Gene therapy method developed to target damaged kidney cells

Gene therapy has gained momentum in the past year, following the federal government’s approval of the first such treatments for inherited retinal diseases and hard-to-treat leukemia. Now, research led by Washington University School of Medicine in St. Louis has shown, in mice, that genetic material can be delivered to damaged cells in the kidneys, a key step toward developing gene therapy to treat chronic kidney disease.

The potentially fatal condition affects 30 million Americans, most of whom don’t realize they have chronic kidney disease. No cure exists, and current treatments for end-stage disease mostly are limited to dialysis and kidney transplant. However, the researchers said gene therapy could provide a way to deliver genes that slow or reverse cell damage that leads to chronic kidney disease.

The findings are published July 5 in the Journal of the American Society of Nephrology.

“Chronic kidney disease is an enormous and growing problem,” said senior author Benjamin D. Humphreys, MD, Ph.D., director of the Division of Nephrology at Washington University. “Unfortunately, over the years, we haven’t developed more effective drugs for the condition, and this reality is leading us to explore gene therapy.”

Diabetes, hypertension and other conditions cause chronic kidney disease, which occurs when damaged kidneys cannot effectively filter waste and excess fluids from the body. Because symptoms such as nausea, vomiting, sleep disturbances and swollen limbs are common and nonspecific to the disease, most people don’t realize they have chronic kidney disease until irreparable organ damage occurs. Advanced chronic kidney disease also leads to cardiovascular disease, and patients with kidney failure have much higher rates of death from cardiovascular causes than those with healthy kidneys.

“Part of the reason there have been so few advances in kidney disease treatment is because the kidney is complex, and we don’t fully understand the disease process,” said Humphreys, the Joseph Friedman Professor of Renal Diseases in Medicine. “However, scientists are making progress, and I am optimistic.”

Credit: CC0 Public Domain

To that end, Humphreys and his team—including researchers from Harvard University and Massachusetts Institute of Technology—focused on whether adeno-associated virus (AAV), a relative of the virus that causes the common cold, could deliver genetic material to targeted kidney cells. Until now, no such virus has been capable of delivering genetic material to the kidney, and the new research provides a proof of concept for this approach.

The researchers evaluated six AAV viruses, both natural and synthetic, in mice and in stem-cell-derived human kidney organoids. A synthetic virus, Anc80, created by one of the researchers proved successful in reaching two types of cells that contribute to chronic kidney disease; these cells secrete proteins that gum up the organ and cause irreversible damage. The researchers also showed that the genetic material carried by Anc80 was transferred successfully to the targeted kidney cells. That same virus also was used by the researchers in gene therapy strategies to treat mice with kidney scarring.

“This was a happy surprise,” Humphreys said. “We were not expecting this.”

However, Humphreys cautioned that researchers are still early in the process. In future research, scientists will encounter several challenges, such as the need to identify a gene that can extensively correct damaged kidney cells, he explained. Another issue involves refining the boundaries of gene delivery to prevent delivery of the synthetic virus to other organs.

“The interesting thing about the adeno-associated viruses is that they persist in the body for many months, potentially giving a therapeutic gene a chance to do its work,” Humphreys said. “Chronic kidney disease is a slowly progressive disease so that is an advantage. After many more years of research, we could envision that patients would need injections maybe twice a year as opposed to every week, like with chemo.

“There has been so little innovation in kidney treatment,” he said. “We believe this is a positive step forward.”

 Explore further: Researchers identify potential new targets for treating kidney disease

More information: “Efficient Gene Transfer to Kidney Mesenchymal Cells Using a Synthetic Adeno-Associated Viral Vector,” Journal of the American Society of Nephrology (2018). DOI: 10.2215/ASN.2018004026

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Malpractice: When Small Oversights Lead to Major Errors

• In large medical groups, where numerous physicians may treat the same patient, extra care must be taken to correctly identify patients and their records.
• Complex systems and processes, which are often necessary for large groups, may also create unintended risks.
• In the following case, there are several points where identity errors could have been caught; physicians need to stay alert and double-check to prevent mistakes that could lead to unnecessary surgery.

The Case

One of the risks in the care given at large medical groups is that many physicians may treat a single patient. Another risk is the complexity of the systems involved and how much trust physicians must place in those systems.

