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Sunday, June 30, 2019

Key events this week – healthcare

Noteworthy events during the week of June 30 – July 6 for healthcare investors.
TUESDAY (7/2): Jazz Pharmaceuticals (NASDAQ:JAZZ): Sunosi update webcast.
WEDNESDAY (7/3): ESMO World Congress on Gastrointestinal Cancer, Barcelona. Celyad (NASDAQ:CYAD): Phase 1 data on CYAD-101 in colorectal cancer. Array BioPharma (NASDAQ:ARRY): Updated data on BRAFTOVI + MEKTOVI + Erbitux in BRAF V600E-positive metastatic colorectal cancer.
SATURDAY (7/6): International Society on Thrombosis and Hemostasis Congress, Melbourne. Bayer (OTCPK:BAYRY): Long-term data on Jivi antihemophilic factor (recombinant) PEGylated-aucl.
FDA action date for Karyopharm Therapeutics‘ (NASDAQ:KPTI) selinexor for penta-refractory multiple myeloma (extended from mid-March).

Time to Jettison Nearly 400 Medical Practices, Review Says

With hindsight, the folly of trying to cure with mercury or an “ice pick” lobotomy is clear, but there was a time they reigned and patients were harmed. A new study takes aim at today’s ineffective medical practices, with an eye toward shortening their transition to obsolescence.
After reviewing 3017 randomized controlled trials (RCTs) published in the past 16 years in three high-impact medical journals, the investigators identified 396 medical reversals or practices found through RCTs to be no better than a previous or lesser standard of care. In 53% of cases, a systematic review confirmed the device, procedure, or practice was indeed a medical reversal.
“Large, well-done randomized trials are essential in helping to determine whether an intervention is effective or not. Studies that are poorly conducted or small in sample size produce spurious results, and these types of studies, because of their nature, can lead to the adoption of ineffective practices or medical reversals,” authors Alyson Haslam, PhD, and Jennifer Gill, MSc, Knight Cancer Institute, Oregon Health & Science University, Portland, told | Medscape Cardiology via email.
Senior author Vinay Prasad, MD, Knight Cancer Institute, has published extensively on the topic, including a previous report of 146 medical reversals published in the New England Journal of Medicine (NEJM) from 2001 to 2010.
In the present study, 13% of all RCTs were medical reversals; 29% of reversals were found in the Lancet, 33% in NEJM, and 39% in the Journal of the American Medical Association.
Most studies (92%) were conducted in high-income countries, with the remainder done in low- or middle-income countries, such as China, Ghana, and India, according to the report, published online June 11 in the open-access journal eLife.
Reversals were found in every specialty, with cardiovascular disease (CVD) was the most common medical category (20%), followed by public health/preventive medicine (12%) and critical care (11%).
CVD examples include the still-debated use of off-pump coronary-artery bypass surgery and the reversal of pulmonary artery catheterization as a therapy for congestive heart failure, identified via the ESCAPE trial and a 2013 Cochrane review.
Interventional cardiologist Robert W. Yeh, MD, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, who was not involved in the study, said the concentration of reversals in cardiology reflects the nature of the specialty.
“What it means to me is that we are willing to subject our therapies to the test; we’re willing to do the hard work of conducting randomized trials,” he told | Medscape Cardiology. “That really is the foundation of cardiology in many ways. It is, I think, if not the most evidence-based disciplines in medicine, certainly one of them.”
The finding also likely relates to the fact that heart disease is the number one killer globally and in the United States.
“Our denominator of therapies is probably larger, so that’s another reason I think we have a number of therapies showing up in this list,” Yeh said. “I don’t view it as a condemnation. I sort of wear it as a badge of honor.”

Direct and Indirect Costs

The study does not address how often the 396 medical reversals continue to be used. This can be very complex because some of the reversals are practices that patients or family can self-prescribe, such as vitamin A supplementation to improve newborn mortality or use of graduated compression stockings to reduce deep vein thrombosis after stroke, Haslam and Gill note.
Use of various practices is also inconsistent or they are being used off-label. Other reversals can be tracked more easily, such as breast cancer screening in women 40 to 49 years of age, but will likely continue because of discordant recommendations.
Although it also was outside the scope of the study to determine whether the implementation of practices later identified as reversals was financially motivated, most reversals (63.9%) were identified because of a nonindustry funded study.
As for why some physicians may be slow to de-implement ineffective practices yet quick to adopt therapies without a strong evidence base, Haslam and Gill observe that it can be hard for physicians to keep up with the published literature because of time constraints. And it takes time to conduct a good randomized study, and “sometimes there isn’t the luxury of time when you have a very sick patient with few good options (e.g., patients with cancer).”
Nevertheless, continued use of low-value practices can erode trust in the medical system and means patients spend time and money on practices that are ineffective, they note. For example, bevacizumab (Avastin) was approved in 2008 for metastatic breast cancer under the accelerated approval program, at a cost of about $88,000 per patient, but the indication was withdrawn in late 2011 after it was shown not to improve overall survival.
“In countries like the US, where there was a 20% increase in spending between 2013 and 2015, and drug prices alone surpassed the increase in aggregate healthcare spending, the identification and disuse of costly and ineffective (or possibly harmful) medications and practices are especially important,” the authors write.
Keeping interventions without a sufficient evidence base from becoming common practice will require systemic changes at all levels — from government to individual practice — and starts with holding treatments to higher standards when granting market approval, Haslam and Gill say.
“Practitioners can critically evaluate treatments, new and old, and choose what to adopt and how to practice to best serve their patients,” they add. “This is happening already but through this research, we hope that more develop critical eyes and demand well-done randomized trials before accepting treatments into their practice. While this may not directly affect systemic changes in companies and governmental agencies, it may influence future decisions and put pressure on these powers to come up with stronger evidence for new practices.”
Haslam and Gill report no relevant financial interests. Prasad reports receiving royalties from his book, Ending Medical Reversal; funding for his work from the Laura and John Arnold Foundation; honoraria for Grand Rounds/lectures from several universities, medical centers, nonprofit groups, and professional societies; serving as a writer for Medscape; and hosting the podcast Plenary Session, which has Patreon backers.
Elife. Published online June 11, 2019. Full text

