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

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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

nihrhsric@contacts.bham.ac.uk

www.hsric.nhir.ac.uk

Copyright © University of Birmingham 2016

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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