Amyotrophic Lateral Sclerosis aka Lou Gherig Disease afflicts the head of the Italian Pharma Agency and was quoted in todays article of EPP patients and his agency balking at Scenesse price, could be cured by Athcar/MSH/Scenesse thru the SuperOxide1
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SOD1[edit]
In 1993, scientists discovered that mutations in the gene (SOD1) that produces the Cu-Zn superoxide dismutase (SOD1) enzyme were associated with around 20% of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disorder, some of which (such as H46R) have a very long clinical course, while others, such as A4V, are exceptionally aggressive. When the defenses against oxidative stress fail, programmed cell death (apoptosis) is upregulated.
A defect in SOD1 could be a loss or gain of function. A loss of SOD1 function could lead to an accumulation of free radicals. A gain of SOD1 function could be toxic in other ways.[44][45]
Aggregate accumulation of mutant SOD1 is suspected to play a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins.[46] Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. Critics have noted that in humans, SOD1 mutations cause only 2% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. To date, the ALS-SOD1 mice remain the best model of the disease for preclinical studies, but it is hoped that more useful models will be developed.
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MrPoonz1
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On Wednesday, July 6, 2016 at 11:48:49 PM UTC-7, MrPoonz1 wrote:
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Mario is actually at the front of ALS research. He has inferred other studies indicating other possible involved genes, and even the T cells being involved as an immunological disruption. He has written books also. This may indicate why an Athcar or a Scenesse may be of therapeutic value in ALS. Still can not state for certain that what the steroidgenisis or the unkown going ons with Athcar or Scenesse may be having. Here below are more genes he mentioned.
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Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis.
Abstract
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
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However, the causes of sporadic ALS remain obscure. Since the discovery of the genetic linkage of mutations in superoxide
dismutase 1 (SOD1) gene with familial ALS patients, one of the highlighted putative mechanisms is that degeneration of MNs is closely linked to involvement of SOD1 in both sporadic and familial cases (Bosco et al. 2010). It is proposed that the occurrence of misfolded SOD1 triggers a cascade of neurodegeneration by “gains-of-function” through activation of glutamate-mediated excitotoxicity, which induces an uncontrolled increase of intracellular calcium concentration (de Carvalho and Swash 2011). Data regarding Inhibitors,research,lifescience,medical cholinergic activity in animal models carrying SOD1 mutations are mainly reported linked to MN loss in the symptomatic phase (Crochemore et al. 2005; Alves et al. 2011). Nevertheless, a question that remains to be solved is how and when cholinergic function is compromised along the neurodegenerative process. In order to answer these questions, we have analyzed the spatiotemporal expression of ChAT, considering local Inhibitors,research,lifescience,medical cholinergic circuitry, efferences, and afferences, within the spinal cord from early presymptomatic until symptomatic Inhibitors,research,lifescience,medical stages of an ALS mouse model. The results obtained highly the importance of the
performance of longitudinal studies to unravel the etiopathogenesis of ALS. Material and Methods Animals Experiments were performed in transgenic mice carrying the mutation G93A in SOD1 gene and in nontransgenic wild-type (WT) littermates considered Inhibitors,research,lifescience,medical controls. SOD1G93A high copy mice (Tg[SOD1-G93A]1Gur) were obtained from the Jackson Laboratory (Bar Harbor, ME), with B16xSJL background. These mice were bred and maintained as hemizygotes by mating transgenic males with F1 hybrid (B6SJLF1/J) females obtained from Charles River Laboratories (Belgium). Animals were bread at the Animal Supply Services, Unidad Mixta de Investigación, Inhibitors,research,lifescience,medical University of Zaragoza, and were cared for and handled in accordance with the guidelines of the European Union Council (86/609/UE) and Spanish regulations (BOE 67/8509-12; BOE 1201/2005) on the use of only laboratory animals. Experimental procedures were approved by the
local Ethics Committee of the Universitat Autònoma de Barcelona. Transgenic mice were identified by polymerase chain reaction amplification of DNA extracted from the tail. Studies were performed in groups of 1-, 2-, and 3-month-old female mice (n = 8 each). One- and 2-month-old SOD1G93A mice are considered to be in early and adult presymptomatic stages of disease, respectively, whereas 3-month-old mice had an early symptomatic phenotype by behavioral (Chiu et al. 1995) and SB939 research buy electrophysiological testing (Mancuso et al. 2011). Immunohistochemistry Animals were anesthetized with sodium pentobarbital (50 mg/kg i.p.), and perfused transcardially with phosphate buffered saline (PBS), followed by 4% paraformaldehyde in 0.1 mol/L PB, pH 7.4 at 4°C.
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Date:
August 24, 2016
Source:
Harvard Medical School
Summary:
Scientists have pinpointed an enzyme that triggers rapid demise of nerve cells in people with ALS. The research team describes a molecular chain of events that culminates in the stripping of the protective coating around axons, the slender projections that carry signals from one neuron to the next.
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FULL STORY
Scientists from Harvard Medical School have identified a key instigator of nerve cell damage in people with amyotrophic lateral sclerosis, or ALS, a progressive and incurable neurodegenerative disorder.
