Biotech Ideas

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CRDF reports 2nd quarter results. Much expanded relationship with PFE. Stock up 22% in AH.


- Advance to first-line RAS-mutated mCRC follows the strong signal from new clinical and preclinical data, and agreement with FDA -

- First-line mCRC represents substantial increase in patient impact and market opportunity over second-line -

- Pfizer Ignite will be responsible for the clinical execution of new first-line mCRC trial with interim topline data expected in mid-2024 -

- Cash position on June 30, 2023 was $89.4 million; sufficient to fund operations into 2025 and through interim topline results from mCRC trial -

- Company will hold a conference call today at 5:00 p.m. ET/2:00 p.m. PT -

SAN DIEGO, Aug. 7, 2023 /PRNewswire/ -- Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company leveraging PLK1 inhibition, a well-validated oncology drug target, to develop novel therapies across a range of cancers, today announced plans to advance the company's lead program to the first-line setting of metastatic colorectal cancer (mCRC) and conduct its new CRDF-004 trial with study execution support from Pfizer Ignite, a new end-to-end service for biotech companies.

Cardiff Oncology is a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers. Our lead asset is onvansertib, a PLK1 inhibitor we are evaluating in combination with standard-of-care (SoC) therapeutics in clinical programs targeting indications such as KRAS/NRAS-mutated metastatic colorectal cancer (mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC), as well as in investigator-initiated trials in triple negative breast cancer (PRNewsfoto/Cardiff Oncology, Inc.)
Cardiff Oncology is a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers. Our lead asset is onvansertib, a PLK1 inhibitor we are evaluating in combination with standard-of-care (SoC) therapeutics in clinical programs targeting indications such as KRAS/NRAS-mutated metastatic colorectal cancer (mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC), as well as in investigator-initiated trials in triple negative breast cancer (PRNewsfoto/Cardiff Oncology, Inc.)More
"Our advance to the first-line mCRC setting is the result of a comprehensive data-driven review coupled with the agreement and support of the FDA. Ultimately, this decision moves Cardiff Oncology into a stronger position to realize the promise of onvansertib for the benefit of patients and all of our stakeholders," said Mark Erlander, Ph.D., Chief Executive Officer of Cardiff Oncology. "We are delighted to expand our relationship with Pfizer and conduct this new first-line trial beginning this fall through Pfizer Ignite, leveraging its clinical execution capabilities and expertise."

The company estimates that there are 48,000 new patients in the U.S. annually in the first-line RAS-mutated mCRC setting for whom there are no ongoing clinical trials and no new treatments approved in the past 20 years.

Dr. Erlander continued: "Key to today's decision has been our discovery of a novel mechanism of action by which onvansertib inhibits angiogenesis by turning off a 'survival switch' for tumorigenesis. This has helped us understand onvansertib's interaction with bevacizumab, and the compelling clinical results we observed in our Phase 1b/2 second-line KRAS-mutated mCRC trial."

The clinical activities of the company's new CRDF-004 trial in first-line RAS-mutated mCRC will be conducted with support from Pfizer Ignite. This expands the relationship established in November 2021 when Pfizer made an equity investment in Cardiff Oncology and nominated Adam Schayowitz, Ph.D., Vice President & Medicine Team Group Lead for Breast Cancer, Colorectal Cancer and Melanoma, Pfizer Global Product Development as a Scientific Advisory Board member.

Pfizer Ignite is a new end-to-end service for biotech companies with high potential science that leverages Pfizer Inc.'s significant R&D capabilities, scale and expertise to accelerate the development of breakthrough therapies.

Cardiff Oncology will maintain full economic ownership and control of onvansertib.

"We believe onvansertib, by inhibiting PLK1, has the potential to play a meaningful role in the treatment of several types of cancer, including the lead program in RAS-mutated mCRC," said Dr. Schayowitz. "We believe that by combining Pfizer's clinical development capabilities and expertise, with onvansertib's promising novel clinical findings, we have an opportunity to accelerate the advancement of this program for the benefit of the many patients in the RAS-mutated mCRC setting."

Cardiff Oncology's new lead program in first-line RAS-mutated mCRC will consist of two trials that will be conducted sequentially. The first trial will be CRDF-004, a Phase 2 randomized trial generating preliminary safety and efficacy data and evaluating two different doses of onvansertib to confirm an optimal dose. Onvansertib will be added to standard-of-care consisting of FOLFIRI plus bevacizumab, or FOLFOX plus bevacizumab. A total of 90 patients will be randomized in a 1:1:1 ratio to either 20mg of onvansertib plus standard-of-care, 30mg of onvansertib plus standard-of-care, or standard-of-care alone. Interim topline results from this trial are expected in mid-2024.

Contingent upon the results of CRDF-004, Cardiff Oncology will initiate a Phase 3, randomized trial with registrational intent. The FDA has agreed that a seamless trial with objective response rate (ORR) at an interim point is an acceptable endpoint to pursue accelerated approval, with progression-free survival (PFS) and trend in overall survival being the endpoints for full approval.