3 Tricks to a Telephone Patient Assessment

Nursing assessments are taught thoroughly in nursing school and used at the bedside every day. Nurses use their senses to gather important information regarding the status of their patients. They are trained to pick up on seemingly insignificant changes in the patient’s status and incorporating it into their overall assessment. Whether it is a change in the patient’s complexion, swelling in their ankles, the new onset of a cough, or the slightest change in a patient’s vital signs, nurses process more information that can be caught by a keen observer.
With an increase in technology use, nurses are more commonly taken away from the bedside. Telehealth is becoming more common for nurses in a variety of care settings. Whether you are looking to improve your assessment skills or are considering a job that requires telehealth, here are some tips to help you assess patients over the phone.
Nurse Out Loud
Nurses often don’t understand how much of their assessment relies on visual cues at the bedside. Given the fact that you are on the phone, you must translate the normal assessment at the bedside to a verbal conversation. When using telehealth, start to verbalize your assessment to your patient over the phone, especially regarding assessments of things that you would otherwise be able to see in person, such as appearance, behavioral changes, and swelling.
Be Descriptive
When assessing a patient over the phone, you must be descriptive. Often patients have difficulty describing things. As a nurse, you have many adjectives that you use that are helpful. Plus, you need to get into the details. You cannot settle for vague generalities such as, “I had a loose bowel movement” or “I’m in pain.” You can facilitate the conversation by asking things like, “Was your pain sharp and stabbing or was it dull and achy?” and “When you passed blood in your stool was it black and tarry or bright red?” The better you can describe common descriptors relating to what the patient is telling you, the better you can accurately assess what they are actually experiencing.
Let the Patient Talk
Listening intently can uncover many valuable details that otherwise might get overlooked. Since patients can have difficulty explaining their symptoms, giving them space and time to get out what they are trying to say can go a long way in understanding what is actually going on. Remember, you are the assessment expert, not the patient.
You are completely dependent on what you can get from the patient during a telehealth assessment. To get a thorough assessment, remember to verbalize your assessment to your patient, be descriptive, and let the patient speak.

Opioid trial in Oklahoma has national implications

With billions of dollars and historic legal precedent on the line, attorneys nationwide are paying close attention to Oklahoma’s ongoing public nuisance trial against opioid manufacturer Johnson & Johnson.
The verdict that comes out of Judge Thad Balkman’s Cleveland County courtroom, although likely to be appealed no matter the ruling, is expected to impact more than 1,600 city, county and local municipality lawsuits against opioid manufacturers that have all consolidated before a federal judge in Ohio.
Cleveland jurors will hear arguments in two of these lawsuits during a bellwether, or test, trial scheduled for Oct. 21. U.S. District Judge Dan Polster is encouraging plaintiffs and drug manufacturers to reach a settlement quickly.
A win for Oklahoma⁠ — complete with a large payout from Johnson & Johnson ⁠— would give plaintiffs involved in this multidistrict litigation increased bargaining power in settlement negotiations.
A defense victory could embolden the drugmakers to fight more cases in an attempt to cut back on their losses, according to University of Kentucky law professor and liability law expert Richard Ausness.
“However it turns out, the Oklahoma trial is a bellwether that gives some indication as to where these other cases are going,” he said. “Both sides are going to be watching it with great interest.”
While every state but Nebraska is pursuing some kind of legal action against opioid manufacturers, Oklahoma was the first to reach the trial stage. Attorney General Mike Hunter alleges Johnson & Johnson caused a public nuisance by using deceptive opioid marketing techniques that led to a statewide health epidemic.
Originally expected to try three drug companies, Oklahoma settled with Purdue Pharma for $270 million on March 26 and Teva Pharmaceuticals for $85 million two months later.