Researchers say the findings of their study, published Aug. 5 in the journal Science, may lead to new therapies to halt the progression of the uniformly fatal disease that affects more than 30,000 Americans. One such treatment is already under development for testing in humans after the current study showed it stopped nerve cell damage in mice with ALS.
The onset of ALS, also known as Lou Gehrig's disease, is marked by the gradual degradation and eventual death of neuronal axons, the slender projections on nerve cells that transmit signals from one cell to the next.
The HMS study reveals that the aberrant behavior of an enzyme called RIPK1 damages neuronal axons by disrupting the production of myelin, the soft gel-like substance enveloping axons to insulate them from injury.
"Our study not only elucidates the mechanism of axonal injury and death but also identifies a possible protective strategy to counter it by inhibiting the activity of RIPK1," said the study's senior investigator Junying Yuan, the Elizabeth D. Hay Professor of Cell Biology at HMS.
The new findings come on the heels of a series of pivotal discoveries made by Yuan and colleagues over the last decade revealing RIPK1 as a key regulator of inflammation and cell death. But up until now, scientists were unaware of its role in axonal demise and ALS.
Experiments conducted in mice and in human ALS cells reveal that when RIPK1 is out of control, it can spark axonal damage by setting off a chemical chain reaction that culminates in stripping the protective myelin off of axons and triggering axonal degeneration -- the hallmark of ALS.
RIPK1, the researchers found, inflicts damage by directly attacking the body's myelin production plants -- nerve cells known as oligodendrocytes, which secrete the soft substance, rich in fat and protein that wraps around axons to support their function and shield them from damage.
Building on previous work from Yuan's lab showing that the activity of RIPK1 could be blocked by a chemical called necrostatin-1, the research team tested how ALS cells in lab dishes would respond to the same treatment. Indeed, necrostatin-1 tamed the activity of RIPK1 in cells of mice genetically altered to develop ALS.
In a final set of experiments, the researchers used necrostatin-1 to treat mice with axonal damage and hind leg weakness, a telltale sign of axonal demise similar to the muscle weakness that occurs in the early stages of ALS in humans. Necrostatin-1 not only restored the myelin sheath and stopped axonal damage but also prevented limb weakness in animals treated with it.
Connecting the Dots
At the outset of their experiments, investigators homed in on a gene called optineurin (OPTN). Past research had revealed the presence of OPTN defects in people with both inherited and sporadic forms of ALS, but scientists were not sure whether and how OPTN was involved in the development of the disease. To find out, researchers created mice genetically altered to lack OPTN. Examining spinal cord cells under a microscope, the scientists noticed that the axons of mice missing the OPTN gene were swollen, inflamed and far fewer in number, compared with spinal cord cells obtained from mice with the OPTN gene. These axons also bore signs of myelin degradation. Strikingly, the researchers noticed the same signs of axonal demise in spinal cord cells obtained from human patients with ALS. Mice with OPTN deficiency also exhibited loss of strength in their hind legs. Further experiments revealed that lack of OPTN was particularly harmful to myelin-secreting cells. Thus, the researchers concluded, OPTN deficiency was directly incapacitating the nervous system's myelin factories. But one question remained: How did the absence of OPTN damage these cells?
A Smoking Gun
Looking for the presence of chemicals commonly seen during inflammation and cell death, the researchers noticed abnormally high levels of RIPK1 -- a known promoter of cell death -- in spinal cord cells from mice lacking OPTN. Moreover, the scientists observed traces of other damaging chemicals often recruited by RIPK1 to kill cells.
"It was as if we saw the chemical footprints of cell death left behind by RIPK1 and its recruits," Yuan said.
That observation, Yuan added, was the smoking gun linking RIPK1's misbehavior to OPTN deficiency. In other words, researchers said, when functioning properly, the OPTN gene appears to regulate the behavior of RIPK1 by ensuring its levels are kept in check, that it is broken down fast and that it is cleared out of cells in a timely fashion. In the absence of such oversight, however, RIPK1 appears to get out of control and cause mischief.
In a closing set of experiments, the researchers examined neurons obtained from mice with the most common inherited form of ALS, one caused by mutations in a gene called SOD1. Indeed, RIPK1 levels were elevated in those cells too. Thus, the investigators said, OPTN may not be the sole gene regulating RIPK1's behavior. Instead, RIPK1 appears to fuel axonal damage across various forms of inherited and acquired forms of ALS.
The findings suggest that RIPK1 may be involved in a range of other neurodegenerative diseases marked by axonal damage, including multiple sclerosis, certain forms of spinal muscular atrophy and even Alzheimer's disease.
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BMJ › jnnp › Online First
12 hours ago - ... El Oussini H , et al . Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis. Brain 2016;139(Pt 4):1106–22.doi:10.1093/brain/aww004 · OpenUrlAbstract/FREE Full TextGoogle ...
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Discussion
In this combined mouse and human study, we showed that ALS is associated with defects in the melanocortin system, the major hypothalamic circuit controlling food intake and energy expenditure. Pioglitazone did not increase weight in ALS patients, thus providing indirect evidence of altered hypothalamic melanocortin pathway. Pathological and functional deficits of melanocortin system were found in ALS mouse models directly demonstrating these defects. These findings further extend the spectrum of defects in ALS and provide a mechanistic explanation for a subset of metabolic signs observed in these patients. Our study also has important implications for the design of therapies to target weight loss in this disease.