"The stand-out results from our Phase 1b/2 second-line mCRC trial of onvansertib were observed in a well-defined subset of patients, namely those who had not previously been treated with bevacizumab in the first-line setting," said Fairooz Kabbinavar, MD, Chief Medical Officer of Cardiff Oncology. "Bev naïve patients in our Phase 1b/2 trial who received FOLFIRI, bevacizumab and onvansertib had a remarkable 73% ORR and 15-month mPFS, comparing favorably against historical controls that report an ORR of approximately 25% with a 7 to 8-month mPFS. Such high levels of efficacy have not been previously observed in 2nd line mCRC. The clinical and preclinical data we are reporting today confirm our initial finding, and based on highly encouraging interactions with the FDA and Pfizer, we are moving into first-line RAS-mutated mCRC where we believe enrollment should occur more quickly given the significantly larger number of first-line patients versus second-line."

Consistent with the strategic decision to focus on first-line RAS-mutated mCRC, Cardiff Oncology will discontinue enrollment in its ONSEMBLE second-line trial to focus resources on its new lead first-line program. This decision is driven by the fact that both trials essentially test the same clinical hypothesis, the importance of deploying the Company's capital efficiently, and the FDA's suggestion that Cardiff Oncology consider focusing on the first-line RAS-mutated mCRC setting.

All other Cardiff Oncology programs remain unaffected by this decision.

Conference Call and Webcast

Cardiff Oncology will host a corresponding conference call and live webcast at 5:00 p.m. ET/2:00 p.m. PT on August 7, 2023. Individuals interested in listening to the live conference call may do so by using the webcast link in the "Investors" section of the company's website at www.cardiffoncology.com. A webcast replay will be available in the investor relations section on the company's website for 30 days following the completion of the call.

About Cardiff Oncology, Inc.

Cardiff Oncology is a clinical-stage biotechnology company leveraging PLK1 inhibition, a well-validated oncology drug target, to develop novel therapies across a range of cancers. The company's lead asset is onvansertib, a PLK1 inhibitor being evaluated in combination with standard-of-care (SoC) therapeutics in clinical programs targeting indications such as RAS-mutated metastatic colorectal cancer (mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC), as well as in investigator-initiated trials in triple negative breast cancer (TNBC) and small cell lung cancer (SCLC). These programs and the company's broader development strategy are designed to target tumor vulnerabilities in order to overcome treatment resistance and deliver superior clinical benefit compared to the SoC alone. For more information, please visit https://www.cardiffoncology.com.

Bladerunner

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>>> Vistagen Therapeutics, Inc. (VTGN), a late clinical-stage biopharmaceutical company, primarily focus to transform the treatment landscape for individuals living with anxiety, depression, and other central nervous system (CNS) disorders. The company's pipeline includes six clinical stage product candidates, including five investigational agents belonging to drugs known as pherines. Its product pipeline comprises PH94B, a fasedienol nasal spray, which is in Phase III development for the treatment of social anxiety disorder; and PH10, a Ituvone nasal spray which is in Phase II development for the treatment of major depressive disorder. In addition, the company is also developing PH15, an early-stage investigational synthetic neuroactive steroid for the treatment of cognition improvement; PH80, an odorless and tasteless synthetic investigational pherine for the treatment of menopausal hot flashes and migraine; PH284, an early-stage investigational synthetic neuroactive steroid for the treatment of wasting syndrome Cachexia; and AV-101, an oral nmdr glycine site antagonist for depression and neurological disorders. Further, it has a license and collaboration agreement with EverInsight Therapeutics Inc. to develop and commercialize to address ophthalmologic and CNS disorders. The company was founded in 1998 and is headquartered in South San Francisco, California. <<<



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Blade, Instead of Ozempic for weight loss, you should check out cardiologist Dr. Steve Gundry (link below). Using his approach, I lost over 50 lbs (from 260 down to 205), and have easily kept it off, just by changing the types of foods consumed and by shortening the 'eating window' down to 8 hours/day (which replicates the natural eating cycle).

Gundry explains why most Americans are 'metabolically inflexible', and literally cannot burn fat at the mitochondrial level. He has numerous best selling books dealing with the various aspects, but following the info in his videos is sufficient to get the basic idea. It's a variation on the Mediterranean diet, but you need to avoid most grains (wheat, corn, soy, etc) since they contain 'lectins' (which cause leaky gut), and avoid processed foods, junk food, etc.

The ancient grains like sorghum and millet are fine, and beans are good but must be pressure cooked. Also lean meats and lots of organic vegetables. On the vegetable side, there are some to be avoided due to their lectin content, but most are fine. Peanuts and cashew are to be avoided (extremely high in lectins), but true nuts like pistachios and walnuts are great. Fruit intake is limited to in season (late summer, fall), although fruits like kiwis and avocados are good to eat all year.

