Genervon ALS drug shows encouraging results

• In two Phase 2a clinical trials, privately-held Genervon Biopharmaceuticals' drug candidate for Amyotrophic Lateral Sclerosis (ALS), GM6 (known as GM604 in the ALS trial and GM608 in a Parkinson's disease study), showed encouraging disease-modifying results albeit in a small number of patients.
• In the ALS study, GM604 significantly reduced the decline in ALSFRS-R versus the historical control (p=0.0047). Seven of eight patients has their ALS disease progression slowed or stopped at week 12 after six doses of GM604. Five of seven treated patients had their forced air capacity (FVC) disease progression slowed or reversed at week 12 compared to historical placebo (-11.5% compared to -4.7% after treatment).
• In the Parkinson's study, the difference in the treated patients' UPDRS scores versus historical placebo at week 12 were statistically significant (p=0.0085). Changes in secondary clinical outcomes measures at week 2 were statistically significant at the one-tailed 10% level for four of eight patients.
• Genervon has submitted these results to the FDA for guidance on how to make GM6 available for ALS and PD patients. GM604 for ALS has been designated Fast Track and an Orphan Drug by the FDA.
• ALS-related tickers:(NYSEMKT:CUR) (NASDAQ:BCLI) (NASDAQ:MNOV) (NASDAQ:BIIB) (NASDAQ:CYTK)
• PD-related tickers: (NASDAQ:ACOR) (CVTS) (NASDAQ:ACAD) (CYNAF) (IPXL) (NASDAQ:TTNP) (OTCPK:SGTH) (NYSE:TEVA) (NASDAQ:ADMS) (NASDAQ:PRAN) (NASDAQ:CHTP) (NASDAQ:PRTA) (NASDAQ:FOLD) (NASDAQ:AVNR) (NYSE:BSX) (NYSE:MRK)

Comments

[Smith On Stocks]

I did not make acknowledge an error. In responding to another comment relating to the mechanism of action my repsonse was "I have no intelligent reply at this point". In the Seeking Alpha thread this came in out of place and appeared to be a response to a question from stocktalk09.

He answered this misplaced response with this caustic comment. "Whether you have an intelligent reply in the future or not, I take this to mean you weren't aware that the patients for the historical control were placebo treated patients. This is stated directly in the trial description and if you had read it then one of what I just wrote should have come as a surprise.

I understand that you told your follower to buy Neuralstem in the mid-$3's, but you have to acknowledge the hypocrisy in you calling Doug out and asking him to make a retraction when you're making statements off the handle without doing your own research."

I obviously know that the historical data related to standard of care patients. Who would possibly think otherwise. There is no change in any of my comments.

[cfriend881]

SMITH ON STOCKS...larry , very well stated , an just for a few grandstand followers from the bleachers pulpit !, there are a few folks that not only follow the latest vetted science,they are the family members or patients in waiting ! So , it quite a different view an experience when you are strapped in the patients SEAT !

[sighter8]

So what is the consensus here? I have great respect for Mr. Smith and his research. To clarify was Mr. Smith acknowledging an error in his initial analysis but remains unmoved by the data? My take is that there is some substance to the trial results but we do need more data as this is an exciting approach.
And what to make of these new comments by infoSA? Somewhat strange in the wording as to try and lead us to believe it is written by a Genervon insider. I would think that even if someone from Genervon was steered toward this article while maybe read it I seriously doubt someone would take the time to compose it.(for what purpose?) It also just regurgitates all the already accessible data on their website. And if it isn't written by a Genervon insider does that lead some credence to Mr. Smith's points he raises in his own article? Or is merely just more comments from stocktalk09 (who while making valid points should play nicer)

[InfoSA]

dear editor, can you replace the last posting with this edited version:

Thank you for your interest in Genervon which has no stock to trade. Genervon is flattered if you think our press release caused price drop of Neuralstem. May be Genervon can shed some light in your interesting discussion.

