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Thursday, January 3, 2019

Study Eases Concern That Common Diabetes Med May Harm Bones


 If you have type 2 diabetes and you’re taking canagliflozin to help control your blood sugar, a new study has some good news for you: The drug doesn’t appear to raise the risk of bone fractures.
Previously, research had suggested this might be the case.
“We were interested in doing this study because there was one randomized trial that said there was an increased risk of bone fractures and another that said there wasn’t. So, we conducted a real-world study with almost 200,000 people with type 2 diabetes,” said study author Dr. Michael Fralick.
“I hope these findings are reassuring to patients and physicians because these are blockbuster medications for type 2 diabetes. This class of medicines can improve blood sugar levels and help reduce heart disease risk,” he said. Fralick is from the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston, and a general internist at the University of Toronto.
Canagliflozin (Invokana, Invokamet) is one drug in a class of medications called SGLT-2 inhibitors. Other drugs in this class include dapagliflozin (Farxiga) and empagliflozin (Jardiance).
These drugs cause the kidneys to remove excess sugar from the blood and excrete it through urine, which lowers blood sugar levels, according to the U.S. Food and Drug Administration. This class of drugs has been linked to a number of complications, including kidney injury and serious genital infections.
Fralick said one way these drugs could potentially increase fracture risk is by lowering bone mineral density.
Dr. William Leslie, author of an editorial accompanying the study, suggested that dehydration may be another way these drugs might be linked to fracture risk. Leslie is a professor of medicine and radiology at the University of Manitoba in Canada.
For the new report, Fralick and his team reviewed data from two U.S. commercial health care databases. They found information on about 200,000 people with type 2 diabetes who were just starting to take one of two different type 2 diabetes medications — canagliflozin or a medication in a class of drugs called GLP-1 agonists, which includes Victoza, Trulicity and Byetta. These drugs haven’t been linked to an increased risk of fractures.
The researchers looked for fractures in the upper and lower arms, as well as the hips and pelvis.
In the end, the study team compared approximately 80,000 people on canagliflozin to about 80,000 treated with GLP-1 agonists. The patients’ average age was 55, and about 48 percent were female.
The study showed a similar risk of fractures in these low-risk, middle-aged populations.
Both Fralick and Leslie said the jury is still out for people who are at a higher risk of fractures, such as elderly people.
This study is “a relatively low-risk population. But, it begs the question, what about higher-risk populations? We need additional safety data,” Leslie said.
The U.S. Food and Drug Administration currently requires canagliflozin labels to carry a warning about the potential fracture risk, and Fralick said it may be too soon to change the labeling, particularly for people at high risk. Both experts said more research is needed.
In the meantime, if you’re concerned about taking canagliflozin, Fralick recommended having a conversation with your health care provider. But, he added, “For people without a high baseline risk, the risk of fracture is very small and the clear benefits to SGLT-2s outweigh that potential risk.”
The findings were published online Jan. 1 in the Annals of Internal Medicine.
More information
Learn more about oral diabetes medications from the American Diabetes Association.
SOURCES: Michael Fralick, M.D., S.M., division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital, Boston, and general internist, University of Toronto, Canada; William Leslie, M.D., professor of medicine and radiology, University of Manitoba, Canada; Jan. 1, 2019, Annals of Internal Medicine, online
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Hospitals’ outpatient revenue nearing inpatient