Anyway, check out Gundry. Not only did I easily lose 50 lbs (less than 1 year), but my high blood pressure returned to normal, and autoimmune problems (primarily related to leaky gut) disappeared. Most of Gundry's diabetes and autoimmune patients (thousands) have been able to go off their meds, as the source of the immune system overactivity (leaky gut) is resolved.

A big key in Gundry's approach is reversing 'leaky gut' (intestinal hyperpermeability) and rebuilding the person's intestinal microbiome, which is extremely critical for good health.. Between over usage of antibiotics in medicine, and glyphosate herbicide residues on wheat, corn, the average American's gut microbiome has been absolutely devastated. Glyphosate / Roundup kills the intestinal flora by blocking the shikimate pathway, which is the same pathway associated with its weed killing ability. Glyphosate was originally patented by Monsanto as an antibiotic.

Gundry also has a lot to say about heart disease and cancer. Check him out -

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>>> Moolec Science Presents 'Piggy Sooy', a Soybean Platform That Can Produce Significantly High Amounts of Pork Proteins


Accesswire

Moolec Science SA

June 26, 2023


https://finance.yahoo.com/news/moolec-science-presents-piggy-sooy-123000813.html


LUXEMBOURG / ACCESSWIRE / June 26, 2023 / Moolec Science SA ((NASDAQ:MLEC) "Company"; "Moolec"), a science-based food ingredient company focused on producing animal proteins in plants through Molecular Farming technology, announced today an outstanding achievement in its Meat Replacements Program for the Soybean platform, as its new "Piggy Sooy" produced a significantly high amount of pork protein.

Piggy Sooy



Piggy Sooy

The animal protein reached a high expression level up to 26.6% of total soluble protein in soy seeds, 4x higher than initially projected by the Company. The result can be directly observed due to the pink color of Moolec's soybeans, the same color as the pig (access the picture by clicking here). After this achievement, the Company's soybean platform was renamed "Piggy Sooy".

The breakthrough accomplishment has led Moolec to file a new patent utilizing a novel approach aiming to provide the Company with a frictionless regulatory pathway going forward.

Moolec's CEO & Co-Founder Gastón Paladini said: "Piggy Sooy represents tangible and visual proof that Moolec's technology has the capacity to achieve significant yields in plants to produce meat proteins. With this groundbreaking achievement, Moolec consolidates its position as a category creator and a pioneer in Molecular Farming for the food industry. Our plant biology team is writing the history of science in food, I couldn't be prouder of them."

This scientific milestone consolidates the Molecular Farming path as one of the most valuable alternative technologies to produce animal proteins, given that plants can function as animal protein factories in a more efficient manner than initially expected. This enhanced efficiency of plants has the potential to improve the economics of the Company's business model.

Moolec Science is producing several meat proteins in plants as functional ingredients to improve the taste, appearance, texture, and nutrition of meat alternatives. Due to its enhanced functionality and final application, the Company also highlighted that these food ingredients could also be potentially commercialized within the ~$600 billion traditional processing meat industry.

Amit Dhingra, Ph.D., Chief Science Officer of Moolec said: "This achievement opens up a precedent for the entire scientific community that is looking to achieve high levels of protein expression in seeds via Molecular Farming." He further emphasized: "Moolec has developed a unique, successful, and patentable platform for the expression of highly valuable proteins in the seeds of economically important crops such as soybeans. This platform has the potential to be used across a wide variety of proteins of interest for a broad range of industries, such as the pharma, cosmetic, diagnostic reagents, and other food industries."

About Moolec Science SA

Moolec is a science-based food ingredient company focused on producing animal proteins in plants through Molecular Farming, a disruptive technology in the alternative protein landscape. Its purpose is to upgrade the taste, nutrition, and affordability of alternative protein products while building a more sustainable and equitable food system. The Company's technological approach aims to have the cost structure of plant-based solutions with the organoleptic properties and functionality of animal-based ones. Moolec's technology has been under development for more than a decade and is known for pioneering the production of a bovine protein in a crop for the food industry. The Company's product portfolio and pipeline leverages the agronomic efficiency of broadly used target crops, like safflower, soybean, and pea. Moolec has a growing international patent portfolio (24, both granted and pending) for its Molecular Farming technology. The Company is run by a diverse team of Ph.Ds and Food Insiders, and operates in the United States, Europe, and South America. For more information, visit moolecscience.com.

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[sgunderbarth]

OCGN getting a nudge. Corp deck https://ocugen.gcs-web.com/static-files/e4bb4434-d94d-4d09-b119-ccfcb30af927

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Candida Auris - >>> A deadly fungal infection is spreading in hospitals. Here's what to know.


by Jennifer Hassan and Fenit Nirappil

The Washington Post

March 21, 2023


https://www.yahoo.com/news/deadly-fungal-infection-spreading-hospitals-164045552.html


A deadly fungal infection is spreading at "an alarming rate" inside health facilities and long-term-care hospitals across the United States, the Centers for Disease Control and Prevention said Monday.

