SNPX, 中重度老年痴呆的希望

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楼主 (北美华人网)

只有数据干货的英文版: https://forums.huaren.us/showtopic.html?topicid=2674429&fid=336 
谢谢斑竹大荣大量,终于不再对我斩草除根了,我再来发个叨唠水分的中文版,方便大家阅读
SNPX是个中重度老年痴呆的微小生药, 前生NTRP去年刚往生,这个小生药长期呆在OTC垃圾堆里,默默无闻。
Synaptogenix, 一群老科学家,兢兢业业搞科研,可惜不懂市场不善宣传,长期不被关注。我写这篇博文,是想让人知道Dr. Alkon和他的团队,做过什么样的努力经历过什么样的失败取得过什么样的成绩和希望。
我是个电脑民工,最近因为投资SNPX,请教Prof Google, 快餐了好多分子生物,激酶, 还有patents, private placement, 好多从来不懂的专业词汇, 胡吃海塞,撑噎了。我把我做的功课贴出来,最终 还是your money  your decision。 
先简单科普AD, Alzheimer’s Disease ,老年痴呆症
我挖到的这份 10/20/2014 Zacks small-cap research on NTRP , 一共19页的报告,第一页是当时出生才两年的NTRP。和现在一样,也是埋在垃圾堆OTC的小微股。
这份报告非常好,花了大量篇幅, 名副其实 Investment Thesis 介绍了老年痴呆症的来龙去脉,以及2014年前后各个药厂AD研发的方向和进程,是我看到的最好的AD扫盲小册子, 推荐。
看到这个报告,真的要感慨,你一定要在合适的时间一见钟情啊~~ 千万别早了
下面介绍涅槃后的SNPX。 
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The best science team
President & CSO  Dr. Alkon 医学院毕业后进入NIH, 30年耕耘脑神经记忆,一直升到医学总监 medical director at NIH NINDS (  National Institute of Neurological Disorders and Stroke ) and Chief of the Laboratory of Adaptive Systems, 1999 洛克斐乐家族出资成立了第一个主攻Alzheimer’s disease研究所, 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。
这段介绍是网站抄的,介绍Dr. Alkon的简历。1999年当时还是美国参议员的Rockefeller IV, 在母亲经历了痛苦的老年痴呆过世以后,以其家族名义资助开办第一个专门针对老年痴呆的研究所,邀请Dr. Alkon 组建了这个以洛克菲勒IV母亲名字命名的AD研究院。
Dr. Alkon的科研文章:   https://www.semanticscholar.org/author/D.-Alkon/3239220 
Principal Investigator:
Dr. Miao-Kun Sun 科研文章: https://www.semanticscholar.org/author/Miao-Kun-Sun/79846544 
所有的papers and patents 都是Dr. Alkon 和 Dr. Sun 两人联名, 这位同胞是Dr. Alkon 的坚实搭档,
Dr. Sun 还主持很多年AD年会汇编 (Research Progress in Alzheimer's Disease and Dementia),  著作等身: https://www.bookdepository.com/author/Miao-Kun-Sun   先贴几篇NTRP/SNPX 公司成立前的前期研究吧: 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  1/12/2011   PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice  2012     Activation of protein kinase C isozymes for the treatment of dementias  
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SNPX这个公司AD研发方向和绝大多数药厂都不一样,挑战的是一个几乎不可能的常识 --- 让神经再生。他们找到并试验了一种海洋生物的天然萃取物 Bryostatins-1,“作用于中重度AD, 借助蛋白激酶刺激神经元突触再生,做过大量的基础研究,数据证明他们的蛋白激酶PKCε 与淀粉酶通路及神经元功能的关系” (带引号的这段话是我根据Tiger大佬的对话写的,如果不对,估计是我外行理解不全,不能影响Tiger ),已经成功做到了让神经触突再生:
