Entera: Single Phase 3l Trial Planned to Support NDA for Osteoporosis Treatment

 Entera Bio Ltd. (NASDAQ: ENTX), (“Entera” or the “Company”) a leader in the development of orally delivered peptides and therapeutic proteins, announced today the successful conclusion of its Type C meeting and agreement from the U.S. Food and Drug Administration (FDA) that a single Phase 3 placebo-controlled study could support a New Drug Application (NDA) submission of EB613 (oral hPTH (1-34), teriparatide tablets) under the 505(b)(2) regulatory pathway. The FDA also agreed that Total Hip Bone Mineral Density (BMD) could serve as the primary endpoint for the registrational study of EB613 in post-menopausal osteoporosis patients.

The single pivotal Phase 3 clinical trial includes a 24-month placebo-controlled duration with change in Total Hip BMD assessed as the primary endpoint. The 2:1 randomization (EB613 vs. placebo) and planned 400 patients exposed to EB613 are expected to be sufficient to support both the safety and efficacy assessments for the NDA. Furthermore, the FDA agreed with Entera’s proposed enrollment of post-menopausal women with osteoporosis based on a BMD T-score of ≤-2.5 to -3.0 and no major fracture history. This patient population is consistent with that studied during Entera’s Phase 2 6-month dose ranging study of EB613, which met all primary and key secondary endpoints of biochemistry and BMD. Finally, Entera intends to submit relative PK data comparing its oral tablet form of teriparatide, EB613 versus the subcutaneous injection of teriparatide, Forteo® to support the 505(b)(2) pathway.

https://finance.yahoo.com/news/entera-bio-announces-fda-agreement-110000125.html

Genes that modulate aging, lifespan

 Scientists led by the University of Tennessee Health Science Center (UTHSC) and the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerlandare exploring the elaborate interplay between genes, sex, growth, and age and how they influence variation in longevity. Their findings, which are being published in the peer-reviewed journal Science, are an important step in understanding why some people live longer than others and provide a basis for future studies to improve healthspan.

Robert Williams, PhD, chair of the Department of Genetics and Genomics in UTHSC's College of Medicine, along with Johan Auwerx, MD, PhD, professor and director of the Laboratory for Integrated and Systems Physiology at EPFL, started a program in 2016 to define genetic factors underlying aging and lifespan. "Finding common molecular pathways that control differences in rate of aging is critical to our understanding of how individuals differ in their health and lifespan," Dr. Williams said. "Such insights may help us work out ways to intervene rationally."

Drs. Williams and Auwerx worked with colleagues at the National Institute on Aging's Interventions Testing Program (ITP), which donated DNA of over 12,000 mice to the project. ITP mice are genetically heterogeneous. Each of the 27,574 mice studied is a full sibling, sharing half its genetic inheritance with each other mouse in the program, and each has a known lifespan, making them an ideal system to study.

EPFL and UTHSC researchers measured the genetic makeup of more than 3,000 mice, all of them genetic brothers or sisters. The mice were then genotyped and allowed to live until their natural death. The researchers then explored the relationship between DNA difference and differences in the lifespan of each mouse. This genetic mapping allowed the teams to define stretches of DNA in genomes that affect longevity. The results show the DNA segments, or loci, associated with longevity are largely specific to sex, with females having a region in chromosome 3 that affects lifespan. When the males who died early due to non-aging-related reasons were removed from the analysis, additional genetic signals started to emerge, suggesting some genetic variations only affect lifespan after a certain age.

In addition to finding genetic determinants of longevity, the researchers explored other contributors. In general, bigger mice die younger. The researchers found that some, but not all, of the genetic effects on longevity are through effects on growth. One of the non-genetic effects may be how early access to food affects growth. They observed that mice from smaller litters tended to be heavier adults and live shorter lives. Mice from larger litters that had to share their mother's milk with more siblings, grew more slowly and lived longer on average. The researchers corroborated these trends of early growth versus longevity in large human datasets with hundreds of thousands of participants.

