Regenerative medicine in the management of musculoskeletal

disorders

Horizon Scanning Centre

January 2013

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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 Centre, University of Birmingham, United Kingdom

www.hsc.nihr.ac.uk

Copyright © University of Birmingham 2013

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CONTENTS Contents Page Number Executive Summary 4 1. Introduction 5

1.1 Clinical need and burden of disease 5 1.2 Aims 5

2. Methods 5 3. Results 7

3.1 Cellular approaches 7 3.2 Products by clinical trial phase 8 3.3 Products by disease area 12

4. Summary of findings 22 5. References 22 Appendices 24

Appendix 1: UK regenerative medicines, organisations and networks 24 Appendix 2: Online search sources 25 Appendix 3: Glossary of terms 27 C

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CO EXECUTIVE SUMMARY Aim To identify emerging applications of regenerative medicine that have the potential to benefit patients with musculoskeletal disorders and to investigate their stage of development. Methods We conducted an initial search to scope the review and identify appropriate contacts and organisations in the UK. We followed this with a more detailed online search to identify developments using pre-determined search terms. Once potential developments had been found we searched clinical trial databases to gather further information on products closer to licensing or launch. Summary of findings Of the 54 products and approaches we identified as either marketed or in late stage clinical development, 7 (13%) were available, CE marked or pre-registration, 4 (7.5%) were in phase III trials, 10 (18.5%) in phase II/III, 18 (33.3%) in phase II and 15 (27.7%) were in an unknown phase of clinical development. Over half (53.7%) of the identified products or approaches were using mesenchymal stem cells, 16 (29.6%) chondrocytes, and 4 (7.5%) umbilical cord-derived stem cells. Twenty one (38.9%) products or approaches were marketed or in late clinical trials for cartilage-related defects, 13 (24%) for osteoarthritis, 7 (13%) for spinal disc conditions, 5 (9.3%) for bone repair, and 8 (14.8%) for other or unknown conditions. Conclusion Our findings fit with other reviews with the majority of the identified approaches and techniques involving chondrocytes or mesenchymal stem cells; and the majority of trials aimed at people with cartilage disorders, arthritis and spinal degeneration. The identification of a small number of products for rarer patient groups including Duchene’s muscular dystrophy and malignant infantile osteoporosis is of interest and may lead to new avenues of therapy. There have been significant advances and breakthroughs in stem cell research for MSDs in the last decade with some products and techniques already licensed for patients with cartilage defects of the knee. As in other disease areas there is, as yet, no agreement on the most effective source or type of cells, or methods for cell harvest, preparation, isolation and delivery. There may also be associated storage and safety issues to be addressed, as well as any remaining regulatory, ethical and funding concerns. Internal review team Beth Boddice, Horizon Analyst; Dr Claire Packer, Director and Clinical Senior Lecturer; and Dr Sue Simpson, Research Fellow.

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1. INTRODUCTION Regenerative medicine and in particular cellular therapy is a rapidly developing field that is being investigated as an option for the restoration of function in many disease areas including musculoskeletal disease. This horizon scanning review summarises developments in regenerative medicine for the treatment of musculoskeletal disorders.

1.1 CLINICAL NEED AND BURDEN OF DISEASE Musculoskeletal disorders (MSDs) encompass over 200 different conditions affecting the muscles, joints and skeleton1. They may be self-limiting with minor back, neck and shoulder pain being common or long-term progressive, disabling conditions1,2. Disabling MSDs include: osteoarthritis, osteoporosis, rheumatoid arthritis, chronic inflammatory diseases, auto immune diseases (including systemic lupus erythematous), chronic pain syndromes or resulting from trauma (amputation, multiple injuries). MSDs are estimated to affect over 8.3 million adults and approximately 10,000 children in the UK1. A study in 2010 found that musculoskeletal problems accounted for 14% of all primary care consultations in the UK3. This ranged from 4% of all consultations for those aged under 15, to 17% of all consultations in those aged 45-643. As well as having a significant influence on health and quality of life, MSDs are a major area of NHS expenditure, costing around £4.76 billion per year1. The impact of MSDs on the general economy is also high and increasing with MSDs being among the most frequent causes of sickness absence, long-term incapacity for work and ill-health retirement4,5. The ageing population in the UK will further increase the demand for treatment of age-related disorders including arthritis and osteoporosis, and trauma caused by road traffic injury is predicted to become the third highest ranked cause of disabling conditions by 20201. Regenerative medicine is increasingly being explored as a potential treatment option for patients with a range of MSDs6,7, and if successful, treatments may eventually be used to stimulate the regeneration of diseased or injured tissues which are currently replaced or untreatable.

1.1 AIMS We aim to identify emerging applications of regenerative medicine that have the potential to benefit patients with MSDs, and to investigate their stage of development. We aim to concentrate on those applications that are in later clinical trial phases.

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2. METHODS We undertook an initial search of online sources to scope the review and to identify appropriate regenerative medicine contacts and organisations based in the UK (Appendix 1) We conducted a detailed online search (Appendix 2) to find developments using combinations of pre-determined search terms including: musculoskeletal regenerative medicine, musculoskeletal stem cells, musculoskeletal stem cell therapy, or musculoskeletal regeneration. Sources used included:

• Medline, Embase and the Cochrane research database • Regulatory authorities • UK research councils • EU framework programme research consortia • Global trial registries • UK regenerative medicine organisations and networks

The resulting information was sifted and grouped where possible. Once we had identified potential developments we searched clinical trial databases to identify developers and specific technologies that are in clinical trials closer to licensing and launch. For technologies in phase II or III trials additional information about complete or ongoing trials was collected.

