Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!
The advancements in the genetics and the growing body of knowledge of embryonic development have altered the search for the cause of Alzheimer’s disease, and many neurodegenerative diseases. The new paradigm fixes the primary cause to lie within the cellular gene transcription mechanism of the neurons leading to their degeneration into a kind of dysfunctional and devolved Franken cells. The amyloid and tau plaques are relegated to secondary effects. Due to the large amount of capital poured into the research and careers, the plaque theory might still try to linger a bit, but the writing is already on the wall and the frustration shall soon set in as trials are failures or at least are presenting the industry with results incommensurable with drugs cost as most of them are monoclonal antibodies.
About one-third of the drugs in the development, targeting the plaque, are now seem to be defunct. Most drugs targeting the neurotransmitters might find some limited synergy with new breed of drugs, but that to be seen though. The future belongs now to those who pursuit the new targets.
See link to reference https://advances.sciencemag.org/content/6/46/eaba5933.
These new targets are likely to be neurotrophic growth factors and some drugs directly or indirectly affecting the cellular transcription mechanism, like Sigma 1 receptors agonists. CRISPR therapies seem not to be ready yet to tackle Alzheimer’s, if at all, can only be limited to familial AD which accounts for just 5% of cases. The field might be also open to RNA interference drugs but this has be proven yet, if ever.
Athira Pharma ($ATHA) sports the ATH-1017 small molecule HGF/c-Met modulator as a drug against Alzheimer’s disease. Some things need to be explained first about HGF/c-Met complex. HGF stands for Hepatocyte Growth Factor. As the names has it was probably first identified in and connected with liver as the name says. Liver is a very peculiar organ in human body because it is the only one able to regenerate. You can remove half the organ from a patient and then see that liver will regrow soon to its previous size.
From what can be read on Wikipedia page about HGF, the most conspicuous facts about the compound are the ability to generate healing and the involvement of the HGF/c-Met complex in oncogenesis that is the process of growth and development of tumors.
In more detail, the interactions of HGF and its receptor c-Met are connected with embryonic growth and wound healing, that at least on the more desired part. These two phenomena require divisions of cells, differentiation into their respective cell fates, and mobility of cells, called motility, in order to allow them to move around and settle into the cell matrix for specific structures for organ or tissue functions to emerge.
We are best familiar with small wound healing. This is possible as autologous stem cells residing in the both edges of cut skin are coxed into dividing, differentiating into proper cell type and migrating into new cell matrix specific to skin, slowly closing the wound. Similarly the rejuvenating effort in the brain would have to rely on autologous stem cells present in the brain. There is a theoretical limit of usefulness of such compounds like ATH-1017 as the research had revealed that the population of those cells in brain dwindles with age and the capability of self regeneration of the brain diminishes, unless ATH-1017 can “rejuvenate” the Franken neurons, either directly or through neurotrophic action from the galia cells. But would that be enough to turn them back from the brink of the total dysfunction? (see first reference) These are my doubts about ATH-1017.
Wound healing is much more complex phenomena as it involves also the immune system, and inflammation. As it has been revealed run away inflammation does immense amount of damage to those suffering from Alzheimer’s. An example later on will be provided.
The word modulator means that the small molecule drug acts as some kind of “amplifier” to the original amount of HGF acting on local c-Met receptor present on the cells in given tissue. HGF is not endocrine compound, that it is not systemwide. Since its presence is localized to a particular tissue the action is local. Such compounds are called paracrine.
The premiss on which the ATH-1017 should help the patients sick with Alzheimers is that the low expression of HGF/c-Met complex existing in Alzheimer’s patients should be helped by modulating it higher. This should cause the fall of inflammation, increase in neuron health as HGF enhances the cell survival, neurogenesis by enhanced cell division, and last but not least the growth of dendrites and creation of new synapses. The list is taken from company presentations, I gather that these were observed in vitro or in murine model. These effect seem mostly to refer to changes induced in existing neurons. These are necessary for ATH-1017 success.
HGF/c-Met modulates the function of NMDA receptor in neurons. NMDA receptor among others regulates the flow of positive ions into the cell. Synaptic health relies on proper flow of ions for its status. Here is an interesting take on the effort to target neurotransmitters and their respective receptors. NMDAs are glutamate receptors and are connected with excitatory system in the brain. Like many features in cell biology there is a dark side to NMDA receptors. Since the receptors are present not only at the synapses, they have another role to play outside of the synapses. Extrasynaptic NMDA receptors form a death signaling complex with TRPM4. There has been years long pursuit of compounds like ATH-1017 and the company claims that the drug increases the expression of NMDA receptors in the synapses vs. the extra synaptic ones without causing any harm to neurons or astrocytes feeding the neurons.
The fear of using modulator for a complex HGF/c-Met which is involved also in oncogenesis is that safety of the drug can be suspected of being in synergy with cells on their way to turn cancerous. Athira Pharma claims that the drug went through complete GLP (Good Laboratory Practice) toxicology testing regiment, and was approved for Phase 1b. I think due to above reasons and others, those seen in animal models, the dosing has been limited to 8 days but lest we forget that this is just phase 1b and not phase 2, we should dismiss any misgivings.
It might be that oncogenesis requires a number of mutations before it can snowballing into fully formed tumors, and even more so to reach the stage ready for metastases. On the other hand, octogenarians’s bodies might have accumulated more mutations so they might be more susceptible to oncogenesis than semi-centennials (50 years old). In general I would accept the verdict of safety.
The 8 day dosing period is too short a period to allow for meaningful measurement of the cognitive abilities so Athira Pharma has selected the more susceptible to change in such short period of time measure that is the latency in P300 response to audible stimuli.