We first observed that pioglitazone did not increase body weight or slow down weight loss in patients with ALS. This was a surprising observation as progressive weight gain has been repeatedly observed in all clinical trials of pioglitazone in multiple non-neurological diseases ( Promrat et al. , 2004 ; Belfort et al. , 2006 ; Sanyal et al. , 2010 ; DeFronzo et al. , 2011 ). Despite this lack of weight gain, ALS patients under pioglitazone displayed all other biomarkers of efficacy, including decreased glycaemia, decreased circulating liver enzymes or increased adiponectin, thus ruling out that patients with ALS simply did not respond to the drug. Interestingly, a series of recent studies dissected out how TZDs lead to weight gain through activation of PPARγ in hypothalamic POMC neurons leading to increased food intake ( Diano et al. , 2011 ; Lu et al. , 2011 ; Ryan et al. , 2011 ; Long et al. , 2014 ). Consistent with the notion that pioglitazone hypothalamic response was blunted in ALS patients, pioglitazone was not able to promote food intake in SOD1m mice. Indeed, the melanocortin system is dramatically affected in these mice, with decreased POMC expression and loss of POMC positive neurons; similar alterations were observed in TDP-43- and FUS-based mouse models pointing out that such defects are a general feature in ALS. As pioglitazone decreases the activity of POMC neurons thus increasing food intake ( Diano et al. , 2011 ), we propose that the already decreased melanocortin tone in ALS prevents the silencing of POMC neurons by pioglitazone. Consistent with this, SOD1 mice displayed hyperphagia in response to short-term fasting, an orexigenic stimulus that also leads to decreased POMC neuronal activity ( Perez-Tilve et al. , 2010 ; Diano et al. , 2011 ). Thus, our results point to a general decrease in melanocortin tone in ALS, leading to both a lack of response to TZDs, and abnormal food intake behaviour in response to fasting.
What is the contribution of impaired melanocortin system to the metabolic phenotypes associated with ALS? The melanocortin system exerts multiple actions on energy metabolism, either dependent on or independent of food intake. First, an expected consequence of decreased melanocortin tone is increased energy intake, especially in response to an orexigenic stimulus such as food deprivation. This is indeed what has been observed in multiple transgenic mouse models of ALS, suggesting that the defect in the melanocortin system translates into a functional deficit. Furthermore, consistent with the observed melanocortin defect, we previously observed slightly increased cumulative food intake in SOD1m mice ( Dupuis et al. , 2004 ). The situation in ALS patients is less clear with respect to energy intake due to a relative lack of studies reporting dietary intake accurately and to confounding effects of dysphagia in advanced ALS patients. However, two case-control studies reported that increased dietary fat intake was associated with ALS ( Nelson et al. , 2000 ; Huisman et al. , 2015 ). Moreover, Huisman et al. ( 2015 ) and collaborators observed that presymptomatic daily energy intake was increased in ALS patients as compared with controls, and this would be consistent with both melanocortin impairment and lack of weight gain under pioglitazone. Second, the melanocortin defect could be responsible for alterations in peripheral metabolic pathways. Indeed, the melanocortin system regulates peripheral lipid metabolism in rodents, by activating cholesterol reuptake by the liver ( Perez-Tilve et al. , 2010 ) and reduces hepatic lipogenesis ( Leckstrom et al. , 2011 ) independently of food intake. In the same line, the melanocortin system is controlling glucose metabolism and insulin response ( Obici et al. , 2001 ). Interestingly, ALS patients have been reported to display increased circulating cholesterol levels ( Dupuis et al. , 2008 ), and glucose intolerance ( Pradat et al. , 2010 ). Third, the melanocortin defect could impair regulation of the autonomic nervous system ( Sohn et al. , 2013 ), and autonomic abnormalities have sometimes been found in ALS patients ( Baltadzhieva et al. , 2005 ). The relationships between these different phenotypes and melanocortin defects are unclear and will have to be clarified in further studies. Importantly, the observed melanocortin defect is unable to explain the weight loss associated with ALS, as, on the contrary, the increased orexigenic drive triggered by POMC deficiency likely compensates for weight loss by increasing food intake. Other mechanisms, either peripheral or central, have still to be identified to explain weight loss.
