A Phase 2/3 Clinical Trial of Trigriluzole for Alzheimer’s Disease

The first patient has been enrolled in a Phase 2/3 clinical trial of trigriluzole (BHV-4157), a novel glutamate modulator for the treatment of mild-to-moderate Alzheimer’s disease (AD). The trial is a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of trigriluzole in patients diagnosed with AD of mild-to-moderate severity (Mini-Mental State Examination scores of 14-24 at screening), and is being conducted in collaboration with the Alzheimer’s Disease Cooperative Study (ADCS) at sites throughout the USA.Howard Feldman, MD, FRCP, Director of the ADCS and Professor of Neurosciences at University of California San Diego School of Medicine added, “The preclinical evidence for the active metabolite of trigriluzole to modulate glutamate and confer neuroprotective effects in patients with AD is compelling, and the new formulation of trigriluzole should improve its pharmaceutical properties with potential for efficacy in AD.”

Alzheimer’s disease is a progressive, fatal neurodegenerative dementia that accounts for 60 ? 80 percent of dementia cases. Alzheimer’s disease currently has no cure. Although there are FDA-approved medications for symptomatic treatment of AD, their clinical benefits are generally limited. Novel therapeutic approaches aimed at normalizing synaptic and extra-synaptic glutamate levels, such as trigriluzole, may offer the potential for symptomatic benefit in AD by improving cognitive function, as well as the potential for disease modification by preventing the loss of synapses.

The Phase 2/3 clinical trial (clinicaltrials.gov identifier NCT03605667) is a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of trigriluzole in patients diagnosed with AD of mild-to-moderate severity (Mini-Mental State Examination scores of 14-24 at screening). Patients who have been taking stable doses of FDA-approved AD medications (AchEI also known as acetylcholinesterase inhibitors and/or memantine) for a minimum of three months prior to screening and who are willing to remain on the same regimen for the duration of the trial may be eligible to participate. Approximately 292 patients will be randomized on a 1:1 basis to receive 280 mg of trigriluzole or placebo, taken orally at bedtime. Duration of treatment will be 48 weeks.

About Trigriluzole
Trigriluzole is a third-generation prodrug and new chemical entity that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. Trigriluzole has a wide range of pharmacological actions, including interactions with several types of ion channels, cellular signaling mechanisms and facilitation of glutamate reuptake. Some potential targets related to trigriluzole’s mechanism of action include (1) reducing presynaptic glutamate release through actions at the voltage-gated ion channels, (2) facilitating glutamate uptake via EAATs located on glial cells, (3) enhancing transmission through synaptic AMPA receptors, (4) altering GABAergic neurotransmission, and (5) effecting neurotrophic agents such as BDNF. Several of these targets of trigriluzole balance abnormalities observed in human AD post-mortem tissue as well as in AD animal models. As such, trigriluzole potentially offers neuroprotective effects at the level of the synapse as well as improved synaptic functioning, mechanisms that could exert both symptomatic and disease-modifying effects in AD.

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Finding New Treatments for Breast Cancer with Brain Metastases

As if Breast Cancer or Brain Cancer alone were not enough to combat — patients with both now?have new hope in light of fledgling research that is showing progress.

Once breast cancer metastasizes into other areas of the body, particularly the brain, it becomes much more dangerous. And while the National Cancer Institute spends more than $500 million dollars per year on breast cancer research, only two to five percent of this funding goes to study how the disease spreads.

A clinical trial is open nationwide through the Academic Breast Cancer Consortium (ABRCC), giving access to an exciting novel drug therapy combination. The tucatinib, palbocilib and letrozole trial is coordinated by ABRCC and currently open for enrollment at the University of Colorado Cancer Center; University of Texas Health and Science Center in San Antonio, TX; Stony Brook University, NY; University of Arizona, Tucson, AZ; and University of New Mexico, Albuquerque, NM and will also be accruing patients at Northwestern University, Chicago, IL.