The test set up relies on detecting oddball sound in steady stream on noise and requires the subject to press a button upon hearing it so it calls for the engagement of attention and memory. Standard setup of electrodes is placed on the scalp of patients. For more information I suggest viewing the presentation on Athira Pharma investors page. I will use slides from this presentation in the post.
The slide presents the comparison between the waveform of healthy age adjusted individual and Alzheimer’s afflicted patients. There are two most conspicuous differences between those two: The Latency which varies from 250ms to 450 ms in healthy subjects and Amplitude. Though these two are semi-independent in general the difference in early and moderate Alzheimer’s is better viewed through the difference in the square of the area under both curves (age-adjusted). The debate of latency vs amplitude rages on and is best presented in abstract to this paper. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad0061
The amplitude of the event-related potential P300 component is sensitive to aging and Alzheimer’s disease (AD). Using a standard 20-electrode configuration, the P300 was measured during an “oddball” task in 14 young normal individuals (YN: 21-41 years), 11 elderly normal individuals (EN: 61-80 years), and 23 probable AD patients (AD: 63-93 years; NINCDS-ADRDA criteria). P300 latencies and amplitudes were measured at PZ. Additionally, algorithmic calculations were made from spline plots across the 11 central electrodes for P300 peak voltage latency and total field energy. The measured versus calculated latencies were in general agreement. Furthermore, the measured P300 voltage amplitude was closely related to the calculated total field energy. P300 voltage latency was significantly prolonged in the elderly, but not more so in AD patients (average latency [ms ± SD]; YN, 315 ± 21; EN, 364 ± 48 and AD, 361 ± 56). P300 amplitude showed the expected pattern of change from young to elderly to AD (average voltage [uV ± SD]; YN, 13 ± 5.1; EN, 8.3 ± 2.8; and AD, 4.9 ± 3.3). Summing the squares of each wave (an indication of power: P = V2 R) showed the expected change with age more strongly than the P300 amplitude (average ± SD; YN, 44,397 ± 32,386; EN, 9,996 ± 7,018; and AD, 3,347 ± 2,971). Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude. Results suggest that the P300 is not obliterated in early AD, but is barely discernable in late AD. The approaches to calculating the P300 described here are potentially useful for measuring specific neural systems affected by aging and AD.
The most important information contained in this quotation is that “Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude.”
Another source I have checked comes to similar conclusions about sensitivity of latency testing vs. changes in cognitive measures like Mini-Mental State Exam. Though Athira Pharma posts it on its page, it rather supports my point.
The latency data is provided on new slide.
I plotted this information and tried to fill-in the hypothetical daily dosing.
The X-axis is the duration of trial in hours, the y-axis is the diminishing latency. Black line is the data taken from the slide. Red line is data filled in based one the former behavior.
From what I see is that in 3 hours there is a rapid fall in latency then followed by slow return to almost previous level. Though I don’t want to discredit the steady average drop in latency over the 8 days, the immediate action depends heavily on concentration of drug soon after injection. In my opinion this form of response is connected to rapid fall of inflammation in the brain due to injection of ATH-1017.
I had seen a video where a medical doctor would inject people with anti-inflammatory drug directly into the space between spine and peridural membrane, in the neck region. Then he would tilt the table on which was the Alzheimer’s patient to allow the CSF flow in the brain and in just an hour the patient would talk of mental fog lifting. I guess every investor in Alzheimer’s stock would get severe case of FUD upon seeing such simple remedy. The video was taken off Youtube and the practitioner was sectioned by regulators as his approach was deemed too unsafe and experimental.
Another reason for sudden change in latency can be placed at the doorsteps of affecting NMDA receptors in positive way. The ATH-1017 showed an extraordinary efficacy in lowering the latency. Now, comes the question to what can this can be attributed. Boosting NMDA function, lowering inflammation or “rejuvenating” neurons? To fully answer this in positive or negative we need cognitive improvement data as planed in ACT-AD phase 2 trial (ADAS-Cog11) which is the gold standard here. The latency or amplitude data is just auxiliary information.
Similar data exists for Anavex Life Sciences Blarcamesine which is more advanced in dosing and results than ATH-1017. This data can be used to speculatively evaluate future prospects of Athira Pharma drug.
If the amplitude and latency be equal and the duration of 12 days comesurable with the 8 days then we have almost the same relative rise in measures. For Blarcamesine it is from 6.5 millivolt to 7.8 millivolt so its is raise to 120% at the end of second period. It is impossible to compare the amplitude as P3b is just one component of P300. Under ATH-1017 latency is reduced from 390 milliseconds to about 300 millieconds latency, raise to 130% in improvement. Upcoming Lift-Ad and ACT-AD pahse 2/3 and phase 2 respectively will reveal the extend to which this similarity in this auxiliary measure is going to pan out as valid indication of durable increase in cognition for Alzheimer’s patients as data will be collected in ADAS-Cog11.
$AVXL’s Blarcamesine is on verge of proving itself to tackle Alzheimer’s like no other drug till now. See my other posts, and this one in particular.
Blarcamesine is a SIGMAR1 agonist, ATH-1017 is a modulator of a growth factor. The former has been almost validated as a potent AD drug and other neurodevelopmental and degenerative diseases drug, probably being first in a new class of drugs. The same might happen will ATH-1017 as it can become a first growth factor drug, and the first competition to SIGMAR1 agonists. Whether this be the case we shall find out in two years time. For now I can voice some doubts, recervations, misgivings, but most of all hope.
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