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公司团队都是老科学家, Dr. Alkon 一生50年都贡献在脑神经科学,和AD死磕30年。俺其实有点担心他们年龄太大,容易死倔。这点从过往的trials里也能看出,现在绝大多数做AD的一期二期trial 都open label, 这帮传统的老学究,唉,怎么讲啊,简直就是老年痴呆附体,每次都是双盲,在NTRP生涯里, 一次又一次的败给安慰剂,可是不改痴心,每次依然是双盲起步。嗯,我心里还是点赞的。 
SNPX/NTRP is one of the most transparent company who posted & shared the data to all researchers and the investors so thoroughly。 大家自己可以点开link, check result tab,太详实了:
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
我简单总结一下每期的得与失 -- 
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Phase1/2-201 6/2014 - 12/2014
P201, the first-in-human study of bryostatin-1 for the treatment of AD, 这个我觉得没必要双盲的,就是试试安全和扎针副作用,教条啊,6个用药病人,后来的延期同情用药,效果很好, 出了篇paper:
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
这个一期试验,最大的收获是 mission impossible became possible, 我看到过一段早期YouTube Dr. Alkon 访谈,他一直对他自己这代人(Dr. Alkon 出生于1942)能否搞出AD药是不抱希望的,AD现在病理不清楚,困难重重,是人类医学的皇冠。直到10年前快70岁了才觉得自己可以一试, “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.  贴个图,
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图里的patient 3 是去年刚过世的 pizza hut 的 co-founder Frank Carney ,这里有个local小电台有关治疗报道的电视新闻 : https://www.kwch.com/content/news/Pizza-Hut-founder-sees-Alzheimers-symptoms-reverse-in-clinical-trial-566116201.html     “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. ”  简直是不可思议的神迹哈,一个重症痴呆的患者,失去了正常生活的能力,经常幻听幻视,用药后几乎就是突然醒过来,恢复了生活能力,还可以基本交流,游泳玩纸牌打桌球,把他的医生都惊到了。唯一的疑虑是,这个Frank Carney 本来就是个神人,在他年轻健康的时候,就做到过一般人做不到的成绩。这次的奇迹,换个别人,可能就不会这么显著了。 
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P2-202  11/2015 - 2/2017 143 participants, 20ug, 40ug and placebo
首先,40ug dose 效果不如20ug,我的理解,脑子里的蛋白酶得动态平衡,太高太低都不行, 40ug dose ,可能太高了也不对付,就像血糖太高太低都不好。我甚至怀疑现在用的20ug 可能还不是最优解,美国人,身高从1米5到2米,体重从80磅到300,都一个剂量,这怎么行。因为剂量不同而效果不同,我觉得SNPX的成败估计就在 finding a proper dosage。可惜,我没看到更多关于剂量选择对比的论文。我一个外行靠直觉能想到的,他们耕耘了一辈子的,肯定也想到过。这个公司最大的问题是不会交流,跟市场,跟投资者的交流。公司那网站简直一团乱麻,不知所云,我一介民工花个周末就可以打理的比现在好多了,俺真想撸袖子自己上哈。
然后,在这组数据里,发现ABBV的memantine likely interfered with bryostatin, NTRP 药物受胆碱酶抑制剂干扰,所以这个二期结果有干扰。 
不过这个trial里的一组sub数据非常好,有临床意义,可惜这个理工直男乱放炮,上来就直率地说,memantine不光跟bryostatin-1八字不合,安慰剂组里也没任何效果(他们重症病人很多都同时用市场上已有的治疗药),得罪了大药厂。这不是第一次得罪了,早在2012年Dr. Alkon 刚开始没想自己开公司,他想和药厂合作做trial,可是那时候AD还是Amyloid的天下,没有药厂认同 这个outlier,这位也不服气,坚持喊Amyloid不行白白浪费了一代人的时间。因为AD理念上的不同,Dr. Alkon 有盟友也有更多因为道不同而带来的rival。这次又乱放厥词,结果NTRP这次不差的数据居然在seeking alpha 被吹毛求疵的大批判,在seeking那说NTRP好话的都被迫删帖道歉了,股价也惨遭脚踝斩。
又发了篇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.