3. RESULTS

3.1 CELLULAR APPROACHES IN MSDS Regenerative therapies for the treatment of MSDs require the suitable application of cells, biomaterials and/or factors as well as consideration of patient’s age, disease, target tissue and environmental factors8.9. Stem cells have been isolated from a number of musculoskeletal tissues including bone marrow, periosteum, perichondrium, tendons, ligaments, muscle, cartilage, bone and synovial membrane or fluid8

. Several of these cell types are being considered for regeneration in MSDs with some progressing to clinical trials (table 1).

Research to understand the ability of MSCs to differentiate into tissue specific lineages is ongoing6. In addition to their ability to form bone, cartilage or muscle tissue, MSCs secrete bioactive small molecules which are thought to inhibit scar formation, supress apoptosis and enhance the efficacy of resident progenitor cells6. Studies have demonstrated the repair capacity of MSCs and even their usefulness in treating critical size cartilage defects6,7,11. These cells may also have the potential to treat skeletal muscle degenerative diseases including Duchenne muscular dystrophy, due to their ability to self-replicate and differentiate into skeletal muscle cells6,7. Despite significant advances the clinical application of MSCs is considered to be a long way from being a routine approach in the current treatment pathway6,7,10.

3.1.1 Mesenchymal stem cells (MSCs) (29 products)

Cell therapy for cartilage and bone repair has been used for more than a decade, with chondrocytes being one of the first cell types to be tested in clinical cell therapy trials6. Numerous clinical trials using different preparations and methods of cell delivery are ongoing. ChondroCelect (table 3, no. 7) an autologous chondrocyte preparation is currently the only approved advanced therapy medicinal product (ATMP) available for clinical use in the European Union (EU).

3.1.2 Chondrocytes (16 products)

Umbilical cord-derived stem cells isolated from embryonic tissue following birth are a promising source of stem cells. They have the potential to differentiate into a variety of cells including bone, cartilage and skeletal muscle12. We identified 4 approaches using umbilical cord-derived stem cells in phase II/III trials (table 3 no. 9, 11, 28; table 4, no. 48).

3.1.3 Umbilical cord-derived stem cells (4 products)

Osteoblasts (bone-forming) and osteoclasts (bone resorbing) are the two main types of bone cells. During bone formation osteoblasts are recruited from mesenchymal stem cells in bone marrow13. Knowledge of osteoblast differentiation has increased during the last decade and is expected to lead to innovative treatments that will enhance bone formation and regeneration especially for conditions including osteoporosis and related bone fracture13. We identified only one approach using osteoblasts in phase II trials (table 3, no. 42)

3.1.4 Osteoblasts and osteoclasts (1 product)

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In October 2010, researchers at Atlanta’s Shepherd Centre rehabilitation centre hosted a phase I clinical trial of hESCs for spinal cord injury sponsored by Geron14,15. Participants were injected with approximately two million hESC-derived oligodendrocyte progenitor cells. These cells obtained from discarded embryos retain the ability for unlimited self-renewal and capacity to differentiate into a wide variety of specialised cell types.These clinical trials were discontinued, but in pre-clinical trials hESCs formed chrondogenic, osetogenic and skeletal myogenic cells14.

3.1.5 Human embryonic stem cells (hESCs)

In the UK, researchers based at the University of Manchester and Central Manchester University Hospitals NHS Foundation Trust have developed a culture procedure using human embryonic stem cells to produce a high yield of chondrocytes. The team are now planning to conduct pre-clinical trials16.

In skeletal muscle, biomaterials play an essential role to support the myogenic process, as in vivo myogenic stem cells reside and differentiate within a three-dimensional environment9. A variety of biomaterials including alginate, collagen, hyaluronan, hydroxyapatite and polyethene-glycol are being explored as scaffolds to study the effects of stem cell proliferation, migration, self-renewal and differentiation9. The required properties of biomaterials are biocompatibility, the ability to block the immune-response in the host muscle, and biodegradability that allows the eventual substitution of the scaffold by the newly formed muscle tissue9.

3.1.6 Biomaterial and scaffolds

Table 1: Cellular approach by clinical trial phase Approach Phase

unknown Phase II Phase

II/III Phase III Marketed TOTAL

Mesenchymal stem cells

3 22 3 0 1 29

Chondrocytes

7 2 0 2 5 16

Umbilical cord-derived stem cells

0 2 1 1 0 4

Osteoblasts or osteoclasts

1 0 0 0 0 1

Acellular scaffold

0 0 0 0 1 1

Other or unknown

3 0 0 0 0 3

3.2 PRODUCTS BY CLINICAL TRIAL PHASE We identified fifty-four individual products and techniques in late stage development for the treatment of MSDs (tables 2, 3 and 4). We found 7 industry-led developments that are currently available, CE marked or pre-registration; 3 approaches that are in industry-led phase III trials and 4 are in phase II/III researcher-led clinical trials (figure 1). There are 26 approaches in phase II clinical trials (20 industry-led, 6 researcher-

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led). We also identified a further 13 products or techniques which are reportedly in clinical trials, although the stage of their development could not be determined.

Five of the 7 products that are already licensed, pre-registration or CE marked use autologous chondrocytes which are harvested and then re-transplanted through surgery or injection into damaged cartilage. This technique has resulted in some beneficial effects. A further product, Autologous Disc Chrondocyte Transplantation (table 3, no. 2) also involves the use of chondrocytes but for the treatment of lumbar disc herniation. The only scaffold implant we identified that has been CE marked and is currently available in Europe is ChrondoMimetic (table 3, no. 6) which has been developed to support the repair of articular defects.

