Title : Safety, pharmacokinetics and target engagement of a novel brain penetrant RIPK1 inhibitor (SIR9900) in healthy volunteers with therapeutic potential for neurodegenerative diseases
Abstract:
Background: Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine protein kinase that regulates inflammatory signalling and induces apoptosis and necroptosis. Activation of RIPK1 has been observed in human pathological samples from individuals with neurodegenerative, autoimmune and inflammatory diseases. Pharmacological inhibition of RIPK1 kinase activity has demonstrated efficacy in numerous animal models, such as Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), etc. RIPK1 may promote the progression of AD through both neuroinflammation and neuron cell necroptosis.
Methods: SIR9900 is a potent and selective novel small molecule RIPK1 kinase inhibitor. This first-in-human, phase I, randomized, double-blind, placebo-controlled study in Australia (ACTRN12623000696695, ACTRN12623000790640) evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single (3-200 mg) and multiple (3-60 mg daily for 10 days) ascending oral doses of SIR9900 in healthy adult (18 to 64 years, n=80) and elderly participants who were healthy or had managed, stable disease(≥65 years, multiple doses at 30 mg, n=8,) between June 2023 and January 2024. The study also included a food effect component.
Results: Overall, oral administration of SIR9900 was safe and well tolerated in healthy adult and elderly participants, with no concerned dose-dependent trends in safety observed. The most reported treatment emergent adverse events (TEAEs) were headache and gastrointestinal disorders. The majority TEAEs were mild, most TEAEs were resolved by the end of the study. No clinically meaningful trends were identified from 12-lead electrocardiogram (ECG), vital signs and laboratory results. SIR9900 was rapidly absorbed with a median time to maximum plasma concentration (Tmax) range of 3.0-4.0 hours and eliminated with a geometric mean plasma half-life (t1/2) ranging from 31.92 to 37.75 hours following single doses. Similar Tmax and t1/2 results were observed following multiple doses. The systemic exposure to SIR9900 on Day 10 was approximately 2 to 4-fold higher than that following a single dose on Day 1. Systemic exposure to SIR9900 increased in a generally proportional manner as the dose increased. No appreciable food effect was observed. A geometric mean value of cerebrospinal fluid (CSF) to unbound plasma ratio was 1.15, potentially indicating a good blood-brain barrier (BBB) permeability. Systemic exposure to SIR9900 was similar between adult and elderly participants. SIR9900 demonstrated a robust PD effect with approximately 90% (84.9% to 98.2%) peripheral target engagement at 3 hours post-dose following single and multiple doses tested, and a sustained RIPK1 activity inhibition effect even at trough levels over the 10-day treatment period of multiple doses once daily.
Conclusion: The favourable safety, PK, and PD profile of SIR9900 with central nervous system (CNS) penetrating potential in healthy adult and elderly participants supports its further clinical development in patients with neurodegenerative diseases, particularly those affecting the central nervous system, such as AD.
Audience Take Away Notes:
- To highlight and draw attention to a novel therapeutic approach for neurodegenerative diseases, such as Alzheimer's Disease (AD)
- To report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) profile of RIPK1 inhibitor SIR9900, providing valuable information to researchers and industries working in this field
- The RIPK1 inhibitor SIR9900 exhibits potential for good blood-brain barrier (BBB) permeability, making it a promising candidate for treating central nervous system diseases
