Thursday, January 24, 2019
Amgen, Allergan say Phase 1/Phase 3 ABP 799 study met primary endpoint
Amgen (AMGN) and Allergan (AGN) announced positive top-line results from a Phase 1/ Phase 3 study evaluating the pharmacokinetics, efficacy and safety of biosimilar candidate ABP 798, a biosimilar candidate to RITUXAN, compared to rituximab in patients with moderate-to-severe rheumatoid arthritis. The results demonstrate that the study met its primary endpoint of pharmacokinetic similarity. Additionally, equivalent efficacy was established and a similar safety profile was demonstrated.The primary objective of the study was PK similarity comparing ABP 798 to rituximab. The PK endpoints of the study were area under the serum concentration-time curve and maximum serum concentration, both of which were within the pre-specified equivalence margin. The pre-specified equivalence in efficacy endpoint was measured by Disease Activity Score 28-joint count C reactive protein change from baseline at week 24. Overall, safety and immunogenicity of ABP 798 were comparable to rituximab. This is the first of two studies intended to form the basis for global regulatory submissions for ABP 798. The second study is being conducted in patients with non-Hodgkin’s lymphoma. “Results from this study show pharmacokinetic and clinical equivalence between ABP 798 and rituximab, further demonstrating Amgen’s commitment to providing patients with access to high-quality, biological therapies,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen. “We look forward to continuing to leverage our experience and expertise in biotechnology to bring more biosimilars to patients.” ABP 798 is being developed as a biosimilar candidate to rituximab, a CD20-directed cytolytic antibody that is approved in many regions for the treatment of adult patients with moderate-to-severe rheumatoid arthritis, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, pemphigus vulgaris, granulomatosis with polyangiitis and microscopic polyangiitis.
https://thefly.com/landingPageNews.php?id=2853145
CV Sciences initiated at Northland
CV Sciences initiated with an Outperform on growing CBD demand at Northland. Northland analyst Mike Grondahl initiated CV Sciences with an an Outperform and $8 price target saying recent passage of the 2018 Farm Bill will drive a wave of CBD demand.
https://thefly.com/landingPageNews.php?id=2853173
Bacterial pathogen found in brains of Alzheimer’s patients
New science uncovers how an unlikely culprit, Porphyromonas gingivalis (Pg) — the bacterium commonly associated with chronic gum disease — appears to drive Alzheimer’s disease (AD) pathology.
A paper published today in Science Advances details how researchers identified Pg in the brains of patients with AD.
University of Louisville researcher Jan Potempa, Ph.D., Department of Oral Immunology and Infectious Diseases in the School of Dentistry, was part of the team of international scientists led by Cortexyme Inc., a privately held, clinical-stage pharmaceutical company.
According to Potempa, although infectious agents have been implicated in the development and progression of Alzheimer’s disease, the evidence of causation hasn’t been convincing.
However, “we now have strong evidence connecting P. gingivalisand Alzheimer’s pathogenesis, but more research needs to be done before P. gingivalis is explicitly implicated in the causation or morbidity of AD.
“An even more notable aspect of this study is demonstration of the potential for a class of molecule therapies targeting major virulence factors to change the trajectory of AD, which seems to be epidemiologically and clinically associated with periodontitis,” Potempa said.
In animal models, oral Pg infection led to brain colonization and increased production of amyloid beta (Aβ), a component of the amyloid plaques commonly associated with AD.
The study team also found the organism’s toxic enzymes, or gingipains, in the neurons of patients with AD. Gingipains are secreted and transported to outer bacterial membrane surfaces and have been shown to mediate the toxicity of Pg in a variety of cells. The team correlated the gingipain levels with pathology related to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a small protein tag that marks damaged proteins.
Seeking to block Pg-driven neurotoxicity, Cortexyme set out to design a series of small molecule therapies targeting Pg gingipains. In preclinical experiments detailed in the paper, researchers demonstrated that by inhibiting the compound COR388, there was reduced bacterial load of an established Pgbrain infection, blocked Aβ42 production, reduced neuroinflammation and protected neurons in the hippocampus — the part of the brain that mediates memory and frequently atrophies early in the development of AD.