3.2.3 CE marked or available for clinical use (7 products)

All the industry-led products we identified in phase III clinical trials are being developed for knee injuries. One product, Neocart, uses a chondrocyte implantation (table 3, no. 8), the second, DeNevo NT Natural Tissue Graft, uses a cartilage tissue graft (table 3, no. 10) and the third, Cartistem, uses allogeneic umbilical cord derived mesenchymal stem cells (table 3, no. 9). The four researcher-led developments in phase II/III trials are examining a variety of cell types including mesenchymal and hematopoietic cells for indications including osteoarthritis, benign bone lesions and infantile osteoporosis.

3.2.4 Phase III (4 products) and phase II/III (10 products)

The majority of products or techniques in phase II trials are investigating autologous or allogeneic mesenchymal stem cells for a variety of indications. Two techniques, one using allogeneic and the other using autologous chondrocytes, are also being explored. A number of these are being investigated as potential treatment options for knee injuries but treatments for degenerative disc disease, chronic low back pain, osteoarthritis, and rheumatoid arthritis are also being investigated. The products/techniques we identified in undetermined phases again appear to be being developed for knee injuries or regeneration of bone. One of the products (table 3, no. 33) is considered to be a tissue engineered product, but further information about this technology is not available in the public domain.

3.2.5 Phase II (18 products)

Table 2 Clinical trials by clinical trial phase and disease area

Condition Therapy Clinical trial phase

Cellular therapy

Gene therapy

Phase unknown

II II/III III Marketed/CE marked

Total

Cartilage-related defects Repair of cartilage defects

8 0 4 0 0 3 1 8

Repair of damaged knee cartilage

5 0 3 0 0 0 2 5

Chrondal and cartilage lesions

2 0 1 0 0 1 0 2

Meniscus tears and regeneration

2 0 0 2 0 0 0 2

Articular defects in knee hip and ankle

1 1 1 0 0 0 1 2

Knee in juries

1 0 0 0 0 0 1 1

Gonarthrosis

1 0 0 0 1 0 0 1

Osteoarthritis Osteoarthritis

6 0 0 3 3 0 0 6

Knee osteoarthritis

6 0 0 4 1 0 1 6

Degenerative arthritis

1 0 0 1 0 0 0 1

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13

11

Spinal disc condition Degenerative disc disease

4 0 0 4 0 0 0 4

Spinal fusion

2 0 0 1 1 0 0 2

Disc herniation and lower back pain

1 0 0 0 0 0 1 1

Other conditions Bone repair, regeneration and healing

5 0 3 1 1 0 0 5

Cruciate ligament reconstruction

1 0 0 1 0 0 0 1

Duchenne Muscular Dystrophy

1 0 0 1 0 0 0 1

Malignant infantile osteoporosis

1 0 0 0 1 0 0 1

Osteoporotic fractures

1 0 0 0 1 0 0 1

Osteonecrosis

1 0 0 0 1 0 0 1

Unknown indication

3 0 3 0 0 0 0 3

Total

53 1 15 18 10 4 7 54

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Figure 1: Industry vs. researcher-led developments by clinical trial phase

0

5

10

15

20

25

30

Marketed/CEMarked

III II/III II Phase unkown

Num

ber o

f pro

duct

s/te

chni

ques

Clinical trial phase

Researcher-led

Industry-led

3.3 PRODUCTS BY DISEASE AREA

We identified 21 products in development for repair of cartilage, cartilage lesions, meniscus tears, for knee injuries and for articular defects; most of these are in industry-led clinical trials (table 2). Five products were already marketed and 7 in phase II or III trials.

3.3.1 Cartilage related defects (21 products)

A product utilising umbilical cord-derived stem cells is in development for the treatment of rheumatoid arthritis (table 3, no. 11). The phase II trial which is aiming to enrol 150 participants is expected to complete in October 2013.

3.3.2 Arthritis (13 products)

RNL Biocompany is reportedly developing RNL Jointstem, which uses adipose tissue-derived mesenchymal stem cells for the treatment of degenerative arthritis (table 3, no. 27). A phase II clinical trial was expected to complete in June 2012 however, at the time of our search there were no publically available results.

Emory University were reportedly conducting a phase II/III clinical trial using mesenchymal stem cells for bone void defects in patients with benign bone lesions

3.3.3 Bone regeneration (5 products)

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(table 4, no. 46). The trial was expected to complete in March 2010, but there are currently no results available in the public domain. Medipost were also conducting phase II trials using Bonestem (table 3, no. 14). This technology uses osteoblasts injected with genetic vectors for bone regeneration; again there is no further information about this technology available in the public domain. RMS Regrow is developing an autologous bone implantation using osteoblasts (table 3, no. 42) that is also reported to be in clinical trials. At the time of our search there was no further information about this technology available. 3.3.4 Spinal disc conditions (7 products) Co.don AG has developed the first Advanced Therapy Medicinal Product (ATMP) for disc herniation and lower back pain available in Europe (table 3, no. 2). Treatment involves an injection of autologous chrondocytes into the vertebral disc. Mesoblast also has three bone marrow-derived mesenchymal stem cell products in development for chronic low back pain, intervertebral disc disease, cervical degenerative disc disease and for use in spinal fusion (table 3, no. 15, 17, 18 and 19). Results from some of these trials should be available in 2013. 3.3.5 Osteoporosis (2 products) We identified one product in development for malignant infantile osteoporosis (table 3, no. 48). This product utilises umbilical cord-derived hematopoietic stem cells and is in a phase II/III clinical trial expected to complete in November 2012. A product for the treatment of osteoporotic fractures using adipose tissue-derived mesenchymal stem cells (table 4, no. 54) is currently in a phase II trial which is aiming to enrol 290 participants and to complete in October 2015. 3.3.6 Osteonecrosis of the femoral head (1 product) A product being developed in Spain uses bone marrow-derived cells for the treatment of osteonecrosis of the femoral head (table 4, no. 50). A phase II trial which is expected to enrol 24 patients is ongoing and is expected to complete in December 2014. 3.3.7 Duchenne muscular dystrophy (1 product) We identified one product which uses umbilical cord-derived mesenchymal stem cells for Duchenne muscular dystrophy (table 3, no. 28). The current phase II trial is expected to complete in October 2013.

