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Expert Financial Analysis and Reporting

Neuralstem: Initial Take on Top Line Results of Phase 2 ALS Trial of NSI-566 Neural Stem Cells (CUR, Buy, $3.08)

The topline data for the phase 2 trial of NSI-566 stem cells were released today. The initial stock reaction indicates that some investors were disappointed with the results as the stock sold off sharply at the opening. However, I view the results as encouraging and believe that if they are replicated in an upcoming phase 2/3 trial, that NSI-566 neural stem cells have a high probability for approval in treating ALS. My buy recommendation on the stock continues. I will write more on the results in this phase 2 trial as the data becomes available. Neuralstem will present at the Barclay’s conference today (March 12) at 2:35 PM EDT and could provide more information. The press release stated:

  • The study met primary safety endpoints. The maximum tolerated dose of 16 million transplanted cells and the surgery was well tolerated.
  • Secondary efficacy endpoints at nine months post-surgery indicate a 47% response rate to the stem cell treatment, as measured by either near-zero slope of decline or positive slope of ALSFRS score in seven out of 15 patients and by either a near-zero decline, or positive strengthening, of grip strength in seven out of 15 patients.
  • The average ALSFRS score for responders at 9 months after treatment was 37. Non-responders scored an average of 14. These scores represent 93%, versus 35%, of the baseline score retained, respectively, by the responders versus non-responders at 9 months, which is a statistically significant difference.
  • As measured by an average slope of decline of ALSFRS, responders' disease progression was -0.007 point per day, while non-responders' disease progression was -0.1 per day, which was again statistically significant.
  • Lung function as measured by Seated Vital Capacity shows that responder patients remained within 94% of their starting scores, versus 71% for non-responder patients.
  • The trial met its primary safety endpoints. Both the surgery and cells were well-tolerated, with one patient experiencing a surgical serious adverse event. In this study, cervical intervention was both safe and well-tolerated with up to 8 million cells in 20 bilateral injections

I will give my first impression of the data. However, I find that it takes time and thought to come to a final conclusion and there is much more to try to understand. There appears to be a sub-set of patients who respond very positively to NSI-566 neural stem cell transplants. In the previous phase 1 trial, five patients had an impressive response out of 12 treated. However, some of the early patients treated in the trial were end stage ALS patients who had little hope of recovery and volunteered for the trial to help determine that the surgery and cells were safe so that they could be implanted in healthier patients who might benefit, like Ted Harrada. There were other patients with bulbar onset disease who don’t appear to respond to the NSI-566 cells.

The response rate in the first phase 1 trial is indeterminate. We know that the numerator is five, but we don’t know the denominator. The minimal possible response rate in phase 1 was 42%. Now, the response rate in the second trial is 7 of 15 or 47%. These two trials seem to establish that the NSI-566 neural stem cells are very effective in a sub-group that may be about 50% of ALS patients.

There was no information on results on the five individual dosing cohorts of the phase 2 study in the press release, but I am sure we will learn more on this. One of the keys going forward will be whether this sub-group of responders can be prospectively defined. The Company said “We believe these types of endpoints, measuring muscle strength, will allow us to effectively predict patients that will respond to treatment, adding a sensitive measure of the therapeutic effects after treatment. Testing this hypothesis will be one of the primary goals of our next trial."

So how good are the results? I think that the thinking on NSI-566 has been overly influenced by the well-publicized, remarkable results experienced by Ted Harrada. This may have caused expectations to be at too high levels. The initial reaction of investors seems to be that the results were alright but perhaps a little disappointing. However, I view these results as encouraging and think this initial reaction is incorrect. There have been no successful trials in ALS to compare these results to. In my mind, I try to compare these results to late stage cancer patients who like ALS patients are in a desperate life threatening condition and usually have no treatment options.

In late stage cancer patients an overall response rate of 47% that is durable over a nine month period as seen with this phase 2 ALS trial would be extremely positive. The checkpoint modulators, Opdivo and Keytruda, are showing durable responses of about 30% in patients with late stage melanoma or lung cancer. These drugs are being hailed as breakthroughs in these diseases. I think that we can view NSI-566 neural stem cells in the same light in regard to ALS. This looks like a breakthrough.

In the 47% of patients who responded to treatment we are seeing durable responses over nine months. One of the key things to look for is whether these responses will be maintained over three years or so as was seen with Ted Harrada and two other patients from the phase 1 trial. Nine months of duration of effect is impressive but two years or more would be outstanding.

The disease states of responders have roughly stabilized over nine months. Let me put this in perspective by looking at the ALSFRS-r score. On this score, a perfectly normal patient would score 48. Most patients are diagnosed with ALSFRS-r scores in the high 30s or low 40S. Deaths, usually from respiratory issues, begin to occur in the 10 to 20 range. The responders had an ALSFRS-r score of 37 at nine months while non-responders averaged 14. This is a remarkable result.