Legal questions
Opioid litigation arose around the turn of the century, when some people addicted to the painkillers unsuccessfully sued drug makers.
About a decade later, local governments seeking monetary relief to combat opioid addiction in their region started filing lawsuits against drug manufacturers. Several of these claims are now part of the multidistrict litigation in Ohio.
It remains to be seen if a public nuisance argument against drugmakers in a trial setting can be successful, according to Ausness. Lawyers in the 1990s won large settlements from tobacco companies using the claim, but were unsuccessful arguing public nuisance against firearms and lead paint makers.
“Even though I think public nuisance is a weak theory, it resonates well,” Ausness said. “Anybody can be negligent, but only really bad people can commit public nuisances. That’s sort of the way it looks to somebody who isn’t an expert in the area.”
A former opioid addict turned church pastor, as well as family members of an OU football player who died from an opioid overdose, were among the state witnesses called during the first two weeks of the trial. While their testimony may have been powerful, its relevance is questionable, according to Ausness. To win a public nuisance argument, a plaintiff must establish that a collective public right has been violated and the defendant had control over the offending activity or condition.
“Bringing in people who were addicted and whose relatives were addicted, it doesn’t really go to any of the elements of a public nuisance,” he said. “After all, the state is suing for economic loss and not personal injuries. I don’t want to criticize the parties, because I have not been following the trial on a day-to-day basis, but it sounds like while the state has been vigorous, they may not be persuasive at this point.”
Johnson & Johnson could also be bolstered by a recent court ruling in favor of an opioid manufacturer in North Dakota. On May 16, a North Dakota judge dismissed a state lawsuit seeking damages against Purdue Pharma, saying the drug maker does not control the product after it enters the market.
“At the very least, the North Dakota ruling provides opioid defendants some leverage in settlement negotiations,” product liability attorney Cameron Turner said in an opinion piece on “Even if they proceed to trial and take an adverse verdict, they now have a potentially dispositive appellate argument that has been accepted by at least one judge.”
A similar ruling occurred in January, when Connecticut Judge Thomas Moukawsher dismissed lawsuits brought against Purdue Pharma by 37 cities and towns in the state. Moukawsher claimed the plaintiffs could not directly show that Purdue caused the opioid problem in their region.
“They (opioid manufacturers) really haven’t lost a case yet. It’s sort of 2-0 at this point,” Ausness said. “I think a victory for the defendants in the Oklahoma case would perhaps be more significant than a victory for the plaintiffs. Nobody likes to lose, but I think they would say we won a few, so now we can afford to lose a few.”
Potential outcomes
Johnson & Johnson’s low overall opioid market share in Oklahoma, combined with the fact that the case is being tried in front of a judge rather than a jury, limits the likelihood of a substantial judgment should Balkman rule in favor of the state, according to Ausness.
“Trial judges can be political, but I think they’re a little less swayed by the emotional stuff that is certainly being generated by the plaintiffs in this case,” he said.
In April, Balkman ruled he, not a jury, would decide the case. Hunter requested a bench trial on the basis that the state is not seeking monetary damages, but rather equitable relief, and therefore is not entitled to a jury trial. Drug manufacturers were mixed on the issue.
While this case may soon influence settlement amounts in Ohio as well as legal strategy in trial cases against drug makers, the battle won’t stop once Balkman delivers a verdict later this summer.
“Whichever way it goes, the losing side is going to appeal,” Ausness said. “There are no intermediate courts in Oklahoma, so it’ll go right to the Oklahoma Supreme Court. So who knows when they’ll render a decision. It’s going to take awhile for the full effect of the case to be realized.”

How obesity re-wires the brain’s neurological food suppression system

Overeating, by cutting the brain’s natural brakes on food intake, may result in neurological changes that continue to fuel pathological eating and lead to obesity, reports a new study in mice. The results demonstrate how diet-induced obesity alters the function of a crucial neurological feeding suppression system – findings that could help identify novel therapeutic targets for eating disorders and obesity in humans. Obesity, a disease that affects more than 500 million adults worldwide and is a large factor in the increased incidence of a myriad of other serious health issues, is often considered to be one of the most pressing global health concerns. While obesity can be linked to a few, rarely occurring medical causes, unhealthy eating habits are widely recognized as the largest determinant. However, little is known about how obesity impacts the brain or underlying neurological mechanisms, to contribute to these adverse eating behaviors. Previous research suggests that the lateral hypothalamic area (LHA), a brain region that mediates physiological functions related to survival, plays a crucial role in controlling eating behavior. In a mouse model of obesity, Mark Rossi and colleagues used a combination of single-cell RNA sequencing and two-photon calcium imaging to identify obesity-related alterations in particular cells within the LHA. The results identified a discrete class of cells – glutamatergic neurons – that functionally put the brakes on feeding to suppress food intake beyond satiation, in ideal conditions. However, in mice fed high-fat, obesogenic diets, Rossi et al. found these neurons to be highly and uniquely modified in a way that disrupted this natural feeding suppression system to promote overeating and obesity. In a related Perspective, Stephanie Borgland discusses the study in more detail.

