Piper Jaffray analyst Sean Wieland kept his Overweight rating and $30 price target on Evolent Health, saying the ruling by a federal judge in Kentucky to vacate the approval for Medicaid work requirement waiver secures continued coverage and mitigates the risk for the company in that state. The analyst notes that further regulatory changes are now expected to boost Evolent’s value proposition and boost demand for its services.
Monday, July 2, 2018
Can aspirin treat Alzheimer’s?
A regimen of low-dose aspirin potentially may reduce plaques in the brain, which will reduce Alzheimer’s disease pathology and protect memory, according to neurological researchers at Rush University Medical Center, who published the results of their study today in the July issue of The Journal of Neuroscience.
“The results of our study identifies a possible new role for one of the most widely used, common, over-the-counter medications in the world,” said Kalipada Pahan, Ph.D., the study’s senior author and lead research investigator, who also is the Floyd A. Davis, MD, Endowed Chair of Neurology and professor of neurological sciences, biochemistry and pharmacology in Rush Medical College.
Alzheimer’s disease is a fatal form of dementia that affects up to 1 in 10 Americans age 65 or older. To date, the FDA has approved very few drugs for the treatment of Alzheimer’s disease-related dementia and the medications that exist can only provide limited symptomatic relief.
The exact cause of Alzheimer’s disease progression is unknown; however, poor disposal of the toxic protein amyloid beta in the brain is a leading mechanism in dementia and memory loss.
Activating the cellular machinery responsible for removing waste from the brain therefore has emerged as a promising strategy for slowing Alzheimer’s disease.
Amyloid beta forms clumps called amyloid plaques, which harm connections between nerve cells and are one of the major signs of Alzheimer’s disease. Building on previous studies demonstrating a link between aspirin and reduced risk and prevalence of Alzheimer’s disease,
Pahan and his colleagues were able to show that aspirin decreases amyloid plaque pathology in mice by stimulating lysosomes—the component of animal cells that help clear cellular debris.
“Understanding how plaques are cleared is important to developing effective drugs that stop the progression of Alzheimer’s disease,” said Pahan.
A protein called TFEB is considered the master regulator of waste removal. The researchers gave aspirin orally for a month to genetically modified mice with Alzheimer’s pathology, then evaluated the amount of amyloid plaque in the parts of the brain affected most by Alzheimer’s disease.
They found that the aspirin medications augmented TFEB, stimulated lysosomes and decreased amyloid plaque pathology in the mice.
“This research study adds another potential benefit to aspirin’s already established uses for pain relief and for the treatment of cardiovascular diseases,” said Pahan. “More research needs to be completed, but the findings of our study has major potential implications for the therapeutic use of aspirin in AD and other dementia-related illnesses.”
More information: Sujyoti Chandra et al, Aspirin induces Lysosomal biogenesis and attenuates Amyloid plaque pathology in a mouse model of Alzheimer’s disease via PPARĪ±, The Journal of Neuroscience (2018). DOI: 10.1523/JNEUROSCI.0054-18.2018 , dx.doi.org/10.1523/JNEUROSCI.0054-18.2018
Chronic pain remains the same or gets better after stopping opioid treatment
Stopping long-term opioid treatment does not make chronic, non-cancer-related pain worse and, in some cases, makes it better, Washington State University researchers have found.
The research marks a crucial first step towards understanding how ending long-term opioid therapy affects patients with different types of chronic pain and could help medical practitioners identify effective, alternative treatments to opioids.
“On average, pain did not become worse among patients in our study a year after discontinuing long-term opioid therapy,” said Sterling McPherson, associate professor and director for biostatistics and clinical trial design at the WSU Elson F. Floyd College of Medicine. “If anything, their pain improved slightly, particularly among patients with mild to moderate pain just after discontinuation. Clinicians might consider these findings when discussing the risks and benefits of long-term opioid therapy as compared to other, non-opioid treatments for chronic pain.”
In the study
McPherson and colleagues at the Veteran Affairs Portland Health Care System and the Oregon Health & Science University used survey responses from 551 VA patients who had been on long-term opioid therapy for chronic, non-cancer-related pain for at least a year before discontinuing the medication.
Eighty-seven percent of the patients were diagnosed with chronic musculoskeletal pain, 6 percent with neuropathic pain, and 11 percent with headache pain, including migraines.
Survey subjects rated their pain over two years, scoring it on a scale of 0-10 where 0 equals no pain and 10 equals the worst possible pain. The researchers used biostatistical analysis and computer modeling to characterize changes in pain intensity 12 months before the patients ended opioid therapy and the 12 months after.
