june 2015 stem-cell-commercialization-anna-cauldwell2

ANNA CAULDWELL, PHDANALYST, CNS, AUTOIMMUNE/INFLAMMATION & OPHTHALMOLOGY

The Commercialization of Stem Cells

Recent advances have shown that stem cells can provide truly restorative and disease-modifying treatment. Stem cells have been used to successfully restore sight to those with vision loss and products are in development for some of the most important and intractable chronic conditions. These treatments offer greater potential over palliative ones and so expectations riding on these therapies are high. Here, we investigate the involvement of biotech and pharma companies in this high-reward, but also high-risk industry.

Historical trendsCiteline’s Pharmaprojects tracks industry-sponsored drug development for human disease since 1980

and since 1995 we have additionally been snapshotting key data points each year. Figure 1 profiles a

year-on-year comparison of the number of stem cell therapies by phase of development. Perhaps

unsurprisingly, the overall trend is of a considerable increase in the number of stem cell therapies in every

phase of development over time. Stem cell therapies started to be developed in the late 1990’s; however,

it wasn’t until the early 2000’s following the discovery of human embryonic stem cells that this area really

started to take off, driven by high expectations about their therapeutic potential. There was an upsurge

in commercial interest and several specialist cell therapy companies were launched whose focus was

on the translation of research into commercially successful products. Recently, there has been a

considerable expansion of late stage candidates — there are currently 87 products in Phase II, Phase III

or Pre-registration, while in 2010 there were only 18. The space is clearly maturing with talk of pivotal

trials becoming commonplace.

Figure 1. Trends in Stem Cell Therapy Development Over Time

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Source: Citeline’s Pharmaprojects®, May 2015

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Figure 2 focuses on the number of drugs currently in each stage of development. This healthy developmental

pipeline has a particularly busy Phase II section with 73 drugs — it is common to see a build-up in this phase

because drugs spend far more time passing through Phase II, than undergoing the much shorter Phase I trials

and so this effect is partly produced by the snapshot nature of the data. Eight stem cell therapies have now

been launched in at least one country in the world (mainly in Australia and South Korea). These products have

been developed to treat osteoarthritis, myocardial infarction, anal fistula, bone regeneration and the

treatment of torn or damaged tendons, ligaments and cartilage. These successes suggest opportunities for

similar clinical candidates to progress.

Figure 2. Number of Therapies by Phase

0 20 40 60 80 10010 30 50 70 90

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Registered

Pre-registration

Phase III Clinical Trial

Phase II Clinical Trial

Phase I Clinical Trial

Preclinical

Where is the development taking place?Citeline’s Sitetrove was used to investigate where in the world this commercial stem cell therapy research is

being undertaken (Figure 3). A large number of trials sites are located in the US and the EU, but a number of

regional regulations have also had a considerable impact on where products are being developed.

Japan is fast becoming a center of importance thanks to regulatory changes which were introduced

at the end of 2014. Japan formally enacted new legislation governing the development, approval and

use of regenerative medicines. The new laws provide a legal framework designed to encourage the

development of novel regenerative therapies and to speed up product approvals in the sector.

This new approval process is similar to the one used in South Korea. Conditional approvals can now be

granted based on safety and efficacy data from Phase II clinical trials instead of full Phase III programs.

These conditional approvals will allow for commercial sales for up to seven years. (Source: PharmAsia

Japan: https://www.pharmamedtechbi.com/publications/pharmasia-news/2014/12/4/japan-regenerative-

medicine-laws-take-effect-encourage-industry).

Sumitomo Dainippon Pharma is one of the Japanese companies investing in this field. It has a joint venture

with Healios KK to commercialize induced pluripotent cell treatments for macular degeneration. Earlier this

year the U.S.-based Athersys entered into a cell therapy alliance with Chugai (Roche). Chugai will develop

and commercialize Athersys’ MultiStem for ischemic stroke in Japan. The alliance is worth $10 million

Source: Citeline’s Pharmaprojects®, June 2015

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upfront to Athersys plus additional development and regulatory milestone payments of up to $45 million.

