Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Frontotemporal Dementia Patients and Healthy Subjects

The primary objective of this study is to evaluate the **safety** and **tolerability** of DNL593 in both healthy participants and those with Frontotemporal Dementia (FTD). This is crucial for determining the potential of DNL593 as a therapeutic agent, ensuring that it can be administered safely without causing adverse effects. The study is divided into three parts: Part A focuses on single doses in healthy participants, while Parts B and C assess multiple doses in participants with FTD-GRN, with Part C extending the evaluation up to 18 months.

Secondary objectives include:

• Part A: Characterizing the serum pharmacokinetics (PK) and cerebrospinal fluid (CSF) concentration of DNL593 following single doses in healthy participants.
• Part B: Characterizing the serum PK and CSF concentration of DNL593 following multiple doses in participants with FTD-GRN, and evaluating changes in plasma neurofilament light chain (Nfl) levels.
• Part C: Characterizing the serum PK and CSF concentration of DNL593 following multiple doses in participants with FTD-GRN.

The clinical trial involves a total of **14 participants** and is focused on individuals diagnosed with **Frontotemporal Dementia (FTD)**. The study population includes both male and female subjects, with age ranges spanning from 18 to 80 years. Participants in Part A are healthy individuals aged 18 to 55 years, while those in Parts B and C are individuals with FTD-GRN aged 18 to 80 years. The trial includes women of non-childbearing potential or those using highly effective contraception, as well as men. Participants are required to have a **Body Mass Index (BMI)** between 18 and 32 kg/m². The selection process for the trial population involves specific criteria, including genetic confirmation of a granulin mutation for Parts B and C. The study considers lifestyle factors such as the use of contraception for participants engaging in sexual activity with women of childbearing potential. The trial also includes a vulnerable population, as indicated by the selection criteria. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of DNL593 in both healthy participants and those with **Frontotemporal Dementia (FTD)**. The trial is structured in multiple parts, with Part A focusing on single doses in healthy participants, and Parts B and C involving multiple doses in participants with FTD-GRN. The study is expected to last up to 18 months, with an estimated end date in June 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, BMI, and genetic testing for the granulin mutation. Following successful screening, participants will be randomized to receive either DNL593 or a placebo. The trial includes regular follow-up visits to monitor safety and collect data on primary endpoints, such as the incidence and severity of treatment-emergent adverse events (TEAEs), and secondary endpoints, including pharmacokinetic parameters and changes in plasma biomarkers.

The end-of-study visit will conclude the participant's involvement, unless they are eligible and choose to continue in the open-label extension (OLE) phase, which is available for those who complete Part B without unresolved clinically significant TEAEs. Participant involvement is expected to last up to 18 months, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety.

The clinical trial involves the administration of **DNL593**, a biological investigational product, formulated as a **solution for injection**. The active substance, DNL593, is a protein of other origin, developed by Denali Therapeutics Inc. The solution is administered **intravenously**. The study evaluates both single and multiple doses of DNL593, with the dosing schedule tailored to the specific phase of the trial. Participant compliance is monitored through regular assessments and documentation of administration.

A **placebo** is utilized in this trial, presented as a sterile lyophilisate in single-dose glass vials. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the study. The placebo serves as a control to evaluate the efficacy and safety of DNL593.

**Famotidine**, a chemical auxiliary product, is included in the trial. It is available in the pharmaceutical form PHF00009MIG and can be administered both **orally and intravenously**. Famotidine is classified under the ATC code A02BA03, indicating its use as a histamine H2-receptor antagonist. The inclusion of famotidine is to manage potential gastrointestinal side effects associated with the investigational treatment.

Additional auxiliary treatments include antihistamines and glucocorticoids, classified under ATC codes R06A and H02AB, respectively. These are available in pharmaceutical forms PHF00245MIG and PHF00170MIG, and can be administered **orally and intravenously**. These treatments are used to manage allergic reactions and inflammation that may arise during the trial.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs), as well as changes from baseline in safety laboratory values, vital sign measurements, ECG results, and physical/neurological examination findings. These parameters will be monitored over a timeframe of up to 18 months.

Secondary endpoints focus on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of **DNL593**. These include serum PK parameters such as Cmax, tmax, Ctrough, AUClast, AUCt, t 1/2, and accumulation ratio, as well as the concentration of **DNL593** in cerebrospinal fluid (CSF) and the CSF:serum concentration ratio. Additionally, the percentage change from baseline in plasma neurofilament light chain (Nfl) at Week 25 will be evaluated. These measurements will also be conducted over a period of up to 18 months.