Stem Cells for Amyotrophic Lateral Sclerosis: ready for efficacy clinical trials?
Atassi N1, Beghi E2, Blanquer M3, Boulis N4, Caponnetto C5, Chiò A6, Dunnett SB7, Feldman E8, Mazzini L9 on behalf of the attendees to the International Workshop on progress in stem cells research for ALS/MND10
1 Neurological Clinical Research Institute (NCRI), Department of Neurology Massachusetts General Hospital, Boston
2 Department of Neuroscience, IRCCS - Institute for Pharmacological Research ‘Mario Negri', Milan
3 Transplant and Cell Therapy Unit, “Virgen de la Arrixaca” University Hospital, University of Murcia
4 Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 5 U.O. Neurology of IRCCS AOU S. Martino – IST, Largo R. Benzi, Genoa, Italy
6ALS Center, ‘Rita Levi Montalcini’ Department of Neuroscience, Neurology II, University of Torino, Turin, Italy
7 Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, South Wales, UK
8Department of Neurology, University of Michigan, Ann Arbor, MI;
9 ALS Centre Department of Neurology “Maggiore della Carità” University Hospital, Novara, Italy 10 Please see Appendix 1.
Even if our knowledge on the molecular basis of ALS has progressed very fast over the last few years, such discoveries have not yet translated into new therapeutics. A critical analysis of the fail-ure of clinical trials of proposed disease-modifying drugs in the past half-century shows potential methodological reasons that account for these negative results [1]. With the advancement of stem cells (SCs) technology, SCs clinical trials have been proposed as a novel therapeutic approach. However, when we consider the use of SCs for treatment, the level of complexity of the organiza-tion of a clinical trial is further increased by the extreme physiological heterogeneity of these cells, the uncertainty about the proper way of delivery, the need of immunosuppression, the high costs and some ethical concerns. Substantial challenges must be addressed and resolved to advance the use of SCs in efficacy trials for ALS. We discuss the most controversial points addressed during an International Workshop intended to bring together international SCs and ALS researchers in a pub-lic discussion on a topic where expertise is very limited. During the meeting a discussion was
started on the basic structure of the ideal clinical trial testing the efficacy and safety of SCs. The current document includes a number of consensus points reflecting the design of phase II/III clini-cal trials.
WHAT HAVE WE LEARNED FROM THE FIRST GENERATION OF CLINICAL TRIALS OF CELL TRANSPLANTATION?
Few studies have addressed the safety of SCs transplantation in small phase I/II clinical trials (2,3,4,5,6). The most consistent results of the first phase 1 clinical trials are the demonstration that ALS patients well tolerated a surgical trial and the intraparenchymal delivery of the cells into the spinal cord is safe in expert hands. Surgery was uncomplicated in all patients and very few side effects were reported. In all trials the most common negative event was transient pain in the site of surgery. The atrophic spinal cord of ALS patients is capable of tolerating at least up to 3 ml of cell suspension and 20 sites of injection at all segments (cervical, thoracic and lumbar) [2,3,4,5,6]. Both Bone Marrow SCs (MSCs and heamatopoietic) and Fetal Neural SCs showed no abnormal growth or tumor formation also in the long term till 9 years for MSCs and 2 years for NSCs. Post-mortem analysis showed the integrity and survival of the grafted cells up to 2.5 years post-transplantation [6-7]. All studies had demonstrated no acceleration in the course of the disease due to the
treatment.
These results are not definitive but they provide clear signals that cellular grafting is feasible in ALS patients and support to move to efficacy trials.
