Synaptogenix SNPX is a tiny biotech company for moderate to severe Alzheimer's disease. Because of my investment in SNPX recently, I consulted Prof. Google and learned a lot of molecular biology, kinases, patents, private placement, and a lot of professional vocabulary that I never understood. I posted my homework here, to broadcast SNPX, to introduce this tiny emerging biotech, let people know what Dr. Alkon and his team have done and achieved in a long journey fighting with Alzheimer's Disease. Your money, your decision. First , simple popular science on AD, Alzheimer’s Disease I found this 19-page report, 10/20/2014 Zacks small-cap research on NTRP. The first page is about NTRP, only two year old at the time. As SNPX is now, NTRP was a microstock buried in the OTC too. This report is great, a very informative investment thesis. It introduces the history of Alzheimer's disease, as well as the direction and progress of AD research of pharmaceutical companies around 2014. It is the best AD brochure I've ever read. I highly recommend it. Now let me introduce the reborn SNPX: The best science team: President & CSO Dr. Alkon - After graduating from medical school, Dr. Alkon entered NIH and worked on neuroscience for 30 years, and then became the medical director at NIH NINDS & Chief of the Laboratory of Adaptive Systems. "In 1999, the Rockefeller family funded the first research institute focusing on Alzheimer’s disease. Dr. Alkon became the founding Scientific Director of the Blanchette Rockefeller Neurosciences Institute. He and his team conducted multidisciplinary research on the molecular and biophysical mechanisms of memory and memory dysfunction in psychiatric and neurological disorders, particularly Alzheimer’s disease. As an internationally recognized pioneer in research on brain-based neural networks and the molecular basis of memory, he has authored hundreds of scientific articles as well as several books." Dr. Alkon publications:https://www.semanticscholar.org/author/D.-Alkon/3239220Principal Investigator Dr. Miao-Kun Sun publications: https://www.semanticscholar.org/author/Miao-Kun-Sun/79846544 Almost all papers and patents are joined by both Dr. Alkon and Dr. Sun. They were long-term partners with each other. Dr. Sun also complied the annual Research Progress in Alzheimer's Disease and Dementia for many years, published tons of books: https://www.bookdepository.com/author/Miao-Kun-Sun A few pre-studies before the establishment of NTRP/SNPX: 11/21/2005 Dual effects of bryostatin-1 on spatial memory and depression6/2006 Protein kinase C pharmacology: perspectives on therapeutic potentials as antidementic and cognitive agents2/14/2008 Synergistic effects of chronic bryostatin-1 and alpha-tocopherol on spatial learning and memory in rats12/2009 Protein kinase C activators as synaptogenic and memory therapeutics3/1/2010 Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics2012 Activation of protein kinase C isozymes for the treatment of dementias The AD research in SNPX is quite different from most pharmaceutical companies. It challenges an almost impossible common sense -- to regenerate neurons. They experimented on Bryostatins-1, a natural extraction from a small marine invertebrate, to regenerate nerve synapses:
The team consists of veteran scientists. Dr. Alkon worked on neuroscience for 50 years, including 30+ years of research on AD. By the same token, I am a little concerned that they have been too deep into the wild and might be stubborn. It could be sensed from their past trials. Nowadays, most AD trials of phase-1 and phase-2 are open label; but this group of old-school scholars always do double-blind. In NTRP's lifetime, it kept losing to the placebo again and again, and every time they still insisted the double blind standard. They earned my admiration. SNPX/NTRP is one of the most transparent companies who posted & shared the data to all researchers and the investors so thoroughly. You can click the links below and check the result tab: Phase 1/2-201 6/2014 - 12/2014https://clinicaltrials.gov/ct2/show/NCT02221947?term=bryostatin&draw=2&rank=1 9 participants Phase 2-202 : 11/2015 - 2/2017https://clinicaltrials.gov/ct2/show/study/NCT02431468 143 participants, 20ug, 40ug and placebo Phase 2-203: 6/20/2018 - 7/25/2019https://clinicaltrials.gov/ct2/show/NCT03560245 108 participants 20µg bryostatin (53) or placebo(55) Phase 2-204: 8/30/2020 - 11/2/2022https://clinicaltrials.gov/ct2/show/NCT04538066 100 participants, on-going, 10 months I am going to summarize the gains and losses of each trial briefly.