也贴个图,very encouraging and very impressive! 现在SNPX婉转了,去掉了以前直接打脸药厂的control 线。当年NTRP刚出数据的时候,control线也分两条,+/- memantine是分开的,清晰表明有没有memantine,没有差别。俺看到那图就心里一惊,太直男莽汉风格了,没必要嘛,至少解释一句,病人少疗程短不足以下结论否定memantine (不光打脸药厂,也打脸FDA哈),你好我好大家都好NTRP也不至于被人倒攻打击。现在,他们被市场教育后也提高了认识,好。

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P2-203 : 6/20/2018 - 7/25/2019 108 participants 20µg bryostatin (53) or placebo(55)   前面提到的phase1/2-201, phase2-202,虽然不被市场认同,一次又一次股价大跌,但是Dr. Alkon的团队却越来越有信心,他们以前一直和转基因老鼠干, 那多简单纯粹哈,用药老鼠考试跑maze,然后化验最后解剖大脑。以前在老鼠上的效果,现在真人也有了具体的数据,希望越来越落在实处。但是,P2-203是意气风发的TITANIC触到的暗礁,直接淹没了NTRP。 
这个P2-203,真是运气背,A significant imbalance (4.8 points) in the baseline Severe Impairment Battery ("SIB") scores occurred ,安慰剂组的病人baseline mean value 比用药组起点高了4.8分,说是 by chance, 我觉得的是试验设计出问题了,低级错误,挑选病人MMSE-2 score 4-15,跨度太大了,重症的4 和中度的15根本不是一个level的,现在的phase 2-204, 病人挑选标准改成 MMSE-2 score 10-18 , 去掉了重症4-9,末端重症很难评估,无谓导入系统误差。
难以解释的是,2019年的九月,NTRP是知道这个客观因素的,他们没有任何说明,任由股票市场再一次脚踝斩。公司董事会也开始了一系列的stategic alternatives 转型自救,这个象牙塔里一直冰清玉洁的小美女,居然委身下嫁了一个臭名昭著的流氓, literally 。结婚前的Metuchen只有一个ED药,这个胆大妄为的流氓,药还没批就大张旗鼓的满世界打广告,急得FDA不得不追出来辟谣 , FDA's OPDP Warns Metuchen Pharmaceuticals Over Misleading DTC Ads 。
现在这个流氓华丽丽的改头换面成PTPI,不光ED药已经批了,还空手白狼从NTRP的嫁妆里顺走了$16M,现在干劲好大,正在联合伟哥一起把ED药搞成 non-Rx,难言之隐让男生悄悄解决。就凭这股流氓干劲,PTPI不错哈。老军医电线杆上的东西,管不管用先不说,市场肯定有。顺便介绍女生难言之隐EVFM, 不孕不育PGNY,LGBTQ的福音。 
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从2019年的九月到2020年的一月,是NTRP彻底沉默的一段时间,这段时间我找不到任何相关新闻。事实上,她的trial 数据没像股价那么糟,这份出炉的P2-203,嗯,兵分两路,各表一枝:
(1).  先说用药组,用药组13周提高4.8分。“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) 可惜糖水安慰剂也成绩不俗, 糖水得了4分,比SAVA治轻症成绩都好, In the placebo group (33 subjects), there was also a statistically 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. 
俺要吐槽糖水!!BCLI,亏啦好多钱啊~啊~啊~~, 栽在安慰剂上,BCLI二期数据很靓丽,史无前例的35%,三期成绩一样重复的靓丽,还是35%,可是见鬼了,糖水安慰剂比市场上以前批过的任何药都有效, 29%, 然后BCLI三期就这么fail了。搞得俺真想糖水创业,专治各种疑难杂症,尤其是那些没药可治的疑难重症!这类事情多了,难免会乱想,人啊,真是有灵的,信则灵,信上帝信安拉信法-轮信神药,或者见佛就拜,只要信都可能管用的,尤其是退无可退的时候真是心诚则灵啊~~,哎,我亏了好多钱~~ 
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言归正传, 市场无情扫荡了NTRP两周后, 接着做下期好了, 后面还一直追加 到$2.7M。期间异常沉默的Dr. Alkon,他是不是把新的fund 当成expanded 同情药了?NIH脑神经,记忆,大脑退行病变这个摊,全都是他以前一手培养的学生,他在那里耕耘了30年才离开的。我买了一本Dr. Alkon 90年代在NIH当 Medical Director of the NINDS and Chief of the Laboratory of Adaptive Systems时写的书 Memory's Voice , 书中他是个观察细致表达流畅的学者,当然不可避免的也有读书人的EGO。
