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Saturday, November 9, 2019

Tandem: Death Of Patient Wasn’t Due To Insulin Pump Malfunction

Tandem Diabetes Care Inc TNDM 3.12% shares traded lower Friday after a report of the death of a patient using Tandem’s T:SLIM X2 insulin pump was added to the Food and Drug Administration’s Adverse Event report system.
The report said the patient’s blood glucose was low at the time of death, but that the cause of death was pending the coroner’s determination.
A Tandem spokesman said the company couldn’t comment in detail because of health privacy rules, but did say the cause of death “was not due to insulin delivery or pump malfunction.

“Hypoglycemia is, unfortunately, a common occurrence in diabetes and can result from any number of causes,” the spokesman said in an email.

The company makes “every effort to reclaim and thoroughly investigate the Tandem device being worn by any customer who experienced a serious injury or death,” the company said.
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Nektar Has New Clinical, Preclinical Data from Immuno-Oncology Pipeline

Nektar Therapeutics (Nasdaq: NKTR) today announced the presentation of five clinical and preclinical data abstracts focused on its immuno-oncology portfolio at the 2019 Society for Immunotherapy of Cancer (SITC) Annual Meeting.
New clinical results from the PIVOT-02 Phase 1/2 study were shared in an oral presentation titled, “Clinical activity of BEMPEG plus NIVO in previously untreated patients with metastatic melanoma: updated results from the Phase 1/2 PIVOT-02 Study” by Adi Diab, MD, Associate Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center during the Combination Phase 1-2 Clinical Trials Session on Saturday, November 9th.
Additional preclinical data presented at the annual meeting highlighted NKTR-255, an IL-15 agonist discovered by Nektar. The presentations demonstrated that NKTR-255 enhanced activity of antibody-dependent cellular cytotoxicity (ADCC) against tumor cells in vitro, and that it also enhanced in vivo efficacy of ADCC-inducing antibodies in models of human solid tumors. NKTR-255 is designed to engage the IL-15 pathway to stimulate and expand natural killer (NK) cells and promote the survival and expansion of memory CD8+ T cells without inducing suppressive regulatory T cells. NKTR-255 is currently being evaluated in a Phase 1/2 clinical trial in patients with either relapsed or refractory Non-Hodgkin’s lymphoma or multiple myeloma.
“The data presented at this year’s SITC meeting continue to showcase the potential of our I-O portfolio, most notably our key IL-2 pathway program, bempeg, and our new IL-15 pathway program, NKTR-255,” said Jonathan Zalevsky, Ph.D., Senior Vice President and Chief Research & Development Officer at Nektar. “The 18-month follow-up data presentation for the Stage IV melanoma patients in our PIVOT-02 study reinforces the promise of BEMPEG and NIVO to work synergistically to achieve a deepening of response over time, while maintaining a favorable safety and tolerability profile. We’re pleased that at this 18 month timepoint, 85% of patients who achieved responses have ongoing responses and median PFS has not yet been reached.”
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Mirati Has Data From Ongoing Clinical Trials Of Sitravatinib-Nivolumab Combo

Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical stage targeted oncology company, today announced the presentation of initial data from its ongoing Phase 2 clinical trial of sitravatinib in combination with nivolumab (OPDIVO®) in metastatic urothelial cancer (mUC) patients with documented progression on a platinum-chemotherapy and checkpoint inhibitor. The data were presented in an oral presentation at the Society of Immunotherapy of Cancer (SITC) 34th Annual Meeting in National Harbor, MD. Preliminary results from the ongoing Phase 1 study of neoadjuvant sitravatinib combined with nivolumab in patients with resectable squamous cell carcinoma of the oral cavity (SNOW trial) were also presented in a poster session.
“Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, Mer), that has the potential to increase responsiveness in patients whose tumors are resistant to checkpoint inhibitors. The initial efficacy data from the Phase 2 clinical trial presented today in patients with checkpoint refractory mUC is promising and extends the clinical benefit data beyond what has already been demonstrated by sitravatinib combined with nivolumab in checkpoint refractory non-small cell lung cancer (NSCLC),” said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer of Mirati. “In addition, we are evaluating sitravatinib in patients who have progressed on checkpoint therapy, including those with NSCLC and renal cell cancer, and we continue to expand development efforts of sitravatinib through our collaboration with BeiGene in multiple indications including NSCLC, renal cell cancer, hepatocellular cancer, ovarian cancer, and gastric cancer.”
The ongoing Phase 2 clinical trial, an open-label, multi-cohort trial, is enrolling patients with advanced or metastatic urothelial cancer who had been previously treated with a platinum-chemotherapy and checkpoint inhibitor and had documented disease progression. Data from Cohort 1 of the trial were presented, where patients must have also received prior platinum-based chemotherapy. Trial objectives included tumor regression, safety and pharmacokinetics.
As of the data cut-off date of October 17, 2019, 22 patients were evaluable for response with at least one radiographic scan:
  • 6/22 evaluable patients achieved a confirmed Complete Response (CR, 1 patient) or Partial Response (PR, 5 patients).
  • 21/22 evaluable patients achieved a CR, PR or stable disease.
  • 4 responding patients have been treated for more than 6 months.
The combination has been well-tolerated and most adverse events (AEs) were Grade 1 or 2.
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What, how much we eat may change our internal clocks, hormone responses

For the first time, a study shows how glucocorticoid hormones, such as cortisol, control sugar and fat levels differently during day and night, feeding and fasting, rest and activity, over the course of 24 hours.
The research conducted in mice found that the time-of-day dependent metabolic cycle is altered by high caloric diet. Since glucocorticoids are widely used drugs for the treatment of inflammatory diseases, these findings published in Molecular Cell suggest that lean and obese patients might respond differently to steroid therapy. Finally, it reveals the biological function of daily rhythms of hormone secretion (high before awakening and feeding, low when sleeping and fasting) as well as daily cycles of sugar and fat storage or release by the liver.
Each cell in the human body is driven by an internal clock which follows the circadian rhythm of 24 hours. It is synchronized with the natural cycle of day and night mainly by sunlight, but also through social habits. In a healthy system, glucocorticoid stress hormones, are produced every morning by the adrenal gland. The secretion of glucocorticoidpeaks before awakening, prompting the body to use fatty acids and sugar as sources of energy, and enabling us to start our daily activities. When the circadian rhythm is disrupted (e.g. through shift work or jetlag) and/or when the glucocorticoid level alters (e.g. through Cushing syndrome or long-term clinical application), profound metabolic dysregulation can be caused — like obesity, type 2 diabetes, and fatty liver disease. The researcher’s goal therefore was to understand the relevance of these daily peaks of stress hormone secretion, the impact of these hormones on our “internal clock” and their role for daily cycles of metabolism.
Glucocorticoids’ metabolic actions in the liver
To study glucocorticoids’ metabolic actions in the liver, the researchers characterized the activity of their receptor, called the glucocorticoid receptor, using novel high throughput techniques. They analyzed mouse livers every 4 hours during day and night. The mice were either in normal condition or fed with high-fat diet. They then used cutting-edge technologies in genomics, proteomics, and bioinformatics to picture when and where the glucocorticoid receptor exerts its metabolic effects. The researchers dissected the impact of daily surges of glucocorticoid release in the 24-hour-cycle of liver metabolism. They could illustrate how glucocorticoids regulate metabolism differently during fasting (when the mice sleep) and during feeding (when they are active), by time-dependent binding to the genome. Furthermore, they showed how the majority of rhythmic gene activity is controlled by these hormones. When this control is lost (in so-called knockout mice), blood levels of sugar and fat are affected. This explains how the liver controls blood levels of sugar and fat differently during day and night.
In a next step, as the glucocorticoid receptor is a widely-used drug target in immune therapies, they investigated its genomics effects after the injection of the drug dexamethasone, a synthetic glucocorticoid that also activates this receptor. “With this experiment,” explains Dr. Fabiana Quagliarini, “we found that the drug response was different in obese mice compared to lean mice. It is the first time to show that diet can change hormonal and drug responses of metabolic tissues.”