What causes the melanocortin defect in ALS? A first obvious potential mechanism is energy deficit. Indeed, SOD1m mice display weight loss due to hypermetabolism, leading to decreased fat mass. These mice also display decreased circulating insulin and leptin levels ( Dupuis et al. , 2004 ). Ablation of leptin in ob/ob mice or fasting is indeed sufficient to cause decreased Pomc mRNA ( Mizuno et al. , 1998 , 1999 ; Ziotopoulou et al. , 2000 ). However, leptin levels are only decreased by 30% in 75-day-old mice ( Dupuis et al. , 2004 ), an age at which we already observe strong Pomc mRNA decreases. We and others had previously observed serotonin loss in ALS ( Turner et al. , 2005 ; Dentel et al. , 2013 ), and we hypothesized that this contributed to melanocortin impairment in SOD1m mice. Indeed, serotonin is a major activator of POMC neurons through the 5-HT 2C receptor, and this occurs through direct electrical stimulation ( Heisler et al. , 2002 ) but also trough transcriptional activation ( Zhou et al. , 2007 ; Lam et al. , 2008 ; Xu et al. , 2008 ). Consistently, loss of 5-HT 2C receptor leads to decreased Pomc mRNA in the hypothalamus ( Wang and Chehab, 2006 ). Our observation of restoration of Pomc mRNA levels, as well as reversal of transient hyperphagia in SOD1m mice by fluoxetine argues for serotonin loss being a primary cause of melanocortin defect. This, however, does not exclude that direct modulation of electrical activity by either decreased leptin or other cues, either extrinsic or intrinsic, further exacerbate the observed defect. Brain serotonin system is itself affected by organismal energy status ( Dwarkasing et al. , 2015 ; Zemdegs et al. , 2015 ) and our data do not exclude that defects in serotonin levels found in ALS patients and models is caused, or contributed by, weight loss and hypermetabolism. Consistent with this notion, decreasing leptin, whose major action is on the melanocortin system, was able to revert partial weight loss and increased energy expenditure in SOD1m mice ( Lim et al. , 2014 ), suggesting that the melanocortin system can be further inhibited by leptin ablation.
What are the consequences of our current findings in ALS? There are at least three consequences of our finding for ALS research. First, melanocortin impairment seems to be a general event occuring in sporadic ALS patients, as well as in animal models caused by disparate mutations leading to ALS. Interestingly, a series of recent studies demonstrated the occurence of similar hypothalamic abnormalities in FTD ( Piguet et al. , 2011 ; Ahmed et al. , 2014 a , b , 2015 ), and in particular, increased AGRP ( Ahmed et al. , 2015 ). Thus, melanocortin impairment appears associated with overall ALS/FTD continuum. It remains to be determined how melanocortin impairment relates with motor neuron degeneration in ALS. Second, this study reinforces the notion of systemic involvement in ALS. That melanocortin impairment appears downstream of serotonin loss, also brings about the notion that circuitry dysfunction might contribute to aspects of ALS phenotype. How these serotonin and melanocortin defects might be related to the spreading of TDP-43 aggregates ( Brettschneider et al. , 2013 ) remains to be resolved. Second, these results have consequences for the design of pharmacological strategies to combat weight loss in ALS. Weight loss in ALS is likely to be multi-factorial, with primary causes such as hypermetabolism, and bulbar involvement, and could be exacerbated secondary to other symptoms such as deficit in upper limbs or depression. Treating weight loss could identify disease-modifying interventions as a hypercaloric diet was recently found to increase survival of ALS patients under gastrostomy ( Wills et al. , 2014 ; Dorst et al. , 2015 ). Many drugs that could be used to prevent weight loss, including atypical anti-psychotics (e.g. olanzapine) inhibit POMC neurons ( Kirk et al. , 2009 ; Weston-Green et al. , 2012 ; Lian et al. , 2014 ). Drugs targeting the cannabinoid system increase body weight by increasing beta-endorphin release from POMC neurons ( Koch et al. , 2015 ). As beta-endorphin is derived from POMC, which is decreased in ALS mice, it appears likely that cannabinoids might not be able to promote food intake through this mechanism in ALS. Thus, our current study provides a note of caution for the use of these drugs to counteract weight loss in the specific context of ALS patients, and suggest that disease progression might impair responsiveness of ALS patients to classical drugs leading to weight gain. A number of neural pathways controlling energy homeostasis have not yet been studied in the context of ALS and could be potential targets for treating weight loss ( Morton et al. , 2014 ). First, pathways involved in the emergency response to glucose deprivation (glucopaenia) such as NPY might be useful, although the precise neurochemical pathways still need to be elucidated. Second, drugs affecting food reward might be of interest to improve the attractability of food during the disease. Last, the existence of emergency neuronal circuits involved in stress-induced anorexia was recently elucidated. Inhibiting these pathways in ALS might also be a possible target for treating weight loss ( Morton et al. , 2014 ). Alternatively, and besides pharmacological treatments, increasing caloric density of the diet is likely an efficient strategy to counteract weight loss ( Wills et al. , 2014 ; Dorst et al. , 2015 ), although current results do not allow us to determine whether lipid enriched or carbohydrate enriched would be more efficient.
In all, our post hoc analysis of the pioglitazone trial revealed that the melanocortin system is profoundly altered in ALS, and that this might be important for understanding and preventing impairment of energy metabolism in ALS patients.
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Maybe now with this study just above which indicates a direct link as to a defect in the melanocotin system leading to ALS, the head of the Italian drug pricing authority should be interested in himself trying to expedite Scenesse approval. Thereby to the benefit of EPP patients and the scientific monetizing solvency of Clinuvel to bring future therapies to ALS and other potential melanocortin therapies.
