Health Policy Advisory Committee on Technology New and Emerging Health Technology Report

Transcription

1 Health Policy Advisory Committee on Technology New and Emerging Health Technology Report Stem cell therapy for non-haematological (autoimmune) indications March 2015

2 State of Queensland (Queensland Department of Health) 2015 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 2, 15 Butterfield St HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD HealthPACT@health.qld.gov.au Telephone: For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, ip_officer@health.qld.gov.au, phone (07) Electronic copies can be obtained from: DISCLAIMER: This Report is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Report is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Report. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Report is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Report was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Report was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This Report was prepared by Prof Paul Scuffham, Dr Tracy Comans, Nicole Moretto and Tom Elliott from The Centre for Applied Health Economics, School of Medicine, Griffith University

3 Table of contents HealthPACT Advisory... iii Executive summary... iv Background... 1 Patient indication... 1 Description of the technology... 1 Reason for assessment... 4 Stage of development in Australia... 4 Licensing, reimbursement and other approval... 4 Impact... 5 Multiple Sclerosis... 6 Systemic Sclerosis Systemic lupus erythematosus Current technology Diffusion of technology in Australia Cost infrastructure and economic consequences Cost analysis Ethical, cultural, access or religious considerations Evidence and Policy Safety and effectiveness for multiple sclerosis Haemopoietic stem cell transplantations for multiple sclerosis Mesenchymal stem cell therapy for multiple sclerosis Safety and effectiveness for systemic sclerosis Haemopoietic stem cell transplantations for systemic sclerosis Safety and effectiveness for systemic lupus erythematosus Haemopoietic stem cell transplantations for SLE Mesenchymal stem cell therapy for SLE Economic evaluation Ongoing research Stem cell therapy for non-haematological (autoimmune) indications: March 2015 i

4 Summary of findings References Search Strategy HTA sites Number of studies included Appendices Appendix A Estimation of the number of patients with relapsing remitting multiple sclerosis failing interferon beta and alemtuzumab, or alemtuzumab only Appendix B Profiles of all included studies for HSCT and MSCT for multiple sclerosis Appendix C Cochrane risk of bias assessment of the direct randomised trials of HSCT for systemic sclerosis Appendix D Profiles of included observational studies for SSc Appendix E Profiles of included studies for SLE Appendix F MS Australia statement on Autologous Hematopoietic Stem Cell Transplant (HSCT) treatment Appendix G MS Australia s statement on stem cells Appendix H NHMRC warns of the risks associated with unproven stem cell therapies in Australia and overseas Stem cell therapy for non-haematological (autoimmune) indications: March 2015 ii

5 HealthPACT Advisory This report was commissioned by HealthPACT in response to jurisdictions noting an increase in the number of patients seeking stem cell transplantation treatment overseas outside of clinical trials, especially in response to extensive press coverage. Many of these patients have not exhausted all of the available medical options to treat their condition and therefore would not fit the selection criteria for stem cell transplantation clinical trials conducted in Australia. Patients seeking this treatment need to be fully informed as to the potential risks and benefits, including that stem cell transplantation is not considered curative but rather aimed at ameliorating disease. It should be noted that although both mesenchymal and haemopoietic stem cells are being used in the treatment of immunological conditions including multiple sclerosis, systemic sclerosis and systemic lupus erythematosus, the use of haematopoietic stem cells is more effective in comparison to mesenchymal but associated with more adverse events. The evidence base for the treatment of severe systemic sclerosis is the most mature and is now an accepted treatment option for this disease based on data from two randomised controlled trials. One of these trials has confirmed a clear benefit of long term mortality for haematopoietic stem cell transplantation in systemic sclerosis. Trials to refine clinical protocols for use in systemic sclerosis are likely to continue. HealthPACT recommends that the treatment of patients with multiple sclerosis and systemic lupus erythematosus with stem cell transplantation should only be conducted under the auspices of an ethics approved controlled trial with informed consent Careful selection of patients for such clinical trials is required, with only those patients who are currently in an active inflammatory phase of the disease, and are therefore most likely to benefit from stem cell transplantation, being considered for enrolment in units with expertise in stem cell transplantation for autoimmune disease. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 iii