In October 2018, Cortexyme announced results from its Phase 1b clinical trial of COR388 at the 11th Clinical Trials in Alzheimer’s Disease Conference. COR388 showed positive trends across several cognitive tests in patients suffering from AD, and Cortexyme plans to initiate a Phase 2 and 3 clinical trial of COR388 in mild to moderate AD in 2019.
Story Source:
Materials provided by University of Louisville. Note: Content may be edited for style and length.
Journal Reference:
- Stephen S. Dominy et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances, 2019 DOI: 10.1126/sciadv.aau3333
Restoring memory function in Alzheimer’s: preclinical study
Research published Jan. 22 in the journal Brain reveals a new approach to Alzheimer’s disease (AD) that may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages.
The team, led by University at Buffalo scientists, found that by focusing on gene changes caused by influences other than DNA sequences — called epigenetics — it was possible to reverse memory decline in an animal model of AD.
“In this paper, we have not only identified the epigenetic factors that contribute to the memory loss, we also found ways to temporarily reverse them in an animal model of AD,” said senior author Zhen Yan, PhD, a SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB.
The research was conducted on mouse models carrying gene mutations for familial AD — where more than one member of a family has the disease — and on post-mortem brain tissues from AD patients.
AD is linked to epigenetic abnormality
AD results from both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.
The epigenetic changes in AD happen primarily in the later stages, when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline, Yan said. A key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.
“We found that in Alzheimer’s disease, many subunits of glutamate receptors in the frontal cortex are downregulated, disrupting the excitatory signals, which impairs working memory,” Yan said.
The researchers found that the loss of glutamate receptors is the result of an epigenetic process known as repressive histone modification, which is elevated in AD. They saw this both in the animal models they studied and in post-mortem tissue of AD patients.
Yan explained that histone modifiers change the structure of chromatin, which controls how genetic material gains access to a cell’s transcriptional machinery.
“This AD-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits,” Yan said.
Potential drug targets
Understanding that process has revealed potential drug targets, she said, since repressive histone modification is controlled or catalyzed by enzymes.
“Our study not only reveals the correlation between epigenetic changes and AD, we also found we can correct the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors,” Yan said.
The AD animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.
“When we gave the AD animals this enzyme inhibitor, we saw the rescue of cognitive function confirmed through evaluations of recognition memory, spatial memory and working memory. We were quite surprised to see such dramatic cognitive improvement,” Yan said.
“At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex.”
The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.
Epigenetic advantage
Brain disorders, such as AD, are often polygenetic diseases, Yan explained, where many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she said, because epigenetic processes control not just one gene but many genes.
“An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function,” she explained.
“We have provided evidence showing that abnormal epigenetic regulation of glutamate receptor expression and function did contribute to cognitive decline in Alzheimer’s disease,” Yan concluded. “If many of the dysregulated genes in AD are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior.”
The study was funded by a $2 million National Institutes of Health grant focused on novel treatment strategies for AD.
Other UB co-authors are Yan Zheng; Aiyi Liu; Zi-Jun Wang, PhD; Qing Cao, PhD; Lin Lin; Kaijie Ma; Freddy Zhang; Jing Wei, PhD; Emmanuel Matas, PhD and Jia Cheng, PhD. Additional co-authors are Guo-Jun Chen of Chongqing Medical University, PhD, and Xiaomin Wang, MD, PhD., of the Beijing Institute for Brain Disorders, Capital Medical University.
Story Source:
Materials provided by University at Buffalo. Note: Content may be edited for style and length.
Journal Reference:
- Yan Zheng Aiyi Liu Zi-Jun Wang Qing Cao Wei Wang Lin Lin Kaijie Ma Freddy Zhang Jing Wei Emmanuel Matas Jia Cheng Guo-Jun Chen Xiaomin Wang Zhen Yan. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain, 2019 DOI: 10.1093/brain/awy354
Cellular process may stop cancer before it starts
Just as plastic tips protect the ends of shoelaces and keep them from fraying when we tie them, molecular tips called telomeres protect the ends of chromosomes and keep them from fusing when cells continually divide and duplicate their DNA. But while losing the plastic tips may lead to messy laces, telomere loss may lead to cancer.
