J&J Esketamine Shows Promise in Depression Clinical Trials

The Janssen, part of Johnson & Johnson, announced results from two long-term Phase III trials of esketamine nasal spray in patients with treatment-resistant depression.

The findings were presented at the Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP) held in Miami Beach, Florida. The first trial evaluated relapse prevention in adults with treatment-resistant depression. The data showed that continuing treatment with esketamine nasal spray with an oral antidepressant beyond 16 weeks had clinically meaningful and statistically significant superiority to just an antidepressant and placebo in delaying time to relapse of depression symptoms.

The trial also showed that patients receiving the drug with an oral antidepressant had a 51 percent less risk of relapse than patients in the antidepressant-plus-placebo group.

The second study was an open-label trial to assess the long-term safety and efficacy of esketamine nasal spray for up to a year. There were no new safety signals and it was similar to those seen in previously completed short-term Phase II and III trials. From an efficacy standpoint, it also showed that esketamine nasal spray plus an oral antidepressant gave sustained improvement in depressive symptoms up to 52 weeks.

“At least 300 million people worldwide live with treatment-resistant depression, and it is important we continue to study and report the results of studies such as these two,” said Maurizio Fava, executive vice chair of the Massachusetts General Hospital (MGH) Department of Psychiatry and executive director of the MGH Clinical Trials Network and Institute (CTNI), in a statement. “The first study shows that esketamine may be beneficial in terms of extending time to relapse for patients with treatment-resistant depression, and the second provides insights related to its safety over the long-term in this patient population.”

Safety results were consistent with the previous Phase II and III trials. The most comment adverse events were metallic taste (27%), vertigo (25%), dissociation (22.4%), drowsiness (21.1%), dizziness (20.4%), headache (17.8%), nausea (16.4%), blurred vision (15.8%) and diminished sense of touch or sensation (13.2%). Most adverse events were seen on the first day of dosing and generally resolved the same day.

The company also stated, “Fifty-five (6.9%) patients experienced 68 serious treatment-emergent adverse events. Of these, five serious treatment-emergent adverse events from four subjects were assessed by the investigator as esketamine nasal spray-related. There were two deaths which the investigator determined to be unrelated to esketamine nasal spray or oral antidepressant use. Laboratory tests, physical examination, and nasal tolerability revealed no trends of clinical concern in patients treated with esketamine nasal spray for up to 52 weeks. No clinically meaningful changes in cognition were found. No cases of interstitial or ulcerative cystitis were reported.”

Esketamine is a low dose of ketamine, a drug of abuse sometimes called “Special K” and used as a horse tranquilizer. The five serious adverse events were apparently depression, delirium, anxiety and delusion, suicidal ideation and suicide attempt.

If the drug were to be approved by the Food and Drug Administration (FDA), it would be the first new pharmacotherapeutic approach to treating refractory major depressive disorder in 50 years.

Antidepressants are typically selective serotonin reuptake inhibitors (SSRIs), such as Prozac and Zoloft, or serotonin-norepinephrine reuptake inhibitors (SNRIs), likes Pristiq or Efexor. They both affect serotonin neutrotransmitters by blocking serotonin reuptake and locking it in the gap between neurons for longer than usual.

Esketamine falls into a newer class of antidepressants, and target NMDA receptors, which regulate the concentrations of the glutamate neurotransmitter in the brain. Another product with a similar method of action under development is ALKS5461, an opioid, by Alkermes That drug is currently under review by the FDA and has a target action date of January 31, 2019.

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Uncovering the role of the ApoE gene in Alzheimer’s

A study conducted at the Massachusetts Institute of Technology has identified why the ApoE4 gene increases the risk of developing Alzheimer’s disease.

Image Credit: Andrii Vodolazhskyi / Shutterstock

Apolipoprotein E (ApoE) is a class of proteins involved in the metabolism of fats, including cholesterol. ApoE surrounds fats to form lipoproteins, which facilitates the transport of fats in the bloodstream. There are three variants of the gene encoding ApoE: ApoE2, ApoE3 and ApoE4.

ApoE3 is the most common variant, being present in 78% of the population, and does not appear to influence the risk of developing Alzheimer’s disease.

However, presence of the ApoE4 gene variant, which occurs in approximately 14% of people, increases the risk for Alzheimer’s disease and lowers the age of onset of the disease. In contrast, the rarest variant ApoE2 reduces the risk of developing Alzheimer’s disease by up to 40%.

It has long been known that the distribution of ApoE gene variants differs considerably among patients with late-onset Alzheimer’s disease (the most common form of the disease).

The proportion of individuals in this subpopulation carrying the ApoE4 is almost three times as high as the general population, whereas the prevalence of the protective ApoE2 gene variant is halved.

