New clues about what goes awry in autistic brains

A team of UCLA-led scientists has discovered important clues to what goes wrong in the brains of people with autism—a developmental disorder with no cure and for which scientists have no deep understanding of what causes it.

The new insights involve RNA editing—in which genetic material is normal, but modifications in RNA alter nucleotides, whose patterns carry the data required for constructing proteins.

“RNA editing is probably having a substantial physiologic effect in the brain, but is poorly understood,” said co-author Dr. Daniel Geschwind, UCLA’s Gordon and Virginia MacDonald distinguished professor of human genetics, neurology and psychiatry and director of UCLA’s Institute for Precision Health. “RNA editing is a mysterious area whose biological implications have not been much explored. We know what only a handful of these RNA editing sites do to proteins. This study gives a new critical clue in understanding what has gone awry in the brains of autismpatients.”

More than 24 million people worldwide are estimated to have autism. In developed countries, about 1.5 percent of children have been diagnosed with autism spectrum disorder as of 2017. The disorder affects communication and behavior, and is marked by problems in social communication and social interaction, and repetitive behaviors.

“We need to understand how a panoply of genetic and environmental factors converges to cause autism,” Geschwind said. “RNA editing is an important piece of the autism puzzle that has been totally under-appreciated.”

The researchers analyzed brain samples from 69 people who died, about half of whom had autism spectrum disorder (which includes autism and related conditions), and about half of whom did not and served as a control group.

Xinshu (Grace) Xiao, the senior author of the research and UCLA’s Maria R. Ross professor of integrative biology and physiology, and her research team analyzed seven billion nucleotides for each brain sample.

Xiao’s team discovered reduced editing in the group members with autism. Specifically, they identified 3,314 editing sites in the brain’s frontal cortex in which the autism patients had different levels of RNA editing from the control group. In 2,308 of those sites, the individuals with autism had reduced RNA editing, said lead author Stephen Tran, a graduate student in UCLA’s bioinformatics interdepartmental program who works in Xiao’s laboratory. In the 1,006 others, they had increased levels of RNA editing, he added.

In the brain’s temporal cortex, the people with autism had different levels of RNA editing from the control group in 2,412 editing sites, with 1,471 of those sites showing reduced editing levels, Tran said. In the brain’s cerebellum, the autism group members had different levels of RNA editing from control group members in 4,340 sites, of which 3,330 sites in the autistic brain had decreased levels. All three of these brain regions are very important in autism.

The research, published in the journal Nature Neuroscience, is the first comprehensive study of RNA editing in autism spectrum disorder.

Xiao said RNA editing can be thought of as RNA mutations, analogous to the DNA mutations that are linked to many diseases.

“The same piece of DNA can generate multiple versions of RNA, and possibly lead to different protein sequences,” said Xiao, director of UCLA’s bioinformatics interdepartmental graduate program. “RNA editing allows cells to create novel protein sequences that are not written in the DNA.”

Scientists had long assumed that a sequence of RNA is a faithful copy of a gene’s DNA sequence—and that RNA is merely the cellular messenger that carries out DNA’s instructions to other parts of the cell. “This assumption was proved to be wrong when RNA editing was first discovered in the 1980s,” Xiao said, “and we are finding many examples where the genetic codes we inherit from our parents are edited in our cells.”

In another major finding, the researchers identified two proteins, called FMRP and FXR1P, that regulate abnormal RNA editing in autism spectrum disorder. FMRP increases RNA editing and FXR1P decreases RNA editing, Tran discovered. The autism group had reduced editing levels regulated by FMRP, as well as reduced RNA editing overall.

“This is the first strong data showing a broad and direct functional role for FMRP and FXR1P in the human brain and autism,” Xiao said.

“Something about what FMRP does is clearly critical to autism pathogenesis,” Geschwind said. “Grace and her team show that these two related proteins are likely responsible for the reduced RNA editing, as well as the occasional increased RNA editing.”

It is currently unknown, he said, whether the changes the people with autism had in RNA editing caused their autism, contributed to the disorder or were a result of it. “We can’t assign causality,” said Geschwind, who praised the research of Xiao’s team as “elegant and brilliant.”

RNA editing may also be disrupted in schizophrenia, bipolar disorder and major depression. The research team plans to continue to study this as well as other brain diseases.

Xiao and Tran replicated their findings by analyzing the frontal cortex from a different group of 22 people who had autism spectrum disorder and a control group of 23 without the disorder. They found the same pattern of editing reduction as they found originally, Tran said.