GM6 is an "innovative endogenous multiple targets receptor mediated signaling regulatory peptide drug" that most people do not understand what does that mean. We broke with tradition and gave as much data as possible in our short press release so that some people who are advance in the science understand what is going on (may be they are the one who is dumping stocks). If novice readers reading the press release they have to read it carefully and do not jump to quick and wrong conclusions. Several hinds may be helpful to comprehend the significance of the two trials, ALS and PD:

1. Contrary to the conventional wisdom to have a thousand patients trial to hopefully find statistical significant efficacy (a generation of ALS patient would have died in the same time frame), we are audacious or confident enough to designed the two concurrent trials (to ensure Genervon did not get lucky with one trial) to determine if a six-dose treatment of GM6 would start the process of disease modification in two different neurodegenerative diseases and if there is drug effect how long would it last up to 10 weeks after a six-dose treatment. If the drug is efficacious, a few patients are enough to proof and obtain the statistical significant data. If the drug is not efficacious even a five thousand patients (cancer) trials would not succeed.
2. The short fall for a small patient sample size trial is that the placebo effect on the placebo patients using the traditional clinical scoring system will make statistical analysis very difficult because of placebo effect whereas a big placebo sample size can mitigate that problem. But the trial will take a very long time. That is why our PIs and FDA agreed to use historical definite ALS placebo control group to compare with the treated definite ALS patients as stipulated in the approved IND. It is a deliberate design decision with approval from FDA and not an afterthought or post hoc analysis.
3. You all have to learn the new biomarkers science because FDA is advocating it and it is coming for sure to determine drug efficacy. Biomarkers are highly sensitive to changes in the underlying disease processes (disease mechanism of action) and are useful in predicting drug efficacy. In addition, biomarker measures are usually immune to the “placebo effect.” The statistical significant disease related biomarker data in Genervon's trials correlated well with the statistical significant clinical data in both the ALS and PD small trials. Please note that GM6 modulated not one but multiple biomarkers at the same time in the same patients to restore homeostasis state. That is the important difference between all the failed single target drug CNS disorder trials and Genervon's multiple targets peptide trials. One should not judge GM6 with the conventional and traditional single target drug development mindset. That is where most people in your discussion group went astray.
4. ALS Biomarker Data: GM604 modulated one target biomarker (SOD1 Plasma and CSF), two efficacy biomarkers (Total TAU Plasma, Complement c3 CSF), two target/efficacy biomarkers (TDP43 Plasma and Cystatin C CSF), and one prognostic biomarker (pNFH CSF). These are highly significant ALS related biomarkers. The following multiple biomarkers have statistical significance or strong trend between the treated and active (not historical since there is no historical data) placebo groups:
1.) Total TAU plasma percentage change reduction from baseline to week 7 when compared between GM604 treated and active placebo groups, p value =0.0369. Total Tau is mainly expressed in neurons of the CNS and is crucial in axonal maintenance and transport; it is a major component of abnormal intraneuronal aggregates in many CNS disorders, including Alzheimer.
2.) Reduction of TDP 43 plasma slope from baseline to week 12 when compared between GM604 treated and active placebo groups, p value =0.0078. TDP 43 is a major diseased protein of ALS and other CNS disorders such as Alzheimer.
3.) SOD1 plasma percentage change at week 2 also showed a significant reduction trend when compared between GM604 treated and active placebo groups, p=0.0550. A single mutant copy of this gene is sufficient to cause ALS in the 90% sporadic ALS patients.
4.) And the slope for GM604 treated patients for SOD1 CSF was reduced by -1.875 (indicating disease reversal) through week 6 whiles the active placebo group increased by 155.226 (increase indicates disease progression).
5. ALS Clinical Data: The clinical data ALSFRS-R and FVC scores:
1.) GM604 significantly reduced the decline in ALSFRS-R versus the historical control, p=0.0047. 7 out of 8 treated patients had their ALS disease progression slowed or stopped at week 12 after initial six doses of GM604.
2.) 5 out of 7 treated patients had their forced air capacity (FVC) disease progression slowed down or reversed at week 12 when comparing with historical placebo. At week 12 FVC of mean value of placebo group is -11.5% (lower capacity is not good) and mean value of treated group is -4.7%.
6. Going for the extra mile Genervon treated a California ALS patient who was first diagnosed with ALS in Q1 2005 and by Q3 2008 was quadriplegic and on a ventilator. After a six-dose treatment of GM604 under a FDA approved single patient compassionate-use IND, the patient’s swallowing volume increased in two weeks to 20cc from a baseline of 10cc. Five weeks after treatment, the patient consumed 240cc of water in 20-25cc bursts without leakage.
7. PD Biomarker Data: Changes in targeted neuroprotective and inflammatory biomarkers suggested drug efficacy and disease modification in the treated patients group, while the active placebo group demonstrated the opposite trend.
1.) GM602 significantly increased the neuroprotective biomarker BDNF at week 2 when compared between GM604 treated and active placebo groups, p value =0.035. BDNF has potent effects on survival and morphology of dopaminergic neurons; its loss could contribute to death of these cells in PD.
2.) GM602 dramatically lowered the levels of the inflammatory biomarker MMP9 at week 2 to -14.88% (lower is better) while the biomarker in the active placebo group increased to +1.31%, an indication of disease progression. MMP9 gene is associated with the risk of PD.
8. PD Clinical Data: The clinical data score used United Parkinson’s Disease Rating Scale (UPDRS):
1.) Comparing the UPDRS of the treated PD patients by GM602 at week 12 and historical placebo PD patients is statistically significant, p=0.0085.
2.) Changes in 4 out of the 8 secondary clinical outcome measures (UPDRS ADL, Schwab & England, Hoehn & Yahr and MOCA) at week 2 (visit 6) were statistically significant at the one-tailed 10% level.