TRANSLATION IN PHASE II/III CLINICAL TRIALS: BARRIERS AND CHALLENGES
Patients selection
In phase I clinical trials in which the primary aim was to assess safety a risk escalation paradigm was adopted [8] . Invasive procedures, in fact, can generally be justified in patients with significant disability to be later extended to less severely affected patients. In phase II/III clinical trials more restrictive inclusion/exclusion criteria should be adopted. The maximum length of disease for the inclusion should be two years from symptom onset and the maximum age 65 years (range:18-65 years). The cells should survive and integrate well in the adult brain and spinal cord, supportive host environment starting to decline in aged individuals. Another key issue is to select homogeneous pa-tients with respect to the natural history (for example by including papa-tients with a similar progres-sion of ALSFRS-R and FVC in the three/six months prior to the intervention). The best instrument for global assessment for clinical trial entry is ALS-FRS-R scale [9]. Other parameters
recom-mended are Forced Vital Capacity (FVC), the optimal indicated value is >60. MIP/MEP, MUNIX, MRC, grip and Ashworth scale and dynamometric measure of strength are also recommended. No definite position on the inclusion of patients with focal variants such as flail arm or flail leg was reached
Outcomes
Patients selection is also intimately connected with study end points. As the focus of clinical trials advances from safety to efficacy, study hypotheses will focus on demonstrating significant delay or reversal of the progression of the disease and possibly the improvement of the pathophysiological targets defined from preclinical supporting. Defining the underlying mechanisms of therapeutic ac-tion may contribute to accurate clinical end point selecac-tion, and detecac-tion of appropriate biomarkers for treatment response. At the present time, however, there are no validated markers of the biologi-cal activity of the cells and of therapeutic efficacy in ALS. The suggested biomarkers of efficacy are PET (i.e. with[11C]PBR28]and [18F]-FDG), CSF (cytokines, Neurofilament Lght Protein, Growth Factors i.e. GDNF). Use of Neuroimaging such as MRI with DTI in transplanted areas are strongly encouraged for safety monitoring.
Multiple biomarkers should be used for a phase II trial and a single endpoint for phase III (i.e. QoL, FVC, muscular strength, time to death or tracheostomy) usually with discussion with Regulatory Agencies (FDA/EMA). The optimal assessment parameters include ALSFRS-R, handgrip strength, QoL, biomarkers, MUNE/MUNIX, EIM, FVC, MIP/MEP, Ashworth scale and time to death. It is strongly recommended to interrupt the trial at the occurrence of severe adverse events including tumors, neurological deterioration or early death
Randomization
While in safety trials controls may not be justified this is essential in efficacy trials, but represents a major issue. The value of including only historical controls is doubtful.
All experts agree that placebo-controlled studies are mandatory to test efficacy and a sham arm is to be included. in phase III trials. However the risks of a sham surgical procedure are higher than a placebo in a medical trial and must be minimized. Parameters of the intervention such as dose, sur-gical technique, time and procedure of anesthesia will be ideally optimized before including a sham arm. Hence preliminary phase IIb studies should be designed in order to find the optimal number of cells for phase III trials. (i.e a three arm dose-finding trial).
The correct control group should undergo identical procedures in every respect, and have delivery of inert cells however ethical and cultural considerations might be an obstacle. The risks of sham procedures must be balanced against scientific desirability. In addition, patients’ denial of sham procedures may compromise recruitment and be in itself a source of bias.
One way of addressing this issue is to use an uneven randomization scheme, which assigns a higher number of active to placebo subjects (i.e. 2: 1, 3: 1) or to split the study in pseudo-placebo/pseudo-sham surgery using a suboptimal number of cells in the "control" group
Immunosuppression
The decision to consider immunosuppression is based on a number of factors, including whether the cellular product is autologous or allogeneic. Immunosuppression is indicated when using allogenic cells but at present, it is unclear how long the treatment should be continued. The decision is related to the type of cells (SCs vs progenitor cells). It should be continued for at least 6 months then it may be gradually discontinued and stopped 2 years later. A lifelong low daily dose of steroids might be considered. Immunosuppression must be discontinued in rapidly deteriorating patients, not to add drug toxicity in a end- stage” situation.
CONCLUSIONS
Cell-based therapies may represent a new therapeutic approach for ALS There is a need to carry out appropriately designed experimental studies to verify the long-term safety and possibly the effi-cacy of these therapies. Specific issues with SC-based treatments inevitably lead to small trials. In particular, this relates to the capacity to produce sufficiently large numbers of standardized cells while meeting safety and quality standards, the higher risks related to surgical delivery, and the high costs. To accelerate the field of cell therapy for ALS, we have highlighted some consensus points and recommendations on the basic structure of phase II/III trials from an international work-shop and identified key translational barriers for further studies. Given the massive failures of neu-roprotective agents for ALS over the past 20 years, these points are based, in part, on the lessons learned from prior failures in the hope of facilitating the successful development of cellular thera-pies for ALS.
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