Beyond characterizing how longevity is affected, the researchers worked to find genes most likely to play a role in longevity determination. They measured the effect of DNA variation on how genes are expressed and compared their analyses with multiple human and non-human databases. From this they nominated a few genes likely to modulate aging rates. They then tested the effects of manipulating these genes in roundworms and found that a subset of gene perturbations did in fact affect the lifespan. The results of this study will be a rich resource of aging genes that will hopefully guide the design of therapies that not only extend lifespan, but also healthspan.

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Story Source:

Materials provided by University of Tennessee Health Science Center. Original written by Lee Ferguson. Note: Content may be edited for style and length.

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Journal Reference:

1. Maroun Bou Sleiman, Suheeta Roy, Arwen W. Gao, Marie C. Sadler, Giacomo V. G. von Alvensleben, Hao Li, Saunak Sen, David E. Harrison, James F. Nelson, Randy Strong, Richard A. Miller, Zoltán Kutalik, Robert W. Williams, Johan Auwerx. Sex- and age-dependent genetics of longevity in a heterogeneous mouse population. Science, 2022; 377 (6614) DOI: 10.1126/science.abo3191

https://www.sciencedaily.com/releases/2022/10/221005162437.htm

Targeting ion channels to manage osteoarthritis pain

 Therapeutically targeting ion channels in nociceptor neurons may be a promising strategy to manage osteoarthritis pain, according to a Northwestern Medicine study published in Cell Reports.

Paul DeCaen, Ph.D., associate professor of Pharmacology, was senior author of the study.

Nociceptor neurons transmit pain signals to the brain using electrical currents generated by voltage-gated sodium channels; when overactive, those channels are commonly observed in cases of osteoarthritis and other aberrant pain conditions.

Targeting the sodium channels to improve osteoarthritis pain management is been explored as a potential therapeutic strategy. Previous work from the DeCaen laboratory demonstrated that a metabolite of tamoxifen, an estrogen receptor modulator, binds to the intracellular exit of the channel, underscoring it's therapeutic potential.

Despite the clear need, efforts in developing novel sodium channel blockers into real therapies has been challenging, according to DeCaen.

"Repurposing tamoxifen metabolites, commonly used to treat breast cancer, presents an alternative strategy which can bypass phase one clinical trials," DeCaen said.

In the current study, DeCaen's team administered a tamoxifen metabolite to mice that had been genetically modified to develop osteoarthritis symptoms. They found the drug bound to two intracellular receptor sites in sodium channels, blocking the entry of ions using a "bind and plug" mechanism and inhibiting sodium channels in inflamed, overactivated nociceptor neurons responsible for osteoarthritic pain.

"To our knowledge, clinical efficacy of tamoxifen metabolites for osteoarthritic pain treatment is untested. Yet many years of oncology clinical data significantly de-risks their use, which may lower overall development costs for their use to treat osteoarthritic pain," DeCaen said.

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New insights into sodium channel structure

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More information: Megan M. McCollum et al, Targeting the tamoxifen receptor within sodium channels to block osteoarthritic pain, Cell Reports (2022). DOI: 10.1016/j.celrep.2022.111248

https://medicalxpress.com/news/2022-10-ion-channels-osteoarthritis-pain.html

Type of RNA that inhibits a broad range of viral infections IDd

 RNA is often described as the single-stranded cousin of DNA, the double-stranded molecule that makes up the genomes of all living organisms. Many types of non-living viruses, however, carry their genetic information in a double-stranded form of RNA (dsRNA). When the human immune system detects the presence of this foreign RNA, it sounds the alarm by increasing the production of protective cytokines called interferons (IFN), which activate the innate immune response against viral invaders.

Scientists have attempted to harness this natural antiviral response by creating therapeutic dsRNAs that mimic features of viral genomes. But meddling with the innate immune system is a double-edged sword. Viral RNA analogs can also activate molecular pathways that lead to excessive inflammation in the body, which could cause more harm than their antiviral benefits.

Now, a group of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University has discovered a new class of immunostimulatory dsRNAs that potently induces the production of two forms of IFN (IFN-I and IFN-III) while limiting the inflammation commonly observed with previous types of RNA-based immunostimulants.

