Over the last decade or so, I have observed a
tempering of what was once a large and growing interest in stem cell therapies
by patients, physicians and investors. I believe this dampening of enthusiasm
has occurred as the public has awakened to some of the realities surrounding
the logistics of the mass production, regulatory approval and eventual
administration of living cells into people. In this article are my opinions as
to why the stem cell industry may be deserving of this love-hate relationship
and why the “stem cell” products currently closest to approval aren’t “stem
cells” at all.
In
February 2004, Dr. Woo Suk Hwang of South Korea announced he had successfully
derived stem cells from a cloned human embryo, an achievement that earned him
the reputation as a ‘national treasure’ in South Korea and the “king of
cloning” throughout the rest of the world. Despite Dr. Hwang’s subsequent
disgrace and conviction for falsifying data, the damage had been done. The
public believed the ability to regenerate organs from “stem cells” was right
around the corner. These events signaled the controversial popularity
surrounding embryonic stem cells (ESCs), the harvesting of which involves the
destruction of embryos. President Bush’s restrictions on research involving
ESCs combined with the opinions of organizations such as the Catholic Church
had a chilling effect but could not contain the public’s interest and
misconceptions that ESCs could regenerate entire organs such as hearts and
livers.
In
2009, Geron Corporation, a US public company dealing with embryonic stem cell
therapy aimed at spinal cord injuries, enjoyed a market value in excess of $1B.
However, in one of the most significant blows to ESCs in particular, the stem
cell industry in general and a wake-up call for Joe Q occurred three years
later when Geron announced that they were exiting the stem cell market. Geron
stated this decision was made after a “strategic review of the costs, value
inflection timelines and clinical, manufacturing and regulatory complexities”
associated with pursuing the continued research and development of ESCs versus
other assets they owned. I would emphasize the regulatory complexities part of
this statement. Geron’s Investigational New Drug (IND) application totaled
21,000 pages, of lot which was devoted to addressing the regulators concerns
that, at the end of the day, how can you approve a product containing ESCs when
ESCs, by definition, forms tumors (teratomas).
However,
obscured in the shadow of the ESCs popularity, preclinical and clinical work
was being conducted on its stepchild, the adult stem cell. For the purpose of
this article, we define ASCs as any cell therapeutic that is not an ESC or
hematopoietic stem cell (HSC), the cell that differentiates into our blood
lineages. Adult stem cells harbor no ethical controversies, as the procurement
of these cells does not entail destroying the embryo. The vast majority of
adult stem cells being used in preclinical and clinical trials for a variety of
indications exist under the general category of mesenchymal stem cells (MSCs),
although these cells come under different names, such as mesenchymal stromal
cells, mesenchymal precursor cells and mesenchymal-like stromal cells. MSCs can
be obtained from several different sources such as bone marrow, adipose tissue,
the placenta and menstrual fluid. Additionally, MSCs can be obtained from the
patient (autologous) or from a source other than the patient (allogeneic).
Several entities are attempting to commercialize their particular MSC and are
represented by companies such as Mesoblast Limited, Athersys Inc., Aastrom
Biosciences, Inc., and Osiris Therapeutics, Inc. which use bone marrow as a
source of their MSCs and Pluristem, which uses the placenta (PLacental eXpanded
cells), Medistem Inc., which uses menstrual fluid and Cytori Therapeutics, Inc.
and TiGenix NV which use adipose tissue. All of the companies mentioned are
allogeneic-based other than Aastrom and Cytori, which are autologous-based
companies. Autologous-based therapies exploit a business model that is not
intended to supply cells for the general population, as allogeneic therapy is
potentially able to provide. Although still believed to fulfill a niche, the
popularity of the autologous “personalized-medicine” approach has softened
since the discovery that allogeneic MSCs are immune competent and can be
administered to patients without histocompatibility matching.
Interestingly,
the mechanism of action of MSCs is not one of differentiation into tissue and
organs. Instead, these cells act as drug delivery devices. They respond to
signals from injured tissue by secreting a cocktail of anti-inflammatory,
angiogenic, and cytoprotective therapeutic proteins that exert their
pharmacologic effects on the injured tissue. Therefore, if you define a stem
cell as Webster’s dictionary does (i.e. a stem cell is an unspecialized cell
that gives rise to differentiated cells), then the MSCs currently in clinical
trials should not rightfully be called “stem” cells.