6 Executive summary This new and emerging health technology report was prepared for HealthPACT with the aim of providing a brief overview of the evidence on the safety, effectiveness and feasibility of stem cell transplantation for (non-haematological) autoimmune diseases within an Australian context. The focus of the report was haemopoietic stem cell transplantation (HSCT) and mesenchymal stem cell therapy (MSCT) for patients with multiple sclerosis (MS), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Both autologous (auto) and allogeneic (allo) forms were assessed. The reason for assessment was the increasing evidence base for autologous haemopoietic stem cell transplantation (auto-hsct) as a treatment for SSc, mounting pressure from the public for stem cell transplantation for MS and the potential for a major cost impact on the public health system. Description and estimate of patient numbers Multiple sclerosis MS is a chronic autoimmune disease of the central nervous system which can lead to a considerable level of disability. The most common subtypes of MS are relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS) and relapsing progressive multiple sclerosis (RPMS). There are also other rare variants of the condition. The prevalence of MS in Australia in 2010 was estimated to be 95.6 per 100,000 population in Australia. It is postulated that of the estimated 850 new cases of RRMS each year, approximately 125 to 187 patients would be refractory to interferon and alemtuzumab, or alemtuzumab only and may be assessed for eligibility for auto-hsct across Australia. It is difficult to estimate the number of patients with SPMS with inflammatory disease that may be suitable for auto-hsct. Systemic sclerosis SSc, also known as systemic scleroderma, is recognised as the most severe connective tissue disorder. SSc affects many different systems throughout the body with the most severe form involving major organs including the pulmonary, cardiac and renal systems. SSc carries a highly increased mortality risk with the major cause of mortality being cardiopulmonary events including interstitial lung disease and pulmonary arterial hypertension. 1 The median survival for patients with SSc related interstitial lung disease is 5 to 8 years. 2 The true prevalence of SSc is difficult to determine with international estimates ranging from three to 24 per 100,000 people. A systematic review of epidemiology suggests an incidence of SSc in Australia of 15 to 23 persons per million per year using data from three Australian sources covering 1993 to Based on Australian registry data and epidemiology of SSc, approximately 30 to 65 patients per year may be a reasonable approximation of the likely demand for stem cell treatment for SSc. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 iv

7 Systemic lupus erythematosus SLE is a chronic autoimmune disease characterised by inflammation across multiple organ systems, a clinical pattern of flares/relapses and remissions, and the presence of autoantibodies. Most patients with SLE have symptoms of the skin and joints, although lifethreatening manifestations can arise in the kidney, lungs, the central nervous system, gastrointestinal system, ophthalmic system, cardiovascular system and haematologic system. Inflammation of the kidney can cause lupus nephritis which can lead to significant illness and can even be fatal. The incidence of SLE in Australia is not well reported although a number of studies have reported the prevalence in population subgroups. The prevalence of SLE in Aboriginal peoples ( cases per 100,000 population) has been reported to be higher than in non-aboriginal peoples ( cases per 100,000 population). 3 Lupus nephritis is a severe form of SLE affecting renal function and therefore would be likely to be the main population requiring stem cell transplantation. The prevalence of lupus nephritis in Australia was found to be 5.5 per 100,000 population. Based on the current population, about 1,200 to 1,300 people would be living with the severe form of SLE in Australia. It is unclear how many of these people would be likely to benefit from stem cell therapies. Diffusion of technology in Australia In Australia, auto-hsct is widely used as a treatment for disorders of the blood and immune system and as supportive treatment for blood-related cancers. There have been over 60 auto-hsct for autoimmune disease performed at St. Vincent s Hospital since The use of allogeneic-hsct for the treatment of autoimmune diseases has been extremely limited. 4 The major concern with allogeneic transplants is the potential for graft-versus-host disease, a severe and potentially life threatening complication which has limited the diffusion of the technology. The technology to produce and use mesenchymal cells for therapy is available in Australia and has been used to treat a variety of conditions. There has been limited use of MSCT for the treatment of autoimmune disease in Australia with one small study published in Crohn s disease. There have been attempts to engage in early phase trials of mesenchymal stem cell therapy in MS in Australia. Cost infrastructure and economic consequences Little economic information was available on stem cell therapies for autoimmune diseases in Australia. This is likely due to the lack of mainstream use of stem cell therapy for autoimmune diseases. It was estimated that the direct cost to government for health and community care for MS in 2010 was $10,721 per patient, with an additional cost of $4,384 and $3,697 attributable to residential care and direct patient out-of-pocket costs, respectively. 5 No cost of illness estimates were available for SSc in Australia. An estimate of the cost for SSc in Canada in a cohort of 457 people with SSc found the direct healthcare Stem cell therapy for non-haematological (autoimmune) indications: March 2015 v