Despite this apparent link, it was not understood why ApoE4 increases the risk of developing Alzheimer’s disease.

To establish why variants of the same gene can have such different impacts on Alzheimer’s disease risk, neuroscientists conducted a comprehensive study of ApoE4 and ApoE3 in brain cells.

They discovered that the ApoE4 gene variant promoted the accumulation of the beta amyloid proteins that comprise the characteristic plaques that form in the brains of patients with Alzheimer’s disease.

ApoE4 influences every cell type that we studied, to facilitate the development of Alzheimer’s pathology, especially amyloid accumulation…ApoE4 is by far the most significant risk gene for late-onset, sporadic Alzheimer’s disease”.

Li-Huei Tsai, Senior Author

The study also demonstrated that the presence of ApoE3 and ApoE4 affected the expression of hundreds of other genes and these effects were greatest in microglial cells, which are responsible for the removal of foreign matter, including amyloid proteins and bacteria.

Microglia functioned at a much slower rate when containing the ApoE4 gene variant compared with ApoE3. In addition, neurons with ApoE4 secreted higher levels of amyloid protein than neurons with ApoE3.

Furthermore, the researchers successfully reversed these effects in brain cells containing the ApoE4 gene by using gene editing technology to convert the gene into the ApoE3 variant.

The results of this study this indicate that in Alzheimer’s disease brain cells produce more amyloid protein, whilst their ability to remove it is dramatically impaired and that these effects are reversible.

It is hoped that the gene expression profiling performed will reveal potential targets for therapeutic intervention. There is the possibility that Alzheimer’s disease risk and symptoms could be reduced by converting ApoE4 to ApoE3 in individuals with high ApoE4 expression.

Source:

Massachusetts Institute of Technology. Press release 31 May 2018.

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Weight gain may be the result of inefficient fat metabolism

Researchers from the Karolinska Institutet have shown that protracted weight gain can, in some cases, be attributed to a reduced ability to metabolise fat.

The team says certain people may need more intensive lifestyle changes if they are to decrease their risk of becoming overweight or developing type 2 diabetes.

We’ve suspected the presence of physiological mechanisms in fatty tissue that cause some people to become overweight and others not, despite similarities in lifestyle, and now we’ve found one.”

Professor Mikael Rydén, Study Author

Rydén and colleagues are now working to develop a way of measuring the body’s ability to break down fat.

For the study, the researchers analysed subcutaneous fat samples taken from the abdomens of women before and after a follow-up period of approximately a decade.

As reported in the journal Cell Metabolism, they found that the ability of the fat cells to release fatty acids in the first tissue sample could be used to predict which women would have developed type 2 diabetes at the end of the study.

This fatty acid release, referred to as lipolysis, is a process the body uses to provide an energy source in muscles.

Researchers differentiate between two types of lipolysis – basal lipolysis, which is ongoing, and hormone-stimulated lipolysis, which occurs in response to an increased need for energy.

Rydén and team found that the fat cells from women who later became overweight showed a high basal, but low hormone-stimulated lipolysis that increased the risk of weight gain and type 2 diabetes by 3 to 6 times.

“It’s a bit like a car that’s at high revs but that’s lost its ability to get into gear when it needs to. The end result is that the fat cells eventually take up more fat than they can get rid of,” explains Rydén.

He says the results now need to be corroborated in larger studies and for men.

We hope to develop a clinically expedient way of identifying individuals at risk of developing overweight and type 2 diabetes, who might need more intensive lifestyle intervention than others to stay healthy.”

Professor Mikael Rydén

Source:

https://www.eurekalert.org/emb_releases/2018-05/ki-ifm053018.php

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Intuitive Surgical OKd by FDA on urological surgery system

Intuitive Surgical, Inc. (Nasdaq: ISRG), today announced a new U.S. Food and Drug Administration (FDA) clearance for the da Vinci SP surgical system for urologic surgical procedures that are appropriate for a single port approach.

The da Vinci SP system provides surgeons with robotic-assisted technology designed for deep and narrow access to tissue in the body. The ability to enter the body through a single, small incision helps surgeons perform more complex procedures. Intuitive anticipates pursuing further regulatory clearances for da Vinci SP, including transoral, transanal, and extraperitoneal applications, broadening the applicability of the SP platform over time.

“The da Vinci SP is the latest in our integrated product family that shows our commitment to improving minimally invasive surgery with technology that can positively impact patient outcomes,” said Gary Guthart, chief executive officer for Intuitive. “Our da Vinci SP compliments da Vinci X^® and Xi^® systems by enabling surgeons to access narrow workspaces while maintaining high quality vision, precision, and control that surgeons have come to trust from da Vinci^® systems.”

