Gene Therapy for Heart Disease Wins Fast-Track Status

Phase 3 trial examines one-time angiogenic treatment

The FDA has granted a fast-track designation for a phase 3 study of Generx (Ad5FGF-4, Angionetics Inc.) cardiovascular angiogenic gene therapy as a one-time treatment for improving exercise tolerance in patients with angina that is refractory to standard medical therapy and is not amenable to conventional revascularization procedures (i.e., coronary artery bypass surgery and percutaneous coronary intervention).

Generx is biologically engineered using an E1-region–deleted, replication-deficient adenovirus serotype 5 vector. It is administered by an interventional cardiologist into the coronary arteries under transient ischemic conditions through the use of a standard balloon catheter.

Generx is distributed into the microvascular pathways of the heart and transfects cardiac cells by binding to cell-surface coxsackievirus–adenovirus receptors (CARs) under the control of a modified cytomegalovirus (CMV) promoter. CARs are found throughout the heart.

Research indicates that the binding of Generx to CARs is enhanced by the induction of transient ischemia and by the use of agents such as nitroglycerin to boost cell permeability during administration. The CMV promoter is capable of driving high levels of transgene protein expression in transfected cells for up to three weeks. This short-term expression is ideal for tissue-regeneration clinical applications requiring the generation of new biologic structures, including the promotion of angiogenesis in the heart, according to the product’s developer.

In September 2016, Angionetics announced clearance from the FDA to conduct a phase 3 study of Generx in patients with refractory angina due to myocardial ischemia. The AFFIRM trial incorporates various research innovations, including 1) enhanced cardiac delivery procedures using standard balloon catheters, supported by research showing that transient ischemia may enhance gene transfer to heart cells; and 2) a more comprehensively characterized target population based on Generx responder data from four prior FDA-cleared clinical studies.

The study population includes patients with refractory angina and documented clinical evidence of myocardial ischemia within the past six months. Patients must have a clinically significant limitation of physical activity due to angina (Canadian Cardiovascular Society [CCS] class 3 or 4) and an angina-limited baseline exercise treadmill test (ETT) duration of three to seven minutes. The trial’s primary efficacy endpoint is the improvement in ETT duration at six months in Generx-treated patients compared with the placebo control group. Secondary efficacy endpoints include changes in patients’ CCS angina class; changes in weekly angina frequency and nitroglycerin use; and the change in quality of life, as assessed using the Seattle Angina Questionnaire.

Source: PR Newswire; February 7, 2017.