Moreover, as recently as April this year Takeda announced that it will work with the Center for iPS Cell

Research Application (CiRA) of Kyoto University on stem cell research in a 10 year program to develop

clinical applications of induced pluripotent stem cells in areas such as heart failure, diabetes mellitus,

neurological disorders and cancer immunotherapy.

Whilst this new regulation enables stem cell therapies to reach the market more quickly, some critics are

concerned about the lack of rigorous testing and argue that stem cell therapies which aren’t assessed in

Phase III trials should only be designated experimental treatments.

Figure 3. Industry-Sponsored Trial Site Locations

Which are the most commercially attractive therapeutic areas to invest in? In order to determine which disease areas are attracting the most R&D investment, we grouped the

indications in Pharmaprojects, as shown in Figure 4. Cardiovascular is the hottest area for stem cell research,

accounting for more than a quarter of all stem cell therapies currently in development. The Phase III pipeline

is dominated by therapies for heart failure, angina and myocardial infarction, making it the most advanced

pipeline among all other therapy areas (Table 1). Currently, conventional management for heart failure does

not address loss or scarring of cardiac muscle cell mass, resulting in a high level of unmet medical need and

an opportunity for regenerative stem cell therapies. A mix of speciality and large pharma are trying to

capitalise in the cardiovascular space, including Bioheart, Teva and Baxter International. Baxter is currently

Source: Citeline’s Sitetrove®, June 2015

5

running a pivotal Phase III trial to evaluate the efficacy and safety of adult autologous CD34+ stem cells to

increase exercise capacity and amelioration of anginal symptoms in patients with chronic myocardial

ischemia, one of the most severe forms of coronary artery disease. The study has enrolled approximately

300 patients in over 40 clinical sites in the US (Trialtrove: https://citeline.com/wp-content/uploads/

TrialtroveID-141015.pdf).

A large number of stem cell products are also in development in the metabolic and neurological

therapeutic areas. Some of the key indications under investigation include hepatic dysfunction, bone

regeneration, spinal cord injury and Parkinson’s disease. Ophthalmology is another up and coming area

for stem cell therapies with treatments for corneal injury, macular degeneration, optic neuritis, macular

oedema and diabetic retinopathy in the clinic. In December last year the EMA approved Holoclar, a

treatment for moderate to severe limbal stem cell deficiency due to physical or chemical burns to the

eye(s) in adults. This was the first advanced therapy medicinal product containing stem cells to

be approved in the EU.

When considering the most commercially attractive cell type to invest in, mesenchymal stem cells

(MSCs) are currently ahead of the field. The ethical concerns and potential for teratoma formation with

embryonic stem cells, and induced pluripotent stem cells, have compromised their utility; whereas,

the unique properties of MSCs have led to their intense investigation as a cell-based therapeutic strategy.

The advantages of MSCs are that they are easily isolated, can be amplified from the bone marrow, are

immunologically tolerated as an allogeneic transplant, and have multi-lineage potential.

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Figure 4. Number of Stem Cell Products by Therapeutic Area

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Table 1. Stem Cell Therapies in Phase III Development or Pre-Registration

THERAPY DESCRIPTION ORIGIN INDICATION COMPANY

PH

ASE

III

MyoCell

myoblasts removed from a patient’s thigh muscle, isolated, grown through their proprietary cell culturing process, and injected directly in the scar tissue of a patient’s myocardium

autologous heart failure Bioheart

carlecortemcel-l/StemEX

ex vivo expanded umbilical cord blood cell graft allogeneic

haematopoietic reconstruction after

chemotherapy in haematological malignancies

Gamida Cell; Teva

stem cell therapy, Baxter

blood-derived selected CD34+ stem cell therapy autologous angina Baxter

International

CX-601 suspension of allogeneic expanded adipose-derived stem cells allogeneic anal fistula TiGenix

CEP-41750/Revascor adult-derived mesenchymal precursor cells allogeneic heart failure Mesoblast;