Factor in an error made by an outsider, and the chance of injury increases.

Sara Tompkins (not her real name) was a 43-year-old patient of Dr IM, an internist at a large, multispecialty medical group. On June 23, Dr IM received a telephone message that Ms Tompkins reported getting “food poisoning on June 22 in Las Vegas.” The next day, Ms Tompkins executed an authorization for the Las Vegas hospital to release all medical records, “including x-rays,” to the medical group where Dr IM practiced.

The records from the Las Vegas hospital revealed a sudden onset of nausea, vomiting, and diarrhea. Though records revealed that an x-ray was taken and that gastroenteritis was diagnosed, no copy of the films or of the radiographic report was included in the transmittal. After several further attempts by Dr IM’s medical group to obtain the films, the Las Vegas hospital finally sent copies of the films and of the report to Dr IM in November. Because Dr IM does not read films, she filled out a “radiographic request form” containing Ms Tompkins’ name and age and sent the unopened envelope to the medical group’s radiology department.

Three days later, Dr R, a radiologist at the medical group, reviewed films of Sara Tompkins dated May 29 of the same year. Dr R’s impression was a “contracted, stone-filled gallbladder.” The next week, Dr IM examined Ms Tompkins and advised her that the film from the Las Vegas hospital revealed that she had gallstones. Dr IM referred the patient to the group’s general surgery department for a possible cholecystectomy and noted that the patient “does complain of recurrent epigastric discomfort over time, but is otherwise feeling well.”

Three weeks later, the patient was examined by a general surgeon at the medical group, who recommended surgery for his diagnosis of chronic calculous cholecystitis. The surgeon performed a laparoscopic cholecystectomy. The pathology report revealed cholecystitis but no stones. It was only after surgery that the group discovered that the films sent from the Las Vegas hospital were for another Sara Tompkins, who was 16 years younger than Dr IM’s patient.

The patient sued Dr IM, Dr R, the general surgeon, the assistant surgeon, and the medical group itself for failing to note the difference in the date of birth between the two “Sara Tompkins.” The plaintiff’s theory against Dr IM was that she should have questioned the situation given the incompatibility between the radiologist’s report of a contracted, stone-filled gallbladder and her own clinical findings.

As it turned out, the patient’s attorney dismissed all of the individual physicians and elected to proceed against the medical group alone. The defense of that group was complicated by the group’s loss of several significant medical records. At arbitration, the patient won an award of nearly $600,000 for the unnecessary loss of her gallbladder.

Any physician casually reviewing the facts of the case can easily spot all of the points at which the identify error should have been caught.

The challenge to physicians practicing in large group settings is to stay alert to the kinds of errors that his or her colleagues may have missed.

This case comes from Medicine on Trial, originally published by Cooperative of American Physicians, Inc., to provide risk management lessons from litigated case histories. The original title was “It’s Always Okay to Verify the Patient’s Age.”

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LabCorp Adding Digital Workflows to Pathology Services Via Philips

LabCorp, the Burlington-based diagnostics and drug-development conglomerate, will add digital workflows into its anatomic pathology services under a new collaboration with Royal Philips, a global health technology company.

LabCorp will initially implement the Philips IntelliSite Pathology Solution in four of its laboratories. A company spokesman declined to say which labs would adopt the system but did confirm that one of them would be in North Carolina.

The system is the only digital pathology solution marketed for primary diagnostic use in the United States, the company said in a news release. It helps pathologists review and interpret digital images of surgical pathology slides that are prepared from formalin-fixed, paraffin-embedded tissue. The goals are to provide improved turnaround times and more precise analysis of tissue samples.

“Digital pathology offers the opportunity for improved efficiency and enhanced collaboration between our pathologists and our customers,” said Gary M. Huff, chief executive officer of LabCorp Diagnostics. “We are pleased to be the first major commercial laboratory to implement the Philips IntelliSite Pathology Solution, and we look forward to working closely with Philips to identify the best way to integrate a digital pathology solution into our anatomic pathology workflow.”

The product is an automated system for creating, viewing and managing digital pathology images. It consists of a scanner, an image-management system, a display and software tools to manage the scanning, storage, presentation, reviewing and sharing of images.

By supporting the transition to digital workflows, Philips seeks to help pathology laboratories simplify access to histopathology information.

