Y-Secretase Modulator RG6289 Produces Dose-Dependent Shift of Amyloid-ß Monomers in Phase 1 Study

In an early-phase, small-scale clinical trial of healthy volunteers, treatment with investigational RG6289 (Roche) resulted in dose-dependent shift in the production of longer and shorter amyloid-ß (Aß) monomers in cerebrospinal fluid (CSF). Overall, these results support the development of RG6289, a new y-secretase modulator (GSM), as a potential treatment for patients with Alzheimer disease (AD).¹

Led by Thomas Mueggler, PhD, a neuroscience researcher at Roche, the trial featured 12 healthy volunteers, aged 46-70 years, who were randomly assigned to either RG6289 (n = 9) or placebo (n = 3). Focusing in on the pharmacologic impact of the therapy, plasma and CSF samples were collected over 36 hours following a single dose administration. Presented at the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1 in Philadelphia, Pennsylvania, results showed a dose-dependent increase in Aß37/Aß40 and Aß38/Aß42 ratios observed up to 36 hours post-dose.

At the highest dose, an approximate 500% and 150% increase from baseline in the ratio of Aß37/Aß40 and Aß38/Aß42, respectively, was measured. Over a 2-week period, multiple ascending doses of RG6289 resulted in increases of approximately 350%, 1100%, 40%, and 400% in Aß37, Aß37/Aß40, Aß38, and Aß38/Aß42, respectively. Throughout this time, investigators observed decreases of 60% and 70% in Aß40 and Aß42, respectively.

Modulating y-secretase has been a compelling therapeutic approach, designed to target amyloid precursor protein processing and Aß-aggregation upstream. The mechanism of action of such modulators is expected to slow down or halt amyloid aggregation, reduce plaque formulation, and delay/prevent cognitive decline. RG6289 is considered a highly potent GSM that has no impact on enzyme activity, no effect on human Notch-1, and has selectivity established for a broad range of potential targets.

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At the 16th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held October 24-27, 2023, investigators presented the dose selection for a phase 2 trial of RG6289 dubbed GABriella. Over an 18-month treatment period, GABriella will investigate safety and tolerability, as well as the agent’s impact on multiple disease-related biomarkers, including amyloid-PET, markers of neurodegeneration, synaptic integrity, and inflammation.²

The selected study population for GABriella is optimized to include those with a high amyloid accumulation rate. In the study, patients must be cognitively unimpaired or have a diagnosis of mild cognitive impairment because of AD per National Institute on Aging-Alzheimer’s Association criteria. Those includes are expected to have a Clinical Dementia Rating-GS of 0 or 0.5. The study also has a centiloid cut-off of 24, and will only allow 15% of patients to have more than 100 centiloids at baseline.

The double-blind, parallel-group, randomized, placebo-controlled study, which began recruiting in the first half of 2024, includes a 2-week baseline period, 72-week treatment period, and 4-week follow-up. In total, an approximate 245 patients will be randomly assigned to either placebo (n = 70) or low (n = 35), intermediate (n = 70), or high (n = 70) doses of RG6289. GABriella’s primary end point is the safety and tolerability of RG6289 while secondary end points assess pharmacokinetic and pharmacodynamic properties of the therapy. Exploratory outcomes include changes in CSF and plasma biomarkers, and MRI sequences, along with changes in the Cogstate Cognitive Test Battery and CDR-SB.

The study excludes those with any condition other than AD that may affect cognition, as well as those with major psychiatric disorders or active inflammatory bowel disease. In addition, those with diabetes, impaired hepatic function or chronic kidney disease will also be excluded. Furthermore, the study excludes those with Fazekas score of 3 and at least 20 mm at the MRI scan.

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REFERENCES
1. Mueggler T, Portron A, Poirier A, et al. Pharmacodynamic effect of a new y-secretase modulator, RG6289, on CSF amyloid-ß peptides in a randomized phase 1 study. Presented at: AAIC; July 28-August 1, 2024. Philadelphia, PA. POSTER: 95213
2. Tortelli R, Vogt A, Gaspar E, et al. A phase 2a study investigating y-secretase modulator in individuals at risk for or at the prodromal stage of Alzheimer disease. Presented at: ADPD 2024. https://medically.roche.com/content/dam/pdmahub/restricted/neurology/adpd-2024/ADPD-2024-presentation-tortelli-a-phase-IIa-study.pdf