Teva

C-Cure bone marrow-derived stem cells differentiated into cardiopoietic cells autologous heart failure Celyad

mesenchymal bone marrow-derived stem cells, Stemedica-1

ischemic tolerant mesenchymal stem cells allogeneic myocardial infarction Stemedica

mesenchymal precursor cells, allogenic, BMT, Mesoblast

adult-derived mesenchymal precursor cells allogeneic

stem cell engraftment; unspecified haemato-

logical cancer

Mesoblast; Teva

PREOB osteoblastic cells derived from bone marrow mesenchymal stem cells autologous osteonecrosis; fracture

healingBone

Therapeutics

Cerecellgram-Spine bone marrow derived mesenchymal stem cells autologous spinal cord injury Pharmicell

Cerecellgram-Stroke bone marrow derived mesenchymal stem cells autologous cerebral ischaemia Pharmicell

rexlemestrocel-L, Mesoblast

proprietary adult-derived mesenchymal precursor cells allogeneic

chronic lower back pain due to moderate

intervertebral disc degeneration of the

lumbar spine

Mesoblast

PR

E-R

EG

Stempeucelex vivo cultured adult bone marrow-derived mesenchymal stem cells

allogeneic limb ischaemia; osteoarthritis

Stempeutics; Cipla

GSK-2696273

CD34+ haematopoietic stem/progenitor cells engineered ex vivo with a retroviral vector encoding the therapeutic gene adenosine deaminase

autologous severe combined immunodeficiency

GlaxoSmith-Kline


7

Which companies are investing in the industry?So who are the key players in this field? We’ve pulled out the companies with four or more products in

development and it’s apparent that most of these are cell therapy specialists (Figure 5). Teva bucks the

trend by being the only top 20 pharmaceutical company on the list.

Biotime is the biggest player in the stem cell field with 9 products in development. Through their

subsidiary companies Cell Cure Neurosciences and OrthoCyte, they are developing OpRegen, (a cell-

based therapy for age-related macular degeneration), and therapies for arthritis. In addition, their

subsidiary ReCyte Therapeutics is using proprietary technology to reverse the developmental aging of

human cells to manufacture young vascular progenitors for the treatment of age-related vascular disease.

Australian company Mesoblast is another key player with 8 stem cell therapies in development.

Mesoblast’s allogeneic regenerative medicine products focus on repair of damaged tissues and

modulation of inflammatory responses in conditions with significant unmet medical needs. The company’s

clinical product candidates focus on four major areas: orthopedic diseases, cardiovascular diseases,

systemic diseases and improving outcomes of bone marrow transplantation in patients with cancer or

genetic diseases. Mesoblast’s remestemcel-L was acquired from Osiris Therapeutics as an off-the-shelf

adult mesenchymal stromal cell product, which has been approved in several countries for acute graft-

versus-host disease, and it is expected to be launched in Japan later this year. Mesoblast had a further

boost recently with Celgene confirming that it will invest $45 million in the company.

Figure 5. Companies With Active Stem Cell Therapy Pipelines

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Mesoblas

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Bharat

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Biotechnology


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The pharmaceutical industry has embraced stem cells as a tool in drug discovery. Most of the major

pharmaceutical companies are using embryonic stem cells or adult stem cells for internal drug discovery

programs. These internal efforts are often enhanced through the expertise of external partnerships with

academics or biotech companies. However, big pharma has historically been slow to invest in developing

stem cell-based regenerative medicine. The barriers facing this industry will be dependent on the type of

cell-based approach under development, but there are also a range of more general concerns that have

worried investors. These include a lack of familiarity with the business model, pricing, concerns over

whether the products can be manufactured on a commercial scale, regulatory concerns and the question

of whether they can be proven safe and offer substantial benefit over existing therapies.

Despite the concerns these truly restorative and disease-modifying treatments offer considerable promise

and the involvement of big pharma has the potential to dramatically support the space in terms of

providing finance, the capability of conducting Phase II/III clinical trials, expertise in communicating with

regulators and lobbying for regulation in their favour, as well as the potential to mass produce and enable

worldwide distribution of cell therapies.