8 cost of $5,038 per patient (2007 Can$) 6. This cost, converted to 2013 Australian dollars using the OECD a purchasing parity index, 7 was $6,328. The Canadian cohort in this study included a wider range of patients than those likely to benefit from HSCT therefore the cost of patients with severe disease would be higher than this estimate. No cost of illness studies were found that reported costs for SLE in Australia. A UK report estimated the cost of a patient with severe SLE as 4,652 per annum equivalent to AUD $10,963. According to the selection criteria of the SLE studies, $10,963 would be a reasonable estimate of the yearly cost of a patient eligible for HSCT as only severe SLE patients are considered for stem cell transplantations. A cost analysis was performed for the purposes of this report only. The average national cost of a primary auto-hsct for MS was estimated to range from AUD $30,364 to $50,765. It was assumed that the same procedure is similar across the three autoimmune diseases. This estimate was based on the cost of undergoing an auto-hsct in one major transplant centre in Australia and may not reflect the cost of undergoing the procedure in other centres throughout Australia. Costs may also differ depending on the types of medications used in the protocol, the severity of patients, and the type of autoimmune condition. For example, there are biosimilar medications for the granulocyte-colony stimulating factor, such as pegfilgrastim, which are less costly than filgrastim. The cost estimate in this report was based on the medications used in a current clinical trial in Australia. The average cost per patient with different autoimmune conditions is relatively similar; however, patients with SSc require an extra day in hospital for the insertion of specialised central venous catheter. For the MSCT procedure, an additional cost of $10,000 to $20,000 per treatment course for the manufacture of mesenchymal stem cells in an accredited facility. However, the costs associated with chemotherapy, in-patient and support costs are less than HSCT. Based on the incidence rates of the three autoimmune diseases and the recommended patient selection for auto-hsct, it is unclear whether there would be capacity within existing hospitals across Australia to accommodate the anticipated increase in demand for stem cell therapies these diseases. However, there would be a significant increased burden on hospital staff. The strong centre effect observed in the European registry and American registry data, which demonstrates that more experienced centres are associated with improved safety and clinical outcomes, highlights the need to limit the procedure to a few specialised sites across Australia. a OECD = Organisation for Economic Co-operation and Development Stem cell therapy for non-haematological (autoimmune) indications: March 2015 vi

9 Review of the clinical evidence A literature search was conducted for each of the three conditions, MS, SSc, and SLE, for HSCT and MSCT. For MS, fifteen studies based on HSCT and four studies based on MSCT, published between 2009 and 2014, were included in this report. For SSc, three randomised controlled trials (RCTs) and six other relevant observational trials, published between 2007 and 2014, were included. For SLE, six studies published between 2009 and 2014 were included for HSCT which consisted of four case series and two comparative studies with concurrent controls. A further six case series studies, published between 2010 and 2014, were found for MSCT for SLE. Summary of multiple sclerosis Interpreting the evidence for stem cell transplantations for MS is challenging as the studies contain different treatment protocols, conditioning regimens, sources of stem cells and definitions for clinical outcomes. There is also limited long-term follow-up data. Most of the fifteen studies of HSCT for MS included in this report used autologous stem cells derived from peripheral blood. The median follow-up ranged from 31 months to 11.3 years. For the case series, the 100-day treatment-related-mortality (100 day TRM) ranged from zero per cent to four per cent and the treatment-related-mortality (TRM) ranged from zero to 14 per cent. For the retrospective analyses, the 100-day TRM and TRM ranged from two to four per cent and from 2.7 to 3.8 per cent, respectively. This reflects the European experience, 8 which reported a fall in mortality associated with autologous HSCT from 7.3 per cent from 1995 to 2000 down to 1.3 per cent from 2001 to This may have been due to improved patient selection and a reduction in the high-intensity conditioning regimens. Progression-free survival was estimated to be between 47.6 to 100 per cent at three years, 45 to 82 per cent at five years, 29.2 to 65 per cent at six years, 48 per cent at nine years and 25 per cent at 15 years. Disease free survival was estimated to be between 62 to 78.4 per cent at three years and 68 per cent at five years. Relapse-free survival was estimated to be 76 per cent to 86.3 per cent at approximately three years and between 85 to 87 per cent at five years. Only three studies reported magnetic resonance imaging (MRI) event-free survival which was estimated to be 100 per cent at 6-12 months, 92 per cent at two years, 100 per cent at three years and 85 per cent at five years. Disability at baseline, as measured by the median score on the Kurtzke expanded disability status scale (EDSS), ranged from 3.1 to 8.0. Disability progression was observed in zero to 58 per cent of patients whilst stabilisation or improvement was shown in 42 to 100 per cent of patients. New gadolinium-enhanced (Gd+) and/or T2 lesions were observed in zero to 24 per cent of patients at follow-up post-transplantation. Quality of life was found to significantly improve as early as six months post-transplantation (p<0.05) and improvements were observed in most of the domains at follow-up. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 vii