Dr. Alkon 在此前自信满满,学术界投资界都对他予以厚望,就在203 开胡前一个月,Dr. Alkon刚在聚光灯下荣获 AD研发的 Cure Coin Award 。P2-202出来的时候,他还能楞着脖子喊,不是我不行,是别的药干扰了疗效,然后被各种冷嘲热讽大批判。这次P2-203又不行了,Dr. Alkon 尴尬到闭关潜水啥都不说,我一度觉得他自己的信心也确实受打击而疑惑了。  这么想来,生药小美妞嫁给流氓股,就像鲜花插牛粪,各有所得,还可以。
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P2-204 : 8/30/2020 - 11/2/2022 100 participants, on-going, 10 months   因为上期203出现过糖水治疗重症痴呆接近NTRP效果的乌龙,这次吸取教训,两头把关。这个phase 2-204, 开局的统计设计请了哈佛的生物统计教授把关,也去掉了没有明显疗效的重症病人(MMSE-2 score 4-9) 。 现在的 试验标准是 MMSE-2 10-18, 分成两个subgroup, 10-14 和 15-18。
时间拉长, 以前都是12周, 现在 搞两轮,每轮11周, 两轮中间停一个月,两轮治疗结束后再等四个月,一共10个月,这10个月一直跟踪评估SIB。希望这次长时间跨度可以帮助降低安慰剂的波动。最后 data lock and analysis 也请了John Hopkinton 的脑神经专家把关当medical advisory,  避免实验报告一出,又是满大街糖水治疗重症痴呆疗效明显。
现在进行时, 100人的双盲,跟踪病人10个月。去年10月已经开始,这是我对204时间线的大致预期: 1. fact -- first dose 10/6/2020; 第一个病人参加药物试验 10/6/2020 2. fact -- about 1/2 patients enrolled and started the treatment now (PR updated on 4/1/2021); 3. guess -- in June all 100 patients enrolled and started the treatment; 大概今年六月所有100个病人都招募到,开始为期10月的疗程 4. guess -- at the end of year, 2 cycles of 11-week doses done ( 30-day break time in between); 2021年底,两轮用药结束, 每轮11周,中间间隔30天 5. guess -- April 2022, check the status 4 months later after the treatment; 2022年4月,用药结束后,四个月的等待观察期,观察停药以后的持续效果 6. guess -- another 3-5 months, data lock and analysis. 另外三到五个月,数据收集和分析
这么估算的话,大概明年8-9月出最终结果。对股价的估计,现在 undervalue 两块钱,五月份应该回暖,年底应该回到本来面目10块到20块吧,然后起起伏伏等消息,命好中了的话,这个还不到$30M的Market Cap 可以超过现在的SAVA(Market cap $2B+), 这是实打实的双盲重症哈。当然更是AD的福音,据说自然界,只有人类有这个病,动物试验使用的老鼠都是插入人的片段转基因人造出来的。  没中的话,只能是倒车接下一波小散,股票估计回到原点吧,生药研发就是这么残酷的。

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这次phase2-204成功的可能性有多高,这个真不敢讲,我先说最近20年AD新药的成功率吧,记得只有2.7%, 风险绝对高,FDA这些年毙了一个接一个的trial,更多的药厂知难而退,早早放弃无谓烧钱,最近15年还没有任何一个三期trial 得到通过。我把SNPX请到的科学顾问贴在这,咱外行只能相信专家了:
(1). Scientific advisory board members: Lee Jen Wei, PhD     https://www.hsph.harvard.edu/l-wei/   https://www.hsph.harvard.edu/profile/l-j-wei/ 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
(2). Biomarker 
AD现在测试标准靠病人的问卷测分我觉得不靠谱,还是社会调查的文科做法。没有不敬,就是觉得误差太大,比如说,同一个问卷,我今天睡了个好觉,可能就跟昨天累伤脾气坏完全不一样。
SNPX是有自己的biomarker 的, 他们完全没宣传,我在2014年底那份 Investment thesis 就 看到了: 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. 
这个biomarker 是有业内高手 Dr. Paula Trzepacz  加持的,看看她的履历,  : On July 15, 2019, she was one of ten researchers to be presented with the first-ever Cure Coin Award (Dr. Alkon 也获此殊荣)during the 2019 Alzheimer’s Association International Conference。 The award honored her work at Ely 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. 
