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Saturday, June 8, 2019

Rapidly removing fluid from ICU patients in kidney failure tied to higher death risk

The faster fluid is removed using continuous dialysis from patients with failing kidneys, the higher the likelihood they will die in the next several months, according to a study published today in JAMA Network Open by University of Pittsburgh School of Medicine researchers.
Nearly two-thirds of critically ill patients with  have extra fluid accumulating in their bodies, which can put pressure on their lungs and cause injury to other organs. To relieve that pressure, clinicians routinely remove the excess fluid from the blood while performing dialysis in the . But there is no guidance on how fast that fluid should be removed.
“We want to get this excess fluid out of our patients before it causes damage but, in removing it, we’re actually causing a controlled loss of fluid that can sometimes cause stress on the heart and lead to dangerously ,” said lead author Raghavan Murugan, M.D., M.S., associate professor in Pitt’s Department of Critical Care Medicine and UPMC physician. “So the question—how rapidly to remove fluid?—has been asked in the critical care community for many years, but there’s been no good answer.”
Previous studies in outpatients who are not critically ill found that routine dialysis—a procedure to remove waste, toxins, salt and extra water from the blood of people whose kidneys have failed—when performed too quickly, is associated with increased risk of death.
Murugan partnered with senior author Rinaldo Bellomo, M.D., Ph.D., a professor of intensive care medicine at the University of Melbourne in Australia to find out if that finding extends to critically ill patients. Their team examined data from 1,434 patients that Bellomo had previously collected for the Randomized Evaluation of Normal vs. Augmented Level of Renal Replacement Therapy trial, which was conducted between December 30, 2005 and November 28, 2008 in 35 intensive care units in Australia and New Zealand.
The research team found that for every 0.5 milliliter increase in fluid removed per kilogram of the patient’s weight per hour (0.5 mL/kg/hr), their risk of death increases. That translates to a 51% to 66% higher risk of death in the next three months for critically ill patients for whom excess fluid is removed at a rate greater than 1.75 mL/kg/hr, compared to  for whom excess fluid is removed at a rate less than 1.01 mL/kg/hr.
For the average older American male, that’s a difference of removing a gallon of fluid in about one day versus a little under two days.
Murugan is quick to point out that his analysis shows association, not causation; until a clinical trial is performed to specifically test the effects of removing fluid faster versus slower, he cannot say for sure that removing fluid slowly is better for the patient. And, in some cases, such as imminent heart failure, Murugan says a more rapid removal of fluid might be warranted to prevent sudden death.
“You have to balance the pros and the cons, and decide how fast to remove fluid based on your patient’s clinical condition,” said Murugan, who also is a member of Pitt’s Clinical Research, Investigation, and Systems Modeling of Acute Illness Center and the Center for Critical Care Nephrology. “But in a patient where I can’t find an immediate need to get fluid out quickly, I’ll be removing fluid at a slower rate until we get definitive results and guidance from a clinical trial.”

Explore further

More information: JAMA Network Open (2019). DOI: 10.1001/jamanetworkopen.2019.5418