Usually small sample size in clinical trials is not good enough to see even a small trend in efficacy for most drug candidates. The fact that GM6 achieved statistical significance in both biomarkers and clinical data in two different indications speak highly of the drug effect of the innovative multiple target peptide drug. Since ALS is very heterogeneous, some patients may need a booster dose after the six-dose treatment once a month or three months as determined by the attending neurologist until the disease is reversed or “cured”.

[fierroargento]

Hello,
First of all thank you for taking the time to publish this and I am looking to understand more on the ALSFRS conclusion.

I work in statistics and develop statistical models, validate them and developed new techniques for my employers on many different topics, so the reason I am asking you this is because I think there are a couple of flaws hinted in the logic below.

I am reading this specifically:
1.) GM604 significantly reduced the decline in ALSFRS-R versus the historical control, p=0.0047. 7 out of 8 treated patients had their ALS disease progression slowed or stopped at week 12 after initial six doses of GM604.
2.) 5 out of 7 treated patients had their forced air capacity (FVC) disease progression slowed down or reversed at week 12 when comparing with historical placebo. At week 12 FVC of mean value of placebo group is -11.5% (lower capacity is not good) and mean value of treated group is -4.7%.

From this I understand that what you are doing is saying that the historical placebo had an average decline of -11.5% with an STD of x and then computing how likely it is that the mean of a population of 7 patients falls at -4.7%. Any derivation of this approach would be incorrect.

These are the questions I have:
1. Did you score your population expected decline per and post treatment? In other words this would normalize by among other things, How was your population study selected and how does it compare to the historical placebo? On such a low number it is very easy to have a significant difference in your population. Things like age, time since diagnosis, years obtained for historical placebo (if you are comparing early 2000 s data then it is likely biased), was the population scored based on these parameters and other parameters to understand what is the real expected decline?
2. Do you have the prior rate of decline of the 7 patients and what was the scoring of these patients expected decline pre and post treatment?

In other words a good historical placebo is not built by comparing averages and standard deviations. You need to score your population including all the relevant data points some of which I mentioned above and have an expected trend and then compare that to the actual results. The validation shouls show two things 1 that the model was predicting either accurately or was predicting a lower decline prior the treatment and that after the treatment the scored model for each individual patient was scoring a higher decline in ALSFRS.

If you are not doing this then your statistics are most likely weak and I encourage you to do so to check if what you are saying holds true.

Please let me know and if you are interested in understanding how this can be properly done please contact me.