Phase1/2-201 6/2014 - 12/2014 P201, the first-in-human study of bryostatin-1 for the treatment of AD. I don't think it's necessary to do double blind in this case, just for safety and side effects of medicine injection. There were 6 patients on the medication, plus some more expanded compassionate usage. The experiment was very encouraging, as a research paper published: Bryostatin Effects on Cognitive Function and PKC? in Alzheimer's Disease Phase IIaand Expanded Access TrialsJ Alzheimers Dis. 2017; 58(2): 521–535. Published online 2017 May 11. Prepublished online 2017 May 2. doi:10.3233/JAD-170161 The biggest achievement of this trial is that the impossible became possible! I watched an old interview of Dr. Alkon on YouTube, he didn't expect a real cure on AD in his generation (Dr. Alkon was born in 1942). The pathology of AD is still unclear, this challenge is the crown of human disease. Around 10 years ago when Dr. Alkon was almost 70 years old, he thought he might give it a try.“The possibly this is an approach that is regenerative is real to me. The question is, can we pursue this to bring to a point to make a standard of care for patients? This is what we're aiming for.”says Dr. Alkon in a local TV report, after an amazing progress made on Patient #3 in the table below： "Within 3 h of the first infusion, Subject #3’s MMSE rose from a baseline of 3 to 12. The MMSE score remained within the 10–12 range for 1-2 weeks, and remained between 5 and 12 thereafter (Fig. 4, green). These improvements of the MMSE roughly paralleled the changes of the ADCS-ADL. Improvements in cognitive function early in the course of treatment were also noted by the health care workers and caregivers. The patient, who had previously been largely immobile and absorbed in constant hallucinations that had occurred for many months prior to the bryostatin trial, became free of hallucinations, became mobile, able to feed himself, care for bodily functions, speak and recognize words, interactconversationally with others, and engage successfully in complex physical activities such as swimming and billiards. " It's truly incredible! The only doubt is that the patient was not an average Joe but Pizza Hut's co-founder Frank Carney. When Frank Carney was young and healthy, he had achieved a lot beyond those ordinary people could possibly do. So the effect of the medicine might be amplified by his own spiritual strength.
P2-202 11/2015 - 2/2017 143 participants, 20ug, 40ug and placebo First，the 40ug dosage was worse than 20ug, I guess the protease in the brain needed to be dynamically balanced. Too high or too low won't work, just like blood sugar. I suspect this 20ug may not be the optimal dosage either. This one-size-fits-all style might be not a good idea for a population with heights spanning from 5 to 6 feet and weights from 80 to 300 pounds. I guess the final judge on SNPX might be to find a proper dosage for each individual person. Unfortunately, I couldn't find any papers focusing on this dosage research. But I guess they must have put it in consideration already. This company's biggest weakness is that it doesn't communicate effectively with the market and with investors. For example, the company's website is quite messy, and it cannot present SNPX's achievements and its products well. Being a software engineer, I almost want to roll up my sleeves and do it myself, a weekend of effort could construct a much better interface for them. In this trial, it was discovered that ABBV's memantine likely interfered with bryostatin (interfered by cholinease inhibitors). A set of subdata without memantine was quite good and clinically significant; I think it's very impressive: However, I don't understand why this encouraging progress had been heavily criticized on SeekingAlpha. A few articles posted by freelance analysts with supportive words on NTRP ended up being deleted on SeekingAlpha. The stock price was knee-cutting. They published another paper: A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease J Alzheimers Dis 2019;67(2):555-570. doi: 10.3233/JAD-180759.
P2-203 : 6/20/2018 - 7/25/2019 108 participants 20µg bryostatin (53) or placebo(55) P2-201 and P2-202, although not being appreciated by the market at all, had stock prices which plummeted time and time again, Dr. Alkon's team became more confident after collecting the first hand data on human trials. They had been working with mice for many years, as mice are simple and straightforward, putting on medicine -> testing in maze -> measuring blood sample -> dissecting brain. Now, real human beings started showing similarly encouraging patterns. However, the next coming P2-203 crashed the entire company, like the iceberg that sunk the Titanic. This P2-203 is really unlucky. A significant imbalance (4.8 points) in the baseline Severe Impairment Battery ("SIB") scores occurred. The baseline mean value in the placebo group was 4.8 points higher than the starting point of the medication group. Although it was said "by chance", I believe it was a problem in patient selection. The participants with MMSE-2 scored 4-15, I think this range is too wide, severe-4 and moderate-15 are two different worlds. In the latest on-going P2-204, participants' baseline scores have been narrowed to MMSE-2 10-18. In September 2019, I guess NTRP might have known about this factor, but the management team didn't have any explanation in PR so the market slaughtered the stock price, again. The company's board of directors started a series of strategic alternatives to survive, NTRP and Metuchen became associates. Originally Metuchen had only one ED drug. They advertised their new drug before it was approved, pushing the FDA to chase out and stop them . With $16M dowry from NTRP, Metuchen rebranded to PTPI. This PTPI began getting motivated and ambitious, and started working with Viagra to make the ED drug non-Rx recently. NTRP married to PTPI, just like planting a flower in cow manure, they might benefit each other mutually, not that bad I suppose. From September 2019 to January 2020, NTRP was completely silent. I couldn't find any news during this period. The 2-203 trial data was not as bad as the stock price: (1). Let me talk about the medicine group first, SIB score increased 4.8 in 13 weeks. "in the patients with MMSE-2 baseline scores 10-15，the baseline value and the week 13 value were used, resulting in pairs of observations for each patient. The changes from baseline for each patient were calculated and a paired t-test was used to compare the mean change from baseline to week 13 for each patient. A total of 65 patientshad both baseline and week 13 values, from which there were 32 patients in the Bryostatin-1 treatment group and 33 patients in the placebo group. There was a statistically significant improvement over baseline (4.8 points) in the mean SIB at week 13 for subjects in the Bryostatin-1 treatment group (32 subjects), paired t-test p < 0.0076, 2-tailed." （2）Unfortuantely, the placebo group also did quite well, sugar water got 4+ points too, even better than SAVA treating mild AD. In the placebo group (33 subjects), there was also a significant increase from baseline in the mean SIB at week 13, for paired t-test p < 0.0144, consistent with the placebo effect seen in the overall 203 study. "This smaller, placebo effect could possibly be due to the imbalance observed even for the Moderate Stratum in the study," stated Dr. Alkon. Please allow me to vent on sugar water ! ! BCLI, I just lost a lot of money recently. BCLI Phase II data was very nice, unprecedented 35% efficacy, the phase III results were repeating nice, still 35%, but sugar water got 29% surprisedly, better than any medicine ever, including those having being approved, then this BCLI Phase III failed on its P value. I really wanted to initiate a new business with sugar water, specializing in the most difficult and complicated diseases !
