Disability caused by brain tissue damage as a result of acute ischemic stroke (AIS) often requires extended hospitalisation and rehabilitation, representing a significant socioeconomic burden.
A major focus of AIS research is the development of neurorestorative stem cell-based therapy that has the potential to repair brain tissue damage and recover lost function. As such, Healios / Athersys, ReNeuron, and SanBio are developing MultiStem, Ren-001, and SB623, respectively. These stem cell-based therapies could offer measurable neurological improvements and potentially reduce the long-term social and financial burden associated with AIS.
Acute ischemic stroke (AIS) and MultiStem cell therapy
Stroke remains one of the major causes of death and disability worldwide. Due to the limited time window for the administration of the only thrombolytic agent, alteplase, only a minority of stroke victims receive this medical therapy. The majority end up with mere palliative care to alleviate the symptoms associated with ischemic brain damage.
AIS is the most common type of stroke, and is caused by a blockage of the blood flow to the brain, leaving the affected part of the brain deprived of oxygen and nutrients. This eventually causes the destruction of brain cells, neuronal connections, and vascular systems with devastating complications. Approximately 25% of patients have neurological deterioration during the first 24–48 hours after stroke, and it is difficult to predict which patients will worsen.
Athersys is developing MultiStem cell therapy in collaboration with Healios. MultiStem consists of undifferentiated human adult stem cells that have the unique ability to promote tissue repair and healing in a variety of ways, including the expression of factors that regulate the immune system, and the formation of multiple cell types.
The Phase II safety and efficacy of multipotent adult progenitor cells in AIS trial (MASTERS) demonstrated that MultiStem was safe and well tolerated, with no infusional or allergic reactions. Although this trial did not demonstrate better global stroke recovery between the MultiStem and placebo groups when administered within 24-48 hours of symptom onset, Healios is planning to initiate a Phase III trial (MASTERS-2) investigating global stroke recovery in an earlier time window—within 18–36 hours after the onset of ischemic stroke.
A Phase II/III trial of MultiStem in AIS (TREASURE) is ongoing in Japan where subjects receive a single dose of 1.2 billion HLCM051 (MultiStem) cells administered within 18–36 hours after the onset of ischemic stroke. A recently announced binding letter of intent (LOI) between Athersys and Healios stated that the companies will expand the collaboration between the existing partners to develop and commercialise the product in extended indications in Japan and China, and provide Athersys with the capital to support its Phase III study in North America and Europe.
Alternative stem cell therapies
However, Athersys is not the only company strengthening its stem cell asset in AIS. SanBio has partnered with Hitachi Chemical’s US subsidiary in manufacturing their proprietary late stage regenerative medicine product, SB623, for rapid commercialisation in Japan and the US markets. A Phase IIb, double-blind, controlled trial of SB623 (ACTIsSIMA) is ongoing, which is investigating the safety and efficacy of SB-623 modified stem cells in patients with chronic motor deficit as a result of AIS.
In the Phase I/IIa study SB623, cells were found to be safe with no dose-limiting toxicities or deaths, and were associated with significant improvement (p<0.001) in clinical outcome endpoints from baseline at 12 months, including European Stroke Scales (ESS), National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer total score, and Fugl-Meyer motor function total score.
ReNeuron, a UK-based clinical-stage stem cell company, is also planning to initiate a Phase IIb study of their stem cell therapy product, ReN-001, for stroke disability. The product candidate is a genetically stable neural stem cell line, designated CTX, which is generated from allogeneic multipotent human neural stem cells.
The CTX cell therapy candidate has the potential to improve the disability of stroke patients through angiogenesis and regenerative activity. Results of the Phase II (PISCES II) study, presented at the American Heart Association International Stroke Conference in January 2018 demonstrated the short- and long-term safety and tolerability of CTX, as well as the meaningful improvements in upper limb function and disability occurring by 12 months after intracerebral administration of CTX in AIS patients with significant upper limb weakness.
The FDA has given regulatory approval for the company to commence a Phase IIb clinical study of CTX for stroke disability, designated PISCES III, which the company plans to initiate in H1 2018 in the US.
Since there are no treatments available beyond the acute phase of AIS besides preventative and rehabilitative measures, stem cell-based therapies will enter an untapped sector of the stroke market, providing treatments for those patients who survived AIS with consequent disabilities.