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Regenerative medicine for gastrointestinal diseases
Horizon Scanning Research and Intelligence Centre
April 2016
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The National Institute for Health Research Horizon Scanning Research and Intelligence
Centre (NIHR HSRIC) is based at the University of Birmingham in the UK. The NIHR
HSRIC aims to supply timely information to key health policy and decision-makers and
research funders within the NHS about emerging health technologies that may have a
significant impact on patients or the provision of health services in the near future. The
scope of our activity includes pharmaceuticals, medical devices and equipment,
diagnostic tests and procedures, therapeutic interventions, rehabilitation and therapy,
and public health activities.
HSRIC reports can be accessed via our website at: www.hsric.nihr.ac.uk
The centre can be followed on Twitter at: @OfficialNHSC.
This report presents independent research funded by the National Institute for Health
Research (NIHR). The views expressed in this publication are those of the author(s)
and not necessarily those of the NHS, the NIHR or the Department of Health.
The NIHR Horizon Scanning Research and Intelligence Centre (HSRIC)
University of Birmingham, United Kingdom
www.hsric.nhir.ac.uk
Copyright © University of Birmingham 2016
We would welcome your views on this report. Please take our brief online survey at this link: https://www.surveymonkey.com/s/X7WW6QX
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TABLE OF CONTENTS
Executive Summary 4 1. Introduction and background 5
1.1 Regenerative medicine 5
1.2 The gastrointestinal system 6
1.3 Gastrointestinal disorders 6
2. Aims 7
3. Methods 8
3.1 Search strategy 8
3.2 Inclusion and exclusion criteria 8
3.3 Filtration 8
4. Results 9
4.1 Regenerative approaches 10
4.2 Products in phase III trials 10
5. Discussion and conclusions 13
Appendices
Appendix 1: Identification sources 14
Appendix 2: Search terms and strategy 15
Appendix 3: Identified regenerative technologies
Table 1: Cancer (1–8) 20
Table 2: Inflammatory bowel disease (9-10) 23
Table 3: Fistula (11-12) 24
Table 4: Faecal incontinence (13-14) 25
Table 5: Liver disease (15-20) 26
References 30
ACKNOWLEDGEMENTS
NIHR Horizon Scanning Research and Intelligence Centre review team:
Tracey Genus, Horizon Analyst
Dr Claire Packer, Director and Medical Advisor
Dr Sue Simpson, Associate Director
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EXECUTIVE SUMMARY
This horizon scanning review aims to identify new and emerging regenerative
technologies for the treatment of gastrointestinal diseases (excluding those primarily of
the mouth, tongue, pharynx and salivary glands) with a view to informing future
research priorities and NHS evaluation activities. Regenerative medicine seeks to
repair, replace or regenerate damaged or diseased cells or tissues to restore normal
function. It may involve de novo generation of lost or damaged tissue by the
transplantation of stem cells or tissues, or the stimulation of endogenous repair
processes by using genes or cells as vehicles for genes, cytokines and small
molecules. Regenerative medicine encompasses a variety of disciplines including cell
engineering, synthetic biology and biochemical engineering.
We identified emerging regenerative medicine approaches in development for
gastrointestinal diseases by searching a wide range of online sources including clinical
trial registries, horizon scanning databases, commercial ‘pharmaceuticals in
development’ databases, and relevant UK organisations and networks. We included
emerging technologies in phase II, II/III or III clinical trials and excluded technologies
with no updated information on clinical trial registries between January 2014 and
December 2015.
We identified 20 products in phase II or III clinical trials that may have the potential to
reach the health market in the UK in the next few years. Eight of the identified products
(40%) targeted cancer, with half of them targeting colorectal cancer, one of the most
common cancer types in the UK. Three products targeted pancreatic cancer, a cancer
with a poor prognosis. Six products (30%) are in development for liver disease, with two
(10%) each for fistula, inflammatory bowel disease and faecal incontinence.
Regenerative techniques in gastrointestinal disease appear to be moving on from
‘simple’ stem cell transplantation to the use of cells in more complex approaches.
These include the stimulation of immune and exogenous repair systems in
inflammatory bowel disease where there are known inflammatory components of the
condition, and the targeting of specific tumour antigens in cancer. The regenerative
approach in conditions such as perianal fistula and faecal incontinence, without an
inflammatory component, remains with the transplantation of allogeneic or autologous
condition-relevant stem cells.
The NIHR Horizon Scanning Research and Intelligence Centre will monitor the
identified products through later clinical development and trials, informing key health
service and research policy and decision makers when appropriate.
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1. INTRODUCTION AND BACKGROUND
This horizon scanning review provides information to healthcare policy and decision
makers and research commissioners about new and emerging technologies and
approaches in the field of regenerative medicine that may be of relevance in the future
diagnosis and management of gastrointestinal disease. It is not intended to provide a
comprehensive list of all new and emerging technologies for gastrointestinal diseases
or to provide complete information on all identified technologies.
1.1 REGENERATIVE MEDICNE
Regenerative medicine seeks to repair, replace or regenerate damaged or diseased
cells or tissues to restore normal function1. It may involve:
transplantation of stem cells, progenitors or tissue
stimulation of endogenous repair processes e.g. with growth factors
the use of cells as delivery vehicles for genes, cytokines and small molecules
Many products will be classified as advanced therapy medicinal products (ATMPs) by
the European Medicines Agency (EMA)2.
