Background: Axonal degeneration has been recognized as a key early contributor to the clinical presentation and pathogenesis of amyotrophic lateral sclerosis (ALS). Activation of the calcium-dependent cysteine protease calpain-2 is considered a critical effector of axonal degeneration. Based on evidence supporting a potential benefit of calpain-2 modulation in ALS and other neurodegenerative diseases, Amylyx developed AMX0114, an antisense oligonucleotide (ASO) inhibitor of calpain-2. This phase 1 study will assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMX0114 in people with ALS. Methods: LUMINA is planned to be conducted at ~15 sites in North America enrolling approximately 48 participants randomized 3:1 to receive AMX0114 or placebo. After study completion, an open-label extension study of AMX0114 will be implemented if data supports a positive benefit-risk profile. Results: The primary endpoints of the study include the incidence of adverse events (AEs), serious AEs, and dose-limiting toxicities. Secondary and tertiary endpoints include PK measurements (plasma and cerebrospinal fluid [CSF] levels of AMX0114), PD biomarkers, and functional measures of ALS progression. Conclusions: LUMINA is a first-in-human study evaluating the safety, tolerability, PK, and PD of AMX0114, the first ASO targeting calpain-2 in adult participants with ALS. Enrollment is planned to begin in Canada in early 2025.

Background: In ALS, determining whether individuals have a substantial response to therapy is a challenge for the field. ALS naturally progresses at variable rates and a personalized approach is required to determine if individuals have a substantial response. A new method to evaluate individual response is proposed and applied to data from the CENTAUR trial of sodium phenylbutyrate/ursodoxicoltaurine (PB/TURSO). Methods: In a post hoc analysis, CENTAUR participants whose actual rate of change from baseline in the ALSFRS-R at week 18 was ≤ their own trial baseline progression rate (ΔFS) were defined as having a substantial individual response in slowing ALS progression. Results: Substantial individual response was observed in a greater proportion of participants receiving PB/TURSO (41%, n=87) vs placebo (19%, n=48; P=0.0076). Conclusions: Response versus ΔFS provides a personalized metric to determine substantial individual response in ALS. ΔFS has been shown to be highly correlated with, but to proportionally underestimate, ALSFRS-R decline in clinical trials. Consequently, those who outperform the ΔFS may be considered to have a substantial individual response. Application to CENTAUR data demonstrates a greater proportion of participants with a substantial individual response in the PB/TURSO arm. These methods may enable greater personalization and analysis of individual response in ALS.

We show that continuous triangular maps of the square I1, F: (x, y) → (f(x), g(x, y)), exhibit phenomena impossible in the one-dimensional case. In particular: (1) A triangular map F with zero topological entropy can have a minimal set containing an interval {a} × I, and can have recurrent points that are not uniformly recurrent; this solves two problems by S.F. Kolyada.

(2) In the class of mappings satisfying Per(F) = Fix(F), there are non-chaotic maps with positive sequence topological entropy and chaotic maps with zero sequence topological entropy.