On to Phase 3 for PLX-PAD

HAIFA, Israel—In what is the company’s single largest grant at once—according to Dr. Karine Kleinhaus, divisional vice president, North America—Pluristem Therapeutics Inc. has been awarded $8 million for its critical limb ischemia (CLI) program in the European Union as part of the Horizon 2020 program. The grant will support the Phase 3 trial of Pluristem’s PLX-PAD (PLacental eXpanded) cells in CLI, which will be a collaborative undertaking by an international consortium led by the Berlin-Brandenburg Center for Regenerative Therapies (BCRT) under the leadership of Prof. Hans-Dieter Volk and Prof. Petra Reinke together with Pluristem. The consortium will advance an extensive scientific program in parallel to the Phase 3 trial, using a variety of analyses to better understand PLX-PAD’s mechanism of action in CLI.

Pluristem’s PLX-PAD program is one of the few to be selected for the European Union’s Adaptive Pathways project. Like the U.S. FDA’s Fast Track designation, the program is meant to decrease the time necessary to get innovative medicines to patients with serious conditions and few treatment options. This pathway is only open to clinical programs in early stages of development.

“We are honored to have been awarded this Horizon 2020 grant designed to support the manufacturing and development of our cell products for potential commercialization. This grant is a vote of confidence and an expression of hope by the European Union that we may be able to provide a regenerative therapy for millions of CLI patients around the world. Pluristem is committed to developing PLX-PAD for patients with peripheral artery disease, and this grant will help us move towards our goal of rapid entry into the European and U.S. markets, given positive results,” said Zami Aberman, chairman and CEO of Pluristem.

The Phase 3 trial in CLI is a double-blind, randomized, placebo-controlled trial in 250 patients with CLI Rutherford Category 5 who are unsuitable candidates for revascularization. Patients will be recruited in the Unites States and Europe and treated with either 300 million cells or placebo, injected twice intramuscularly, with the second dose administered two months after the first. The primary endpoint for the study will be time to amputation and death. This is planned as a single pivotal trial for regulatory approval in both Europe and the United States.

Nearly two million people in the U.S. suffer from CLI, says Kleinhaus, and while most patients will eventually need revascularization to replace or clear out blood vessels, about half aren’t candidates for such a procedure. Of those who can’t get such treatment, within a year some 30 percent face a major amputation and 20 percent will be dead, she adds. In Phase 1 trials in the U.S. and Germany in CLI, when compared to a placebo in a Sanofi trial, PLX-PAD reduced the change of death or amputation a year after treatment by 59 percent.

Pluristem’s PLX-PAD product is derived from donated placentas and expanded using the company’s patented technology. Kleinhaus says that due to the efficiency of their technology, Pluristem can generate about 25,000 doses from a single placenta. PLX-PAD helps to regenerate muscle, leading to faster repair, less scarring and stimulation of new blood vessels.

This is far from the first grant the company has received to develop its products, Kleinhaus tells DDNews. Pluristem has received more than $20 million from the Israeli government for R&D and clinical trials.

In addition, their work has elicited interest across the Atlantic, as well, as she notes that “the U.S. National Institutes of Health (NIH) are doing an entire development program for our second product in the indication of acute radiation syndrome,” which the NIH is funding itself. The NIH has conducted multiple small animal studies, Kleinhaus explains, and is now are working on a large dose-selection animal study.

And those aren’t the only indications progressing for PLX-PAD. In late July, Pluristem announced that it’s moving to begin a Phase 3 trial to evaluate PLX-PAD cells in recovery following surgery for femoral neck fracture, the most common kind of hip fracture. The design of the trial protocol is underway, with plans to meet with the FDA later in the year to discuss it. Across the pond, Pluristem has submitted the protocol to the EMA after consulting with the Adaptive Pathways Project Group.

In a previous Phase 2 trial, PLX-PAD cells were found to induce significant muscle regeneration in patients who had undergone total hip replacement surgery; compared to placebo, those treated at the time of surgery saw a 500-percent improvement in muscle force and a 300-percent improvement in muscle volume six months after surgery.

Hip fractures are common in elderly individuals in the wake of falls due to osteoporosis and muscle loss associated with aging. One-year mortality rates for hip fractures range from 12 to 37 percent, and roughly half of patients faced with these incidents do not regain their ability to live independently. According to the United States Agency for Healthcare Research and Quality, some 310,000 patients were hospitalized with hip fractures in the United States in 2013, accounting for 30 percent of all hospitalized patients. All told, treatment costs for hip fractures reach $10 billion to $15 billion per year in the United States.

“The femoral neck, the hip fracture surgery, is obviously a huge and growing indication, and something we’re super excited about,” says Kleinhaus. “The CLI trial is a huge leap forward for us; this is a huge indication, huge patient suffering, and very life-threatening with poor treatment options. And as a company, it’s a $12-billion global market. It’s a huge market with an unmet need, so for us, entering pivotal trials in the U.S. and Europe for this massive market, it’s a big deal and we’re really starting to think toward marketing.”