Low-carb ‘keto’ diet (‘Atkins-style’) may modestly boost cognition in older adults

In a pilot study of 14 older adults with mild cognitive problems suggestive of early Alzheimer’s disease, Johns Hopkins Medicine researchers report that a high-fat, low-carbohydrate diet may improve brain function and memory.
Although the researchers say that finding participants willing to undertake restrictive diets for the three-month study — or partners willing to help them stick to those diets — was challenging, those who adhered to a modified Atkins diet (very low carbohydrates and extra fat) had small but measurable improvements on standardized tests of memory compared with those on a low-fat diet.
The short-term results, published in the April issue of the Journal of Alzheimer’s Disease, are far from proof that the modified Atkins diet has the potential to stave off progression from mild cognitive impairment to Alzheimer’s disease or other dementias. However, they are promising enough, the researchers say, to warrant larger, longer-term studies of dietary impact on brain function.
“Our early findings suggest that perhaps we don’t need to cut carbs as strictly as we initially tried. We may eventually see the same beneficial effects by adding a ketone supplement that would make the diet easier to follow,” says Jason Brandt, Ph.D., professor of psychiatry and behavioral sciences and neurology at the Johns Hopkins University School of Medicine. “Most of all, if we can confirm these preliminary findings, using dietary changes to mitigate cognitive loss in early-stage dementia would be a real game-changer. It’s something that 400-plus experimental drugs haven’t been able to do in clinical trials.”
Brandt explains that, typically, the brain uses the sugar glucose — a product of carbohydrate breakdown — as a primary fuel. However, research has shown that in the early stage of Alzheimer’s disease the brain isn’t able to efficiently use glucose as an energy source. Some experts, he says, even refer to Alzheimer’s as “type 3 diabetes.”
Using brain scans that show energy use, researchers have also found that ketones — chemicals formed during the breakdown of dietary fat — can be used as an alternative energy source in the brains of healthy people and those with mild cognitive impairment. For example, when a person is on a ketogenic diet, consisting of lots of fat and very few sugars and starches, the brain and body use ketones as an energy source instead of carbs.
For the current study, the researchers wanted to see if people with mild cognitive impairment, often an indicator of developing Alzheimer’s disease, would benefit from a diet that forced the brain to use ketones instead of carbohydrates for fuel.
After 2 1/2 years of recruitment efforts, the researchers were able to enroll 27 people in the 12-week diet study. There were a few dropouts, and so far, 14 participants have completed the study. The participants were an average age of 71. Half were women, and all but one were white.
To enroll, each participant required a study partner (typically a spouse) who was responsible for ensuring that the participant followed one of two diets for the full 12 weeks. Nine participants followed a modified Atkins diet meant to restrict carbs to 20 grams per day or less, with no restriction on calories. The typical American consumes between 200 and 300 grams of carbs a day. The other five participants followed a National Institute of Aging diet, similar to the Mediterranean diet, that doesn’t restrict carbohydrates, but favors fruits, vegetables, low- or fat-free dairy, whole grains and lean proteins such as seafood or chicken.
The participants and their partners were also asked to keep food diaries. Prior to starting the diets, those assigned to the modified Atkins diet were consuming about 158 grams of carbs per day. By week six of the diet, they had cut back to an average of 38.5 grams of carbs per day and continued dropping at nine weeks, but still short of the 20-gram target, before rising to an average of 53 grams of carbs by week 12. Participants on the National Institute of Aging diet continued to eat well over 100 grams of carbs per day.
Each participant also gave urine samples at the start of the dietary regimens and every three weeks up to the end of the study, which were used to track ketone levels. More than half of the participants on the modified Atkins diet had at least some ketones in their urine by six weeks into the diet until the end; as expected, none of the participants on the National Institute of Aging control diet had any detectable ketones.
Participants completed the Montreal Cognitive Assessment, the Mini-Mental State Examination and the Clinical Dementia Rating Scale at the start of the study. They were tested with a brief collection of neuropsychological memory tests before starting their diets and at six weeks and 12 weeks on the diet. At the six-week mark, the researchers found a significant improvement on memory tests, which coincided with the highest levels of ketones and lowest carb intakes.
When comparing the results of tests of delayed recall — the ability to recollect something they were told or shown a few minutes earlier — those who stuck to the modified Atkins diet improved by a couple of points on average (about 15% of the total score), whereas those who didn’t follow the diet on average dropped a couple of points.
The researchers say the biggest hurdle for researchers was finding people willing to make drastic changes to their eating habits and partners willing to enforce the diets. The increase in carbohydrate intake later in the study period, they said, suggests that the diet becomes unpalatable over long periods.
“Many people would rather take a pill that causes them all kinds of nasty side effects than change their diet,” says Brandt. “Older people often say that eating the foods they love is one of the few pleasures they still enjoy in life, and they aren’t willing to give that up.”
But, because Brandt’s team observed promising results even in those lax with the diet, they believe that a milder version of the high-fat/low-carb diet, perhaps in conjunction with ketone supplement drinks, is worth further study. As this study also depended on caregivers/partners to do most of the work preparing and implementing the diet, the group also wants to see if participants with less severe mild cognitive impairment can make their own dietary choices and be more apt to stick to a ketogenic diet.
A standardized modified Atkins diet was created and tested at Johns Hopkins Medicine in 2002, initially to treat some seizure disorders. It’s still used very successfully for this purpose.
According to the Alzheimer’s Association, about 5.8 million Americans have Alzheimer’s disease, and by 2050 the number is projected to increase to 14 million people.
Other authors on the study were Alison Buchholz, Bobbie Henry-Barron, Diane Vizthum, Dimitrios Avramopoulos and Mackenzie Cervenka, all of Johns Hopkins.
This research was supported by the William and Ella Owens Medical Research Foundation, the BrightFocus Foundation and the National Center for Advancing Translational Sciences (UL1-TR001079). The Hass Avocado Board donated avocados to participants.
Cervenka has consulted for Nutricia and Sage Therapeutics. She has received grants from Nutricia and Vitaflo. Henry-Barron has consulted for Nutricia and Vitaflo and lectured for Nutricia.