The seated vital capacity (SVC) score also seemed to indicate that respiratory function was significantly improved in the responders relative to the non-responders. I need to do more work on the interpretation of these results.

I think that the next trial of NSI-566 could begin in coming months. If these phase 2 results are replicated, I think that it could be the basis for approval. One of the key issues in the potential commercialization of NSI-566 in ALS will be the ability to prospectively define who will benefit. This is a complicated surgery. I think that many or most patients faced with a 50/50 chance of the surgery being able to prolong their life by at least the nine months seen so far, would opt to go ahead. However, it could be a deterrent for some.

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  1. ” The responders had an ALSFRS-r score of 37 at nine months while non-responders averaged 14.”

    I guess the non-responders averaged 14 sacred the market as they were declining more rapidly than normal placebo patients whose slope of decline is around 1 point/month. And I found they used the word “average” which may be adversely affected by some rapid progressing non responders who died during the course.

    Non-responders’ SVC seemed to be inline with placebo pts declining around 3% every month. So maybe non-responders have more severe form of ALS?

    This initial response may urge management to disclose more information more rapidly.

    If the stabilizations in P2 replicate what we saw in P1, I will call this trial extremely successful. Now I have mixed feelings.

    Actually I wrote my first response in a previous blog. I repost it here.

    Top line data out.

    I have to say I have mixed feelings about the data. It’s very encouraging to see 47% of pts have their disease stabilized. But the non-responders’ ALSFRS-r scores seemed to decline too quickly, much quicker than normal placebo pts.

    And we lack several key information like how did the last cohort respond as pts from that group received both cervical and lumbar injections? Was there a dose dependent effect seen?

    Non responders respiratory function preserved better compared to their ALSFRS-r scores. Does this mean some kind of response?

    I hope I will know more answers to the above questions in the coming weeks.

  2. I am also curious about the design of the next trial. It seemed they will do a controlled trial. I wonder which will be the primary endpoint? response rate between the two groups? As the next trial will probably still be an open label trial, what if pts randomized to control group don’t want to stay in the trail, like previous NWBO and CLDX trials?

  3. Thanks for this Larry. Around when do you think the results of the next trial would be, using a conservative range?

  4. Let me gather a little more information before responding

  5. The press release seemed to have relatively little information. Maybe this is because of the job you’ve done educating your readers on NSI-566. I was struck by what seems to be an extremely rapid rate of decline for the non-responders. As you described it, they went from the ALSFRS score typical of a newly diagnosed patient to an end of life score in 9 months. The study excluded bulbar patients who presumably have shorter life expectancy.

    If it weren’t for the repeated statements about safety I would wonder if the surgery and the recovery from the surgery causes more harm than good.

    The investigators think initial grip strength is a predictor of success. Given that there were 7 responders and 8 non-responders it would seem that it is too small a sample size to be trying to identify the subgroup where the treatment is effective. It would also seem that if this is the basis for the selection of candidates for the Phase III study then that study would have an unusually high risk of failure.

  6. All good points.

  7. Watched the Barclays presentation. It seemed that Adam Feuestein presented accurate numbers:

    Average ALS FRS score at entry of 40 with ending score for the responders of 37 and 14 for the non-responders for an average of just under 25. The rule of thumb would expect an average score at the end of 9 months to be 31.

  8. Isn’t the main news that 47% of the group responded? If this group instead got whatever standard treatment is already provided (or lack thereof), should we expect a significant amount of the group to have such an outcome?

  9. This is exceptionally positive data.

  10. I listened to the webcast. I think Mr. Garr didn’t do a good job explaining the correlation between the grip strength and responders/non-responders. Mr. Garr mentioned that grip strength is an indicator of how many motor neurons remain live in the cervical area. I admit this may be a very good theory, but he didn’t present any data to support this theory which baffled me. He seemed not aware of AF’s attack and the street’s suspicion at all……

  11. Following up on my earlier post at 3:45 about the ALSFRS scores, after the presentation, I had in my notes 14 as the average final score for the non-responders but from looking at the slide in the presentation, I don’t understand how that could be the case. It looks like four of the eight non-responders died before the end of the 9 month period. However, from eyeballing the graph, it looks like none of them nit a score of 14. It would seem that the four surviving non-responders at the end of the 270 day period had an average ALSFRS of around 18 or 19. The average score at surgery was probably 37 (very roughly). This implies that the non-responders declined at about double the average rate rather than triple which the numbers I reported earlier imply.

  12. I think it may be that the possible importance of grip strength was not likely to be seen until this trial.

    It seems that the seriousness of many other factors in the initial trial would likely have masked this more subtle difference.