P2-204 : 8/30/2020 - 11/2/2022 100 participants, on-going, 10 months Based on the hard lessons learned from previous trials, SNPX did 2 major changes on the new trial design: 1. Participants narrowed to MMSE-2 score 10-18, dividing into 2 subgroup 10-14 and 15-18; 2. Lengthen the trial time, from 12 weeks to 10 months, to reduce the placebo group's fluctuation . SNPX invited Dr. Lee Jen Wei, a tenured Professor of Biostatistics at Harvard University for the trial design, to avoid the silly mistake occurred in Phase 2-203; It also invited a neuroscientist from John Hopkinton as a medical advisory for the final data lock and analysis , to avoid another news immensely spreading in the street that sugar water is effective in treating severe AD. Below time line is my estimation on this latest phase2-204: 1. fact -- first dose 10/6/2020; 2. fact -- about half patients enrolled and started the treatment (PR updated on 4/1/2021); 3. guess -- in June all 100 patients enrolled and started the treatment; 4. guess -- at the end of year, 2 cycles of 11-week doses done ( 30-day break time in between the cycles); 5. guess -- April 2022, check the status 4 months later after the treatment; 6. guess -- another half year, data lock and analysis. I expect the stock price to rise soon, stabilize at May, catch more news/attention at the end of year, expose the interim data at the beginning of 2022, then wait for the final call at around Q2/Q3 2022. I feel confident on its rising this year, but I won't bet on the final result, it'll be too dangerous. Only a 2.7% success rate in the past 2 decades for all AD drugs, there is no ANY one passed phase 3 yet in past 17 years. If SNPX luckily did well with P < 0.001 ( a benchmark reference, Pfizer's AD drug Aricept got a placebo-adjusted change of 5.9 SIB improvement in six months), SNPX will explode like a bomb, so I definitely will save some lottery tickets. Look at what's happening to SAVA, stock market bought their post-hoc data excitingly, totally out of my expecting. If it fails, the stock price will u-turn to its beginning point. The life of an emerging biotech is very tough and cruel.
Guess the chance of Phase2-204 I am just a software engineer so I tend to believe the professionals, here is the company's scientific advisory board members: Martin R. Farlow Chairperson MDhttps://medicine.iu.edu/faculty/730/farlow-martin Paul Coleman, PhDhttps://touchneurology.com/editorial-board/martin-r-farlow-md/ Marwan Sabbagh. MD https://lasvegasmedicaldistrict.com/marwan-n-sabbagh-md/ Daniel F. Hanley Jr. MD https://www.hopkinsmedicine.org/profiles/details/daniel-hanley Lee Jen Wei, PhD https://www.hsph.harvard.edu/l-wei/ Biomarker AD’s diagnosis still heavily relies on a set of questionnaires, in my humble opinion, this is too subjective and difficult to be consistent. For example, in the same questionnaire, if a person had a good night's sleep tonight, their score might be much better than yesterday's when the same person was exhausted and in a bad mood. SNPX has its own biomarker, I found this important info in the previously mentioned Investment thesis available in 2014: "In addition to bryostatin-1, the company is developing an AD diagnostic test based on biomarkers that are regulated by PKC. Using fibroblasts from a simple skin biopsy, a series of in vitro tests are used to amplify the expression of these biomarkers. The skin fibroblast displays the same basic pathophysiology indicative of AD as a neuron in the brain. Preliminary studies in 140 patients with Alzheimer’s Dementia, dementia of other etiologies, and age-matched controls, including 51 patients with autopsy-confirmed diagnoses, were reported to show sensitivity ≥ 97% and specificity ≥ 96%, suggesting a low risk of incorrect diagnosis. " This biomarker had been blessed by the AD Diagnostics Scientific Advisory expert Dr. Paula Trzepacz , Dr. Trzepacz was the Chief Medical Officer at Neurotrope in 2016. Look at her resume, : "On July 15, 2019, she was one of ten researchers to be presented with the first-everCure Coin Award （ by the way, Dr. Alkon honored with this award too ）during the 2019 Alzheimer's Association International Conference. The award honored her work at Eli Lilly and Company in the development of Amyvid, the amyloid PET imaging agent, which is the first of its kind to be approved by the FDA for Alzheimer's detection. "