A somatic cell therapy medicinal product2 is a product that
contains or consists of cells or tissues that have been subject to substantial
manipulation so that biological characteristics, physiological functions or
structural properties relevant for the intended clinical use have been altered, or
of cells or tissues that are not intended to be used for the same essential
function(s) in the recipient and the donor; and
is presented as having properties for, or is used in or administered to human
beings with a view to treating, preventing or diagnosing a disease through the
pharmacological, immunological or metabolic action of its cells or tissues.
A gene therapy medicinal product2 is a product obtained through a set of
manufacturing processes aimed at the transfer (either in vivo or ex vivo), of a
prophylactic, diagnostic or therapeutic gene (i.e. a piece of nucleic acid), to
human/animal cells and its subsequent expression in vivo. The gene transfer involves
an expression system contained in a delivery system known as a vector, which can be
of viral, as well as non-viral origin. The vector can also be included in a human or
animal cell.
A tissue engineered product2 is a product that contains or consists of engineered
cells or tissues, and is presented as having properties for, or is used in or administered
to human beings with a view to regenerating, repairing or replacing a human tissue. A
tissue engineered product may contain cells or tissues of human or animal origin, or
both. The cells or tissues may be viable or non-viable (if non-viable then the product
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may not be classified as an ATMP). It may also contain additional substances, such as
cellular products, bio-molecules, biomaterials, chemical substances, scaffolds or
matrices.
1.2 THE GASTROINTESTINAL SYSTEM
The gastrointestinal system consists of the digestive tract (or alimentary canal) and its
accessory organs and is responsible for the digestion and metabolism of food, and the
absorption of the resulting nutrients.
The gastrointestinal tract consists of the mouth, pharynx, oesophagus, stomach, small
and large bowel, and anus. The small bowel (or small intestine) consists of the
duodenum, jejunum and ileum; and the large bowel (or large intestine) consists of the
caecum; the ascending, transverse, descending and sigmoid colon; and the rectum and
anal canal. The accessory digestive organs include the tongue, salivary glands,
pancreas, liver and gallbladder and biliary tract.
1.3 GASTROINTESTINAL DISORDERS
Gastrointestinal disorders and diseases can be the result of congenital defects,
inherited gene mutations, tissue damage or loss, autoimmune diseases, and tumours.
Common gastrointestinal conditions include:
1.3.1 CANCER AND DYSPLASIA
Dysplasia and cancer can occur at any point in the gastrointestinal tract and the
associated organs. Common cancers in the UK include colorectal, anal, pancreatic,
oesophageal, stomach, oral, and liver cancer3.
1.3.2 INFLAMMATORY BOWEL DISEASE
The two main subtypes of inflammatory bowel disease are ulcerative colitis and Crohn’s
disease. They are thought to arise from a combination of defective mucosal immune
regulation in the gut and exposure to unknown environmental factors and luminal
antigens4.
Ulcerative colitis is characterised by mucosal inflammation of the rectum and/or colon.
Typical symptoms include diarrhoea, rectal bleeding, tenesmus and increased stool
urgency and frequency. Complications can include toxic megacolon and colorectal
dysplasia or cancer.
Crohn’s disease is characterised by transmural and sometimes granulomatous
inflammation of the gastrointestinal tract, most commonly in the ileum and colon.
Typical symptoms are abdominal pain, fatigue and diarrhoea. Complications can
include intestinal stenosis, fistulas, intra-abdominal abscesses, peritonitis and cancer5.
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1.3.3 FISTULA - PERIANAL AND RECTOVAGINAL
A perianal fistula (anal fistula or fistula in ano) is an abnormal tract connecting the
anorectal mucosa (epithelialized surface of the anal canal) to the perianal skin or
perineum6. A rectovaginal fistula, also known as an enterovaginal fistula is a tract that
connects the rectum to the vagina. Fistulas typically develop after rupture or drainage
of an abscess6 or are associated with inflammatory bowel disease. Up to 50% of
people with Crohn’s disease will have an anal fistula and up to 9% of these are
rectovaginal fistula7. Perianal fistulae are more common in men, mostly between the
ages of 20 and 408.
1.3.4 FAECAL INCONTINENCE
The anal canal is surrounded by two layers of muscle, the involuntary internal anal
(IAS) sphincter and the voluntary external anal sphincter9. Faecal incontinence is the
involuntary loss of stool or flatus and may be caused by anatomical damage to these
muscles resulting from trauma (congenital, obstetric, surgical, accidental or iatrogenic)
or a degenerative disorder affecting the smooth muscle of the IAS10.
1.3.5 LIVER DISEASE
The liver is affected by many conditions both acute (with a short natural history) and
chronic (with a history over many months and years). Liver disease can be caused in
many different ways including11:
poor nutrition and metabolic syndrome leading to non-alcohol fatty liver disease
(non-alcohol steatohepatitis), cirrhosis and liver cancer,
alcohol misuse and abuse leading to liver damage and liver cirrhosis,
acute and chronic hepatitis from viral infections or other harmful substances,
which can progress to liver cirrhosis and liver cancer,
inherited liver disorders such as haemochromatosis (causing the accumulation
of iron), Wilson’s disease (causing the accumulation of copper) and alpha-1
antitrypsin deficiency, and
hepatic veno-occlusive disease where small veins in the liver can become
obstructed.
2. AIMS
The aim of this horizon scanning review is to identify new and emerging technologies in
the field of regenerative medicine for the treatment of gastrointestinal diseases with a
view to informing future research priorities and NHS evaluation activities.
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3. METHODS
3.1 SEARCH STRATEGY
We identified new and emerging regenerative medicine approaches in development for
gastrointestinal conditions by searching a wide range of online sources (Appendix 1)
including:
clinical trial registries;
horizon scanning databases;
commercial pharmaceuticals in development databases;
regulatory authorities; and
relevant UK organisations and networks.