While patients differed widely in the intensity of pain they experienced before and after stopping opioids, as a whole, their pain did not get worse and remained similar or slightly improved.
“Our results indicate that long term opioid therapy does not effectively manage patient pain intensity any more effectively than not receiving long-term opioid therapy,” McPherson said. “There are a variety of treatments available for the management of chronic pain other than opioids and our hope is that this research will help promote conversations about these alternatives between doctors and their patients.”
Next steps
McPherson plans to collect additional data and conduct qualitative interviews with patients over the next year to try and determine why some patients experience greater reductions in pain than others after discontinuing long-term opioid therapy
“As part of our study, we grouped our patients into one of four categories based on the amount of pain they reported before and after discontinuing long-term opioid therapy,” McPherson said. “We are now going to try and understand what different mechanisms may be at work for reducing or increasing chronic pain for each of these sub-groups. Our hope is this will lead to being able to target specific sub-populations with different types of treatment for their chronic pain. In addition, we hope to continue to characterize potential adverse effects from being discontinued from long-term opioid therapy.”
A national problem
Backaches, headaches and other chronic, non-cancer-related pains affect one-third of Americans and will afflict even more as the prevalence of diabetes, obesity, arthritis and other diseases grows in the United States’ aging population.
From the early 1990s through 2012, powerful opioid painkillers were increasingly used to treat these maladies in the United States. But a growing number of opioid-related overdose deaths has caused U.S. doctors and policymakers to reexamine this approach. According to the Centers for Disease Control and Prevention, more than 63,600 Americans died from drug overdose deaths in 2016, a toll five times higher than in 1999. Two thirds of these deaths, 42,249, involved opioids.
McPherson’s study, which appears in the June edition of the journal Pain, is one of the first to investigate what, if any, are the potential adverse effects of discontinuing long term opioid therapy for chronic, non-cancer-related pain.
Explore further: Opioid tapering may improve outcomes for chronic pain sufferers
More information: Sterling McPherson et al, Changes Ii Pain Intensity Following Discontinuation of Long-Term Opioid Therapy for Chronic Non-Cancer Pain, PAIN (2018). DOI: 10.1097/j.pain.0000000000001315
Well-known animal health drug could stop outbreaks of malaria and Zika
Medicines given to household pets to kill fleas and ticks might be effective for preventing outbreaks of malaria, Zika fever and other dangerous insect-borne diseases that infect millions of people worldwide, according to a new study led by scientists at Calibr, a non-profit drug discovery institute closely affiliated with Scripps Research and TropIQ Health Sciences, a Dutch social enterprise.
The researchers found that a class of drugs called isoxazolines, sold in veterinary products such as fluralaner (Bravecto ) and afoxolaner (NexGard ) to protect pets from fleas and ticks, also kills species of disease-carrying mosquitos that feed on human blood.
The research team, led by TropIQ’s Koen Dechering, Ph.D. and Calibr’s Matt Tremblay, Ph.D., determined via experimental studies on mosquitoes and computer modeling that giving isoxazoline drugs to less than a third of the population in areas prone to seasonal outbreaks of insect-borne diseases could prevent up to 97 percent of all cases of infection. The results of the study were published today in the Proceedings of the National Academy of Sciences.
“Insect-borne infectious diseases remain primary causes of severe illnesses and fatalities worldwide, and new approaches to preventing outbreaks of these diseases are critically needed,” said Peter Schultz, Ph.D., chief executive officer of Calibr and Scripps Research. “Our findings suggest that isoxazolines might be effective at controlling outbreaks of diseases carried by mosquitos and other insects in regions with limited medical infrastructure.”
Millions of people each year contract malaria, Zika fever and other insect-borne diseases that are particularly prevalent in tropical and sub-tropical regions. In 2016, an estimated 216 million people contracted malaria worldwide and 445,000 died from the disease (mostly children in the African Region), according the US Centers for Disease Control. Zika, a mosquito-borne disease that can cause birth defects in infants born to infected mothers, has spread rapidly around the planet in recent years and is now found in 90 countries.
Mosquitoes aren’t the only carriers of such diseases. Leishmaniasis, caused by protozoan parasites transmitted by sandflies, is endemic to parts of Africa, South America, the Middle East and India. Though far less prevalent than malaria, forms of leishmaniasis that affect internal organs can be fatal if untreated.
