Mallinckrodt bails on mid-stage study of Acthar Gel in Lou Gehrig’s disease

Citing safety concerns, Mallinckrodt (NYSE:MNK) terminates its Phase 2b clinical trial, PENNANT, evaluating Acthar Gel (repository corticotropin injection) in patients with amyotrophic lateral sclerosis (ALS). The specific issue was a higher-than-expected rate of pneumonia in the treatment group compared to the placebo group.

Another factor was the lack of a clear efficacy signal. The independent Data and Safety Monitoring Board noted that there was not a great enough proportion of subjects who completed week 36 to provide a definitive determination of a treatment effect.

https://seekingalpha.com/news/3478283-mallinckrodt-bails-mid-stage-study-acthar-gel-als

Novel therapy administered after TBI prevents brain damage

An experimental treatment given to mice after a traumatic brain injury (TBI) reduced damage almost to the levels of mice that never had a TBI, researchers at UT Health San Antonio reported. The study was published July 4 in the Journal of Cerebral Blood Flow and Metabolism.

The scientists hope to convert the discovery into a simple and effective treatment for use in emergency rooms or by first responders shortly after a TBI has occurred in military and civilian settings. Currently, no treatment options exist for TBI patients.

“After a traumatic brain injury, about 40% of mice experience a seizure within one week, and many continue to experience seizures for years, leading to epilepsy disease,” said study senior author Mark S. Shapiro, Ph.D., professor of cellular and integrative physiology at UT Health San Antonio. “This closely parallels what happens in human patients, followed by cognitive dysfunction and changes in emotional state.”

Damaging effects

After a TBI, dangerous inflammation occurs throughout the brain, causing nerve cells to die and the blood-brain barrier, which is critical to maintaining normal brain function, to break down, said lead author Fabio A. Vigil, Ph.D., postdoctoral fellow in Dr. Shapiro’s lab.

Preventing abnormal electrical activity

The novel therapy increases the activity of “M-type” KCNQ potassium ion channels, which are proteins that can halt uncontrolled electrical currents in nerve cells. Abnormal currents begin immediately after a TBI, even before a seizure has a chance to occur, and the therapy aims to counteract this, thus nipping in the bud this destructive chain of events.

“No seizures were observed in the treated mice whatsoever,” Dr. Vigil said.

Neurologist’s perspective

“We need treatments that alter some of the disabling consequences of TBI,” said study co-author Jose E. Cavazos, M.D., Ph.D., a neurologist and epilepsy specialist at UT Health San Antonio. “Current antiseizure medications don’t prevent the development of post-traumatic epilepsy. Our study examined this critically important therapeutic gap, and proposes a novel pharmacological intervention shortly after TBI that might prevent post-traumatic epilepsy.”

If such a therapy can be developed, it would be a game-changer for patients, Dr. Cavazos said. Approximately 6% of all epilepsy cases are caused by head trauma.

“Think about the possibility of taking a medication shortly after the injury and preventing disabling epileptic seizures months to years later,” Dr. Cavazos said.

Post-trauma impact

Study co-author Robert Brenner, Ph.D., of UT Health San Antonio, provided expertise in seizures and seizure monitoring. He said the study’s most important finding is that reducing excess electrical activity in the central nervous system via a therapy such as this has beneficial post-trauma effects that extend well beyond action as an anticonvulsant. These effects include reducing dangerous inflammation and widespread cell death.

Ongoing and future research

This therapeutic approach is being evaluated for its suitability in humans, Dr. Shapiro said. This includes assessments of its chemical properties, stability, and effects on other organs such as the heart.

Future directions are to test newly developed compounds that have similar action to the compound used in this study, but with highly increased potency and selectivity for KCNQ potassium ion channels in the brain.

###

Acknowledgments

This study was funded by multiple investigator grants from the U.S. Department of Defense through the Congressionally Directed Medical Research Programs.

All experiments were approved by the Institutional Animal Use and Care Committee at UT Health San Antonio and followed the National Institutes for Health’s Guide for Care and Use of Laboratory Animals. The experiments reported here followed the Animal Research: Reporting In Vivo Experiments guidelines.

