MEDI3726, also known as ADCT-401, is being developed by MedImmune (a subsidiary of AstraZeneca) for the treatment of advanced metastatic castration-resistant prostate cancer. Although several novel therapies, such as Zytiga (abiraterone acetate) and Xtandi (enzalutamide), are available to treat this type of prostate cancer, the disease eventually progresses in almost all patients.

How MEDI3726 works

MEDI3726 is a chemical construct consisting of an antibody (J591) that is linked to tesirine, a compound that is toxic to the cells. The antibody J591 specifically recognizes and binds to a protein called prostate-specific membrane antigen (PSMA). PSMA is present in almost all types of prostate cancer and is particularly abundant in metastatic castration-resistant prostate cancer. Normal healthy cells do not express PSMA protein.

Thanks to the presence of the antibody, MEDI3726 specifically binds to PSMA proteins on the surface of cancer cells and delivers the toxic drug to them. Upon binding, the drug gets transported inside the cells where it causes damage to the genetic material of the cell. The damage leads to the death of the cancer cells.

MEDI3726 in clinical trials

MEDI3726 demonstrated remarkable superior antitumor activity in preclinical studies, but it remains to be seen how well it works in clinical settings. To test the effects of MEDI3726 in people, a Phase 1/1b, multicenter, open-label, dose escalation, and dose expansion trial (NCT02991911) was begun in January 2017. The study is recruiting adult participants with metastatic castration-resistant prostate cancer who have received prior treatment with Zytiga or Xtandi, with or without a prior taxane-based chemotherapy.

The trial aims primarily to assess the safety and tolerability of MEDI3726 and describe its dose-limiting toxicities, as well as to determine the maximum-tolerated or maximum-administered dose of the drug. The secondary objectives are to evaluate MEDI3726 for its anti-tumor activity, safety, and tolerability in combination with Xtandi, as well as its pharmacokinetics (how it moves witihin the body) and immunogenicity (its ability to trigger an immune response) alone and in combination with Xtandi. The trial aims to enroll a total of 224 patients and is expected to be completed by 2021.

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