The new dsRNA molecules dramatically inhibited the ability of many viruses with pandemic potential—including SARS-CoV, SARS-CoV-2, MERS-CoV, and multiple influenza A strains—to infect human cells, in both traditional cell culture as well as in complex human Organ Chip models of the lung. In a mouse model of COVID-19, the dsRNA reduced the amount of the virus in the animals' bodies by more than 1,000-fold. The results are published today in Molecular Therapy—Nucleic Acids.

"These new dsRNAs are an attractive treatment option for COVID-19 because SARS-CoV-2 infection produces an imbalanced immune response in which the protective IFN reaction is suppressed while the inflammation reaction is elevated. By preferentially increasing IFN-I, our dsRNA has the potential to correct this imbalance, and could be used to treat many other viral diseases as well," said co-first author Haiqing Bai, Ph.D., a former Wyss Technology Development Fellow who is now Director of Preclinical Development at Xellar Biosystems.

Serendipitous discovery, systematic sleuthing

For years, Bai and other members of Wyss Founding Director Don Ingber's lab have been developing new treatments for viral diseases using their human Organ Chip platform. Prior to 2020, the team was working on identifying genes in human lung cells that regulate their responses to influenza A infection, which at the time was the virus of highest pandemic concern. They started by using CRISPR-Cas9 screening to identify host genes that might inhibit the proliferation of the influenza virus. One of their top candidates from the screening was a gene called DGCR5, which produces a long, noncoding RNA sequence rather than a protein. To see how DGCR5 impacted infection rates, they "knocked down" the gene by designing three different double-stranded small interfering RNAs (siRNAs) to interfere with the gene's expression, then delivered the siRNAs into cultured lung cells.

The researchers found that this mixture reduced DGCR5 levels by more than 80% and inhibited influenza A infection by more than 90%. Excited by these results, they started testing the siRNAs individually as well as some additional DGCR5-specific siRNA sequences. To their surprise, while nine of the ten siRNAs they created significantly reduced DGCR5 gene expression, only one of them inhibited viral infection. It seemed that DGCR5 activity might not be the driver of viral infection rates.

When they investigated further, they confirmed that this particular siRNA caused the upregulation of multiple genes that are involved in the IFN signaling pathway. Additional studies revealed that the siRNA exclusively activated one of three signaling pathways that can trigger IFN production, known as the RIG-I pathway, which is an essential component of the innate immune response. The researchers began to suspect that they had discovered a new class of dsRNAs that stimulated the immune system via a previously unknown mechanism of action.

They got to work systematically generating and testing more than 200 variations on the original dsRNA sequence to tease out that mechanism. They identified a particular string of nucleotides, called a "motif," that was consistently present on one end of dsRNAs with high IFN-stimulating activity: a cytosine (C) on one strand and three guanines (GGG) on the other strand. Because the C binds to one G of the GGG sequence in the motif, there is an "overhang" of two Gs at the end of each dsRNA. When many copies of the dsRNA are present, the overhanging Gs of one molecule can bind to those of another molecule via an unusual phenomenon called G-G Hoogsteen base pairing. The resulting dsRNA dimers then directly bind to RIG-I very effectively, causing its activation and the subsequent IFN response.

"That was very interesting to us, because previous studies had shown that RIG-I can be activated by 'blunt-ended' duplex dsRNAs that lack overhangs, and that almost any type of overhang can prevent RIG-I binding. But the unique G-G binding behavior we observed effectively creates blunt-ended dsRNAs that can potently activate RIG-I, so in this case, the overhang is crucial to the activity of our novel dsRNA," said co-first author Longlong Si, Ph.D., a former Wyss Technology Development Fellow who is now a Professor at the Shenzhen Institute of Advanced Technology in China.

From flu to COVID and beyond

To see how effective their newly discovered dsRNAs were in living cells, the researchers tested one of them head-to-head against a synthetic immunostimulant that mimics viral infections called poly(I:C). When they applied the two treatments to human epithelial cells, they found that the dsRNA produced a less inflammatory antiviral response, while the more inflammatory poly(I:C) caused much broader changes in gene expression and impacted other biological processes that are essential for normal cell function.

Taking it one step further, the team then tested the dsRNA in human Lung Airway and Alveolus Chips previously developed at the Wyss Institute to replicate complex human organ tissue and functions in vitro. They introduced the dsRNA into healthy chips and saw that IFN-I expression increased between 12- to 40-fold. When they then added influenza A to the Organ Chips, they found that the dsRNA suppressed infection by 80-90%.