10 Stem cell transplantation is more efficacious in patients in the inflammatory stages of the condition (i.e. RRMS, and SPMS with episodes of relapsing remitting). As the condition progresses to SPMS, the disease shifts to a neural degenerative disorder and the treatment is no longer effective. According to updated guidelines, 4 the ideal target patient indications for auto-hsct for MS, are patients with MS in the relapsing remitting phase (characterised by clinical manifestations of high inflammatory activity and the presence of Gd+ enhancing lesions and/or new T2 lesions on MRI imaging scans) with aggressive progression failing one or more lines of treatment. Patients with severe malignant MS would also be suitable candidates for the procedure. Patients with SPMS who have evidence of some inflammatory disease activity and who have deteriorated may also be considered for auto-hsct. If the disease has progressed to a point where the patient have lost the ability to walk (approximately EDSS >6), auto-hsct is no longer a suitable treatment option (except for malignant forms of MS). Only four small case series for MSCT for MS met criteria for inclusion in this report. All included studies used autologous stem cell transplantation using mesenchymal stem cells derived from bone marrow. Common adverse events were fever, headaches, difficulty walking/standing and infections with no deaths reported across any of the four studies. Disease progression, as measured by the EDSS, significantly reduced in one study and was shown to improve in 34 per cent (13 patients), stabilise in 55 per cent (21 patients) and worsen in 11 per cent (4 patients) of patients in the other three included studies at six months with nearly 80 per cent improved or stable at 12 months. At follow-up, new T2, enlarging lesions or Gd+ lesions were found in zero to 71 per cent of patients. There is some research emerging on the combined effects of multiple therapies including stem cell transplantations in conjunction with other therapies as treatment for MS. For example, recent studies have explored the combination of non-myeloablative HSCT with a consolidation therapy of mitoxantrone, 9 HSCT with infusion of mesenchymal stem cells, 10 and failed non-myeloablative HSCT followed by natalizumab. 11 This area of research is still in its infancy, however may provide possible treatment options in the future. MS is generally not considered to be a fatal disease unlike the severe forms of SSc and SLE and the current TRM of auto-hsct for MS at one to two per cent remains a significant concern. Auto-HSCT remains a relatively experimental treatment for MS and should only be performed in a clinical trial setting, under the guidance of a human research ethics committee and with full informed consent. The safety and efficacy of stem cell therapies for autoimmune disorders and its benefits compared to existing standard therapies needs to be demonstrated through RCTs prior to becoming an accepted treatment option. Currently this level evidence is only available for SSc. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 viii

11 Summary of systemic sclerosis The results in trials to date support HSCT as an effective treatment for severe SSc. Patient selection is critical with high TRM in patients with cardiopulmonary involvement and in current and previous smokers. From the available evidence, auto-hsct had a worse short term safety profile than the comparison (cyclophosphamide) with more short term mortality and serious adverse events, particularly haematologic, respiratory, cardiovascular and common viral infections. TRM ranged from 0 to 23 per cent across the RCTs and observational studies. Auto-HSCT has a clear benefit on long term mortality. In the one RCT (van Laar et al. 2014) 12 reporting a comparison of mortality, a significant benefit was found for auto-hsct at five years despite the increased early mortality due to treatment. Mortality at around five years was similar in the RCTs to the observational studies at around 20 per cent. This compares favourably to estimates of mortality in SSc with major organ involvement of around 40 to 50 per cent at five years. 13 The results of longer term follow up support the hypothesis that HSCT is safer if baseline cardiac assessment is favourable and HSCT should be instituted before the SSc has caused cardiac abnormalities in order to maximise the benefit. The transplantation procedure used to treat patients with SSc has undergone changes since it was first implemented, primarily related to the increased screening of patients for cardiac complications to reduce TRM. In order to appropriately ascertain risk, screening should include echocardiogram, confrontational right heart catheterisation, including a fluid challenge test and cardiac MRI, however screening will increase the cost of the procedure. 14, 15 The improved procedures should have an impact on reducing the early mortality associated with auto-hsct therefore making it a safer treatment option. Summary of systemic lupus erythematosus HSCT and MSCT are both promising treatments for SLE, though they are still in the naïve stages of being proven clinically effective. The evidence available for this report came from six HSCT studies and six MSCT studies. Only two studies included an alternative treatment, a conventional treatment, which diminished the ability of this report to comment on the effectiveness of the treatments. 16, 17 No RCTs comparing HSCT or MSCT to standard treatment were found. The safety of HSCT and MSCT differed greatly across the 12 studies, supporting the claim of a strong centre effect / learning curve being involved in stem cell transplantation therapies. 18 The 100-day TRM of the HSCT studies varied from zero per cent in Song et al. (2011) 17 to per cent in Farge et al. (2010). 19 Only Farge et al. (2010) 19 judged deaths within their study to be by TRM. Song et al. (2011) 17 was unable to prove that HSCT was superior to conventional treatment with respect to overall survival. It was shown that Stem cell therapy for non-haematological (autoimmune) indications: March 2015 ix