Protein offers protection against nerve degeneration in ALS model

Increasing the levels of the anti-aging protein hormone Klotho improves the neurological deficits and prolongs life span in an experimental model with Amyotrophic Lateral Sclerosis (ALS). In addition, brain immune cells called microglia play an important role in protecting the brain against inflammation and, likely, motor neuron loss in this model.
ALS or Lou Gehrig’s disease, is a devastating neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive muscle atrophy and paralysis, which is fatal within three to five years of diagnosis.
Researchers from Boston University School of Medicine (BUSM) have previously shown that increasing Klotho protein levels is beneficial in experimental models of Alzheimer’s disease and multiple sclerosis. “Here we now show that Klotho is also neuroprotective in an ALS model. Thus, increasing Klotho levels would be a logical treatment for age-related neurodegenerative and neuroinflammatory diseases,” explained corresponding author Carmela Abraham, PhD, professor of biochemistry at BUSM.
Unfortunately, very few treatments are available to ALS patients today. “We propose that increasing the levels of the Klotho protein would significantly alleviate the neurologic manifestations, improve the quality of life and prolong life span in patients with ALS. If one was to extrapolate the results of this study, increasing Klotho by only 50 percent would prolong life by approximately 300 days.”
According to Abraham, anything that increases Klotho levels is neuroprotective. For example, it has been shown that exercise increases Klotho. “This may be relevant for healthy individuals or patients newly diagnosed with ALS. Additionally, in the cases of familial ALS, family members who wish to be tested and discover that they are carriers of an ALS gene could start exercising or start Klotho boosting therapy, once it becomes available.”
BUSM’s Ella Zeldich, PhD, is the study’s first author.
These findings appear online in the Journal of Molecular Neuroscience.
Funding for this study was provided by National Institutes of Health grants R01-AG052465 and R56-AG051638.

Potential way to grow new teeth for patients

A group of histologists and dentists from School of Biomedicine, Far Eastern Federal University (FEFU), teamed up with Russian and Japanese colleagues and found cells that are probably responsible for the formation of human dental tissue. Researchers propose to apply the study outcome within the development of bioengineering techniques in dentistry aimed at growing new dental tissue for patients. A related article is published in the International Journal of Applied and Fundamental Research.
FEFU scientists used human prenatal tissues to study the early stage of development of the embryonic oral cavity during the period when the teeth were set up – from the 5th to the 6th week. They have recognized several types of cells that are involved in the formation of one of the teeth rudiments — the enamel (dental) organ. Among them, chromophobe cells with elongated spindle-shaped form have been identified which are also responsible for the development of human teeth in the first weeks of embryo formation. The data obtained can provide a fundamental basis for the development of bioengineering therapies in dentistry and gastroenterology.
‘Numerous attempts to grow teeth from only the stem cells involved in the development of enamel, dentin and pulp, i.e. ameloblasts and odontoblasts, were not successful: there was no enamel on the samples, teeth were covered only by defective dentin. The absence of an easily accessible source of cells for growing dental tissue seriously restricts the development of a bioengineering approach to dental treatment. To develop technologies of tissue engineering and regenerative medicine — promising methods of treatment in dentistry — the cells identified by us may become the clue to the new level of quality dental treatment. Natural implants that are completely identical to human teeth will no doubt be better than titanium ones, and their lifespan can be longer than that of artificial ones, which are guaranteed for 10-15 years. Although for a successful experiment, we still have a lack of knowledge about intercellular signaling interactions during the teeth development.’ said Ivan Reva, Senior Researcher of the Laboratory for Cell and Molecular Neurobiology, School of Biomedicine, FEFU.
The scientist noted that large chromophobe cells reside not only the place where the teeth of the embryo form, but also exist at the border where the multilayers squamous epithelium of the oral cavity passes into the cylindrical epithelium of the developing digestive tube. This means that the new bio-engineering approach is relevant not only for growing new dental tissue but also for growing organs for subsequent transplantation and likely will be applied in gastroenterology.
The development of new biological approaches for the teeth reconstruction with stem cells is one of the most pressing tasks in dentistry for the upcoming years. There are still a lot of questions challenging the researchers. For example, scientists have yet to figure out how in the earliest stages of human embryo development, from the seemingly homogeneous, and in fact, multilayered ectoderm, which is located in the forming oral cavity, different types and forms of teeth develop. However, it is already clear that more kinds of cells are engaged in the earliest stages of human teeth formation than it was previously supposed. Thanks to the research of FEFU scientists in cooperation with their colleagues from Russia and Japan, it also became clear that the crown of the tooth and its root have different mechanisms of formation.
This work was supported by the FEFU Scientific Foundation, within the framework of the state task 17.5740 / 2017 / 6.7.