[InfoSA]

Thank you for your interest in Genervon which has no stock to trade. Genervon is flattered if you think our press release caused price drop of Neuralstem. May be Genervon can shed some light in this interesting discussion. GM6 is an innovative multiple targets receptor mediated signal regulatory peptide drug that most people do not understand. We broke with tradition and gave as much data as possible in our short press release so that some people who are advance in the science understand what is going on. If novice readers reading the press release they have to read it carefully and do not jump to quick and wrong conclusions. Several hinds may be helpful to comprehend the significance of the two trials, ALS and PD:
1. Contrary to the conventional wisdom to have a thousand patients trial to find efficacy (a generation of ALS patient would have died in the same time frame), we are audacious or confident enough to designed the two concurrent trials (to ensure Genervon did not get lucky with one trial) to determine if a six-dose treatment of GM6 would start the process of disease modification in two different neurodegenerative diseases and if there is drug effect how long would it last up to 10 weeks after a six-dose treatment.

2. The short fall for a small patient sample size trial is that the placebo effect on the placebo patients using the traditional clinical scoring system will make statistical analysis very difficult whereas a big placebo sample size can mitigate that problem. That is why our PIs and FDA agreed to use historical definite ALS placebo control group to compare with the treated definite ALS patients as stipulated in the approved IND.
3. The clinical data ALSFRS-R and FVC scores:
1.) GM604 significantly reduced the decline in ALSFRS-R versus the historical control, p=0.0047. 7 out of 8 treated patients had their ALS disease progression slowed or stopped at week 12 after initial six doses of GM604.
2.) 5 out of 7 treated patients had their forced air capacity (FVC) disease progression slowed down or reversed at week 12 when comparing with historical placebo. At week 12 FVC of mean value of placebo group is -11.5% (lower capacity is not good) and mean value of treated group is -4.7%.

4. You all have to learn the new biomarkers science because FDA is advocating it and it is coming for sure. Biomarkers are highly sensitive to changes in the underlying disease processes and are useful in predicting drug efficacy. In addition, biomarker measures are usually immune to the “placebo effect.”

5. ALS Biomarker Data: GM604 modulated one target biomarker (SOD1 Plasma and CSF), two efficacy biomarkers (Total TAU Plasma, Complement c3 CSF), two target/efficacy biomarkers (TDP43 Plasma and Cystatin C CSF), and one prognostic biomarker (pNFH CSF). These are highly significant ALS related biomarkers. The following multiple biomarkers have statistical significance or strong trend between the treated and active (not historical since there is none) placebo groups:
1.) Total TAU plasma percentage change reduction from baseline to week 7 when compared between GM604 treated and active placebo groups, p value =0.0369. Total Tau is mainly expressed in neurons of the CNS and is crucial in axonal maintenance and transport; it is a major component of abnormal intraneuronal aggregates in many CNS disorders, including Alzheimer.
2.) Reduction of TDP 43 plasma slope from baseline to week 12 when compared between GM604 treated and active placebo groups, p value =0.0078. TDP 43 is a major diseased protein of ALS and other CNS disorders such as Alzheimer.
3.) SOD1 plasma percentage change at week 2 also showed a significant reduction trend when compared between GM604 treated and active placebo groups, p=0.0550. A single mutant copy of this gene is sufficient to cause ALS in 90% of sporadic ALS patients.
4.) And the slope for GM604 treated patients for SOD1 CSF was reduced by -1.875 through week 6 whiles the active placebo group increased by 155.226 (increase indicates disease progression).

6. Going for the extra mile Genervon treated a California ALS patient who was first diagnosed with ALS in Q1 2005 and by Q3 2008 was quadriplegic and on a ventilator. After a six-dose treatment of GM604 under an approved single patient compassionate-use IND, the patient’s swallowing volume increased in two weeks to 20cc from a baseline of 10cc. Five weeks after treatment, the patient consumed 240cc of water in 20-25cc bursts without leakage.

7. Usually small sample size in clinical trials is not good enough to see even a small trend in efficacy for most drug candidates. The fact that GM6 achieved statistical significance in both biomarkers and clinical data in two different indications speak highly of the drug effect of the innovative multiple target peptide drug. Since ALS is very heterogeneous, some patients may need a booster dose after the six-dose treatment once every month or three months as determined by the attending neurologist until the disease is reversed or “cured”.

[SA Editor Douglas W. House]

Great comments all. This is a superb example of how our subscribers can thoroughly vet clinical trial data. Yes, fierroargento, the small number of trial subjects and short time frame are noteworthy, but as another commenter stated, it's difficult to recruit a large number of ALS patients. Informed observers such as those commenting here know how to apply the proper context to such data. Using CUR as an example, Genervon has a long way to go in its development efforts.