Then the COVID-19 pandemic hit, and the team pivoted their studies from influenza to SARS-CoV-2 and the related coronaviruses SARS-CoV, MERS-CoV, and the common cold virus HCoV-NL63. Their dsRNA took the change in stride, inhibiting MERS-CoV and HCoV-NL63 infection of a mammalian cell line derived from monkeys by more than 90%, and SARS-CoV by more than 1,000-fold. It also inhibited SARS-CoV-2 infection of a human epithelial cell line by a stunning 99.99%.

These studies were completed in collaboration with Matthew Frieman's group from the University of Maryland School of Medicine and Benjamin tenOever from the Icahn School of Medicine at Mount Sinai (now the Grossman School of Medicine at New York University).

Finally, they tested the dsRNA in a mouse model of COVID-19 with collaborators Dong Yang and Colleen Johnsson, Ph.D. at the University of Tennessee Health Science Center. When they infected the treated mice with SARS-CoV-2, the dsRNA reduced the viral load in the animals' lungs by more than 1,000-fold compared to animals treated with a scrambled dsRNA sequence.

"The COVID-19 pandemic has made it painfully clear that we need broad-spectrum therapeutics that are capable of attenuating infection by a wide variety of viruses, rather than developing a bespoke treatment for each individual disease as it arises. I'm hopeful that this RNA therapeutic technology, whose chemical and physical properties make it easily manufacturable at large scales, will become a widely used approach for fighting future pandemics," said Don Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and Boston Children's Hospital, and Hansjörg Wyss Professor of Bioinspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

In addition to treating viruses, these novel dsRNAs could treat bacterial, fungal, and parasitic infections, as well as conditions like cancer and autoimmune diseases that could benefit from increased IFN production. They could also be used as an adjuvant to enhance the activity of other vaccines.

The authors say that it is important for future studies to establish the optimal timing of treatment, as activating IFN too late in an infection may exacerbate inflammation, as well as to investigate the possibility of administering the dsRNA directly to the upper airway (for example, via an inhaler) to minimize systemic immune activation.

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Soybean study designs and implements a more effective and less toxic bio-fungicide

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More information: Longlong Si et al, Self-assembling short immunostimulatory duplex RNAs with broad-spectrum antiviral activity, Molecular Therapy—Nucleic Acids (2022). DOI: 10.1016/j.omtn.2022.08.031

https://medicalxpress.com/news/2022-10-rna-inhibits-broad-range-viral.html

Less than 1/3 of FDA regulatory actions backed by research or public assessments

 Less than a third of regulatory actions taken by the US Food and Drug Administration (FDA) are corroborated by published research findings or public assessments, finds a study published by The BMJ today.

The researchers say their findings, based on analysis of drug safety signals identified by the FDA from 2008 to 2019, suggest that either the FDA is taking regulatory actions based on evidence not made publicly available, or that more comprehensive safety evaluations might be needed when potential safety signals are identified.

Monitoring the safety of a medicine once it is available to patients (known as post-marketing pharmacovigilance) is essential for monitoring drug safety.

The US Food and Drug Administration (FDA) receives more than 2 million adverse event reports annually through its Adverse Event Reporting System (FAERS) and reviews all potential safety signals to determine if regulatory action is needed.

In 2007, the FDA Amendments Act required the FDA to publish quarterly reports of safety signals from FAERS, providing an opportunity to examine them to better understand this pharmacovigilance system.

A team of US researchers therefore decided to analyze safety signals identified within the FAERS database. They investigated how often these signals resulted in regulatory actions and whether they were corroborated by additional research.

They found that from 2008 to 2019, 603 potential safety signals identified from the FAERS were reported by the FDA, of which about 70% were resolved, and nearly 80% led to regulatory action, most often changes to drug labeling.

In a separate in-depth analysis of 82 potential safety signals reported in 2014-15, at least one relevant study was found in the literature for about 75% of the signals, but most of these studies were case reports or case series.

However, less than a third (30%) of regulatory actions were corroborated by at least one relevant published research study, and none of the regulatory actions were corroborated by a public assessment, reported by the Sentinel Initiative.