12 progression free survival was significantly improved in the HSCT group, suggesting patients stay in remission longer due to HSCT. 17 The MSCT studies did not judge any death to be TRM, although Wang et al. ( and ) reported a 100-day TRM of 2.5 per cent and 2.29 per cent, respectively. The MSCT studies had an overall mortality range of 0.0 per cent (follow-up of 8.25 and 17.2 months) to 7.5 per cent (follow-up of 12 months). A number of parameters were used to demonstrate the decrease in disease activity after HSCT or MSCT. In both HSCT and MSCT studies, each study which reported the systemic lupus erythematosus disease activity index (SLEDAI) analysis, found the average SLEDAI score to significantly decrease after transplantation. Decreasing SLEDAI scores represent diminishing disease activity, with remission reached at SLEDAI scores < three. The MSCT studies found 24h proteinuria, serum albumin levels and anti-dsdna levels to positively change, representing statistically significant decreases in disease activity after treatment. There is no economic information available on SLE and stem cell transplantations in Australia. No Australian data exists to estimate number of potential SLE patients that would meet the treatment criteria, and be able to estimate the cost per annum. Cost-effectiveness analysis A search of health technology assessment (HTA) databases revealed stem cell transplantations for each of the relevant conditions, revealed three health technology assessments for MS, one health technology assessment for SLE, and no health technology assessments for SSc. Of these, only one publication was available which reported on an exploratory cost-effectiveness analysis in the UK evaluated the incremental costeffectiveness of auto-hsct versus mitoxantrone in the treatment of patients with SPMS. The results of the cost-utility analysis revealed auto-hsct as cost-effective compared with mitoxantrone at a threshold accepted by policy makers in the UK. These results are not generalisable for auto-hsct as a treatment for other subtypes of MS (e.g. RRMS) due to different comparators, other autoimmune diseases, or other types of stem cell transplantations (e.g. MSCT). Ongoing research Stem cell transplantation is an intervention currently of high interest to research teams with a large volume of research currently underway. For MS, 42 studies were found on clinical trial registries on stem cell transplantation for MS of which 30 studies are registered as active/recruiting/complete; 12 studies (HSCT), 21 studies (MSCT), and 3 studies (other). One multi-centre RCT (MIST phase) based in USA, Sweden, Brazil and the UK comparing auto- HSCT versus standard of care treatment is currently underway and will provide pivotal evidence on the outcomes of HSCT. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 x

13 There are 22 studies on stem cell transplantation for SSc of which 15 studies are registered as active/recruiting, three trials registered as complete and four trials registered as either terminated or withdrawn. Two RCTs are underway with results expected in For SLE, 14 studies on stem cell transplantation were found. Most of the current trials were based on HSCT. There are no RCTs registered for HSCT for SLE. There is one double blind RCT comparing MSCT versus cyclophosphamide which will be first clinical trial with the ability to judge the efficacy of MSCT in SLE patients. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 xi

14 Background Register ID WP 194 Technology name Patient indication Stem cell therapy for non-haematological (autoimmune) indications Patients with multiple sclerosis, systemic sclerosis and systemic lupus erythematosus Description of the technology Stem cells are a type of cell that are defined by their ability to multiple themselves (selfrenew) and change into different types of specialist cells (differentiate). There are two main groups of stem cells: tissue stem cells and pluripotent stem cells (Table 1). Tissue stem cells are (multipotent) have the ability to differentiate into a limited number of cell types. Tissue stem cells include adult stem cells, cord blood stem cells and fetal stem cells. Pluripotent stem cells are able to differentiate into any type of cell and include embryonic stem cells and induced pluripotent stem cells. Table 1 Classification and types of stem cells Group Description Type of stem cells Source of stem cells Adult stem cells Part of human body (e.g. bone marrow) Tissue stem cells Differentiation into a limited number of cell types Cord blood stem cells Umbilical cord blood Fetal stem cells Aborted fetuses Pluripotent stem cells Differentiation into any type of cell Embryonic stem cells Induced pluripotent stem cells Embryos Part of human body (e.g. skin) The current report will focus on treatment involving tissue stem cells, specifically adult stem cells, which can be isolated from the bone marrow. These are sub-classified into haemopoietic and mesenchymal stem cells. Stem cell therapy refers to transplanting stem cells into the body (stem cell transplantation) and drug therapies that target stem cells in the body. Stem cell transplantations have been proposed as a treatment for severe autoimmune diseases. The objective of the treatment is remove the autoreactive immune cells and to introduce stem cells (either from the patient or a donor) to reset or replace the patient s immune system. The two main types of stem cell transplantations for autoimmune diseases are haemopoietic and mesenchymal (Figure 1). Haemopoietic stem cell transplantation (HSCT) refers to the transplantation of multipotent haemopoietic stem cells derived from bone marrow, peripheral blood, or umbilical cord blood. Mesenchymal stem cell therapy (MSCT) refers to the transplantation Stem cell therapy for non-haematological (autoimmune) indications: March

15 of multipotent mesenchymal stromal cells derived from bone marrow, umbilical cord, adipose tissue, placenta, teeth and menstrual fluid. 7, 22 For stem cell transplantations, stem cells may be obtained from the patient (autologous), a matched donor (allogeneic), or an identical twin (syngeneic). Stem cell transplantation / stem cell therapy Haemopoietic stem cell transplantation (HSCT) Mesenchymal stem cell therapy (MSCT) Autologous Allogeneic/syngeneic Autologous Allogeneic/syngeneic (auto-hsct) (allo-hsct) (auto-msct) (allo-msct) Figure 1 Common types of stem cell transplantations in autoimmune diseases The autologous haemopoietic stem cell transplantation (auto-hsct) procedure is outlined in Figure 2 and involves the following steps: 1. Mobilising - Mobilising of haemopoietic stem cells from bone marrow or peripheral blood, typically with granulocyte-colony stimulating factor and cyclophosphamide. 2. Collecting or harvesting - Collecting or harvesting the haemopoietic stem cells by leukaphersis/plasmapheresis and selection for CD34+ cells. - Purifying and concentrating of the haemopoietic stem cells in the laboratory. - Freezing or cryopreserving the cells in the laboratory. 3. Conditioning and reinfusing - Immunoablative conditioning (chemotherapy) to destroy the immune system, typically with cyclophosphamide with or without anti-thymocyte globulin. - Reinfusing the thawed haemopoietic stem cells into the patient. Stem cell therapy for non-haematological (autoimmune) indications: March