Long-term islet transplant recipients show near-normal glucose control

Continuous glucose monitoring (CGM) evaluations in islet transplant recipients who have been insulin independent for an average of 10 years show near-normal glycemic profiles and time-in-range metrics, according to data presented by the Diabetes Research Institute at the University of Miami Miller School of Medicine. The findings, which were accepted as a late-breaking poster at the American Diabetes Association (ADA) 79th Scientific Sessions, June 7-11, 2019 in San Francisco, CA, demonstrate that islet transplantation can be a successful long-term cell therapy for select patients with type 1 diabetes.
The DRI team evaluated five of its adult subjects who received intrahepatic (in the liver) islet transplants between 2002—2010 and have since remained insulin independent for seven to 16+ years. During their last study follow-up, the subjects completed a 7-day, non-blinded CGM to assess their glycemic profiles. Compared to current recommended CGM goals for adults with type 1  on a hybrid closed-loop system, all patients demonstrated improved CGM time-in-range, reduction in glucose variability, and prevention of hypoglycemia.
In addition, time in the more stringent glucose range of 70-140 mg/dL was 83.1%, with a mean sensor glucose (SG) value of 116 mg/dL and an average HbA1c of 5.7%. The ADA’s recommended HbA1c goal is <7% for adults with diabetes.
“Using continuous glucose monitoring, we now have the ability to accurately evaluate patients’ glucose profiles and their variability. The CGM data we have obtained from our islet transplant patients clearly demonstrates that islet transplantation can result in glucose levels that are close to those in people who do not have type 1 diabetes, even 10 years or more after undergoing the cell-replacement procedure,” said David Baidal, M.D., assistant professor of medicine and member of the DRI’s Clinical Islet Transplant Program. One of the principal investigators of the study, Dr. Baidal is presenting the results at the ADA conference.
“Although not all subjects remain insulin independent, like the subjects described in this presentation, after an islet transplant a significant number of them continue with excellent graft function for over 10 years that allows them to have near-normal glucose metabolism in the absence of severe hypoglycemia on small doses of insulin,” said Rodolfo Alejandro, M.D., director of the Clinical Cell Transplant Program and also a principal investigator of the study. Dr. Alejandro will be presenting these results at the upcoming 17th World Congress of the International Pancreas & Islet Transplant Association, July 2-5, 2019 in Lyon, France.
“This report confirms the superiority of transplantation of insulin-producing cells compared to insulin therapy, with  control results that were even better than the goals of CGM in hybrid closed-loop systems. Hopefully, this will be of assistance in bringing islet transplantation closer to FDA approval, allowing the treatment to be made available to U.S. patients, as has already been the case in several other countries, for many years,” said Camillo Ricordi, M.D., Stacy Joy Goodman Professor of Surgery and director of the Diabetes Research Institute, who was recently named the world’s leading expert in islet transplantation by Expertscape. Dr. Ricordi is well-known for inventing the machine (Ricordi Chamber) that made it possible to isolate large numbers of islet cells from the human pancreas and for performing the first series of successful clinical islet transplants that reversed diabetes after implantation of donor purified islets into the liver of recipients with diabetes.
In type 1 diabetes, the insulin-producing islets cells of the pancreas have been mistakenly destroyed by the immune system, requiring patients to manage their blood sugar levels through a daily regimen of insulin therapy. Islet transplantation has allowed some patients to live without the need for insulin injections after receiving a transplant of donor cells. Some patients who have received islet transplants have been insulin independent for more than a decade, as DRI researchers have published. Currently, islet transplantation remains an experimental procedure limited to a select group of adult patients with type 1 diabetes.
In 2016, the National Institutes of Health-sponsored Clinical Islet Transplantation Consortium reported results from its Food and Drug Administration (FDA)-authorized Phase 3 multi-center trial, of which the DRI was a part, indicating that islet transplantation was effective in preventing severe hypoglycemia (low blood sugar levels), a particularly feared complication in type 1 diabetes that can lead to seizures, loss of consciousness and even death. The study was a significant step toward making transplantation an approved treatment for people with type 1 diabetes and reimbursable through health insurance, as it is in several other countries around the world.

