Phase 2 Randomized Double-Blind Placebo-Controlled Study of Ponsegromab in Cancer Cachexia with Elevated GDF-15 Concentrations

The primary objective of this study is to evaluate the effect of **ponsegromab** compared with placebo on body weight in participants with cancer cachexia and elevated concentrations of GDF-15. This is clinically relevant as cancer cachexia is a multifactorial syndrome characterized by severe body weight, fat, and muscle loss, which significantly impacts patient quality of life and survival.

Secondary objectives include:

• Evaluating the effect of ponsegromab compared to placebo on physical activity and gait as measured by wearable digital sensors.
• Assessing the effect on appetite-related symptoms using the Functional Assessment of Anorexia/Cachexia Therapy (FAACT).
• Evaluating the impact on anorexia/appetite, nausea, vomiting, and fatigue using the Cancer Related Cachexia Symptom Diary (CRCSD), a Pfizer-developed instrument.
• Characterizing the safety and tolerability of repeated subcutaneous administrations of ponsegromab compared to placebo.

The clinical trial involves a total of **115 participants** diagnosed with **cancer cachexia**, specifically targeting individuals with elevated concentrations of GDF-15. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have a documented histologic or cytologic active diagnosis of non-small cell lung cancer (NSCLC), pancreatic cancer (PANC), or colorectal cancer (CRC) and must be currently receiving or have completed standard care treatment for these conditions. The trial population was selected based on specific inclusion criteria, including a body mass index (BMI) of less than 20 kg/m² with involuntary weight loss of more than 2% within six months prior to screening, or involuntary weight loss of more than 5% within the same period, regardless of BMI. Additionally, participants must have serum GDF-15 concentrations of at least 1.5 ng/mL and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 3 or lower, with a life expectancy of at least four months. The trial includes individuals who are willing and able to comply with all scheduled visits, treatment plans, laboratory tests, and other study procedures. The study also considers lifestyle factors, ensuring participants can adhere to the necessary requirements throughout the trial duration.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, and tolerability of **Ponsegromab** in patients with **cancer cachexia** and elevated concentrations of GDF-15. The trial aims to assess the effect of Ponsegromab compared to placebo on body weight over a 12-week period. The study is structured to include an initial double-blind treatment phase followed by an optional open-label treatment period. The trial is expected to conclude by March 2025, with recruitment having commenced in November 2022.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, cancer diagnosis, cachexia status, and serum GDF-15 levels. Eligible participants will be randomized to receive either Ponsegromab or placebo, administered as a **solution for injection** via subcutaneous use. The primary endpoint is the change in body weight from baseline at Week 12. Secondary endpoints include changes in physical activity, gait, FAACT sub-scale scores, and CRCSD-related symptoms, as well as the incidence of adverse events and laboratory test abnormalities.

Study visits will occur at regular intervals throughout the trial, with assessments conducted to monitor safety, efficacy, and compliance with the treatment regimen. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data points. Participants are expected to be involved in the study for approximately 12 weeks, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study procedures.

The clinical trial involves the administration of **Ponsegromab (PF-06946860)**, a humanised IgG1 monoclonal antibody targeting Growth/differentiation factor 15 (GDF15). This investigational medicinal product is provided as a **solution for injection** and is administered via the **subcutaneous route**. The maximum daily dose is 400 mg, with a total treatment period not exceeding 12 weeks. The formulation is of biological/biotechnological origin, specifically a protein of other origin, and is not classified as an Advanced Therapy Investigational Medicinal Product (ATIMP). The administration schedule and participant compliance are monitored throughout the study to ensure adherence to the dosing regimen.

The study also includes a **placebo** comparator, designed to match the **Ponsegromab (PF-06946860) solution for injection** in appearance and administration method. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the efficacy and safety of Ponsegromab. Compliance with the placebo administration is similarly monitored to maintain the integrity of the study results.

The efficacy of Ponsegromab in the clinical trial will be assessed primarily by evaluating the **change from baseline body weight** at Week 12. This primary endpoint is designed to measure the effect of Ponsegromab compared to placebo in patients with cancer, cachexia, and elevated concentrations of GDF-15. Secondary endpoints include changes from baseline in physical activity and gait endpoints, which will be measured using remote digital sensors at Week 12. These endpoints encompass moderate to vigorous physical activity time, sedentary activity time, non-sedentary activity time, total vector magnitude, mean activity level during a 6-minute walk test (M6min), mean gait speed, and the 95th percentile gait speed.

Additionally, changes from baseline in the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) sub-scale scores at Week 12 will be evaluated, specifically the FAACT-ACS and FAACT-5IASS scores. The trial will also assess changes from baseline scores for questions from the Cancer-Related Cachexia Symptom Diary (CRCSD) at Week 12, focusing on anorexia/appetite, nausea and vomiting, and fatigue. The incidence of adverse events, safety laboratory tests, vital signs, and ECG abnormalities will also be monitored as part of the secondary endpoints. These assessments will be conducted at specified timepoints, with the primary focus on Week 12, to determine the efficacy and safety profile of Ponsegromab in the study population.