The items in my post are culled directly off the company's PR. Due to the real-time nature of our reporting we don't have the time (nor the expertise) to corroborate/confirm or evaluate the statistics. Our platform relies on informed subscribers to offer their interpretation/opinions on the information.

It's next to impossible to attribute a medical stock's movement to a PR like Genervon's. They're volatile by nature, as we know all too well. CUR, for example, has rebounded 31% from yesterday's low of $2.12. The stock has been in a downtrend since it peak of $4.81 on June 4. There were four separate attempts to surmount the $4.80 price level, but none prevailed. Correction began. From a technical perspective, a base hasn't formed so there is no way to know what the support level is yet. In any event, a PR like this one won't be the driver of its price movement.

[japester]

I'm afraid you are wrong in "a PR like this one won't be the driver of its price movement" since the huge downturn, not a downtrend, began shortly after this PR began making the rounds. You are correct that it is a volatile stock, and so it is highly agitated by PR's, rumor and inuendo.

From a recent article by the Washington Post re manipulation of NWBO:

"Biotech stocks are particularly vulnerable to manipulation by the shorts. They tend to be small, with low share prices and relatively few shares actively traded. And because of the high risk involved — relatively few biotech companies ever succeed — share prices tend to be volatile, easily moved by rumors and news of regulatory action."

[fierroargento]

Doug,

I work in advanced statistics.

The data presented here is not at all strong.
There are several weak points:
1. Short time frame only 12 weeks
2. Few patients
3. FVC reduction of 4.7% on average (it is quite a big decline despite they say it is better than placebo as the disease has quite fat tails in this time frame of just 12 weeks)
4. No significant improvement identified where there is a clear reversal of the disease

The only thing this grants is to continue working over a larger pool of patients.

Not only it is inconclusive but it is somehow irrelevant from a statistical perspective. AS per SOS request I would think it will be good if you do a retraction of the release.

I am long Neuralstem because I did see in their trials evidence of data that is statistically significant due to duration and reversal/partial reversal of the disease (1200 days observation now with a couple of people reporting significant sustained improvements plus the lead investigator giving remarks of her being jazzed with what she had submitted to the FDA in August).

[Smith On Stocks]

I am not adverse to using historical control, but there are uncertainties. The statistical significance suggested in this case is based on the difference in the downward slope of the ALSFRS-r lines for the drug group and the historical control group. There is great subjectivity involved in coming up with the slope of historical controls; this can be highly variable depending on the patient characteristics of drug group versus historical control and the time interval over which the slope is determined. Also, in the BENEFIT-ALS trial there is strong evidence of a placebo effect. I know that some KOLs are saying that the time frame for judging the true slope of the ALSFRS-r data should be done over a one half year to one year time frame. If this is true, the drug group in this trial which was followed for three months could gave benefited from a placebo effect. I readily admit that this is all conjecture on my part. However, in a clinical trial that is randomized, the company should first report results for the drug versus control and then if they want to show the results versus historical controls fine. Based on the data they have presented I think that we can only say at this point the drug was safe in this trial. I am curious to see all of the results and I am particularly interested to see if there is stability or improvement in the control group which would signal that there is a placebo effect. My guess is that there is.

[jenny2014]

Doug, it's a convenient excuse to reject an article with "it offers nothing new". In fact, Terry's article offered quite some up-to-date information about NWBO. For example, the latest 55 info arm, which is critical to have a glimpse of potential result of trial P3. So far, none of any SA NWBO articles mentioned that 'info arm'. Isn't it something new?!

On the way, based on Terry, the rejection reason is because of overly bullish. That's also laughing. Terry did list NWBO risks in his article. Every stock has risk. Every Warren Buffett's BRK-A. What's going to happen if Warren Buffett is gone due to aging? Will BRK-A behave like those bond funds when founder 'Bond King' leaves?! What SA does to the articles from Terry and/or Smith, sounds like pushing good girls into prostitution.