Dr. Trzepacz was the Chief Medical Officer at Neurotrope in 2016. 她已离开了NTRP。

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(3). PKC 这个方向有前景么?我觉得有,但是成败在找到合适的,个体化的剂量。
用PKC来研发AD, 这两天刚出数据的 AVXL 也是这个方向,手法完全相反, Anavex 2-73 indirectly inhibits protein kinase C。我觉得SNPX 和 AVXL 都有可能成功,在AD病情的不同阶段,用正反不同的手法平衡一系列激酶的方法,可能殊路同归。这个不是我这个外行能啃明白的,就是一个直觉吧。
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奇葩的 PR 和 CFO
我自己关注的是NTRP/SNPX的research and trial, NTRP犯错更多的是管理, 尤其PR这块,不会做PPT,复杂数据不会去繁就简,简明扼要。SAVA这方面,不得不赞神一般的高手, 神到俺已经不敢相信了, LOL。这里说NTRP去年犯的两个大错误吧,真是扼腕叹息,投资前浪拍在沙滩上几乎血本无归,给俺们后浪送来了现在MC不到$30M, 股价$2的地板价:
(1).  1/22/2020, 早上九点,PR说,我们数据不差的,最新数据再次肯定一贯的好成绩,我胡汉三又回来了。市场欢腾,股价从地板价一跃而起几乎4倍; 然后,还没到吃中饭时间呢,PR又出来说,我们还拉到了new offering 11M shares at $1.65 per share, 这个时候,市场价的$3.8直接piaji跟着回到1块6。咳,你重来一遍,先说,俺们又被看好了,搞到新钱$18M, 然后,喝口水再说,俺们不光有钱了,诗和远方更清晰了, blabla,  是不是效果好多了。朝三暮四被一群猴子痛扁,朝四暮三能哄得这群不过脑子的猴子高兴坏了。
(2).  12/8/2020 官宣  NTRP 1:5 reverse split  and  spin off to new symbol SNPX, 12/10/2020 这两动作居然同一天操作,结果悲剧了 SNPX 总股数缩到原来的20%, 可是股价却还和原来一样!如果,如果这两个动作分两天进行,先RS, 流通股小5倍,股价自动涨5倍;然后再换名字, SNPX不至于莫名其妙的丢了80%市值。这个没人知道的长年默默无闻的,根本没有交易量没有关注的小生药,就这样被奇葩CFO操的死去活来。俺刚看好她的时候,天天蹲点都买不到,根本没有交易量。
CFO最近又喊要缩股, yahoo上哭声骂声一片,俺才趁乱攒到了。SNPX要缩股的原因是要把股价凑到$4块,从OTC uplist to Naz。奇葩CFO在股价3块多的时候喊reverse split, 喊完没几天,股价就piaji 到2块以下了,缩股招来了闻腥舔血的short, 又一个骚操作啊~~
beyondBet
吐槽了这么多,来点鼓舞士气的, 这个资产翻了100倍的作业可以抄 
Haywood George Weaver, 不到十年资产翻了100倍,从$5M到$500M。去年年底时是200倍,那是$5M到$1B。 可惜今年初SRPT又腰斩,生药体质就是这样,大起大落,不含糊的。  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 had 1:6 reverse split and changed to SRPT, and the company started flying after rs, more than 10x around 10 months later, almost 200x at the end of 2020
他现在分散投资,眼光和我一样,也看上了SNPX。喝喝,可叹他下手早,去年投了1M shares,就是前面提到的$1.65 的 private offering, 一通折腾脚踝斩,NTRP 1:5 缩股到SNPX。今年再接再厉,上个月又投了$2M在SNPX(每股$1.59x1.24m shares), 大户,前后花了$3.7M,搞到1.4M shares ,均价$2.57,比我买的贵哈,今天 3/19/2021 市价也才$2.15。当然,这类有爆发潜力的股票,不必在乎现在起点处的小差别了。
此君喜欢缩股换名字,当年SRPT就是这样的,名字从AVII换成SRPT,同时1:6 Reverse Split, 美其名曰 Enacts Reverse Stock Split to Strengthen Financial Base 。现在又走在新长征的老路上, NTRP 改成了SNPX, 下个月估计又要RS 
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H. Weaver 持股9.7%, 再来看看SNPX最大股东, 持股9.99%的 Intracoastal Capital LLC:
consist 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. 这个 investment firm 在 8/15/2018  先知先觉的赌了900K shares of SAVA, 便宜啊,$1.97 purchased 907446 shares,  Overall 5.01% Ownership:  
Cassava Sciences Inc (SAVA)   HEALTH CARE    907,446    6,188,781.72       5       13G       2018-12-31
那时候SAVA还不叫SAVA,刚从止痛药PTIE转型AD药: https://whalewisdom.com/filer/stock_history/intracoastal-capital-llc/ptie   

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小生药不容易,SAVA 四个月后忍受了一轮腰斩,跌倒 $0.85; 一年后坐了一趟过山车,$10块脚踝斩到$1块6;今年二月初竟然神奇冲到$138, 两年多后终于守到盆满钵满了。
这个Intracoastal Capital 现在是SNPX最大股东,喜欢SAVA的同学也可以抄作业。
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再说一下 药源

药源 Bryostatin 是海洋天然产物,George R. Pettit 发现的。Pettit年轻时非常帅,是国家地理杂志的常客, 他常年出海打捞海洋生物然后萃取分析,发现过非常多的天然药物,是个大牛教授。
Bryostatin 1 is a natural product derived from the marine invertebrate Bugula neritina. 从 Blanchette Rockefeller Neurosciences Institution开始,就一直是National Cancer Institution 免费提供。这个药最早是从癌症药开始受关注的,已经被不同实验室做过1500多人的各种trial,现在还有儿童急性白血病的进行时, 至今没有出现过大的副作用的报道,所以安全性有数据支持。 公平说,SAVA从一款消炎止痛药起步也没啥,英雄不问出处。因为货源有限,一直是针剂,上个月SNPX和斯坦福刚签约 exclusive licensing agreement with Stanford University for synthetic Bryostatin for all neurologic indications,以后可以口服,随便大碗吃了。
这个合成药是斯坦福一个牛人(此人还有别的绝活,等他以后上市,一定追)2017年就搞出来的,这段
出神入化的有机合成
  都被我挖出来了,赞!