Searches were conducted using pre-defined search terms for gastrointestinal disorders
as well as for regenerative medicine and cellular approaches (Appendix 2).
3.2 INCLUSION AND EXCLUSION CRITERIA
We included:
technologies in development for the treatment of gastrointestinal diseases
emerging technologies reported to be in phase II, II/III or III clinical trials,
either commercially sponsored or, if non-commercially sponsored in clinical trials
in the EU or sponsored by the NIH in the USA, and
cell-based extracorporeal bioartificial liver assist devices which, although they do
not fall into the definition of a regenerative approach, use a cellular approach
that may stimulate endogenous repair by releasing bioactive factors such as
cytokines.
We excluded:
technologies in development for conditions of the mouth, tongue, pharynx and
salivary glands,
technologies specifically targeting infectious disease e.g. hepatitis B virus, rather
than effects of that disease,
technologies already registered and/or available for clinical use for the specific
indication in the UK, and
technologies noted to be discontinued on commercial databases of
pharmaceuticals in development and/or with no updated information on clinical
trial registries between January 2014 and December 2015.
3.3 FILTRATION
Where available, we used our inclusion criteria as filtration terms during searches of the
identification sources. For sources where there were no automated filtration options, we
captured all technologies and studies irrespective of development phase, trial country
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or funder type. All identified technologies were downloaded or entered into excel
spreadsheets and any duplicates removed. The remaining entries were manually
filtered to select those which appeared to meet the review’s inclusion criteria.
We searched for additional information in commercial databases (Pharmaprojects
https://citeline.com/ and Adis Insight http://adisinsight.springer.com/) and a clinical trial
database (ClinicalTrials.gov http://clinicaltrials.gov/) to enable the final filtering of the
identified technologies.
4. RESULTS
We identified almost 1,400 technologies and approaches in our initial searches, with
1,318 being removed in the initial filtration steps (Figure 1). After the collection of
additional information and final filtration, 20 technologies for gastrointestinal diseases
remained. The 20 technologies are listed and summarised in Appendix 3: Tables 1-5.
Figure 1: Horizon scanning review identification and filtration flow diagram
Of the identified technologies eight (40%) are in development for cancer, six (30%) for
liver disease, and two (10%) each for fistula, inflammatory bowel disease and faecal
incontinence (Table 1). Of the cancers, four products are in development for colorectal
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cancer (one phase III, one phase II/III and two phase II), three for pancreatic cancer
(one phase III and two phase II) and one for oesophageal cancer (phase II).
4.1 REGENERATIVE APPROACHES
The included technologies used different regenerative approaches which differed
depending on the gastrointestinal disorder:
all cancers are being targeted by cell therapies which aim to increase immune
stimulation with or without genetic modification to the cells, or genetic
modification of cells leading to localised drug activation,
inflammatory bowel disorders are being targeted using cell therapy aiming to
stimulate exogenous repair, and
all other disorders are being targeted using cell therapy with cell transplantation
or with extracorporeal cell therapy devices.
There is an almost even split between the use of an allogeneic (nine technologies) and
an autologous (10 technologies) approach, which is consistent between the conditions
(Table 2), and only one purely gene therapy product.
Five (25%) of the identified technologies are in phase III trials, two (10%) in phase II/III
trials and 13 (65%) in phase II trials (Table 2). Sixteen (80%) of the technologies are or
have completed industry sponsored clinical trials and four (20%) are in academically-
led UK or EU-based trials.
We found a few tissue engineering solutions in our initial searches including
decellularized liver scaffolds for later seeding with stem cells, but they were all
excluded in our initial filtering stage because they were in very early research and/or
there was no evidence of ongoing development or recent clinical trials. We also found
several other extracorporeal cell therapy systems for liver failure, but all apart from the
ELAD System (technology no. 15) were excluded as there was no evidence of recent
or ongoing clinical development.
4.2 PRODUCTS IN PHASE III TRIALS
We found five technologies in phase III commercially-sponsored clinical trials, four of
which are likely to be licensed through the EMA ATMP regulations route.
The final product in phase III trials is an extracorporeal liver assist device (ELAD) from
Vital Therapies. The product was reported not to have reached its survival primary
endpoint in an earlier trial in this patient group (company website), but showed promise
in younger patients without significant kidney and blood clotting dysfunction. Following
this result, in October 2015 all other ongoing trials in other related patient groups were
terminated. Vital Therapies are in the planning stages for a trial in a more constrained
group of patients with alcohol induced liver decompensation (VTI-308, NCT02612428).
Table 1: Number of technologies by condition and underlying mechanism of action
Immune
stimulant
Immune
stimulant
with genetic
modification
Localised drug
activation with
genetic
modification
Gene
therapy
Cell
therapy,
exogenous
repair
stimulant
Cell
therapy
Extracorporeal
cell therapy TOTAL
Cancer 2 4 1 1 0 0 0 8
Colorectal cancer 2 1 1 4
Oesophageal cancer
1 1
Pancreatic cancer 2 1 3
Inflammatory
bowel disease 0 0 0 0 2 0 0 2
Fistula 0 0 0 0 0 2 0 2
Faecal
incontinence 0 0 0 0 0 2 0 2
Liver disease 0 0 0 0 0 5 1 6
Total 2 4 1 1 2 9 1 20
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Table 2: Number of technologies by condition, cellular approach and clinical trial phase
Approach Clinical trial phase
Allogeneic Autologous Gene therapy II II/III III Total
Cancer 3 4 1 5 1 2 8
Colorectal cancer 0 3 1 2 1 1 4
Oesophageal cancer 0 1 0 1 0 0 1
Pancreatic cancer 3 0 0 2 0 1 3
Inflammatory bowel disease
1 1 0 1 0 1 2
Fistula 2 0 0 1 0 1 2
Faecal incontinence
0 2 0 2 0 0 2
Liver disease 3 3 0 4 1 1 6
Total 9 10 1 13 2 5 20
5. DISCUSSION AND CONCLUSIONS
We have identified 20 regenerative medicine products for gastrointestinal disease in
phase II or III clinical trials that may have the potential to reach the health market in the
UK in the next few years. Some of these products may prove to be effective in
stimulating the immune system or tissue regeneration to increase cancer cell clearance
(and potentially survival) or to restore tissues and function.
