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It did improve performance in normal mice, but I don't think they'll go down that road in humans before patents expire.
Also worth mentioning:
Juno was acquired for $9 billion based on $3 billion in potential sales for a drug in phase 1.
https://www.fiercebiotech.com/biotech/celgene-confirms-9bn-juno-buyout-sees-3bn-sales-for-jcar017
If Alzheimer's is expected to bring in tens of billions in sales...well, you do the math.
Assuming results are confirmed, the warrants alone will bring in over $100 million for the company. Then there's the extensive IP portfolio which will keep competitors away until at least 2035.
While a partnership is certainly a possibility, I don't see why BP wouldn't prefer to add these patents to their portfolio and speed up development through an outright acquisition. After all, Celgene did acquire Juno last year for $9 billion just to gain access to their CAR-T cancer drug pipeline, and they haven't even started any P3 trials to this day.
Would you prefer to wait for some rinky dink startup to develop their potentially revolutionary drug through a partnership, or wouldn't you rather just absorb the company into yours so you can use your vast BP resources to quickly get it approved for as many indications as possible and start raking in multiple tens of billions in sales?
My personal guess is they announce it on either September 9th or 16th.
Definitely not expecting anything before labor day though.
Of course it can fail. Maybe the patients mysteriously died during the trial and it's all being covered up. Maybe they manage to accidentally delete all the data before it can be presented.
You never know.
The $10 September calls say positive results could immediately get this up to $50.
The +400% implied volatility certainly shows something big is coming up, no matter what direction you believe this thing will go.
Options trading is going nuts for September/October.
They're buying contracts for more shares than the volume for regular shares.
The market is clearly not impressed.
A $60 million valuation for a potential $20 billion drug is a sign that nobody believes this company just yet (except a few that can't afford to buy the entire company).
Will the new results change that? Let's find out in a few weeks.
As someone that also has a slow metabolism, I have never had a problem with medicines that wasn't fixed by increasing the dosage. Even local anesthesia doesn't work on me in normal doses, so I'll ask the doctor to give me more and then it'll work again.
Something being new doesn't necessarily make it better. I still fix my headaches by using the ancient method of drinking more water and getting more sleep. I don't need ibuprofen for that.
If I ever get Alzheimer's I will choose the drug that has proven its synaptogenic effect in placebo-controlled trials and has no significant side effects in much higher doses, not one of the countless drugs that claim to slow the decline just so I can watch my brain rot away over a longer time period.
People in a life or death situation do not care about what's new. They care about doing whatever it takes to not die.
Time will tell who's right and who's wrong. All we can do is make our bets and wait.
I doubt that. Even Dr. Ryan has talked about starting a pivotal P3 trial, so I assume they'll get that one going and maybe a bioequivalence study at the same time. Then if everything works out as expected, I'm guessing it won't hit markets until 2021, even if the FDA does slap some breakthrough therapy label on it.
As I've said before, I believe the top-line data in a few weeks will be a milestone, not the finish line. Some may disagree and will sell their shares on day one. Personally I'm more interested in waiting another year or two to see what this company is really capable of once the warrants are cashed in and they can afford to pursue several indications at once.
Safety and optimal dose has already been confirmed, so they could immediately start with phase 2b trials for any additional indications.
That's hilarious
What's funny is that their drug is just a combination of Wellbutrin and cough medicine.
If that's worth a billion before phase 3 trials, who knows how much a patented drug for repairing brain damage could be worth.
6 weeks from last PR is next week, but I'm personally leaning more towards an early September release in 2-3 weeks.
We could've avoided the entire 2008 financial crisis if people had just "looked at the data" and noticed the extreme amounts of bad mortgages propping up the system.
Sooner or later the lies collapse under their own weight and reveal the truth.
