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Breaking biotech о компании Cassava Sciences (русские субтитры).


Hi everyone, welcome to Breaking Biotech Thanks to everyone who watches me today

My name is Matt, and if you like this channel you can help me, You can help him by likeing or subscribing You can also help my channel by leaving a review I am glad to be with you again and really appreciate all the support you give me The number of my subscribers is growing, so please keep talking about my channel to friends Today we’ll talk about Cassaca Sciences and Alzheimer's

Cassava itself is a pretty small company, but lately, its value estimate has grown significantly We will discuss data from preclinical trials and phase 2b clinical trials published this fall Then I will tell you my doubts about their results, which will be published Finally, we summarize the results of 2019 and review the portfolio for the past week

This is the plan for today Let's get down to business Cassava Sciences is trading on the NASDAQ with the ticker SAVA On Friday, January 10, their closing rate was $ 815 per share, and now the company’s value is estimated at 140 million dollars

And, as I said, about a month ago the value of their shares was 1 dollar with a trifle That is, they have grown quite well lately, and I think there are good reasons for this, but we'll talk about this later The company used to be known as Pain Therapeutics (PTIE), her main development was the drug Remoxy, which was a prolonged oxycodone The company developed it to reduce the level of dependence in patients, but faced a lot of problems with the FDA, who just didn’t see what benefits the drug will bring to patients (You can read more about the opioid crisis in the USA in our article, the link under the video is a comment of a translator) As a result, the company abandoned the development of this drug, rebranded and now positioning itself as a company, specializing in neuroscience and focusing on Alzheimer's disease

There is one molecule in the development of the company and one diagnostic test related to Alzheimer's disease But in today's issue we’ll only talk about this molecule and its potential in the treatment of Alzheimer's disease But first, we need to discuss Alzheimer's So, for those who do not know: Alzheimer's disease is a chronic neurodegenerative disease Its symptoms include disorientation, speech problems, mood changes, loss of motivation, as well as behavioral problems

Risk factors for this disease (because we don’t know what causes it) include family history, history of head injuries, depression, high blood pressure So this is a whole conglomeration of phenomena, about which we don’t know how they influence the development of AD, but we know what they do One of the problems of AD is that its diagnosis is often delayed, and its symptoms are often mistaken for the symptoms of normal aging We know that the mechanisms of AD development are still not understood I touched on this in one of my previous videos and will put together a playlist for those who want to better understand

I talked a lot about Biogen and their attempt to influence asthma through an antibody to amyloid beta, and how it did not work But what we discuss today is interesting because it is a different mechanism We know that amyloid beta is able to bind to receptors on neurons, and somehow this leads to hyperphosphorylation of the tau protein And, as we will see later, this can be changed with chemicals, and perhaps this will lead to an improvement in the patient's condition There are many hypotheses for the development of AD, and we still do not know what is the primary mechanism

The currently existing therapies do not change the course of the disease, but affect the symptoms The long-approved Dinapezil is an acetylcholinesterase inhibitor, preventing the negative effects of AD Other existing drugs are amantadine and memantine, NMDA receptor antagonists also help patients Now about the assessment of the size of the BA market Worldwide, there are 26

5 million patients with diagnosed AD and 58 million such patients in the United States alone And these numbers are growing along with how demographic indicators are changing: namely, baby boomers Now they have reached the age when the probability of diagnosing AD is high On the right is the revenue estimate from previously approved AD drugs The most notable of these is Aricept, which peaked at $ 3

5 billion in 2009 and 2010 In total, revenue from all four drugs amounted to $ 65 billion in 2009 Obviously, disease-modifying drugs have huge potential Another circumstance that we must keep in mind is that a drug that can change the course of the disease, can bring more profit even more than Aricept

So, let's talk about the main molecule of Cassava Sciences – PTI-125 This drug is a small molecule capable of binding to filamine A, when he is in a special conformation, and I will talk about this a little later The role of filamine A is to act as a scaffold protein And this is a very important function, because often proteins simply hang randomly and must come together to mediate signal transmission Filamine A is one of various scaffold (scaffold?) Cell proteins

It has been shown that he is able to assemble 90 different proteins together to transmit a signal through the cell And I understand that this sounds blurry, but imagine all the signaling pathways that allow cell interaction And filamine A is just one of many The hypothesis is that amyloid beta outside the cell binds to the alpha-7 nicotinic receptor, and when this happens, filamine A is activated inside the cell and causes the transmission of the intracellular signal One concept of this hypothesis is that the binding of amyloid beta and the alpha-7 nicotinic receptor leads to hyperphosphorylation of the tau protein