The majority of identified products target cancer, with half of them targeted at colorectal
cancer, one of the most common cancer types in the UK. Three products target
pancreatic cancer, with one product in phase III trials. If efficacy is proven this product
may be important as people with this type of cancer have particularly poor survival
chances.
Regenerative techniques in gastrointestinal disease appear to be moving on from
‘simple’ stem cell transplantation to the use of cells in more complex approaches.
These include the stimulation of immune and exogenous repair systems in
inflammatory bowel disease where there are known inflammatory components of the
condition, and the targeting of specific tumour antigens in cancer. The regenerative
approach in conditions such as perianal fistula and faecal incontinence, without an
inflammatory component, remains with the transplantation of allogeneic or autologous
condition-relevant stem cells.
The NIHR Horizon Scanning Research and Intelligence Centre (HSRIC) has a system
for monitoring the progress of pharmaceuticals and ATMP through final clinical trials
and providing advanced notice of products as they approach 20 months of likely
licencing and launch to the UK health market. HSRIC has already written a drug
briefing on 1 product – CX601 for perianal fistula associated with Crohn’s disease, and
will produce similar briefings on the other products in due course.
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APPENDIX 1: IDENTIFICATION SOURCES
Clinical trial registries and research publications
Web address
ClinicalTrials.gov http://www.clinicaltrials.gov/
UKCRN Portfolio Database http://public.ukcrn.org.uk/search/
WHO International Clinical Trials Registry
http://www.who.int/trialsearch/Default.aspx
Horizon scanning databases and NIHR HSC sources
Web address /Reference
Canadian Dataset (2013) Li, Atkins and Bubela. The global landscape of stem cell clinical trials. Regenerative Medicine 2014;9(1):27-39.
EuroScan http://euroscan.org/
NIHR BRCs and BRU annual dataset (2013)
Confidential internal document from NIHR NETSCC
NIHR HSRIC Database Confidential internal database
Drug specific sources Web address
Adis Insight http://adisinsight.springer.com/
Pharmaprojects https://citeline.com/products/pharmaprojects/
Stem cell and regenerative medicine sources
Web address
LifeMap Discovery http://discovery.lifemapsc.com/
Regulatory authorities Web address
European Medicines Agency (EMA)
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000301.jsp&mid=WC0b01ac05800862c0
Relevant groups and networks Web address
Alliance for Regenerative Medicine (ARM)
http://alliancerm.org/
California Institute for Regenerative Medicine (CIRM)
http://www.cirm.ca.gov/
Cell and Gene Therapy Catapult https://ct.catapult.org.uk/
Regener8 https://www.regener8.ac.uk/
StemCells Australia http://www.stemcellsaustralia.edu.au/
UK Stem Cell Foundation http://www.ukscf.org/
UniverCELL Market https://www.univercellmarket.com/
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APPENDIX 2: SEARCH TERMS AND STRATEGY
We used classifications such as the International Statistical Classification of Diseases and Related Health Problems 10th revision (ICD 10) and MeSH headings to develop a list of relevant gastrointestinal diseases for use when manually searching sites. We undertook scoping searches to determine the best search terms and approaches to each identification source and used search strategies developed in previous horizon scanning reviews in the field.
CLINICAL TRIAL REGISTRIES
CLINICALTRIALS.GOV
Search information:
Used advanced search
Recruitment: all studies
Countries: all countries
Funder: all types
Limits:
o phase 1-4
o date last updated 01/01/2011 – 17/02/2015
Search terms: “artificial organ” OR “bioartificial organ” OR “advanced therapy medicinal product” OR bioengineering OR “cellular therapy” OR “tissue therapy” OR regenerations OR “regenerative medicine” OR “stem cell” OR “tissue engineered” OR “tissue engineering” OR “gene therapy” OR “genetic therapy” AND “inflammatory bowel disease” OR “ulcerative colitis” OR “Crohn’s disease” OR “diverticulitis” OR “functional gastrointestinal disorders” OR “perianal fistulae” OR “faecal incontinence” OR “gastrointestinal cancer” OR “liver cancer” OR “liver disease” OR “liver transplantation”.
