Therapeutics

PRI-002

Overview

Name: PRI-002
Synonyms: RD2, contraloid acetate
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 (April 2015 conference news; Brener et al., 2015; Zhang et al., 2019).

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 who 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.

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 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 doing.

For details on these trials, see clinicaltrials.gov

Last Updated: 06 Jan 2021

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References

News Citations

  1. Vienna: Can a D-Peptide Turn Tiger Into Pussycat?

Paper Citations

  1. . 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. . 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. . QIAD assay for quantitating a compound's efficacy in elimination of toxic Aβ oligomers. Sci Rep. 2015 Sep 23;5:13222. PubMed.
  4. . 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. . 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. . 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. . The Aβ oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology. Sci Rep. 2017 Nov 24;7(1):16275. PubMed.
  8. . Aβ Oligomer Elimination Restores Cognition in Transgenic Alzheimer's Mice with Full-blown Pathology. Mol Neurobiol. 2018 Jul 12; PubMed.
  9. . 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.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Do We Need Anti-Prion Compounds to Treat Alzheimer's Disease?. Molecules. 2019 Jun 15;24(12) PubMed.
  2. . Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers. Sci Rep. 2019 Apr 5;9(1):5715. PubMed.