The gap between U.S. hospitals’ outpatient and inpatient revenue continued to shrink in 2017 as more patients elect to get care in cheaper outpatient settings, and some believe a flip is inevitable in the coming years.
The American Hospital Association’s 2019 Hospital Statistics report showed hospitals’ net outpatient revenue was $472 billion and inpatient revenue totaled nearly $498 billion in 2017, the latest year for which the report covers, creating a ratio of 95%, up from 83% in 2013.
“It certainly reflects continued efforts from hospitals to make sure that people get the right care at the right time in the right setting,” said Aaron Wesolowski, the AHA’s vice president of policy research and analytics. “We’ve seen inpatient utilization drops in recent years and outpatient has increased.”
Hospital profits reached $88 billion in 2017, a 12.5% increase over the previous year and a 27% increase from 2013. Total net revenue reached $1 trillion in 2017, compared with $998 billion in 2016. Expenses in that time were $966 billion, up from $920 billion. The AHA provided Modern Healthcare with an exclusive copy of the report.
The jump in profit in 2017 was higher than in recent years. In 2016, profits increased 4%, compared with a 0.25% decline in 2015.
During that time, operating revenue increased just 4.6% in 2017, a lower rate than 2016 and 2015. During the same time, nonoperating revenue, which includes investment income, jumped 92%, slightly lower than 2016’s 103% spike. Wesolowski attributes the slowed operating revenue growth to stabilizing utilization.
“That’s certainly a heavy driver,” he said.
The data illustrate the continued slow bleed of patients out of hospitals. Admissions to the 5,262 U.S. community hospitals and their nursing home units increased by less than 1% to 34.3 million in 2017, from 34 million in 2016. Community hospitals include nonfederal, short-term general and special hospitals. Inpatient days were largely unchanged at 186.2 million during that time. Both inpatient surgeries and births declined slightly between 2016 and 2017 to 9.1 million and 3.7 million, respectively.
But the gradual decline in inpatient volumes didn’t translate into a significant outpatient boost in 2017. Outpatient surgeries were mostly flat at 19 million, as were emergency room visits at 144.8 million. Outpatient visits inched up by a modest 1.2% year-over-year, to 766 million in 2017. Those numbers generally include urgent care and ambulatory surgery center visits, except for cases when the facilities are not directly affiliated with a specific hospital, AHA spokeswoman Marie Johnson wrote in an email.
Even as outpatient volumes were relatively flat year-over-year, net outpatient revenue increased 5.7% between 2016 and 2017. Chuck Alsdurf, director of healthcare finance policy and operational initiatives at the Healthcare Financial Management Association, said it’s not surprising to see outpatient revenue grow as procedures increasing shift into outpatient settings. He said part of that is driven by the CMS’ two-midnight rule created in 2013, which directs Medicare contractors to deem a hospital admission legitimate if it spans two midnights.
“Typically when things move from inpatient to outpatient, especially on a procedural basis, the charges go down, as well as the payment,” Alsdurf said.
Eventually, Alsdurf predicts hospitals’ outpatient revenue will eclipse inpatient revenue, but that’s still several years out.
The amount hospitals reported having spent on uncompensated care was $38.4 billion in 2017, the same as in 2016.
There were 6,210 total hospitals in the U.S. in 2017, according to the AHA’s data. That’s nearly 9% more than a decade earlier, in which the U.S. had 5,708 hospitals, but slightly fewer than in 2016, in which there were 6,168. The total hospitals figure includes not-for-profit, investor-owned, state and local government-owned hospitals and veterans hospitals.
The number of rural community hospitals declined nearly 8% between 2017 and 2013, to 1,875, while the number of urban hospitals increased nearly 2% during that time to 3,387.
Among community hospitals, 3,494 were part of a system in 2017, up from 3,467 in 2016 and 3,322 in 2013. Fewer hospitals are members of group purchasing organizations in 2017 compared with 2016: 3,583 versus 3,726.
The number of full-time and part-time community hospital employees increased slightly to 4.5 million and 1.6 million, respectively, in 2017.
Adjusted expenses per inpatient stay were higher at not-for-profit hospitals in 2017 compared with their investor-owned counterparts. Not-for-profits spent $13,504 per inpatient stay, while investor-owned hospitals spent $10,273 for the same stay. That number was even higher for state and local government hospitals: $14,015.
That’s not surprising given investor-owned hospitals have a completely different operating model, Alsdurf said. They staff differently, and their scale allows them greater purchasing power and efficiency. Plus, there’s pressure from Wall Street.
“I still think the biggest reason is because they’re run to make money for the investors,” he said. “So there is a different goal.”