NGM Bio to Present New Data from Phase 1b Study at American Diabetes Assn

NGM Biopharmaceuticals, Inc. (Nasdaq: NGM), a clinical stage biotechnology company focused on developing transformative therapeutics for patients, today announced that it will present new data from a Phase 1b study of NGM313 at the 79th Scientific Sessions of the American Diabetes Association (ADA) taking place in San Francisco June 7 – 11, 2019.
As part of their ongoing strategic collaboration, NGM and Merck, known as MSD outside the United States and Canada, announced in January 2019 that Merck exercised its option to license NGM313, now renamed MK-3655. Merck intends to advance MK-3655 into a Phase 2b study to evaluate the effect of MK-3655 on liver histology and glucose control in NASH patients with or without diabetes. NGM313 (MK-3655) is an investigational agonistic antibody that selectively activates the β-Klotho/FGFR1c receptor complex. The Phase 1b randomized, open-label, active-controlled parallel group study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of NGM313 in obese, insulin resistant subjects with non-alcoholic fatty liver disease (NAFLD). NGM presented data from the Phase 1b study at the European Association for the Study of the Liver’s (EASL) The International Liver Congress™ (ILC) in April 2019 and the AASLD’s The Liver Meeting® in November 2018.
The new data to be presented at a late breaker poster presentation at the ADA meeting include the evaluation of whole-body insulin sensitivity of a single dose of NGM313 compared to daily dosing of pioglitazone (45 mg), as determined by a two-step hyperinsulinemic, euglycemic clamp.
As previously presented, the Phase 1b data demonstrated that a single dose of NGM313 resulted in a statistically significant reduction in liver fat content, and improvements in multiple metabolic parameters, including improved insulin sensitivity, reduced HbA1c and fasting glucose levels, lowered triglycerides and LDL-C, and raised levels of HDL-C. NGM313 was well-tolerated, with no serious adverse events. All adverse events observed during the course of the study were deemed mild, with increased appetite and injection site reactions being the only adverse events reported in at least 10% of the NGM313-treated subjects (n=17).

Biotech week ahead, June 10

Biotech stocks staged a steady recovery last week. ASCO presentations dominated the headlines, with Iovance Biotherapeutics Inc IOVA 3.36% and Mirati Therapeutics Inc MRTX 2.94% among the biggest gainers. The IPO calendar was empty and there were a slew of clinical trial readouts that swayed stocks.
The following are key catalysts expected in the unfolding week.

Conferences

  • American Diabetes Association 79th Scientific Sessions: June 7-11 in San Francisco, California.
  • 24th World Congress of Dermatology: June 10-15 in Milan, Italy.
  • Goldman Sachs 40th Annual Global Healthcare Conference: June 11-13 in Rancho Palos Verdes, California.
  • The Annual European Congress of Rheumatology of the European League Against Rheumatism: June 12-16 in Switzerland.
  • 24th European Hematology Association Congress: June 13-16 in Amsterdam, Netherlands.

PDUFA Dates

Merck & Co., Inc. MRK 1.14% awaits the FDA’s ruling on its sBLA for Keytruda as a first-line treatment option for patients with recurrent or metastatic head and neck squamous cell carcinoma. The PDUFA date is set for June 10.

Clinical Trial Readouts

American Diabetes Association 79th Scientific Sessions Presentations

NGM Biopharmaceuticals Inc NGM 3.09%: updated Phase 1b data for NGM313/MK-3655 (NASH and Type 2 diabetes)on June 9.

EULAR Annual European Congress Of Rheumatology Presentations

GALAPAGOS NV/S ADR GLPG 3.77% and Gilead Sciences, Inc. GILD 2.56%: already-released Phase 3 data for Filgotinib from FINCH 1 study (rheumatoid arthritis), June 12; Phase 3 data for Filgotinib from FINCH 3 study (rheumatoid arthritis), June 15.
Nektar Therapeutics NKTR 0.06%: Phase 1b data for NKTR-358 (systemic lupus erythematosus), June 13.
Corbus Pharmaceuticals Holdings Inc CRBP 3.41%: Phase 2 open-label data for Lenabasum (dermatomyositis), June 14; Phase 2 open-label data for Lenabasum (systemic sclerosis).
Kezar Life Sciences Inc KZR 3.91%: already-released initial Phase 1b topline data for KZR-616 (lupus), June 14.

