The U.S. Food & Drug Administration (FDA) has approved a Special Protocol Assessment (SPA) for a Phase III clinical trial of pegylated arginine deiminase (ADI-PEG 20, Polaris Group) in patients with advanced hepatocellular carcinoma (HCC).

ADI-PEG 20 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.

Arginine, one of the 20 amino acids that are essential for protein synthesis and survival of cells,isusually produced by the normal cells in the human body. Certain cancer cells, such as liver cancer cells, are unable to produce arginine andbecome dependent upon an external supply of arginine to survive and grow. Arginine deiminase (ADI) is an enzymewhich is isolated from certain bacteria. In its formulated form, ADI-PEG 20 is a biologic being developed to treat cancers carrying thismajor metabolic defect that renders them, unlike normal cells, unable to make arginine internally. ADI-PEG 20systemically depletes the external supply of arginine and causes these arginine-dependent cancer cells to die while leaving the normal cells unharmed.


In the trial drugarginine deiminase (ADI)is formulated with polyethylene glycol (PEG)whichincreases 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 ( (pegaspargase, Oncaspar?), has been used as front-line therapy against childhood leukemia for over 20 years with few serious side effects.

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

Hepatocellular carcinoma
Hepatocellular carcinoma is one of the most common cancers worldwide, resulting in approximately 700,000 deaths annually. Infection with hepatitis B or C and alcohol consumption are highly associated with the development of the disease. The prognosis for patients with hepatocellular carcinoma is poor as chemotherapy often does not result in prolonged survival, and liver transplantation only increases the survival of selected patients. Despite all forms of current treatment, life expectancy for most patients is only one year post-diagnosis.

The randomized, placebo-controlled, global trial will enroll approximately 600 patients who have failed prior systemic chemotherapy. The primary endpoint of the study is overall survival.

Ghassan Abou-Alfa, M.D., of Memorial Sloan-Kettering Cancer Center in New York, is the principal investigator of the study. “ADI-PEG 20 has demonstrated medical benefit in prior studies in multiple indications with a remarkable safety profile,” said Abou-Alfa. “I am delighted to lead this study to explore ADI-PEG 20 as a viable option for patients with advanced liver malignancies.”

The Special Protocol Assessment or SPA is a mechanism that allows the FDA and drug developers to reach an agreement prior to study initiation about the design and size of a Phase III trial. It will form the primary basis of an efficacy claim in a marketing application.

“The SPA agreement with the FDA is a key step in our plans for the clinical development of ADI-PEG 20,” said John Bomalaski, M.D., executive vice president, medical affairs, of Polaris. “We are pleased to move ADI-PEG 20 into a pivotal PhaseIII trial and to be working with such well-established hepatocellular carcinoma experts.”

Leo Chen, M.D., the lead investigator of the Phase II HCC study in Taiwan, stated, “Our Phase II study demonstrated that ADI-PEG 20 was effective and well-tolerated in patients with advanced liver cancer, and we look forward to the opportunity to further assess the efficacy and safety of this drug in a large randomized Phase III study.”

The lead investigator in China, Shukui Qin, M.D., president of the Chinese Society of Clinical Oncology(CSCO) and chair of the Chinese Liver Cancer Study Group, added, “Approximately half of the liver cancer-related deaths in the world are in China. We have been watching the development of this drug, and we are excited to become an active participant in this pivotal global study.”

In addition to HCC, multiple other cancers have been reported to have a high degree of arginine-dependency. Early-to-mid-stage clinical trials have yielded positive results in patients with metastatic melanoma, and Phase II trials for Small Cell Lung Cancer (SCLC) and Mesothelioma are currently ongoing.

ADI-PEG 20 has been granted orphan drug status for hepatocellular carcinoma in the United States and Europe (EU/3/05/289). It has also been granted orphan drug status for melanoma in the United States.

Polaris also plans to initiate clinical studies in prostate cancer, pancreatic cancer, leukemia, lymphoma and sarcoma this year.

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