Did you know?
17 million people suffer a stroke every year, and it is the leading cause of long-term disability in the world. While there are some available treatments available for treating an ischemic stroke, patients must receive these treatments within only a few hours of having a stroke. Unfortunately, only a modest percentage of stroke patients arrive to the hospital in time to receive these treatments.
Athersys is developing MultiStem cell therapy for the treatment of ischemic stroke, which may be delivered to a patient up to 36 hours after the stroke. This dramatically opens up the time window for treatment, allowing up to 90-95% of the stroke patients to be eligible to receive the therapy.
MASTERS-2 (MultiStem® Administration for Stroke Treatment and Enhanced Recovery Study) - Phase 3
Our clinical focus in the neurological area involves evaluating the efficacy of MultiStem cell therapy to treat ischemic stroke.
We are currently enrolling patients in our MASTERS-2 Study, a Phase 3 clinical trial for the treatment of ischemic stroke using MultiStem that is being conducted primarily in North America and Europe. This pivotal, 300-patient clinical trial has been designated under a Special Protocol Assessment, or SPA, by the FDA for the design and planned analysis. The SPA provides agreement from the FDA that the protocol design, clinical endpoints, planned conduct and statistical analyses are acceptable to support a regulatory submission for marketing approval if the trial is successful. Results from the MASTERS-2 trial, together with other available clinical data, could provide the foundation of the regulatory package for commercial approval.
The FDA has granted this program Fast Track designation, which means that the program is eligible for rolling submission of the Biologics License Application, or BLA, accelerated approval and priority review, facilitating a timely regulatory review. Fast Track designation may be awarded if a drug is targeted at a serious unmet medical need and shows some advantage over available therapy, such as showing superior effectiveness, effect on serious outcomes, improved effect on serious outcomes or certain other advantages.
The European Medicines Device Agency, or EMA, granted the program a Final Scientific Advice positive opinion establishing alignment between European and United States regulators about the potential for approval based on the success of the MASTERS-2 study, which further expedites development.
This program has also received the Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA, which was established under the landmark 21st Century Cures Legislation. The RMAT designation may be obtained for eligible cell therapy and other regenerative medicine and advanced therapies when the FDA agrees that preliminary clinical evidence indicates that the therapy has demonstrated the potential to address unmet medical needs for a serious or life-threatening disease or condition. The designation enables sponsors to interact with the FDA regarding multidisciplinary strategic development plans, including expediting manufacturing development plans for commercialization to support priority review and accelerated approval.
Visit the MASTERS-2 website
TREASURE trial (Treatment Evaluation of Acute Stroke for Using in Regenerative Cell Elements)
We and our partner, HEALIOS K.K. (Healios) announced topline data in May 2022 for the TREASURE trial being conducted in Japan to evaluate the safety and effectiveness of administration of MultiStem to stroke patients. This double-blind, randomized, placebo-controlled study enrolled 206 patients and was conducted at 48 leading stroke centers in accordance with Japan’s new regulatory framework for regenerative medicine therapies. This framework is designed to expedite the development and commercialization of promising and innovative regenerative medicines that are shown to exhibit safety and demonstrate potential effectiveness. This program has also received Priority Review designation status in Japan under the Sakigake regulatory framework for innovative therapies.
Topline results:
- Improvement in pre-specified measures of functional “independence” and good outcomes, such as mRS ≤2, Barthel Index ≥95 and Global Recovery, associated with MultiStem treatment.
- The primary endpoint, Excellent Outcome at 90 days, did not reach statistical significance in this population.
- Overall, consistent improvement in essentially all measured functional outcomes over time through one year, supporting long-term impact on and continued improvement in the quality of life of treated patients.
- High potential for success on Athersys’ MASTERS-2 primary outcome measure, mRS shift, suggested by the results for the TREASURE patients who were representative of the current enrollment for MASTERS-2.
- No material differences in safety outcomes, including mortality and life-threatening adverse events between the treatment and placebo groups.
The Athersys and Healios teams plan to continue to analyze the TREASURE results as additional data becomes available, including the impact on biomarkers and more detailed evaluation of important factors associated with the treatment effect, among other things. Furthermore, Athersys plans to support regulatory engagement, including together with Healios in Japan, to advance the ischemic stroke program forward on its regulatory path. With respect to the MASTERS-2 study, Athersys intends to continue its proactive efforts to improve enrollment through site-expansion and site-productivity initiatives to complete enrollment as soon as possible. For more information, refer to the press release.
The Completed Phase 2 (MASTERS) Study
In 2016, we completed a Phase 2 study of MultiStem cell therapy to treat patients suffering a moderate to severe ischemic stroke and announced the positive one-year follow-up data and final results from the study at the International Stroke Conference.
The randomized, double-blind, placebo-controlled trial was conducted at 33 clinical sites in the United States and the United Kingdom. In 2015, we announced interim results, and although the study did not achieve the pre-specified efficacy endpoint, we observed favorable tolerability and promising evidence of efficacy, especially when patients were treated within 36 hours of the occurrence of a stroke. In 2016, we announced the final one-year results from the Phase 2 study, which showed statistically significant clinical improvement when evaluating all subjects, as evidenced by the proportion of patients treated with MultiStem that achieved an “Excellent Outcome”. This measure reflects complete, or essentially complete, recovery in each of three well-established clinical rating scales that are used to evaluate stroke patients.
