Catheter-Delivered Gene Therapy Yields Positive Signal in Advanced Heart Failure


    Endomyocardial injection of DNA encoding stromal cell-derived factor 1 (SDF-1) in patients with chronic ischemic heart failure tends to attenuate cardiac remodeling, according to a phase II study published online June 8, 2015, ahead of print in the European Heart Journal. While the gene therapy failed to meet its primary efficacy endpoint, significant functional improvement was seen in those with the lowest levels of  LVEF.

    Catheter-Delivered Gene Therapy Yields Positive Signal in Advanced Heart Failure

    The data are encouraging enough to support larger clinical studies “to determine if the benefits in cardiac structure and function observed [here] impact the clinical endpoints of heart failure hospitalizations and death,” say Marc S. Penn, MD, PhD, of the Summa Cardiovascular Institute (Akron, OH), and colleagues.

    The investigators enrolled 93 patients (mean age 65 years; approximately 89% men) with ischemic heart disease an average of more than 10 years after their latest MI. All were on stable, guideline-based medical therapy and had an implantable defibrillator, an LVEF no greater than 40%, a Minnesota Living With Heart Failure Questionnaire (MLHFQ) of at least 20, and a 6-minute walk distance (6MWD) of no more than 400 meters. Participants were randomized to receive endomyocardial injections of 15 mg (n = 32) or 30 mg (n = 30) of plasmid-based SDF-1 (pSDF-1; JVS-100; Juventas Therapeutics; Cleveland, OH) or placebo (n = 31) via a helical infusion catheter (Helix; BioCardia; San Carlos, CA) at 16 sites.

    The groups were fairly well matched for baseline characteristics. Mean LVEF was 29%, left ventricular end-systolic volume (LVESV) was 154 mL, and N-terminal pro brain natriuretic peptide (NTproBNP) was 1,120 pg/mL.

    In preclinical research, the chemokine SDF-1 has been shown to recruit endogenous stem cells, reduce programmed cell death, and promote vessel regeneration, the authors say. In the proprietary JVS-100 therapy it is encoded in a nonviral DNA pSDF-1, which induces expression in local tissue for more than 2 weeks.

    Almost all patients (96%) received the prespecified 15 injections, and overall delivery was “well tolerated,” Dr. Penn and colleagues say. There was a similar transient increase in troponin I in all groups. Four patients had small pericardial effusions that resolved after 1 day without intervention. None experienced hemodynamic perturbation or arrhythmia following delivery. Over 12 months, major adverse events included 3 deaths, 8 heart failure hospitalizations, 11 cases of treated ventricular tachycardia, and 6 ACS events in the 2 treatment groups.

    Similar Improvements in Study Groups, Controls

    Significant improvements over baseline were seen in the composite 6MWD and MLHFQ score (primary endpoint) at 4 months for both treatment groups (P ≤ .001). But because the placebo group experienced similar gains, a relative improvement over placebo in the composite score was not achieved (P = .89). 

    At 12 months, patients who received the 30-mg dose of SDF-1 showed a trend toward improved LV function compared with controls (delta LVEF -2% vs 1.5%; P = .20).

    Myocardial response was also analyzed according to low (< 26%), intermediate (26%-31%), and high (≥ 32%) tertiles of LVEF. At 12 months, patients in the low category (n = 31) who received a 30-mg dose of pSDF-1 had an increase in LVEF compared with controls. They also showed trends toward improved LVESV, stroke volume, and NTproBNP level (table 1).

    Table 1.  Changes in Heart Failure Parameters in Highest-Risk Patients at 12 Months: 30-mg pSDF-1 vs Placebo

    Post hoc analysis suggested that older and diabetic patients were no less responsive to pSDF-1 than other patients.

    “The strategy of delivering substantial quantities of target gene as an alternative to stem cells for native cardiac repair is based on the current leading hypothesis that the primary mechanism of stem cell benefit is a paracrine effect,” the authors explain.