New insights for Chronomedicine and metabolic disease therapy
Glucocorticoids are a group of natural and synthetic steroid hormones such as cortisol. They have potent anti-inflammatory and immunosuppressive properties which can control the activity of the immune system. This is why they are widely exploited in medicine. The major drawback is that glucocorticoids also cause severe side effects by virtue of their ability to modulate sugar and fat metabolism: Patients may develop obesity, hypertriglyceridemia, fatty liver, hypertension or type 2 diabetes.
“Understanding how glucocorticoids control 24-hour-cycles of gene activity in the liver and consequently blood levels of sugar and fat, provides new insights into ‘Chronomedicine’ and the development of metabolic disease. We could describe a new link between lifestyle, hormones and physiology at the molecular level, suggesting that obese people may respond differently to daily hormone secretion or to glucocorticoid drugs. These mechanisms are the basis for the design of future therapeutic approaches,” highlights Prof. Henriette Uhlenhaut.
Story Source:
Materials provided by Helmholtz Zentrum München – German Research Center for Environmental Health. Note: Content may be edited for style and length.
Journal Reference:
  1. Fabiana Quagliarini, Ashfaq Ali Mir, Kinga Balazs, Michael Wierer, Kenneth Allen Dyar, Celine Jouffe, Konstantinos Makris, Johann Hawe, Matthias Heinig, Fabian Volker Filipp, Grant Daniel Barish, Nina Henriette Uhlenhaut. Cistromic Reprogramming of the Diurnal Glucocorticoid Hormone Response by High-Fat Diet. Molecular Cell, 2019; DOI: 10.1016/j.molcel.2019.10.007
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Preclinical data published on new drug combination to treat neuroblastoma

Neuroblastoma is the most common cancer outside of the brain in infants and young children and often fails to respond to therapy. Though it can appear in several areas of the body, it commonly develops as a solid tumor most frequently found in or adjacent to the adrenal glands, which sit atop the kidneys.
Patients diagnosed with high-risk neuroblastoma typically undergo intensive treatments that can include surgery, radiation therapy, chemotherapy and myeloablative chemotherapy, which is chemotherapy followed by a bone marrow or . Regardless of which treatment is used, the five-year overall survival rate for these  is approximately 50%, and 50%-60% will experience a relapse.
To help improve the treatment outcomes for neuroblastoma patients, C. Patrick Reynolds, M.D., Ph.D., director of the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine’s Cancer Center, and a team of colleagues recently completed a study using fenretinide, one of several derivatives of vitamin A known as retinoids, to boost the effects of venetoclax, an inhibitor of a protein known as BCL-2 that helps neuroblastoma  survive and grow.
Reynolds’ team included fellow TTUHSC Cancer Center investigators Thinh H. Nguyen, Balakrishna Koneru, Sung-Jen Wei, Ph.D., Wan Hsi Chen, Monish Ram Makena, Ph.D., Eduardo Urias and Min H. Kang, Pharm.D. Molecular Cancer Therapeutics published their study, “Fenretinide via NOXA induction, enhanced activity of the BCL-2 inhibitor venetoclax in high BCL-2-expressing neuroblastoma preclinical models,” in September.
Fenretinide was originally developed years ago in an effort to prevent breast . Reynolds said he started studying it because he had seen vitamin A derivatives produce major survival improvement in neuroblastoma during a large national clinical trial he conducted previously.
“In studying this drug, we found one of the key issues was that, unlike the other vitamin A derivatives that caused the  to just stop growing and become more mature, fenretinide worked through different mechanisms and killed the cells.”
One of the problems, Reynolds said, was the drug’s formulation. At the time, it was an oral capsule that was not achieving the kind of levels that would really kill the cells in patients. Working with the National Cancer Institute, Reynolds and fellow TTUHSC Cancer Center investigator Barry Maurer, M.D., Ph.D., developed two novel fenretinide formulations, one an oral formulation and the other an intravenous formulation.
