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Purpose Elevated dopamine synthesis capacity is part of the pathophysiology of schizophrenia thought to underlie psychosis. Drugs that reduce this phenomenon could thus be potential treatments for these disorders. In this study, we evaluated the ability of the trace amine-associated receptor 1 (TAAR1) partial agonist ralmitaront to reduce presynaptic dopamine synthesis capacity. Procedures Ralmitaront (3 mg/kg, i.p.), a TAAR1 partial agonist, was evaluated using [18F]DOPA PET for its ability to modulate presynaptic dopamine synthesis capacity in naïve mice as well as mice in an induced hyperdopaminergic state following acute cocaine administration (20 mg/kg, i.p.). Results Cocaine treatment on its own did not induce elevated dopamine synthesis capacity when compared to the control group. Pretreatment with ralmitaront significantly reduced dopamine synthesis capacity when given either alone (44%) or in combination with the psychostimulant cocaine (50%) when compared to the control group. Conclusions The TAAR1 agonist ralmitaront reduces striatal dopamine synthesis capacity, indexed as KiMod, both in naïve animals and when given prior to acute cocaine. This indicates the potential of TAAR1 agonism to address disorders characterized by striatal hyperdopaminergia.

Mutated HTT , resulting in mutant huntingtin, causes Huntington’s disease. A phase 1–2a trial of intrathecal delivery of an antisense oligonucleotide targeting HTT mRNA in 34 persons with Huntington’s disease showed a dose-dependent reduction of mutant huntingtin in cerebrospinal fluid and no serious adverse events in those who received the drug.

Amyloid β (Aβ) has been confirmed as a therapeutic target in AD by recent findings in Phase 3 trials with anti‐Aβ antibodies. Modulators of γ‐secretase (GSMs) are an emerging complementary approach to target amyloid. GSMs “modulate” the interaction between γ‐secretase and amyloid precursor protein (APP), leading to a reduced production of long, amyloidogenic Aβ42 and Aβ40 and to concomitantly increased levels of the shorter, non amyloidogenic Aβ37 and Aβ38. This change in processivity of γ‐secretase results in a reduced formation of soluble and insoluble Aβ aggregates and plaque deposits. Unlike inhibitors of γ‐secretase or BACE1, GSMs do not inhibit the activity of γ‐secretase and thus do not block the processing of APP and of other substrates. In addition, non‐clinical studies showed that GSMs may have beneficial effects on synaptic integrity and Aβ‐associated neuro‐inflammation. The clinical relevance of higher Aβ37 and Aβ38 ‐levels for a reduced risk of cognitive decline have been described in observational cohorts (vonKienlin et al. 2018; Cullen et al. 2022). Nevertheless, to date the effects of GSMs on brain function and course of disease in people living with AD have not been investigated. Our novel orally available GSM RG6289 has completed the Phase 1 study in healthy young and elderly volunteers. Safety, pharmacokinetic and pharmacodynamic data from this study support the further clinical development of the molecule. The Phase 2 study in individuals with AD is expected to start this year. Challenges of developing in clinic a new mechanism of action, as well as considerations regarding how to best position this molecule for AD will be discussed in this presentation.

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

Background RG6289 is a novel, potent and selective oral γ‐secretase modulator (GSM) in development for Alzheimer’s disease (AD). In the Entry‐into‐Human study in healthy volunteers, RG6289 demonstrated a favorable safety and tolerability profile, along with the anticipated pharmacodynamic effect of reducing amyloidogenic Aβ42 and increasing the shorter, non‐amyloidogenic isoforms Aβ38 and Aβ37 in both cerebrospinal fluid and plasma. This presents the baseline characteristics of the population recruited into the ongoing GABriella Ph2a study. Method GABriella is a randomized, double blind, placebo‐controlled, multi‐center, parallel group, dose‐range finding study investigating the safety, tolerability and the effect of RG6289 on key AD‐related biomarkers. The study includes individuals aged 60 to 85 years who are amyloid positive (≥24 centiloids on amyloid PET) and either cognitively unimpaired (CU) or with mild cognitive impairment (MCI) due to AD, diagnosed according to the NIA‐AA research framework criteria 2018. Clinical Dementia Rating Scale ‐ global score (CDR‐GS) at screening can be either 0 or 0.5. The trial includes three dose levels and one placebo arm and aims to recruit approximately 245 individuals who will be treated for 72 weeks. Result As of April 11th 2025, 96% of the targeted participant number has been randomized, with a mean age of 72 years (SD: 5) and a mean BMI of 25,1 (SD: 3,5). 55% are females. 15% are cognitively unimpaired, and 85% have a diagnosis of MCI due to AD. 9% have a CDR‐GS of 0, and 91% have a CDR‐GS of 0.5. 36% are on anticholinesterase standard‐of‐care therapy. The mean amyloid load at baseline is 76.8 centiloids (SD: 25.5). Recruitment is expected to be completed shortly. Conclusion GABriella is the first clinical trial assessing the effects of a brain‐penetrant, potent, and selective GSM in amyloid‐positive individuals, who are either CU or have MCI due to AD. This study will provide critical insights into the safety, tolerability, and pharmacodynamic effects of RG6289 on key AD‐related biomarkers. The results will contribute to understanding the potential of GSM therapy in the early stages of AD.