“Digital pathology opens new, innovative ways to help laboratories and hospital systems improve workflows and provide better patient care,” said Marlon Thompson, general manager of Philips Digital Pathology Solutions. “Together with LabCorp, we can accelerate the digital transformation of pathology and intensify collaboration between laboratories and healthcare professionals.”

Dorothy (Dot) Adcock, M.D., chief medical officer for LabCorp Diagnostics, said digital pathology has the potential to improve patient care. “The opportunity to more quickly access tissue images for analysis, to collaborate more readily with specialty pathologists around the globe, and to provide a faster diagnosis can improve patient care in often challenging areas of cancer diagnosis,” she said.

LabCorp has about 60,000 employees worldwide and reported net revenues of over $10.2 billion in 2017.

Philips, which generated 2017 sales of EUR 17.8 billion, has about 74,000 employees in more than 100 countries.

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Biopharma Catalysts on July’s FDA Calendar

Here is a calendar of some of the biggest companies expecting clinical trial and U.S. Food and Drug Administration (FDA) updates in July.

It’s worth mentioning that these dates may be subject to change due to various internal and outside factors. Some of these changes are positive developments and some can be disasters if a company is deeply financed.

As a side note about the Prescription Drug User Fee Act (PDUFA): a Priority Review designation is granted to medicines that the FDA determines have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.

AbbVie Inc. (NYSE: ABBV) and Neurocrine Biosciences Inc. (NASDAQ: NBIX) are expecting to have a PDUFA date in July for their New Drug Application (NDA) for elagolix in endometriosis-associated pain. If approved, elagolix will be the first new oral medical management treatment option for endometriosis-associated pain in more than a decade.

Durect Corp. (NASDAQ: DRRX) is also expecting a PDUFA date for its NDA of RBP-7000 in late July. The schizophrenia treatment has a target action date of July 28, 2018.

GlaxoSmithKline PLC (NYSE: GSK) has a meeting with the FDA’s Pulmonary-Allergy Drugs Advisory Committee scheduled for July 25. The meeting is in regards to the firm’s supplementary Biologics License Agreement (sBLA) for its chronic obstructive pulmonary disease (COPD) treatment, mepolizumab.

Zynerba Pharmaceuticals Inc. (NASDAQ: ZYNE) is scheduled to present data of ZYN002 at the 16th NFXF (National Fragile X Foundation) International Fragile X Conference in Cincinnati, July 11 to 15. ZYN002 is the first and only pharmaceutically produced cannabidiol, a non-psychoactive cannabinoid, formulated as a patent-protected permeation-enhanced gel for transdermal delivery through the skin and into the circulatory system. ZYN002 is being developed for patients suffering from Fragile X syndrome and certain refractory epilepsies.

Progenics Pharmaceuticals Inc. (NASDAQ: PGNX) has a PDUFA date set for July 30 for its malignant pheochromocytoma and paraganglioma treatment, Azedra.

Catalyst Biosciences Inc. (NASDAQ: CBIO) is scheduled to present interim data from its Phase 2 study of Marzeptacog alfa (MarzAA) on July 18. This data will be pertaining to the subcutaneous efficacy trial in individuals with hemophilia A or B with inhibitors to evaluate the ability of MarzAA to minimize spontaneous bleeding episodes.

Theravance Biopharma Inc. (NASDAQ: TBPH) is expected to report data from its Phase 2a study in patients with symptomatic neurogenic orthostatic hypotension by end of July 2018. Specifically, this data is in regards to its TD-9855 (norepinephrine serotonin reuptake inhibitor).

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Teva’s decision to move North American HQ leaves other sites in jeopardy

Teva Pharmaceutical Industries Ltd. will relocate its U.S. headquarters into a planned New Jersey facility, the company confirmed on Thursday. The Israeli drugmaker (NYSE: TEVA), which currently hosts its U.S. headquarters in the Philadelphia area and a specialty pharmaceutical business in Overland Park, announced in December that it would cut 14,000 jobs and consolidate its seven U.S. locations into one main campus.

The planned headquarters at Parsippany-Troy Hills will involved expanding an existing Teva location to 350,000 square feet, the Philadelphia Business Journalreports. The New Jersey Economic Development Authority approved $40 million in performance-based tax credits over 10 years for the project, which is expected to bring in or create 800 positions.