Big losers : PR and CFO I have said a lot regarding NTRP/SNPX's research and trials, since their science is the reason I believe in and invest in SNPX. NTRP made tons of mistakes in management and communication, especially PR and CFO, repeating these mistakes constantly. Let's talk about two big mistakes NTRP made last year: (1). 1/22/2020, in the early morning, PR announced that the latest data confirmed the positive result. The market was jubilant for NTRP, the stock price jumped from the floor with momentum; but before lunch time arrived, PR came out again and announced it had a new round of offering with 11M shares at $1.65 per share - well, what do you expect - the stock price fell from $3.8 to $1.6 immediately. If we could rewind the scene, let’s announce the news in a different sequence, saying, "we just got in a new $18M," then, take a break, educate the market NTRP's poetry and have the outlook getting clearer and closer, and so on. Have you heard of an ancient Chinese fable called Three acorns or Four, the art of the communication? (2).12/8/2020 NTRP announced a 1:5 reverse split and change their name to SNPX. On 12/10/2020, these two actions operated on the same day. Suprisingly, the total shares of SNPX reduced to 20%, but the stock price was the same! If only these two actions were carried out in two days, RS first, the outstanding shares were made 5 times smaller, the stock price would automatically rise 5 times, SNPX would not have lost 80% of its market value inexplicably. Now the CFO has asked for a reverse split again, in order to make the stock price above $4 artificially, so that SNPX could be uplisted to Nasdaq from OTC. Not sure when the management team planed this RS. Calling RS again reminded the investors of their fresh nightmare just happened a couple of months ago, and RS easily attracted a pack of shorters, shorting this tiny bleeding emerging biotech. After the RS announcement the stock price slipped from $3 to $2. What a nice plan!
OK, time for excitement, let's copy rich people's homework! According to the table below, the assets of H. Weaver have increased 200 times in the past eight years, from $5M in 2012 to $1B in 2020. https://fintel.io/i/haywood-george-weaver? 1. bought more than 5M shares AVII on 2/13/2012 , at price ~$1 (split-adjusted); 2. on 7/11/2012, AVII changed to SRPT and had 1:6 reverse split, Enacts Reverse Stock Split to Strengthen Financial Base , After RS, SRPT jumped 10x around 10 months later, almost 200x at the end of 2020. In above table, Mr. Weaver bought 1M shares of NTRP in February 2020 . I guess it's the $1.65 new offering I mentioned before, so it suffered through a 1:5 reverse split. He bought 1.24M shares at $1.59 last month, now he has collected 1.44M shares with a total cost of $3.7M, at an average of $2.57 per share. Mr. Weaver holds 9.7% ownership. Let’s take a look at SNPX’s largest shareholder, Intracoastal Capital LLC, which holds 9.99%, consists of (i) 1,000,000 shares of Common Stock and (ii) warrants to purchase 446,000 shares of Common Stock. The figure does not include additional warrants to purchase shares of common stock that are held by Intracoastal, as they are subject to a 9.99% ownership blocker. On 8/15/2018, this investment firm presciently bet 900K shares of SAVA, $1.97 each, overall 5.01% Ownership: Cassava Sciences Inc (SAVA) HEALTH CARE 907,446 6,188,781.72 5 13G 2018-12-31 Back then, SAVA was not called SAVA, it instead was called PTIE Pain Therapeutics, and just switched to AD from a painkiller company: https://whalewisdom.com/filer/stock_history/intracoastal-capital-llc/ptie Life is never easy for any emerging biotech. Four months later, SAVA fell to $0.85; and a year later, SAVA plummeted from $10 to $1.6. Two years later, SAVA finally burst out with huge success on its stock price. I felt extremely lucky that I could sell most of my SAVA at $130 ( started with $30, $60 gradually) , though I am still doubting its simufilam drug. Now this Intracoastal Capital has become the largest shareholder of SNPX, anyone who likes SAVA could also copy Intracoastal Capital's diversity on SNPX.
Source of Bryostatin-1 Structures of Bryostatin-1 and an analog effective in the Activation of PKCε :
Bryostatin-1 is a natural product derived from the marine invertebrate Bugula neritina. It has been provided from the National Cancer Institution ( free of charge) to NTRP/SNPX since the Blanchette Rockefeller Neurosciences Institution. This drug first received attention for cancer drugs. It has been tested in various laboratories for more than 1,500 people already without any safety issue. Because of the limited supply, it has always been used as an injection. Last month ( February 2021), SNPX signed an exclusive licensing agreement with Stanford University for synthetic Bryostatin for all neurologic indications, and Bryostatin-1 will be taken orally in the future. This synthetic drug was
invented by a talented professor in Stanford
in 2017. I guess oral drugs must have been practiced in recent years. There should be no difference in efficacy between synthetic drugs and marine natural substances, before signing the supply contract with Stanford. Now, everything is ready.