Here's what to know about the highly drug-resistant fungus - a strain of a kind of yeast known as Candida auris (or C. auris for short) that the CDC says "presents a serious global health threat."

While healthy people are not likely to contract the infection, those with lower immunity and people living in nursing homes are more likely to fall sick and be unable to fight the infection, and the outcome can be fatal.

What is Candida auris?

Candida is a family of yeasts that can be found on the skin and inside the body. Usually, the fungus lives in areas such as the mouth, throat, gut and vagina, without causing health problems. Common types of Candida include "Candida albicans," which causes the yeast infection thrush.

Sometimes, however, certain types of Candida can cause infection in older people and those battling other health issues.

C. auris was first discovered in the ear canal of a patient in Tokyo in 2009. It can enter the body during medical treatment, including operations or when urinary catheters, tubes or drips are inserted. It can also infect surgical wounds.

While the number of cases recorded by the CDC is only in the thousands, it is considered a serious global public health threat because it is drug resistant and has the potential to spread among the most medically vulnerable. It is also difficult to identify using standard laboratory methods, and it has caused outbreaks in health-care environments across the country.

What are the symptoms?

Candida auris can enter the bloodstream and spread throughout the body, causing invasive infections. Fever and chills that don't improve after antibiotic treatment for suspected bacterial infections are the most common symptoms of invasive candidiasis, the CDC notes.

The infection can aggravate various parts of the body, including the ears, heart, kidneys, eyes and brain.

How is the fungus transmitted?

The infection spreads easily from person to person - especially within hospital environments and among the medically vulnerable. It can also be spread through contact with infected surfaces and lingers on objects including hospital equipment such as bed rails, chairs and windowsills.

The infection can also be resistant to certain cleaning products, making it harder for the fungus to be eradicated from hospital wards.

People can also carry the infection without experiencing symptoms, unknowingly spreading the infection to other people who may be more at risk, such as people in long-term health-care facilities, including nursing home patients on ventilators, those with diabetes and cancer patients.

Those who take lots of antibiotics or antifungal medications appear to be at highest risk of infection, according to the CDC.

Between 30 percent and 60 percent of hospitalized people who develop bloodstream infections are estimated to die, according to CDC data. However, the CDC notes that many of these patients had other serious illnesses that increased their risk of death.

The CDC says more work is needed to understand how the infection spreads.

Which U.S. states has the fungus been identified in so far?

C. auris was diagnosed in a handful of patients in the United States in 2016, where clinicians on American soil had been warned by health officials to be on the lookout for the infection.

It has since been detected in more than 20 states, with the most cases recorded in Nevada, California, Florida New York, Illinois and Texas in the past 12 months, according to case counts provided to the CDC by local and state health departments.

Fungal infections from Candida auris tripled nationally from 476 in 2019 to 1,471 in 2021, the CDC said Monday.

Where else in the world have outbreaks been reported?

Since it was first reported in Asia in 2009, the fungus has been reported in a slew of countries, including Colombia, India, Israel, Kenya, Kuwait, Pakistan, South Korea, Venezuela and Britain.

Transmission of the infection was facilitated by international travel, according to the CDC, though experts say that climate change may also be fueling the infection. The infection also worsened amid the coronavirus pandemic, which hospitalized more people around the world, overburdening health-care staff who were forced to reuse personal protective equipment.

Clinical cases of C. auris soared about 60 percent in 2020 compared to 2019, according to a 2022 report from the CDC that noted the global pandemic "likely intensified spread of C. auris and hindered detection of additional cases."

One leading theory suggests that Candida has evolved to survive in a warming world, while other theories suggest that widespread use of antifungal drugs along with heavy use of fungicide on crops may have sparked the emergence of the fungus.

How can the spread be prevented?

The CDC says that several infection control measures can help prevent C. auris, including adherence to hand hygiene and thoroughly cleaning hospital environments. Equipment that is shared among patients, such as blood pressure cuffs, temperature probes and ultrasound machines, should be thoroughly disinfected frequently.

Alcohol-based hand sanitizer, gowns and gloves should also be used to reduce the spread of infection inside health-care facilities.

According to the CDC, those who have the infection and their close contacts do not have to self-isolate and can participate in social activities as long as they maintain good hand hygiene.

How is the infection diagnosed and treated?

The infection is difficult to identify with standard laboratory methods because the yeast can be mistaken for other organisms, so specific technology is needed, the CDC says.

While the CDC says most C. auris infections are treatable with antifungal medications called echinocandins, some strains of the infection have developed a resistance to antifungal drugs, making it harder to treat patients, and cases of reinfection have also been recorded.

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>>> Researchers discover way to combat superfungi


The News Glory

06/07/2023


https://thenewsglory.com/researchers-discover-way-to-combat-superfungi/


Researchers discover way to combat superfungi

A study conducted at USP reveals that brilacidin, a new drug tested for illnesses ranging from bacterial skin infections to Covid-19, can kill resistant strains of fungi when combined with two classes of antifungals available on the market.

