ADI-PEG 20 (Oncology)

ADI-PEG 20 is arginine deiminase (ADI) formulated with polyethylene glycol having an average molecular weight of 20 kilodaltons (PEG 20). It is a novel protein therapeutic that has demonstrated anti-tumor activity and safety in Phase I & II clinical trials of patients with metastatic melanoma or hepatocellular carcinoma. Administered by intramuscular injection, it catabolizes circulating arginine to yield citrulline and ammonia.

Urea Cycle

ADI is a microbial enzyme that degrades arginine, an amino acid crucial to tumor cell metabolism and growth of certain cancers. Normal human cells are able to synthesize arginine from metabolic precursors via the urea cycle (see left image). One of the steps in this pathway involves the argininosuccinate synthase (ASS) catalyzed conversion of citrulline to argininosuccinate. Some cancer cells from tumors such as melanoma, hepatocellular carcinoma, pancreatic cancer, prostate cancer, mesothelioma, and others are deficient in ASS and must instead obtain arginine from the blood for growth and survival. Therefore, depleting arginine from the blood can control tumor growth and even eliminate arginine-requiring cancers without damage to normal tissue cells.

ADI is formulated with polyethylene glycol (PEG) of 20,000 dalton molecular weight to increase the circulating half life and decrease antigenicity of ADI. Similar pegylation technology has been used with microbially-derived therapeutic proteins for systemic delivery of other anticancer drugs. Asparaginase provides a successful example of a microbial protein that, in its pegylated form (Oncaspar®), has been used as front-line therapy against childhood leukemia for over 20 years with few serious side effects.

Formulating the ADI with PEG also allows for the drug to be administered by intramuscular (i.m.) injection which avoids possible complications known to be associated with multiple intravenous administrations. Furthermore, i.m. injections can readily be administered in an outpatient hospital setting, in a physician's office or even in a patient's home.

ADI-PEG 20 has been granted orphan drug status for hepatocellular carcinoma in the United States and Europe. It has also been granted orphan drug status for melanoma in the United States. The FDA has offered Special Protocol Assessment in the United States and the EMEA has offered Protocol Assistance in Europe.

Broad patent protection has been obtained through a number of patents issued or pending in the United States and worldwide.