Table 3: Products in development: industry-led

No Developer Technology name Cell type/approach Indication Trial information Marketed/CE marked

1 Bio Tissue AG Chrondotissue Mesenchymal stem cell technology.

Articular defects in knee, ankle and hip

CE marked, and reportedly available. No information available on use in UK. Associated with TransTissue Technologies. Cells obtained using standard marrow stimulating procedures, cells transplanted through arthroscopic procedure.

2 Co.don AG

Autologous Disc Chondrocyte Transplantation (ADCT)

Autologous cultured chondrocytes.

Disc herniation and lower back pain

Vertebrae disc tissue removed as part of discectomy surgery and blood sample used to culture chondrocytes. Cells are then injected in the vertebrae disc. A phase III trial involving 52 patients with lumbar disc herniation resulted in decreased back pain and disability compared with those who had sequestrectomy. Therapy is regulated as an advanced therapy medicinal product (ATMP) and is launched in Germany, Greece, Italy, Spain, Austria, Switzerland, and Belgium.

3 Co.don AG

Matrix-associated Autologous Cartilage Transplantation (ACT3D)

Autologous cultured chondrocytes.

Articular cartilage defect Cartilage removed from effected joint, chondrocytes are then cultured for approximately seven weeks and re-injected into the lesion.

4 Genzymne Cariticel Autologous cultured chondrocytes.

Knee injuries

Marketed and available in Europe. Chondrocytes are harvested from patient's articular cartilage, expanded in cell culture and then injected into defective cartilage. In clinical trials Carticel significantly improved knee function, in 41 patients with knee cartilage damage.

5 Genzymne MACI ( Matrix-induced Autologous Chondrocyte Implantation)

Autologous cultured chondrocytes.

Damaged knee cartilage Phase III clinical trial (SUMMIT, NCT00719576) of MACI is underway to support approval, no further information on timings available in the public domain.

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6 Orthomimetics Limited

ChondroMimetic Autologous multi-layered tissue-regeneration scaffold

Articular cartilage damage in knee, ankle or other joint

A collagen based implant/scaffold that supports the repair of defects involving both articular cartilage and bone - defects that can result from sports injuries, surgical intervention and other trauma. CE marked and available in Europe.

7 TiGenix Ltd ChondroCelect Autologous chondrocytes

Cartilage defects of the knee in patients with osteoarthritis

Only approved cell therapy (ATMP) available for clinical use in the EU. The Marketing Authorisation Application was supported by results from the phase III TIGACT 01 trial (NCT00414700), showed that at 12 and 18 months ChondroCelect as a first-line therapy formed regenerated tissue superior to the repair tissue formed following microfracture (primary endpoint).

PIII 8 Histogeneics NeoCart Autologous chrondocyte

implantation Cartilage defects associated with osteoarthritis and sports injuries

NCT01066702 designed to compare efficacy and safety of NeoCart compared with surgical intervention. Aim to enrol 240 patients. A phase II trial that enrolled 39 patients with grade III chrondal injury found that NeoCart improved pain and function compared with microfracture surgery. NeoCart was also associated with greater clinical efficacy two years following treatment17.

9 Medipost Co Ltd. CartiStem Allogeneic, umbilical

cord blood-derived mesenchymal stem cells

Knee articular cartilage injury or defect

NCT01041001 to compare Cartistem to microfracture treatment. Aim to enrol 104 patients. Estimated study completion January 2011. Currently registered and used in Asia and Eastern Europe for osteoarthritis. No trial results identified.

NCT01626677 is a long-term follow-up study comparing Cartistem to microfracture treatment. Aims to enrol 103 patients with completion expected in May 2015.

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10 Zimmer Holdings DeNovo NT Natural Tissue Graft

Cartilage allograft tissue Repair of articular cartilage

A single-stage procedure with fibrin fixation that eliminates the need for harvesting a periosteal flap. NCT01347892, NCT01670617, NCT01329445 and NCT00791245 all ongoing trials in participants with knee injuries.

PII 11 Alliancells

Bioscience Corporation Limited, China

Umbilical cord-derived mesenchymal stem cells

Intravenous infusion of umbilical cord derived- mesenchymal stem cells

Rheumatoid arthritis NCT01547091 to assess safety. Aim to enrol 150 participants, with estimated completion October 2013.

12 Azellon Cell Therapeutics

Cell Bandage Autologous bone marrow derived stem cells grown on structural bio- scaffold then transplanted on to patient’s knee..

Meniscus tears Recruitment in clinical trial commenced in August 2012, preliminary results expected in 2013.

13 International Stemcell Services Limited, India

Bone marrow derived stem cells

Delivery of autologous bone marrow derived stem cells directly into knee joint

Osteoarthritis NCT01152125 to assess safety and efficacy. Aim to enrol 10 participants. Expected completion January 2012. No results publically available (January 2013)

14 Medipost Bonestem Adult mesenchymal stem cells

Bone regeneration in bone disorders including chronic osteomyelitis and avascular osteonecrosis.

Stem cells inserted with genetic vectors, and a biocompatible semi-solid polymer. No recent development reported.

