Pexa-Vec (JX594/TG6006) is an engineered oncolytic vaccinia virus armed with a GM-CSF gene that promotes an immune response. Pexa-Vec is designed to selectively target and destroy cancer cells through three different mechanisms of action: the lysis (breakdown) of cancer cells through viral replication, the reduction of the blood supply to tumors through vascular targeting and disruption, and the stimulation of the body's immune response against cancer cells.
The lead indication for Pexa-Vec is the most common form of liver cancer, hepatocellular carcinoma (HCC). According to recent statistics, there are nearly 750,000 cases of liver cancer diagnosed annually on a global basis and nearly 700,000 deaths due to this disease, making it the third most common cause of cancer-related death worldwide. In the European Union, there were over 48,000 cases and over 46,000 deaths due the disease in 2008, the most recent statistics available. In the U.S. over 30,000 new cases were expected to be diagnosed in 2013, with over 21,000 deaths projected from the disease. HCC is estimated to account for over 80% of all liver cancer, according to the American Cancer Society.
Early stage liver cancer can sometimes be successfully treated with surgery in patients with sufficient healthy liver tissue, and liver transplantation may also be an option. Patients whose tumors cannot be surgically removed may choose ablation (tumor destruction) or embolization, a procedure that cuts off blood flow to the tumor. For patients diagnosed at an advanced stage of disease, treatment options are limited, with one drug, sorafenib (Nexavar), approved for the treatment of HCC in patients who are not candidates for surgery. With a low five-year survival rate, especially for patients diagnosed at later stages of disease, and limited available therapies, new treatments are urgently needed.
Phase 1 and Phase 2 clinical trials in multiple cancer types to date have shown that Pexa-Vec appears to induce tumor shrinkage and/or necrosis (tissue death) and to be generally well tolerated by patients. Objective tumor response has been observed in a variety of cancers, including HCC, colon, and kidney cancer, and long-term survival has been observed in HCC in these early-stage studies. Clinical trials are ongoing in HCC, renal cell carcinoma (kidney cancer) and colorectal cancer.
The lead indication for Pexa-Vec is HCC. In a Phase II dose-finding trial involving mainly first-line HCC patients, Pexa-Vec appeared to show activity. In the trial, there was a significant difference in median overall survival between the group of patients receiving a high dose of Pexa-Vec versus those receiving a low dose (14.1 months for the high-dose group versus 6.7 months for the low-dose group). The difference between the two groups persisted over time, as shown in the graph below.
In September 2013, Transgene announced that a Phase IIb trial – the TRAVERSE study – evaluating Pexa-Vec in patients with second-line HCC did not meet its primary endpoint of overall survival in this challenging-to-treat patient population. The Company indicated that sub-analyses from the TRAVERSE study and additional data analyses were ongoing to determine the best development path for Pexa-Vec, including a decision on whether to initiate a Phase III trial with Pexa-Vec in first-line HCC.
Orphan drug designation has been granted for Pexa-Vec for HCC by both the U.S. Food & Drug Administration (FDA) and the European Medicines Agency.
In March, 2014, Transgene, with its partners, SillaJen and Lee’s Pharmaceutical announced a late-stage clinical development plan for Pexa-Vec.
Lead Program - The planned Phase 3 trial will assess Pexa-Vec followed by sorafenib in the first-line treatment of patients with advanced HCC. This global study will be conducted in Europe, Asia and North America. It is expected to enroll approximately 600 patients. Patients will be randomized 1:1 to either receive Pexa-Vec immediately followed by sorafenib or to receive sorafenib alone. Sorafenib (Nexavar®) is currently considered the global standard of care and is the only product approved for the first-line treatment of advanced HCC. The study is expected to start recruitment by mid-2015.
Additional Studies - A study evaluating Pexa-Vec and metronomic doses of cyclophosphamide in solid tumors, mainly in breast cancer and soft tissue sarcoma, is planned to be initiated this year. The study is being funded by the Institut National du Cancer (INCa) and sponsored by the Bergonié Institute (Bordeaux, France). Cyclophosphamide given at metronomic doses is used classically in combination with immunotherapeutics to potentiate their activity.
Other trials to complement and strengthen the program are also planned and include:
- A trial in the pre-surgery (neo-adjuvant) setting in solid tumors to gain a better understanding of Pexa-Vec activity in the actual tumor environment.
- A trial evaluating Pexa-Vec in combination with an immune checkpoint inhibitor, based on the rationale of gaining synergy and potency in combining two immunotherapy classes. This type of combination approach holds high promise in oncology.
The partners are also considering a Phase 1/2 study in combination with sunitinib malate (Sutent®) for renal cell cancer.
In September 2010, Transgene and Jennerex Biotherapeutics announced that they had entered into an exclusive partnership to develop and commercialize Pexa-Vec for the treatment of solid tumors in Europe, the Commonwealth of Independent States (CIS) and the Middle East
(see press release of September 8, 2010). Under the terms of the agreement, Jennerex and Transgene are co-developing Pexa-Vec worldwide, with Transgene responsible for clinical development in its licensed territories, pursuant to the Pexa-Vec global development plan. Transgene is responsible for commercialization in its licensed territories.
As part of this agreement, Transgene made an upfront equity investment in Jennerex. Jennerex is further eligible to earn a total of $116 million in development and registration milestones, as well as royalties on sales. In addition, Jennerex has an option for co-promotion and profit-sharing in the five major European countries.
In November 2013, SillaJen, Inc., a long-time shareholder of Jennerex, announced the signing of a definitive merger agreement to acquire Jennerex. Transgene, a shareholder of Jennerex, supported the proposed acquisition and gave its consent to the agreement (see press release of November 26, 2013). The development and commercialization agreement for Pexa-Vec between Transgene and Jennerex remains intact, with SillaJen taking over Jennerex’s responsibilities.
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