Table 2 shows the stem cell products being developed by the top pharma companies. There’s been a

steady increase in the number of therapeutic products in development year-on-year since the late 2000’s

with many well-recognised names joining the fray. For several companies the “tipping point” has been

reached and the potential benefits are starting to outweigh the risks. Indeed, not only has there been an

increased number of pharmaceutical stem cell assets; but also the opening of large separate units and

programs (e.g. Neusentis of Pfizer) and a trend for more partnership with academic institutions, which

illustrates the growth in this sector. It seems that big pharma has moved from being curious about the stem

cell therapy industry to being increasingly committed.

In contrast to the key players shown in Figure 5, who were mostly developing their own products, the big

pharma companies are more likely to be in-licensing products for development. These companies often

take the observer’s chair as a company works to complete a crucial leg of the R&D journey. Teva has the

most products in active development with 7 in total. The company has licensee agreements in place with

Mesoblast, BioTime and Gamida Cell. In addition, Teva has three products in Phase III development

including Revascor which is currently in a global, pivotal, 1,700-person trial in congestive heart failure

(Trialtrove: https://citeline.com/wp-content/uploads/TrialtroveID-125374.pdf).

Novartis broadened its position in the stem cell space in 2014 by investing $35 million in Gamida Cell.

This development came after Novartis announced in September 2013 that it had partnered with Regenerex

to gain access to their stem cell technology. Johnson & Johnson is another big name which has recently

shown its commitment to this field by betting $12.5 million on the Capricor Therapeutics cell therapy

program for cardiovascular applications, notably CAP-1002, through its subsidiary, Janssen Pharmaceuticals,

Inc. In addition, through Janssen Pharmaceuticals, J&J invested in ViaCyte’s VC-01 combination product

being developed for type 1 diabetes. The agreement provides Janssen with an option in the future to

consider a transaction related to the VC-01 combination product.

Despite these investments, there is also an increasing realization of just how long a road stem cell research

has to travel and this has triggered some companies to back out of the area. For instance, Osiris offloaded

its mesenchymal stem cell platform and Prochymal to Mesoblast, after Sanofi decided not to sign up to a

$1.25 billion collaboration that came with a $130 million upfront payment. Even so, other companies are

showing that they are still prepared to invest — Chiesi and AstraZeneca entered the space just this year

with their own preclinical candidates.

9

Table 2. Stem Cell Therapies Being Developed by Big Pharma

THERAPY DESCRIPTION COMPANY

PR

EC

LIN

ICA

L

anticancers, MedImmune anti-cancer stem cell therapies to directly and specifically attack tumor cells AstraZeneca

(Originator)

epidermolysis bullosa therapy, Chiesi

ex-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced with a LAMB3-encoding retroviral vector for epidermolysis bullosa

Chiesi (Originator)

HLS-001 iPS cell-derived retinal pigment epithelial cells for age-related macular degene

Dainippon Sumitomo Pharma (Licensee)

PF-05206388 embryonic stem cell derived retinal pigment epithelium for wet age-related macular degeneration Pfizer (Originator)

Multistem multipotent adherent progenitor cells for ischemic stroke Roche (Licensee)

Parkinson’s therapy, Cell Cure embryonic stem cell-derived mid-brain progenitor cell therapy Teva (Licensee)

NeurArrest embryonic stem cell-derived neural progenitor cell therapy for multiple sclerosis Teva (Licensee)

PH

ASE

II

Cenplacel-L placental-derived adherent stem cell product for Crohn’s disease Celgene (Originator)

SB-623 allogeneic neural stem cell therapy for cerebral ischaemia Dainippon Sumitomo Pharma (Licensee)

GSK-2696275 ex vivo gene therapy based on insertion of a lentiviral vector expressing human Wiskott-Aldrich syndrome protein into autologous CD34 positive haematopoietic stem cells

