In line with our focus this month on ‘emerging techniques and approaches’, we’ve brought together a panel of experts to discuss emerging therapies in multiple sclerosis (MS) in a two-part discussion. How extensive is our current knowledge of the mechanisms behind MS? What are the primary targets for existing therapies and future treatments? How could MS therapies change in the next 10 years? We’ve also incorporated the questions that you wanted to ask our experts, including the use of hematopoietic stem cell transplantation (HSCT) as a treatment option and how adult stem cells fare in relation to other stem cell sources.
Bringing together insights from across research and the pharmaceutical industry, our experts are Rick Munschauer (MedDay Pharmaceuticals, MA, USA), Luke Lairson (The Scripps Research Institute, CA, USA) and Valentina Fossati (New York Stem Cell Foundation, NY, USA). You can read the second installment of the discussion below, which focuses on the use of stem cells as a treatment option, and what further research is on the horizons for MS.
Catch up on Part I here, where our experts discuss the mechanisms, therapies and challenges involved in the research field.
A paper on HSCT as an effective and safe treatment for patients with relapsing MS made headlines recently – could you tell us more about this and the challenges involved?
Valentina Fossati: Several clinical trials have been testing the safety and efficacy of blood stem cell transplantation in MS. These studies are somewhat still limited in the number of patients enrolled, which is why we do not yet have definitive conclusions. However, the data are very promising and for some patients the treatment seemed to be highly effective in stopping the relapses. In particular, patients affected by an aggressive form of the disease, with frequent relapses and within 10 years from diagnosis received the most benefits from the transplantation. Unfortunately the procedure of blood stem cell transplantation is highly invasive: blood stem cells are isolated from the patient, who is then subjected to chemotherapy treatment (called a conditioning regimen) to eliminate any residual immune cells from the blood. This leaves the patient highly vulnerable to infections and there is a concrete risk of fatalities. For example, in the study conducted in Canada by the team of Mark Freedman (published in 2016), one patient out of 24 died. Because of the much safer profile of the first-line therapies currently approved, for the majority of patients it is not recommended to enroll in a therapy trial that carries fatal risks. The option of being enrolled in a blood stem cell transplantation trial is currently recommended for patients with highly active relapsing–remitting (RR) MS, as shown by clinical relapses and MRI lesion activity, within 5 years from the diagnosis, and who are not responsive to first-line approved medications.
How do adult stem cells fare in relation to other stem cell options?
VF: There are two types of adult stem cells currently used for transplantation: blood stem cells and mesenchymal stem cells. There is also a clinical trial in Italy to test the safety and efficacy of fetal neural stem cells, which are isolated from aborted fetuses. There are currently no trials with embryonic stem cell-derived cells (ESCs) or induced pluripotent stem cell-derived cells (iPSCs) in MS. Some studies are considering the possibility of generating oligodendrocyte progenitor cells from ESCs or iPSCs for cell transplantation to promote remyelination. Safety studies will be needed at the preclinical phase before being able to test this treatment in humans. ESCs have been used in the dish to test for new pro-myelinating compounds; for example, ketoconazole was identified by screening drugs in ESC-derived oligodendrocyte progenitor cells.
At present, there are several stem cell treatments that are deemed safe/effective for MS compared with current traditional MS drugs. What is holding back the progression for this?
VF: See also previous answers. Blood stem cell transplantation (i.e., autologous hematopoietic stem cell transplantation [AHSCT]) demonstrated impressive results in some patients, but it is not as safe as first-line treatments, meaning that there are several side effects, including fatalities, due primarily to the conditioning regimen (chemotherapy given to the patient after isolating the cells from the bone marrow). Other risks include opportunistic infections, infertility, febrile neutropenia, allergic and autoimmune complications. At the moment clinicians need to evaluate the risk/benefits ratio, and decide on a case-by-case basis the optimal options for the patients. There are several ongoing studies that aim at reducing the side effects and recent data presented at neurology meetings are encouraging in this direction. For example, two studies were presented at the American Academy of Neurology’s Annual Meeting (21–27 April, CA, USA). In one study, none of the 19 patients from MS centers across the world, treated with AHSCT, had clinical relapses following the procedure and there were no fatalities reported. A second study compared around 50 patients treated with AHSCT with a similar number of patients on approved medications. Again, no fatalities were reported and AHSCT outperformed in RR patients with more than two relapses per year. In RRMS, AHSCT is today a viable option in some appropriate MS centers.
In your opinion, what further research is needed to advance the development of therapies targeting MS?
Rick Munschauer: This is a question that I’ve thought about a great deal. There is a very long list of interventions that could plausibly be beneficial in MS including drugs modifying inflammation, neurodegeneration and repair. Some of these are novel molecules that can be RNA or even DNA therapeutics functioning at the level of gene expression or inhibition, others may address mechanisms of apoptosis; others may modulate neurodevelopment. For example, how can we take an oligodendrocyte precursor and transform this into a cell that migrates to a demyelinated axon and then remyelinates aggressively? There is a plethora of possible opportunities.
Our major challenge is that we have more options for treating patients than we have the time and people with MS to examine them in the traditional way. Speaking through the lens of a clinical researcher in the pharmaceutical industry, I think one of our biggest challenges is how to develop methodologies that will allow us to evaluate interventions in a very efficient and timely fashion. What I’m advocating for is a paradigm shift in preclinical and clinical development allowing for high-throughput screening of interventions in neurodegeneration and neurorepair. This can begin with early studies that involve a new generation of imaging technology. We can now measure change in myelin, axonal integrity, and loss of both grey and white matter volume by MRI accurately. Such imaging techniques will be essential in the assessment of new therapies or combination of therapies. Unless we demonstrate such target engagement and biologic proof-of-concept, either in animal models or early human models, we will not be able to advance the field of MS therapeutics. However, this is only half of the challenge.