Thus, we again come to the beta-amyloid hypothesis and the tau hypothesis: amyloid beta affects tau hyperphosphorylation, and the latter is associated with the destructive effect associated with amyloid beta PTI-125 binds to filamine A when it is in conformation due to the binding of amyloid beta and the alpha-7 nicotinic receptor And when PTI-125 binds to filamine A, it is able to repair the conformation of filamine A, preventing it from transmitting a harmful signal and stopping tau hyperphosphorylation There is another mechanism that includes CD14, TLR4 and neuroinflammation, but I won’t talk about it today The ability of PTI-125 to influence beta-amyloid-mediated tau hyperphosphorylation is probably the primary mechanism by which the drug generally has any effect

This is the premise on which the company developed its drug And I will tell you about the evidence that shows that this is true So, I show you the results of the Western blot from the laboratory that developed the drug And what they did was take the human hippocampus, treat it with beta-amyloid with and without PTI-125 for a certain amount of time And they saw that when the hippocampus was treated with amyloid beta without PTI-125, there was a big increase in tau phosphorylation

Those who listen – just take a word But when treated with PTI-125, they saw a dose-dependent decrease in phosphorylation and nitrosylation of tau This indicates that PTI-125 is able to interfere with the relationship between amyloid beta, alpha-7 nicotinic receptor and tau phosphorylation Thus, we hope by preventing the development of Alzheimer's disease and cognitive impairment associated with it So these were in vitro results

Now I will move on to the results of phase 2a of clinical trials and we will see if there was an effect in trials on living people The first thing they did was pharmacokinetics That is, they looked at how this drug behaves when it enters a person This medication is taken twice daily at a 100 mg dose And what they saw here is the ability of the medicine to remain in the necessary system of the human body for a long time

In this trial, it was important to understand that the drug is absorbable and that there is an adequate dose of the drug The accumulation of the drug between day 1 and 28 was not observed, he acted in a similar manner on the first day and on the 28th It's good We can also see that the elimination half-life is 12 hours, and the dosage method suggests that there is enough drug in the body And if the drug is effective, with these parameters it should work

Changes in biomarkers were shown only from baseline to 28 days And I will talk about this timeline later because I think this is due to the cognitive effects that we look forward to from phase 2b In general, what we see here are tau levels, amyloid beta levels, thin polypeptide neurofilament, neurogranin, as well as YKL40 protein And we see in the picture, in addition to beta-amyloid, that in the cerebrospinal fluid, as well as in plasma, a fairly significant decrease in the levels of these proteins was observed We see that for beta-amyloid there was an increase in cerebrospinal fluid (CSF) and in plasma

And this is a slightly strange correlation, but in fact, an increase in the level of amyloid beta in the CSF correlates with a decrease in the level inside the cells or in the intercellular space So it’s actually useful If you look at individual patients, the data is a little easier to read Each patient responded well to the drug, but there are two patients in whom amyloid beta levels have decreased in CSF, which is not good This means that within the cells and intercellular space, the level of beta-amyloid has increased

To look at the amyloid beta data, I will enlarge this block And we can see that, besides these two patients, all the others had increased levels of amyloid beta in the CSF, which is useful if we want to treat Alzheimer's disease With plasma biomarkers, the same thing, just instead of CSF, plasma was considered Everything is a little more diverse here, but overall the trend was going in the right direction I will not spend too much time on this

It is also seen that the level of beta-amyloid in plasma has increased I think that the ratio of the level of beta-amyloid in plasma and inside the cells is a more convincing indicator, than the ratio of the level of beta-amyloid in the CSF and inside the cells, but it goes in the right direction Researchers also looked at cytokines, considering the effect of PTI-125 on neuroinflammation This effect was small, but also went in the right direction So this is good too

And they also provided the results of a Western blot The researchers wanted to see if phosphorylation and nitrosylation of tau decreased after taking PTI-125 Western blot is not a good quantitative method for such things but he gives some insight into what is happening Although I perceive these results with some skepticism, since at one time he spent a lot of time doing this method In general, my claim to him, especially to the results on plasma samples, is that it’s difficult to normalize them, because you need to be sure that the amount entered is comparable to the standard, and here their standard is tau, but we don’t really know what to compare tau with