16 Figure 2 Illustration of autologous haemopoietic stem cell transplantation procedure 23 The conditioning regimens include myeloablative conditioning (cyclophosphamide with total body irradiation or busulfan) and nonmyeloablative conditioning (cyclophosphamide with or without anti-thymocyte globuline. Myeloablative conditioning is associated with higher treatment-related-mortality (TRM) and is less suitable for patients with autoimmune disease. The auto-hsct procedure is relatively similar across multiple sclerosis (MS), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Allogeneic haemopoietic stem cell transplantation (allo-hsct) involves mobilisation, collection, and the harvest of haemopoietic stem cells from a human leukocyte antigen matched healthy donor. MSCT using bone marrow derived mesenchymal stem cells involves the aspirate of a small volume of bone marrow and then the isolation and culture expansion of the mesenchymal stem cells in an accredited manufacturing facility. Administering the mesenchymal stem cells to the patient can be via injection using the following methods: intravenous (vein); intrathecal (space around spinal cord); or intraparenchymal (brain). Company or developer Not applicable. Stem cell therapy for non-haematological (autoimmune) indications: March

17 Reason for assessment The technology of stem cell transplantations for autoimmune diseases has been assessed in this new and emerging health technology report for a number of reasons including: - increasing evidence for auto-hsct as superior to the current treatment for severe SSc; - mounting pressure from the public for stem cell transplantation to be made available to treat patients with MS; and - results of the current phase III trial for auto-hsct for MS which are expected to be released over the next few years. If the results are considered to have significant health benefits in a subgroup of patients with MS, it is likely that there would be a major cost impact on the public health system as multiple sclerosis is a large patient group associated with significant morbidity. Stage of development in Australia Yet to emerge Experimental Investigational Nearly established Established Established but changed indication or modification of technique Should be taken out of use Licensing, reimbursement and other approval The Therapeutic Goods Administration (TGA) is the regulatory authority for all devices, drugs and biological in Australia and is responsible for the regulation of the importation, manufacture and supply of stem cells. Stems cells intended to be used for therapeutic purposes are required to be listed on the reference database of the TGA, the Australian Register of Therapeutic Goods. Under the Therapeutic Goods Act 1989, Therapeutic Goods (Excluded Goods) Order No. 1 of 2011, human tissues and cells intended for use in humans are exempt from regulation by the TGA for medical practices with registered medical practitioners under specified medical conditions. b In partnership with the Australian Health Practitioner Regulation Agency, the Medical Board of Australia is responsible for the regulation of medical practice in Australia. Before new stem cell treatments are made available to the public, clinical trials should be used to establish their safety and efficacy. In Australia and overseas, clinical trials should be b Human tissue and cells, intended for use in humans, are declared not to be therapeutic goods if they are collected from a patient who is under the clinical care and treatment of a medical practitioner registered under a law of a State or an internal Territory; and manufactured by that medical practitioner, or by a person or persons under the professional supervision of that medical practitioner, for therapeutic application in the treatment of a single indication and in a single course of treatment of that patient by the same medical practitioner, or by a person or persons under the professional supervision of the same medical practitioner. For more information, see the Therapeutic Goods Administration website at Stem cell therapy for non-haematological (autoimmune) indications: March

18 registered with World Health Organization (WHO) approved clinical trial registries. According to the National Health and Medical Research Council (NHMRC), HSCT is the only stem cell treatment that is recognised as a safe and effective treatment to re-establish the blood and immune system for specific medical conditions. 24 The NHMRC has released information guidelines 25 for medical practitioners on stem cell treatments in Australia in which it states that there are some medical practitioners in Australia and overseas that are providing stem cell treatments that may not have been shown to be effective. Australian Therapeutic Goods Administration approval Yes ARTG number (s) No Not applicable Technology type Technology use Speciality Technology setting Procedure Therapeutic Haematology Specialist hospital Impact Alternative and/or complementary technology Additive and substitution (i.e. technology can be used as a substitute in some cases, but may be used in combination with current technologies in other instances). Stem cell therapy for non-haematological (autoimmune) indications: March