GlaxoSmithKline (Originator)

GSK-2696274ex vivo gene therapy based on insertion of a lentiviral vector expressing arylsulfatase A (ARSA) into autologous CD34 positive haematopoietic stem cells for metachromatic leukodystrophy


CAP-1002 allogeneic cardiosphere-derived stem cells for heart failure and myocardial infarction

Johnson & Johnson (Licensee)

HSC-835 LFU835-expanded umbilical cord blood haematopoietic stem cells for leukaemia & lymphoma Novartis (Originator)

Multistem multipotent adherent progenitor cells for irritable bowel disease and ulcerative colitis Pfizer (Licensee)

MPC-25-ICallogeneic stem cell therapy based upon proprietary adult-derived mesenchymal precursor cells for intra-coronary treatment of acute myocardial infarction

Teva (Licensee)

PDA-002 placental derived stem cells for peripheral arterial disease & diabetic foot ulcers Celgene (Originator)

PH

ASE

III

Stem cell therapy, Baxter blood-derived selected CD34+ st em cell therapy for angina Baxter International

(Originator)

Revascor allogeneic stem cell therapy based upon its proprietary adult-derived mesenchymal precursor cells for heart failure & myocardial infarction Teva (Licensee)

MPC-CBE allogeneic stem cell therapy based upon its proprietary adult-derived mesenchymal precursor cells for bone marrow transplantation Teva (Licensee)

Carlecortemcel-l cord blood-derived ex vivo expanded CD34-positive stem/progenitor cells for haematopoietic reconstruction after chemotherapy in haemato-logical malignancies

Teva (Licensee)

VC-01 pancreatic endocrine ß-islet cells derived from embryonic stem cells for type I and II diabetes Pfizer (Licensee)

OpRegen retinal pigmented epithelial cells derived from human embryonic stem cells for dry age-related macular degeneration Teva (Licensee)

CNTO-2476 allogeneic umbilical cord tissue-derived cell therapy Johnson & Johnson (Originator)

PR

E-R

EG

GSK-2696273

autologous stem cell therapy that consists of CD34+ haematopoietic stem/progenitor cells engineered ex vivo with a retroviral vector encoding the therapeutic gene adenosine deaminase for ADA severe combined immune deficiency


Stempeucel ex vivo cultured adult bone marrow-derived mesenchymal stem cell product for osteoarthritis & critical limb ischemia, other indications Cipla (Licensee)


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ConclusionsThe worldwide stem cell therapy market and development pipelines are poised to grow at a considerable

rate. Increased global awareness, as well as funding and commitment from larger pharmaceutical companies,

are propelling the growth of this industry. Allogeneic stem cell therapies enable the treatment of many

patients from the same cell bank in an off-the-shelf manner and we expect that these therapies will offer the

greatest commercial opportunities. The advantages of allogeneic stem cell products over autologous

products are that they have wider therapeutic applications and the batch to batch consistency means greater

product reproducibility for clinical trial outcomes and widespread clinical use. The opportunity for batch

production also significantly lowers costs compared with patient-specific autologous products and pricing

is critical to both patient accessibility and therapy development. Currently approved allogeneic stem cell

therapies include remestemcel-L (Mesoblast) for graft-versus-host disease and Cartistem (Medipost).

To develop stem cell therapies on a commercial scale it’s essential that stem cell populations can be expanded

successfully. Much work has been done to expand the growth of stem cells from classical cell culture flasks to

novel multilayer vessels, microcarriers and bioreactors; however cell expansion still remains a major challenge.

Many biotech and pharma companies are developing their own proprietary processes to facilitate this and, in

addition, are developing technologies for cryopreservation. Due to the importance of cell expansion and cell

preservation we expect this to be an area of considerable innovation in the coming years.

Overall, despite the complexity of many diseases and the risks involved in developing stem cell therapies,

the pace of research in this industry continues to increase, with new advances announced regularly. It will be

interesting to monitor this field over the coming decade to see if its considerable potential can be realised.

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