24th European Hematology Association Congress Presentations

Kura Oncology Inc KURA 4.85%: Additional Phase 2 data for Tipifarnib (relapsed or refractory peripheral T-cell lymphoma), June 13.
bluebird bio Inc BLUE 3.79%: Phase 3 data for LentiGlobin in HGB-212 (transfusion-dependent beta thalassemia), June 14; updated Phase 1/2 data for LentiGlobin in HGB-204 (beta-thalassemia), June 14; updated Phase 3 data for LentiGlobin in HGB-207 (non-β0/β0 transfusion-dependent thalassemia), June 14.
Beigene Ltd BGNE 2.32%: updated Phase 1 data for Zanubrutinib (Waldenström’s macroglobulinemia), June 14; Phase 2 data for Tislelizumab (relapsed or refractory classical Hodgkin lymphoma), June 14.
Global Blood Therapeutics Inc GBT 1.15%: Phase 3 data for GBT440 (sickle cell disease), June 14.
Blueprint Medicines Corp BPMC 2.13%: updated Phase 1 data for Avapritinib BLU-285 (advanced Systemic mastocytosis), June 14.
ArQule, Inc. ARQL 2.04%: Phase 1a data for ARQ 531 (B-cell malignancies), June 14.
Regeneron Pharmaceuticals Inc REGN 2.38%: updated Phase 1 data for REGN1979 (non-Hodgkin lymphoma).
Sunesis Pharmaceuticals, Inc. SNSS 1.73%: updated Phase 1/2 data for SNS-062 ( advanced B-cell malignancies).
Sutro Biopharma Inc STRO 1.1%: Phase 1 initial safety data for STRO-001 (non-Hodgkin lymphoma), June 15.
Forty Seven Inc FTSV 3.11%: Phase 2 data for 5F9 + rituximab (non-Hodgkin lymphoma), June 15.
Geron Corporation GERN 2.9% : updated Phase 2 data for Imetelstat (Myelodysplastic syndromes), June 15.

24th World Congress of Dermatology Presentations

Incyte Corporation INCY 1.23%: Phase 2 data for ruxolitinib (atopic dermatitis), June 14; Phase 2 data for ruxolitinib (vitiligo), June 15

Weight Loss and Delays to Progression of Type 2 Diabetes

In a comparison of two different diet and two different weight management programs, results of the international PREVIEW intervention study found a low, similar rate of progression to type 2 diabetes (T2D) among people with prediabetes who had initially lost weight on a low-calorie diet (LCD), according to a symposium presentation today titled “PREVIEW Study Results—Prevention of Diabetes through Lifestyle Intervention and Population Studies Around the World” at the American Diabetes Association’s® (ADA’s) 79th Scientific Sessions® at the Moscone Convention Center in San Francisco. The study showed no difference between either of the post-weight loss diet or exercise-management programs, with the participants who had initially lost weight in all groups having a three-year incidence rate of T2D of 4%, which was much lower than anticipated.

In order to identify the most effective lifestyle patterns for the prevention of T2D in a population of people who have prediabetes and are overweight, researchers around the globe began “PREVention of diabetes through lifestyle Intervention and populations studies in Europe and around the World” (PREVIEW). The study’s aim was to determine the effects and interactions of different types of diets and different exercise regimens on the development of new cases of T2D in patients with prediabetes.
“Further work is needed to explore the reasons for such successful prevention of type 2 diabetes, however, it is likely that the initial weight loss combined with thorough education and support in the components in either nutrition plan, in addition to a physical activity program, led to successful lifestyle changes and maintenance of at least some of the initial weight loss in most of the people completing the trial,” said one of the lead investigators Ian Macdonald, BSc, PhD, professor of metabolic physiology at the University of Nottingham. “The inclusion of an initial period of a low-calorie diet achieving significant weight loss, preceding a well-structured and effectively delivered weight maintenance program, may be a major feature of future diabetes prevention programs.”
PREVIEW is, to-date, the largest multi-national trial to address T2D prevention in adults with prediabetes through nutrition and exercise. The study began in 2013 and enrolled 2,223 participants using intervention centers in DenmarkFinland, the United Kingdomthe NetherlandsSpainBulgariaAustralia, and New Zealand. The 36-month intervention consisted of two phases: a two-month period of rapid weight reduction achieved using an LCD (800 kcal/day), followed by a 34-month randomized diet and exercise phase for weight loss maintenance consisting of four treatment arms. The impact of a high-protein, low-glycemic index (GI) vs. moderate protein, moderate-GI diet in combination with moderate or high-intensity physical activity on the incidence of T2D and the related clinical end-points were investigated.