In the world of biotech, the failure rate is 9 out of 10. AF utilized this statistics to his full advantage. He is smart enough to build his name in that part. With that industry statistics, the genius part is to recognize the only 1 out of 10, not predicting the 9 of out of 10 like AF does. By the way, don't you know AF's blog post delete comments?! If you really want to see the comments, you don't need to go far. You only need to see the lengthy rebuttal comments in those NWBO shorty articles.

SA did a good job in providing a debating platform for all kinds of traders, investors, etc. Whenever I read an SA article, I pay much attention on the comments than the article itself. Seeing the trend in the coverage of NWBO, (for example, even permitting boiler room operator Pearson to accuse NWBO of pumping), I hope SA will not turn its back against itself and become AF 2nd. If SA does, I can understand it too: running a business always needs money.

Doug, here I will stop my argument with you. I am merely a tiny tiny tiny retail investor, hoping to make some profit, in the meantime, also want my money to have a meaningful place in the combat against cancer. I have no money, labor, time, and any resource to fight AF. AF controls propaganda machines, has time and connection, plus enormous back-supporting money. If you want me to fight against him, it's like cracking eggs on a rock. I will and have to immediately surrender and yield. No choice!

Hope to see your retrace piece on CUR too.

[adamfeuerstein]

If you had something even semi-intelligent to offer about any stocks, perhaps Doug and the rest of the Seeking Alpha team would take you seriously. Instead, you spout accusations without a shred of evidence.

[jenny2014]

My greatest pleasure to have you such important figure coming here. Who notified you? Anyway, welcome, my whole-hearted welcome! But sorry, I have no time for you. Investment is not my job, only pocket money for lunch.

[SA Editor Douglas W. House]

jgons: Since I don't know the details of any rejection of NWBO articles, I can't comment specifically on it. In general, if an author has an article rejected, it is probably because it offers nothing new. NWBO has been written about extensively so if you or someone else are considering writing a new one, then focus on a new perspective.

I assure you that there is no conspiracy, bias or strong opinion one way or another in our organization about any company. We welcome well-thought-out analyses, long or short, on all firms.

If you feel that strongly about Mr. Feuerstein's NWBO musings, then you have the option of creating your own blog posts right here on the SA site. Spirited debate is a hallmark of a free market. The best way to uncover the truth is by doing the research. I don't follow AF routinely, but when I read the comments to his blog posts, I rarely see any data supporting the contrary opinions. Most are emotional reactions. I've been investing/trading for some years now. If I encounter new information that is contrary to my position, I don't get angry or upset. I research it. If I'm right, I ignore it. If I'm wrong, I take action. Being stubborn or emotionally attached to an investment is dangerous to one's nest egg.

[jenny2014]

Thanks a lot, Doug. Hope your comment is sincere.

On the other hand, why does SA consistently reject long articles on NWBO these days? Instead, permit the highly misleading articles from Bio Hawk. I don't like to see my beloved SA turning into another notorious AF. However, I have all the reasons to suspect after witnessing so many manipulations and lies from AF. It's crazy for some political science major to publish about 19 articles against NWBO in a year. If no psychological problem, the only logical explanation has to be shot for the money for some organized group.

[SA Editor Douglas W. House]

Mr. Smith won't be ignored and there's no conspiracy one way or the other. I'll check further on this later today.

[jenny2014]

Smith, I bet you will be ignored.

Not only your article, but Terry's below article is also rejected by SA. It looks like some kind of organized move behind. "Repeat a lie a thousand times and it becomes the truth." Why utilizing propaganda machine to lie? Most likely there are financial incentives behind such move.

"Northwest Biotherapeutics: A Variety Of Possibilities With The Future Of Immunotherapy Treatments"

http://bit.ly/1tbQF8U

[Smith On Stocks]

Doug. In this trial the four placebo patients did as well or better on the ALSFRS-r scale than those on the drug. The company faced with this disappointing result that showed GM640 was no better than placebo searched the literature and compared the drug results in these 8 drug treated patients to an undisclosed group of historical controls. This must be viwed with great caution. Also, the numerical improvement in FVC was not statistically significant and could well have occurred by chance. In your bullet points, you suggest that this drug produced statistically significant improvements in ALSFRS-r and is disease modifying. The correct interpretation is that there is no difference between GM640 and placebo on the ALSFRS-r scale, there is no evidence of a clinical benefit and there is certainly no evidence of a disease modifying effect. The only thing that can be clearly stated about the trial is that in this small 12 patient trial there were no safety concerns and no clear clinical evidence of a therapeutic effect.
Your article seems to have been the cause of a decrease in the price of Neuralstem from $3.05 on the close on October 17th to and intraday low of $2.12 on the next trading day October 20th and the stock is now trading at $2.69. Would you consider issuing a retraction or clarification of your article in line with the analysis I have made.