These are observational findings, and the researchers acknowledge some important limitations. For example, they did not evaluate regulatory actions taken in other countries in response to these safety signals, which might have informed the FDA's actions, nor could they consider unpublished studies or other data accessible to the agency but not publicly available.

Nevertheless, they say these findings "highlight the continued need for rigorous post-market safety studies to strengthen the quality of evidence available at the time of regulatory action, as well as the importance of ongoing efforts to leverage real world data sources to evaluate and resolve signals identified from the FAERS and support FDA regulatory decisions."

In a linked editorial, experts argue that regulators should publish all evidence underlying their responses to drug safety signals to reduce harm and ensure public trust in medicines.

The COVID-19 pandemic has exposed the tension underlying regulatory decisions and the public's right to know about serious risks associated with medical interventions, they write. This same tension exists more broadly in medicine safety.

"Safety signals are an important step, but radical transparency about available evidence and the basis for regulatory judgments is needed to reduce harm caused by medicines, as is adequate follow-up to ensure safer use," they conclude.

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Drug side effects across pediatric development stages identified, shared publicly

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More information: Characterization and corroboration of safety signals identified from the US Food and Drug Administration Adverse Event Reporting System, 2008-19: cross sectional study, The BMJ (2022). DOI: 10.1136/bmj-2022-071752

https://medicalxpress.com/news/2022-10-fda-regulatory-actions.html

Alzamend Neuro Adds Healthy Subjects to Ongoing Phase IIA Trial for AL001 in Alzheimer’s

 Alzamend pursuing additional indications of bipolar disorder, major depressive disorder and post-traumatic stress disorder for AL001

 

ATLANTA--(BUSINESS WIRE)-- Alzamend Neuro, Inc. (Nasdaq: ALZN) (“Alzamend”), an early clinical-stage biopharmaceutical company focused on developing novel products for the treatment of Alzheimer’s disease (“Alzheimer’s”), bipolar disorder, major depressive disorder (“MDD”) and post-traumatic stress disorder (“PTSD”), today announced it has dosed its first healthy adult subject in its Phase IIA multiple ascending dose (“MAD”) study of AL001 in subjects with dementia related to Alzheimer’s. This blinded, placebo-controlled trial (AL001-02) was initiated in May 2022 and is designed to evaluate the safety and tolerability of AL001 under multiple-dose, steady-state conditions and determine the maximum tolerated dose.

Alzamend is also pursuing AL001 for the treatment of bipolar disorder, MDD and PTSD. Based upon a recommendation by the U.S. Food and Drug Administration (“FDA”) after its review and commentary on Alzamend’s pre-investigational new drug (“IND”) briefing package for development of AL001 for bipolar disorder, MDD and PTSD, the ongoing clinical trial in Alzheimer’s patients has been expanded. As the safety and tolerability of AL001 would need to be tested in healthy and elderly adults before Alzamend could initiate later-stage testing of AL001 for bipolar disorder, MDD and PTSD, the addition of healthy and elderly adults to the on-going AL001-02 clinical trial would expedite the timing of further clinical trials. Alzamend will test AL001 in four healthy adult and elderly adult cohorts of eight subjects under MAD conditions.

AL001, a novel lithium-salicylate-L-proline engineered ionic cocrystal lithium delivery system, is under development as an oral treatment for patients with Alzheimer’s disease, and more recently for other neurodegenerative and neuropsychiatric disorders. AL001 has the potential to deliver benefits of marketed lithium carbonate while mitigating or avoiding current toxicities associated with lithium. In a Phase I relative bioavailability comparison of AL001 to lithium carbonate completed in March 2022, AL001 was shown to be bioequivalent at 50% less the dosage of lithium carbonate and the shapes of the lithium plasma concentration versus time curves were similar. Additionally, AL001 salicylate plasma concentrations were observed to be well tolerated and consistently within safe limits and the safety profiles of both AL001 and the marketed lithium carbonate capsule were benign.

https://www.biospace.com/article/releases/alzamend-neuro-announces-addition-of-healthy-subjects-to-ongoing-phase-iia-clinical-trial-for-al001-in-alzheimer-s-subjects/

America deserves answers on Biden’s cognitive function

 Though I have never examined President Joe Biden nor read through his full health records, nevertheless, as a practicing internist who treats many elderly patients, I have reason to be concerned. What exactly is his level of cognitive function?