The researchers found RNA editing alterations in genes of critical neurological relevance to autism, including CNTNAP2 and CNTNAP4, NRXN1 and NRXN3, ANK2, NOVA1 and RBFOX1.

Xiao and Tran used powerful methods of bioinformatics and statistics to identify the RNA editing sites, including a method similar to GIREMI that Xiao designed in 2015 with Qing Zhang, a former postdoctoral scholar in her laboratory.

In searching for causes of diseases, most research has focused on searching for mutations in the DNA. “What was missing, until recently,” Xiao said, “is to look for RNA mutations that are not coded in the DNA. These changes in the RNA could have similar impact as DNA mutations.”

This study may eventually lead to new treatments for autism, but likely not for many years, the researchers said.

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More information: Stephen S. Tran et al, Widespread RNA editing dysregulation in brains from autistic individuals, Nature Neuroscience(2018). DOI: 10.1038/s41593-018-0287-x

https://medicalxpress.com/news/2019-01-team-uncovers-critical-clues-awry.html

Eli Lilly to report Q4 earnings one week earlier than previously scheduled

Eli Lilly announced that it has revised the date for its fourth-quarter and full-year 2018 financial results announcement. The company will now announce results on Wednesday, February 6, one week earlier than previously scheduled. Lilly will also conduct a conference call on that day at 9 a.m. ET, the company stated.
https://thefly.com/landingPageNews.php?id=2856225

Medtronic launches new spine surgery robot following Mazor acquisition

Medtronic’s new integrated robotic spine surgery system has begun treating its first U.S. patients, just months after last year’s acquisition of Mazor Robotics and a clearance from the FDA.

The medtech giant recently launched the Mazor X Stealth Edition, which combines Medtronic’s navigation platform with Mazor’s robotic guidance systems. The device provides three-dimensional planning tools and real-time visualization in the operating room for guided procedures.

“As part of our Surgical Synergy strategy, we believe Mazor X Stealth Edition will accelerate the advancement and adoption of robotic-assisted and navigated surgical technologies in spine,” saidGeoff Martha, president of Medtronic’s restorative therapies group, in a release.

The merger of robotics and navigation into a single platform may provide more predictable and reliable procedure workflows, said Jeffrey Gum, M.D., an orthopedic spine surgeon at Norton Leatherman Spine Center in Louisville, Kentucky, one of the first locations to employ the system.

“Computerized surgical planning, 3D assessment of spine anatomy, robotic guidance and live navigation feedback are designed to provide a higher degree of accuracy throughout the surgical procedure,” Gum added.

The surgical robot, which converts standard 2D fluoroscopic projections into a 3D image, was first used at Norton Healthcare as well as at Reston Hospital Center in Virginia, and Medtronic said it plans to roll out the system to different regions throughout the year.

The Mazor X Stealth Edition received 510(k) clearance from the FDA in November 2018, after Medtronic acquired Mazor earlier that September in a $1.6 billion deal—the culmination of a series of investments in the Israel-based robotics company beginning in May 2016.

https://www.fiercebiotech.com/medtech/medtronic-launches-new-spine-surgery-robot-following-mazor-acquisition

Gut immune cells linked to obesity, heart disease

Some people just never gain excess weight no matter what they eat, a phenomenon many diet experts attribute to a healthy balance of eating and burning calories. But Massachusetts General Hospital (MGH) researchers believe a type of immune cell in the gut is key to controlling the body’s metabolism and may be a therapeutic target for conditions such as obesity and heart disease.

The cells are called intraepithelial T lymphocytes, and they exist in the lining of the small intestine. To study them, the researchers started with a protein called integrin beta 7, which is known to direct immune cells to the gut. They observed that in mice that were lacking the gene that encodes the protein, more food was converted into energy instead of being stored as fat. The rodents also showed many other signs of higher metabolic activity: They burned more glucose in brown fat and were more glucose-tolerant. They also had lower triglyceride levels and better fat tolerance than did control mice.

The MGH scientists reported their findings in a study in the journal Nature.

“The [beta 7-negative] mice become metabolically hyperactive and, even when consuming a diet very high in fat and sugar, are able to resist metabolic diseases such as obesity, hypertension, hypercholesterolemia, diabetes, and atherosclerosis,” said senior author Filip Swirski, Ph.D., in a statement.

Intraepithelial T cells appear to regulate metabolism via GLP-1, which is known for its ability to increase insulin secretion and glucose uptake, the MGH researchers reported. In fact, GLP-1 and its receptor are already targeted in Type 2 diabetes therapies such as Novo Nordisk’s Victoza and Eli Lilly’s Trulicity. When intraepithelial T cells are present, GLP-1’s activity seems to be limited, leading to a metabolism slowdown and energy conservation in the form of fat accumulation, according to the MGH team.