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Mallinckrodt forced to ax ALS study testing its controversial Acthar gel
Mallinckrodt, the current maker of Acthar — a drug first developed in the 1950s — said on Tuesday said it was abandoning its quest to market the gel in patients with Lou Gehrig’s disease.
The company was testing the drug in a phase II study designed to enroll 213 patients — when an independent data and safety monitoring board recommended axing the trial due to the lack of an efficacy signal, and pneumonia occurring at a higher rate in Acthar-treated patients.
The disease, whose cause is largely unknown, garnered international attention after the New York Yankees’ Lou Gehrig abruptly retired from baseball in 1939, after being diagnosed with Amyotrophic lateral sclerosis (ALS), an invariably fatal neurological disorder that attacks nerve cells located in the brain and the spinal cord responsible for controlling voluntary muscles.
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Steven Romano
“It is critical to stress, however, that these findings do not impact the current positive benefit/risk profile of Acthar for use in current on-label indications,” reiterated Mallinckrodt’s chief scientific officer Steven Romano in a prepared statement. Achtar is used to treat infantile spasms in very young children.
Acthar’s list price has been hiked from $40 per vial in 2001 to a whopping $38,892 as of April 2019 — according to a recent Reuters report. Extracted from the pituitary glands of slaughtered pigs, it’s manufactured essentially the same way as it was in the 1950s.
Mallinckrodt $MNK acquired the drug in 2001 with its takeover of Questcor. It’s approved for 19 indications altogether — and accounts for a little over a third of the specialty biopharmaceutical company’s roughly $3.2 billion in net sales last year.
Endpoints News has contacted Mallinckrodt for comment.
The UK-based drugmaker has long elicited the ire of regulatory agencies for its marketing practices, particularly in relation to Acthar. After the Federal Trade Commission — along with the states of Alaska, Maryland, New York, Texas and Washington — alleged Mallinckrodt had taken advantage of its monopoly to repeatedly raise the price of Acthar and acquired the rights to its greatest competitive threat to keep competition at bay, the company agreed in 2017 to part with $100 million to settle those charges. This June, the US Department of Justice joined two whistleblower lawsuits in alleging that the company used a foundation as a conduit to pay illegal kickbacks in the form of copay subsidies for Acthar so it could market the drug as “free” to doctors and patients while increasing its price between 2010 and 2014.
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AUTHOR
Natalie Grover
REPORTER
nat...@endpointsnews.com
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PR Newswire PR NewswireJuly 16, 2019
STAINES-UPON-THAMES, United Kingdom, July 16, 2019 /PRNewswire/ -- Mallinckrodt plc (MNK), a leading global specialty biopharmaceutical company, today announced that it is permanently discontinuing its Phase 2B study designed to assess the efficacy and safety of Acthar® Gel (repository corticotropin injection) as an investigational treatment for amyotrophic lateral sclerosis (ALS). The drug is not U.S. Food and Drug Administration (FDA)-approved for the ALS indication. Please see Important Safety Information for Acthar Gel below.
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Mallinckrodt made the decision to halt the trial after careful consideration of a recent recommendation by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB was created by the company following industry best practice to ensure the safety of patients participating in a clinical study. This oversight is accomplished through ongoing review of semi-blinded information as the study is being conducted, and is typically done when there is limited information available in the patient population being studied.
The recommendation was based on the specific concern for pneumonia, which occurred at a higher rate in the ALS patients receiving Acthar Gel compared to those on placebo; the board also mentioned other adverse events specific to this patient population. The DSMB noted the proportion of patients who have completed Week 36 – the primary endpoint target – precludes a definitive determination of a treatment effect. The lack of a clear efficacy signal for this ALS patient population combined with the potential risk of pneumonia led to the board's recommendation.
After careful analysis, Mallinckrodt agreed that the study should be permanently halted in the interest of patient safety for this fragile population, one for which pneumonia is a particularly serious condition. Enrollment in the study will cease immediately, and those patients already enrolled will be tapered off the drug before discontinuing use.
"Mallinckrodt's primary focus is on the safety of patients and, while ALS patients are among those most in need of new therapies and treatment options, we believe this is the right decision. It is critical to stress, however, that these findings do not impact the current positive benefit/risk profile of Acthar for use in current on-label indications," said Steven Romano, M.D., Executive Vice President and Chief Scientific Officer at Mallinckrodt. "Though the probability of success for the ALS population was acknowledged as being low, this study was initiated based on compelling analyses carried out following the completion of a small pilot study and we were hopeful it would have translated into a benefit for this group of patients in great need of effective therapies. We thank the DSMB, the investigators and the patients who participated in the study."
This action does not affect any other ongoing clinical studies for Acthar Gel. Mallinckrodt is committed to responsible and ethical scientific exploration that adds to the body of clinical and economic data for critical illnesses. Mallinckrodt has invested more than $500 million into Acthar Gel's modernization, specifically initiating company-sponsored clinical studies building on substantial clinical experience as well as previously completed and largely independent clinical case series and smaller trials; modernizing manufacturing; and expanding medical affairs and research activities. The company's investment into Acthar Gel and these activities remains an important focus.
