Ponsegromab: On Track to Become the First Approved Treatment for Cancer Cachexia (Wasting Syndrome)

The Importance of Cancer Cachexia and the Need for Treatment

• Cancer cachexia is a serious complication often encountered in advanced stages of cancer and can frequently adversely affect the course of treatment.
• Cachexia is characterized by involuntary weight loss, loss of muscle mass, and impaired physical function. It is a complex process involving multiple factors, with loss of appetite and metabolic changes among its main drivers.
• Affecting more than 50% of cancer patients, this syndrome not only lowers quality of life but also adversely affects treatment response and overall survival.
• However, at present, no drugs are approved to treat this condition.
• Current treatment options include drugs such as low-dose olanzapine (Zyprexa and similar products) and short courses of progesterone analogues (such as Megace and Borea), but their effectiveness is limited and they can cause serious adverse effects.

Pfizer presented clinical trial results indicating a major advance in this field. The data, presented at the 2024 ESMO Congress and also published on 14 September in the New England Journal of Medicine (NEJM), show that ponsegromab produced weight gain and improved appetite and physical activity in patients with cancer cachexia. More importantly, Pfizer believes these results confirm that the GDF-15 protein targeted by ponsegromab is a major driver of cachexia.

The Role of GDF-15 and the Development of Ponsegromab

Recent studies have shown that growth differentiation factor 15 (GDF-15) plays an important role in the development of cancer cachexia. GDF-15 is a cytokine released during the body’s stress response and triggers loss of appetite and weight loss. Animal models have shown that inhibiting GDF-15 alleviates cachexia symptoms. In this context, ponsegromab targets GDF-15 and blocks its interaction with this cytokine’s receptor, GFRAL. It was developed as a subcutaneously administered monoclonal antibody for this purpose.

Clinical Study Design

NEJM published a phase 2 clinical study investigating ponsegromab’s effects on cachexia. It included 187 patients with cancer cachexia, randomized to four groups receiving different ponsegromab doses (100 mg, 200 mg, or 400 mg) or placebo. All patients received a total of three injections of ponsegromab or placebo, given every four weeks. The primary aim was to assess changes in body weight after 12 weeks. Secondary objectives examined effects on appetite, physical activity, and cachexia symptoms.

Patient Profile and Baseline Findings

Most participants had advanced cancer. Of the patients, 40% had non-small cell lung cancer, 32% pancreatic cancer, and 29% colorectal cancer. The median age was 67, and most had a lean body build. All participants were required to have serum GDF-15 levels of at least 1500 pg/ml, enabling a clearer assessment of cachexia’s relationship with GDF-15.

Results: Ponsegromab’s Effectiveness

By the end of the study, weight gain had occurred at all three ponsegromab doses and was significant compared with placebo:

• Group receiving 100 mg ponsegromab: median weight gain of 1.22 kg (95% confidence interval 0.37-2.25).
• Group receiving 200 mg ponsegromab: median weight gain of 1.92 kg (95% confidence interval 0.92-2.97).
• Group receiving 400 mg ponsegromab: median weight gain of 2.81 kg (95% confidence interval 1.55-4.08).

The chart above shows clear weight gain with different ponsegromab doses compared with placebo. The 400 mg ponsegromab group had the greatest weight gain. The chart demonstrates ponsegromab’s effectiveness in treating cachexia and shows greater effectiveness with increasing doses.

Significant improvements in appetite and physical activity were also observed, particularly at the 400 mg dose. Patients receiving 400 mg ponsegromab showed an increase in physical activity duration compared with placebo, amounting to 72 minutes per day. These results show that, beyond weight gain alone, ponsegromab also positively contributes to patients’ overall quality of life and physical function.

Detailed Subgroup Analysis

The study also examined ponsegromab’s effectiveness across different cancer types and patient groups in detail. In patients with colorectal cancer, the difference between ponsegromab and placebo was a weight gain of 4.94 kg. Analyses by serum GDF-15 level also found that patients with higher GDF-15 levels showed greater weight gain.

A Revolution in Palliative Care

Ponsegromab stands out as a revolutionary development in palliative care. It has been shown not only to promote weight gain but also to significantly improve appetite loss and other symptoms of cancer cachexia. In the study, patients receiving ponsegromab had markedly reduced appetite loss, with a notable difference from placebo. In particular, appetite improved by 4.12 points in the 100 mg ponsegromab group and 4.50 points in the 400 mg ponsegromab group. These findings suggest that ponsegromab could be a promising solution for cachexia and could transform palliative care approaches.

Safety and Adverse Effects

Ponsegromab’s safety profile was generally favorable. Compared with placebo, patients receiving ponsegromab experienced adverse effects less frequently. The most common adverse effects were diarrhea, anemia, and fever. Rare serious adverse effects included abdominal pain and shortness of breath. However, these occurred at very low rates and were not considered directly related to treatment.

Conclusion and Future Prospects

This phase 2 study showed ponsegromab to be a promising treatment option for cancer cachexia. Its findings confirm that GDF-15 is a major cause of cachexia and show that ponsegromab alleviates symptoms by suppressing this cytokine’s effects.

Ponsegromab’s results are highly important at a time when more treatment options for cancer cachexia are needed. However, larger studies of its effectiveness and safety are required. Future studies should particularly address questions such as its long-term effects on quality of life and its use in other cancer types.