The All-D-Peptide PRI-002: Preclinical PoC and Clinical Phase Ib Data from Alzheimer’s Disease Patients
Dieter Willbold
Director, Forschungszentrum Jülich
It is well accepted that development and progression of Alzheimer´s disease are mainly driven by soluble amyloid protein (Aβ) oligomers. Because the Aβ molecules in their monomeric and oligomer form are chemically identical, the sole difference between them is their three-dimensional structure. Toxic oligomers and fibrils grow and replicate constantly by recruiting monomers into the respective conformation within the oligomers and fibrils, thereby replicating and propagating prion-like throughout the brain. We have designed an all-D-peptide, PRI-002 (alias RD2 in publictaions) that is stabilizing Aβ monomers in their intrinsically disordered native monomer conformation, thus destabilizing Aβ oligomers and ultimately disrupting and disassembling them (back). PRI-002 is orally available, non-immunogenic and crosses the blood brain barrier [1]. It has demonstrated target engagement in vitro, in vivo and ex vivo [2, 3, 7]. This includes also ex vivo target engagement with AD patient brain tissue derived Aβ oligomers [7]. Treatments in three different transgenic mouse models in three different laboratories yielded improved cognition and deceleration of neurodegeneration [2-5]. Oral treatment of old-aged transgenic AD mice with full blown pathology reversed cognitive and behavioral deficits to levels indistinguishable from healthy wild-types [3]. The in vivo correlation of Aβ oligomer elimination and reversal of deficits supports the promising role of Aβ oligomer prions as the target for causal treatment of AD. PRI-002 has entered clinical development and has proven to be safe and tolerable in healthy volunteers [6] as well as in mild cognitively impaired (MCI) due to AD patients, and patients with mild AD. Safety, biomarker and cognition data will be presented.
[1] Leithold et al., Pharm Res. 33, 328-336 (2016). [2] van Groen et al., Sci. Rep. 7, 16275 (2017). [3] Schemmert et al., Mol. Neurobiol. 56, 2211 (2019). [4] Kutzsche et al., Molecules 22, 1693 (2017). [5] Schemmert et al., Neurobiol. Dis. 124, 36 (2019). [6] Kutzsche et al., Alzheimers Dement (N Y) 6, e12001 (2020). [7] Kass et al., Cell Rep. Med. (2022).
Dieter Willbold studied biochemistry in Tübingen (Germany), Bayreuth (Germany) and Boulder (Colorado, USA). He completed his PhD in 1994 at the University of Bayreuth. After some more years in Bayreuth and a couple of research visits, e.g. at the Sackler School of Medicine of the Tel-Aviv University, he was leading his junior research group at the Institute for Molecular Biotechnology in Jena, Germany. In 2001 Willbold became an associate Professor at the Heinrich Heine University in Düsseldorf. Since 2004, he is Full Professor at the Institute of Physical Biology in Düsseldorf and Director of the Institute of Complex Systems at the Forschungszentrum Jülich. His main interests are protein interactions with physiological and artificial ligands, high resolution structural biology, neurodegeneration, neuropathic pain and autophagy. Since quite some years, Willbold is very much engaged in drug development for Alzheimer’s and other neurodegenerative diseases, and has co-founded the companies Priavoid and attyloid in 2017 and 2018, respectively.