Finally, to be fair, I also post some counter-party data These are the opposite opinions on PKCδ research. To be honest, I don't quite understand the details, but from my own understanding, the biochemical chain is more of a dynamic balance. Current AD studies are still in a dark tunnel, quite similar to a group of blind people touching an elephant, some touch the tail, thin and soft, and others touch the thigh, thick and strong: 7/15/1997 Demyelination induced by protein kinase C-activating tumor promoters in aggregating brain cell cultures The present results suggest that PKC activation resulted in severe demyelination and partial loss of the oligodendrocyte-differentiated phenotype. 6/4/2018 Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion–transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics. 11/27/2018 PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5 Our data suggest that PKCε acts as an early developmental inhibitor of dendritic spine formation, in contrast to its emerging pro-synaptic roles in mature brain function. Moreover, we identify a substrate of PKCε, Ephexin5, whose early-elevated expression in developing neurons may in part explain the mechanism by which PKCε plays seemingly opposing roles that depend on neuronal maturity.
Because of my investment in SNPX recently, I consulted Prof. Google and learned a lot of molecular biology, kinases, patents, private placement, and a lot of professional vocabulary that I never understood. I posted my homework here, to broadcast SNPX, to introduce this tiny emerging biotech, let people know what Dr. Alkon and his team have done and achieved in a long journey fighting with Alzheimer's Disease.
Your money, your decision.
First , simple popular science on AD, Alzheimer’s Disease I found this 19-page report, 10/20/2014 Zacks small-cap research on NTRP. The first page is about NTRP, only two year old at the time. As SNPX is now, NTRP was a microstock buried in the OTC too. This report is great, a very informative investment thesis. It introduces the history of Alzheimer's disease, as well as the direction and progress of AD research of pharmaceutical companies around 2014. It is the best AD brochure I've ever read. I highly recommend it.
Now let me introduce the reborn SNPX:
The best science team: President & CSO Dr. Alkon - After graduating from medical school, Dr. Alkon entered NIH and worked on neuroscience for 30 years, and then became the medical director at NIH NINDS & Chief of the Laboratory of Adaptive Systems. "In 1999, the Rockefeller family funded the first research institute focusing on Alzheimer’s disease. Dr. Alkon became the founding Scientific Director of the Blanchette Rockefeller Neurosciences Institute. He and his team conducted multidisciplinary research on the molecular and biophysical mechanisms of memory and memory dysfunction in psychiatric and neurological disorders, particularly Alzheimer’s disease. As an internationally recognized pioneer in research on brain-based neural networks and the molecular basis of memory, he has authored hundreds of scientific articles as well as several books." Dr. Alkon publications: https://www.semanticscholar.org/author/D.-Alkon/3239220 Principal Investigator Dr. Miao-Kun Sun publications: https://www.semanticscholar.org/author/Miao-Kun-Sun/79846544 Almost all papers and patents are joined by both Dr. Alkon and Dr. Sun. They were long-term partners with each other. Dr. Sun also complied the annual Research Progress in Alzheimer's Disease and Dementia for many years, published tons of books: https://www.bookdepository.com/author/Miao-Kun-Sun A few pre-studies before the establishment of NTRP/SNPX: 11/21/2005 Dual effects of bryostatin-1 on spatial memory and depression 6/2006 Protein kinase C pharmacology: perspectives on therapeutic potentials as antidementic and cognitive agents 2/14/2008 Synergistic effects of chronic bryostatin-1 and alpha-tocopherol on spatial learning and memory in rats 12/2009 Protein kinase C activators as synaptogenic and memory therapeutics 3/1/2010 Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics 2012 Activation of protein kinase C isozymes for the treatment of dementias
The AD research in SNPX is quite different from most pharmaceutical companies. It challenges an almost impossible common sense -- to regenerate neurons. They experimented on Bryostatins-1, a natural extraction from a small marine invertebrate, to regenerate nerve synapses:
Phase 1/2-201 6/2014 - 12/2014 https://clinicaltrials.gov/ct2/show/NCT02221947?term=bryostatin&draw=2&rank=1 9 participants
Phase 2-202 : 11/2015 - 2/2017 https://clinicaltrials.gov/ct2/show/study/NCT02431468 143 participants, 20ug, 40ug and placebo
Phase 2-203: 6/20/2018 - 7/25/2019 https://clinicaltrials.gov/ct2/show/NCT03560245 108 participants 20µg bryostatin (53) or placebo(55)
Phase 2-204: 8/30/2020 - 11/2/2022 https://clinicaltrials.gov/ct2/show/NCT04538066 100 participants, on-going, 10 months
I am going to summarize the gains and losses of each trial briefly.