There are three well-established predictive markers of breast cancer. They are estrogen receptors (ER), progesterone receptors (PR), and the growth factor receptor HER2, these receptors may be blocked with targeted drugs to stop cancer growth. Breast cancers lacking these three markers are referred to as ?triple-negative? but clinicians and scientists are quickly learning more about cancers that have all three receptors, which are often called ?triple-positive.? There are treatments against each target individually, but when multiple drivers are present, as in ?triple-positive? breast cancer, blocking one often results in cancer nimbly switching to driving its growth with the other two.

The study combines tucatinib, which inhibits HER2, with letrozole targeting ER and PR hormone receptors, and the drug palbociclib, which targets CDK proteins that help cancer cells rush through the process of replication. The three had not been tried together until Elena Shagisultanova, MD, PhD, a breast cancer specialist at UCH, hypothesized there could be a way to target all three drivers at the same time with better results than targeting combinations of any two.

?When metastatic cancer spreads to the brain, it can be especially challenging,? says Dr Peter Kabos, the National Medical Director of the Academic Breast Cancer Consortium (ABRCC) and the Kabos Research Lab for Breast Cancer at UC Denver. ?Many medications aren?t effective in the brain, but exciting early clinical trial data for tucatinib shows that it may be one of the drugs that can penetrate the blood-brain barrier to combat brain metastases.

The trial is funded by the Pfizer ASPIRE Award in Breast Cancer Research. Cascadian Therapeutics and Pfizer are providing the study drugs tucatinib and palbociclib. For more information about trial eligibility and participation, contact brad.mackay@ucdenver.edu or emily.berens@ucdenver.edu

Article excerpted with permission from the University of Colorado Cancer Center blog — for the complete story, click here.

Orphan Drug Designation for Treatment of ALS – Amyotrophic Lateral Sclerosis

On March 29, 2018 the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development granted Orphan Drug Designation (ODD) to experimental therapeutic EH301 for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease.

The Orphan Drug Designation submission included data from a 2017 double-blind placebo-controlled European pilot study in humans. To expand on the results of the pilot study, Elysium Health expects to initiate a placebo-controlled study in collaboration with Mayo Clinic to evaluate EH301 in up to 150 adults with ALS by the fourth quarter of 2018. The granting of ODD to EH301 does not alter the standard regulatory requirement through adequate and well-controlled studies to support FDA approval, and there is no guarantee EH301 will be approved for the treatment of ALS by FDA.

Elysium Health Chief Scientist Dr. Leonard Guarente remarked that “There is a great deal of work to be done to address the need for continued research to better understand and to treat all neurodegenerative diseases. We believe that the FDA’s granting of Orphan Drug Designation for EH301 for ALS underscores the need for novel treatments for this rare condition.”

ALS is a rare neurodegenerative disease that affects nerve cells that control voluntary muscles throughout the body to produce movements including talking, eating, walking, and breathing. ALS is progressive, meaning it gets worse over time. As the nerves lose the ability to control muscles, the muscles become weak and eventually lead to paralysis. Most people with ALS succumb to respiratory failure, usually within three to five years from when symptoms first appear. Please visit the ALS website for more information.

The FDA’s ODD program provides orphan status to drugs intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. It is estimated that there are approximately 15,000-20,000 Americans with ALS. Please see the NIH ALS Fact Sheet for details.

Additional information can be found on the Christopher & Dana Reeve Foundation website regarding current therapies and disease trends.

Disclosure: Mayo Clinic has a financial interest in Elysium Health. All revenue Mayo Clinic receives will be used to fund its not-for-profit mission in medical research and education.

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Huntington’s Disease Molecule Can Kill Cancer Cells

Scientists have destroyed numerous types of human cancer cells with a toxic molecule characteristic of fatal genetic illness Huntington?s disease.

The researchers hailed the molecule?which has killed both human and mouse ovarian, breast, prostate, liver, brain, lung, skin and colon cancer cell lines in mice?as a ?super assassin.? Their results were published in the journal EMBO Reports.

