Pluristem Fast Forwards Placental Cell Therapy Into US-EU Pivotal Trial

Off-the-shelf placental cell therapy for peripheral artery disease will move from Phase I to registration stage study in US and Europe in early 2017, following “positive feedback” from FDA.

Source: Pluristem

Pluristem's placental cell therapies are all manufactured at company's own facility, which is located in the Matam high technology park, Haifa. Facility has capacity to produce 150,000 doses per year.

Israeli biotech Pluristem Therapeutics Inc. is moving its off-the-shelf placental cell therapy PLX-PAD straight from Phase I to a modestly-sized single pivotal trial to enable filings in the US and Europe in peripheral artery disease in early 2017, after getting a green light on protocol plans from FDA.

Pluristem has a three-dimensional culturing platform it is using to develop hematopoietic stem cells from umbilical cord blood. These types of stem cells are thought to have lower risk for triggering an immune response and the company says that there is no need for tissue or genetic matching.

Pluristem plans to develop cell therapies for a range of conditions, including inflammatory, ischemic and hematological disorders. (Also see "Video: Pluristem Says Its Placental Stem Therapy Offers "Off The Shelf" Promise" - Pink Sheet, 25 Feb, 2016.)

The company’s lead candidate – Placental eXpanded (PLX-PAD) cells – is being developed for critical limb ischemia (CLI), a common, chronic cardiovascular condition associated with blockage of arteries in the legs, which in turn can lead to gangrene and/or amputation and death. Pluristem’s hypothesis is that PLX-PAD helps heal injured muscle through the secretion of proteins that spur muscle regeneration, including proangiogenic and immunomodulatory proteins.

Some two million people have CLI in the US and another three million in Western Europe, the company estimates, and since the condition is associated with diabetes, the number is on the rise.

About a third of patients will need major limb amputation and one-fifth will be dead within a year, Karine Kleinhaus, divisional VP for North America, noted in an interview.

Typically surgical revascularization is the treatment of choice, but only about half of patients are eligible and the rest don't have many options beyond supportive care – it's those patients that Pluristem is targeting with PLX-PAD.

Green Light

The company’s plan to move from Phase I to pivotal testing in light of unmet medical need got a boost recently, as the company announced Aug. 2 that FDA provided “positive feedback” about its registrational trial protocol.

The study would involve 250 patients in the US and Europe, testing the placental cells against placebo, using the primary endpoint of time to amputation and death, which the company describes as the gold standard measure for this indication.

FDA appeared to be “very positive” about the pivotal Phase III protocol, and the company is very comfortable with moving forward, Kleinhaus said.

The company provided data to FDA from two single-arm studies in 27 patients for this indication, which suggested a 59% risk reduction for amputation and death, compared to what would be expected typically. Additionally, FDA had data from a study of PLX-PAD for muscle injury after hip replacement, another indication Pluristem is pursuing, safety data from a Phase II study of 170 patients with intermittent claudication, and data on the mechanism of action, Kleinhaus said.

The pivotal trial would serve as a registrational study for Europe and the US. Pluristem has an agreement with the European Medicines Agency to get accelerated approval for conditional marketing, through the EMA's adaptive pathways pilot. However, the agency has not yet signed off on the pivotal trial protocol.

Pluristem does not have breakthrough therapy status in the US and intends to file for full approval, not accelerated approval.

In the pivotal trial planned for the US and Europe, patients in the test arm will get two intramuscular injections of 300 million cells each, spaced two months apart.

Allogeneic cell therapies like Pluristem’s face questions about the consistency of the product, because the allogeneic nature means they are derived from different donors, and about the ability to ramp up manufacturing processes. (Also see "Cell Therapy Developers Debate Challenges As Big Pharma Drags Its Feet " - Scrip, 12 Nov, 2015.)

In addition to Pluristem, other companies developing products derived from the placenta include Celgene Corp., Osiris Therapeutics Inc. and Saneron CCEL Therapeutics Inc.(see chart below).