The new potential application of the medicine, now patented and described in the journal Nature Communications, was discovered by researchers from the Faculty of Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP), in the interior of São Paulo, supported by FAPESP.

The problem of drug resistance is a challenge recognized by the WHO (World Health Organization), but the process of developing a new drug is very expensive and time-consuming.

“For this reason, we sought to identify the antifungal activity of chemical molecules that were already known, but which until then had not been studied in terms of their effects on controlling fungal growth. In this case, we started by exploring 1,400 chemical compounds until we arrived at this one”, says Thaila Fernanda dos Reis, postdoctoral fellow at FCFRP-USP and first author of the article.

Thanks to the use of different methods, the researchers concluded that the combination of brilacidin with two different antifungal drugs (caspofungin or voriconazole) has the ability to kill resistant strains of several species of fungus that cause infections in humans, such as Aspergillus fumigatus, the causative agent of invasive pulmonary aspergillosis.

Aspergillosis is a common infection in patients admitted to intensive care units (ICUs), which can lead to death in between 60% and 90% of individuals. It also affects patients with a certain degree of immune impairment, such as those undergoing cancer treatments.

In addition to combinations with antifungals for lung infections, brilacidin alone blocked the growth of the A. fumigatus and disease development in an animal model of keratitis, an infection that affects the cornea.

The eye disease affects 1 to 2 million people a year worldwide, especially in tropical countries with great agricultural activity. In the United States and other developed countries, the use of contact lenses contaminated with mold is the main risk factor.

Mechanism of action

Drug resistance occurs when the microorganism (fungus, bacteria or virus) finds a way to survive and continue to multiply even in the presence of the drug that should have stopped its growth.

Therefore, it is important to have drug options that act in different ways on the pathogen, in order to eradicate the infection even when the strain is resistant to some drug. However, while there are nine classes of antibacterials, there are only four classes of antifungals commercially available.

Caspofungin, for example, is an antifungal that has been available on the market for a long time. Its mechanism of action consists of inhibiting the synthesis of the cell wall, a structure that surrounds the plasma membrane and maintains the integrity of the fungal cell.

When in contact with the drug, however, not infrequently, the fungus activates a repair system, which bypasses the action of the drug and allows it to survive in its presence. Hence the potential of the combination of caspofungin and brilacidin. In tests, the presence of the new molecule disabled the repair system triggered by caspofungin.

“Caspofungin does not kill the fungus A. fumigatus, but hinders its multiplication. This is often enough for the host’s immune system to control the infection, but not always. That is why it is important to identify drugs capable of acting in synergy with One of the options would be to create a single drug that combined caspofungin and brilacidin simultaneously, so that they could act together”, summarizes Gustavo Henrique Goldman, a professor at FCFRP-USP who coordinated the study.

Superfungi

Another advantage of brilacidin is that the combination with caspofungin or voriconazole had action against different species of fungus.

In tests with animal models, in addition to A. fumigatus, the combination of brilacidin with caspofungin was effective in inhibiting other fungal species such as Candida albicans, Candida auris and Cryptococcus neoformans.

Called “superfungi” because of their high drug resistance, some of these strains have been blamed for serious nosocomial infections. Recently, they have become more common due to the large number of hospitalizations in ICUs due to the COVID-19 pandemic.

The synergistic action of brilacidin with voriconazole, in turn, was effective both against A. fumigatus and against Mucorales, a fungus that occurs mainly in India and Pakistan and causes serious deformations of the face.

For the effects to be proven in humans, however, clinical trials are needed. Together with the company that owns the brilacidin patent, the North American Innovation Pharmaceuticals Incorporated, the researchers are now looking for a Brazilian company that can license the medicine in the country and carry out the clinical tests, necessary to prove the effects in humans and, in case of successfully make the drug available on the market.

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>>> Axsome aims to give its balance sheet a boost


https://www.fool.com/investing/2023/06/28/as-the-bull-roars-shareholders-hate-how-these-2-co/?source=eptyholnk0000202&utm_source=yahoo-host&utm_medium=feed&utm_campaign=article


Shares of Axsome Therapeutics were down 9% early Wednesday morning. The biopharmaceutical company specializing in treatments for central nervous system disorders announced that it would sell shares of common stock.

Axsome's motivation is clear. As a biotech with a pipeline of candidate drugs, Axsome needs cash in order to run late-stage clinical trials on its most promising treatments, and the proceeds from the offering will go toward both existing and potential new clinical programs in the future. In addition, Axsome will need capital to expand its commercialization efforts for its already-approved Sunosi drug for sleep disorders and its antidepressant drug Auvelity.

The filed prospectus did not indicate a specific number of shares that Axsome intends to sell. However, the offering will fall under an existing shelf registration statement.