Regardless
of whether they are categorized as “stem” cells or not, allogeneic MSCs have
emerged as the regenerative medicine industry’s best chance of developing
commercial products over the near term. This is the unrecognized potential of
cell therapy. ASCs were the king. Allogeneic MSCs are now the king. Allogeneic
cell therapy products are already being marketed for Graft versus Host Disease
(GvHD), a complication of bone marrow transplantation, and Diabetic Ulcers.
More importantly, however, are the allogeneic MSCs in advanced clinical trials
for important indications. Companies are currently involved in Phase II or III
clinical trials for degenerative indications that include Rheumatoid Arthritis,
Inflammatory Bowel Disease, Diabetes, Emphysema, Ischemic Heart Disease,
Congestive Heart Failure, Osteoarthritis, Ischemic Stroke, Peripheral Artery
Disease, Bone Marrow Transplantation and Muscle Injury. Examining these
indications reveal why allogeneic MSC-related products will be the reason the
“stem cell” regenerative medicine industry should be highly successful in the
future.
Cell Therapy in South Korea
Just
recently, Pluristem announced the initiation of South Korean sites in the Phase
II study assessing (PLX) cells in the treatment of intermittent claudication
(IC). Patient screening is now underway at three clinical centers, making South
Korea the fourth country to participate in this randomized, double-blind, and
placebo controlled Phase II trial. The trial has been ongoing at clinical sites
in the U.S., Israel and Germany with an enrollment target of 150 patients. The
study is being conducted by CHA BioTech (Kosdaq: CHA) under an exclusive
licensing agreement for the use of PLX cells for peripheral artery disease
(PAD) in South Korea. Under the terms of Pluristem’s licensing agreement with
CHA, if there is regulatory approval for a PLX product in South Korea Pluristem
and CHA will establish a joint venture (JV) co-owned by the parties; they will
share the revenues and income generated through sales of PLX cell therapies in
the South Korean market. It is estimated that one million people in South Korea
suffer from PAD and this number is expected to grow. These products have the
potential to significantly modify degenerative diseases where the current
relief enjoyed in the past by patients has only been symptomatic.
Zami Aberman
Chief Executive
Officer
Pluristem
Therapeutics, Inc
Zami Aberman Chairman
& CEO joined Pluristem in September 2005 and changed the Company’s strategy
towards cellular therapeutics. Mr. Aberman’s vision to use the maternal section
of the Placenta (Decidua) as a source for cell therapy, combined with
Pluristem’s 3D culturing technology, led to the development of the Company’s
unique products. Mr. Aberman has 20 years of experience in marketing and management
in the high technology industry. He has held positions of Chief Executive
Officer and Chairman in Israel, the USA, Europe, Japan and Korea. He has
operated within high-tech global companies in the fields of automatic optical
inspection, network security, video over IP, software, chip design and
robotics. Mr. Aberman serves as the Chairman of Rose Hitech Ltd., a private
investment company. In the past he has served as the Chairman of VLScom Ltd., a
private company specializing in video compression for HDTV and video over IP
and as a Director of Ori Software Ltd., a company involved in data management.
Prior to that, he
served as the President and CEO of Elbit Vision Systems (EVSNF.OB), which
supplies inspection systems for the microelectronics industry. Mr. Aberman has
served as President and CEO of Netect Ltd., specializing in the field of
internet security software and was the Co-Founder, President and CEO of
Associative Computing Ltd., which developed an associative parallel processor
for real-time video processing. He has also served as Chairman of Display
Inspection Systems Inc., specializing in laser based inspection machines and as
President and CEO of Robomatix Technologies Ltd. (RBMXF. OB). In 1992, Mr.
Aberman was awarded the Rothschild Prize for excellence in his field from the
President of the State of Israel. Mr. Aberman holds a B.Sc. in Mechanical
Engineering from Ben Gurion University in Israel.