P201, the first-in-human study of bryostatin-1 for the treatment of AD. I don't think it's necessary to do double blind in this case, just for safety and side effects of medicine injection. There were 6 patients on the medication, plus some more expanded compassionate usage. The experiment was very encouraging, as a research paper published:
Bryostatin Effects on Cognitive Function and PKC? in Alzheimer's Disease Phase IIa and Expanded Access Trials J Alzheimers Dis. 2017; 58(2): 521–535. Published online 2017 May 11. Prepublished online 2017 May 2. doi: 10.3233/JAD-170161
The biggest achievement of this trial is that the impossible became possible! I watched an old interview of Dr. Alkon on YouTube, he didn't expect a real cure on AD in his generation (Dr. Alkon was born in 1942). The pathology of AD is still unclear, this challenge is the crown of human disease. Around 10 years ago when Dr. Alkon was almost 70 years old, he thought he might give it a try.“The possibly this is an approach that is regenerative is real to me. The question is, can we pursue this to bring to a point to make a standard of care for patients? This is what we're aiming for.”says Dr. Alkon in a local TV report, after an amazing progress made on Patient #3 in the table below：
"Within 3 h of the first infusion, Subject #3’s MMSE rose from a baseline of 3 to 12. The MMSE score remained within the 10–12 range for 1-2 weeks, and remained between 5 and 12 thereafter (Fig. 4, green). These improvements of the MMSE roughly paralleled the changes of the ADCS-ADL. Improvements in cognitive function early in the course of treatment were also noted by the health care workers and caregivers. The patient, who had previously been largely immobile and absorbed in constant hallucinations that had occurred for many months prior to the bryostatin trial, became free of hallucinations, became mobile, able to feed himself, care for bodily functions, speak and recognize words, interactconversationally with others, and engage successfully in complex physical activities such as swimming and billiards. " It's truly incredible! The only doubt is that the patient was not an average Joe but Pizza Hut's co-founder Frank Carney. When Frank Carney was young and healthy, he had achieved a lot beyond those ordinary people could possibly do. So the effect of the medicine might be amplified by his own spiritual strength.
First，the 40ug dosage was worse than 20ug, I guess the protease in the brain needed to be dynamically balanced. Too high or too low won't work, just like blood sugar. I suspect this 20ug may not be the optimal dosage either. This one-size-fits-all style might be not a good idea for a population with heights spanning from 5 to 6 feet and weights from 80 to 300 pounds. I guess the final judge on SNPX might be to find a proper dosage for each individual person. Unfortunately, I couldn't find any papers focusing on this dosage research. But I guess they must have put it in consideration already. This company's biggest weakness is that it doesn't communicate effectively with the market and with investors. For example, the company's website is quite messy, and it cannot present SNPX's achievements and its products well. Being a software engineer, I almost want to roll up my sleeves and do it myself, a weekend of effort could construct a much better interface for them.
In this trial, it was discovered that ABBV's memantine likely interfered with bryostatin (interfered by cholinease inhibitors). A set of subdata without memantine was quite good and clinically significant; I think it's very impressive:
However, I don't understand why this encouraging progress had been heavily criticized on SeekingAlpha. A few articles posted by freelance analysts with supportive words on NTRP ended up being deleted on SeekingAlpha. The stock price was knee-cutting.
They published another paper: A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease J Alzheimers Dis 2019;67(2):555-570. doi: 10.3233/JAD-180759.
P2-201 and P2-202, although not being appreciated by the market at all, had stock prices which plummeted time and time again, Dr. Alkon's team became more confident after collecting the first hand data on human trials. They had been working with mice for many years, as mice are simple and straightforward, putting on medicine -> testing in maze -> measuring blood sample -> dissecting brain. Now, real human beings started showing similarly encouraging patterns. However, the next coming P2-203 crashed the entire company, like the iceberg that sunk the Titanic.
This P2-203 is really unlucky. A significant imbalance (4.8 points) in the baseline Severe Impairment Battery ("SIB") scores occurred. The baseline mean value in the placebo group was 4.8 points higher than the starting point of the medication group. Although it was said "by chance", I believe it was a problem in patient selection. The participants with MMSE-2 scored 4-15, I think this range is too wide, severe-4 and moderate-15 are two different worlds. In the latest on-going P2-204, participants' baseline scores have been narrowed to MMSE-2 10-18.
In September 2019, I guess NTRP might have known about this factor, but the management team didn't have any explanation in PR so the market slaughtered the stock price, again. The company's board of directors started a series of strategic alternatives to survive, NTRP and Metuchen became associates. Originally Metuchen had only one ED drug. They advertised their new drug before it was approved, pushing the FDA to chase out and stop them . With $16M dowry from NTRP, Metuchen rebranded to PTPI. This PTPI began getting motivated and ambitious, and started working with Viagra to make the ED drug non-Rx recently. NTRP married to PTPI, just like planting a flower in cow manure, they might benefit each other mutually, not that bad I suppose.
From September 2019 to January 2020, NTRP was completely silent. I couldn't find any news during this period. The 2-203 trial data was not as bad as the stock price:
(1). Let me talk about the medicine group first, SIB score increased 4.8 in 13 weeks. "in the patients with MMSE-2 baseline scores 10-15，the baseline value and the week 13 value were used, resulting in pairs of observations for each patient. The changes from baseline for each patient were calculated and a paired t-test was used to compare the mean change from baseline to week 13 for each patient. A total of 65 patients had both baseline and week 13 values, from which there were 32 patients in the Bryostatin-1 treatment group and 33 patients in the placebo group. There was a statistically significant improvement over baseline (4.8 points) in the mean SIB at week 13 for subjects in the Bryostatin-1 treatment group (32 subjects), paired t-test p < 0.0076, 2-tailed."