In the past couple of weeks, Axsome has told investors that it expects its top treatments to generate as much as $11.5 billion in revenue in the U.S. market at peak sales, which dramatically exceeds what most analysts following the stock had projected. Moreover, if Auvelity pans out as a possible treatment that could help Alzheimer's disease as well as those looking to quit smoking, then it could dramatically expand its addressable market and add to Axsome's overall success.

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>>> Has the Serotonin Hypothesis Been Debunked?

Not really. It never meant anything.


Psychology Today

Nassir Ghaemi M.D., M.P.H.

October 1, 2022 |


https://www.psychologytoday.com/us/blog/mood-swings/202210/has-the-serotonin-hypothesis-been-debunked#:~:text=The%20serotonin%20hypothesis%20of%20depression%2C%20popular%20from%20the%201990s%20until,was%20proven%20to%20begin%20with.


KEY POINTS

The serotonin hypothesis of depression never was a legitimate scientific hypothesis that could be proven or disproven.

It was meaningless in the sense of being too broad, and clearly false when defined more narrowly.

A recent review paper simply points out the absence of evidence for it, which was well-known for decades.


The serotonin hypothesis of depression, popular from the 1990s until now, is false, and has been known to be false for a long time, and never was proven to begin with. The norepinephrine hypothesis of depression, which preceded the serotonin hypothesis in the 1960s to the 1980s, also was false, and has been known to be false for a long time, and never was proven to begin with. The same holds for the dopamine hypothesis of schizophrenia, which began in the 1960s and 1970s, and more generally for the “chemical imbalance” metaphor for all mental illness.

All of these are major oversimplifications, which most scientists realize are major oversimplifications, but which the general public and many clinicians have assumed to be true. A recent review paper merely documents the absence of much if any scientific evidence for these oversimplified false hypotheses. So it’s not new scientifically at all. The first author of the review has been a major critic of psychiatric medications in general, especially serotonin reuptake inhibitors (SRIs), and thus the main purpose of the paper may be to seek to undermine the use of SRIs. It may indeed do so for the general public and those clinicians who have believed the false concepts of chemical imbalance and/or the serotonin hypothesis of depression. But for scientists and researchers, the use of SRIs is completely unrelated to these false metaphors. The use of SRIs should be based solely on the efficacy data shown for those agents in randomized clinical trials. Those data are indeed weak, and thus, I hold the view that SRIs should be used much less than they are, and for shorter durations, but this view has nothing to do with the already known false concepts of a serotonin theory of depression.

Another feature of the paper, which usually isn’t acknowledged, is that the absence of a relationship between measures of serotonin and “depression” also is expected and routine because that is the case with any biological marker of any kind in psychiatry in the past 40 years and any DSM-based diagnosis. By “depression” these studies usually mean DSM-defined “major depressive disorder” (MDD), and almost all studies for the last 40 years find that no biological marker correlates with most DSM diagnoses (with important exceptions in schizophrenia and bipolar illness). The problem is that DSM diagnoses are not biologically valid because they are not scientifically based; they are not based solely on scientific evidence but rather are social constructions of the American psychiatric profession. Hence they are not useful for biological research and almost always produce negative results, as in this paper. The NIMH leadership acknowledged this major problem in 2013 when the DSM-5 came out and since that time the NIMH policy has been to not use DSM diagnoses for biological research. So again this review is only documenting what is already known in general: Most DSM diagnoses, like MDD, do not correlate with any biological measure, like serotonin.

More generally: It is obvious that these false views are based on backward logic. Since SRIs improved depressive symptoms somewhat in clinical trials (though much less than people believe), it was assumed that depression had a basis in “low” serotonin. This would be like saying that since aspirin is a prostaglandin inhibitor, and it reduces fever, then fever is a prostaglandin disorder. In fact, prostaglandin effects is just one way to reduce fever, and it is only a last step to reducing fever. The real way to reduce fever is to stop the cause of fever earlier in the process, as with antibiotics for the bacteria that cause infections that produce fever.

Similarly with SRIs and serotonin. SRIs are only symptomatic drugs; they reduce symptoms of depression somewhat, just as aspirin reduces symptoms of fever. Their mechanism, increasing serotonin, may have nothing at all to do with the psychiatric diseases that cause depression, such as manic-depressive illness, just as the mechanism of aspirin has nothing to do with the infectious diseases that cause fever.

Also, the brain just doesn’t work that way. It’s not about “high” this or “low” that. There are many chemicals in the brain interacting with each other in a very complex manner, with negative and positive feedback loops, so that there is no sense at all to say that anything in the brain relevant to any illness has to do with simply having too much or too little of any chemical. Further, besides the chemicals often discussed, like serotonin, norepinephrine, and dopamine, there are hundreds of other proteins, called second messengers, that relay information inside neurons related to these chemicals. And those second messengers interact with each other in a myriad of ways. If SRIs partially influence depression by their effects on serotonin – even if we accept this simple statement – those effects are then transmitted by hundreds of other proteins and second messengers in ways that are far too complex to describe.