我猜口服药的试验这几年一直在同时进行的,应该是三年多过来,人工合成药和海洋纯天然物质药效没有差别,所以今年二月终于和斯坦福互签 world wide 特供合同。
现在,万事具备。 
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最后,公平起见,我也贴几个反方数据
这几个是擂台反方,不看好PKCδ的研究方向的。实话说,外行我看不太懂,我自己的理解,生化链更多的是个平衡关系,环环相扣动态平衡。现在很多AD研究类似于盲人摸象,有人摸到尾巴,又细又柔,有人摸到大腿,又粗又壮:
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. 
欢迎大家关注这个SNPX小微股 
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SNPX除了AD药, 还有几个pipeline:
The FDA has granted Orphan Drug Designation to Neurotrope 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

deanregal1
alzheimer's的neurosicence开发太难做了,多少大公司强大的R&D teams,clinic trials数据和quantum aws分析都到不了endpoint efficacy target,Biogen, Eli Lilly or Roches都在做,小公司更难,所以它股价要么就是这样走sideways,要么能一飞冲天,risk rewards很难吸引serious investors,5刀以下的很多股,不要说个人,很多funds有限制,都不能碰
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以4/7/2021 股东会为准,SNPX一共只有270位股东。
前天出了一份  SEC form S-1A  , amended registration statement,专门细说股权,太细说了,快进到68-71页,私募的77位大小股东一个不漏全暴露了,哈哈。 As of April 7, 2021, we had 14,032,516 outstanding shares of Common Stock issued and outstanding held by approximately 270 stockholders of record.
我做了一点简单加法, 重大发现是,SNPX真正意义的流通股,咱们小散有可能买来买去的流通股,居然还不到1M shares,  adding those private offering + insider holding , already ~ 33M shares , out of total 33,970,468  shares  of  Common  Stock  outstanding,  which  assumes  the  issuance  and  sale  of  19,937,952  shares  of  Common  Stock,  upon  full exercise of the Investor Warrants, Pre-Funded Warrants and Placement Agent Warrants . 现在一共有14M 流通股,但绝大多数在私募手里,这些早期就开始死忠的私募粉,我觉得他们不会在2块钱亏钱卖股的。减掉私募持股,减掉员工持股(很少),只剩下1百万不到的真正意义的流通股 。  
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我挑重点再说几点吧:
1. 这个季度烧钱好快,100个病人的phase 2 trial, 已经付了$10M; 申请Nasdaq 上市,申请费用以及为此耗资准备的股东会,也花了好多钱。不过,现有的资金,加上一年期和五年期的warrants,足够烧到2022年底,可以撑完 AD phase 2b 和另外一个Fragile X 的phase1 trial。 It's from the January money raise. 9+ million of the 28+ million is already factored in to the 14+ million current O/S. Another 9+ million warrant shares can only be redeemed within 12 months of this past January. Those are priced above $2 so will bring in tons of cash if utilized. The remaining 9+ million, if ever exercised, would bring in tons more cash. 37+ million dollars if totally utilized and bring the total O/S count to approx 32 million shares. Net, net is we have 14 million o/s currently. 9+ million come off the books next year one way or another and then we can only guess how many of the last warrant class will be used.