“Those formulations had considerable activity in neuroblastoma, which is a very malignant cancer,” Reynolds said. “It’s often difficult to get patients to have any response at all when they develop recurrent disease, and the fact that we could get multiple complete responses to fenretinide alone was very encouraging, though what we wanted was a drug combination that was very well tolerated.”
Reynolds started working with a drug developed by AbbVie called venetoclax very early in its inception. The drug targets protein molecules called BCL-2, one of several anti-death molecules that exist in our cells. BCL-2 is used for various functions in a normal cell, but cancer cells use the protein to help defeat cancer therapy. Some of these cancer cells, including several types of neuroblastoma, have a tendency to overexpress BCL-2 in order to survive and grow.
“The idea is to inhibit those molecules that defeat the chemotherapy with the venetoclax because it specifically targets the BCL-2 molecules,” Reynolds said. “The drug actually worked against lymphomas in adults and was registered and approved for use by the FDA.”
The Reynolds lab had previously worked with drugs from AbbVie that targeted multiple BCL-2 families, but venetoclax targeted very specific BCL-2 molecules without producing some of the toxicities that often occur in patients.
“One of the goals in this study was to find out if venetoclax, which is now in routine use for a type of leukemia and lymphoma, would enhance the fenretinide as we had seen before with similar drugs,” Reynolds said. “And in fact, that was the case.”
Nguyen, an M.D./Ph.D. student who was the study’s lead author, conducted additional cell culture work that demonstrated the fenretinide-venetoclax combination was very effective against the .
Using xenografts, which are cancer cells taken from humans and grown in mice, Nguyen saw that fenretinide produces a significant number of unstable molecules that contain oxygen and easily react with other cell molecules. This process, known as reactive oxygen species, is one way by which fenretinide kills cancer cells.
However, this reaction also upregulated, or activated, a pair of transcription factors, which proteins help to turn on or turn off specific genes by binding to nearby DNA. In this case, the transcription factors were increasing the amount of NOXA. NOXA blocks MCL-1, a protein that can replace BCL-2 and help cancer cells survive. Thus, NOXA is a protein that overcomes a key mechanism of resistance to venetoclax, causing cancer cell death.
“What is happening is we are taking out the BCL-2 in the cell with venetoclax, but the cell defends itself by upregulating MCL-1,” Reynolds said. “Then the fenretinide comes in and triggers the upregulation of NOXA, which in turn takes out the MCL-1. That’s why the combination of these drugs was so lethal for the cancer cells and really not that toxic at all for normal cells.”
One of the obstacles in trying to get cancer therapy to work, especially with targeted agents like fenretinide and venetoclax, is identifying patients that are likely to respond positively to the treatment. To do this, researchers look for biomarkers, which are unique characteristics that can be used to identify cancers that are likely to respond to a particular type of treatment. Reynolds said Nguyen was able to show that a high expression of BCL-2 is a biomarker that identifies neuroblastoma patients that will respond very well to the fenretinide-venetoclax combination.
“That’s a key point,” Reynolds said. “If you don’t have the biomarker and you treat patients, some will respond to the treatment and some won’t. Going into a clinical trial, I really like to be able to look at the patients and say ‘this patient is likely to respond, let’s put them on that trial and try this drug.’ The team identified a biomarker that can be applied clinically if this goes into clinical trial, though one of the challenges to taking this into the clinic is finding funding resources that actually enable the making of the fenretinide that can go into these children.”
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Glutamine-blocking drug slows tumor growth, strengthens anti-tumor response

A compound developed by Johns Hopkins researchers that blocks glutamine metabolism can slow tumor growth, alter the tumor microenvironment and promote the production of durable and highly active anti-tumor T cells.
The drug, a “prodrug” version of the glutamine antagonist DON, was designed so that the active form of the drug is functional within the . In theory, this compound could be used across a wide spectrum of cancer types, says Jonathan Powell, M.D., Ph.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, and colleagues due to the critical role of glutamine in promoting the metabolism necessary for prodigious tumor growth.