Salk Institute scientists studying the relationship of telomeres to cancer made a surprising discovery: a cellular recycling process called autophagy — generally thought of as a survival mechanism — actually promotes the death of cells, thereby preventing cancer initiation.
The work, which appeared in the journal Nature on January 23, 2019, reveals autophagy to be a completely novel tumor-suppressing pathway and suggests that treatments to block the process in an effort to curb cancer may unintentionally promote it very early on.
“These results were a complete surprise,” says Jan Karlseder, a professor in Salk’s Molecular and Cell Biology Laboratory and the senior author of the paper. “There are many checkpoints that prevent cells from dividing out of control and becoming cancerous, but we did not expect autophagy to be one of them.”
Each time cells duplicate their DNA to divide and grow, their telomeres get a little bit shorter. Once telomeres become so short that they can no longer effectively protect chromosomes, cells get a signal to stop dividing permanently. But occasionally, due to cancer-causing viruses or other factors, cells don’t get the message and keep on dividing. With dangerously short or missing telomeres, cells enter a state called crisis, in which the unprotected chromosomes can fuse and become dysfunctional — a hallmark of some cancers.
Karlseder’s team wanted to better understand crisis — both because crisis often results in widespread cell death that prevents precancerous cells from continuing to full-blown cancer and because the mechanism underlying this beneficial cell death isn’t well-understood.
“Many researchers assumed cell death in crisis occurs through apoptosis, which along with autophagy is one of two types of programmed cell death,” says Joe Nassour, a postdoctoral fellow in the Karlseder lab and the paper’s first author. “But no one was doing experiments to find out if that was really the case.”
To investigate crisis and the cell death that typically ensues, Karlseder and Nassour used healthy human cells to run a series of experiments in which they compared normally growing cells with cells they forced into crisis. By disabling various growth-limiting genes (also known as tumor-suppressor genes), their group enabled the cells to replicate with abandon, their telomeres getting shorter and shorter in the process.
To know which type of cell death was responsible for the major die-off in crisis, they examined morphological and biochemical markers of both apoptosis and autophagy. Although both mechanisms were responsible for a small number of cells dying in the normally growing cells, autophagy was by far the dominant mechanism of cell death in the group in crisis, where many more cells died.
The researchers then explored what happened when they prevented autophagy in the crisis cells. The results were striking: without cell death via autophagy to stop them, the cells replicated tirelessly. Furthermore, when the team looked at these cells’ chromosomes, they were fused and disfigured, indicating that severe DNA damage of the kind seen in cancerous cells was occurring, and revealing autophagy to be an important early cancer-suppressing mechanism.
Finally, the team tested what happened when they induced specific kinds of DNA damage in the normal cells, either to the ends of the chromosomes (via telomere loss) or to regions in the middle. Cells with telomere loss activated autophagy, while cells with DNA damage to other chromosomal regions activated apoptosis. This shows that apoptosis is not the only mechanism to destroy cells that may be precancerous due to DNA damage and that there is direct cross-talk between telomeres and autophagy.
The work reveals that, rather than being a mechanism that fuels unsanctioned growth of cancerous cells (by cannibalizing other cells to recycle raw materials), autophagy is actually a safeguard against such growth. Without autophagy, cells that lose other safety measures, such as tumor-suppressing genes, advance to a crisis state of unchecked growth, rampant DNA damage — and often cancer. (Once cancer has begun, blocking autophagy may still be a valid strategy of “starving” a tumor, as a 2015 study by Salk Professor Reuben Shaw, a coauthor on the current paper, discovered.)
