A First-in-Human, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of Intrathecally Administered LTX-002 in Adult Participants with Amyotrophic Lateral Sclerosis

The primary objective of this first-in-human study is to evaluate the **safety** and **tolerability** of **intrathecally** administered **LTX-002** in adult participants with **amyotrophic lateral sclerosis** compared to **placebo**. This assessment is clinically relevant as it establishes the foundational safety profile of this **antisense oligonucleotide** delivered via **intrathecal** route in patients with **ALS**, a progressive neurodegenerative disease affecting motor neurons.

The secondary objective is to evaluate the **pharmacokinetics** of LTX-002 following intrathecal administration in adult participants with amyotrophic lateral sclerosis. This characterization provides essential data on drug exposure, distribution, and elimination patterns following direct delivery to the **central nervous system**, which is critical for informing dose selection and dosing regimens in subsequent clinical development phases.

This clinical trial enrolled a total of **26 participants** diagnosed with **Amyotrophic Lateral Sclerosis** (ALS). The study population included both **male and female participants** aged **18 to 75 years** at the time of consent. Participants were required to have a diagnosis of ALS according to **Gold Coast criteria** with symptom onset less than **36 months** prior to screening. The trial population was selected based on specific health parameters, including a **slow vital capacity** (SVC) of at least 50% of predicted value adjusted for sex, age, and height measured from a sitting position, and a **body mass index** ranging from 18 to 40 kg/m². Participants taking **riluzole**, **edaravone**, or **sodium phenylbutyrate** combined with **taurursodiol** were required to maintain a stable dose for at least 30 days prior to treatment initiation. Screening assessments confirmed that coagulation parameters, including **platelet count**, **International Normalization Ratio**, **prothrombin time**, and **activated partial thromboplastin time**, were within normal ranges. Participants of childbearing potential and their partners were required to use two effective methods of contraception throughout the study period. The trial included a vulnerable population as defined by regulatory standards.

This is a first-in-human, double-blind, placebo-controlled, multiple ascending dose study designed to evaluate the safety and tolerability of intrathecally administered LTX-002 in adult participants with amyotrophic lateral sclerosis. The investigational medicinal product LTX-002 is an antisense oligonucleotide containing LTX-002 sodium as the active substance, administered via intrathecal bolus injection to the intrathecal space. The placebo consists of a corresponding volume of sterile artificial cerebrospinal fluid solution formulation intended for intrathecal administration, identical to the investigational medicinal product but without active substance. This Phase 1/2 clinical trial is categorized as Category 2 and is expected to commence recruitment in January 2026, with an estimated completion date in June 2031.

Eligible participants include males and females aged 18 to 75 years with a diagnosis of amyotrophic lateral sclerosis per Gold Coast criteria and symptom onset less than 36 months prior to screening. Participants must have a slow vital capacity of at least 50% of predicted value adjusted for sex, age, and height from the sitting position. Body mass index must be between 18 and 40 kg/m². Participants taking riluzole, edaravone, or sodium phenylbutyrate plus taurursodiol must be on a stable dose for at least 30 days prior to Day 1 and remain at that dose until the final study visit on Day 169. Coagulation parameters including platelet count, International Normalization Ratio, prothrombin time, and activated partial thromboplastin time should be within normal ranges at screening. Female participants of childbearing potential with male partners and male participants with female partners of childbearing potential must use two effective methods of contraception, with at least one being highly effective, from Day 1 until 3 months after the last dose of study drug.

The primary endpoints focus on safety and tolerability assessment through incidence and severity of adverse events, treatment-emergent adverse events, and serious adverse events. Additional safety parameters include clinical laboratory tests encompassing serum chemistry, hematology, and urinalysis, electrocardiograms, vital signs measurements including blood pressure, heart rate, respiratory rate, and body temperature, as well as physical and neurological examinations. Secondary endpoints evaluate cerebrospinal fluid levels of LTX-002 and single-dose plasma pharmacokinetic parameters for the first and last of the three doses. These pharmacokinetic parameters include maximum plasma concentration, time to maximum concentration, area under the curve from time zero to the last measurable concentration, area under the curve from time zero to infinity, lag time if applicable, apparent volume of distribution, terminal elimination rate constant, terminal elimination half-life, and apparent clearance. Where data are available, dose proportionality will be tested using a power model approach.

Participant involvement in the study extends until Day 169, which represents the final study visit. The trial employs a multiple ascending dose design with participants receiving three doses of either LTX-002 or placebo administered intrathecally. Participants must be medically able to undergo study procedures and adhere to the visit schedule at the time of study entry as determined by the principal investigator. Conditions that may lead to early termination from the study are not explicitly specified in the available protocol information.

**LTX-002** is an **antisense oligonucleotide (ASO)** investigational medicinal product containing **LTX-002 sodium** as the active substance, which is of nucleic acid origin. The product is manufactured by Leal Therapeutics, Inc. and is supplied as an **injection** for intrathecal administration. LTX-002 is administered via **intrathecal bolus injection to the intrathecal space**. This clinical trial evaluates multiple ascending doses of LTX-002 in adult participants with **amyotrophic lateral sclerosis**.

The **placebo** used in this study is identical to the investigational medicinal product but contains no active substance. The placebo consists of a corresponding volume of sterile **artificial cerebrospinal fluid (aCSF)** solution formulation intended for intrathecal administration. The placebo is manufactured under the same manufacturing authorization and good manufacturing practice quality person certification as LTX-002. The placebo is administered via the same route and schedule as the active treatment to maintain blinding in this double-blind, placebo-controlled study design.

Efficacy will be assessed through the evaluation of secondary endpoints focusing on pharmacokinetic parameters. Cerebrospinal fluid levels of LTX-002 will be measured to determine drug distribution in the central nervous system. Single-dose plasma pharmacokinetic parameters will be assessed for the first and last of the three doses, including maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t), area under the concentration-time curve from time zero to infinity (AUC0-∞), lag time if applicable (Tlag), apparent volume of distribution (Vd/F), terminal elimination rate constant (λz), terminal elimination half-life (T1/2), and apparent total body clearance (CL/F). Where data are available, AUC0-∞, AUC0-t, and Cmax will be tested for dose proportionality using a power model approach.