So how should clinicians explain depression to their patients? This is what I do and recommend:

“Depression is not a disease; it is a set of symptoms, like fever, chills, and night sweats. I would be a bad doctor if I just gave you anti-fever pills and anti-chill pills and anti-night sweat pills, instead of treating the infection that caused all those symptoms. Similarly, antidepressants like SRIs improve the symptoms of depression somewhat, but don’t get at the cause. Just like aspirin and Tylenol can improve the symptoms of fever somewhat, but don’t get at the cause. We might use antidepressants short-term for symptom benefit, but we should also try to find the disease that is causing your depression, such as manic-depressive illness.”

THE BASICS

What Is Depression?

Further, I could say: “Depression is not a ‘chemical imbalance’ because there is no ‘chemical balance.’ These are false metaphors. The brain is complex and many chemicals are active in many different directions in the brain. Your depression may be biological disease, in which chemicals are functioning abnormally, but it’s not about just having too much or too little of anything. And it’s not about getting everything into some ‘balance.’ It’s about treating the disease itself.”

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(also - the 'placebo effect' can be a very significant factor with antidepressant meds. The placebo effect is sometimes in the 50% range in clinical trials)



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>>> Study drugs make people worse at problem solving, not better


The Economist

June 20, 2023


https://finance.yahoo.com/news/study-drugs-people-worse-problem-171714158.html


FOR MORE THAN six months Americans have been struggling to get their hands on medications like dextroamphetamine (better known as Adderall) and methylphenidate (Ritalin). Officially, these stimulant drugs—alongside another, Modafinil (Provigil)—are used to treat attention-deficit hyperactivity disorder (ADHD).

Unofficially, the drugs are also popular with devotees of “nootropics”—chemicals that supposedly boost brainpower. Students and workers in industries from tech to finance take the medications in the hope they will improve concentration and ability to get things done. But a new paper suggests that this may be ill-advised. The drugs seem to make people slightly worse at solving problems, not better.

In a paper published on June 14th in Science Advances, a group of researchers led by Peter Bossaerts, an economist at the University of Cambridge, tested how Adderall, Provigil and Ritalin affected 40 healthy people’s ability to perform optimisation problems. They used the “knapsack task”, in which participants had to work out which items to put into a bag. The idea was to maximise the value of the items without exceeding the carrying weight of the sack. The researchers used several trials of varying difficulty, each with different weight limits and lists of items.

The participants visited the lab on four separate days. On each day they were given either a placebo pill or one of the drugs under study. The study was double-blind, meaning neither the participants taking the pills nor the experimenters handing them out knew which had been administered on which day. They found that participants achieved slightly worse end results on the task after taking a drug. The drugs did not impair people’s ability to find an optimal solution. Participants managed this in around half of the trials, whether they took the drugs or the placebo pills. But they did cause a small drop in the value of participants’ knapsacks across all trials, by making the non-optimal solutions worse.

Perhaps more striking was how drugs changed the way people attacked the task. After taking Adderall or Ritalin (but not Provigil) the participants spent far longer working on their knapsacks than they did when they had taken the placebo pill. (Participants were given four minutes to complete each trial but could submit an answer earlier if they thought they had found a good solution). When given Ritalin in particular, subjects were around 50% slower at completing trials. That was roughly equivalent to the delay expected from going from the easiest to the most difficult trial in the placebo session.

This extra time was spent moving items in and out of the knapsack, somewhat erratically. The authors assessed the productivity of each move by measuring how much it increased the value of a sack, and found that participants were about 9% less productive when they had taken one of the study drugs compared with a placebo pill. “It was like they were trying to solve a jigsaw puzzle by randomly throwing pieces in the air,” says Dr Bossaerts.

The authors argue that although the drugs made people more motivated and helped them put more effort into the task, this was more than cancelled out by the fact that the drugs decreased the quality of all that effort. In other words, although people tried harder, they became far less competent. Just how much the drugs hindered performance seemed to depend on how good a participant was without them. Star performers during the placebo session fell to the bottom of the pack when they had taken the drugs.

Popping stimulants is commonplace in industries like software and finance. One survey of 6,500 American college students reported that 14% had used the drugs for non-medical reasons. This latest study adds to a growing pile of evidence suggesting that such drugs do little to improve cognitive performance in people who do not need them. For tech bosses looking for efficient employees, and workers hoping to clock off at a reasonable hour, the stimulant shortage may be a good thing.

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>>> Aaron Rodgers talks about mental heath at a psychedelics conference


San Diego Union Tribune

by JESSE BEDAYN

6-21-23


https://www.msn.com/en-us/sports/nfl/aaron-rodgers-talks-about-mental-heath-at-a-psychedelics-conference/ar-AA1cPMMC


An eclectic crowd of thousands — podcasters, vendors, startups, seekers — swarmed a psychedelics conference in Denver this week to experience everything from a dimly lit hall packed with kaleidoscope art and a wide-ranging lineup of speakers from a former Republican governor to NFL star quarterback Aaron Rodgers.