The da Vinci SP system includes three, multi-jointed, wristed instruments and the first da Vinci fully wristed 3D HD camera. The instruments and the camera all emerge through a single cannula and are properly triangulated around the target anatomy to avoid external instrument collisions that can occur in narrow surgical workspaces. The system enables flexible port placement and excellent internal and external range of motion (e.g., 360-degrees of anatomical access) through the single SP arm. Surgeons control the fully articulating instruments and the camera on the da Vinci SP system, which uses the same surgeon console as the da Vinci X and Xi systems.

“Intuitive continues to bring tomorrow’s surgery today by addressing surgeon and patient needs, as well as working closely with hospitals to systematically improve the overall experience in the operating room,” said Salvatore J. Brogna, Intuitive executive vice president and chief operating officer.

Since the initial U.S. FDA clearance in April 2014 for the da Vinci SP surgical system, Intuitive invested in important platform refinements. Intuitive plans to launch the da Vinci SP surgical system in the United States in a measured fashion, with customer shipments beginning in the third quarter of 2018.

https://bit.ly/2sv2ZVD

3 Possible Outcomes Of Clinical Hold On Crispr Therapeutics Sickle Cell Candidate

Shares of Crispr Therapeutics AG CRSP 6.36% fell more than 7 percent Thursday morning after the U.S. Food and Drug Administration said it placed a clinical hold on the company’s therapy.

What Happened

The FDA placed a clinical hold on the Investigational New Drug application for Crispr’s CTX001 for the treatment of sickle cell disease, Crispr and its partner Vertex Pharmaceuticals Incorporated VRTX 1.69% said in a press release. The hold is subject to the companies answering certain questions from the FDA as part of its review of the IND.

Why It’s Important

The details of the FDA’s hold are not revealed to the market, so the overall implications for Crispr aren’t fully known, Chardan’s Gbola Amusa said in a research report. Three outcomes are possible, the analyst said:

• A hold can be based on concerns over Crispr’s specificity or editing efficiency (overall sector risk).
• A hold can be based on an element of the CTX001 production or an aspect of the trial design (company-specific risk).
• A “rapid resolution” would help mitigate a negative impact on the CTX001 program and the gene editing space.

Chardan has a Buy rating on Crispr with a $72.50 price target.

What’s Next

Crispr and Vertex expect to receive additional information on the FDA’s list of questions in the “near future” and will “work rapidly” with the FDA toward a solution, the press release said.

https://bit.ly/2Hcy9GE

More Drivers Killed Under the Influence of Drugs Than Alcohol

SOME 22.3 PERCENT OF fatally injured motorists who were tested for drugs tested positive for marijuana in 2016, a figure that researchers say has “increased substantially” in recent years as states have legalized the drug for recreational or medicinal use, according to a new report.

The finding, in a study released Thursday by the Governors Highway Safety Association, was one of several regarding the growing prevalence of drugs in vehicle fatalities. The report also found that 44 percent of drivers killed in automobile accidents in 2016 who were tested for drugs tested positive for one or more substances – a number that was up 28 percent from 10 years prior. That figure eclipsed the 37.9 percent who were known to have been tested for alcohol and tested positive – a figure that actually fell in the last decade, from 41 percent in 2006.

The report was intended to draw attention to the need to incorporate a drug message into programs that encourage motorists not to drive while impaired. It noted that marijuana was the most commonly found drug. Jim Hedlund, author of the study, says “marijuana use has become more normalized” as states across the country decriminalize the drug.

“If use is up, use by drivers is up,” Hedlund says.

Hedlund attributes the decline in alcohol-related deaths to the “broad societal consensus” that drunk driving is wrong. There’s a “strong societal consensus. It’s [drunk driving] is bad,” he says. “Everyone knows it’s bad.” However, this way of thinking hasn’t caught up to drug-impaired driving yet. That’s where education comes in.

“That’s the next step. Precisely to provide that education,” Hedlund says.

The report suggests that some of the strategies used to decrease drunk driving can be applied to prevent people from driving while on drugs. However, several challenges come with that. A driver can consume a vast number of drugs that would be difficult to test for. Additionally, no nationally accepted method exists for testing drug-impaired drivers, and different drugs have different effects on different people.

Among recommendations to reduce drug-impaired driving, the study points to the need to develop impairment-assessment tools, such as oral-fluid devices and marijuana breath-test instruments, to support the drug-impaired-driving prosecution process by increasing law enforcement training, authorizing electronic search warrants for drug tests, and to educate prosecutors and judges on drug-impaired driving.