    In the earlier trial, the first 6 patients were well into the progression of their disease; there were two clear bulbar-onset patients in cohort D; there were at least two atypical ALS patients with very long duration of ALS, who basically remained the same after treatment; and then there were 4 patients who showed considerable slowing of progression and/or improvement.

    That accounts for nearly all of the patients in the initial trial.

    Having accounted for those various fairly big factors in the inclusion/exclusion criteria of this just completed trial, I would think that they would only in this trial have the chance to see this perhaps important, but more subtle factor as a potentially determining one.

    It may be that those with grip strength below some threshold at baseline could not only not respond as well to treatment, but also respond more poorly than average to, with more difficulty attempting to recovery from, an invasive surgery on their back.

    Of course, as was stated in the press release, grip strength at baseline being an important predictive factor of success… still needs to be confirmed in the next trial.

    But it does make sense to me that in controlling for most of the big factors working against patients in the earlier trial might finally allow them to see a more subtle differentiating factor possibly at play.

    (My apologies if this is hard to read. I’m new to these tiny cell phone screens and keypads and don’t have access to anything else at this time, ;-).)

  13. Most patients received the cervical surgery, yet lower limbs most often affected first…
    As discussed by Garr in his presentation, and I believe by Eva Feldman in other places… typically in ALS, weakening starts in the limbs of the lower body, and then progresses to the upper body.

    I believe one of the inclusion criterion was for patients to be ambulatory (or partially so), was it not?

    If so, that may mean that for many of these patients (those receiving only cervical surgery), some change downward in ALSFRS-R scores would be expected.

    Because most patients (all but the final cohort) only received the cervical surgery (directed at nerves serving mostly the upper body), I would expect that we would see some overall decline in the general ALSFRS-R score for many of these patients for a time… as a reflection of progressive weakening in the lower body.

    At some point, perhaps scores testing the lower body can’t decline much further; whereas, if the upper body of many of these cervical patients responds positively to treatment (at least as far as the most vital aspects of breathing, swallowing, etc), then maybe, over time, we might expect to see some stabilization of ALSFRS-R scores, even if at a lower level than baseline… due to reaching perhaps a limit in decline of lower body functioning, while also reflecting some stabilization at a higher level for at least some upper body functions (particularly breathing, swallowing, etc.).


    With the above in mind, I’m thinking that for as many patients for whom long-term testing is possible, long-term data will be very important in telling us if something like the above turns out to be the case, at least for the initial 4 cohorts, who only received surgery on the cervical area of their spinal cord (and via an ascending dosing protocol).

  14. Here is my second thought about the data so far:

    One disappointment: Only one pt in the last cohort is a responder.

    1st positive: 5 of 7 responders are in the cohorts with 6 million cells or more. So it may be a dose dependent effect favoring the high dose group. The disappointing data in the last cohort may happen by chance because of only 3 pts involved.

    2nd positive: Pt #303 was leveling off at month 15 instead of 9. And pt #304 was stable at month 12. It gives hope that eventually 3 to 5 pts could replicate what we saw in the P1 who held up to 3 years. But we will not know that for another two years ;-(

    3rd positive: The 8 non-responders had a much quicker decline in ALSFRS-r which could mean they were unusual rapid progressors. But their breathing which declined with a normal rate at 3 points per month performed much better compared to their unusual rapidly ALSFRS-r decline. And because 15 pts all got cervical injections, there may be an effect on breathing after all.

  15. One additional note about the potential dose dependent effect.

    Tom Coleman (should be pt #302) was the second pt into this P2 trial who got only 2 million cells. He wrote the following in May 2014

    “After many letters, emails, and phone calls I was accepted into the trial and had surgery on September 11, 2013. My condition immediately improved. I could walk long distances without the use of any devices, climb ladders and stairs; basically my condition was reversing every day. This is when I was going to announce my condition publicly. Unfortunately, like the book “Flowers for Algernon”, or the movie “Charlie”, my condition reversed again as fast as I improved. I declined back to the state before surgery. I am now wheel-chair bound, have lost the use of my upper body and am losing my voice.”

    So he had a period of rapid recovery which enabled him to “walk long distances without the use of any devices, climb ladders and stairs”. And on the non-responders ALSFRS-r slide, I did find that #302’s 1st visit was better than his baseline. But unfortunately his disease came back shortly after this miraculous recovery and this brave man passed away in Nov 2014.

    I think apparently this therapy was beneficial to him albeit it only worked for a short period of one month or two. The reason for this may be attribute to not enough cells injected or something else unknown.

    In the upcoming weeks, I hope the company could disclose every pt data or at least provide median aggregated data on ALSFRS and SVC at month 3, 6 as well as 9 which could give outsiders better perspective on the real meanings of the results.

  16. There’s an interesting thread on the yahoo mb, started by a neurologist, who has a part I and a part II within that thread (via the initial post and a follow-up comment):


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