The conference, put on by a psychedelic advocacy group, took place months after Colorado’s voters decided to join Oregon in decriminalizing psychedelic mushrooms. While it’s a sign of growing cultural acceptance for substances that proponents say may offer benefits for things like post-traumatic stress disorder and alcoholism, medical experts caution that more research is needed on the drugs’ efficacy and the extent of the risks of psychedelics, which can cause hallucinations.

Rodgers, who’ll soon debut with the New York Jets after years with the Green Bay Packers, spoke Wednesday night with podcaster Aubrey Marcus. Rodgers described taking ayahuasca with his teammates as “radically life-changing,” and claimed many other pro athletes have reached out to him.

“I found a deeper self love,” said Rodgers of his ayahuasca experience. “It unlocked that whole world of what I’m really here to do is to connect, to connect with those guys, and to make those bonds and to inspire people.”

The organization hosting the conference, the Multidisciplinary Association for Psychedelic Studies, is the largest U.S. advocacy group. It has strategized to reach the full political spectrum, said Nicolas Langlitz, a historian of science who’s researched the boom and bust of psychedelic movements.

“At the time when any topic gets politically polarized, ironically, these super-polarizing substances now get bipartisan support," Langlitz said. Still, he added, the conference is “purely designed to promote the hype."

“Any kind of overselling is not good for science because science should be accurate rather than pushing things," he said. “It’s a tradeoff. (The conference) generates interest, it generates ultimately more research, even though the research might be skewed toward positive results.”

Psychedelics are illegal at the federal level, though acceptance and interest in studying their potential benefits has grown. For example, some researchers believe psilocybin, the compound in psychedelic mushrooms, changes the way the brain organizes itself and can help users overcome things like depression and alcoholism.

The drugs themselves — and the interest in them — are not new. Mid-last century, Aldous Huxley, Timothy Leary and Ken Kesey helped spur the use of psychedelics during the counterculture movement, and optimism brimmed among some psychologists over the drugs’ potential.

But the Nixon administration criminalized psychedelics, pushing them underground.

“In both cases you have this upwelling of exuberance that may or may not be irrational,” said author Michael Pollan, who wrote a book on psychedelics and will be speaking at the conference. “But I think a big difference (now) is that the enthusiasm for the potential of psychedelics cuts across a much more representative slice of the population — it’s not about a counterculture."

Republican strongholds, including Utah and Missouri, have or are considering commissioning studies into the drugs, partly inspired by veterans’ stories. Former Texas Republican Gov. Rick Perry spoke Wednesday about helping get a bill passed in the Texas legislature in 2021 to fund a study of psilocybin for veterans, though he doesn't support recreational use. In Congress, similar veteran-focused proposals brought progressive Democratic Rep. Alexandria Ocasio-Cortez from New York and far-right Rep. Matt Gaetz from Florida into an unlikely alignment.

Public interest also appears to be growing. Just six years ago in Oakland, California, the Multidisciplinary Association for Psychedelic Studies held a conference with roughly 3,000 attendees and a smattering of lesser-known speakers and die-hard proponents.

This time, organizers estimate at least 10,000 attendees. Other famous speakers will include former NHL player Daniel Carcillo, who owns a company specializing in psychedelic therapies; Olympic silver-medal figure skater Sasha Cohen; rapper and actor Jaden Smith; comedians Reggie Watts and Eric Andre, top-10 podcaster Andrew Huberman; and Carl Hart, the chair of Columbia University's psychology department.

Recruiting that celebrity support for psychedelics is part of MAPS' public relations strategy, founder Rick Doblin said. When asked whether platforming a non-expert like Rodgers could mislead the public, Doblin demurred, adding it would be “dangerous” for anyone to claim that there are no risks to taking psychedelics.

Doblin said taking MDMA should happen “only under the direct supervision of a therapist, it's never a take-home medicine.” He also emphasized what many speakers echoed during the first day about psychedelics being paired with mental health professional: “The treatment is not the drug, it’s the therapy that the drug makes more effective."

That was a more tempered approach than his introductory speech, when, to an overflowing theater, Doblin espoused grandiose goals such as “net-zero” trauma by 2070 through the use of psychedelics.

The American Psychiatric Association has not endorsed the use of psychedelics in treatment, noting the Food and Drug Administration has yet to offer a final determination. The FDA did designate psilocybin as a “breakthrough therapy” in 2018, a label that’s designed to speed the development and review of drugs to treat a serious condition. MDMA, often called ecstasy, also has that designation for PTSD treatment.

Both Pollan and Langlitz believe further research is key — especially as the nation faces an unprecedented mental health crisis and people struggle to find adequate treatment. But, Langlitz said, it's important to let research shape the narrative.

“I would just try to keep my mind open to the possibility that in retrospect we will tell a very different story from the one that the protagonists of psychedelic therapies are currently predicting,” he said.

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