Swirski speculated that humans might have developed that conservation mechanism during long periods when food was scarce. “Now with food so abundant, this energy-saving mechanism can backfire and lead to unhealthy outcomes,” he said.

Many researchers have looked to the gastrointestinal tract, where food is digested and absorbed, for clues to metabolic disorders. The gut microbiome is a popular target. A team at the University of Pennsylvania recently discovered that disruption of the biological clock and a previous history of obesity can change the gut microbiome in a way that makes people susceptible to obesity.

Findings by Swirski and colleagues shed new light on the link between “gut metabolic food sensors and cardiovascular disease, and might open new therapeutic avenues to treat patients with a host of related conditions,” said Michelle Olive, Ph.D., an official at the NIH’s National Heart, Lung, and Blood Institute, which funded the study.

Of course, some key questions still await answers, including the exact mechanism by which these cells affect GLP-1 and metabolism, and whether there are indeed fewer of them in people with a higher basal metabolism. Swirski added that more research needs to be done to figure out how to translate the finding into therapies to treat metabolic disorders.

https://www.fiercebiotech.com/research/gut-immune-cells-linked-to-obesity-cardiovascular-disease

Amgen hunts for deals of all sizes to combat forthcoming sales decline

A couple of Big Pharma players have come out against megamergers in recent weeks. But Amgen isn’t one of them.

On Tuesday’s fourth-quarter earnings conference call, CEO Bob Bradway said his company continues to “look across the waterfront of smaller and larger deals.”

“Obviously, there are more smaller ones than larger ones, so we tend to spend more of our time looking at those,” he said. But he added that the company believes it has the flexibility, the balance sheet and the management resources to look at deals of all sizes, and “with stocks down considerably from where they were a year ago, I would expect that we would continue to look,” he said.

Of course, that’s not the only reason Amgen’s looking around. With two biosimilar competitors now out to get Amgen mammoth Neulasta—and generics looming for blockbuster Sensipar—its 2019 guidance “calls for a ‘decline’ in revenue and EPS vs. consensus ‘flattish,’” Jefferies analyst Michael Yee wrote in a note to clients.

Analysts have been positing for months that the California biotech could be on the hunt for a growth-booster, with Bernstein’s Ronny Gal suggesting last July that Alexion could make a good fit. The company is big enough to offset Amgen’s sales decline and “not crazy valued,” he wrote to clients at the time.

One thing’s for sure: If Amgen does go after a major buy, it won’t have to fight Pfizer or Roche in the process. Executives at both companies have recently declared their disinterest in inking a major deal, citing the disruption integrations can bring to other key activities such as pipeline development.

And if it doesn’t? Amgen will need to look to its new launches to help it tread water as copycats bite into its big sellers. One of them, migraine-fighter Aimovig, is off to a hot start; in the fourth quarter, it raked in $95 million, doubling Wall Street’s $47 million estimate.

“Aimovig reached over 150,000 patients during 2018 and represents a strong launch trajectory,” commercial chief Murdo Gordon said on the call.

Repatha surprised the Street, too, turning in sales of $159 million that beat estimates by $13 million. That performance followed Amgen’s decision to slash the PCSK9 drug’s list price by 60% to just $5,850 per year before rebates and discounts.

“The experience with Repatha has been very good through the fourth quarter,” and “we’re optimistic that we’ll continue to make good inroads this year,” Gordon said.

Overall, the company recorded sales of $6.23 billion for the quarter, coming in $407 million ahead of consensus. Earnings per share also topped forecasts by 18 cents at $3.42. For this year, Amgen expects revenues to hit between $21.8 to $22.9 billion, with EPS checking in between $11.55 and $12.75.

https://www.fiercepharma.com/pharma/amgen-hunts-for-deals-all-sizes-to-combat-forthcoming-sales-decline

Test run of drug prices in ads exposes a loophole—and pharma’s already using it

It’s no surprise that listing the high price of a drug in advertising would discourage consumers. But add in an offer to help cover the cost—with copay or coupon assistance—and viewers are fine with a pricey option, a new study found.

Research published in JAMA last week found that even when the price in a mock-up ad was a whopping $15,500 per month, viewers were still likely to be interested when the ad also noted that eligible patients may pay “as little as $0 per month.” And that’s an offer already common in drug advertising.

The researchers initiated the study to find out what effect, if any, the Trump administration’s proposal to force list prices into TV commercials might have on consumer response.

