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Autologous Stem Cell Therapy for Multiple Sclerosis DeMISTified-Pharma-Intelligence


Phase III MIST trial data presented at the 2018 annual meeting of the American Academy of Neurology (AAN) highlight autologous hematopoietic stem cell therapy (aHSCT) as a radically novel prospect for multiple sclerosis (MS) treatment, with an unprecedented curative potential. Certainly, aHSCT’s potential to reverse disability is markedly distinct from currently available disease-modifying therapies (DMTs), which can only slow disability progression. Protocols for aHSCT currently require relapsing-remitting MS (RRMS) patients to have previously failed conventional approved therapies, hence threatening sales of Gilenya (fingolimod; Novartis/Mitsubishi Tanabe), Lemtrada (alemtuzumab; Sanofi/Bayer), Mavenclad (cladribine; Merck KGaA), and Tysabri (natalizumab; Biogen). aHSCT represents a high-risk, high-reward treatment strategy that could transform the lives of niche, aggressive RRMS patients whose options are scant. This potentially one-off therapy would abolish lifetime treatment costs, as well as render expensive DMTs redundant. Ultimately, MIST marks the precipice of a paradigm shift in the established approach to MS treatment.

MIST Trial Data

Exciting interim MIST trial data elucidated the significant efficacy of aHSCT over DMTs. This Phase III study investigated highly active RRMS patients who experienced >2 relapses within the prior year despite receiving DMTs. The study met its primary endpoint in terms of treatment failure, with aHSCT patients 10 times less likely to fail treatment than those on DMTs during the mean three-year follow-up period. Encouragingly, positive results were also demonstrated across an array of secondary endpoints, most notably including a reversal of disability. Table 1 below summarizes the full dataset from the MIST trial, which was conducted across sites in the US, UK, Sweden, and Mexico.


Table 1. Results of the MIST trial [1] [2]




Difference between treatment and control

Treatment description



aHSCT versus DMT

Number of patients




Number of evaluable patients




Percentage treatment failure with mean follow up of three years (range 1–5 years) (%)

(Endpoint = Primary)

6 (3 of 52)

60 (30 of 50)


Mean change in EDSS score from baseline to one year





Percentage NEDA at four years (%)





Percentage EDSS failure-free survival at five years (%)





Percentage change in T2 lesion volume (%)




Treatment failure was defined as EDSS >1.0 point sustained 6 months after 1 year of treatment, assessed by a blinded neurologist, while NEDA was defined as no relapses, no disability progression, no new or enlarging MRI lesions.


DMTs (number of patients) used in the control arm were: natalizumab (22), dimethyl fumarate (18), fingolimod (13), interferons (10), glatiramer acetate (8), and mitoxantrone (5). Other immune drugs used in the control arm include corticosteroids (39), cyclophosphamide (2), and rituximab (2).

aHSCT = autologous hematopoietic stem cell therapy; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; NEDA = no evidence of disease activity


Efficacy of aHSCT

The impressive efficacy of aHSCT in terms of expanded disability status scale (EDSS) reduction is unparalleled. Marketed DMTs have been limited to slowing disability progression, as opposed to demonstrating the 1.1 reduction in EDSS score that was remarkably evident with aHSCT. Moreover, at four years, there was a stark contrast in terms of no evidence of disease activity (NEDA) between the two arms, with 80% for aHSCT and 0–5% for the control arm. The complete absence of relapses, disability progression, and new or enlarging magnetic resonance imaging (MRI) lesions in aHSCT-treated patients drives home the sustained impact of this therapy as a potentially curative treatment.

It is promising that aHSCT’s efficacy in terms of EDSS was evident during the first year post-enrolment. Moreover, efficacy remained apparent for up to five years, with a low rate of treatment failure (6% = three patients) during follow-up. This indicates that treatment benefits are tangible relatively soon after aHSCT, and corroborates that positive benefits persist years later. Furthermore, incorporating numerous standard DMTs in the active comparator arm, including gold-standard Tecfidera (dimethyl fumarate; Biogen), only strengthens the data.

Safety and Tolerability of aHSCT

Thus far, aHSCT has appeared to be safe, with no deaths, no grade IV toxicity, and no early or late opportunistic infections such as fatal progressive multifocal leukoencephalopathy (PML), which is associated with some approved MS therapies like Tysabri. While there was one case of bacteremia during the vulnerable stage of neutropenia with aHSCT, there was no sepsis or hypotension.


aHSCT Procedure

Figure 1. Autologous Hematopoietic Stem Cell Transplantation

Autologous Hematopoietic Stem Cell Transplantation

Adapted from Multiple Sclerosis Trust [3]. CYC = cyclophosphamide; r-ATG = rabbit anti-thymocyte globulin

Stem cell therapy is an intensive procedure that is typically used to treat cancers including leukemias and lymphomas. aHSCT aims to reset the immune system in MS patients (see Figure 1). The critical component of non-myeloablative aHSCT for MS is chemotherapy to partially eliminate the immune system, thus destroying auto-reactive cells. Following ablation, patients’ own harvested stem cells are reintroduced. These stem cells then differentiate into new, antigen-naïve immune cells without memory of MS. For a period, the patients are in an aplastic phase with little immune protection; hence, it is vital that they receive antimicrobial prophylaxis. Recovery times can take up to a year or sometimes longer [3].

Disease Background

MS is a chronic autoimmune and neurodegenerative disease that is estimated to affect at least 2.3 million people globally [4]. Inflammatory demyelination involving B and T cells within the central nervous system is a hallmark of this disease. In turn, demyelination leads to scar tissue formation, called sclerosis, along the covering of nerve cells. This process results in neurological symptoms associated with MS. MS is clinically heterogeneous – depending upon the site of the lesions associated with demyelination in the CNS. Primary symptoms of MS include cognitive dysfunction, muscle spasms, pain, fatigue, weakness, visual problems, numbness, bladder dysfunction, and difficulty walking [5].