UKCRN PORTFOLIO DATABASE
Search information:
Specialty: all
Research summary: any
Searched all content up to and including 25/02/2015
Searched in ‘Research summary’ search tool for the terms: advanced therapy medicinal product; ATMP; artificial organ; bioartificial organ; bioengineered; bioengineering; cell based therapy; tissue based therapy; cell therapy; cellular therapy; regeneration; regenerative medicine; stem cell transplantation; stem
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cell; tissue based therapy; tissue engineered; tissue engineering; gene; genetic, and hepatology; gastroenterology; Manually searched results for the terms: inflammatory bowel disease; ulcerative colitis; Crohn’s disease; diverticulitis; functional gastrointestinal disorders; perianal fistulae; gastrointestinal cancer; liver cancer; faecal incontinence; liver transplantation
WHO INTERNATIONAL CLINICAL TRIALS REGISTRY (ICTRP)
Search information:
Combined search of basic and advanced search tools
Recruitment: all studies
Searched all contents up to and including 17/02/2015
Search terms: advanced therapy medicinal product OR artificial organ OR bioartificial organ OR bioengineer* OR tissue therapy OR cell therapy OR regenerat* OR regenerative medicine OR stem cell OR tissue engineer* OR gene therapy OR gene*therapy OR genetic therapy Simple search results searched manually for the terms: inflammatory bowel OR ulcerative colitis OR Crohn OR diverticulitis OR fistula (perianal/Crohn’s) OR gastrointestinal OR liver OR incontinence (faecal/fecal) in the ‘Public_title’ and ‘scientific_title’ fields. Advanced search: AND inflammatory bowel OR ulcerative colitis OR Crohn OR diverticulitis OR fistula OR gastrointestinal OR liver OR incontinence
HORIZON SCANNING DATABASES AND NIHR SOURCES
EUROSCAN
Search information:
Members only search by specialty: Gastrointestinal, pancreatic and liver disease.
Filtered by date.
Searched all content last modified between 01/01/2010 and 19/02/2015
results manually searched for the terms:
artificial organ OR bioartificial organ OR advanced therapy medicinal product OR ATMP OR bioengineering OR cellular therapy OR tissue therapy OR regeneration OR regenerative medicine OR stem cell OR tissue engineered OR tissue engineering OR gene therapy OR gene*therapy OR genetic therapy
CANADIAN DATASET 2013 (LI ET AL 2014)
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Search information:
Searched the ‘condition’ field in supplementary table 3 for any gastrointestinal
diseases
DRUG SPECIFIC SOURCES
ADIS INSIGHT
Search information:
The following fields and limits were selected and added to the ‘query builder’: Limits
Phase: I, I/II, II, II/III, III
Update:
o date >01/01/2010
o update type = new or significantly modified profiles
o update subject: new profile OR active status review OR regulatory status
OR licensing status OR trial update OR company name changes OR
scientific update OR all phase changes
Search terms: Therapeutic area: Cell therapies OR Bio/Chemical Class: Growth factor OR Stem cell therapies OR Stem cell factors OR Tissue extracts OR Cell therapies OR Haematopoietic-cell-growth-factors OR Stimulated-dendritic-cell-vaccines OR gene therapies OR genetic therapy AND Indication: Digestive system disorders: inflammatory bowel disease OR ulcerative colitis OR Crohn’s disease OR diverticulitis OR gastrointestinal disorders OR rectal fistula OR gastrointestinal cancer OR liver cancer OR faecal incontinence OR liver disorders OR liver failure OR liver cirrhosis OR liver transplant rejection
PHARMAPROJECTS
Search information:
Subscription service
Advanced search by ‘therapeutic class’ combined with a search by ‘disease’
Limits:
o Phase I, II, III
o Pre-registration
o Approved: Registered or launched
o Inactive: suspended or no development reported
o Latest change date 01/01/2010 – 23/02/2015
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Search terms:
Therapeutic Class: Stem cell therapy OR Cellular therapy, other OR Gene therapy OR Gene delivery vector AND Disease: Inflammatory bowel disease OR Colitis, ulcerative OR Crohn's disease OR Diverticulitis OR Constipation, functional OR Dyspepsia, functional OR Gastrointestinal disease, unspecified OR Perianal fistula OR Cancer, gastrointestinal, neuroendocrine OR Cancer, gastrointestinal, stomach OR Cancer, gastrointestinal, stromal OR Cancer, gastrointestinal, unspecified OR Cancer, liver OR Cirrhosis, liver OR Fibrosis, liver OR Liver dysfunction, unspecified
REGULATORY AUTHORITIES
EUROPEAN MEDICINES AGENCY (EMA)
A manual search of the scientific recommendations on advanced therapy medicinal
products (ATMPs) listed between 01/01/2010 and 19/02/2015 for the terms:
Inflammatory bowel disease; ulcerative colitis; Crohn’s disease; diverticulitis; functional
gastrointestinal disorders; perianal fistulae; gastrointestinal cancer; liver cancer; faecal
incontinence; liver transplantation; liver disease
STEM CELL AND REGENERATIVE MEDICINE SPECIFIC SOURCES
LIFEMAP DISCOVERY
A search of the ‘Regenerative Medicine’ tab for any gastrointestinal and liver disease
topics: 20/02/2015
RELEVANT GROUPS AND NETWORKS
ALLIANCE FOR REGENERATIVE MEDICINE (ARM)
A manual search for any gastrointestinal or liver disease topics in ‘Related disease news’ in the ‘Regenerative Medicine’ section of the ARM website: 19/02/2015.
CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE (CIRM)
A manual search for any gastrointestinal or liver disease topics using the ‘search grants’ query builder in the ‘our progress’ tab choosing ‘disease focus’ Intestinal Disease and Liver Disease: 19/02/2015.
GENE AND CELL THERAPY CATAPULT (CTC)
A manual search for any gastrointestinal or liver disease topics in the ‘Cell therapy landscape: UK clinical trials database’: 19/02/2015
REGENER8
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A manual search for any gastrointestinal or liver disease topics in the ‘case studies’ and ‘news’ sections of the website: 19/02/2015.
UK STEM CELL FOUNDATION
A manual search for any gastrointestinal or liver disease topics in the research focus section: 20/02/2015.
