Moving forward in the US and Japan
Athersys announced agreement with the FDA with regard to an SPA for its Phase III MASTERS-2 trial of MultiStem in ischemic stroke. It will be a randomized, double-blind, placebo-controlled 300-patient trial where MultiStem treatment will be administered within 18-36 hours post-stroke. If approved, it will be a major improvement over the current standard of care, tPA, which requires treatment within 3-4.5 hours of a stroke and leads to the vast majority of patients being untreated.
The primary endpoint will be disability, as measured by the shift in mRS scores at three months. The mRS clinical assessment evaluates overall patient disability using a score ranging from 0 to 6 (see Exhibit 1).
Exhibit 1: mRS grading and descriptions
Grade |
Description |
0 |
No symptoms |
1 |
No significant disability: ability to carry out all usual duties and activities |
2 |
Slight disability: unable to perform all previous activities but able to look after own affairs without assistance |
3 |
Moderate disability: requiring some help but able to walk without assistance |
4 |
Moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs with assistance |
5 |
Severe disability: bedridden, incontinent and requiring constant nursing care and attention |
6 |
Death |
Description |
No symptoms |
No significant disability: ability to carry out all usual duties and activities |
Slight disability: unable to perform all previous activities but able to look after own affairs without assistance |
Moderate disability: requiring some help but able to walk without assistance |
Moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs with assistance |
Severe disability: bedridden, incontinent and requiring constant nursing care and attention |
Death |
Source: Banks et al., Stroke, 2007 March; 38(3):1091-6
In contrast to endpoints that only evaluate patients achieving good or excellent recovery, the mRS shift analysis focuses on evaluating patient improvement across the disability spectrum. When assessing patients in the 126-patient MASTERS-1 trial, the mRS shift analysis was not significant on an intent-to-treat basis. However, it was significant at day 90 (p=0.028) when assessing patients under the original trial protocol, which included patients treated with MultiStem up to 36 hours, and excluded patients receiving the combination of both tPA and mechanical reperfusion therapy. Improvement among patients treated with MultiStem within 36 hours, including those who received a combination of tPA and mechanical reperfusion therapy, was significant at day 7 and day 30, but only trended at day 90 (p=0.127) and was not statistically significant (see Exhibit 2).
In the MASTERS-2 trial, 300 patients will be enrolled, randomized 1:1 MultiStem to placebo and patients will be treated in the 18- to 36-hour post-stroke window, a time frame that should increase the chance of success of the trial based on the MASTERS-1 data.
Exhibit 2: mRS shift analysis from Phase II trial
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Source: Athersys – analysis of the improvement in disease severity (mRS) at 7, 30, and 90 days. Note: Columns represent all patients treated with MultiStem within 36 hours after stroke (left) and the same population but excluding patients that received both tPA and MR per the original trial protocol (right).
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We currently expect the trial to launch in 2017 with data in 2019, enabling an approval for MultiStem in 2020 in the US instead of 2021 as we had previously expected.
In Japan, the PMDA successfully completed the review of the Clinical Trial Notification (CTN), the Japanese equivalent of the IND, which will allow the ~200-patient pivotal study to start. We expect recruitment to commence officially sometime before the end of 2016, with an approval in 2019.
The primary endpoint will be the proportion of patients achieving Excellent Outcome, which requires an mRS score of ≤1, a National Institutes of Health Stroke Scale (NIHSS) score of ≤1 and a Barthel Index score of ≥95, reflecting essentially an almost full recovery at day 90. NIHSS focuses on neurological impairment and measures 11 items (eg level of consciousness/awareness, body movement issues) and the output is a score between 0 and 42 (higher integers signify a more severe stroke). The Barthel Index is also a widely used scale that judges the ability of patients to function in activities of daily living through questions on bowel/bladder control, grooming, feeding, bathing etc. In total, 10 items are scored with each item scored in five-point increments for a total potential score of 100, which signifies no disability at all (see Exhibit 3).
Exhibit 3: Barthel Index interpretation
Score |
Interpretation |
80-100 |
Independent |
60-79 |
Requires minimal help |
40-59 |
Partially dependent |
20-39 |
Very dependent |
<20 |
Totally dependent |
Score |
80-100 |
60-79 |
40-59 |
20-39 |
<20 |
Interpretation |
Independent |
Requires minimal help |
Partially dependent |
Very dependent |
Totally dependent |
Source: National Institutes of Health
In the Phase II trial, on an ITT basis, 15.4% of patients in the treatment arm achieved an Excellent Outcome compared to 6.6% in the placebo arm (p=0.10) which, while trending positive, is not statistically significant. However, significance was achieved when excluding patients who were not treated within 36 hours of their stroke and those who received both t-PA and MR in a post-hoc analysis (p=0.03).
Exhibit 4: Excellent Outcomes in MultiStem Phase II trial at 90 days and one year
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Source: Athersys. Note: *Excluding patients receiving tissue plasminogen activator and mechanical reperfusion.
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Based on discussions with management, we expect that the lessons from the prior clinical trial are being applied to optimize the design of the trial in Japan and the MASTERS-2 study. In Japan, we do not expect the inclusion of patients that receive treatment with both tPA and MR. In the MASTERS-2 trial, we anticipate that if those subjects are included it will be limited to a small percentage, and stricter screening and characterization criteria will be applied to address any of the issues observed in the prior trial. Since both trials are larger in size than the Phase II study and the focus will be on treating patients within the 18- to 36-hour treatment window, it should make hitting the endpoints more achievable.