The most common disease course is RRMS, which 85% of MS patients initially present with [6]. RRMS is characterized by intermittent attacks that are linked to residual disabilities. The vast majority of approved DMTs are indicated for the treatment of RRMS. Currently available DMTs are immunomodulators, anti-inflammatory, and immunomodulatory drugs. aHSCT is appropriate for a subpopulation of aggressive inflammatory RRMS that is typically characterized by frequent relapses, high MRI activity, and rapid disability accumulation [7].


Market Analysis

Since aHSCT is only suitable for a specific population of MS patients with severe RRMS that is treatment-refractory, it will pose a threat to DMTs reserved for highly active RRMS. aHSCT is an intensive treatment that will be consigned to a later line of therapy, for patients with few effective treatment options. Thus, it is unlikely to compete with DMTs prescribed for the wider RRMS population. Figure 2 below highlights Datamonitor Healthcare’s forecast sales for DMTs targeting highly active RRMS that are now at risk from serious competition [8]. Anticipated combined sales across the across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) for Gilenya, Lemtrada, Mavenclad, and Tysabri amount to $4.8bn in 2018 (see Table 2).

Figure 2. Sales of marketed disease-modifying therapies targeting highly active relapsing-remitting multiple sclerosis across the US, Japan, and five major EU markets, by brand, 2016–25

Autologous Hematopoietic Stem Cell Transplantation


Table 2. Sales of marketed disease-modifying therapies targeting highly active relapsing-remitting multiple sclerosis across the US, Japan, and five major EU markets, by brand ($m), 2016–25

























































Grand total











Source: Datamonitor Healthcare’s Forecast: Multiple Sclerosis, November 2017


aHSCT is completely unique compared to available DMTs and is poised to fulfill critical unmet need for patients. A survey of 231 neurologists across the US, Japan, and five major EU markets, performed by Datamonitor Healthcare in May 2016, emphasized that the most pressing need in the MS market was for curative treatments [5]. aHSCT has the outstanding potential to offer a one-off treatment to patients, which could replace expensive lifelong therapy and therefore have substantial cost-saving implications. The cost of a year’s treatment may fall in line with marketed brands [9]. No pharmaceutical companies were involved in the MIST trial, with university centers likely to carry out this novel treatment as it becomes more widespread [1].

Barriers to Uptake

Existing cost infrastructures may not be amenable to aHSCT and patients may face difficulty accessing treatment. Additionally, there may be hesitance towards utilizing such an aggressive treatment in chronic MS patients as it is usually reserved for acute cancer patients who would die without treatment. aHSCT requires patients to tolerate a potent chemotherapy regimen that ablates the immune system. Consequently, patients must endure the aplastic phase during which they are extremely vulnerable to lethal opportunistic infections, therefore stringent monitoring and prophylactics are vital. aHSCT can be a demanding treatment for patients, necessitating a considerable recovery period.

It is also important to note that MIST was a relatively small trial with long-term data beyond five years yet to be released. Scrip Intelligence reported that patients treated in the MIST trial will be followed up until 2021 [10]. Longer-term follow up data will be key to consolidating aHSCT’s applicability for the MS treatment paradigm, as it is necessary to confirm that the therapy is indeed an efficacious one-off treatment and to establish its long-term safety and tolerability profiles. In addition, it would be interesting to ascertain how aHSCT compares clinically with new rising star Ocrevus (ocrelizumab; Roche), which is set to boast blockbuster sales, as Ocrevus was not yet available at the time of the trial.


[1] Burt RK (2018) Non-myeloablative hematopoietic stem cell transplantation (HSCT) is superior to disease modifying drug (DMD) treatment in highly active Relapsing Remitting Multiple Sclerosis (RRMS): interim results of the Multiple Sclerosis International Stem Cell Transplant Trial. Presented at the American Academy of Neurology meeting, 21–27 April 2018, Los Angeles.

[2] Burt RK, Balabanov R, Snowden JA, Sharrack B, Oliveira MC, et al. (2018) Non-myeloablative hematopoietic stem cell transplantation (HSCT) is superior to disease modifying drug (DMD) treatment in highly active Relapsing Remitting Multiple Sclerosis (RRMS): interim results of the Multiple Sclerosis International Stem cell Transplant (MIST) Randomized Trial (S36.004). Neurology, 90(15 Supplement), S36.004. Available from: [Accessed 15 May 2018].

[3] Multiple Sclerosis Trust (2017) Stem Cell Therapy. Available from: [Accessed 9 May 2018].

[4] Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O (2018) Multiple Sclerosis. The Lancet, 391(10130), 1622–36. Available from: [Accessed 9 May 2018].

[5] Datamonitor Healthcare’s Treatment: Multiple Sclerosis, November 2017.

[6] Multiple Sclerosis International Federation (2013) Atlas of MS 2013: Mapping Multiple Sclerosis Around the World. Available from: [Accessed 22 July 2016].

[7] Fernández Ó (2017) Is there a change of paradigm towards more effective treatment early in the

course of apparent high-risk MS? Multiple Sclerosis and Related Disorders, 17, 75–83. Available from: [Accessed 16 May 2018].

[8] Datamonitor Healthcare’s Forecast: Multiple Sclerosis, November 2017.

[9] BBC News (2018) Stem cell transplant 'game changer' for MS patients. Available from: [Accessed 16 May 2018].

[10] Scrip (2018) Excitement Over MS Stem Cell Transplant 'Game Changer' Data. Available from: [Accessed 16 May 2018].

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