Data Support Feasibility and Dose Selection for XC001 in Phase 2 Portion of EXACT Study in Refractory Angina

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XyloCor Therapeutics’ encoberminogene rezmadenovec (XC001) has shown positive data among the 2 highest doses assessed, with the 1×10^11 viral particles dose selected for continued study.

Thomas Povsic, MD, PhD, professor of medicine at Duke University School of Medicine

Thomas Povsic, MD, PhD

Data from the phase 1 dose-escalation EXACT study (NCT04125732) of encoberminogene rezmadenovec (XC001; XyloCor Therapeutics), published in Circulation: Cardiovascular Interventions, suggest that the epicardial delivery of the therapy via minithoracotomy is feasible and well-tolerated among patients with refractory angina.1 The data included were from the June 2, 2020, time point to June 25, 2021.

The highest dose assessed was 1×1011 viral particles, which was deemed tolerable by investigators with a dose-response elicited among the 12 patients who were included in the 4 dosing cohorts (1×109, 1×1010, 4×1010, and 1×1011 viral particle) in total exercise duration, myocardial perfusion deficit, and angina class. This dose will be carried forward into the phase 2 portion of the study, according to study lead author and national principal investigator Thomas Povsic, MD, PhD, professor of medicine at Duke University School of Medicine, and colleagues.

“The results from the phase 1 study provided the mechanistic underpinning that was the catalyst for the successful completion of the phase 2 EXACT trial,” Povsic said in a statement.2 “Patients with refractory angina are highly symptomatic and have an exceedingly poor quality of life.”

In July 2023, Povsic sat down with CGTLive to discuss the trial design and the surgical delivery of the gene therapy. He said that “everything we saw in phase 1 was very encouraging and suggested to us that we had a dose that might be efficacious. While there was some risk with surgical delivery, the adverse events that were observed were all expected and related to the actual surgery. We didn't see anything, safety-wise, that was related to the therapy itself. So that was very encouraging that we could go forward with the highest dose as well as the fact that we saw a dose-response and improvement in exercise times, angina frequency, and [Canadian Cardiovascular Society] angina class was all very reassuring.”

READ MORE: PKP2 Gene Therapy Cleared for Cardiomyopathy Trial

Povsic et al noted in their work that novel treatments are sorely needed for patients with refractory angina, and XC001, which uses adenoviral-5 vector coding for all 3 major isoforms of vascular endothelial growth factor, has shown promise to fill this need with its sustained 12-month safety and efficacy signals. Previously, it has shown enhanced local angiogenesis in preclinical models. Patients included in the open-label, single-arm EXACT study had class II to IV angina while on maximally tolerated medical therapy, as well as demonstrable ischemia on stress testing, and angina limitation on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15, 0.1-mL injections of XC001.

The primary outcome was safety via adverse event (AE) monitoring over 6 months. In total, 17 serious AEs were reported in 7 patients, though none were determined to be related to the study drug. Among those, 6 serious AEs in 4 patients were related to the thoracotomy, and 3 nonserious adverse events were deemed possibly related to the study drug.

Assessment of efficacy included the difference from baseline to months 3, 6, and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life. The 2 lowest doses evaluated did not show improvements in total exercise duration, myocardial perfusion deficit, or angina frequency. But there did seem to be improvements in all parameters with the 2 higher doses, Povsic et al noted.

"We are thrilled with the publication of these EXACT trial results in Circulation: Cardiovascular Interventions, a highly-regarded and influential international journal for cardiovascular research," Howard Dittrich, MD, the chief medical officer of XyloCor, and an adjunct professor of medicine and chair of the Board of Directors of the François M. Abboud Cardiovascular Research Center at the University of Iowa Carver College of Medicine, said in a statement.2 “We would like to acknowledge all of the authors for their contributions in highlighting the promise of XC001 and thank patients and their families for their participation in the EXACT trial. Our team is singularly focused on continuing to unlock the transformative potential of XC001 for improving outcomes in cardiovascular disease.”

The results from the 6-month time point were announced in January 2023,3 showing decreases in ischemic burden on cardiac positron emission tomography imaging. Additionally, nearly half of the participants were able to engage in normal physical activity without angina at 6 months posttreatment, despite substantial limitations prior to dosing.

REFERENCES
1. Povsic TJ, Henry TD, Traverse JH, et al. EXACT Trial: Results of the Phase 1 Dose-Escalation Study. Circ-Cadiovasc Inte. 2023;0:e012997. doi:10.1161/CIRCINTERVENTIONS.123.012997
2. Results from XyloCor Therapeutics’ Phase 1 Portion of EXACT Trial of XC001 for Cardiovascular Disease Published in Circulation: Cardiovascular Interventions. News release. XyloCor Therapeutics. August 3, 2023. Accessed August 4, 2023. https://www.businesswire.com/news/home/20230803967906/en/Results-from-XyloCor-Therapeutics%E2%80%99-Phase-1-Portion-of-EXACT-Trial-of-XC001-for-Cardiovascular-Disease-Published-in-Circulation-Cardiovascular-Interventions
3. Xylocor Therapeutics reports positive topline safety and efficacy results from phase 2 EXACT clinical trial of XC001 novel gene therapy for refractory angina. News release. XyloCor Therapeutics. January 26, 2023. Accessed August 4, 2023. http://www.xylocor.com/pdfs/XyloCor-Phase-2-Results-Press-Release-2023.pdf
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