About the PENNANT Trial
The Phase 2B clinical study is titled "A Multicenter, Double Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Acthar Gel in the Treatment of Subjects with Amyotrophic Lateral Sclerosis." The study targeted enrollment of patients ages 18 to 75 with ALS and symptom onset (defined as first muscle weakness or dysarthria) ≤ two years prior to the screening visit. Subjects were randomized on a 2:1 basis to receive subcutaneous (SC) Acthar Gel 0.2 mL (16 units) daily or SC matching placebo 0.2 mL daily for 36 weeks.
The efficacy of Acthar Gel was assessed using standard measures of functional decline, including change from baseline in the ALS Functional Rating Scale-Revised, assessed after 36 weeks of therapy.
About ALS
ALS is a progressive neurodegenerative disease that affects motor neuron cells in the brain and the spinal cord. Motor neurons reach from the brain and the spinal cord to the muscles throughout the body. The progressive degeneration of the motor neurons in ALS eventually leads to their demise and when the motor neurons die, voluntary and involuntary muscle movement is lost. With the progressive loss of motor neurons, people with ALS may lose the ability to speak, eat, move and breathe.1
Acthar Gel (repository corticotropin injection) Indications
Acthar Gel is an injectable drug approved by the FDA for the treatment of 19 indications. Of these, today the majority of Acthar Gel use is in these indications:
Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
The treatment of symptomatic sarcoidosis
Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age
Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus
The treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease
Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus
Treatment during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis)
Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation
IMPORTANT SAFETY INFORMATION
Contraindications
Acthar should never be administered intravenously
Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar
Acthar is contraindicated where congenital infections are suspected in infants
Acthar is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction or sensitivity to proteins of porcine origins
Warnings and Precautions
The adverse effects of Acthar are related primarily to its steroidogenic effects
Acthar may increase susceptibility to new infection or reactivation of latent infections
Suppression of the hypothalamic-pituitary-axis (HPA) may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment
Cushing's syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms
Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium and potassium levels may need to be monitored
Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy
Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding
Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression, and psychosis. Existing conditions may be aggravated
Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis
Prolonged use of Acthar may produce cataracts, glaucoma and secondary ocular infections. Monitor for signs and symptoms
Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity
There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver
Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients
Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy
Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
Adverse Reactions
Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain
Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes mask other seizures, which become visible once the clinical spasms from IS resolve
Other adverse events reported are included in the full Prescribing Information.
Please see full Prescribing Information.
ABOUT MALLINCKRODT
Mallinckrodt is a global business consisting of multiple wholly owned subsidiaries that develop, manufacture, market and distribute specialty pharmaceutical products and therapies. The company's Specialty Brands reportable segment's areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. Its Specialty Generics reportable segment includes specialty generic drugs and active pharmaceutical ingredients. To learn more about Mallinckrodt, visit www.mallinckrodt.com.
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This release includes forward-looking statements with regard to Acthar Gel including expectations specific to this Phase 2B study, as well as its potential impact on patients. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: clinical trial results; satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; issues with product quality, manufacturing or supply, or patient safety issues; and other risks identified and described in more detail in the "Risk Factors" section of Mallinckrodt's most recent Annual Report on Form 10-K and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law.
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> http://www.agenziafarmaco.gov.it/en/content/chairman-board-prof-mario-melazzini The main and only substantial gene defect known which is related in the abstracts as causative to the destruction of motor neurons in the brain appears to be related to what Scenesse can alleviate. The SOD1 gene allele apparently in these patients, (including the discoverer/hypothezizor of Black Holes in the 1960s Stephen Hawking) is related to the reactive oxygen species super oxides probably a byproduct of improper copper atoms attenuation. The copper atom is the basis of the tyrosine protein chain when emulaine and more so phenoemulaine are created, which also creates free radical oxygen. Super Oxides have an atomic attraction to attach to a nearby available electron imbalance. And they will steal it from a healthy protein chain and thus damage that close proximity protein.
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> I recently posted that Mallinkrodpt which acquired Athcar from AbiVie had a successful trial apparently with Athcar in ALS disease. Presumption is that it is not the ACTH but the melanocyte stimulating hormone within the ACTH that is alleviating the ALS symptoms by neutralizing the free radicals thru the msh immune response. Fortuitously, Mario has provided his email in the link and I will start filling up his iPhone with related links.
Parkinson’s disease medication may benefit ALS sufferers
© koto_feja/Getty
© koto_feja/Getty
A medication used to treat Parkinson’s disease could help patients with amyotrophic lateral sclerosis (ALS), according to a new drug screen performed on reprogrammed patient cells.
A Japanese team that included scientists from Tohoku University Graduate School of Medicine generated induced pluripotent stem cells from the blood of patients with ALS — the motor neuron disease that famous physicist Stephen Hawking suffered from.
The researchers grew the stem cells into motor neurons — the brain cells that deteriorate in ALS — and then tested a library of more than 1,200 previously approved drug compounds for agents that would stave off neurodegeneration.
Ropinirole, a drug that activates dopamine receptors in the brain, emerged as the top hit. It helped protect neurons derived from people with both familial and sporadic ALS. The authors are now planning a randomized clinical trial to test ropinirole in ALS patients.
