 29 PubMed.
  11. Willuweit A, Humpert S, Schöneck M, Endepols H, Burda N, Gremer L, Gering I, Kutzsche J, Shah NJ, Langen KJ, Neumaier B, Willbold D, Drzezga A. Evaluation of the 18F-labeled analog of the therapeutic all-D-enantiomeric peptide RD2 for amyloid β imaging. Eur J Pharm Sci. 2023 May 1;184:106421. Epub 2023 Mar 6 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Willbold D, Kutzsche J. Do We Need Anti-Prion Compounds to Treat Alzheimer's Disease?. Molecules. 2019 Jun 15;24(12) PubMed.
  2. Elfgen A, Hupert M, Bochinsky K, Tusche M, González de San Román Martin E, Gering I, Sacchi S, Pollegioni L, Huesgen PF, Hartmann R, Santiago-Schübel B, Kutzsche J, Willbold D. Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers. Sci Rep. 2019 Apr 5;9(1):5715. PubMed.
  3. Leguizamon Herrera VL, Buell AK, Willbold D, Barz B. Interaction of Therapeutic d-Peptides with Aβ42 Monomers, Thermodynamics, and Binding Analysis. ACS Chem Neurosci. 2022 Jun 1;13(11):1638-1650. Epub 2022 May 17 PubMed.
  4. Post J, Kogel V, Schaffrath A, Lohmann P, Shah NJ, Langen KJ, Willbold D, Willuweit A, Kutzsche J. A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model. Molecules. 2021 Mar 13;26(6) PubMed.
  5. Bhatt N, Kayed R. Quantification and targeting of elusive neurotoxic amyloid oligomers. Cell Rep Med. 2022 May 17;3(5):100636. PubMed.
  6. Kass B, Schemmert S, Zafiu C, Pils M, Bannach O, Kutzsche J, Bujnicki T, Willbold D. Aβ oligomer concentration in mouse and human brain and its drug-induced reduction ex vivo. Cell Rep Med. 2022 May 17;3(5):100630. PubMed.
  7. Schemmert S, Camargo LC, Honold D, Gering I, Kutzsche J, Willuweit A, Willbold D. In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer's Disease. Int J Mol Sci. 2021 Jun 18;22(12) PubMed.
  8. Elfgen A, Santiago-Schübel B, Hupert M, Schemmert S, Schartmann E, Tusche M, Gering I, Zafiu C, Kutzsche J. Oral absorption enhancement of the amyloid-β oligomer eliminating compound RD2 by conjugation with folic acid. Eur J Pharm Sci. 2021 Jan 1;156:105581. Epub 2020 Oct 6 PubMed.