Phase II Open-Label Study on Safety, Tolerability, Pharmacokinetics, and Efficacy of AG13909 in Adults with Cushing's Disease

The primary objective of this Phase II, multi-site, open-label, dose-titration trial is to evaluate the effects of **Lu AG13909** in adult participants with **Cushing's Disease**. This condition is characterized by excessive production of cortisol, a hormone that can lead to serious health complications. The trial aims to assess the impact of Lu AG13909 on cortisol levels, which is clinically relevant as it may offer a therapeutic option for managing cortisol excess in Cushing's Disease. Additionally, the trial will investigate the safety and tolerability of Lu AG13909, ensuring that the treatment is not only effective but also safe for patients. The pharmacokinetic parameters of Lu AG13909 will also be evaluated to understand how the drug is absorbed, distributed, and processed by the body, which is crucial for optimizing dosing regimens and ensuring effective treatment outcomes.

The clinical trial involves a total of **6 participants** diagnosed with **Cushing's Disease**, a condition characterized by excessive cortisol production. The study population includes both male and female adults, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on a confirmed diagnosis of adrenocorticotropic hormone (ACTH) driven Cushing's Disease of pituitary origin, as per current guidelines. They are generally healthy apart from their condition and any associated well-controlled comorbidities such as diabetes mellitus and hypertension. The trial does not include a vulnerable population. Participants' lifestyle factors such as diet and physical activity are not specified, but those on medical treatment for hypercortisolism must complete pre-defined washout periods before baseline assessments. The selection criteria ensure that participants have a morning plasma ACTH level above the lower limit of normal and a 24-hour urinary free cortisol level greater than 1.5 times the upper limit of normal, confirming the presence of the disease.

The clinical trial is a Phase II, multi-site, open-label, dose-titration study designed to evaluate the **safety**, tolerability, pharmacokinetics, and efficacy of Lu AG13909 in adults diagnosed with **Cushing's disease**. This trial aims to assess the effects of Lu AG13909 on cortisol levels, its safety profile, and pharmacokinetic parameters, including absorption, distribution, and processing by the body. The trial is expected to commence recruitment on June 1, 2024, and conclude by February 15, 2028, with a maximum treatment period of 910 days for participants.

Participants will be involved in a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of adrenocorticotropic hormone (ACTH) driven Cushing's disease, elevated morning plasma ACTH levels, and evidence of pituitary origin of excess ACTH. Following the screening, participants will undergo baseline efficacy assessments after completing any necessary washout periods for those on medical treatment for hypercortisolism. The trial will include multiple follow-up visits to monitor the primary endpoints, which include the urinary free cortisol (UFC) complete response and the number of participants with treatment-emergent adverse events (TEAEs). Pharmacokinetic endpoints will also be assessed, such as maximum observed plasma concentration (Cmax), minimum observed concentration (Ctrough), and systemic clearance (CL) of Lu AG13909.

The trial design does not incorporate a control group, as it is open-label, and participants will receive Lu AG13909 either via subcutaneous or intravenous administration. The expected length of participant involvement is up to 1037 days, depending on the specific pharmacokinetic assessments required. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or the participant's decision to withdraw consent. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, with the primary focus on participant safety and the collection of robust data to evaluate the investigational product's efficacy and safety profile.

The clinical trial involves the administration of **Lu AG13909**, a humanized anti-ACTH monoclonal antibody, to evaluate its safety, tolerability, pharmacokinetics, and efficacy in adults with Cushing's disease. **Lu AG13909** is provided in two pharmaceutical forms: a **solution for injection** and a **solution for infusion**. The solution for injection is administered via the **subcutaneous route**, while the solution for infusion is administered **intravenously**. Both forms are produced by H. Lundbeck A/S and contain the active substance **AG13909**, which is a protein of other origin. The trial does not specify a maximum daily or total dose amount, and the maximum treatment period is set at 910 days.

In addition to the experimental medication, the trial may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The trial aims to assess the impact of **Lu AG13909** on cortisol levels, a critical factor in managing Cushing's disease, and to gather data on how the drug is absorbed, distributed, and processed by the body.

The efficacy of Lu AG13909 in the treatment of **Cushing's disease** will be assessed through several primary endpoints. The primary efficacy endpoint is the Urinary Free Cortisol (UFC) Complete Response, defined as the mean UFC (mUFC) being less than or equal to the Upper Limit of Normal (ULN) at the end of the intravenous/subcutaneous titration period. This endpoint will be evaluated over a time frame of up to 490 days. Additionally, the number of participants experiencing treatment-emergent adverse events (TEAEs) will be monitored over a period of up to 1023 days to assess the safety and tolerability of the treatment.

Pharmacokinetic (PK) parameters will also be evaluated as part of the efficacy assessment. These include the maximum observed plasma concentration (Cmax) and the nominal time corresponding to the occurrence of Cmax (Tmax) for Part A, with a time frame of up to 323 days. For both Part A and Part B, the minimum observed concentration (Ctrough) and the nominal time corresponding to the occurrence of Ctrough (Ttrough) will be measured over a period of up to 659 days. Additional PK endpoints include the area under the plasma concentration curve at steady state (AUC0-tau,ss), systemic clearance (CL), elimination half-life (t½), apparent volume of distribution (Vd), and subcutaneous bioavailability (F), all assessed over a time frame of up to 1037 days.