Huntington?s disease is a progressive illness caused by an excess of a specific repeating RNA sequence in the Huntington gene, which is present in every cell. The defect causes the death of brain cells, and gradually worsens a person?s physical and mental abilities. The disease has no cure.

Researchers believe that the defect may be even more powerful against cancer cells than nerve cells in the brain, and the team hopes it can be harnessed to kill cancer cells without causing Huntington?s symptoms.? ?This molecule is a super assassin against all tumor cells,? said senior author Marcus Peter, a professor of cancer metabolism at Northwestern University Feinberg School of Medicine, Chicago, in a press statement. ?We?ve never seen anything this powerful.?

Peter collaborated with Feinberg colleague Shad Thaxton, associate professor of urology, to deliver the molecule in the form of nanoparticles to mice with human ovarian cancer. The targeted molecule decreased tumor growth with no toxicity to the mice.

First author Andrea Murmann, a research assistant professor who discovered the cancer-killing mechanism, used the molecule to kill numerous other human and mouse cancer cell lines. Building on previous research into a cancer ?kill switch?, Murmann looked to diseases associated with low rates of cancer and a suspected RNA link.? ?I thought maybe there is a situation where this kill switch is overactive in certain people, and where it could cause loss of tissues,? Murmann said in the statement. ?These patients would not only have a disease with an RNA component, but they also had to have less cancer.?

There is up to 80 percent less cancer in people with Huntington?s disease than the general population.? Murmann recognised similarities between the kill switch and the toxic Huntington?s disease RNA sequences.? Based on their results, the team believe the ?super assassin? molecule could be used to fight cancer in humans. ?We believe a short-term treatment cancer therapy for a few weeks might be possible, where we could treat a patient to kill the cancer cells without causing the neurological issues that Huntington?s patients suffer from,? Peter said.? The scientists next aim to refine the molecule?s delivery method to improve tumor targeting, and to stabilize the nanoparticles for storage.

By Katherine Hignett – Displayed with permission from Newsweek via RePubHub License; Cancer Cells courtesy of PixaBay FREE LIC CC0?

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AI-Driven Discovery of Novel Predictors of Parkinson’s

The discovery was powered by patient data from the Parkinson’s Progression Markers Initiative, sponsored by the Michael J. Fox Foundation for Parkinson’s Research.

GNS Healthcare (GNS), a leading precision medicine company, announced the discovery of genetic and molecular markers of faster motor progression of Parkinson’s Disease (PD) patients, the LINGO2 gene together with a second genetic variant, along with demographic factors.

The publication describing the discovery, titled “Large-scale identification of clinical and genetic predictors of Parkinson’s disease motor progression in newly-diagnosed patients: a longitudinal cohort study and validation,” appears in the journal The Lancet Neurology. This discovery may accelerate the development of new drugs and better match new drugs to individual patients.

“Being able to use these predictors in the clinical setting will lead to faster and significantly cheaper clinical trials and accelerate the availability of new Parkinson’s Disease drugs for patients in need,” said Colin Hill, Chairman, CEO, and co-founder of GNS Healthcare. “A major hurdle in Parkinson’s research is that rates of progression are extremely varied. Some patients progress very quickly while others do not. With accurate predictors of rates of progression, we will be able to remove uncertainties from drug development and patient response, reduce the number of clinical trial enrollees required by as much as twenty percent, and speed up the development of effective new drugs.”

REFS?, the GNS causal machine learning (ML) and simulation platform was used to transform the longitudinal genetic and clinical patient data from 429 individuals (312 PD patients and 117 controls) into computer models that connect the genetic and molecular variation of patients to motor progression rates. These computer models were used to simulate the future effects of the genetic and prognostic variables on motor outcomes, essentially predicting the motor progression rate for each patient. The models were validated in an independent longitudinal study, and clearly demonstrated the ability to prospectively differentiate between patient progression rates.