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Nature Medicine 24, 1579–1589 (201
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Als
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The porphyrias are a group of diseases united by a series of defects in heme metabolism , a key molecule for the transport of oxygen in the blood; since there are eight enzymes involved in the metabolic pathway of heme, porphyrias can be considered as a group of sisters, each with its own biochemical characteristics, although some are united by symptomatic manifestations that also include photosensitivity, i.e. the appearance of areas of inflammation, accompanied by severe pain, on the skin exposed to the sun. Francesca Granata has experienced porphyria since she was a child, but she has never been afraid to 'step out of the shadows' to shed light on this little-known condition.
To be exact, Francesca is affected by erythropoietic protoporphyria , a form of disease due to a defect in the production of the ironchelatase enzyme and which among the symptoms reports photosensitivity. In a recently organized TED Talk , Francesca told her story , explaining that due to the rashes and severe pain following exposure to the sun, her life, since the age of two, has been relegated to the shadows. Because of the pathology, in fact, the effects of sunlight on the skin are not limited to trivial redness, but are a perennial cause of suffering, such as burns; and they also arise only if a patient walks down the street or drives a car on a hot summer day. After a life of pain and frustration, Francesca enrolled in the Faculty of Biology to find the key to the problem and give an explanation to her condition . It was during the course of Biochemistry that he became acquainted with the molecular mechanism at the origin of his disease and, on this basis, he underwent the tests that confirmed the presence of erythropoietic protoporphyria. Since then, Francesca has continued to work in the world of medicine, becoming a researcher-patient and striving to facilitate the diagnosis of many children affected by her same problem.
" Today a drug against erythropoietic protoporphyria exists and could alleviate the suffering of patients: unfortunately, in Italy it has been included in reimbursement band C and not in A. Therefore it is not available in a homogeneous way throughout the national territory", explains Francesca . The drug he talks about is afamelanotide (trade name Scenesse®) that the Italian Medicines Agency (AIFA) has approved by inserting it among the non-reimbursable drugs by the National Health Service: therefore, the costs for the purchase are borne by the 'Hospital and the Region (Official Gazette No. 202 of 30.08.16, p. 27). A situation that has remained unchanged despite the fact that in 2019 the afamelanotide was approved by the Food and Drug Administration(FDA) without cost limitations, and the following year this approval was also implemented by the Australian Medicines Agency. “For years, I and the IPPN association , made up of patients with scientific expertise, have been fighting for this situation to change . In Italy, not all regions have the drug available which, being in a regional reimbursement range, in certain areas is not purchased and made available to patients. Thus a national inhomogeneity is created which puts many sick people in serious difficulty ”.
The efficacy of afamelanotide has now been amply demonstrated not only by the historic publication in The New England Journal of Medicine , which led to the approval of the drug, but also by recent publications in the Expert Review of Clinical Pharmacology and Orphanet Journal of Rare Disease . However, the problem remains. “When the clinical trial was carried out, patients were given up to 6 doses of the drug per year,” explains Francesca Granata. "Unfortunately, at the time of marketing, the European Medicines Agency (EMA) , in its final report (EMA / CHMP / 601433/2014),recommended the use of at least 3-4 doses and the national regulatory agencies accepted the suggestion as an imposition, limiting the number of doses . But since this molecule is able to stimulate melanogenesis, a greater number of administrations results in a wider coverage. The safety profile of the drug is very good, therefore it is essential that patients receive it continuously and not only during the summer months. And since it is a palliative drug, that is, it treats the symptoms of the disease but does not eliminate the root cause, the negotiation of price and dosage has become complex. We are working to overcome this obstacle, trying to make people understand that erythropoietic protoporphyria is a serious and disabling disease ".
Francesca is not alone in this undertaking. Together with her, other patients are working on two difficult fronts: on the one hand to bring the disease out of the shadows; on the other to ensure that there is no lack of the drug that can cure it. Thus, in addition to promoting serious and targeted information on what porphyrias are, facilitating the diagnosis of many people, their battle serves to ensure that patients can have equal access to that treatment that, for many rare diseases, is still denied.
- 01-27-2021 - I suffer from porphyria, can I get vaccinated against COVID-19?
- 14-10-2021 - Acute hepatic porphyria: complex neurological manifestations treated with givosiran
- 09-28-2021 - Porphyria neuropathy: the importance of differential diagnosis
- 08-24-2021 - Acute hepatic porphyria: too many affected people do not know they are
- 07-13-2021 - Porphyria: Valentina's fight against pain, to return to the sea
- 03-06-2021 - Acute intermittent porphyria: chronic symptoms even in sporadic and latent forms
- 06-04-2021 - Acute hepatic porphyria, the drug givosiran is now reimbursable in Italy
- 09-03-2021 - Protoporphyria, the Phase III study on the molecule MT-7117 is also active in Italy
- 22-02-2021 - Acute hepatic porphyria, first administration of the drug givosiran at San Gallicano
- 18-01-2021 - Acute hepatic porphyria: less disease attacks with givosiran
- 2020-12-28 - Porphyria: the most common symptoms during an attack are convulsions and disturbances of consciousness
- 08-12-2020 - Acute hepatic porphyria: from the RNAi technique a new drug available to patients
- 04-11-2020 - Acute hepatic porphyria: on average six attacks occur per year
- 29-04-2020 - Acute hepatic porphyria, a virtual exhibition to tell the disease
- 04-28-2020 - Porphyria, you need to be a fighter to face the disease
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- David Wright
Associate Professor of Medical Imaging, Monash University
David Wright receives funding from the NHMRC and FightMND. He has previously received funding from the Bethlehem Griffiths Research Foundation to investigate glymphatic function in ALS.