Their study, published online Nov. 7 in Science, reveals surprising differences in the metabolic pathways fueling cancer  and effector T cells, pathways that were thought previously to be very similar. These differences could be exploited as a “metabolic checkpoint” in treating cancer, Powell says.
“By targeting , we were not only able to inhibit tumor growth and change the tumor microenvironment, but also alter the T cells in a way that we markedly enhanced immunotherapy for cancer,” he says.
Although glutamine metabolism is a component of all cells of the body, the DON prodrug selectively targeted tumor cells because they are the “hungriest” for glutamine, said Powell. “What’s emerging in metabolic therapy—and to me this is why it’s incredibly exciting—is that a treatment like ours becomes selective because it preferentially affects the cells that have the greatest demand.”
Powell and colleagues tested the DON prodrug, dubbed JHU083, in mice models of colon cancer, lymphoma and melanoma.
“In the beginning, our thought was that if we could target tumor metabolism, we could achieve two goals: slow tumor growth and alter the tumor microenvironment,” says Powell. The tumor microenvironment—the cells, blood vessels and nutrients in the vicinity of tumors—is very hostile to the  because it is usually acidic, hypoxic and nutrient-depleted. “This immune shield that the tumor creates around itself is in a sense a direct result of tumor metabolism,” he says.
In mice, treatment with JHU083 led to a significant decrease in  and improved survival in many different cancer models, by derailing tumor cell metabolism and its effects on the tumor microenvironment, the research team found. In a number of the mice, treatment with JHU083 alone led to durable cures. These cures were facilitated because the metabolic therapy unleashed the natural anti-tumor immune response. When the researchers reinjected these cancer-free mice with new tumors, they found that almost all the mice rejected the new tumor, suggesting that the JHU083 treatment had produced a powerful immune memory to recognize and attack the new cancer.
They also treated the mice with JHU083 and an anti-PD-1 checkpoint inhibitor, a type of immunotherapy drug that removes restraints  place on immune cells. “Initially, we thought we would need to use the two therapies sequentially in order to avoid any potential impact of the metabolic therapy on the immunotherapy,” says Powell. “Remarkably, however, it turned out that the combined treatment worked best when we gave them simultaneously.” Concurrent treatment with the drugs produced improved anti-tumor effects compared with anti-PD-1 therapy alone.
“We found that JHU083 was having a very positive, very direct effect on the immune cells, and we had to investigate why,” Powell said.
After analyzing and comparing gene expression in the treated tumor cells and a type of immune cell called effector T cells, Powell and colleagues noted differences in gene expression related to metabolism, which allowed them to guess at how the T cell was fueling itself compared with the tumor.
They found some similarities, but fundamentally the metabolic programming of  and the effector T immune cells was quite different, and it is those differences the researchers exploited by giving the glutamine-blocking drug.
The differences allowed the effector T cells to respond to the glutamine blockage by producing long-lasting, highly effective tumor-infiltrating T cells that seemed to be invigorated rather than exhausted in the . “By blocking glutamine , we were making these cells more persistent, more like an immune memory cell,” Powell noted.
The group also demonstrated that treating the tumors with JHU083 enhanced the efficacy of adoptive cellular therapy, a type of immunotherapy in which immune T cells are collected and grown in large numbers in the laboratory before being given to patients to boost the immune response against . These findings suggest that this new approach may also be used to enhance a promising type of adoptive cell therapy called CAR-T. In future studies, Powell and colleagues want to examine how JHU083 combines with different types of immunotherapy to explore whether certain tumors can overcome the metabolic trap laid by JHU083.
Potentially, tumors that develop  to avoid the impacts of JHU083 could find themselves in a “blind alley,” said Powell. “By adding an additional metabolic antagonist, you could potentially get rid of the resistant tumors as well.”