15 Mesoblast, USA Mesenchymal stem cells (MSB-CAR001)

Two intra-discal injections of allogeneic adult mesenchymal stem cells combined with hyaluronic acid

Chronic low back pain due to degenerative disc disease

NCT01290367 to assess safety and efficacy. Aim to enrol 100 participants, with estimated completion July 2015.

16 Mesoblast, USA MSB-CAR001 in combination with hyaluronan

Mesenchymal precursor cells

Anterior cruciate ligament reconstruction

NCT01088191 to evaluate safety and efficacy. Aim to enrol 24 patients, with primary completion estimated in June 2013.

17 Mesoblast, USA NeoFuse combined with MasterGraft Matrix

Bone marrow derived mesenchymal precursor cells

Degenerative disc disease

NCT00996073 to assess safety and preliminary efficacy. Aim to enrol 24 patients with primary completion expected July 2014.

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18 Mesoblast, USA NeoFuse combined with MasterGraft Matrix

Bone marrow derived mesenchymal precursor cells

Cervical degenerative disc disease (patients undergoing multi-level anterior cervical discectomy and fusion with anterior cervical plate fixator

NCT01097486 9 and NCT01106417 to evaluate safety. Aim to enrol 36 patients in trials combined with estimated primary completion expected in June 2013.

19 Mesoblast, USA NeoFuse Allogeneic mesenchymal precursor cells combined with MasterGraft resorbable ceramic granules

Posterolateral spinal fusion

NCT00549913 to assess feasibility, safety, and tolerability. Aim to enrol 40 patients with completion anticipated in October 2013.

20 Osiris Therapeutics Chondrogen Mesenchymal stem cells

Regeneration of meniscus in the knee

NCT00225095 placebo-controlled trial enrolled 55 participants. To evaluate the safety and effectiveness of Chondrogen when injected directly into the knee. At 6 months, the trial met its primary endpoint of safety, but failed to show a significant increase in the volume of meniscus compared with placebo. Approximately 30% of patients had an improvement in baseline cartilage or joint condition.

21 Osiris Therapeutics Chondrogen Mesenchymal stem cells

Osteoarthritis One-year data from NCT00225095 demonstrated significant improvements in pain and degenerative bone changes associated with osteoarthritis. The trial evaluated 50 patients for 2 years, and a long-term safety trial monitored patients for an additional 3 years (Study 551; NCT00702741).

22 ProChon Biotech BioCart Autologous chondrocytes

Traumatic and cartilage lesions of the knee

Launched in Israel in 1998 and also commercially available in Greece. Phase II clinical trials are underway in the US.

23 Red de Terapia Celular, Barcelona

MSV-allo Intra-articular transplantation of allogeneic mesenchymal stem cells, expanded ex vivo

Knee osteoarthritis NCT01586312 to assess safety. Aim to enrol 30 participants, with estimated completion September 2013.

24 Red de Terapia Celular, Barcelona

Mesenchymal stem cells

Articular injection of autologous mesenchymal stem cells

Knee osteoarthritis NCT01183728 to assess feasibility and safety. Aim to enrol 12 participants with estimated completion June 2013.

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25 Red de Terapia Celular, Barcelona

Bone marrow derived stem cells

Intervertebral fusion with instrumented posterolateral of autologous mesenchymal stem cells

Intervertebral disc disease

NCT01513694 to assess efficacy. Aim to enrol 15 participants no results available and no completion date information available in public domain (January 2013).

26 Regeneus, Australia HiQ Cell Single treatment with autologous adipose derived mesenchymal stem cells

Knee osteoarthritis Primary outcome reduction in pain, quality of life will also be assessed. No further information available.

27 RNL Bio Company Ltd, Korea

Mesenchymal stem cells (RNL-JointStem)

Intra-articular infusion of adipose tissue derived mesenchymal stem cells

Degenerative arthritis NCT01300598 to assess safety. Aim to enrol 18 participants. Estimated completion September 2012. No results publically available (January 2013)

28 Shenzhen Beike Bio-Technology Co., Ltd, China

Umbilical cord-derived mesenchymal stem cells

Intravenous infusion of umbilical cord-derived mesenchymal stem cells

Duchenne muscular dystrophy

NCT01610440 to assess safety and efficacy when therapy is combined with rehabilitation programme. Aim to enrol 15 participants and estimated completion October 2013.

29 Stempeutics Research, India

Allogenic mesenchymal stem cells

Single intra articular dose of ex vivo cultured adult allogeneic mesenchymal stem cells

Knee osteoarthritis NCT01453738 to assess safety and tolerability. Aim to enrol 60 patients with estimated completion July 2014. NCT01448434 to assess safety and tolerability of two cell doses. Aim to enrol 72 participants with completion expected February 2013.

30 TissueGene TissueGene-C (TG-C)

Allogeneic chondrocytes (TGF-β1 producing)

Osteoarthritis Human chondrocytes genetically modified to produce transforming growth factor-beta 1 (TGF-β1). TGF-β1 catalyses the rapid repair of injured tissue without the need for invasive surgery. Phase II development is underway in the US and South Korea.

In clinical trials

31 Allocart Allogeneic cartilage repair therapy

Progenitor cells Cartilage repair In early clinical trials. Developers have received grants from the UK Technology Strategy Board (TSB).

32 Bio Tissue AG Bioseed-C An autologous 3-dimensional chondrocyte graft.

Articular defects in knee, ankle and hip

Reportedly available but no information available on use in UK.

33 Bio Tissue AG Bioseed-oral bone No information available.

Not known Not known.