The study asked 580 Americans to view one of five different ads for the same made-up drug. Two of the print ads bore a $15,500 price tag; one version included a payment assistance offer and the other didn’t. The second set of ads priced the drug at $50, one with payment assistance and the other without. The fifth ad didn’t include a price.

In the lower-priced set, consumers showed little change in response across four measures—whether they would ask their doctor about the drug, ask their insurer, research the drug online, or take the drug—with or without the assistance offer.

But viewing the high-priced ad without the payment modifier “significantly reduced the likelihood” that participants would act on the ad at all. When they watched the ad that dangled a $0 copay, the “results were significantly mitigated,” the researchers found.

That means pharma companies that talk about patient financial assistance in their advertising are more likely to retain a consumer’s interest even if the ad includes a high list price. The study essentially showed that pharma companies already have a workaround if the Trump proposal becomes law and they are forced to show list prices in ads.

That wasn’t the researchers’ intent, though, as one of the authors emphasized. The researchers were simply investigating what might happen if drug prices are included in ads, he said.

“Given that the coupon or copay programs are already in place, we wanted to know would the (drug ad price) proposal work? Our evidence would suggest that while the policy wouldn’t hurt anything, it might not be as effective as it could be (unless) the policy also did something to curb those copay assistance programs,” said Clemson University professor Jace Garrett, Ph.D., who co-authored the study with Ge Bai, Ph.D., at Johns Hopkins University and William Taylor, Ph.D., at Brigham Young University.

https://www.fiercepharma.com/marketing/test-run-drug-pricing-ads-consumers-opt-out-pricey-drugs-but-perk-back-up-for-payment

Pfizer Xtandi blows by J&J Erleada with hot start in new prostate cancer field

You may not see it in sales numbers yet, but Pfizer and Astellas’ Xtandi is crushing Johnson & Johnson’s Erleada in the nonmetastatic, castration-resistant prostate cancer market—according to Pfizer’s executives, at least.

Xtandi, which launched in the blockbuster indication last July on the back of data from the Prosper trial, has picked up a market share quadruple Erleada’s in six months, Angela Hwang, president of Pfizer’s biopharmaceuticals group, told investors on Tuesday’s fourth-quarter conference call. Looked at another way, Xtandi has staked out a piece of the market equivalent to the combined share of Erleada on one hand and chemo on the other.

Why aren’t sales telling that story? “New patients are coming into therapy—new patients are coming every day. So you may not see the full impact of this pool of patients which is still accumulating,” she said, adding that, “it will take time to realize.”

Xtandi pulled in $189 million in U.S. sales for Pfizer in the fourth quarter, up 12% from the $168 million it posted in the same period of 2017. In the nonmetastatic field, Erleada—the follow-up drug to Xtandi’s longtime nemesis Zytiga—got the head start, winning an approval last February, thanks to a trial that “essentially delivered” an “identical” outcome to Prosper, Barclays analyst Geoff Meacham wrote at the time, acknowledging that “cross-trial comparisons are fraught with issues.”

Xtandi also had its original indication—in metastatic castration-resistant prostate cancer-chipping into its quarterly top line, though, and Hwang said Pfizer’s growth strategy in the metastatic arena has been “focused on driving uptake among urologists.”

“Today, more than 30% of our new scripts are written by urologists, and we’re continuing to see market share growth in this segment,” she said.

There’s just one problem with counting on that market, though: Zytiga generics, which came into focus after key J&J defeats in court in 2018.

That’s where the nonmetastatic green light becomes even more clutch for Xtandi.

“Xtandi … has indications that are different from Zytiga’s,” Hwang said, noting that “we expect the Zytiga generics to have a minimal impact on our business.” She also pointed to Xtandi’s different dosing frequency, as well as the fact that it doesn’t bear Zytiga’s requirement for coadministration with the steroid prednisone, a fact that’s been one of Xtandi’s talking points from the get-go.

“I think that all of these will stand well in terms of making switching less likely and for the impact on Xtandi to be minimal as we expect,” she said.

And Pfizer and Astellas are hoping to widen that lineup of additional indications, too. The opportunity “we’re really excited about,” she said, lies in the hormone-sensitive prostate cancer market, where patients tend to stay on therapy the longest. After releasing data last December in metastatic hormone-sensitive patients—a group that swells by about 38,000 new patients per year, Hwang said—Pfizer is prepping for discussions with regulators about a potential new nod. And it’s studying Xtandi in nonmetastatic hormone-sensitive patients, too.

https://www.fiercepharma.com/marketing/pfizer-s-xtandi-blows-by-erleada-hot-start-new-prostate-cancer-field