PartnersMonash University provides funding as a founding partner of The Conversation AU.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the most common form of motor neuron disease. People with ALS progressively lose the ability to initiate and control muscle movements, including the ability to speak, swallow and breathe.
There is no known cure. But recently, we studied mice and identified a new target in the fight against this devastating disease: the brain’s waste clearance system.
Neurodegenerative diseases – including Parkinson’s disease, Alzheimer’s and multiple sclerosis – share many similarities, even though their clinical symptoms and disease progression may look very different. The incidence of these diseases increase with age. They are progressive and relentless, and result in gradual loss of brain tissue. We also see waste proteins accumulate in the brain.
Our new research looked at how the glymphatic system, which removes waste from the brain, could prevent ALS.
Inside our bodies, long protein chains fold to form functional shapes that allow them to perform specific tasks like creating antibodies to fight off infection, supporting cells or transporting molecules.
Sometimes this process goes awry, resulting in “misfolded” proteins that clump together to form aggregates. Misfolded protein can grow and fragment, creating seeds that spread throughout the brain to form new clusters.
The accumulation of waste proteins begins early in the neurodegenerative disease process – well before the onset of symptoms and brain loss. As researchers, we wanted to see if eliminating or slowing the spread of these waste proteins and their seeds could halt or slow the progression of disease.
Targeting waste removalThe glymphatic system removes waste, including toxic proteins, from the brain.
This brain-wide network of fluid-filled spaces, known as Virchow-Robin spaces, is mostly switched off while we’re awake. But it kicks into gear during sleep to distribute compounds essential to brain function and to get rid of toxic waste.
This may explain why all creatures, great and small (even flies), need sleep to survive. (Interestingly, whales and dolphins alternate their sleep between brain hemispheres, keeping the other hemisphere awake to watch for predators and alerting them to breathe!)
Unlike us, dolphins sleep with one side of their brain at a time. Unsplash/NOAA, CC BYAs we age, sleep quality declines and the risk of neurodegenerative disease, including ALS, increases.
Sleep disturbances are also a common symptom of ALS and research has shown a single night without sleep can result in increased accumulation of toxic waste protein in the brain. As such, we thought glymphatic function might be impaired in ALS.
Read more: Longer naps in the day may be an early sign of dementia in older adults
Ageing miceTo investigate this, we looked to mice. The animals were genetically modified to express human TDP-43 – the protein implicated in ALS. By feeding these mice food containing an antibiotic (doxycycline), we were able to turn the TDP-43 protein expression off and they aged normally. But when the mice are switched to normal food, TDP-43 expression is turned on and misfolded proteins begin to accumulate.
Over time, the mice display the classical signs of ALS including progressive muscle impairments and brain atrophy.
Using magnetic resonance imaging (MRI) to see brain structure, we investigated glymphatic function in these mice just three weeks after turning on TDP-43 expression.
As we watched the glymphatic system go to work, we saw the TDP-43 mice had worse glymphatic clearance than the control mice that had not been genetically modified. Importantly, these differences were seen very early in the disease process.
Our study provides the first evidence the glymphatic system might be a potential therapeutic target in the treatment of ALS.
Not all sleep is equal. Sleep includes both rapid eye movement (REM) and non-REM sleep. This latter stage includes slow wave sleep – when the glymphatic system is most active. Sleep therapies that enhance this phase may prove to be particularly beneficial for preventing diseases like ALS.
Sleep position is also thought to affect glymphatic clearance.
Research conducted in rodents has demonstrated glymphatic clearance is most efficient in the lateral (or side-sleeping) position, compared to either supine (on the back) or prone (front-lying) positions. The reasons for this are not yet fully understood but possibly relates to the effects of gravity, compression and stretching of tissue.
Read more: ‘Sleeping on it’ helps you better manage your emotions and mental health – here’s why
Lifestyle choices may be helpful in improving glymphatic function too. Omega-3, found in marine-based fish, has long been considered to be beneficial to health and reduced risk of neurodegenerative diseases. New research shows these benefits may be partly due to the positive effect of Omega-3 on glymphatic function.
Moderate consumption of alcohol has been shown to improve waste clearance. In mouse studies, both short and long-term exposure to small amounts of alcohol were shown to boost glymphatic function while high doses had the opposite effect.
Exercise has also been shown to be beneficial.
All these studies show small lifestyle changes can improve brain waste clearance to minimise the risk of neurodegenerative disease. Next, research needs to focus on therapies directly targeting the glymphatic system to help those already suffering from these debilitating diseases.
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Stacy MorfordEnvironment + Climate Editor