STEMCELLS AUSTRALIA
A manual search of the condition ‘Diseases of gastrointestinal system’ in ‘Stem cell clinical trials’ in the ‘About stem cells’ section of the StemCells Australia website: 20/02/2015.
APPENDIX 3: IDENTIFIED REGENERATIVE TECHNOLOGIES
TABLE 1: CANCER
No Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
Phase III
1 OncoVAX
Pre-registration in
Switzerland
Vaccinogen Autologous tumour
cell vaccine, immune
stimulant
Colorectal cancer
(stage 2) adjuvant
to surgery
Three intradermal doses of
autologous tumour cells
combined with Bacillus
Calmette-Guerin (BCG)
adjuvant, booster at 6 months.
NCT02448173, ACTIVE phase
IIIb; USA; randomised
controlled; planned n=550;
expected completion July 2020.
2 Algenpantucel-L,
HyperAcute-
Pancreas
NewLink Genetics
Corporation
Allogeneic tumour
cell vaccine,
genetically modified
immune stimulant
Pancreatic cancer,
borderline
resectable or
unresectable,
adjuvant therapy
Two intradermal doses of
allogeneic pancreatic cancer
cells with mouse gene α(1,3)-
galactosyltransferase encoding
for enzyme alpha-galactosidase.
NCT01836432, PILLAR phase III;
unresectable disease; USA;
randomised controlled;
planned n=280; expected
completion June 2017.
NCT01072981, IMPRESS phase
III; USA; resected disease;
randomised controlled; n=722;
expected completion June
2016.
Phase II/III
3 MelCancerVac DanDrit Biotech Autologous dendritic
cell vaccine, immune
stimulant
Colorectal cancer,
(stage 4), adjuvant
therapy
Intradermal autologous
dendritic cells with melanoma
cell line lysate expressing a
broad range of antigens
(particularly MAGE family
VIVA trial; planned phase III
trial; Italy; randomised
controlled; planned n=172.
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No Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
antigens).
Phase II
4 FANG vaccine, Bi-
shRNAfurin
Gradalis Autologous T cell
vaccine, genetically
modified immune
stimulant
Colorectal cancer
with liver
metastases ; post-
operative adjuvant
in combination
with chemotherapy
4-12 intradermal inoculations of
autologous tumour cells loaded
with vector plasmid encoding
granulocyte-macrophage
stimulating factor (rhGM-CSF)
and furin bifunctional shRAN
(bi-shRNA).
NCT01505166, FANG-CLM
phase II; USA; randomised
controlled; n=60; expected
completion March 2016.
5 TroVax, MVA-5T4 Oxford BioMedica Pox virus gene
therapy, immune
stimulant
Colorectal cancer,
inoperable
metastatic;
adjuvant therapy
Intramuscular modified vaccinia
virus Ankara (MVA) virus vector
encoded with tumour-
associated oncofoetal antigen
5T4 (OBA1).
EudraCT2010-024380-41,
TaCTiCC; UK; randomised
controlled; planned n=54;
expected completion
December 2015.
6 GVAX Pancreas,
CG8123 in
combination with
CRS-207 vaccine
Aduro BioTech,
ANI
Pharmaceuticals,
Bristol-Myers
Squibb
Allogeneic tumour
cell vaccine,
genetically modified
immune stimulant
Pancreatic cancer,
metastatic; in
combination with
cyclophosphamide
Intradermal genetically
modified tumour cells secreting
granulocyte-macrophage colony
stimulating factor (GM-CSF).
With CRS-207, a genetically
modified mesothelin antigen
expressing vaccine.
NCT01417000, phase II; GVAC
with or without CRS-207; USA;
randomised controlled;
planned n=93; expected
completion November 2015.
NCT02004262, ECLIPSE phase
II; GVAX and CRS-207; US and
Canada; randomised
controlled; n=303; expected
completion December 2016.
NCT02243371, STELLAR phase
22
No Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
II; GVAX and CRS-207; USA;
randomised controlled;
planned n=94; expected
completion January 2019.
7 NovaCaps,
Cell-in-a-Box® live-
cell
encapsulation,
encapsulated CYP
2B1-expressing
cells
PharmaCyte
Biotech,
Austrianova
Allogeneic tumour
cell line, genetically
modified, localised
drug activation
Pancreatic cancer,
locally advanced,
inoperable,
unresponsive to
paclitaxel and
gemcitabine, in
combination with
ifosfamide
Implantation of cellulose
encapsulated genetically
modified human embryonic
kidney 293 (HEK 293) cells,
carrying cytochrome P450
isoform 2B1 gene. Cytochrome
P450 2B1 converts ifosfamide to
its cytotoxic metabolite at the
site of administration.
Planned phase IIb trial; USA, EU
and Australia; randomised
controlled; unknown planned
recruitment; unknown end
date.i
8 New York
oesophageal
squamous cell
carcinoma 1 (NY-
ESO-1) antigen
targeting T cells
Christie Hospital
NHS Foundation
Trust, University
College London
Hospitals
Autologous T cell
vaccine, genetically
modified, immune
stimulant
Oesophageal
Cancer, after pre-
conditioning
chemotherapy and
with interleukin
Single infusion of autologous
genetically modified T cells.
