Trial progress of apelixin in inhibiting excessive blood vessel growth diseases

PhosphatidylinositolSomatic recessive gain-of-function mutations in the gene encoding PI3K are responsible for the rare disease PIK3CA-related overgrowth spectrum (PROS). PROS can widely affect multiple parts such as skin, bones, blood vessels, fat, and connective tissue, so its clinical manifestations are extremely diverse. In particular, the disease does not attack all cells in the body. In patients with PROS, gain-of-function mutations in the α-catalytic subunit of PI3K, PIK3CA, can be observed, which further lead to bone and soft tissue deformities and tumor formation.

For patients aged 2 years and older who require systemic therapy, Alpelisib provides a new treatment option. In April 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to this drug in the form of a once-daily oral formulation to reduce and prevent lesions in patients with PIK3CA-related overgrowth spectrum. It is worth mentioning that, prior to its approval for the treatment of PIK3CA-related overgrowth spectrum, Apelvis (brand name: Piqray) has been used to treat postmenopausal women and men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer.

The FDA's approval of Apelvis was based on an observational, retrospective chart review study, EPIK-P1, of patients who received Apelvis through the Compassionate Use Managed Access Program. While detailed reports on the EPIK-P1 trial have not yet been made public, data from this retrospective chart review, available from the drug package insert, reveal the safety and efficacy of Apelvis in the treatment of PIK3CA-associated overgrowth spectrum.

The primary outcome of the study focused on patient response to treatment at week 24. In the EPIK-P1 study, treatment response was defined as: 1) a reduction of more than 20% in the volume of at least one lesion; 2) an increase in volume of no more than 20% in any one lesion; 3) no new lesions. The calculation of the lesion volume relies on the clinician's analysis of the imaging data. According to the Apelvis report, 74% of participants experienced disease reduction, and 27% of patients achieved the above-mentioned criteria for response. This result was confirmed by a blinded independent central review. Even more encouraging is that 70% of patients who responded remained in remission after 6 months of treatment, and 60% of patients who responded remained in response after 12 months of treatment.

Apelix as aPI3K inhibitors have demonstrated unique therapeutic potential in PROS patients. They can not only slow down the progression of existing lesions, but also effectively prevent the occurrence of new lesions. However, when using apelix, we also need to be aware of possible drug interactions between it and other drugs such as CYP3A4 inducers and CYP2C9 substrates. In addition, side effects that may occur in patients treated with Apelvis include, but are not limited to, hypersensitivity reactions, serious cutaneous adverse reactions, hyperglycemia, pneumonia, diarrhea, and embryo-fetal toxicity. Despite these potential adverse events, the existing research literature has fully demonstrated the substantial clinical benefits of apelvis for many patients with the PIK3CA-related overgrowth spectrum.