Oral treatment with the all-d-peptide RD2 enhances cognition in aged beagle dogs - A model of sporadic Alzheimer's disease.

Disease-modifying therapies to treat Alzheimer's disease (AD) are of fundamental interest for aging humans, societies, and health care systems. Predictable disease progression in transgenic AD models favors preclinical studies employing a preventive study design with an early pre-symptomatic treatment start, instead of assessing a truly curative approach with treatment starting after diagnosed disease onset. The aim of this study was to investigate the pharmacokinetic profile and efficacy of RD2 to enhance short-term memory and cognition in cognitively impaired aged Beagle dogs - a non-transgenic model of truly sporadic AD. RD2 has previously demonstrated pharmacodynamic efficacy in three different transgenic AD mouse models in three different laboratories. Here, we demonstrate that oral treatment with RD2 significantly reduced cognitive deficits in cognitively impaired aged Beagle dogs even beyond the treatment end, which suggests in combination with the treatment dependent CSF tau oligomer decrease a disease-modifying effect of RD2 treatment.

Safety and pharmacokinetics of the orally available antiprionic compound PRI-002: A single and multiple ascending dose phase I study.

INTRODUCTION: PRI-002 is an orally available anti-amyloid beta (Aß) prionic compound developed for direct disassembly of toxic Aß oligomers relevant to Alzheimer's disease. METHODS: Two placebo-controlled clinical phase I trials with oral dosing of PRI-002 were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg PRI-002 or placebo) in 40 participants followed by a multiple ascending dose study with daily 160 mg PRI-002 for 14 days or 320 mg for 28 days in 24 participants. The main objectives were safety, tolerability, and evaluation of pharmacokinetic (PK) parameters. RESULTS: PRI-002 was safe and well tolerated after single and multiple oral administration up to the highest doses. PRI-002 was absorbed rapidly and drug exposure increased proportional to dose. During repeated daily administration, the drug accumulated by a factor of about three. Steady-state conditions were reached after 1 to 2 weeks. CONCLUSIONS: The safety and PK results encourage further clinical development of PRI-002.