（2）Unfortuantely, the placebo group also did quite well, sugar water got 4+ points too, even better than SAVA treating mild AD. In the placebo group (33 subjects), there was also a significant increase from baseline in the mean SIB at week 13, for paired t-test p < 0.0144, consistent with the placebo effect seen in the overall 203 study. "This smaller, placebo effect could possibly be due to the imbalance observed even for the Moderate Stratum in the study," stated Dr. Alkon.
Please allow me to vent on sugar water ! ! BCLI, I just lost a lot of money recently. BCLI Phase II data was very nice, unprecedented 35% efficacy, the phase III results were repeating nice, still 35%, but sugar water got 29% surprisedly, better than any medicine ever, including those having being approved, then this BCLI Phase III failed on its P value. I really wanted to initiate a new business with sugar water, specializing in the most difficult and complicated diseases !
Based on the hard lessons learned from previous trials, SNPX did 2 major changes on the new trial design:
1. Participants narrowed to MMSE-2 score 10-18, dividing into 2 subgroup 10-14 and 15-18; 2. Lengthen the trial time, from 12 weeks to 10 months, to reduce the placebo group's fluctuation .
SNPX invited Dr. Lee Jen Wei, a tenured Professor of Biostatistics at Harvard University for the trial design, to avoid the silly mistake occurred in Phase 2-203; It also invited a neuroscientist from John Hopkinton as a medical advisory for the final data lock and analysis , to avoid another news immensely spreading in the street that sugar water is effective in treating severe AD. Below time line is my estimation on this latest phase2-204:
1. fact -- first dose 10/6/2020; 2. fact -- about half patients enrolled and started the treatment (PR updated on 4/1/2021); 3. guess -- in June all 100 patients enrolled and started the treatment; 4. guess -- at the end of year, 2 cycles of 11-week doses done ( 30-day break time in between the cycles); 5. guess -- April 2022, check the status 4 months later after the treatment; 6. guess -- another half year, data lock and analysis.
I expect the stock price to rise soon, stabilize at May, catch more news/attention at the end of year, expose the interim data at the beginning of 2022, then wait for the final call at around Q2/Q3 2022. I feel confident on its rising this year, but I won't bet on the final result, it'll be too dangerous. Only a 2.7% success rate in the past 2 decades for all AD drugs, there is no ANY one passed phase 3 yet in past 17 years. If SNPX luckily did well with P < 0.001 ( a benchmark reference, Pfizer's AD drug Aricept got a placebo-adjusted change of 5.9 SIB improvement in six months), SNPX will explode like a bomb, so I definitely will save some lottery tickets. Look at what's happening to SAVA, stock market bought their post-hoc data excitingly, totally out of my expecting.
If it fails, the stock price will u-turn to its beginning point. The life of an emerging biotech is very tough and cruel.
Martin R. Farlow Chairperson MD https://medicine.iu.edu/faculty/730/farlow-martin Paul Coleman, PhD https://touchneurology.com/editorial-board/martin-r-farlow-md/ Marwan Sabbagh. MD https://lasvegasmedicaldistrict.com/marwan-n-sabbagh-md/ Daniel F. Hanley Jr. MD https://www.hopkinsmedicine.org/profiles/details/daniel-hanley Lee Jen Wei, PhD https://www.hsph.harvard.edu/l-wei/
Biomarker AD’s diagnosis still heavily relies on a set of questionnaires, in my humble opinion, this is too subjective and difficult to be consistent. For example, in the same questionnaire, if a person had a good night's sleep tonight, their score might be much better than yesterday's when the same person was exhausted and in a bad mood.
SNPX has its own biomarker, I found this important info in the previously mentioned Investment thesis available in 2014:
"In addition to bryostatin-1, the company is developing an AD diagnostic test based on biomarkers that are regulated by PKC. Using fibroblasts from a simple skin biopsy, a series of in vitro tests are used to amplify the expression of these biomarkers. The skin fibroblast displays the same basic pathophysiology indicative of AD as a neuron in the brain. Preliminary studies in 140 patients with Alzheimer’s Dementia, dementia of other etiologies, and age-matched controls, including 51 patients with autopsy-confirmed diagnoses, were reported to show sensitivity ≥ 97% and specificity ≥ 96%, suggesting a low risk of incorrect diagnosis. "
This biomarker had been blessed by the AD Diagnostics Scientific Advisory expert Dr. Paula Trzepacz , Dr. Trzepacz was the Chief Medical Officer at Neurotrope in 2016. Look at her resume, :
"On July 15, 2019, she was one of ten researchers to be presented with the first-ever Cure Coin Award （ by the way, Dr. Alkon honored with this award too ）during the 2019 Alzheimer's Association International Conference. The award honored her work at Eli Lilly and Company in the development of Amyvid, the amyloid PET imaging agent, which is the first of its kind to be approved by the FDA for Alzheimer's detection. "
(1). 1/22/2020, in the early morning, PR announced that the latest data confirmed the positive result. The market was jubilant for NTRP, the stock price jumped from the floor with momentum; but before lunch time arrived, PR came out again and announced it had a new round of offering with 11M shares at $1.65 per share - well, what do you expect - the stock price fell from $3.8 to $1.6 immediately. If we could rewind the scene, let’s announce the news in a different sequence, saying, "we just got in a new $18M," then, take a break, educate the market NTRP's poetry and have the outlook getting clearer and closer, and so on. Have you heard of an ancient Chinese fable called Three acorns or Four, the art of the communication?