Lilly’s tirzepatide demonstrates benefits in data at American Diabetes Assn

Results from several studies of Eli Lilly and Company’s (LLY) investigational dual GIP and GLP-1 receptor agonist (RA), tirzepatide, reinforce its potential in lowering A1C and body weight in people with type 2 diabetes. Early research results also support tirzepatide’s potential benefit in treating other metabolic conditions. The following findings were presented in oral and poster presentations at the American Diabetes Association’s® 79th Scientific Sessions® in San Francisco:
  • improvements in markers of beta cell function (how cells in the pancreas produce, store and release insulin) and insulin sensitivity (how cells in the body respond to insulin) that help explain efficacy;1
  • efficacy and improved tolerability with lower initial doses and smaller subsequent dose escalations;2
  • significant A1C and body weight reductions in Japanese people with type 2 diabetes after just eight weeks of treatment;3 and
  • improvements in markers of non-alcoholic steatohepatitis (NASH, liver inflammation and cell damage caused by liver fat) in people with type 2 diabetes.4
“These new tirzepatide data build upon the positive results seen in people with type 2 diabetes to date,” said Juan P. Frias, M.D., Medical Director and Principal Investigator, National Research Institute. “The results offer additional evidence of tirzepatide’s potential to meaningfully reduce A1C and body weight in people with type 2 diabetes and treat other metabolic conditions.”

Search launched for first patient proven spontaneously cured of Alzheimer’s

Has any Alzheimer’s disease (AD) patient ever been proven cured spontaneously of the usually fatal disease, without medical intervention? That’s what Alzheimer’s Germ Quest, Inc., wants to find out. They’re offering a $100,000 reward to the physician who provides the best case. Presently there is no curative for AD, and it is considered 100 percent fatal.

“Researchers can get valuable clues to a disease’s cause and possible therapy from studying even a single spontaneously-cured individual,” says Leslie Norins, M.D., Ph.D., the CEO. “We want to find such an unusual AD patient if one exists, and get the details for scientists to review. Speedier progress against Alzheimer’s is vital.”
“It might have been reported as a miracle. So, we contacted the authorities of the Catholic Church to see if they had records of any miraculous cures of AD,” Dr. Norins says.
The Catholic evaluator and registrar of miracles is the Congregation for the Causes of Saints, part of the Curia at the Holy See, in Rome. “Their letter to me says they know of none,” says Dr. Norins. We also got negative reports from the research librarians at Catholic University of America and the University of Notre Dame.
Next, Dr. Norins says he searched both the medical and lay literature, using both PubMed and Google, and again turned up no spontaneous cures of AD.
So, he says, “We’re creating our own dragnet through this global search. Because physicians are the local professionals best able to diagnose AD and assess a possible spontaneous cure, we are targeting them. We’re asking any doctor who has convincing evidence to submit that case via our website, ALZgerm.org, where they’ll find all the details.”
Dr. Norins cites as inspiration the single patient whose proven cancer spontaneously disappeared, leading Dr. Steven Rosenberg of the National Cancer Institute to begin his productive studies of immunological remedies for cancer. Other single-patient discoveries include the “Philadelphia chromosome” in leukemia, and the “Berlin patient” for white cell resistance to HIV.
Alzheimer’s Germ Quest, Inc. is a self-funded public benefit corporation headquartered in Naples, Florida. It sponsors the $1 Million Challenge Award for the scientist who provides persuasive evidence that AD is caused by an infectious agent.