Society pays heavy price for failure to diagnose and treat conduct disorder

Much greater awareness, improved diagnosis and enhanced treatment are all required in order to reduce the burden on society of the severe behavioural condition conduct disorder, according to a new expert review led by the University of Bath (UK).
Conduct Disorder (CD), which is a common and highly impairing psychiatric disorder, usually emerges in childhood or adolescence and is characterized by severe antisocial and aggressive behaviour, including physical aggression, theft, property damage and violation of others’ rights.
Its prevalence is estimated at around 3% in school-aged children and it is a leading cause of referral to child and adolescent mental health services. Yet paradoxically it is one of the least widely recognised or studied psychiatric disorders, and funding for research into CD lags far behind many other childhood disorders.
What the evidence shows is that CD is associated with an exceptionally high individual, societal and economic burden. The health and personal burden of CD is seven times greater than that of attention-deficit/hyperactivity disorder (ADHD), a much more widely known disorder. Whilst it is likely that children diagnosed with ADHD may also show signs of CD, very few will be diagnosed or receive treatment for the CD. CD is also associated with a greater health burden than autism.
This failure to tackle and treat CD in children and adolescents led the researchers to write the new Nature Reviews paper which calls for a greater awareness of the condition, and more funding to improve our understanding and ability to treat the disorder.
The review – a comprehensive overview of all aspects of CD, its diagnosis, clinical management and long-term impact – highlights the negative consequences and adult outcomes that can occur if it is not correctly diagnosed or treated.
In particular it reveals the high physical and mental health burden on patients and their families. In children, CD is associated with a higher risk of developing ADHD, oppositional defiant disorder and developmental language disorders; while for teenagers, comorbidities can include depression, anxiety, alcohol and substance abuse. Up to 50% of individuals with CD develop antisocial or borderline personality disorder in adulthood, along with more serious criminal behaviour and gang involvement.
It also finds that young people with CD are more likely to have children earlier, with more unplanned pregnancies, to become dependent on benefits, homeless or even to attempt suicide. Such behaviours have a huge detrimental effect on an individual and their families. In addition, those with CD display parenting problems which often mean that their own children are at higher risk for developing CD.
However, the researchers suggest that with the correct diagnosis, management for the condition is possible with the support of Child and Adolescent Mental Health Services (CAMHS). Their study highlights the value of both training parents in better supporting children with CD, and skills training for children and adolescents with the condition to help them improve their social and problem-solving skills and their ability to regulate emotions. Combined, the authors suggest, these approaches can have profound impacts on a patient’s well-being and longer-term life chances.
Lead author Dr Graeme Fairchild from Bath’s Department of Psychology hopes the study can act as a catalyst to improve the diagnosis and treatment of children with CD, and to highlight the societal impact of the condition which he suggests requires more government funding and charity involvement.
He explains: “Despite the fact that it is associated with a very high personal, familial, and societal burden, Conduct Disorder is under-recognised and frequently goes undiagnosed and untreated. The government have committed to increasing the funding for the treatment of child and adolescent mental health problems. They should take this opportunity to improve the diagnosis and treatment of children and teenagers with Conduct Disorder by investing in training in evidence-based treatments for this condition and ensuring that the families in question can access Child and Adolescent Mental Health Services. Research in other European countries and the United States has shown that this kind of investment will pay for itself over time.”
Recent other publications from Dr Fairchild have identified brain wiring differences in children with conduct disorder as well as altered brain activity in antisocial girls.