NCT01795976, EudraCT 2012-
005327-33, ATTACK-OG; single
group assignment, open label;
UK; planned n=28; expected
completion August 2018.ii
Participant recruitment
suspended Sept 2015.
i PharmaCyte Biotech management interviewed to discuss key aspects of new pancreatic cancer clinical trial design. Press release Oct 2015. http://www.pharmacytebiotech.com/pharmacyte-biotech-management-interviewed-to-discuss-key-aspects-of-new-pancreatic-cancer-clinical-trial-design/
ii This trial is noted as suspended on the UK Clinical Research Network portfolio, but no date or reason is given for the suspension. http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=14133
23
TABLE 2: INFLAMMATORY BOWEL DISEASE
No. Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
Phase III
9 Prochymal,
Remestemcel-L,
JR-0301, MSC-100-
IV, OTI-010, OTI-
011, OTI-020, OTI-
021
Mesoblast Ltd. Human adult
mesenchymal stem
cells; allogeneic
bone-marrow
derived stromal
cells; exogenous
repair stimulant
Crohn's disease,
refractory, moderate
to severe
Multiple intravenous
infusions.
NCT00482092, CRD 603; USA,
Australia and New Zealand;
randomised controlled;
planned n=330; expected
completion December 2018.
Extension studies:
NCT00543374, CRD 610; n=98;
completed.
NCT00294112, OSIRIS-601-602;
n=10; completed.
NCT01233960, CRD 611; re-
treatment; n=120; expected
completion July 2017.
Phase II
10 Ovasave,
Ova-Treg
TxCell; Ferring
Pharmaceuticals
Regulatory type 1 T
lymphocytes that
recognise
ovalbumin;
autologous,
exogenous repair
stimulant
Crohn's disease,
refractory
Multiple intravenous
injections.
Tr1 cells migrate preferentially
to inflammation and act
through the secretion of anti-
inflammatory cytokines.
NCT02327221, EudraCT2014-
001295-65, TXC-CD002-2011;
phase IIb, EU including UK;
randomised controlled;
planned n=160; expected
completion 2016/2017.
24
TABLE 3: FISTULA
No. Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
Phase III
11 CX601
Anticipated
launch in 2017 –
company press
release.
TiGenix Expanded adipose-
derived
mesenchymal adult
stem cells; allogeneic
Crohn’s perianal
fistula, complex;
refractory to
previous drug
therapy
Single intra-lesion injection.
HSRIC briefing April 2015
http://www.hsric.nihr.ac.uk/to
pics/cx601-alofisel-for-complex-
perianal-fistula-in-adults-with-
non-active-or-mildly-active-
luminal-crohns-disease-second-
line/
NCT01541579, Cx601-0302,
ADMIRE-CD phase III; EU not
including UK; randomised
controlled; n=289; expected
completion July 2015.
Phase I/II
12 Bone marrow
derived
mesenchymal
stem cells
Leiden
University
Medical Center
Bone marrow
derived
mesenchymal stem
cells; allogeneic
Crohn’s perianal
fistula, refractory
Intra-lesion injection post
curettage.
NCT01144962, EUCTR2009-
015680-14-NL; Netherlands;
randomised 3-dose and
control; n=22; Positive results
published. iii
iii Ilse Molendijk, , Bert A. Bonsing et al. Allogenic Bone Marrow–Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients
With Crohn’s Disease. Gastroenterology. 2015;149(4):918-927. doi:10.1053/j.gastro.2015.06.014
25
TABLE 4: FAECAL INCONTINENCE
No. Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
Phase II
13 CEL-02, RCD-2,
RCD2
Celogos;
CELLforCURE,
Rouen
University
Hospital
Myoblasts (muscle
precursor cells);
autologous
Faecal incontinence,
severe; refractory to
treatment
Intra-muscular injection NCT01523522, MIAS phase II
/III; France; randomised; n=24;
completed October 2015, no
results identified.
14 ICEF-15, NPJ-
5007
Innovacell
Biotechnologie
AG
Skeletal muscle-
derived cells;
autologous
Faecal incontinence Intra-muscular injection EUCTR2010-021463-32, STEFFI
phase IIb; EU including UK;
randomised controlled;
planned n=250; expected
completion not known.
26
TABLE 5: LIVER DISEASE
No. Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
Phase III
15 ELAD System,
cell-based
extracorporeal
liver assist
device
Vital Therapies Human liver cell sub-
clone of the human
hepatoblastoma cell
line HepG2, VTL C3A
cells, allogeneic
Orphan designation
in EU and USA for
acute liver failure.
Alcohol induced
liver
decompensation.
Acute on chronic
hepatitis
including acute
alcoholic
hepatitis.
Acute Liver
Failure (ALF)
Extracorporeal, bio-artificial liver
support system. Plasma fluid
(ultrafiltrate) is circulated
through four metabolically-active
cartridges containing cloned,
immortalized human
hepatoblastoma cells (VTL C3A
cells).
Uses central venous line,
concomitant heparin treatment,
in a single continuous session of
3-10 days on 1 set of cartridges.
VTL C3A cells may mimic some
liver cell functions e.g.
production of specific live
proteins and P450 enzyme
functions. But does not replicate
all liver cell functions and
ammonia removal, amino acid
metabolism, cytochrome P450s
NCT0261248, VTI-308, phase III
trial planned; alcohol induced
liver decompensation,
randomised controlled trial,
USA and EU including UK,
planned n=50, first patient
enrolment expected by mid-
2016, results expected mid-
2018.
NCT01471028, VTI-208, phase
III; UK, USA, Australia and Spain;
alcohol induced liver
decompensation; randomised
controlled; n=203 (12 UK
patients); with 5-year
extension. Interim trial results
in Nov 2015 - did not meet
primary endpoint of increase in
survival at 91 days (HR 1.027;
p=0.9).
27
No. Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
and drug metabolism functions
remain low.