Hard to say when I can't check any placebo controlled trial that proves it
Great find, thanks. Not much new but here's what I got:
- Alkon once more confirming results in Q3
- Believes it could be used for preventative care and earlier stage patients due to its MOA
- 20 dose has "virtually no safety issues" and "does no harm"
- Apparently PKCe plays an important part in childhood brain development, which Bryostatin activates again
- An explanation for why it could be used preventatively: It not only activates PKCe but also regulates the gene responsible for making it
- Down the line they want to go for moderate patients and even preventative care
- Two independent groups seem to have gotten great results with Bryostatin in both MS patients and Parkinson's patients
- Mentions positive results in Stroke, Fragile X and Autism
- Bryostatin seems to have a "platform of diseases" it could treat
- Had "very very positive results" in stroke models and managed to reverse the damage caused by the stroke, not only in strokes caused by blood clots, but also in the ones caused by hypoxia where neurons are destroyed because of oxygen failing to reach the brain (for example because of anesthesia during surgeries, hanging, strangulation, carbon monoxide poisoning and near-drowning)
- Talks about "tens of billions of dollars per year, north of 30 billion, maybe more" in potential sales just for AD because of how many AD patients there are in the US and how many more there will be in the future
- Believes regenerative treatments are going to be the "way of the future"
In general he explains a lot of what we already know in a detailed way that's easy to understand, so that's nice too.
I've added the link to the ibox.
About 18% of the shares traded in the last 10 days have been short sales.
That doesn't change the fact that having no baseline to compare results to makes it worthless.
Analyzing poop with an AI is not going to change the fact that there is no baseline to compare the results to.
You simply cannot claim that a drug works without having proof of it beating placebo.
I think you're misunderstanding what precision medicine really means.
Precision medicine is the customization of healthcare, with medical decisions, treatments, practices, or products being tailored to the individual patient.
You can develop precision medicine with or without placebo-controlled trials.
But again, if there is no control group to compare results against, the trial is worthless, regardless if you use precision medicine or not.
You need a placebo group to confirm the drug actually has an effect and that the results aren't caused by external factors unrelated to the drug.
You can't claim you're improving patients over baseline if you never even compared them against a baseline group in the first place.
You can't say that x is better than y if you've never compared x against y.
This is not rocket science.
There is not a single sentence in that statement that argues against using placebo controls.
Again:
Trials without placebo controls are worthless.
At this point we're so close we don't have to entertain anything.
Whatever the results may be, we'll see what the market thinks immediately after.
Human beings are not cars, nor is the human brain a battery.
Looks like there's a lot of $5 puts expiring worthless today.
Destroying unused connections and growing new ones is basically what our brains do on a daily basis anyways.
We learn new things and new connections are formed. Stop using certain knowledge and those connections will wither and die over time in order to make way for other knowledge that is used more frequently, hence why we forget things.
You could explain this theory to a 5 year old child without using convoluted jargon, and that to me is a sign this might be the real deal.
Occam's razor.
Dirk?
There's this time lapse video of neurons interacting with each other:
I'm not necessarily saying they're right, but damn, there sure is a lot of evidence out there supporting their claims.
"If it looks like a duck, swims like a duck, and quacks like a duck..."
Notes for the latest paper:
- "However, problems with multiple clinical trials of amyloid-targeting therapeutics, including an effective removal of neurotoxic Aß species, and licensed AD therapeutic drugs are their lack of effectiveness in targeting the pathophysiological core underlying the dementia: functional deficits/loss of synapses and neurons beyond the brain’s ability to repair. Synapses permit a neuron to pass a signal, chemical or electric, to another cell and are adaptive in operation and structure according to functional demands. Both acquisition of memory and its consolidation/reconsolidation involve restructuring of synapses and their operations [9]. For all the unsettled issues in AD, one finding is clear: the synaptic deficit/loss, revealed among many other pathologies, is highly correlated with the levels of dementia in AD patients [10–12] (Box 1). Within 2–4 years of AD onset, brain biopsies are reported to have a decrease in the number of synapses by 25–30% in the frontal and temporal cortexes [13], most severe (by 44–55%) in the hippocampus [11,14], both in the degenerated and surviving neurons (about 38% loss [12,13]).
- "Mammalian brains operate on an efficiency principal of keeping the number of synapses modest for a particular function, since signal transfer through synapses is rather expensive in energy cost [19]. Powered through plasticity, the brain, however, can remodel its structure and operation of synapses/network for new challenges. The downside of this efficiency, the lack of abundance in neural connections, is its vulnerability to injury/damage, especially when this remodeling/regeneration ability is compromised."
- "Mammalian brains have a certain capacity to regenerate/remodel synapses/neural networks when facing injury, disorders, and cognitive challenges. Cognitive impairment becomes evident only when injury/damage/cognitive demands reach a threshold by which the brain can no longer initiate and sustain the required responses."
