Magazine Article | November 1, 2019

Taking It All The Way To Phase 3 Clinical Trials

Source: Life Science Leader

By Wayne Koberstein, Executive Editor, Life Science Leader magazineFollow Me On Twitter @WayneKoberstein

Yaky Yanay
Most biopharma startups have an exit strategy, typically a takeover by a legacy company with more than sufficient size and expertise to complete clinical development and commercialize new products. But with a changing mix of new players entering the field of biopharma innovation, more development sponsoring startups plan to take their creations through all three phases of clinical trials and, if successful, onto the market on their own. Pluristem Therapeutics offers one example of how a new company in drug development can build the needed infrastructure to maintain its independence as a sponsor.

For this company, independence began with manufacturing — creating new technology and constructing new facilities to implement mass production of the company’s proprietary placental-cell therapeutics. Unique business challenges, from funding to IP to recruitment of talent, arose from the company’s choice of path, but it has succeeded in taking its lead products into ongoing Phase 3 trials.


Manufacturing was so important because of the company’s chosen modality: placenta-derived, mesenchymal-like adherent stromal cells, or in Pluristem’s parlance, PLX (PLacental eXpanded) cells. Building such an extensive and specialized manufacturing platform — one that opened up a range of therapeutic applications — effectively committed the company to a long-term development path.

“It is important to understand that Pluristem’s technology allows for a platform of cell-derived product. The vast secretion profile of the cells enables us to develop several treatments for different indications using the same product,” says Yaky Yanay, CEO and president. “Throughout the years, we’ve worked hard to secure non-dilutive third parties’ funding in order to support the company’s clinical development and reach partnerships while possessing proven assets.” With the aim of becoming “a successful, profitable, leading global cell-therapy company,” Pluristem is implementing a commercialization strategy that combines direct sales and commercial licensing.

Although going public more than 10 years ago to get started, the company has mainly relied on stocks and other non-dilutive sources to fund its entire clinical development program through its first potential product approval.

A current example is the company’s homeland defense projects funded and conducted by the U.S. government. But in the future, as Yanay explains, “the company plans to pursue licensing agreements for several indications and territories while also conducting direct sales in strategic indications.”

A large part of the company’s financing has gone into developing the manufacturing capacity for clinical trials and perhaps beyond. Production of PLX cells has unique complications that could only be addressed by custom-building the bioreactor processes and facilities. It is apparently not something that can be scaled up in stages as the clinical trials progress. Perhaps as is typical with cell-based therapeutics, full-scale, high-quality production must be an early to long-term necessity.

Yanay adds detail: “Especially when dealing with public health, the product must be precise, with minimum room for errors and high batch-to-batch consistency. Furthermore, when seeking marketing approval, the manufacturing facility should apply strict regulatory demands. Early in Pluristem’s development, the company understood the need to develop the first tightly controlled, completely automated, efficient, and scalable cell-manufacturing technology in order to produce the highest quality cell-therapy products on a commercial scale.”

He cites the FDA’s approval of the company’s CMC (chemistry, manufacturing, and controls). The manufacturing facilities for PLX cells have been approved by the FDA, PMDA (Pharmaceuticals and Medical Devices Agency), and the German, EU, South Korean, and Israeli regulatory agencies.


Pluristem itself is a product of the Israeli tech sector, having risen out of research at two leading universities, which developed the method of expanding stem cells in 3-D matrices. “The concept was, technologically, to eliminate the use of a flask or petri dish and build a system that mimics the human body environment. But the mindset behind it was also targeting formerly overlooked cell types,” says Yanay.

In 2006, the company narrowed its focus to cell types that fit certain criteria. They must allow manufacturing to move beyond matrix-based expansion, suitable only for single projects, to larger-scale, sustained production resembling a pharmaceutical equivalent. The resulting cells must be allogeneic and highly potent to optimize treatment results. And the cells must come from “an ideal source,” which turned out to be, as Yanay describes it, the amazing intersection of mother and baby, the placenta.

“It is an unbelievable situation in nature to have two independent biological systems living together without a response of one against the other, even when it is a surrogate mother. And the organ that modulates all these amazing immunological discussions is the placenta. But when we started, nobody did placenta. People thought, after nine months, it is dead tissue. But you would be amazed how vivid a living tissue it is. In the placenta itself, you have the maternal and fetal tissues in the one organ. But today we use that fact to build a range of products.”

Naturally, the most immediate challenge raised by the general resistance to placental-cell development was funding. The non-dilutive financing Pluristem sought would depend on some persuasion — mainly by educating investors on the therapeutic potential of the placenta, including the mechanisms it offered and its amenability to the company’s production strategy.

Investors also needed to see action. So, when Yanay joined Pluristem 12 years ago, he pushed the company to choose its target indications, focus its technology on them, and move products into clinical studies as soon as possible. The initiative had the additional effect of motivating the manufacturing push.

“In 2006, we said, ‘We’re going to take this product all the way to the market. We’re not going to license it.’ Very early, we invested a lot of money building a manufacturing facility, understanding that we need to control production of the cells. The cells are expensive, but this is a critical pathway. We had to convince our investors, who said we should get the product approved first, and then do manufacturing. In cell therapy, culturing and controlling the cells is a critical part of developing the product, so we needed to do that before getting to market. This all caused discussions, but our view ultimately prevailed.”


Pluristem is committed to taking its products all the way to Phase 3 — from advance planning, to building critical infrastructure, and of course, to actual late-stage confirmation trials. Its three leading clinical programs are all now in advanced trials. Lead product, coded PLX-PAD, is in trials targeting critical limb ischemia (CLI) and muscle regeneration following hip fracture surgery. Product PLX-R18 is in an advanced Phase 3-parallel trial for treatment of acute radiation syndrome (ARS). It has earlier-stage programs such as a Phase 1 study in incomplete recovery following bone marrow transplantation, a Phase 1-2 study in chronic graft-versus-host disease (cGvHD), and it has completed a Phase 2 study in intermittent claudication. The ARS program has the interesting twist of following the FDA animal rule pathway. Efficacy studies for this indication are not permitted in humans.

Pluristem’s products generally aim at tissue regeneration or protection, as Yanay explains. “Some of our products use the maternal side of the placenta. These cells are very strong cells that can secrete a lot of anti-inflammatory biologics, which support regeneration, as in muscle regeneration. But the so-called baby cells secrete a lot of factors supporting the health of cells, which offers a much better recovery, and we use it today for treating patients after bone marrow transplantation.”

This quietly effective paradigm is what Pluristem hopes to attain in its new products and in future ones. In all cases, even when it has the help of partners, it obviously intends to bring its treatments onto the market, sell them there, and become a commercial player in cell therapy. Others will observe and learn.

Editor's Note:Yanay was also interviewed back in 2017 for the article "Pharma Field Trips: Is Hosting The FDA A Good Idea?"