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Wave Life Sciences Duchenne Trial Selected for FDA Design Pilot


Wave Life Sciences Ltd. (WVE), a biotechnology company focused on delivering transformational therapies for patients with serious, genetically-defined diseases, today announced that the planned Phase 2/3 efficacy and safety trial for its lead Duchenne muscular dystrophy (DMD) clinical program has been selected for the U.S. Food and Drug Administration (FDA) pilot program for complex innovative trial designs (CID). The selection was based on the design of Wave’s Phase 2/3 clinical trial of suvodirsen (WVE-210201), an investigational therapy for boys with DMD who are amenable to exon 51 skipping. This marks the first time that the FDA has selected clinical protocols for its CID pilot program that was announced in August 2018.
In evaluating submissions for the CID pilot program, the FDA considered two key criteria: the innovative features of the trial design and the therapeutic need (i.e., therapies being developed for use in disease areas where there are limited or no treatment options). Wave’s application for the CID pilot program includes a plan to leverage DMD historical control data to augment the placebo arm of the suvodirsen Phase 2/3 clinical trial, among other innovative design elements. Through this pilot program, Wave intends to reduce the number of patients required to deliver conclusive clinical efficacy results, thereby minimizing the number of patients required in the placebo treatment arm and potentially accelerating study completion. As a participant in the pilot program, the company will also have additional opportunities to meet with FDA staff to discuss the design elements of the trial, including the use of Bayesian methods to adapt the trial and allow for more efficient and productive clinical determinations. Details of Wave’s Phase 2/3 trial design will be presented at upcoming scientific meetings.
“In designing our clinical trials, we are constantly looking to maximize the probability of a definitive result, incorporate the feedback of patients and their families, and reduce the burden on those who are already bravely enduring the challenges associated with serious, genetically-defined diseases. The FDA’s recognition of our plan reflects the thoughtful and collaborative way in which we approach clinical development,” said Michael Panzara, MD, MPH, Chief Medical Officer of Wave Life Sciences. “We look forward to further discussions with the FDA in the coming months and sharing learnings from our trial design with others in the rare disease drug development community to drive greater efficiency and productivity in future clinical studies.”
Wave anticipates initiating the global, placebo-controlled Phase 2/3 efficacy and safety clinical trial of suvodirsen in DMD patients amenable to exon 51 skipping in 2019. The trial is designed to measure clinical efficacy and dystrophin expression, and Wave intends to use the results of this trial to seek regulatory approvals globally. Currently, suvodirsen is being studied in an ongoing open-label extension (OLE) study and Wave expects to deliver an interim analysis of dystrophin expression from this study in the second half of 2019.
The FDA CID pilot program is an initiative under the 21st Century Cures Act, with an objective to modernize clinical trial design, help streamline and advance drug development and inform easier regulatory decision-making. In order to qualify for the CID pilot program, companies must intend to provide substantial evidence of efficacy through a complex, novel design that incorporates innovative trial design elements such as seamless trial designs, modeling and simulations to assess trial operating characteristics, the use of biomarker enriched populations, complex adaptive designs, Bayesian models and other benefit-risk determinations, among others. For more information, visit https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm617212.htm.
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Vertex, Arbor to Collaborate on Novel Proteins for Gene-Editing Therapies