- "Memory impairment and dementia are the consequences of synaptic/neuronal deficits. The intrinsic neuro-regeneration capacity in the mammalian brain has been shown to be very limited, even after eliminating multiple known inhibitory signals [47]. In the adult mouse brain, most axons cannot regenerate sufficiently, even with precise laser-mediated lesions that produce minor scarring [48]. This low endogenous capacity for neuro-regeneration in mammalian brains does not mean, however, that this capacity cannot be enhanced to achieve dramatic outcomes. Spines are highly dynamic and capable of remodeling and restoring their original structure, location, and function [49], when triggered with appropriate therapeutics, such as neurotrophic activators (see below)."
- "With a focus on reversing synaptic and neuronal loss in AD, we have developed a therapeutic strategy that has shown a neurorestorative potential (i.e., to restore lost synapses in AD brains in preclinical studies) [9,95], as well as the concomitant potential to prevent apoptosis [9,96–98], reduce Aß oligomers, lower hyperphosphorylated tau [9,97–100], mRNA stabilization of growth factor mRNAs, and reduce oxidative stress [101]. Activators of PKCe (Figure 2) with bryostatin-1, a relatively selective and powerful PKCe activator with clinical safety profile at appropriate doses [102], and DCP-LA (Figure 3) have been shown to increase synaptic numbers via synaptic growth factors [103,104]. Bryostatin-1, a macrocyclic lactone, enhances BDNF expression/secretion and synaptic remodeling/synaptogenesis in the brain and produces several other anti-AD effects, such as antiapoptosis, anti-inflammation, antiamyloidosis, antitauopathy, and antioxidant, at therapeutic doses [10,105]."
- "Evidence supports the notion that cognitive deficits occur only when synapses/neural network cannot be appropriately maintained through neuronal/synaptic repair and synaptogenesis/neuro-regeneration to meet cognitive demands, indicating that synaptic deficiency should be the focused therapeutic target. The synaptic deficiency hypothesis (Figure 1), consistent with enormous evidence that an early failed maintenance in synaptic integrity triggers neurodegeneration in the brain and cognitive decline, does not rule out the pathological contribution of neurotoxic Aß and tauopathy to synaptic/cognitive deficits in AD and potential therapeutic benefits of anti-Aß and antitauopathy."
- "Accumulating evidence, to date, suggests that structural and functional deficits of synapses are at the core of the underlying pathophysiology in AD (see Outstanding Questions). In clinical trials, AD therapeutics that target synaptic loss and dysfunction (i.e., to slow, halt, or reverse progression of the disorders at the level of synapses), via synaptogenic molecular cascades such as the PKC-BDNF signaling pathway, show promising results [105]. This differs from the failure of 300–400 AD drug candidates in recent years [116]. The key to effective neurotrophic therapy in AD appears to require a sustained and appropriate PKC-BDNF activity in the brain, guiding against the aging/disease-related neurodegenerative process. A too-high level of PKC-BDNF activity can also be neurotoxic [117,118]. Overcoming the self-repair limitation in the mammalian brain would transform how AD patients, and others with memory disorders, are treated clinically."
I finally got around to reading the two latest papers. Here's some notes for the first paper if anyone's interested:
- "In the brain, ePKC interacts with several neuronal receptors and neuromediators including N-methyl-d-aspartate(NMDA), gamma-aminobutyric acid (GABA) synapses, BDNF (Brain-derived neurotrophic factor), SIRT1 (Sirtuin1), and SIRT5 [34,35]."
The effect on NMDA receptors isn't anything new, but independent confirmation is always nice. What really caught my attention though was that it also has an effect on SIRT1, which if I recall correctly is a gene being studied at Harvard for life extension purposes. Not really relevant for Neurotrope, but still interesting to know.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172519/
- "These results suggested that the activation of ePKC reduced ischemic/reperfusion damage by a significant decrease in blood flow during reperfusion after ischemia [32]. Similar protective evidences for ePKC were reported by using an Oxygen Glucose Deprivation (OGD) model, (in vitro ischemia) highlighting the role of NMDA receptors in cerebral ischemic tolerance [36]."
