No Limb-Ischemia Wound-Healing Gains From Gene Therapy: STOP-PAD

Marlene Busko

April 12, 2018

ORLANDO, Florida — Patients with critical limb ischemia who underwent successful below-knee revascularization and also received an experimental gene therapy did not show improved healing of their wounds 3 months later.

Researchers had hoped that injections of JVS-100 (Juventus Therapeutics) would restore flow within small blood vessels and thereby promote wound healing in the patients with severe peripheral arterial disease (PAD), foot ulcers, and gangrene. JVS-100 is a nonviral DNA plasmid that encodes angiogenic stromal cell–derived factor-1 (SDF-1).

Only about a quarter of patients who received the gene therapy at two different doses or placebo showed complete wound healing by 3 months, said Mehdi H Shishehbor, DO, MPH, PhD, from University Hospitals Harrington Heart & Vascular Institute, Cleveland, Ohio.

Moreover, the wounds grew larger in about one fourth of the patients in both the treatment and control groups, noted Shishehbor when presenting the phase 2 SDF1 Plasmid Treatment for Patients With Peripheral Artery Disease (STOP-PAD) study in March at the American College of Cardiology (ACC) 2018 Annual Scientific Sessions.

Two Takeaways

Even though the trial was "negative," it had at least two important takeaways, Shishehbor told | Medscape Cardiology,

"When we've performed these complex peripheral-vessel revascularization procedures," he said, "we were always under the impression that we were going to improve the blood flow," and that the problem would be "fixed."

In the current study, however, most patients showed improved macrovascular blood flow with no improvement in microvascular flow, he said. "We do a good job with the big arteries, but we have no therapies for the little arteries."

And, Shishehbor said, even though an effort was made to limit the study to "patients that potentially can heal, still a significant portion of them required minor amputation."

An important aspect of the study is its consideration of PAD "as a macro- and microvascular phenomenon," according to Marie D Gerhard-Hermann, MD, Brigham and Women's Hospital, Boston, Massachusetts.

"I think that's a point everybody needs to take home. Regardless of what happened in this trial, that was huge," said Gerhard-Hermann as a panelist during a discussion after Shishehbor's presentation of the study.

Poor Microvascular Perfusion

STOP-PAD enrolled patients with critical limb ischemia at 25 centers in the United States; they had at least one wound of less than 25 cm2 that had not healed for at least 2 weeks, as well as low blood flow to the toes as indicated by a toe-brachial index (TBI) of 0.51 or less (normal TBI is at least 0.71).   

Of 129 such patients with successful revascularization of major leg arteries, 109 were left with persisting poor microvascular perfusion, with a mean TBI of 0.26 despite the procedure.

Within 12 days of revascularization,104 were randomly assigned to receive intramuscular injections of 8 mg JVS-100 (n = 34), 16 mg JVS-100 (n = 36), or placebo (n = 34).

Wound-healing scores at 3 months after revascularization, the study's primary efficacy outcome, didn't differ significantly among the three groups.

Seven patients in each of the two gene therapy groups required amputations, including one major amputation in each  group. In the placebo group, five patients underwent amputations, none of them major.

Seven patients in the lower-dose and three in the higher-dose gene therapy group experienced a major adverse limb event, defined as major amputation or clinically driven target-lesion revascularization. Three patients in the control group, or 8.8%, had such an event.

The Achilles Heel

From the panel, Gerhard-Hermann asked whether any assessment was made of "local microperfusion at the sites of the injection."

Shishehbor said there was no good way to demonstrate whether gene transfection — that is, its capacity for entering the target cells — or transcription once inside the cells was successful.

"That is the Achilles heel of our study," he said, "because we can't assess that in humans unless we take off their legs, which is what we are trying to prevent."

Patients in the current study received a second round of injections 3 months after revascularization. Shishehbor said he "anxiously awaits 6-month results," which will help determine the next steps in the line of research.

The study was funded by Juventus Therapeutics. Shishehbor discloses receiving consultant fees/honoraria from Abbott Laboratories, Shockwave Medical, Medtronic, Boston Scientific, Volcano, Terumo, Phillips, Spectranetics, and BioClinica. Gerhard-Hermann had no relevant financial disclosures.

American College of Cardiology (ACC) 2018 Annual Scientific Sessions. Abstract 409-08. Presented March 12, 2018.

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