Pluristem notes that it is able to make 20,000 doses, each with 300 million cells, from a single placenta. A CMC/manufacturing facility in Haifa has already been approved by regulators in the US, EU, Japan, Israel and Korea for Phase II, Phase III and marketing of PLX-PAD. Keeping manufacturing in-house helps ensure consistency from batch to batch, the company says.

Partner Wanted

Pluristem's stock price traded up by 4.14% to close at $1.51 on the day of the news, Aug. 2. Pluristem has a market capitalization of $130m and had $38m in cash at the end of March, with an annual burn rate of $22m, and will be able to fund the pivotal study on its own while continuing to pursue grants.

In addition to the US and Europe, Pluristem has secured a path toward accelerated approval in Japan. But while it will move forward on its own with the US/European study, in Japan the company plans to wait for a partner before it begins pivotal testing.

Kleinhaus said that the company is looking for a partner in Japan to bear additional research costs and commercialize the product in that country.

Open Media

Open Media

Pluristem Therapeutics chairman and CEO Zami Aberman explains to Mike Ward, global director of content for Informa Pharma Insights Biotech Showcase annual meeting in 2016.

Pluristem also plans to move PLX-PAD into a pivotal study in muscle injury after hip surgery.

The National Institute of Allergy and Infectious Diseases is testing another one of Pluristem's candidates – PLX-R18 – in acute radiation syndrome. In a study of mice given high-dose radiation, 100% of treated animals survived versus 30% on placebo, which is “astonishing,” Kleinhaus said.

After dose-selection animal trials and if all goes well – Pluristem will know the outcome in a few months – the NIAID will move straight into a pivotal trial for this indication, the exec said, at no cost to the company.

Pluristem also plans to start a Phase I study of PLX-R18 cells as a treatment for insufficient hematopoietic recovery after hematopoietic cell transplantation soon.

Placental Derived Cell Therapies In The Pipeline*
Product	Stage of Development/Indication(s)
Osirus’s OTI1501	Phase III: Diabetic foot ulcer.
Celgene’s PDA002	Phase II: Diabetic foot ulcer, diabetic neuropathy, peripheral arterial disease.
Celgene's PDA001	Phase II: Crohn's disease.
Pluristem’s PLX-PAD	Phase II: Intermittent claudication, muscle injury after hip replacement. Phase I: Critical limb ischemia, pulmonary arterial hypertension, thromboangiitis. Preclinical: Graft-versus-host disease, interstitial lung disease, preeclampsia.
Pluristem’s PLX-R18	Phase I: Bone marrow transplantation. Preclinical: Acute radiation injury, stem cell transplantation.
Pluristem’s PLX-BMT	Phase I: Bone marrow transplantation.
UCB/Celgene’s umbilical-cord derived stem cells	Phase I: Hematological malignancies.
Celgene/Human Longevity’s PSC100	Phase I: Sarcopenia.
Celgene’s CSC1	Preclinical: Oncology.
Pluristem’s PLXORTHO	Preclinical: Musculoskeletal disorders.
Pluristem’s PLXBMT	Preclinical: Bone marrow transplantation.
Pluristem’s PLXIBD	Preclinical: Inflammatory bowel disease.
Pluristem’s PLXMS	Preclinical: Multiple sclerosis.
Pluristem’s PLXNEURO	Preclinical: Pain.
Pluristem’s PLXSTROKE	Preclinical: Ischemic stroke.
Saneron’s CCEL Therapeutics U-Cord-Cell Program	Preclinical: Alzheimer’s disease, amyotrophic lateral sclerosis, myocardial infarction, stroke.
Batu Biologics’s ValloVax allogeneic placental cells	Preclinical: Solid tumors.
*Includes amniotic membrane/tissue, umbilical cord cells and other cell types derived from the placenta and treatments that have dehydrated placental cells for wound healing.
Source: MedTrack