"PKCs phosphorylate and regulate the dopamine transporter, -amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid(AMPA)-type glutamate receptors (AMPARs), NMDA-type glutamate receptors (NMDARs), -aminobutyric acid (GABA) receptors, -opioid receptor, and metabotropic glutamate receptor 5 (mGluR5) receptors [51–53]."
Memantine is an NMDAR blocker. If Bryostatin works by activating endogenous repair mechanisms and those mechanisms need NMDAR to work properly, it makes perfect sense why patients on Memantine showed no improvement in the last trial.
- "In the brain of patients with AD, the levels of PKCs are significantly reduced and PKCs signaling is impaired in terms of activity and translocation to the cellular membrane [48,49]. Therefore, a direct effect of PKCs in AD, as an etiopathogenic cause or as consequence of neurological damage, is highly suggestive [44]."
"However, ePKC levels were 21% and 30% lower in the particulate fraction of aged hippocampi (78.92 2.85, p < 0.05) compared to the young (100 8.68, p < 0.05) and middle-aged (108.85 9.54, p < 0.05) groups respectively (Figure 2c)."
"Loss in PKCs expression and function have been indicated as one among the first markers of neuronal death [21]. Therefore, impairment in PKCs is surely implicated in neurological age-related disorders, such as cerebral ischemia, brain injury, and cognitive impairment [4,18]."
If PKCs are involved in protecting the brain, and their levels drop as we age, it could explain why AD mostly affects older people.
Where did you get that from? I haven't heard a peep about deltas or upward trends from the current trial.
The previous trial shows what's likely to happen, but it's not a guarantee.
Alright, so what do you think of the data?
I'm curious to know why you believe this trial will fail when they're simply repeating what they've already done before in a smaller population.
Emotions and blind devotion are a great way to lose a lot of money.
One company has more than a decade of research by many different parties backing up their claims. The other is employing models, prints new shares like there's no tomorrow, cashes out millions for their executives and runs trials without placebo control groups in foreign countries.
"Look at the data" isn't just a fancy catchphrase. It means you should look at the science and form your own opinion about it instead of relying on what the company tells you to make you feel good.
Before results? Not a chance.
Discussions and negotiations take time. Analyzing results takes time. I very much doubt we'll hear anything from anyone for at least a month or two.
Maybe the FDA will have something to say about the results before January. As for Wall Street, they probably wouldn't have any offers ready until early next year.
Good results would be a spark, not an instant fire.
In a "few weeks" actually. Q3 still has another 6 weeks left in it.
If you look at the last trial you'll notice the pre-announcement stock price is completely irrelevant to what comes next.
Kind of interesting how the market is basically doing the opposite now compared to last time.
If these are all shorts betting on a fail then imagine the short squeeze that positive results would cause.
I seem to have completely missed that they released their 10Q last week: https://www.sec.gov/Archives/edgar/data/1513856/000114420419038612/tv526735_10q.htm
Anyways, here's some of my notes:
- They burned through $7,402,070 in cash the last 6 months, but $2,104,816 of that went to paying off debts, which means the burn rate was more like $5,297,254.
- Assuming a constant burn rate, they have enough cash to stay afloat for the next two years. However, there are about $26 million worth of warrants expiring next year, which could dramatically extend that timeline.
- "As of August 2, 2019, there were 13,021,542 shares of the registrant’s common stock, $0.0001 par value per share, issued and outstanding."
This means the shares are worth $1.6 in pure cash alone, and that the market is currently valuing the actual company at less than $60 million.
- 56,267 warrants were exercised this year for $4.37 each, bringing in $245,886 for the company.
- No options were exercised the last 6 months.
- "Of the total screened patients, 111 have been randomized and 108 have completed dosing. We believe we will have trial data completed during the third quarter of 2019."
- "On May 23, 2019, we issued warrants to purchase 25,000 shares of common stock to Core IR as compensation for investor relations services. On June 1, 2019, we issued warrants to purchase 90,000 shares of common stock to Katalyst Securities LLC as compensation for financial advisory services. On June 5, 2019, we issued warrants to purchase 24,000 shares of common stock to GP Nurmenkari Inc. as compensation for investor relations services. Also on June 5, 2019, we issued warrants to purchase 24,000 shares of common stock to Spartan Capital as compensation for public relations services."