Vertex Pharmaceuticals Incorporated (NASDAQ:VRTX) and Arbor Biotechnologies (Arbor) today announced that the two companies have entered into a strategic research collaboration focused on the discovery of novel proteins including DNA endonucleases to advance the development of new gene-editing therapies for cystic fibrosis and four other diseases to be selected later. Arbor has developed a protein biodiscovery platform that includes a comprehensive set of technologies and techniques, integrating machine learning, genome sequencing, gene synthesis, and high-throughput screening that will augment Vertex’s efforts to develop gene-editing approaches for the treatment of serious diseases.
“Our strategy of developing transformative medicines for serious diseases is based on addressing causal human biology with innovative therapeutics,” said David Altshuler, M.D., Ph.D., Executive Vice President, Global Research and Chief Scientific Officer of Vertex. “Arbor’s proprietary high-throughput screening platform will enhance our ongoing efforts to develop innovative gene-editing therapies.”
“Vertex has a proven track record in discovering and developing innovative medicines and is an ideal partner for Arbor,” said David Walt, Ph.D, Arbor Co-Founder. “We believe that by using our powerful biodiscovery platform we will be able to identify complementary and next generation tools to enhance Vertex’s pipeline of transformative medicines and new gene-editing therapies.”
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Jazz, Codiak in alliance with $76M ante and up to $1B-plus in milestones



Codiak CEO Doug Williams has notched his first collaboration deal.
The biotech exec and his team are collecting a $56 million upfront from Jazz Pharmaceuticals $JAZZ as Codiak ramps up 5 translational programs using its exosome platform, with two of the cancer targets in public sight — NRAS and STAT3. There’s another $20 million on the table for near-term preclinical goals, with a $200 million package of milestones per target and a royalty arrangement for success.
Significantly, Williams says that the alliance includes an opt-in on 2 programs that Codiak can co-commercialize, which would mark a major change for the biotech.
Williams, a longtime biotech exec who managed Biogen’s R&D ops for one stretch, says he’s known Jazz CFO Matt Young for quite awhile now, which helped opened the door to this deal.
“There’s a growing realization in Jazz and globally that exosomes are an interesting approach to developing therapeutics,” he notes. And it’s a good add-on for Jazz as they explore new ways to “drug the undruggable” in oncology and other therapeutic fields.
It’s a good development for Codiak, Williams adds, allowing some extra financing on top of the $168.5 million he’s already raised for the company, expanding the pipeline and staff — which now sits at 60.
They’ve been working on using exosomes as a kind of cellular freight service, carrying payloads of nucleic acids, proteins, small molecules and more through the various roadblocks your body uses to check the spread of threatening substances. By hijacking the system, Codiak is looking to create a whole new way to drug the currently undruggable. And their first in-house effort focused on jumping on board these nanoparticles with an siRNA targeting KRAS that has shown promise in a variety of models for pancreatic cancer.
That should set up a move into the clinic with their own product in 2020.
The deal with Jazz, meanwhile, leaves Codiak in charge of maneuvering the 5 programs through Phase I/II studies, with Jazz left in charge of any additional clinical work they elect to pursue.
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No-Baseline-Needed Concussion Test OK’d


An eye-tracking test for concussion that requires no baseline assessment is cleared for U.S. marketing, said neurodiagnostics company Oculogica.
To be sold as EyeBOX, the 4-minute, non-invasive test is approved for use in patients ages 5 to 67. Oculogica said it’s the first such test to win FDA marketing authorization. Patients watch a short video with their heads placed in a chin-and-forehead rest similar to those commonly used in optometry clinics. Eye movements are analyzed with a proprietary algorithm.
Initial distribution will be limited to “select, qualified sites,” the firm said.
Approval (via the FDA’s “de novo” authorization pathway for novel, low- to moderate-risk devices) was based primarily on a 282-patient clinical study involving children and adults presenting to emergency departments and concussion clinics with head injuries. Patients were evaluated within 2 weeks of injury. Full results have not yet been published.
One journal paper involving another Oculogica study indicated that, in children with suspected concussion, the test achieved 72% sensitivity with 84% specificity when patients were evaluated an average of 22 weeks after injury.
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Which Bariatric Surgery Needs Most Revisions Over the Decades?