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34 Cell Marix AB HyCel Human cartilage cells Cartilage repair Cells harvested from healthy joint cartilage area. The cells are cultured with patient’s own serum. Final product is transplantated these cells are then able to organize into a complex hyaline like cartilage tissue.

35 Cell Marix AB ACT Therapy Autologous chondrocytes

Symptomatic full-thickness localized chondral lesions and osteochondritis dissecans in the knee joint.

Transplantation of autologous chondrocytes. No further information available.

36 CellGenix CartiGro Autologous chondrocytes

For repair of large isolated cartilage defects of the knee joint.

Reportedly successfully applied in more than 1,500 patients since 2000. No further information available.

37 Celling Technologies Autologous stem cells

Autologous stem cells Bone repair Highly concentrated autologous stem cells. No further information available.

38 Educell ChrondoArt 3D Autologous cultivated chondrocytes

Cartilage repair- new joint

Specimen of healthy cartilage taken from articular surface. Chondrocytes are then isolated and cultivated. Once cells have multiplied sufficiently (usually after 4-5 weeks), a graft (a suspension of chondrocytes or chondrocytes on a collagen or alginate-agarose based scaffold) is implanted into the lesion, under a patch of collagen membrane.

39 Karocell Chronodocytes Autologous cultivated chondrocytes

No information available No information available.

40 Orthofix Trinity multipotential cellular bone matrix

Mesenchymal stem cells

Regeneration of bone in orthopaedic conditions

A cellular and tissue-based allograft product selectively depleted of immunogenic cells, creating a rich source of stem cells which stimulate osteogenesis. Bone matrix also functions as an osteoconductive scaffold to support bone growth. In early clinical trials-not confirmed.

41 RMS Regrow Chrondon (Autologous Cartilage Implantation)

Autologous chondrocytes

Cartilage repair in severe knee pain

Transplantation of chrondocytes into damaged area of the knee. In clinical trials, no further information available.

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Table 4: Products in development – researcher led

No. Research

Centre Cell type/approach Indication Trial information

Phase II/III 45 Cairo

University, Egypt

Bone marrow mesenchymal stem cell implantation

Early osteoarthritis and articular cartilage defects

NCT00891501 to assess effectiveness. Aim to enrol 25 participants with completion expected in December 2014.

46 Emory University, USA

Mesenchymal stem cells Bone void defects in patients with benign bone lesions

NCT00851162 to assess efficacy. Aim to enrol 50 participants. Completion was expected in March 2010, but no further trial updates or results available (July 2012) and study withdrawn January 2013.

47 Masonic Cancer Center, USA

Allogeneic hematopoietic stem cell transplantation

Severe osteoarthritis NCT00775931 to assess efficacy and safety. Aim to enrol 20 participants with completion expected October 2015.

48 Tehran University of Medical Sciences, Iran

Umbilical cord derived haematopoietic stem cells

Malignant infantile osteoporosis

NCT01087398 to assess efficacy and safety of hematopoietic stem cells derived from umbilical cord blood or haploidentical donor. Aim to enrol 10 participants with completion expected in November 2012. No results available (January 2013).

42 RMS Regrow Autologous Bone Implantation (ABI)

Osteoblasts Bone healing for fractures, congenital bone defects, maxillofacial defects, reconstructive surgery and osteomyelitis

Osteoblasts are harvested, cultured and then injected or implanted at the site where new bone formation is desired. In clinical trials, no further information available.

43 TiGenix and Arcarios

Adult stem cell therapies - TiGenix; MeniscoCelect TGX003

Mesenchymal stem cells Cartilage disorders, osteoarthritis and musculoskeletal disorders

In early clinical trials.

44 TransTissue Technologies

Autologous chondrocyte implantation

Mesenchymal stem cells Cartilage repair following trauma or regeneration

Repair of mesenchymal tissues – not confirmed.

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Phase II 49 Banc de Sang

i Teixits, Barcelona

Ex vivo expanded autologous bone marrow mesenchymal stem cells

Spinal fusion in spinal degenerative disease

NCT01552707 to assess safety and feasibility. Aim to enrol 62 participants. No further trial information available.

50 Banc de Sang i Teixits, Barcelona

Ex vivo expanded autologous bone marrow mesenchymal stem cells

Osteonecrosis of the femoral head

NCT01605383 to compare stem cell treatment to the standard treatment of isolated core decompression. Aim to enrol 24 participants with primary completion expected December 2014.

51 Banc de Sang i Teixits, Barcelona

Autologous bone marrow derived mesenchymal stem cells (MSC)

Repairing articular cartilage in gonarthrosis

NCT01227694 to assess efficacy and safety. Aim to enrol 15 patients with completion expected in January 2013.

52 National University of Malaysia, South East Asia

Intra-articular autologous mesenchymal stem cells

Osteoarthritis NCT01459640 to assess efficacy. Aim to enrol 50 participants, with completion anticipated in March 2014.

53 Royan Institute, France

Intra-articular injection of bone marrow- derived mesenchymal stem cells

Severe knee joint osteoarthritis NCT01504464 to evaluate therapeutic effects. Aim to enrol 40 patients. This study was completed in September 2012. No trial results available. (January 2013)

54 University Hospital, Basel, Switzerland

Adipose tissue derived mesenchymal stem cells

Osteoporotic fractures (osteogenic component in composite grafts)

ROBUST (NCT01532076) designed to assess effectiveness of mesenchymal cells versus acellular bone graft substitutes. Aim to enrol 290 patients with completion expected in October 2015.