Some use proteins like albumin, just as a metric that shows how much was added in each sample But they didn’t show this here, which I don’t like but they showed a significant reduction in tau, as well as its phosphorylation and nitrosylation on day 28 Let us suppose But this is phase 2a of clinical trials, and I think, in general, it shows that, apparently, the effect of PTI-125 for 28 days is and it reduces the biomarkers associated with AD Now I want to express doubts: because there are reasons for which it turns out, all these results are just noise, but there is no real effect

And one of the things that seems interesting to me is that partial agonists and positive allosteric modulators of alpha-7 nicotinic receptors have already failed in CI It can be assumed that if the interaction of beta-amyloid and these receptors is affected, the condition of a patient with AD can be improved During the development of the disease, the binding of amyloid beta to the alpha-7 nicotinic receptor can occur in femtomolar concentrations, which means that this binding is very specific And if there is an antibody nearby that has less affinity for this receptor than amyloid beta, then treatment of patients at a late stage of the disease will not affect the development of the disease in general So here the PTI-125 may be useful, but it would be great to see confirmation of its target in previous studies

Another thing we should keep in mind is that filamine A enters the signaling pathway later, so there may be something else related to amyloid beta that causes the disease Another catch is that most preclinical trials were done in the same laboratory, which does not cause delight, maybe I just don’t trust the academy, but it would be great to see confirmations these preclinical results from other unrelated laboratories Of course, the company itself showed in phase 1 and 2a that something is still working, but still And finally, the results of phases 2a and 2b are only 28-day data Is it long enough to see the effect? And finally, the results on plasma and CSF suggest that there is some effect, but do not indicate directly

This must also be borne in mind And now about the stock Recent growth has been heavily driven by insider buying: their director, Robert Sanford, bought shares for $ 1 million when they were at $ 22 And it caused a stir among retail investors, the stock price reached $ 10 and then fell slightly to $ 8

But this insider purchase is not very inspiring When the results of phase 2a were originally published, stock prices rose slightly, but people were not convinced But when they saw that Robert Sanford was buying stocks, everyone jumped right there The next reason for the increase in the amount of shares is the publication of the results of phase 2b, what will happen in 2020, most likely in the second quarter The primary endpoints are again all the same biomarkers in the CSF

Secondary endpoints are more important and include cognitive functions And, of course, it will be cognitive functions that interest everyone, because it will already be the primary endpoints for the future CI, which will be very important for submission to the FDA Now, their net cash is sitting at around $ 17 million, and, as I said, they are trading at a market cap of $ 140 million and now they have a relatively generous assessment of the company, given all the factors But their operating costs since the beginning of the year were only $ 33 million, while in 2018 it was $ 5

9 million That is, they’re not just burning tons of money, but if they want to get to phase 3, their costs will increase significantly, and they will have to somehow find money to finance this business In general, in the end, I can not speak out neither for nor against And the reason for this is that I think that 28 days is too short to see significant cognitive function I looked at several different phase 2 CIs and their length, some of them last 52 weeks, some only 24, and among them there are a couple that go only 28 days

In part, I like short-term CI, which shows changes in biomarkers, but to measure changes in cognitive functions, I think it takes a longer time In the end, what I will say now is: I am not taking any position now, I think the secondary endpoints will fail, but since these are secondary endpoints, I think changes in CSF biomarkers will justify the next CI, which will be much longer and more extensive, with a large number of patients And it will already be more likely to see changes in cognitive abilities And so, after this phase 2b, I think the stock price will drop due to the failure of the secondary endpoints, but I think it will be a good opportunity to buy shares and when they already do a longer and more extensive CI, they’ll likely see changes in cognitive performance, because there will be more patients and the CI will be long enough to see the effect Then I will take a position

In general, I think that the company is very interesting, and I am happy that I looked at their results So that’s all I had for Cassava Sciences Leave comments, share your thoughts, and tell me where I'm wrong And now about the upcoming events JP Morgan Conference Begins January 13th there will be a bunch of everything, about every biotech company worthy of discussion will be there

We almost got involved in a war with Iran, which did not directly affect the biotech sector, but this is an event because of which people do not want to hold risky assets But it seems like the war was prevented Let's see how it goes I keep in mind the AIMT PDUFA, which will be at the end of January 2020 And I have a list of biotech companies

Now about the results of 2019 You can see on my screen what I ended up at 145%, which is about half of what XBI did Happenes I think my main loser was Bluebird Judging by the percentages, Marker Therapeutics also dipped steeply But the winner was Amarin All in all, 2019 was a pretty good year

Source: Youtube

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