“There is still so much to understand about the progression of chronic, debilitating illnesses like Parkinson’s disease,” said Jeanne C. Latourelle, D.Sc., a co-author of the study and Director of Precision Medicine, GNS Healthcare. “The validation of our models in this study underscores the power of our REFS? technology and its ability to accelerate the development of effective therapies for patients in need.”

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New Study Shows Spinal Cord Stimulation Reduces Opioid Use For Chronic Pain

ONE YEAR AFTER IMPLANT, 93 PERCENT OF PATIENTS WHO CONTINUED SCS THERAPY HAD LOWER AVERAGE DAILY MORPHINE-EQUIVALENT DOSES THAN PATIENTS WHO HAD THEIR SCS SYSTEM REMOVED

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New research has found spinal cord stimulation (SCS) therapy can be key to reducing or stabilizing the use of opioids in patients battling chronic pain. In a new study, researchers examined opioid usage data from more than 5,400 patients both prior to and after receiving an SCS system implant. In an SCS system, an implanted device similar to a pacemaker delivers low levels of electrical energy to nerve fibers, interrupting pain signals as they travel to the brain to reduce the sensation of pain. Researchers have found that average daily opioid use declined or stabilized for patients receiving a successful SCS system compared to patient use of opioids prior to an implant.

In addition, while opioid usage was not different for the two groups at time of implant, patients who underwent a successful SCS implant had significantly lower opioid use one year after their implant. Patients who had their SCS system removed saw their opioid use increase again over time.

In 5,400-patient study, average daily opioid use declined or stabilized in patients receiving SCS system, while patients who had SCS system removed had higher opioid use over time.? The study, which the researchers believe makes a compelling case for considering SCS therapy earlier in the chronic pain care continuum, were presented at the 2017 North American Neuromodulation Society (NANS) annual meeting by Ashwini Sharan, M.D., director of Functional and Epilepsy Surgery at Vickie and Jack Farber Institute for Neuroscience at Jefferson and president of NANS.? The study was sponsored by Abbott (NYSE: ABT), a global leader in the development and manufacture of SCS systems and therapy options, such as the company’s proprietary BurstDR? stimulation.

Currently, more than 2.1 million people in the U.S. suffer from substance abuse related to opioid pain relievers, while worldwide an estimated 15.5 million people are now classified as opioid dependent. Chronic pain is often a driver of opioid use as patients seek relief and improvements to their quality of life. Fortunately for patients, SCS therapy has been clinically proven to offer meaningful relief to patients suffering from chronic pain.? There is potential to improve outcomes by implanting SCS systems earlier, before chronic opioid use, according to authors.

“Given the epidemic of opioid addiction and abuse, these findings are important and confirm that spinal cord stimulation therapy can offer strong benefits for patients struggling with chronic pain,” said Sharan. “Based on these results, we concluded it may be possible to improve outcomes by offering our patients spinal cord stimulation earlier, before opioid dependence and addiction can occur.”

ABOUT THE STUDY:
For their analysis, the research team assessed private and Medicare insurance claims data from 5,476 patients who received an SCS system to treat chronic pain associated with a host of conditions (excluding pain related to cancer). The data were collected between January 2010 and December 2014. The data confirmed that many patients are often prescribed increasing dosages of opioids prior to receiving an SCS system. The researchers also found:
? SCS therapy is effective for patients at any level of opioid usage prior to implantation.
? Opioid use declined or stabilized in 70 percent of patients who received an SCS system.
? Among patients who had their SCS system explanted, opioid use was higher at one year compared to those who continued with SCS therapy.

The researchers further suggested patient outcomes could be improved if SCS were implanted earlier in recognition of the clinical practice to provide increasing dosages of opioids over time. These conclusions help build upon prior research, such as results of a large multicenter randomized controlled trial in patients with failed back surgery syndrome (FBSS) that showed trends in opioid reduction or cessation among SCS patients. In addition, new technologies released in the U.S. in 2015 and 2016 hold promise to improve outcomes further and may reduce common complications resulting in explant such as the undesired changes in paresthesia, issues with charging, pain at the implantable pulse generator (IPG) site, and loss of pain relief.

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