Most worrying is the area of executive function, which includes the ability to plan, pay careful attention to detail, perform tasks, concentrate on detailed information and most of all make decisions. It goes without saying that the president as this country’s chief executive must have a very high level of executive function.

The best way to approach Biden’s apparent multiple memory lapses and periods of disorientation is not to speculate based on video clips alone but to demand full disclosure and transparency, especially of a president almost 80 years old with a significant medical history. If he decides to run again, I’m on record demanding full health transparency of all candidates for higher office, tracing back to when John McCain was 71 and running for president in 2008. I called it “the McCain Protocol” in 2016 when both Donald Trump and Hillary Clinton were over 70 and running for president.

The president has been known to stumble through speeches and have gaffes.

REUTERS

I would prefer Biden have a cognitive neuropsychiatric test right now, much as Trump underwent the Montreal Cognitive Assessment when he was in office and released the results. 

Of course, there’s substantial precedent for ill presidents hiding their ailments from the public, from Woodrow Wilson’s severe case of Spanish flu (which arguably affected the Treaty of Versailles) and subsequent stroke to Franklin Roosevelt’s heart failure to the extent of Dwight Eisenhower’s heart disease to John Kennedy’s Addison’s disease, all while still in office.

There’s reason to pause before demanding full disclosure by a sitting president for fear of sending a message of weakness — more than Biden is already doing with his erratic behavior — to our enemies. Still, annual presidential physicals are now routine, and there comes a point where impairment is substantial enough that the impact of the illness is more dangerous than the need to present a strong face.

Has this president reached that point? We don’t know.

But there are reasons to be concerned based on what we do know. Last fall, the president’s physician, Dr. Kevin O’Connor, released a letter summarizing his latest physical. Most troubling was the report his gait had stiffened significantly over the prior year. This was attributed to degenerative arthritis, but there was no MRI, no cognitive test reported and no evaluation from a neurologist included.

Though the letter was reassuring in that it stated there was no evidence for Parkinson’s disease or stroke, still, detail was sorely lacking — and in fact a stiffening gait can be associated with multiple conditions (including white matter damage or normal pressure hydrocephalus) that cause cognitive decline. With another presidential physical coming up soon, it’s time to include a comprehensive cognitive exam. 

Biden has not taken a cognition test like Trump did.

CNP / Polaris

Back in 1988, Biden had two brain aneurysms surgically clipped and he sustained a brain bleed, both of which medical literature has shown to lead to long-term risks of cognitive decline. Not only that, but atrial fibrillation, an arrhythmia the president has had for more than a decade, has also been found to be associated with cognitive problems as well as silent damage to the brain, according to the recent Swiss Atrial Fibrillation Cohort study. 

Most recently, the president survived COVID, and though he did not appear to suffer from post-COVID complications, there’s still a significant risk it exacerbated pre-existing neurological issues if they exist. 

Simply being over the age of 75 carries with it a higher risk of cognitive impairment of at least 20%. 

There are 40 million people in America with mild cognitive impairment, much of which is not diagnosed. But when it comes to the president of the United States, piloting the ship over the rough waters of international and domestic crises, dealing with Russian President Vladimir Putin and Chinese President Xi Jinping, not to mention the Mexican drug cartels, the border crisis and a faltering economy, what is mild in someone’s grandfather instantly becomes magnified by the demands of the highest office.

The president should certainly be cognitively tested if he decides to run again and the results released at that point if not sooner. Add an MRI and a formal neurological assessment for good measure.

I know many neurologists who aren’t reassured by general statements from the president’s doctor and would like to see a more comprehensive evaluation administered and reported with the upcoming annual physical.

Dr. O’Connor has an obligation based on medical ethics to determine the functionality of the president. This ongoing assessment should include a full neurological evaluation. 

Marc Siegel, M.D., is a clinical professor of medicine and medical director of Doctor Radio at NYU Langone Health and a Fox News medical analyst.

https://nypost.com/2022/10/04/america-deserves-answers-on-president-bidens-cognitive-function/