“Research on insect-borne diseases has predominantly focused on control of insect populations through use of insecticides and prevention of bites through distribution of bednets, but these approaches have not been fully effective in controlling outbreaks” says Koen Dechering, CEO of TropIQ Health Sciences. “Vaccines are largely lacking for most diseases and drugs to treat people who have contracted the disease are losing efficacy because of emerging resistance.”
The international research team investigated a new strategy, the possibility of giving humans isoxazolines to block transmission of diseases by insect vectors. Isoxazolines are sold in veterinary products such as fluralaner (Bravecto ) and afoxolaner (NexGard ) that protect pets from fleas and ticks.
When administered orally the drugs absorb into the bloodstream and spreads throughout the animal’s body, where it remains active for up to three months. While well-tolerated in dogs and cats, the drugs kill blood-sucking fleas and ticks that feed on the blood of treated animals by damaging the insects’ nervous systems.
The Calibr and TropIQ scientists and their collaborators tested two of the drugs, fluralaner and afoxolaner, and found they also kill species of disease-carrying mosquitos and sand flies that feed on human blood infused with the insecticides. The drugs also were effective against insect strains that are resistant to common insecticides.
Based on existing data from studies of the drugs in animals, the researchers estimated that a single human dose of the drugs would convey an insecticide effect against mosquitos and sand flies lasting 50-90 days.
“In many regions where seasonal outbreaks are endemic, medical infrastructure is such that delivery of medical care is on an intermittent basis,” said Matt Tremblay, Ph.D., the chief operating officer of Calibr and Scripps Research and a senior author on the PNAS paper. “Isoxazolines could be administered prior to the beginning of seasonal disease outbreaks to convey protection until the threat diminishes at the end of the season.”
The drugs may not work as vaccines, since a treated person could still contract a disease from an insect bite. But an insect that bites an infected person taking the drugs would die before it could transmit the disease to other people, an effect that, when multiplied over a large population, would reduce the overall number of infections.
Working with collaborators at Imperial College London, in the UK, the researcher team used computer epidemiology models to estimate that that giving the drugs to just 30 percent of the population in a region where Zika fever is common could prevent more than 97 percent of cases. Looking at malaria incidence, their modelling showed that in areas with low and very seasonal transmission, such as Senegal, Sudan, Madagascar, Namibia, Botswana and Zimbabwe, giving isoxazolines to 30 percent of the population could prevent more than 70 percent of infections.
Regions with greater numbers of cases and year-round outbreaks would see a smaller percentage reduction, but the overall reduction in these areas could be dramatic. The Democratic Republic of the Congo has 16-20 million malaria cases annually, for instance, so a 30 percent reduction would prevent as many as 6 million cases.
Based on safety studies of isoxazoline use in animals, the drugs have a good chance of being safe if repurposed for human use. The research team is planning to evaluate the efficacy of the drugs in humans and anticipate these studies will take around two years.
Explore further: Uptick in vector-borne illnesses in US and what it means to you
More information: Marie Miglianico el al., “Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases,” PNAS (2018). www.pnas.org/cgi/doi/10.1073/pnas.1801338115
New types of cancer immunotherapy shows promise in early tests
Much cancer immunotherapy research has focused on harnessing the immune system’s T cells to fight tumors, “but we knew that other types of immune cells could be important in fighting cancer too,” says Ashish Kulkarni at the University of Massachusetts Amherst. Now he and colleagues at Brigham and Women’s Hospital, with others, report that in preclinical models they can amplify macrophage immune responses against cancer using a self-assembling supramolecule.
As immune cells, macrophages usually eat foreign invaders including pathogens, bacteria and even cancer cells, Kulkarni explains, but one of the two types do not always do so. Macrophage type M1s are anti-tumorigenic, but M2s can be recruited by tumor cells to help them grow. Also, tumor cells overexpress a protein that tells the macrophages, “don’t eat me.” In this way, pro-tumorigenic macrophages may make up 30 to 50 percent of a tumor’s mass, says the biomedical engineer and lead author of the new study.
Kulkarni adds, “With our technique, we’re re-programming the M2s into M1s by inhibiting the M2 signaling pathway. We realized that if we can re-educate the macrophages and inhibit the ‘don’t eat me’ protein, we could tip the balance between the M1s and M2s, increasing the ratio of M1s inside the tumor and inhibiting tumor growth.” Details appear in the current online issue of Nature Biomedical Engineering.