Hedlund outlined additional recommendations, including raising public awareness about the impairments certain drugs have on the body, and working with pharmacists to improve communication between drugmakers and consumers.

https://bit.ly/2Jn9PqI

Health-care workers are committing suicide in unprecedented numbers

As America focuses on one epidemic — the opioid crisis — another goes entirely ignored. American health-care workers are dying by suicide in unprecedented numbers. Earlier this month, a medical student and a resident at NYU medical school completed suicide less than a week apart.

My junior colleague took her life just 11 days before her 35th birthday. I had supervised her as she transitioned into practice from fellowship. She said that the way I said her name foretold if the conversation pointed to a weakness or a strength in her patient assessment. My last sight of her was as she drove off to her new job. Less than six months later, she made a life-ending choice.

A scan of her suicide note, asking that I be notified, was emailed to me. I did not show it to anyone. The news of her suicide was announced by an email in the department. We all went about our business, as if suicide by a young colleague is usual. And perhaps, in a way it is.

After all, physician suicide — and more broadly health-care worker suicide — is a huge issue in the U.S. In my own experience, I have lost six colleagues to suicide — five physicians and one physician assistant. That does not include the suicides that I have heard about through the whisper network at work.

My junior colleague was among an estimated 400 physicians who took their lives in 2016. Many physicians know more doctors than patients who have taken their lives. Physicians and nurses complete suicide more often than do average Americans; rates are even higher for women in bothprofessions. Respect, fear and love for our colleagues often leads us to list the cause of death differently on death certificates. We frequently self-medicate, so suicides may instead be listed as accidental. Phrases to describe the scope like “an entire medical school class a year” or “a doctor a day” have particularly ominous meanings for physicians.

All of the physicians that I knew who took their lives were American medical graduates, a worrisome statistic if it reflects the general trend. A full 24 percent of physicians in the U.S. are international medical graduates; my specialty, pathology, is about 40 percent international graduates.

Although a recent report of suicides among residents does not suggest differential suicide rates among international and American medical graduates, the data may be limited by the nature of the study. The number for nurse or other health-care worker suicide is unknown, since we do not even track these numbers. Earlier this year, the National Academy of Medicine released a paper to raise awareness of nurse suicide, calling for a closer look at another facet of this epidemic. The high suicide rates correlate with the high rates of depression among physicians and nurses.

Why physicians and health-care workers are more likely to complete suicide is unknown. It perhaps has to do with a work-related mental health syndrome called disengagement and burnout, which has reached epidemic proportions in health-care providers and nurses. Excessive pressures and expectations at work, paired with seemingly unattainable goals for quality and productivity as well as societal loss of trust in physicians, has led to a loss of meaning of work and of self for physicians. This is not the norm that physicians or nurses expected when we answered the call to be care-providers.

Regardless of why medical workers tend to die by suicide, there needs to be a call to arms to do something about it. Health-care organizations need to more proactively report suicide in their workforce, so we can begin to understand the drivers for suicide in health-care workers. The information needs to be granular enough to identify risks by specialty and work-type.

More immediately, institutions need to develop procedures and processes for grief recovery support for colleagues of the deceased. Many institutions shy away from even mentioning suicide at the workplace. There is concern for suicide contagion, an increased tendency toward suicide in the already predisposed upon hearing of a suicide. There is stigma to talking about suicide among leaders, and fear that it will cast a shadow on them or their organization.

But, that is the wrong response. Colleagues suffer when one of their own is lost to suicide. One spends a third of one’s life at work. Sustained relationships at work are particularly important in an environment that is so stressful. The responsibility for another’s well-being and the ever-present risk for potential harm to another from a misjudgment extracts a heavy emotional toll on health-care providers.

We perhaps even blame ourselves more when we lose a colleague to suicide. Why did I not see it? Could I have done something to prevent it? One wonders about one’s self worth and one’s ability to care for patients when one fails a colleague and friend. One institution at least, UCSD, has heard this call to action and created the Healer Education and Assessment Referral program, which promotes self-assessment for depression and provides support for all health-care workers in the setting of a coworker’s suicide. But more needs to be done — at a department level, at an institutional level and at a national level.

Postvention programs to provide support for survivors of a co-worker suicide need to be developed in the profession. Structured prevention strategies to reduce suicide need to be developed as has been done for the police and military — two other at-risk professions for suicide. Leaders need to be trained to give support to their providers, so providers can heal and continue in their job of caring for their patients, after one of theirs is lost to suicide.

Vinita Parkash M.D. is an associate professor of pathology at the Yale School of Medicine. She is a Public Voices fellow with the OpEd Project, which is an organization that focuses on increasing the number of women thought leaders contributing to key commentary forums and media outlets.

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