[biopeon]

Smith, could you please clarify your convo with Genervon and the info they presented to you? Thank you.

[Smith On Stocks]

I spoke with them in detail about their technology. In the conversation we had, they explained it as a master regulator of transcription factors that control gene expression throughout this central nervous system, According to the Company. this master regulator peptide can correct malfunctioning of genes in the CNS and therefore have a direct effect on any disease that occurs in the CNS, not just ALS. This is the first time that I have heard of this biology and the attempt to harness it. In doing further research based on this conversation, I have found some academics who are working in the area and hope to have a conversation with them. As you may know, I have a keen interest in ALS through extensive work I have done on Neuralstem and Cytokinetics and I am fascinated by new ideas. At this point, I have no opinion on whether this has the potential to be developed into a commercial product.

In addition, I was curious about the decision of the company to compare the results of 8 ALS patients treated with their drug to an historical control rather than the four patients who were randomized in the trial. To say the least, I found this strange. They gave me no information on these four patients other to say that there was no statistically significant difference on the ALSFRS-r scale between drug and control. They would not confirm whether results were the same, slightly better or slightly worse for the drug,just that there was no statistical significance. This was a small part of the conversation although important. Everything else in my website article is based on the press release. The link to my article is http://bit.ly/1tclESj
I am not adverse to using historical controls as they can be important. However, it is difficult to find data that might suggest how placebo patients in other ALS trials might perform over a three week period on the ALSFRS-r scale. The ALSFRS-r scale is highly subjective and subject to placebo effect in the short term. Some key opinion leaders have suggested that the ALSFRS-r scale might be best used to measure therapeutic effect at one year or greater intervals because of this. I have suspected that this might have played a role in the failure of the Cytokinetics" BENEFIT-ALS trial.
The Company has also pointed to results in some biomarkers that were tracked in the trial and which the Company pointed to in their press release as being predictors of outcomes in ALS. There are no validated markers for ALS that I am aware of. Given this and my lack of understanding of the biomarkers they were using, I spent no time on biomarkers. However, the FDA is extremely keen in finding markers for ALS and if this company has done so, it would be important. Also the principal investigator in this trial, the distinguished Merit Cudkowitz of Mass General, is very keen on coming up with biomarkersfor research. Again, this is something that I am interested in looking into.

[biopeon]

Thank you for the update!

[SA Editor Douglas W. House]

Mr. Smith: Excellent point.

[Smith On Stocks]

In the press release, it said that in the ALS trial that there were 8 patients randomized to drug and 4 to placebo. However, the press release stated that the drug treated patients were compared to historical controls rather than the four placebo patients randomized to the trial. This is very strange. Also, we have only aggregate data on the 8 patients and no baseline or endpoint data on the 8 patients in regard to ALSFRS-r or SVC. This makes it very difficult to interpret the data.

[CamH]

And while I appreciate the extra 5%, $CYNAF rose almost 10% on this as well?

[Sighhhh]

Neuralstem is down 20% on the day on THIS news? Can investors grow tf up...

[MichaelJ8]

u think its investors who are doing this? its traders... plain and simple.

[Biotech Beast]

One tailed statistical testing, good lord. How low must we set the bar. If genervon has submitted for guidance, the guidance will be "run a bigger trial." What a waste of time.

[MichaelJ8]

not for ALS. There is such a small population pool to deal from . You really have to hold ALS trials to a different standard.

[Biotech Beast]

Really... We are talking about 8 patients here. If the guidance doesn't include running a bigger trial, it will be because it goes without saying. Biogen idec managed to recruit 943 patients for a phase 3 trial of dexpramipexole, although this was one of the bigger trials for ALS, it shows that several hundred patient trials are possible. Trophos ran a 512 patient trial, cytokinetics ran a 711 patient phase IIb trial.
8 patients...