Background γ‐Secretase modulators (GSMs) represent a promising therapy for Alzheimer’s disease (AD). GSMs selectively reduce amyloidogenic long Aβ peptides (e.g.: Aβ42) while simultaneously increasing shorter, non‐amyloidogenic, Aβ species (Aβ38 and Aβ37). Here we report the results of pharmacodynamic (PD) effects of RG6289, a novel, potent and selective, orally bioavailable GSM, in a Entry‐in‐Human (EiH) Phase I study including data from serial cerebrospinal fluid (CSF) sampling. Method In a Phase I study in healthy volunteers, the PD effects of RG6289 were investigated following single and multiple ascending oral doses of RG6289 or placebo. Plasma and CSF samples were collected over 36 hours after single dose administration in a dedicated serial CSF sampling part of the study. Samples were analyzed using the Elecsys® plasma and CSF assays to assess effects of RG6289 on Aβ metabolism (Aβ42, Aβ40, Aβ38, Aβ37) Result For serial CSF sampling, 12 healthy volunteers (46‐70 years) were randomized to receive a single dose of RG6289 (n = 9) or placebo (n = 3). Data from serial CSF sampling were highly variable and concentrations of all Aβ monomers increased over the sampling period after administration of placebo. A dose‐dependent increase in Aβ37/Aβ40 and Aβ38/Aβ42 ratios was observed up to 36 hours post dose. At the highest dose, an approximate 500% and 150% increase from baseline in the ratio of Aβ37/Aβ40 and Aβ38/Aβ42, respectively, was measured. Multiple ascending oral administration of RG6289 for 2 weeks resulted in an increase in Aβ37, Aβ37/Aβ40, Aβ38 and Aβ38/Aβ42 up to approximately 350%, 1100%, 40% and 400%, respectively, whilst there was a decrease in Aβ40 and Aβ42 of up to approximately 60% and 70%, respectively. Conclusion In humans, RG6289 produced a dose‐dependent shift in the production of longer (Aβ40 and Aβ42) and shorter (Aβ37 and Aβ38) Aβ monomers in CSF. The results from this study support the further clinical development of RG6289 for the treatment of AD with the goal to reduce production of Aβ42, increase the levels of smaller Aβ species and slow‐down or halt Aβ aggregation and accumulation as an approach to altering AD progression.

RG6289 is a novel, potent and selective oral γ-secretase modulator (GSM) in development for Alzheimer's disease (AD). In the Entry-into-Human study in healthy volunteers, RG6289 demonstrated a favorable safety and tolerability profile, along with the anticipated pharmacodynamic effect of reducing amyloidogenic Aβ and increasing the shorter, non-amyloidogenic isoforms Aβ and Aβ in both cerebrospinal fluid and plasma. This abstract presents the baseline characteristics of the population recruited into the ongoing GABriella Ph2a study. GABriella is a randomized, double blind, placebo-controlled, multi-center, parallel group, dose-range finding study investigating the safety, tolerability and the effect of RG6289 on key AD-related biomarkers. The study includes individuals aged 60 to 85 years who are amyloid positive (≥24 centiloids on amyloid PET) and either cognitively unimpaired (CU) or with mild cognitive impairment (MCI) due to AD, diagnosed according to the NIA-AA research framework criteria 2018. Clinical Dementia Rating Scale - global score (CDR-GS) at screening can be either 0 or 0.5. The trial includes three dose levels and one placebo arm and aims to recruit approximately 245 individuals who will be treated for 72 weeks. As of April 11th 2025, 96% of the targeted participant number has been randomized, with a mean age of 72 years (SD: 5) and a mean BMI of 25,1 (SD: 3,5). 55% are females. 15% are cognitively unimpaired, and 85% have a diagnosis of MCI due to AD. 9% have a CDR-GS of 0, and 91% have a CDR-GS of 0.5. 36% are on anticholinesterase standard-of-care therapy. The mean amyloid load at baseline is 76.8 centiloids (SD: 25.5). Recruitment is expected to be completed shortly. GABriella is the first clinical trial assessing the effects of a brain-penetrant, potent, and selective GSM in amyloid-positive individuals, who are either CU or have MCI due to AD. This study will provide critical insights into the safety, tolerability, and pharmacodynamic effects of RG6289 on key AD-related biomarkers. The results will contribute to understanding the potential of GSM therapy in the early stages of AD.