Over the course of 20 years, just over one-quarter of bariatric surgery patients underwent revisional procedures, researchers reported.
In a follow-up analysis of participants from the Swedish Obese Subjects (SOS) study, 27.8% of adult patients underwent a first-time revisional surgery — accounting for 559 patients out of 2,010 — Stephan Hjorth, PhD, of the University of Gothenburg, and colleagues wrote in JAMA Surgery.
Among these revisional surgeries, conversions to other bariatric procedures were the most common, making up nearly 18% of these surgeries. This was followed by around 6% of revisions accounting for corrective surgeries, while 4.5% were reversals back to normal gastrointestinal anatomy.
The reasons for revisional surgery included weight-associated indications; band- or staple-related technical complications; and surgical-associated complications including infection, stoma stenosis, stoma dilatation, pouch enlargement, reflux, and nausea.
Between the three surgeries assessed — banding, vertical banded gastroplasty (VBG), and gastric bypass (GBP) — people who underwent banding were the most likely to undergo any type of revisional surgery over the maximum 26-year follow-up period. Nearly 41% of patients who underwent banding had a revisional surgery.
Revisions were less common for vertical banded gastroplasty patients, occurring in around 28% of patients. Revisions were the least common among those who underwent gastric bypass, with only 7.5% of these patients undergoing revisions.
As for reversal surgeries, those with banding were five times more likely to have a surgery reversal compared with those with VBG (40.7% vs 7.5%; HR 5.19, 95% CI 3.43-7.87, P<0.001). Banding and VBG patients were most likely to undergo a reversal or a conversion to gastric bypass.
However, when it came specifically to corrective surgeries — which mostly occurred within the first 10 years postoperatively — these generally had similar rates of incidence between all three types of surgeries, ranging from 5.3% of those with VBG to 7.1% of GBP patients.
“The greater weight loss after GBP is the likely main reason for a lower request for conversions in this subgroup compared with the subgroups that undergo banding and VBG,” wrote the researchers.
When broken down by surgery type, the most common reason for a revisional surgery among those who had banding was band-associated problems, such as migration stenosis or slippage. Among banding patients, nausea and weight-related indications were also common reasons for revision.
As for VBG patients, the most common indication for revisional surgery was staple-related disruptions, accounting for 10% of these patients. Nausea due to stenosis and collar migration were also common indications for revision. The most common indications for revisional surgery for gastric bypass patients were reflux-associated and esophagus-associated complications.
“The dominant reason for corrective revisional surgery was bile reflux (including esophagitis), which occurred only in patients with loop technique GBP,” the researchers noted, adding how “this demonstrates the superiority of the Roux-en-Y technique with regard to the need for secondary interventions.”
In an accompanying commentary, Ricardo Cohen, MD, of Oswaldo Cruz German Hospital in Brazil, praised the study, writing that “although the SOS study started in the 1990s and operative techniques have evolved, it brings answers about bariatric revisional surgery and raises thoughts regarding choosing the best index bariatric procedure.”
Cohen also pointed out that although the small percentage of gastric bypass patients included in the cohort was a limitation, it’s still apparent that this surgery accounted for fewer revisionary surgeries. “Among more than 200 Roux-en-Y gastric bypass procedures, only five (2.3%) required any reoperation,” he said.
“Revisional surgery carries a higher complication rate than the primary procedure, but if needed, it should not be denied,” Cohen added, also noting the growing number of reported revisions with the recently popular sleeve gastrectomy. Ultimately, he said, “maybe a wiser movement is to start with the right choice and curb the need for reoperations.”
The study was funded by the National Institutes of Health, Svenska Vetenskapsrådet, and a Sahlgrenska University Hospital ALF Research grant.
Näslund reported fees for consulting and lectures from Baricol AB, Sweden, outside the study; no other study authors reported disclosures.
Commentator Cohen reported financial relationships with Ethicon-JJ and serving on the scientific advisory board of GI Dynamics.
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