2. 这是warrents 细节: 这部分是NTRP遗留过来的,全都亏废了 157,791 Series A Warrants to purchase up to 157,791 shares of Common Stock with an exercise price of $49.41 per share ; 623,250 Series B Warrants to purchase up to 623,250 shares of Common Stock with an exercise price of $19.76 per share ; 906,264 Series C Warrants to purchase up to 906,264 shares of Common Stock with an exercise price of $9.88 per share;  and 2,221,820 Series D Warrants to purchase up to 2,221,820 shares of Common Stock with an exercise price of $3.95 per share. 
下面是1/21/2021 新发的warrents, 主力买家还是上面亏死过的同一拨死忠粉,我一点不介意签的价钱是$1.725, $2.1275: (ii) an aggregate of up to 9,335,533 shares of Common Stock that are issuable upon the conversion of the Series E Warrants;  (iii) an aggregate of up to 9,335,533 shares of Common Stock that are issuable upon the conversion of Series F Warrants;  (iv) an aggregate of up to 333,333 shares of Common Stock that are issuable upon the conversion of the Pre-Funded Warrants;  and (v) an aggregate of  933,553  shares  of  Common  Stock  that  are  issuable  upon  the  conversion  of  the  Placement  Agent Warrants. 
记得有看到,如果股价超过5块,公司有权力取消up to 50%的warrents, 时限记不清了。还记得有一条专门对付恶意收购,说任何个人或机构,持股超过15%的话,所有股东(当然15%的除外)拥有以市场价一半的价钱,购入同样股数的权力。蛮好玩的,我不知道这会是什么样的骚操作,估计以恐吓为主。
3. 研发专利,NTRP前身的洛克菲勒基金(10几年一共投入过$200M研发资金)将拥有部分未来商业利润的1.5% - 5% ,跟咱们报税一样,阶梯上升。 
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最让我笃定的是,short没地方跑了,我这一个多月买进的SNPX,大部分是short强行砸的。S-1A form 上的77位股东拥有的SNPX,全部泡水里了好几年了,不可能在这个价位亏钱卖,新的一场戏大幕即将徐徐打开,今年肯定先不急的。我自己攒的,加上我知道的yahoo上的几个队友攒的,剩下的零头,已经不够cover 300K+ short position 了。俺被short砸的满头包的苦日子,快熬出来了 
           Short Volume      Short Volume Ratio 2021-04-09 5,237 43.49 2021-04-08 600 3.51 2021-04-07 8,638 28.57 2021-04-06 14,602 24.06 2021-04-05 39,519 70.97 2021-04-01 15,470 35.04 2021-03-31 19,672 38.45 2021-03-30 2,480 12.26 2021-03-29 11,980 62.00 2021-03-26 17,191 41.68 2021-03-25 7,978 49.70 2021-03-24 4,425 56.90 2021-03-23 3,945 43.24 2021-03-22 10,895 71.05 2021-03-19 11,965 83.83 2021-03-18   5,321 99.25 2021-03-17 24,079 76.87
accumulated short interest: 03/31/2021 241,690 03/15/2021 195,495 02/26/2021 188,666 02/12/2021 188,930 01/29/2021 164,423
春风扬柳,满目新绿了 
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回复 21楼deanregal1的帖子
谢谢关注,AD是个充满失败的行业,最近17年没有一个药厂过关。
以买彩票的心态,买一点看戏吧 
HalloweenKanga
这么多年没有公司真正做出什么好的老年痴呆的药,都是PPT,这只股票交易量也太小了,不好操作。我站边上看看就是了。
beyondBet
这个股票大部分时间都没有交易量,14M的流通股,有13M握在私募手里,只有不到1M的真正意义的流通股,买SNPX的 小散,多数也和我一样是买彩票等看戏的,所以也都不卖。
最近两月的active sells mostly conducted by shorting
lovesunshine
关注一下吧
千渔千寻
厂持
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回复 29楼千渔千寻的帖子
看到了, $2.5 买了500股, 谢谢信任和支持  
我昨天这个价位买了3万股 
beyondBet
昨天 $2.5 和 $2.55 都是我买的,主要是趁东风怼short亮亮肌肉 
twptwp
支持做这项研究的公司,新闻能坚持下去,不管结果如何。
m
maodouchong
单独的药股都是炒作,不要碰