Elevated dopamine synthesis capacity is part of the pathophysiology of schizophrenia thought to underlie psychosis. Drugs that reduce this phenomenon could thus be potential treatments for these disorders. In this study, we evaluated the ability of the trace amine-associated receptor 1 (TAAR1) partial agonist ralmitaront to reduce presynaptic dopamine synthesis capacity.PurposeElevated dopamine synthesis capacity is part of the pathophysiology of schizophrenia thought to underlie psychosis. Drugs that reduce this phenomenon could thus be potential treatments for these disorders. In this study, we evaluated the ability of the trace amine-associated receptor 1 (TAAR1) partial agonist ralmitaront to reduce presynaptic dopamine synthesis capacity.Ralmitaront (3 mg/kg, i.p.), a TAAR1 partial agonist, was evaluated using [18F]DOPA PET for its ability to modulate presynaptic dopamine synthesis capacity in naïve mice as well as mice in an induced hyperdopaminergic state following acute cocaine administration (20 mg/kg, i.p.).ProceduresRalmitaront (3 mg/kg, i.p.), a TAAR1 partial agonist, was evaluated using [18F]DOPA PET for its ability to modulate presynaptic dopamine synthesis capacity in naïve mice as well as mice in an induced hyperdopaminergic state following acute cocaine administration (20 mg/kg, i.p.).Cocaine treatment on its own did not induce elevated dopamine synthesis capacity when compared to the control group. Pretreatment with ralmitaront significantly reduced dopamine synthesis capacity when given either alone (44%) or in combination with the psychostimulant cocaine (50%) when compared to the control group.ResultsCocaine treatment on its own did not induce elevated dopamine synthesis capacity when compared to the control group. Pretreatment with ralmitaront significantly reduced dopamine synthesis capacity when given either alone (44%) or in combination with the psychostimulant cocaine (50%) when compared to the control group.The TAAR1 agonist ralmitaront reduces striatal dopamine synthesis capacity, indexed as KiMod, both in naïve animals and when given prior to acute cocaine. This indicates the potential of TAAR1 agonism to address disorders characterized by striatal hyperdopaminergia.ConclusionsThe TAAR1 agonist ralmitaront reduces striatal dopamine synthesis capacity, indexed as KiMod, both in naïve animals and when given prior to acute cocaine. This indicates the potential of TAAR1 agonism to address disorders characterized by striatal hyperdopaminergia.

Objective Recent advances in understanding Spinal Muscular Atrophy (SMA) etiopathogenesis prompted development of potent intervention strategies and raised need for sensitive outcome measures capable of assessing disease progression and response to treatment. Several biomarkers have been proposed; nevertheless, no general consensus has been reached on the most feasible ones. We observed a wide range of measures over 1 year to assess their ability to monitor the disease status and progression. Methods 18 SMA patients and 19 healthy volunteers (HV) were followed in this 52‐weeks observational study. Quantitative‐MRI (qMRI) of both thighs and clinical evaluation of motor function was performed at baseline, 6, 9 and 12 months follow‐up. Blood samples were taken in patients for molecular characterization at screening, 9 and 12 month follow‐up. Progression, responsiveness and reliability of collected indices were quantified. Correlation analysis was performed to test for potential associations. Results QMRI indices, clinical scales and molecular measures showed high to excellent reliability. Significant differences were found between qMRI of SMA patients and HV. Significant associations were revealed between multiple qMRI measures and functional clinical scales. None of the qMRI, clinical, or molecular measures was able to detect significant disease progression over 1 year. Interpretation We probed a variety of quantitative measures for SMA in a slowly‐progressing disease population over 1 year. The presented measures demonstrated potential to provide a closer link to underlying disease biology as compared to conventional functional scales. The proposed biomarker framework can guide implementation of more sensitive endpoints in future clinical trials and prove their utility in search for novel disease‐modifying therapies.

BackgroundHD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype. A drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production.Design/methodsIn this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTTRx or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent DSMB review of safety, PK and target engagement prior to dose escalation.ResultsIONIS-HTTRx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma. Significant, dose-dependent reductions in CSF mutant HTT (mHTT) were observed.ConclusionsASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTTRx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD.Study Supported By: Ionis Pharmaceuticals