To address both the M2 “re-education” problem and to enhance the macrophages’ capacity to eat tumor cells, the researchers used what they call a bi-functional or “one-two punch,” says Kulkarni. He and research technician Anujan Ramesh, with colleagues in India and at Harvard Medical School’s Brigham and Women’s Hospital, used a multi-component supramolecular system that self-organizes at the nanoscale to deliver an antibody inhibitor plus a drug inside the tumor. “This is the first time anyone has combined these two, a drug that targets M2 macrophages and an antibody that inhibits ‘don’t eat me signal,’ in one delivery system,” Kulkarni notes.
He adds, “We feel this new approach provides a complementary one that can be used along with other therapies. We tested it in melanoma and breast cancer preclinical models, two aggressive cancers, and we plan to try it on different types of cancer and in combination with other current therapies like T-cell-based therapies now used in clinics.”
The researchers tested the supramolecular therapeutic in animal models of the two forms of cancer, comparing it directly with a drug currently available in the clinic. Mice that were untreated formed large tumors by Day 10, they report. Mice treated with currently available therapies showed decreased tumor growth. But mice treated with the new supramolecular therapy had complete inhibition of tumor growth. The team also reported an increase in survival and a significant reduction in metastatic nodes.
Co-author Shiladitya Sengupta at Brigham and Women’s Hospital says, “We can actually see macrophages eating cancercells,” citing confocal microscopy images in the paper that show macrophages engulfing cancer cells.
Kulkarni says next steps are to continue testing the new therapy in preclinical models to evaluate safety, efficacy and dosage. The supramolecular therapy they have designed has been licensed and they hope to move the therapeutic into clinical trials if preclinical testing continue to show promise.
Explore further: Removing the enablers: Reducing number of tumor-supporting cells to fight neuroblastoma
More information: Ashish Kulkarni et al, A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer, Nature Biomedical Engineering (2018). DOI: 10.1038/s41551-018-0254-6
Rockwell Medical files suit against former CEO Chioini,former CFO Klema
Rockwell Medical filed a lawsuit in the United States District Court for the Eastern District of Michigan against the company’s former CEO Rob Chioini, former CFO Thomas Klema, board member Ron Boyd and former board member Patrick Bagley.The Lawsuit alleges that Chioini, Klema, Boyd and Bagley have for years mismanaged the company, promoting self-enrichment and poor corporate governance at the expense of Rockwell Medical’s shareholders, employees and patients in need of the Company’s life-changing drug, Triferic. Their recent continued attempts to paralyze the Board’s and the Company’s ability to operate follows a long-line of wrongful acts that are outlined in the Lawsuit. In addition, the Lawsuit outlines the timing and rationale for the Board’s decision to terminate Chioini and Klema. Ben Wolin, Chairman of the Board, said, “Importantly, the five independent directors of the Board are continuing to make progress on the significant efforts underway to put the company on stable footing, including identifying and hiring a new CEO and CFO, engaging a new audit firm and implementing our new Triferic commercialization strategy.” Mr. Wolin added, “We recognize how both upsetting and confusing these events resulting from the harmful actions taken by Chioini, Klema, Boyd and Bagley must be for our investors. We will continue to vigorously defend the Company and take actions that are in the best interest of the Company and all our stakeholders.”
Celyad’s CAR-T Pipeline Has Potential: Wainwright
CELYAD SA/ADR CYAD 4.34% bolstered its entirely bullish cohort of analysts Monday with a fresh buyer.
The Rating
HC Wainwright analyst Edward White initiated coverage of Celyad with a Buy rating and $45 price target.
The Thesis
The chimeric antigen receptor therapy, or CAR-T, pipeline is led by CYAD-01, a treatment for solid and liquid tumors that’s in a Phase 1 dosing escalation study.
“We believe that by targeting eight different ligands, CYAD-01 is differentiated from currently approved CAR-T therapies and those in development,” the analyst said, noting that early safey data is “compelling.”
The drug demonstrated the world’s first complete response in relapsed/refractory acute myeloid leukemia, White said. The affected patient was still surviving 10 months after treatment, well beyond median the AML survival rate of below four months, he said.
If Phase 1 results prove positive, White said he expects a Phase 2 pivotal trial to begin in 2020 on a trajectory for 2022 approval.
In solid tumors, CYAD-01 demonstrates the potential to disrupt blood supply and modulate the immunosuppressive environment, according to HC Wainwright.
Early data from the dose escalation portion of the Phase 1 study in colorectal cancer yielded promising activity, and full figures are expected in November, White said.
“CYAD-01 could usher in a paradigm shift in cell-based immuno-oncology for solid tumors.”
Assuming 2022 approval, HC Wainwright forecast 2026 revenue of $596 million for colorectal cancer and $239 million for AML.
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