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More information: Robert D. Leone et al, Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion, Science (2019). DOI: 10.1126/science.aav2588
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Common muscle relaxant causes severe confusion in patients with kidney disease

One in 25 patients with very low kidney function were admitted to hospital with severe confusion and other cognitive-related symptoms a few days after being prescribed a common muscle relaxant.
A new study from ICES Western, Western University and Lawson Health Research Institute has shown that patients with  who were prescribed a high dose of the drug , were more likely to be admitted to hospital for disorientation and confusion, than those who weren’t prescribed the drug. Their results are being published on November 9 in the high impact journal, JAMA and are being presented at the same time at the American Society of Nephrology meeting in Washington, D.C.
“When we looked at people with low  function (30 per cent or less) who received a high dose of baclofen from their prescriber, approximately one in 25 were being admitted to hospital with severe confusion, typically over the next few days, ” said Dr. Amit Garg, Professor at Western’s Schulich School of Medicine & Dentistry and Scientist at ICES and Lawson. “If you compare that to a group of people who had low kidney function who didn’t get baclofen, that risk is less than one in 500, so it’s quite a dramatic difference between the two groups.”
The research was initiated because of observations that nephrologists were noting in clinic at London Health Sciences Centre.
Dr. Peter Blake, Professor at Schulich Medicine & Dentistry, Lawson scientist and coauthor on the study says this drug is commonly prescribed for muscle spasms and muscle pain, and is also prescribed off-label for alcoholism, gastro-esophageal reflex disease, and trigeminal neuralgia. He says it is widely prescribed because it has not previously been associated with serious side-effects.
More than eight million prescriptions for the drug were handed out in the United States in 2016, and despite numerous case reports linking baclofen with cognitive symptoms in patients with , this is the first population-based  to look at the association between the two.
“It came to my clinical attention dealing with patients with advanced kidney failure, that this drug that is generally thought to be relatively harmless, appeared to be the precipitant of severe confusion,” said Dr. Blake. “These are patients who had previously been very oriented, and they were suddenly extremely confused and when you took a history, we understood that they had recently started this drug, baclofen.”
Using ICES data, the research team looked at a group of approximately 16,000 people in Ontario with kidney disease who started a new dose of baclofen between 2007 and 2018. They divided the patients into two groups, a group that received a high dose, and a group that received a low dose of the drug and compared both to a group of almost 300,000 kidney disease patients who were not prescribed the drug at all.
About 20 per cent of older adults live with kidney function of less than 60 per cent. The research team found that 1.11 per cent of such patients (108/9707) who started a high dose of the drug baclofen were admitted to hospital with cognitive-related symptoms, versus 0.42 per cent (26/6235) with the low dose. They found that the group most at risk had the lowest kidney function, 3.78 per cent of patients with kidney function less than 30 per cent were hospitalized with these symptoms after starting a high dose of baclofen (26/687).
“We found that in current practice most patients are getting a similar dose of baclofen no matter what the level their kidney function is,” said Dr. Garg who is concerned about this discrepancy in dosing because prescribing guidelines already suggest a lower dose for patients with kidney dysfunction that isn’t being followed. “We also found that the risk for hospitalization for severe confusion was higher amongst patients who received doses that were higher versus doses that were lower.”
The authors hope this study will better inform physicians and pharmacists about the use of baclofen for patients with kidney disease. “This study shows quite clearly the potential harm of this drug.
When a patient with low kidney function presents to the hospital with confusion, when their medication list is reviewed baclofen should be considered as a potential culprit. We’re hoping regulatory agencies will now take a look at this and perhaps add a new black box warning for baclofen. With this new information prescribers should reconsider risk-benefit, and should be quite cautious before they prescribe this drug. When they believe the  is indicated, a low dose should be considered, and patients and their families should be warned about what to look out for in terms of side effects.”
The authors also say patients should not stop their prescription medications without talking to their doctor.
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More information: Flory T. Muanda et al, Association of Baclofen With Encephalopathy in Patients With Chronic Kidney Disease, JAMA (2019). DOI: 10.1001/jama.2019.17725
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