Stroke experts have long realized that minimizing time to treatment for stroke victims is a critically important consideration (i.e., “time is brain”). Current forms of treatment aimed at successfully reperfusing patients using treatment with tPA or mechanical thrombectomy are limited to patients that can be treated the first few hours after the stroke has occurred. While beneficial in many patients, these treatments are associated with meaningful risks that increase over time, precluding treatment beyond a narrow window (i.e., a few hours). This narrow time window limits treatment to a small percentage of patients that suffer an ischemic stroke.
However, the results from our Phase 2 clinical trial suggest that intravenous administration of MultiStem cell therapy to patients up to 36 hours post-stroke may provide a safe and effective form of intervention that could meaningfully improve recovery and longer-term outcomes. This represents a more substantial time window than current standard of care that could enable treatment of a much greater percentage of stroke patients.
The study enrolled subjects who received intravenously either MultiStem treatment or placebo one to two days following the stroke. Of the patients evaluated in the study, 65 patients were in the MultiStem treatment group and 61 patients were in the placebo group, and among the MultiStem subjects, 31 received MultiStem treatment within 36 hours following the stroke (in accordance with the original study protocol).
How We Measured Excellent Outcome Using Three Standard Stroke Scales
Functional and neurological deficit and recovery following the ischemic stroke were evaluated using three standard methods for clinically evaluating patients: the NIH Stroke Scale (NIHSS), the Modified Rankin Scale (mRS) and the Barthel Index (BI).
The NIHSS assesses neurological impairment and motor skill deficits and is a quantitative scale from 0 to 42, where higher numbers represent a greater degree of disability. Examples of assessment questions include evaluating whether a patient can raise their arm, move their leg, answer questions, speak clearly, visual field, etc. For illustrative purposes, a score of 20 is considered a severe stroke, a score of 10 is a moderate stroke, and a score of 2 or 3 is a mild stroke. A score of 0 to 1 using the NIHSS is considered an excellent outcome by clinicians.
The mRS is an ordinal scale from 0 to 6 which measures the amount of disability resulting from the stroke. This scale is focused on evaluating overall disability level, such as by assessing whether the patient is conscious, bedridden, mobility constrained, etc. and takes into consideration the level of care required. The mRS is typically measured at time points after treatment (e.g. 30 days, 90 days or beyond) to evaluate recovery progression. A score of 0 or 1 is considered by doctors to be an excellent outcome, meaning little to no disability.
The BI is a 100 point scale that assesses the ability of the patient to independently perform activities of daily living, or whether they require some or extensive assistance. Examples of assessment questions include evaluating whether the patient can feed themselves, walk unassisted, dress themselves, use the bathroom on their own, bathe unassisted and engage in other activities. This scale is important, because it directly measures the patient’s ability to engage in activities of daily living and quantifies the level of assistance required from caregivers. Scoring higher on this scale is desirable and achieving a score of 95 to 100 is considered an excellent outcome.
Our Phase 2 trial was designed to evaluate patient recovery 90 days and 365 days after one-time treatment shortly after the stroke event, with the primary endpoint being assessed at 90 days post-stroke. MultiStem treatment was associated with faster recovery, a greater proportion of patients achieving an Excellent Outcome (defined clinically as excellent outcomes in each of the three scales: mRS 0-1, NIHSS 0-1 and BI ≥95), as well as lower rates of mortality and life threatening adverse events (AEs), infections and pulmonary events, at the 90-day evaluation point.
Moreover, the results for all subjects treated in the study demonstrate that on average MultiStem-treated subjects continued to improve relative to patients receiving placebo through one year and had a significantly higher rate of Excellent Outcome at one year (p=0.02). The relative improvement in Excellent Outcomes was even more pronounced in the patients who received MultiStem treatment within 36 hours of the stroke (p < 0.01)
Additional highlights from the one-year follow-up data analyses include:
- Intravenous MultiStem treatment was well tolerated by ischemic stroke patients;
- Lower average initial hospital days, shorter time in Intensive Care, and lower mortality, life threatening adverse events and infections were observed for MultiStem subjects compared to those receiving placebo;
- Among all treated MultiStem subjects, there was a higher proportion of subjects who achieved excellent mRS outcomes (≤1), 27.7% compared to 13.1% in the placebo group (p=0.04), and among MultiStem subjects treated within 36 hours of stroke, 32.3% achieved an excellent mRS outcome (p=0.03, compared to all placebo subjects), and;
- Substantial improvements were also observed in the Barthel Index. Among all treated subjects, 61.5% of MultiStem patients had an excellent Barthel Index (≥95) outcome compared to 44.3% of placebo patients (p=0.05). Furthermore, 67.7% of the subset of early-treated MultiStem patients achieved an excellent Barthel Index outcome, representing a 23.4% difference with the incidence for all placebo patients (p=0.03).
We believe that the benefits to patients, their families and the healthcare system as a whole from a faster and more effective recovery, are substantial, and could represent a significant value to society. The ability to improve quality of life for patients and their families, and substantially reduce or eliminate the need for full time institutional care, professional home care, or family care would represent a major advance in stroke care. In addition, we believe the potential market for a new therapy to treat stroke could be $15 to $20 billion or more, annually.