19 Patient Indication and Setting Multiple Sclerosis Disease description and associated mortality and morbidity Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (i.e. the brain, spinal cord and optic nerves). It is characterised by demyelination caused by the body s immune system attacking its own myelin sheaths (covering that surrounds the axons of the nerve fibres). The resulting inflammation and damaged myelin and axons lead to a disruption of the transmission of electrical signals to the brain. The symptoms of MS are dependent upon the areas of the central nervous system involved and can vary significantly between patients. Symptoms include numbness, tiredness, muscle weakness, sensitivity to heat, problems with balance and co-ordination, bladder and bowel symptoms, cognitive changes, and visual disturbances. The cause of MS remains largely unknown, however it has been proposed that autoimmunity (auto-reactive T and B cells), genetics and environmental factors (such as Epstein-Barr virus, human herpes virus 6, low vitamin D levels, smoking, and sun exposure) may all play a role. The most common subtypes of multiple sclerosis are outlined in Table 2 below, and include: relapsing remitting multiple sclerosis (RRMS); secondary progressive multiple sclerosis (SPMS); primary progressive multiple sclerosis (PPMS); relapsing progressive multiple sclerosis (RPMS); and other rare MS variants (e.g. Marburg s disease (malignant MS), Balo s concentric sclerosis, Schilder s diffuse sclerosis, relapsing optic neuritis). The latest diagnostic criterion for MS is the revised 2010 McDonald criteria (previously Poser and Schumacker criteria). It is estimated that approximately 75 per cent of patients with multiple sclerosis are female. The average age of onset of MS in Australia is usually between 20 to 40 years of age. Stem cell therapy for non-haematological (autoimmune) indications: March

20 Table 2 Overview of types of multiple sclerosis Type of MS Features Disease course Relapsing remitting multiple sclerosis (RRMS) Fluctuation of symptoms with periods when symptoms worsen (relapses) and periods when symptoms improve (remission). 85 per cent of patients are initially diagnosed with RRMS. Secondary progressive multiple sclerosis (SPMS) Initial RRMS disease course, followed by steady worsening of disease with or without occasional relapses and remissions. Primary progressive multiple sclerosis (PPMS) Steady worsening of disease without any remissions. PPMS is less common. Relapsing progressive multiple sclerosis (RPMS) Steady worsening of disease from onset with relapses (with or without partial recovery). In 2012, a total of 149 deaths (53 males and 96 females) were registered with MS being the underlying cause and 249 registered deaths (83 males and 166 females) were associated with multiple causes, including MS, in Australia. 26 In general, MS is not considered to be a fatal condition and does not significantly reduce life expectancy. 27 MS can often lead to a considerable level of disability. The Kurtzke expanded disability status scale (EDSS) 28 is a scale used to measure the severity of the disability in neurological impairment in people with MS. The EDSS scale is based on eight functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral and other) and ranges from 0 (normal function) to 10 (death) with higher scores representing greater levels of disability (Figure 3). The scale has 0.5 unit increments. An EDSS score of 1.0 to 4.5 refers to fully ambulatory patients whilst patients with impairments in walking are indicated by a score of 5.0 to 9.5. Stem cell therapy for non-haematological (autoimmune) indications: March

21 Figure 3 Kurtzke expanded disability status scale (EDSS) (MS Decisions) 29 Number of patients The 2009 Australian Bureau of Statistics (ABS) Survey of Disability, Ageing and Carers estimated the number of people living with MS in Australia to be 23,700 individuals (0.1% of the population) with the true prevalence estimated to be between 21,150 and 26,250 individuals. 30 Of the estimated 23,700 Australians with MS in 2009, core-activity limitation was reported as profound (19.8%), severe (28.2%), moderate (11.9%), mild (15.5%), or no disability (22.7%). It is estimated that the number of people diagnosed with MS will increase by four per cent per year. 31 The prevalence of MS in Australia in 2010 was estimated to be 95.6 per 100,000 based on pharmaceutical prescription data for MS prescription medications which is similar to an estimate of 89.3 per 100,000 based on client membership of the Multiple Sclerosis Society database. 5 Based on the pharmaceutical data, the number of people living with MS in Australia in 2010 was estimated to be 21,283 people (Table 3). The number is likely to be underestimated as not all people diagnosed with MS may be on medication due to being in remission. Table 3 Number of people with multiple sclerosis in Australia, 2010, based on prescriptions, by state NSW Vic Qld SA WA Tas ACT NT TOTAL Number of people with MS 6,268 6,637 3,179 1,760 2, ,283 Percentage of cases of MS by State 29.5% 31.2% 14.9% 8.3% 10.9% 3.4% 1.7% 0.2% 100% Abbreviation: MS: multiple sclerosis A recent Australian study 32 used pharmacoepidemiology of MS disease-modifying drugs for RRMS between 2005 and 2008 to estimate the overall prevalence of MS (all subtypes) to be 68.4 per 100,000 people and the prevalence of RRMS in Australia to be 31.1 per 100,000 Stem cell therapy for non-haematological (autoimmune) indications: March