Mini ‘magic’ MRI scanner could diagnose knee injuries more accurately

Researchers at Imperial College London have developed a prototype mini MRI scanner that fits around a patient’s leg.
The team say the device – which uses so-called ‘magic angle’ effect – could potentially help diagnose knee injuries more quickly, and more accurately.
In a proof-of-concept study using animal knees, the results suggest the technology could be used to show all the structures of the knee.
The scientists say the device (which looks like a large metal ring through which a patient places their leg) could help diagnose conditions such as anterior cruciate ligament injuries – particularly common among footballers.
Furthermore, the small size of the device could enable it to be used in local clinics and even GP surgeries, potentially reducing NHS waiting times for MRI scans.
The research was funded by the National Institute for Health Research.
Currently, key components of the knee joints such as ligaments and tendons are difficult to see in detail in the MRI scans, explains Dr Karyn Chappell, a researcher and radiographer from Imperial’s MSK Lab: “Knee injuries affect millions of people – and MRI scans are crucial to diagnosing the problem, leading to quick and effective treatment. However we currently face two problems: connective tissue in the knee is unclear on MRI scans, and people are waiting a long time for a scan.”
Dr Chappell added: “This can cause particular problems for women, as they are at greater risk of anterior cruciate ligament injuries. The reasons for this are unclear, but it could be linked to hormones such as oestrogen making ligaments more elastic, leading to more joint injuries.”
Knee injuries commonly affect one of three areas: the tendons (which attach muscle to bone), the meniscus (a cushioning pad of cartilage that prevents the bones of the joints rubbing together), or the ligaments (tough bands of connective tissue that hold bones in a joint together).
Following knee injury a doctor may refer a patient for a MRI scan to help establish which part of the joint is injured. MRI scans use a combination of radio waves and strong magnets to ‘flip’ water molecules in the body. The water molecules send out a signal, which creates an image.
However, tendons, ligaments and meniscus are not usually visible with MRI, due to the way water molecules are arranged in these structures, explains Dr Karyn Chappell.
“These structures are normally black on an MRI scan – they simply don’t produce much signal that can be detected by the machine to create the image. This is because they are made mostly of the protein collagen, arranged as fibres. The collagen fibres hold water molecules in a tight configuration, and it is in fact water that is detected by the MRI. If you do see a signal it suggests there is more fluid in the area – which suggests damage, but it is very difficult for medical staff to conclusively say if there is injury.”
To overcome this problem, Dr Chappell harnessed the power of a phenomenon called the ‘magic angle’: “The brightness of these tissues such as tendons and ligaments in MRI images strongly depends on the angle between the collagen fibres and the magnetic field of the scanner. If this angle is 55 degrees the image can be very bright, but for other angles it is usually very dark.”
The team explain the magic angle is achieved in their scanner because they are able to easily change the orientation of the magnetic field. While the patient sits comfortably in a chair, the specially designed magnet (which uses motors and sensors similar to those found in robots in car factories) can rotate around the leg and the orientate magnetic field in multiple directions.
This is not possible in current hospital MRI scanners, which are also much more expensive than the prototype scanner.
“Previously the magic angle phenomenon was thought of as a problem, as it could mean medical staff mistakenly thinking the knee is injured. However, I realised that if we took a number of scans around the knee, we could use the signal produced by the magic angle effect to build a clear picture of the knee structures,” explained Dr Chappell.
“Specifically, we can combine images obtained at different magnet angles and not only increase the brightness, but also see how the collagen fibres are arranged. This enables us to establish the pattern of collagen fibres in the knee structures, which is crucial information ahead of treatments such as repairing a torn meniscus,” added Dr Chappell.
“At the moment, it’s very difficult to see which direction the collagen fibres run in a meniscus. This is important because sewing across the fibres will effectively repair a tear in the meniscus. However if the stitch is in the same direction as the fibres, the repair may fail.”
In a new study, published in the journal Magnetic Resonance in Medicine, the multi-disciplinary team scanned the knee joints of six goats and ten dogs in a conventional MRI scanner.
All of the dog legs were donated by the Royal Veterinary College, having been donated for research by dog owners following the death of their pet.
Dogs suffer from knee injuries and arthritis similar to humans, making them a good subject for the study.
The results showed that using the magic angle can accurately detect ligament and tendon damage.
The team say now they know magic angle scanning can be used to visualise the knee, combining this with the new prototype mini scanner could enable knees to be accurately scanned with this technology – and hope to progress to human trials of the ‘mini’ scanner within a year.
Dr Chappell explained: “Although this is an early-stage proof-of-concept study, it shows the technology could potentially be used to accurately detect knee injury. We now hope to enter human trials – and explore if this technology could be used for other joints such as ankles, wrists and elbows.”

Saturday, June 29, 2019

Karyopharm awaits a verdict on selinexor

A delayed decision on Karyopharm’s selinexor is the pick of the bunch for July.
On the US approvals front a quiet June is about to give way to an even quieter July. But the fact that 2019 has, so far, been a relatively slow year for the FDA will not bother Karyopharm if it can get the nod for its lead candidate, selinexor.
The project is due a decision in multiple myeloma by July 6, a three-month delay to its original PDUFA date, and approval is far from assured. Assets from Merck & Co and Shield Therapeutics are also in line for consideration, while Celgene’s Otezla could get a thumbs-up in a new indication, Behçet’s disease, as Bristol-Myers Squibb looks for a buyer for the product.
The FTC said this week that Bristol would have to sell the psoriasis drug for its purchase of Celgene to go through; investors reacted by knocking nearly $6bn off Bristol’s market cap.
Approval in Behçet’s is unlikely to make much difference to Bristol’s negotiations: the inflammatory condition is rare in the US and Europe. Celgene previously said it would also seek a supplemental approval for Otezla in moderate to severe scalp psoriasis in the second quarter.
Take two for selinexor
Meanwhile, Karyopharm’s investors face a nervous wait over selinexor, which is awaiting a decision in relapsed/refractory multiple myeloma patients who have received at least three prior therapies. The company’s share price plunged in February after an FDA advisory panel recommended delaying approval until readout of the Boston trial in earlier-line patients.
The subsequent delay gave investors hope that accelerated approval could still be within reach, with analysts speculating that the company had submitted some of the Boston data to the agency early (Karyopharm’s selinexor delay could speed approval, March 15, 2019).
There are concerns about toxicity with selinexor, but the very sick population that Karyopharm is initially targeting could work in the company’s favour. Still, even if it is approved it might remain a last-ditch option, and moving into earlier lines of therapy could be another story. In February, EvaluatePharma sellside consensus put 2024 selinexor sales at $1.2bn; expectations have now dropped to $370m.
ProjectCompanyPDUFA dateProduct NPV ($m)
SelinexorKaryopharmJul 61,646
MK-7655AMerck & CoJul 16
FeraccruShield TherapeuticsJul 2796
Source: EvaluatePharma.
Merck & Co is set to hear by mid-July on its latest antibacterial, a combination of relebactam, imipenem and cilastatin known as MK-7655A. The project is due a verdict in complicated urinary tract and intra-abdominal infections caused by certain Gram-negative bacteria in adults with limited or no alternative therapies.
Merck recently bagged approval for Zerbaxa, another antibacterial combination product, in the new use of pneumonia. Although there is a big need for new antibiotics, the market for such products is far from lucrative.
Meanwhile, a positive decision on the oral iron supplement Ferracru would give its originator, Shield Therapeutics, a big boost. The product is already available in Europe for the treatment of iron deficiency in patients with or without anaemia.
Finncap analysts expect Ferracru to get the US nod for iron deficiency anaemia, but noted that a general iron deficiency label would double the addressable market.
Shield’s future had looked dim after the failure of the Aegis-CKD trial in early 2018, but the UK company later carried out a new analysis, with better results. Earlier this year, the Aegis-H2H trial found that Ferracru was non-inferior to injectable iron. Shield will have to hope that this data package will be enough to convince the FDA.
Another project that could be due a nod is Samsung Bioepsis’s Humira biosimilar Imraldi, which was accepted for review by the FDA in September. Three other Humira biosimilars have US approval – Amgen’s Amjevita, Novartis’s Hyrimoz and Boehringer’s Cyltezo – although Humira’s maker, Abbvie, has agreements with most of their manufacturers to keep them off the market until 2023.
Product CompanyEvent typeDate
OtezlaCelgenesNDA for Behçet’s diseaseJul 21
ImraldiSamsung BioepisHumira biosimilar; FDA accepted filing in Sep 2018Possibly July
Source: EvaluatePharma.