    Why Sicker Hearts Respond More

    The decision to analyze the results by level of LVEF function was prompted by earlier animal data suggesting that the benefit of pSDF-1 was “more pronounced in hearts with more advanced cardiac dysfunction,” Dr. Penn and colleagues observe. In addition, the current results indicate that functional improvement is dose dependent and appears to persist up to 12 months despite relatively brief expression of pSDF-1, the investigators add.

    There are several possible explanations for the greater response in sicker hearts, the authors write.  Previous research has shown that in chronic ischemia, cardiac myocytes in the border zone express SDF-1 receptors, which leads to diminished contractility. Transient overproduction of SDF-1 suppresses receptor expression, helping to restore contractility. Moreover, improvement in border zone structure and function induces global LV remodeling. “Patients with greater LV dysfunction are likely to have a greater volume of myocardial tissue under stress; therefore, a greater demonstrable response to SDF-1 overexpression,” they explain.

    Importantly, the investigators point out, the degree of LV remodeling seen here has been associated in another study with reductions in heart failure hospitalization and mortality at 2 years in patients receiving guideline-directed medical therapy and resynchronization.

    Finally, the authors say, the safety and remodeling data—together with the nonviral nature of the DNA vector—support investigation of whether greater clinical benefits may be reaped with repeat administration of pSDF-1.

    How Safe Is Delivery?

    However, in a telephone interview with TCTMD, Eduardo Marbán, MD, PhD, of Cedars-Sinai Medical Center (Los Angeles, CA), challenged the authors’ characterization of the therapy as “well tolerated.” Troponin I spikes—some clinically meaningful—and an ACS incidence of more than 10%—especially coming after about a decade free of MIs—are concerning, he said. In addition, the 4 cases of pericardial effusion were likely caused by perforation.

    Another key area of concern for Dr. Marbán was the large volume of the injections, which he said amounts to 10% of the mass of the entire ventricle and about 40% of that of the infarct border zone, which is not distensible.

    With regard to efficacy, the study is negative, he said, adding that the benefit seen in 1 LVEF group based on 1 dose was not convincing. “If you look at enough subgroups of enough small samples, you’ll find something that works,” he commented. “There is no indication that this [effect] is real.”

    Dr. Marbán acknowledged that the study stems from “a deliberate and progressive translational effort based on a good scientific rationale. But even though the biologic itself may have merit, the way it is being delivered in large volumes using screw-in helical catheters may be making it difficult to see an effect.

    “I don’t think the translational potential for this therapy looks very bright on the basis of this study,” he concluded.

    Nonetheless, according to a recent Juventas press release, JVS-100 has been granted Fast Track designation by the FDA, which also approved a phase IIb double-blind, sham-controlled trial. Called STOP-HF2, the study is expected to enroll up to 180 heart failure patients with an LVEF no higher than 35% and an NTproBNP level of at least 500 pg/mL who will receive 2 30-mg doses of JVS-100 6 months apart.

     


    Source:
    Chung ES, Miller L, Patel AN, et al. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized phase II trial. Eur Heart J. 2015;Epub ahead of print.

    Disclosures:

  • The study was funded by Juventas Therapeutics; research on SDF-1-based gene therapy was funded by the Skirball Foundation.
  • Dr. Penn reports being the founder and chief medical officer of Juventas Therapeutics and being eligible for royalties from and equity in the company.
  • Dr. Marbán reports being the founder of and serving on the scientific advisory board of Capricor Therapeutics.

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  • Small Heart Failure Studies Show Positive Trends for Cell Therapy
  • Repeat Cell Therapy for Chronic Heart Failure Being Tested in Randomized Trials

Catheter-Delivered Gene Therapy Yields Positive Signal in Advanced Heart Failure

Endomyocardial injection of DNA encoding stromal cell-derived factor 1 (SDF-1) in patients with chronic ischemic heart failure tends to attenuate cardiac remodeling, according to a phase II study published online June 8, 2015, ahead of print in the European Heart Journal. While the gene therapy failed to meet its primary efficacy endpoint, significant functional improvement was seen in those with low LVEF.

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