22 (Figure 4). This data supports a latitude gradient effect with the prevalence lower in the northern states of Australia and higher in the southern states of Australia. Mean prevalence of treated RRMS (per 100,000 people) Figure 4 Map of Australia illustrating the mean prevalence of treated RRMS by state, 2005 to MS is a disease of the nervous system (International Classification of Diseases, ICD-10 code G35) and (ABS code 607). In , the number of separations (episodes of care) of patients with a primary diagnosis of MS admitted to Australian hospitals was 19, According to updated guidelines, 4 the ideal target patient indications for auto-hsct for MS, are ambulatory patients (i.e. approximately EDSS <6) patients with: - rapidly progressing RRMS refractory to one or more lines of treatment; - SPMS with inflammatory activity who have deteriorated; and - severe malignant MS. Based on an incidence of 1,000 new cases of MS (all subtypes) per year, 85 per cent would be diagnosed with RRMS. It is estimated that of the 850 new cases of RRMS, approximately 125 to 187 patients would be refractory to interferon and alemtuzumab, or alemtuzumab only (Appendix A) and may be assessed for eligibility for auto-hsct across Australia. A proportion of these patients who are referred by their neurologist for auto-hsct, who met all of the inclusion/exclusion criteria, and agree to undergo the procedure, may be eligible for the auto-hsct treatment. It is difficult to estimate the number of patients with SPMS with inflammatory disease that may be suitable for auto-hsct. Stem cell therapy for non-haematological (autoimmune) indications: March

23 Systemic Sclerosis Disease description and associated mortality and morbidity Systemic sclerosis (SSc), also known as systemic scleroderma, is part of a group of conditions known as scleroderma and is recognised as the most severe connective tissue disorder. The aetiology of SSc remains unknown. SSc is an autoimmune disorder that involves endothelium dysfunction and excessive production of collagen due to altered fibroblasts. 34 This results in fibrosis of the skin and internal organs which in severe cases leads to organ failure and death. 35 SSc is sub-categorised depending on the extent of skin involvement: limited cutaneous SSc affects mainly the fingers, toes and face and the diffuse form affects large areas of the skin including the torso. A third subset with no skin involvement, sine scleroderma, is sometimes used. Figure 5 outlines the types of scleroderma. Scleroderma Localised scleroderma Systemic sclerosis Morphea Linea scleroderma Limited cutaneous systemic sclerosis Diffuse cutaneous systemic sclerosis Figure 5 Types of scleroderma Localised forms of the disease affect only the skin and related tissues, and will not progress to the systemic form. These localised forms, while they can have a severe impact on quality of life depending on the extent of skin involvement, are not life threatening. Similar to other autoimmune disorders, SSc is more common among females with around 4:1 females to males. 36 SSc affects many different systems throughout the body. Complications of SSc include digital vasculopathy (Raynaud s phenomenon, digital ulcers), pulmonary arterial hypertension, interstitial lung disease, scleroderma renal crisis and gastrointestinal disease. 37 Less than one third of those with this form of the disease will go on to develop the severe form. 36 Stem cell therapy for non-haematological (autoimmune) indications: March

24 SSc carries a highly increased mortality risk. Scleroderma renal crisis develops in 10 to 15 per cent of patients and was a major cause of mortality before ACE inhibitors c became widely available in the 1980s. 36 Renal crisis is currently managed well with optimal medical therapy. The major cause of mortality is now attributable to cardiopulmonary events including interstitial lung disease and pulmonary arterial hypertension. 1 The median survival for patients with SSc related interstitial lung disease is 5 to 8 years. 2 Interstitial lung disease occurs in both diffuse and limited cutaneous forms of the disease 38 and is found in around 40 per cent of patients with SSc. 34 Long term data shows a 2.5 times higher risk of death compared to the general population based on 40 years of observational studies. 35 This risk has remained relatively stable over time although there is a trend towards longer survival of patients in the last few decades due to the improvement in the treatment of renal crisis. 39 Number of patients The true prevalence of SSc is difficult to determine with international estimates ranging from three to 24 per 100,000 people. 40 There are no estimates for the prevalence of SSc in Australia; however, there are an estimated 100,000 people with SSc in the United States. 36 The Australian Rheumatology Association maintains the Australian Scleroderma Interest Group (ASIG) database. This database recruits patients from 12 sites across Australia and has over 1,000 Patients with SSc enrolled. 41 As of 2011, 88 per cent of patients were female and 26 per cent had diffuse disease. Twenty-four per cent of the cohort had significant interstitial lung disease and 11 per cent had pulmonary arterial hypertension using gold standard right heart catheterisation. 41 A systematic review of epidemiology suggests an incidence of SSc in Australia of 15 to 23 persons per million per year using data from three Australian sources covering 1993 to Based on the current population of 23.7 million people, this predicts that there will be 356 to 545 new cases of SSc diagnosed yearly in Australia. Based on the proportion in the Australian registry approximately 85 to 130 of these new cases will develop significant interstitial lung disease. Given that a proportion will respond well to current therapies and a proportion would be ineligible due to major organ involvement precluding stem cell treatment or for other medical reasons, it is estimated that between 30 to 65 patients may be a reasonable estimate of likely demand for stem cell services per year. c ACE inhibitors = angiotensin-converting-enzyme inhibitors Stem cell therapy for non-haematological (autoimmune) indications: March