Pivotal data readouts for Ardelyx and Rhythm will set the tone for next year

Both Ardelyx and Rhythm Pharmaceuticals are looking for phase III clinical wins to kick off filing discussions for pipeline leads.
Welcome to your weekly digest of approaching regulatory and clinical readouts.The next six months are going to be very busy for Ardelyx, which expects a raft of data with its lead project, tenapanor, in a number of indications.
First up is the phase III Amplify trial, looking at tenapanor as an adjunctive therapy to phosphate binders for patients with end-stage renal disease. The multipurpose asset is also looking to land its first approval, with a PDUFA decision in irritable bowel syndrome with constipation (IBS-C) due by September 12.
Tenapanor, a small molecule, targets the NHE3 transporter in the gut, resulting in the excretion of excess phosphate. While not in itself a treatment for renal disease it could reduce the pill burden of patients using phosphate binders, and therefore increase compliance.
The primary endpoint of the 214-patient Amplify study is change in serum phosphate levels after four weeks with tenapanor versus placebo. The project is also being tested as monotherapy in the phase III Phreedom study, which is due to read out in the fourth quarter. If it is successful in both trials it could become the only phosphate-lowering drug approved as a mono and adjunctive therapy.
In terms of IBS-C, tenapanor is designed to act directly in the gut to reduce absorption of sodium; this increases fluid in the gut, loosening stool and alleviating constipation. However, the project has had several setbacks in this setting, leaving it significantly behind the industry leader, Allergan’s Linzess.
Annual indication sales ($m) 
Analysts now forecast a launch in IBS-C in 2021. Given Linzess’s headstart, and the fact tenapanor has so far lagged on efficacy and adverse events, the latter will face a tough time achieving the $443m of IBS-C revenues expected in 2024. A partner could help Ardelyx drive sales, and the company has previously said it was in discussions; these could accelerate if tenapanor is approved.
If all of these catalysts turn out to be positive it could make for a year-end turnaround for Ardelyx, which has recently seen its shares fall by 15%.
Hungry for success
Meanwhile, Rhythm Pharmaceuticals is expected to announce topline data from two pivotal trials of its lead project, setmelanotide, in two ultra-rare genetic obesity disorders in the third quarter.
Patients with the diseases, homozygous pro-opiomelanocortin (POMC) deficiency and leptin receptor (LepR) deficiency, have insatiable hunger and suffer from obesity at an early age.
Setmelanotide is designed to activate the melanocortin-4 pathway, which should lead to increased energy expenditure and reduced appetite.
The primary endpoint of both studies is the number of setmelanotide-treated patients who achieve 10% reduction in weight from baseline after 52 weeks versus placebo. The studies also include a double-blind, placebo-controlled, eight-week withdrawal period to measure weight and hunger scores when the therapy is stopped.
If the results are positive a US filing could be on the cards for the end of 2019 or early 2020. So far, if phase II studies are anything to go by, the omens look good for approval. In phase II patients reported body weight reductions of 10-30% after 52 weeks, and setmelanotide has not demonstrated the cardiovascular side effects that have plagued previous MC4 receptor agonists.
However, even if setmelanotide succeeds in the clinic, its commercial chances look less clear, with questions remaining over the size of the market. Indeed, consensus sellside forecasts from EvaluatePharma put 2024 sales at just $47m.