In an email Friday, Teva said that it would continue to maintain a presence in Pennsylvania, but did not confirm any details about its Overland Park offices.

As for Teva’s future in the Kansas City area, the company began winnowing down its workforce in December. It cut 57 jobs from its Overland Park headquarters for Teva Neuroscience, which reported 388 employees in 2017.

A Florida-based health care company, AssistRx Inc., will take over a portion of its Overland Park offices and rebadge roughly 200 of Teva’s employees. In April, Teva confirmed it sold AssistRx its patient services and solutions segment, which provided on-call nurses and support for patients using Teva’s specialty products, such as treatments for multiple sclerosis and Parkinson’s disease.

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Hospitals see $218B in federal payment cuts from 2010 to 2028

Cumulative reductions in federal payments to hospitals from 2010 to 2028 are estimated to reach $218.2 billion, according to a study commissioned by the Federation of American Hospitals and the American Hospital Association (AHA).

The study, conducted by economics consulting firm Dobson DaVanzo & Associates in Vienna, Virginia, examined how 11 pieces of legislation combined with regulatory changes by the Centers for Medicare and Medicaid Services (CMS) would affect cumulative federal payments to hospitals from 2010 through 2028. The payment reductions are beyond those enacted under the Affordable Care Act.

Overall, federal payments to hospitals will be reduced by $218.2 billion over the 18-year period, according to the report. The largest reduction is attributable to hospital documentation and coding adjustments ($79.3 billion). Sequestration is expected to reduce Medicare hospital payments by an estimated $73.1 billion. Original Affordable Care Act reductions to the federal Medicaid Disproportionate Share Hospital allotments were further cut by $25.9 billion. Modification of the definition of off-campus hospital outpatient departments will cut hospital payments by $13.2 billion. Cuts to post-acute-care provider payments are estimated to reach $6.1 billion. New criteria for Medicare payments are expected to reduce long-term-care hospital payments by $5.9 billion, while extending Medicare’s hospital transfer policy to hospice will result in $5.5 billion in cuts. The impact of the bad debt reimbursement reduction for hospitals totals $5 billion, and clarification of the three-day payment window results in a $4.2 billion reduction.

“Continued cuts of this magnitude represent a troubling trend for hospitals and health systems as many struggle with declining reimbursements for services provided in and out of the hospital,” AHA president and CEO Rick Pollack said in a statement.

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Dr Reddy’s bullish about better sales in Europe in FY19

Dr Reddys Laboratories today expressed hope of higher sales this year in Europe, a key market, as it has overcome some of the regulatory issues that had hit its performance in the last quarter of FY18.

The drug maker also said it wants to have a strong pipeline of difficult-to-manufacture complex formulations that address key therapeutic needs to counter the pricing pressures in the USA as it is difficult to predict how long these trends will last.

There was also a regulatory hiccup when the Federal Institute for Drugs and Medical Devices (BfArM) of Germany audited” Dr Reddy`s formulation unit 2 at Bachupally here, the company said in its latest annual report.

This resulted in the good manufacturing practices (GMP) compliance certificate not being renewed in August, 2017. Corrective work was immediately undertaken.

After a follow-up audit, the GMP non-compliance status was withdrawn in January, 2018. However, stoppage in sale to Europe for four months led to lesser revenues, it said.

“Thankfully, this is over, and we expect to increase sales in FY 2019, Dr Reddy`sChairman and Co-Chairman K Satish Reddy and G V Prasad respectively said in the report.

Prasad is also the CEO of the pharma company.

Having launched operations in France, Italy, Romania and Spain, the drug maker should be working on generating higher revenues from these countries, and to increase its market presence in Europe in the near future, they said.

The companys management has accepted several challenging goals for FY2019 which include better plant management, an unwavering focus on institutionalising best-in-class manufacturing and quality practices, the report said.

Bringing about greater efficiency in Research and Development and product development, and driving hard to perform better in sales in the USA, Europe, India and the emerging markets were also among the challenges, it said.

The total revenues of the company in FY18 was pegged at Rs 14,203 crore.

Though, Dr Reddys registered eight per cent growth in revenues form Europe to Rs 822 crore during last year, the Q4 of the Fy 18 revenues from the region declined by 17 per cent year-on-year.

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