Status: U.S. filing expected in 2010

Organizations involved:

Vical Inc. – Manuf; R&D; Tech.; USA mark.; Intl. mark.

AnGes MG Inc. – Asia mark.; Japan mark.

Description: Allovectin-7 is a formulation of a plasmid (pBR322) gene therapy containing a HLA-B7 heavy chain and and beta-2 microglobulin genes (for in vivo expression of HLA-B7 and beta-2 microglobulin), which together form a Class I Major Histocompatibility Complex (MHC-I) antigen, encapsualted in (complexed with) DMRIE/DOPE [1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleoylphosphatidyl-ethanolamine] cationic liposome-like lipid mixture carrier. The lipids facilitate uptake of the DNA by tumor cells. Injection of Allovectin-7 directly into tumors is designed to stimulate an immune response against both local and distant metastatic tumors.

Nomenclature: HLA-B7 & microglobulin plasmid, rDNA/lipid complex [BIO]; Allovectin-7 [TR]; velimogene aliplasmid [INN]; DNA (plasmid VCL-1005) [CAS]; 296251-72-4 [CAS]; VCL-1005 plasmid DNA formulated with a lipid-based system, DMRIE/DOPE [(±)-N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)- 1-propanaminium bromide/dioleoylphosphatidylethanolamine] [CAS]; VCL-1005 [SY]

Biological.: Allovectin-7 consists of plasmid DNA encoding the genes for HLA-B7 heavy chain and 2-microglobulin inserted into a simplified eukaryotic expression vector (pBR322). Expression of both genes is driven by the Rous Sarcoma Virus-Long Terminal Repeat (RSV-LTR) promoter. The two genes are separated by cap-independent translational enhancer, an internal ribosomal entry site (IRES), that permits coexpression of both genes from a single promoter. The plasmid is complexed with a cationic lipid mixture, DMRIE/DOPE: 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleoyl-phosphatidyl-ethanolamine.

Recognition of foreign antigens by the immune system requires presentation of antigen peptide fragments in the context of MHC class I or class II molecules. However, many tumor cells, including melanoma cells, frequently have zero or reduced levels of MHC class I expression on their cell surfaces that can limit the recognition and lysis of these tumor cells by class I-restricted T cells. This loss of MHC class I expression is believed to be one mechanism by which tumor cells evade immune recognition and rejection. In experimental tumor models, variation in the expression of MHC class I antigens has been shown to exert a decisive influence on local tumor growth and metastases. It is possible to reintroduce MHC class I expression in tumors by DNA-based therapy. Preclinical studies have shown that direct gene transfer of an allogeneic MHC class I gene into murine tumor cells results in the induction of a specific cellular immune response and the subsequent rejection of tumor cells.

Loss of or mutations in 2-microglobulin have been reported as possible mechanisms for deficient MHC class I expression in tumor cells. Thus, the 2-microglobulin gene was also included in Allovectin-7 to allow for expression of the complete MHC class I complex on the tumor cell surface. HLA-B7 antigen is infrequently expressed in the U.S. population (about 20% of U.S. Caucasians) and thus allows for a potential allogeneic immune response in most patients. All together, Allovectin-7 provides several potential immune-stimulating functions: expression of a foreign and highly immunogenic cell surface protein (i.e., HLA-B7 in HLA-B7 antigen-negative patients), an increased antigen-presentation signal (antigen presented in the context of HLA-B7), and replacement of 2-microglobulin for increased surface expression of the patient’s own MHC-class I molecules.

Injection of Allovectin-7 directly into tumor lesions results in tumor cell expression of HLA-B7 and ß2 microglobulin, directing an immune response against metastatic tumors through several mechanisms. In HLA-B7 negative patients, a vigorous allogeneic immune response may be initiated against the foreign MHC class I antigen. In all patients, ß2 microglobulin may reconstitute normal class I antigen presentation and/or increase tumor antigen presentation to the immune system. In any patient, an innate pro-inflammatory response may occur that induces tumor responses following intralesional injection of thep DNA/lipid complex. Each of these mechanisms initially causes recognition of the tumor at the local site to allow a then sensitized immune response to recognize un-injected tumors at distant metastatic sites.

Companies.: Allovectin-7 is being developed and is manufactured by Vical Inc.

AnGes MG, Inc. is assisting with funding of Allovectin-7 development,. including funding the pivotal AIMM trial. In exchange, AnGes receives exclusive marketing rights in Japan and other key Asian countries; and Vical will pay AnGes tiered royalties based on defined sales levels in the U.S., and fixed royalties on rest-of-world sales. AnGes is obligated to pay Vical royalties on product sales in the specified Asian countries, plus certain sales-based milestone payments if defined sales levels are achieved. Each company is responsible for obtaining regulatory approvals in countries where it plans to market Allovectin-7.

FDA class: Biologics BLA

Status: Allovectin-7(R) has been granted orphan drug designation for the treatment of invasive and metastatic melanoma.

Allovectin-7 is being developed through a Special Protocol Assessment (SPA) with the FDA for a Phase III trial of high-dose (2 mg) Allovectin-7 in certain patients with recurrent stage III or stage IV melanoma. The SPA specifies the trial objectives and design, clinical endpoints, and planned analyses expected to be needed for product approval. Patients may have been previously treated with surgery, adjuvant therapy, and/or biotherapy, but cannot have been previously treated with chemotherapy. The patients are randomized on a 2:1 basis; with ~250 patients treated with Allovectin-7 and ~125 treated with their physician’s choice of either of two chemotherapy agents, dacarbazine or temozolomide. The primary endpoint is a variation on progression-free survival that compares the two trial arms for objective responses that are ongoing at six months or more after randomization. The study also evaluates safety and tolerability as well as survival as secondary endpoints.

Trials: In 2001, Vical conducted a large Phase II trial evaluating Allovectin-7 at high dose (2 mg) as a single agent for patients with Stage III or IV metastatic melanoma. The data showed that the trial had a total of 15 responders among the 127 patients receiving the high dose (11.8%), with four of the patients having complete responses and 11 having partial responses. The Kaplan-Meier estimated median duration of response was 13.8 months. The Kaplan-Meier median survival was 18 months. The safety profile was excellent with no reported Grade 3 or Grade 4 adverse events associated with Allovectin-7. Based on advice from its own experts and FDA in an End-of-Phase II meeting, Vical designed the Phase 3 AIMM trial.

     In Dec. 2009, Vical reported that an independent Safety Monitoring Board (SMB) for the company's Phase IIIAIMM trial of Allovectin-7 in patients with metastatic melanoma has completed the trial's third scheduled safety analysis. The SMB recommended that the trial continue per the protocol. The trial was expected to complete enrollment of the planned 375 subjects in the next few weeks.. AIMM (Allovectin-7 Immunotherapeutic for Metastatic Melanoma) is a pivotal trial of Allovectin-7 as first-line therapy in chemotherapy-naive patients with Stage III or IV metastatic melanoma, in accordance with a Special Protocol Assessment (SPA) agreement completed with FDA. The SPA specifies the trial objectives and design, clinical endpoints, and planned analyses expected to be needed for product approval.