4. SUMMARY OF FINDINGS Of the 54 products and approaches we identified as either marketed or in late stage clinical development, 7 (13%) were available, CE marked or pre-registration, 4 (7.5%) were in phase III trials, 10 (18.5%) in phase II/III, 18 (33.3%) in phase II and 15 (27.7%) were in an unknown phase of clinical development. Over half (53.7%) of the identified products or approaches were using mesenchymal stem cells, 16 (29.6%) chondrocytes, and 4 (7.5%) umbilical cord-derived stem cells. Twenty one (38.9%) products or approaches were marketed or in late clinical trials for cartilage-related defects, 13 (24%) for osteoarthritis, 7 (13%) for spinal disc conditions, 5 (9.3%) for bone repair, and 8 (14.8%) for other or unknown conditions. Our findings fit with other reviews in this area, with the majority of the identified approaches and techniques involving chondrocytes or mesenchymal stem cells; and the majority of trials aimed at people with cartilage disorders, arthritis and spinal degeneration7. The identification of a small number of products for rarer patient groups including Duchene’s muscular dystrophy and malignant infantile osteoporosis is of interest and may lead to new avenues of therapy. There have been significant advances and breakthroughs in stem cell research for MSDs in the last decade with some products and techniques already licensed for patients with cartilage defects of the knee. As in other fields there is, as yet, no agreement on the most effective source or type of cells, or methods for cell harvest, preparation, isolation and delivery. There may also be associated storage and safety issues to be addressed, as well as any remaining regulatory, ethical and funding concerns.

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5. REFERENCES

1 Department of Health. A Joint Responsibility: doing it differently - the

musculoskeletal services framework. London DOH; July 2006. 2 Jordan KP, Kadam UT, Hayward R et al. Annual consultation prevalence of

regional musculoskeletal problems in primary care: an observational study. BMC Musculoskeletal Disorders 2010; 11: 1471-2474.

3 Department of Health. Programme Budgeting Data 2009-10. http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/Managingyourorganisation/Financeandplanning/Programmebudgeting/DH_075743 Accessed 22 June 2012.

4 Waddell G. Preventing incapacity in people with musculoskeletal disorders. British Medical Bulletin 2006; 77: 55-69.

5 Harkness EF, Macfarlane GJ, Silman AJ et al. Is musculoskeletal pain more common now than 40 years ago? Two population-based cross-sectional studies. Rheumatology 2005; 44: 890-895.

6 Maclean S, Khan WS, Malik AA, Anas S, Snow M. The potential of stem cells in the treatment of skeletal muscle injury and disease. Stem Cells International Online 2011; doi; 10.1155/2012/282348.

7 Andews A. Moving stem cell therapies into the orthopaedic clinic: what will it take? Nature 2012; doi: 10.10.1038/bonekey.2012.181.

8 Gates B, Karthikeyan T, Fu F et al. Regenerative medicine for the musculoskeletal system based on muscle-derived stem cells. The Journal of the American Academy of Orthopaedic Surgeons 2008: 16; 68-76.

9 Guan X MD, Furth ME, Childers MK. Stem cell use in musculoskeletal disorders. American Academy of Physical Medicine and Rehabilitation 2011; 3: S95-S999.

10 Steinert A, Racwitz L, Gilbert F et al. Concise review: The clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives. Stem Cells and Translational Medicine 2012; 237-247.

11 Stoddart M, Grad S, Gantenbein B et al. Stem cells for musculoskeletal regenertation. European Cells and Materials 2008; 6: 39.

12 Fan CG, Zhang QJ, Zhou JR. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Review 2011; 7: 195-207

13 Arvidson K. Abdallah BM, Applegate LA et al. Bone regeneration and stem cells. Journal of Cellular and Molecular Medicine 2011; 4: 718-746.

14 Adis Insight Research programme: embryonic stem cell therapies - Geron/University of Edinburgh/University Campus Suffolk

http://bi.adisinsight.com/frames.aspx Accessed 12 November 2011. 15 BBC News. Stem cell trial halted. http://www.bbc.co.uk/news/health-15740133

Accessed 11 November 2011. 16 Manchester University. Scientists turn stem cells into cells for cartilage repair.

http://www.Manchester.ac.uk. Accessed 12 October 2012. 17 Crawford DC, DeBeradino TM, Williams RJ. NeoCart, an autologous cartilage

tissue implant, compared with microfracture for treatment of distal femoral cartilage lesions. Journal of Bone and Joint Surgery 2012; 94: 979-89.

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APPENDIX 1: UK REGENERATIVE MEDICINES ORGANISATIONS AND NETWORKS UniverCell Market https://www.univercellmarket.com/ Source of up-to-date information for the global stem cell and regenerative medicine community. Renger8 http://www.regener8.ac.uk/home.html The translational centre for regenerative medicine that brings together the work of UK scientists with UK and international industry to advance the development of tools and technologies to accelerate therapies through to clinic. East of England Stem Cell Network (EESCN) http://www.cambridgenetwork.co.uk/directory/orgprofile/default.aspx?objid=67752 EESCN is the UK's largest regional stem cell network, representing the interests of world class researchers, clinicians and businesses involved in regenerative medicine and stem cell science, as well as providing opportunities for public engagement. London Regenerative Medicine Network ((LRMN) http://www.lrmn.com/ The London Regenerative Medicine Network is the world's largest cell therapy and regenerative medicine network with in excess of 5,500 members representing all the stakeholder groups including: the general public, patients, patient advocates, students, scientists, engineers, clinicians, charities, government organisations and business people. Merica Stem Cell Alliance (previously Northeast England Stem Cell Institute) http://www.msca.ls.manchester.ac.uk/ Alliance’s collaborators have established notable regional Centres of Excellence, lead major science-driven companies, and collectively maintain a skill set which supports the translation of basic research to innovative therapies. Scottish Stem Cell Network (SSCN) http://www.sscn.co.uk/ The aim of the network is to bring together scientists and clinicians in order to improve the rate at which laboratory research translates into therapeutic benefits for patients. The SSCN works with the entire stem cell community in Scotland, including academic institutions, clinical and industry-based research groups, as well as suppliers in the field. The Social Science Stem Cell Initiative http://www.york.ac.uk/res/sci/introduction.html The ESRC Social Science Stem Cell Initiative was set up in 2005 with the broad aim of supporting a range of activities to build research capacity and raise awareness in the UK social science community regarding the emerging field of stem cell science.