NCT00973817, VTI-206, phase
II/III; USA and UK; acute on
chronic hepatitis (included
acute alcoholic hepatitis, AAH
cohort); randomised controlled
open label; n=62; complete,
initial results shows for AAH
cohort differences in survival
favoured ELAD, but were not
significant.
NCT01829347, VTI-210, phase
III, EU including UK and USA;
severe acute alcoholic hepatitis;
randomised, open label;
planned n=18; trial terminated
Oct 2015.
NCT01875874, VTI-212; phase
II; USA; acute liver failure; single
group; planned n=40; trial
terminated Oct 2015.
Phase II
16 HepaStem,
Promethera
Biosciences
Human adult liver-
derived progenitor
cells, HHALPC,
Urea cycle
disorder (UCD) or
Crigler-Najjar
Up to 4 infusions over 8 weeks. NCT02489292, HEP002, phase
II, up to 12 years old with UCD;
open label; EU not including UK,
28
No. Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
allogeneic (CN) syndrome in
children and
adolescents.
planned n=20; expected
completion March 2017.
NCT01765283 HEP001,
EudraCT2011-004074-28; phase
I/II; up to 17 years with UCD or
CN; EU including UK; dose
finding randomised; planned
n=20; completed April 2015 but
no results identified.
NCT02051049, HEP002,
EudraCT2014-000650-11; long-
term safety extension of
NCT01765283; expected
completion October 2018.
17 Heparesc,
HHLivC
Cytonet GmbH
& Ci KG
Human liver cells
from non-
transplantable donor
livers, allogeneic
Urea cycle
disorders in
children up to 3
years of age
Infusion into liver via portal vein,
as a bridge to possible future
transplantation.
Heparesc was given a negative
opinion by the CHMP EMA,
NCT00718627 CCD02, phase II;
Germany; open label
uncontrolled; planned n=15;
completed December 2015 but
no results identified.
29
No. Name Developer(s) Cell type/approach Indication Other technology description
Trial information
(study reference; no. of
patients; expected end date)
confirmed after a re-examination
of the evidence presented. iv
NCT01195753 CCD05, phase II;
USA and Canada; open label
uncontrolled; planned n=15;
due to complete December
2015.
18 Livercellgram
Pharmicell Ltd. Bone marrow-
derived
mesenchymal stem
cells; autologous
Liver cirrhosis,
alcoholic
Infused into liver via hepatic
artery.
NCT01875081, PMC-BD-CT-P-
002, REVIVE phase II; South
Korea; randomised controlled;
planned n=72; expected
completion September 2015.
19 G-CSFv
mobilised
CD133+ bone
marrow stem
cells
University of
Birmingham
Bone marrow
derived CD133+
stem cells,
autologous
Liver cirrhosis,
compensated
Repeated infusions of
granulocyte colony stimulating
factor (GCSF) mobilised CD133+
bone marrow stem cells.
ISRCTN91288089, REALISTIC
phase II, UK; open label
randomised; planned n=81;
completed February 2015, no
results identified.
20 Bone marrow
mononuclear
Andalusion
Initiative for
Advanced
Therapies, Spain
Bone marrow-
derived stem cells;
autologous
Hepatic lesion
e.g. cancer
requiring
extended hepatic
resection
Infused into liver via portal vein
prior to extended hepatic
resection.
NCT01745731, EudraCT 2009-
017793-20, phase II;
randomised controlled; Spain;
n=13; expected completion
December 2015.
iv On 25 June 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for the medicinal product Heparesc, intended for the treatment of urea cycle disorders. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003750/smops/Negative/human_smop_000842.jsp&mid=WC0b01ac058001d127 v G-CSF: granulocyte colony stimulating factor; Lenograstim (Chugai Pharma UK Ltd)
30
10. REFERENCES
1 Medical Research Council. A strategy for UK Regenerative Medicine. Medical
Research Council. March 2012 2 European Medicine Agency. Reflection paper on classification of Advanced Therapy
Medicinal Products. MA/CAT/600280/2010 rev1. May 2015. 3 Cancer Research UK. Cancer Statistics for the UK.
http://www.cancerresearchuk.org/health-professional/cancer-statistics 4 Talley N J, Locke G R, Moayyedi P et al. GI Epidemiology: Diseases and Clinical
Methodology. 2nd Edition. John Wiley & Sons. 2014. ISBN: 978-0-470-67257-0. 5 National Institute for Health and Care Excellence. Crohn's disease: management.
Clinical Guideline CG152. NICE Oct 2012. https://www.nice.org.uk/guidance/cg152 6 Fox A, Tietze PH and Ramakrishnan K. Anorectal conditions: anal fissure and
anorectal fistula. FP Essentials 2014;419:20-27
http://europepmc.org/abstract/MED/24742084 7 Zhu Y F, Tao G Q, Zhou N et al. Current treatment of rectovaginal fistula in Crohn’s
disease. World Journal of Gastroenterology. 2011;17(8):963–967 8 NHS Choices. Anal fistula. 11 April 2012. http://www.nhs.uk/conditions/anal-
fistula/Pages/Introduction.aspx 9 British Medical Journal. Clinical Review. Management of faecal incontinence in adults.
BMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c2964 10 Scholefield JH, Walker D. Faecal incontinence: the ‘Cinderella’ disorder. Colorectal
Disease. The Association of Coloproctology of Great Britain and Ireland.
2014;16(Suppl 1):1–4. 11 NHS Choices. Liver disease. 6 November 2014. http://www.nhs.uk/conditions/liver-
disease/Pages/Introduction.aspx