Gene therapy improves symptoms for patients with ‘no-option’ treatment-resistant angina
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Key takeaways:
- Gene therapy may be an effective treatment for “no-option” refractory angina.
- XC001 improved exercise capacity and angina symptoms for patients with advanced CAD
Gene therapy improved exercise capacity and blood flow and reduced chest pain occurrence and nitroglycerine use for patients with advanced ischemic heart disease, a speaker reported.
The results of the small, single-arm, open-label, phase 2 EXACT trial were presented at the Society for Cardiovascular Angiography and Interventions Scientific Sessions and simultaneously published in Circulation: Cardiovascular Interventions.
“‘No-option’ refractory angina is a disabling condition with increasing prevalence and is characterized by inadequate blood flow to the heart. It has an estimated prevalence of close to 2 million patients in the U.S. These patients, by definition, have exhausted all medical and surgical options in terms of revascularization,” Kenta Nakamura, MD, interventional cardiologist at the University of Washington Medical Center, said during a press conference. “While the disease carries low mortality, it is associated with poor quality of life.
“Therapeutic angiogenesis using endogenous growth factors has been proposed for several decades to address this unmet need,” Nakamura said. “Specifically, vascular endothelial growth factor A has been studied the most. In this study, the drug of interest, XC001, is an engineered adenoviral vector to increase local levels of VEGF in the ischemic myocardium.”
XC001 (XyloCor) is a novel adenoviral-5 vector designed to induce VEGF, according to the presentation.
For the present study, 32 patients with no-option refractory angina despite revascularization and optimal medical therapy underwent surgery to receive a direct cardiac injection of XC001.
Nakamura and colleagues evaluated the safety and exploratory 12-month efficacy of VEGF-A gene therapy in this cohort with advanced CAD.
The trial was conducted at 14 enrolling sites in the U.S. from February 2020 to July 2022.
The researchers reported no serious adverse events related to XC001 itself, including no systemic constitutional or off-target effects of the gene therapy.
Overall, 63% of the cohort experienced serious adverse events during follow-up, of which 41% occurred within 14 days and were related to the surgery but were either expected or resolved. Sixty-three percent of serious adverse events were deemed unrelated to the drug or surgery and included one death from respiratory failure due to COVID-19.
Improvement in exercise tolerance was observed as early as 3 months, with an overall mean increase of 115.5 seconds at 12 months from baseline (95% CI, 59.1-171.9).
Similarly, improvement in perfusion deficit on PET was observed as early as 3 months, with an overall mean deficit reduction of 10.2% at 12 months from baseline (95% CI, 0.8 to 21.2).
Angina frequency was also reduced from an average of approximately 13 events per 2 weeks to fewer than five (mean change, 8.8; 95% CI, 4.6 to 13).
Additionally, nitroglycerin use was reduced from an average of seven uses per 2 weeks to fewer than four (mean change, 4.7; 95% CI, 9 to 0.5).
“XC001 is safe and it’s well tolerated. There were no off-target or systemic effects of adenoviral expression,” Nakamura said during the press conference. “There were expected complications related to the surgical delivery. I will note that this is a highly morbid population, the majority of which have undergone prior CABG. Percutaneous transendocardial delivery may offer improved safety and improved efficacy.
“Improvement in a variety of efficacy measures support a sustained biologic effect,” he said. “We saw a signal of efficacy in both objective and subjective measures to at least 12 months. There were improvement in objective ischemic deficits and time to ST depression, which support the underlying mechanism of therapeutic angiogenesis in the trial. This all warrants further investigation in larger randomized controlled trials.”
Reference:
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Nakamura K, et al. Featured clinical research part 1. Presented at: Society for Cardiovascular Angiography and Interventions Scientific Sessions; May 2-4, 2024; Long Beach, Calif.
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