The researchers are from the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. Dr. Shapiro is a professor in the Department of Cellular and Integrative Physiology. Dr. Vigil is a postdoctoral fellow and Dr. Robert Brenner an associate professor in the same department. Dr. Jose Cavazos is a professor in the Department of Neurology and assistant dean and director of the South Texas Medical Scientist Training Program. James Lechleiter, Ph.D., a study co-author, is a professor in the Department of Cell Systems and Anatomy, UT Health San Antonio.

https://www.eurekalert.org/pub_releases/2019-07/uoth-nta071619.php

Exercise offers protection against Alzheimer’s

Higher levels of daily physical activity may protect against the cognitive decline and neurodegeneration (brain tissue loss) from Alzheimer’s disease (AD) that alters the lives of many older people, researchers from Massachusetts General Hospital (MGH) have found. In a paper in JAMA Neurology, the team also reported that lowering vascular risk factors may offer additional protection against Alzheimer’s and delay progression of the devastating disease. The findings from this study will be presented at the Alzheimer’s Association International Conference (AAIC) in Los Angeles by the first author of the study, Jennifer Rabin, PhD, now at the University of Toronto, Sunnybrook Research Institute.

“One of the most striking findings from our study was that greater physical activity not only appeared to have positive effects on slowing cognitive decline, but also on slowing the rate of brain tissue loss over time in normal people who had high levels of amyloid plaque in the brain,” says Jasmeer Chhatwal, MD, PhD of the MGH Department of Neurology, and corresponding author of the study. The report suggests that physical activity might reduce b-amyloid (Ab)-related cortical thinning and preserve gray matter structure in regions of the brain that have been implicated in episodic memory loss and Alzheimer’s-related neurodegeneration.

The pathophysiological process of AD begins decades before clinical symptoms emerge and is characterized by early accumulation of b-amyloid protein. The MGH study is among the first to demonstrate the protective effects of physical activity and vascular risk management in the “preclinical stage” of Alzheimer’s disease, while there is an opportunity to intervene prior to the onset of substantial neuronal loss and clinical impairment. “Because there are currently no disease-modifying therapies for Alzheimer’s disease, there is a critical need to identify potential risk-altering factors that might delay progression of the disease,” says Chhatwal.

The Harvard Aging Brain Study at MGH assessed physical activity in its participants – 182 normal older adults, including those with elevated b-amyloid who were judged at high-risk of cognitive decline – through hip-mounted pedometers which counted the number of steps walked during the course of the day.

“Beneficial effects were seen at even modest levels of physical activity, but were most prominent at around 8,900 steps, which is only slightly less than the 10,000 many of us strive to achieve daily,” notes co-author Reisa Sperling, MD, director of the Center for Alzheimer’s Research and Treatment, Brigham and Women’s Hospital and Massachusetts General Hospital and co-principal investigator of the Harvard Aging Brain Study.

Interventional approaches that target vascular risk factors along with physical exercise have added beneficial properties, she adds, since both operate independently. Vascular risk factors measured by the researchers were drawn from the Framingham Cardiovascular Disease Risk Score Calculator, and include age, sex, weight, smoking/non-smoking, blood pressure, and whether people are on treatment for hypertension.

Through ongoing studies MGH is working to characterize other forms of physical activity and lifestyle changes that may help retard the progress of Alzheimer’s disease. “Beta amyloid and tau protein build-up certainly set the stage for cognitive impairment in later age, but we shouldn’t forget that there are steps we can take now to reduce the risk going forward – even in people with build-up of these proteins,” says Chhatwal. “Alzheimer’s disease and the emergence of cognitive decline is multifactorial and demands a multifactorial approach if we hope to change its trajectory.”

###

Chhatwal is assistant professor of Neurology, MGH and Sperling is professor of Neurology, MGH. Other co-authors are Jennifer Rabin, PhD, MGH Department of Psychiatry; Keith Johnson, MD, MGH Department of Neurology; and Hannah Klein, BSc, MGH Department of Neurology. Support for the study includes funding from the National Institutes on Aging.

https://www.eurekalert.org/pub_releases/2019-07/mgh-eop071219.php

Physical Activity-β-Amyloid Link With Cognition, Neurodegeneration in Normal Seniors

Jennifer S. Rabin, PhD^1,2; Hannah Klein, BSc³; Dylan R. Kirn, MPH^3,4; et alAaron P. Schultz, PhD^3,5; Hyun-Sik Yang, MD^3,4; Olivia Hampton, BSc³; Shu Jiang, PhD³; Rachel F. Buckley, PhD^3,4,6,7; Anand Viswanathan, MD, PhD⁸; Trey Hedden, PhD⁹; Jeremy Pruzin, MD³; Wai-Ying Wendy Yau, MD³; Edmarie Guzmán-Vélez, PhD¹; Yakeel T. Quiroz, PhD^1,3; Michael Properzi, BEng, BCompSc³; Gad A. Marshall, MD^3,4; Dorene M. Rentz, PsyD^3,4; Keith A. Johnson, MD^3,4,5,10; Reisa A. Sperling, MD^3,4,5; Jasmeer P. Chhatwal, MD, PhD^3,4

Author Affiliations Article Information

JAMA Neurol. Published online July 16, 2019. doi:10.1001/jamaneurol.2019.1879

Key PointsQuestion  Does physical activity moderate the associations of β-amyloid (Aβ) burden with longitudinal cognitive decline and neurodegeneration in clinically normal older adults?