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APPENDIX 2: ONLINE SEARCH SOURCES Regulatory authorities Web Address European Medicines Agency (EMEA)

http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp&jsenabled=true

Human Fertilisation and Embryology Authority (HFEA)

http://www.hfea.gov.uk/

Human Tissue Authority (HTA) http://www.hta.gov.uk/ Medicines and Healthcare Products Regulatory Agency (MHRA)

http://www.mhra.gov.uk/index.htm

US Food and Drug Administration (FDA)

http://www.fda.gov/

UK government departments Web Address Department of Health (DH) http://www.dh.gov.uk/en/index.htm Department for Business, Innovation and Skills (BIS)

http://www.bis.gov.uk/

UK research councils Web Address Biotechnology and Biological Sciences Research Council (BBSRC)

http://www.bbsrc.ac.uk/

Economic and Social Research Council (ESRC)

http://www.esrc.ac.uk/

Engineering and Physical Sciences Research Council (EPSRC)

http://www.epsrc.ac.uk/pages/default.aspx

Medical Research Council (MRC) http://www.mrc.ac.uk/index.htm Science and Technology Facilities Council (STFC)

http://www.stfc.ac.uk/

Technology Strategy Board (TSB)

http://www.innovateuk.org/

Learned Societies Web Address Academy of Medical Sciences (AMS)

http://www.acmedsci.ac.uk/

British Pharmacological Society (BPS)

http://www.abpi.org.uk/Pages/default.aspx

British Society for Cell Biology (BSCB)

http://www.bscb.org/

British Society for Developmental Biology (BSDB)

http://www.bms.ed.ac.uk/services/webspace/bsdb/welcome.htm

International Society for Cellular Therapy (ISCT)

http://www.celltherapysociety.org/

International Society for Stem Cell Research (ISSCR)

http://www.isscr.org//AM/Template.cfm?Section=Home

International Society of Differentiation (ISD)

http://www.isdifferentiation.org/

Royal Academy of Engineering http://www.raeng.org.uk/ Royal College of Surgeons of http://www.rcseng.ac.uk/

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England (RCS) Royal Pharmaceutical Society of Great Britain (RPSGB)

http://www.rpharms.com/home/home.asp

Royal Society http://royalsociety.org/ Tissue and Cell Engineering Society (TCES)

http://www.tces.org/

Tissue Engineering International & Regenerative Medicine Society (TERMIS)

http://www.termis.org/

EU Framework Programme Research Consortia

Web address

ES TOOLS http://www.estools.eu/ EuroStemCell http://www.eurostemcell.org/ Miscellaneous Web address Association of the British Pharmaceutical Industry (ABPI)

http://www.abpi.org.uk/Pages/default.aspx

BioIndustry Association (BIA) http://www.bioindustry.org/ California Institute for Regenerative Medicine (CIRM)

http://www.cirm.ca.gov/

Centre of the Cell http://www.centreofthecell.org/ ESRC Social Science Research Initiative

http://www.york.ac.uk/res/sci/introduction.htm

Stem Cells for Safer Medicines Ltd

http://www.sc4sm.org/

Stem Cell Patents http://www.stemcellpatents.com/ UK Intellectual Property Office (UKIPO)

http://www.ipo.gov.uk/

UniverCELLMarket https://www.univercellmarket.com/ Free Patents Online Search Engine

http://www.freepatentsonline.com/

The Heart.org http://www.theheart.org/article/597863.do

Research Publications and Trials in progress

Web address

ClinicalTrials.gov http://www.clinicaltrials.gov/ WHO International Clinical Trials Registry

http://www.who.int/trialsearch/Default.aspx

EU Clinical Trials Register https://www.clinicaltrialsregister.eu Current Controlled Trials http://www.controlled-trials.com/mrct/ UKCRN Portfolio Database http://public.ukcrn.org.uk/search/ ClinicalStudyResults.org http://www.clinicalstudyresults.org/home/ The Cochrane Library (Clinical trials)

http://www.cochrane.org/

PubMed, Medline & Medline in Progress, & EMBASE

http://www.elibrary.bham.ac.uk/

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APPENDIX 3: GLOSSARY OF TERMS Advanced-therapy medicinal products (ATMPs): are medicines for human use that are based on gene therapy, somatic-cell therapy or tissue engineering. Allogeneic: cells from a genetically similar, but not identical donor. Autologous: cells originating from the recipient rather than from a donor Embryonic stem cells: pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Induced pluripotent cells: (iPS cells or iPSCs) are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of specific genes. Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem cells, in many respects, such as the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still under investigation. Mesenchymal stem cells: multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells).

Pluripotent stem cells: can give rise to any foetal or adult cell type. However, alone they cannot develop into a foetal or adult animal because they lack the potential to contribute to extra embryonic tissue, such as the placenta.

Progenitor cell: a biological cell that, like a stem cell has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its ‘target cell’ The most important difference between stem cells and progenitor cells is that stem cells can replicate indefinitely, whereas progenitor cells can only divide a limited number of times. Controversy about the exact definition remains and the concept is still evolving.