Karlseder, who holds the Donald and Darlene Shiley Chair, adds, “This work is exciting because it represents so many completely novel discoveries. We didn’t know it was possible for cells to survive crisis; we didn’t know autophagy is involved with the cell death in crisis; we certainly didn’t know how autophagy prevents the accumulation of genetic damage. This opens up a completely new field of research we are eager to pursue.”
Next the researchers plan to more closely investigate the split in cell-death pathways whereby damage to chromosome ends (telomeres) leads to autophagy while damage to other parts of chromosomes leads to apoptosis.
Story Source:
Materials provided by Salk Institute. Note: Content may be edited for style and length.
Journal Reference:
- Joe Nassour, Robert Radford, Adriana Correia, Javier Miralles Fusté, Brigitte Schoell, Anna Jauch, Reuben J. Shaw & Jan Karlseder. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature, 2019 DOI: 10.1038/s41586-019-0885-0
Novo Nordisk: UK launches Ozempic (semaglutide)
Ozempic(semaglutide), a new once-weekly GLP-1 analogue injection for the treatment of type 2 diabetes, is now available in the UK, Novo Nordisk UK has announced.
It works by mimicking the function of the GLP-1 (human glucagon-like peptide-1) hormone produced in the gut that lowers post-meal blood glucose levels and also slows glucose absorption into the bloodstream.
Ozempicshould be used alongside diet and exercise, as monotherapy when metformin is considered inappropriate due to intolerance or contraindications or in addition to other medicinal products for the treatment of diabetes, when type 2 diabetes is insufficiently controlled.
Cardiovascular disease is the number one cause of death and disability in type 2 diabetes worldwide. Leading charity Diabetes UK recently warned that people with type 2 diabetes are up to twice more likely to die prematurely from avoidable complications than those without the condition. In the latest data available from NHS Digital (2016/17) 33% of people living with type 2 diabetes did not meet their blood glucose (HbA1c) target of 7.5%4. Alongside this nine out of 10 are overweight or obese.
The EU licensing of Ozempicis based on results from the SUSTAIN clinical trial programme which consistently demonstrated:
superior glycaemic control compared to dulaglutide, exenatide once weekly, sitagliptin and insulin glargine U100
superior and sustained weight loss compared to dulaglutide, exenatide once weekly, sitagliptin and insulin glargine U100
cardiovascular benefits vs placebo both in addition to standard of care in people with type 2 diabetes at high risk for CV events
Ozempichas received positive recommendation by the two UK health technology assessment (HTA) bodies, All Wales Medicines Strategy Group (AWMSG) and Scottish Medicines Consortium (SMC). Ozempicis recommended as a treatment option for restricted use within NHS Wales and NHS Scotland in the treatment of insufficiently controlled type 2 diabetes mellitus in adults as an add-on therapy to oral antidiabetic medicines or basal insulin.
Dr Reddy’s Launches Propofol Generic in US
Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY, along with its subsidiaries together referred to as “Dr. Reddy’s”) today announced the launch of Propofol Injectable Emulsion, USP, a therapeutic equivalent generic version of DIPRIVAN (propofol) Injectable Emulsion, USP, approved by the U.S. Food and Drug Administration (USFDA).
Dr. Reddy’s is committed to providing affordable and innovative medicines for healthier lives. To that end, Dr. Reddy’s neither condones nor supports the off-label use or misuse of its drugs. In the strongest possible terms, Dr. Reddy’s objects to the use of any of its products to facilitate or otherwise aid lethal injections. Consistent with this position, Dr. Reddy’s uses distribution controls to market Propofol Injectable Emulsion, USP. Dr. Reddy’s will not accept orders from correctional facilities and prison systems whose intended use of the product is to aid in lethal injection. We require the same commitment from our wholesalers and distributors.
The Diprivan brand and generic had U.S. sales of approximately $310 million MAT for the most recent twelve months ending in November 2018 according to IMS Health*.
Dr. Reddy’s Propofol Injectable Emulsion, USP is available in 10 mg/mL vials for Single Patient Use Only.
Please click here for Full Prescribing Information.
Diprivan is a trademark of Fresenius Kabi USA, LLC.
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