Findings  In this study of 182 individuals, greater baseline physical activity attenuated Aβ-related cognitive decline and gray matter volume loss. In models adjusting for vascular risk, physical activity remained significant, and lower vascular risk was independently associated with slower Aβ-related cognitive decline and gray matter volume loss.

Meaning  Interventional approaches that target both physical activity and vascular risk factors may have additive beneficial effects on delaying the progression of Alzheimer disease.

Abstract

Importance  In the absence of disease-modifying therapies for Alzheimer disease, there is a critical need to identify modifiable risk factors that may delay the progression of Alzheimer disease.

Objective  To examine whether physical activity moderates the association of β-amyloid (Aβ) burden with longitudinal cognitive decline and neurodegeneration in clinically normal individuals and to examine whether these associations are independent of vascular risk.

Design, Setting, and Participants  This longitudinal observational study included clinically normal participants from the Harvard Aging Brain Study. Participants were required to have baseline Aβ positron emission tomography data, baseline medical data to quantify vascular risk, and longitudinal neuropsychological and structural magnetic resonance imaging data. Data were collected from April 2010 to June 2018. Data were analyzed from August to December 2018.

Main Outcomes and Measures  Baseline physical activity was quantified with a pedometer (mean steps per day). Baseline Aβ burden was measured with carbon 11–labeled Pittsburgh Compound B positron emission tomography. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC; median [interquartile range] follow-up, 6.0 [4.3-6.3] years). Neurodegeneration was assessed with longitudinal structural magnetic resonance imaging (2 to 5 scans per participant; median [interquartile range] follow-up, 4.5 [3.0-5.0] years), with a focus on total gray matter volume and regional cortical thickness. Physical activity and Aβ burden were examined as interactive predictors of PACC decline and volume loss in separate linear mixed models, adjusting for age, sex, education, apolipoprotein E ε4 status, and, where appropriate, intracranial volume. Secondary models adjusted for vascular risk and its interaction with Aβ burden.

Results  Of the 182 included participants, 103 (56.6%) were female, and the mean (SD) age was 73.4 (6.2) years. In models examining PACC decline and volume loss, there was a significant interaction of physical activity with Aβ burden, such that greater physical activity was associated with slower Aβ-related cognitive decline (β, 0.03; 95% CI, 0.02-0.05; P < .001) and volume loss (β, 482.07; 95% CI, 189.40-774.74; P = .002). Adjusting for vascular risk did not alter these associations. In these models, lower vascular risk was independently associated with slower Aβ-related PACC decline (β, −0.04; 95% CI, −0.06 to −0.02; P < .001) and volume loss (β, −483.41; 95% CI, −855.63 to −111.20; P = .01).

Conclusions and Relevance  Greater physical activity and lower vascular risk independently attenuated the negative association of Aβ burden with cognitive decline and neurodegeneration in asymptomatic individuals. These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease.

https://jamanetwork.com/journals/jamaneurology/fullarticle/2738357?guestAccessKey=48e9f272-0f8b-4546-826b-6aefa64b17c6&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=071619

Inovio down 7% after hours on reboot

Citing a sharper strategy on its late-stage HPV assets, Inovio Pharmaceuticals (NASDAQ:INO) implements a cost-cutting initiative aimed at reducing its cash consumption by 25%. Key points:

Phase 1/2 study evaluating INO-5401 in advanced bladder cancer terminated.

Workforce cut by 28%.

Management will host a conference call tomorrow, July 17, at 8:00 am ET to discuss its plans.

Shares are down 7% after hours.

https://seekingalpha.com/news/3478258-inovio-7-percent-hours-reboot

Nu Skin -19% AH after slashing guidance

Nu Skin (NYSE:NUS) now expects Q2 EPS in the range of of $0.82- $0.84 vs. a consensus of $0.93; Revenue in the range of $622M – $623M vs. a consensus of $671.81M.

The company’s revised revenue outlook for 2019 is $2.48 to $2.52B (cons. $2.77B) and EPS of $3.20 to $3.35 (cons. $3.94).

“We are adjusting our guidance for the year primarily due to a reduced revenue outlook in Mainland China following the government’s 100-day campaign to review and inspect the health products and direct selling industries,” said Ritch Wood, chief executive officer.

Shares -19% AH.

https://seekingalpha.com/news/3478271-nu-skin-minus-19-percent-ah-slashing-guidance

Stryker target raised to $230 from $218 by Morgan Stanley

Maintains Overweight

https://www.benzinga.com/stock/SYK/ratings