(2).12/8/2020 NTRP announced a 1:5 reverse split and change their name to SNPX. On 12/10/2020, these two actions operated on the same day. Suprisingly, the total shares of SNPX reduced to 20%, but the stock price was the same! If only these two actions were carried out in two days, RS first, the outstanding shares were made 5 times smaller, the stock price would automatically rise 5 times, SNPX would not have lost 80% of its market value inexplicably.
Now the CFO has asked for a reverse split again, in order to make the stock price above $4 artificially, so that SNPX could be uplisted to Nasdaq from OTC. Not sure when the management team planed this RS. Calling RS again reminded the investors of their fresh nightmare just happened a couple of months ago, and RS easily attracted a pack of shorters, shorting this tiny bleeding emerging biotech. After the RS announcement the stock price slipped from $3 to $2. What a nice plan!
According to the table below, the assets of H. Weaver have increased 200 times in the past eight years, from $5M in 2012 to $1B in 2020.
https://fintel.io/i/haywood-george-weaver?
1. bought more than 5M shares AVII on 2/13/2012 , at price ~$1 (split-adjusted); 2. on 7/11/2012, AVII changed to SRPT and had 1:6 reverse split, Enacts Reverse Stock Split to Strengthen Financial Base , After RS, SRPT jumped 10x around 10 months later, almost 200x at the end of 2020.
In above table, Mr. Weaver bought 1M shares of NTRP in February 2020 . I guess it's the $1.65 new offering I mentioned before, so it suffered through a 1:5 reverse split. He bought 1.24M shares at $1.59 last month, now he has collected 1.44M shares with a total cost of $3.7M, at an average of $2.57 per share.
Mr. Weaver holds 9.7% ownership. Let’s take a look at SNPX’s largest shareholder, Intracoastal Capital LLC, which holds 9.99%, consists of (i) 1,000,000 shares of Common Stock and (ii) warrants to purchase 446,000 shares of Common Stock. The figure does not include additional warrants to purchase shares of common stock that are held by Intracoastal, as they are subject to a 9.99% ownership blocker.
On 8/15/2018, this investment firm presciently bet 900K shares of SAVA, $1.97 each, overall 5.01% Ownership: Cassava Sciences Inc (SAVA) HEALTH CARE 907,446 6,188,781.72 5 13G 2018-12-31 Back then, SAVA was not called SAVA, it instead was called PTIE Pain Therapeutics, and just switched to AD from a painkiller company:
https://whalewisdom.com/filer/stock_history/intracoastal-capital-llc/ptie
Life is never easy for any emerging biotech. Four months later, SAVA fell to $0.85; and a year later, SAVA plummeted from $10 to $1.6. Two years later, SAVA finally burst out with huge success on its stock price. I felt extremely lucky that I could sell most of my SAVA at $130 ( started with $30, $60 gradually) , though I am still doubting its simufilam drug. Now this Intracoastal Capital has become the largest shareholder of SNPX, anyone who likes SAVA could also copy Intracoastal Capital's diversity on SNPX.
Structures of Bryostatin-1 and an analog effective in the Activation of PKCε :
Bryostatin-1 is a natural product derived from the marine invertebrate Bugula neritina. It has been provided from the National Cancer Institution ( free of charge) to NTRP/SNPX since the Blanchette Rockefeller Neurosciences Institution. This drug first received attention for cancer drugs. It has been tested in various laboratories for more than 1,500 people already without any safety issue. Because of the limited supply, it has always been used as an injection. Last month ( February 2021), SNPX signed an exclusive licensing agreement with Stanford University for synthetic Bryostatin for all neurologic indications, and Bryostatin-1 will be taken orally in the future.
This synthetic drug was
Now, everything is ready.
These are the opposite opinions on PKCδ research. To be honest, I don't quite understand the details, but from my own understanding, the biochemical chain is more of a dynamic balance. Current AD studies are still in a dark tunnel, quite similar to a group of blind people touching an elephant, some touch the tail, thin and soft, and others touch the thigh, thick and strong:
7/15/1997 Demyelination induced by protein kinase C-activating tumor promoters in aggregating brain cell cultures The present results suggest that PKC activation resulted in severe demyelination and partial loss of the oligodendrocyte-differentiated phenotype.
6/4/2018 Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion–transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.
11/27/2018 PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5 Our data suggest that PKCε acts as an early developmental inhibitor of dendritic spine formation, in contrast to its emerging pro-synaptic roles in mature brain function. Moreover, we identify a substrate of PKCε, Ephexin5, whose early-elevated expression in developing neurons may in part explain the mechanism by which PKCε plays seemingly opposing roles that depend on neuronal maturity.
The FDA has granted Orphan Drug Designation for Bryostatin-1 as a treatment for Fragile X. A recent paper on Nature.com Published: 22 October 2020
Chronic bryostatin-1 rescues autistic and cognitive phenotypes in the fragile X mice