The other half is related to improvements in the late phase clinical trials process. Currently it takes approximately 7–10 years for a drug to go from first-in-humans to EMA or US FDA approval. That traditional construct does not facilitate the rapid development of therapies for MS. We must rethink both trial design and outcome measures. In this instance, I applaud the EMA and the FDA for advancing the concept of adaptive trial design to shorten the clinical development process. With both advances in proof-of-concept studies and registrational trials, we should see a rapid improvement in clinical trial design.
Another area with the potential to accelerate the development of new MS therapies relates to developing the next generation of outcome measures for clinical trials. Classically, MS studies have all relied on a measure of disability, the Expanded Disability Status Scale (EDSS). But that measure has high inter- and intra-observer variability, is examiner-dependent and may not reflect the true function of a patient on a therapy. For example, EDSS does not adequately assess fatigue, cognition, vision, upper extremity function, or the role of an MS patient in society. There is an urgent need to develop better techniques for comprehensive, observer-independent disease monitoring capable of measuring a clinically meaningful treatment effect. However, we have a fair distance to go before the regulatory agencies will adopt such new measures. The research community needs to develop new tools and techniques to more expeditiously establish both the safety and efficacy of these interventions in a fashion that is acceptable to regulators.
Are there any technological developments required for us to gain a better insight into the clinical progression of the disease?
VF: For sure any technical advancement will be beneficial, there are many areas currently in huge expansion, not just for MS but for all other incurable disorders affecting our society: developing better machines for imaging, better software to analyze the data, software for collecting all the clinical data from the patients in a way that they can be shared with other institutions, creating a huge database accessible to all researchers, remotely controlled devices that patients can carry without the need of going to the hospital, and last but not least artificial intelligence, such as applying deep learning to the interpretation of biological data.
Looking ahead, how do you anticipate the way MS therapies will change in the next 10 years?
Luke Lairson: There is reason for hope that therapies for MS will continue to improve in a significant way over the course of the next 10 years. The approaches used to tackle this disease will likely involve combination therapies that address all aspects of disease. A well-defined highly effective combination of drugs may exist, which target not only the inflammatory and remyelination aspects of disease, but also axonal protection and the function of CNS resident pro-inflammatory cells. In addition, considerations associated with diet and exercise will clearly play an important role in the development of an optimal approach for the treatment of this disease.
VF: Because of all the developments mentioned above this is really an exciting time for MS research. Maybe 10 years is a short time frame and there will not be dramatic changes for the patients, but within these 10 years there will be significant progress for a more long-term future. I also think that there will be more attention to lifestyle, diet, exercise and decreasing stress; relatively easy things that the patients can do, feeling more in control of the disease, sometimes with a significant psychological impact that ultimately improves the patient’s general wellbeing.
RM: In summary, I think we’ll have better personalized medicine. We’ll be able to select the right treatment for the right patient at the right time. In the relapsing forms of MS, there is no question that drugs that modulate the immune system will be a very important platform therapy. Biomarkers, either biologic or imaging, can be expected to more specifically inform our treatment decisions in the future. In addition, I believe that ‘big data’ will also inform the process for optimizing therapy.
Our knowledge of the treatment of MS will become increasingly sophisticated. I suspect that in 10 years’ time we’ll recognize that aggressive early immunotherapy is the preferred approach in some and platform immunomodulatory therapy in most. The next generation of therapies, however, needs to focus on this issue preventing neurodegeneration and facilitating repair. The therapeutic goals in MS will also evolve from slowing progression to stabilizing or even reducing impairment.
About the experts
Frederick Munschauer (Rick) – MedDay Pharmaceuticals
Frederick Munschauer, who also goes by the name Rick, is the Global Head of Medical at MedDay Pharmaceuticals (MA, USA), a company that is in clinical development for drugs for the progressive form of MS and other indications in neuroscience. Before joining industry 9 years ago, Dr Munschauer was the Smith Professor and Chair of Neurology at the University of New York at Buffalo (NY, USA) and has been involved in MS research for 30 years.
Luke Lairson – The Scripps Research Institute
Luke Lairson obtained his BSc in Biochemistry from the University of Guelph (Canada) and his PhD in Chemistry from the University of British Columbia (Vancouver, Canada). He performed postdoctoral research, in the fields of chemical biology and regenerative medicine, as a Canadian Institute of Health Research (CIHR) fellowship at The Scripps Research Institute (CA, USA). Dr Lairson worked as a Research Investigator at the Genomics Institute of the Novartis Research Foundation (GNF; CA, USA), in the fields of regenerative medicine and preclinical drug development. He went on to become a founding member of the California Institute for Biomedical Research (Calibr; CA, USA), where he served as Director of High Throughput Discovery and Principal Investigator. He is currently an Assitant Professor in the Department of Chemistry at the Scripps Research Institute, where his lab is focused on the identification of mechanisms and potential drug candidates for the treatment of demyelinating diseases.
Valentina Fossati – New York Stem Cell Foundation
Valentina Fossati is a New York Stem Cell Foundation (NYSCF; NY, USA) Senior Investigator at the NYSCF Research Institute, where she focuses on advancing preclinical studies of neurodegenerative and neuroinflammatory disorders, including multiple sclerosis; utilizing human induced pluripotent stem cell-derived brain cell studies. Dr Fossati established highly reproducible protocols to generate oligodendrocytes, astrocytes, microglia and neuronal cell types and is developing culture systems with multiple cell types to identify and target the key pathogenic mechanisms leading to neurodegeneration and/or demyelination in progressive MS, Alzheimer’s disease and other disorders of the CNS.