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Wednesday, December 26, 2018

Genetic and Device-Oriented Approaches to Treating Obesity


Obesity is, without a doubt, a problem. A 2017 study found that more than 700 million adults and children worldwide are obese, calling it a “rising pandemic.”
Researchers at the University of Wisconsin-Madison have developed a battery-free, easily implantable device, about a third the size of a penny, that helped laboratory rats lose weight. In fact, the rats lost almost 40 percent of their body weight.
The research was published in the journal Nature Communications.
What the device does is create gentle electric pulses from the way the stomach naturally churns and delivers those pulses to the vagus nerve. The vagus nerve connects the brain and the stomach. This stimulation convinces the brain into thinking the stomach is full after only eating a little bit of food.

“The pulses correlate with the stomach’s motions, enhancing a natural response to help control food intake,” stated Xudong Wang, a UW-Madison professor of materials science and engineering.
The device would also be removable, so the results would not be permanent. In their study, they removed the devices after 12 weeks and the rats went back to their normal eating patterns—and resultant weight gain.
The U.S. Food and Drug Administration (FDA) has already approved a system called the Maestro System, by ReShape Lifesciences, that hits the vagus nerve with high-frequency shocks, but it requires a complicated control unit and a heavy battery that has to be recharged.
Luke Funk, surgery professor in UW-Madison’s Division of Minimally Invasive, Foregut and Bariatric Surgery, stated, “One potential advantage of the new device over existing vagus nerve stimulators is that it does not require external battery charging, which is a significant advantage when you consider the inconvenience that patients experience when having to charge a battery multiple times a week for an hour or so.”
In some ways, the device powers itself the way a self-winding watch does, by using the body’s motion to harvest energy.
Wang and his team are beginning testing the device in larger animal models, and if those are successful, will move into human trials. Wang is a leading expert in wearable and implantable capacitive electricity-generating devices. His has also invented implantable nanogenerators that create energy from people’s heartbeats and breathing, and a motion-powdered bandage for wound healing.
It was only two weeks ago that researchers at Flinders University in Australia, working with mice, removed a single gene called RCAN1, which led to the animals not gaining weight, even after drastically overeating high-fat foods for several weeks. That research was published in the journal EMBO Reports.
“We know a lot of people struggle to lose weight or even control their weight for a number of different reasons,” stated Damien Keating, who led the international research team. “The findings in this study could mean developing a pill which would target the function of RCAN1 and may result in weight loss.”
RCAN1 creates a protein that is a feedback inhibitor of the calcium-activated protein phosphatase calcineurin (CN) and suppresses two different mechanisms of what is called non-shivering thermogenesis (NST). An increase in NST burns calories as heat instead of storing them as fat.
And last week, researchers at UC San Francisco published research in the journal Science describing their use of CRISPRa, a modified form of gene editing, to stimulate the activity of certain genes. Two genes, SIM1 or MC4R, are critical for regulating hunger and satiety. Mutations in either of these genes are often found in severely obese people. When both copies of the genes function normally, the individual is typically able to control his or her food intake. But when one copy doesn’t function, they have an uncontrollable appetite.
They used CRISPRa to target gene sequences that regulate the activity of SIM1 or MC4R, then used a virus as a vector to introduce the CRISPRa constructs into the hunger-control regions of the mice brains. The result was the mice that received the constructs churned out more SIM1 or MC4R than those that didn’t. And the mice did not become obese.
All of which is likely good news down the road, as the world grapples with a ready supply of high-calorie foods and often sedentary lifestyles related to technology. A recent study in CA: A Cancer Journal for Clinicians, noted that excess body weight was linked to approximately 4 percent of cancers worldwide. It is also linked to numerous other diseases, including heart disease and diabetes.

Flexibility: A must at every age


Flexibility is a component of all types of movement—from everyday activities to the most rigorous exercises. Being flexible helps you stay mobile and avoid injury.
Yet  training often gets lost in the shuffle or pushed to the bottom of the list after cardio and .
Its  is to increase your range of motion—how far you can reach when, for instance, you bend from side to side, or raise your arm overhead to grab an item from a high shelf.
Flexibility is best achieved through , which are stretches you ease into and hold for 10 to 30 seconds while inhaling and exhaling—no bouncing, no holding your breath.
As you start a stretch, focus mentally on the muscles you’re targeting. Extend just to the point of discomfort; you shouldn’t feel any pain.
Here are three moves that target the lower body.
For your hamstrings, sit on the floor with your legs straight in front of you. Think of your hips as a hinge and, with a straight back, lower your chest toward your thighs until you feel the stretch in the backs of your thighs. Repeat 3 to 5 times.
For your hips, stand up straight, facing a sturdy chair or table in case you need it for support. Raise the heel of your right foot behind you and use your right hand to press it toward your backside without moving your thigh or your hip out of alignment. Repeat 3 to 5 times, then switch legs and repeat.
For your calves, step forward with your right leg. Keep your left heel flat on the ground and press your left hip forward as you redistribute your weight over your right leg. Repeat 3 to 5 times, then switch legs and repeat.
Note: It’s important that muscles are warm before you do static stretches. They’re a great follow-up after every , but do at least 2 or 3 focused sessions per week, targeting all muscle groups, and always after a minimum of 10 minutes of light activity.
More information: The American Council on Exercise has more about increasing flexibility, along with other exercises you can do on your own.

Most shorted stocks log record gain


One notable factor in Wall Street’s monster rally on Wednesday was a record gain in an index of stocks that have the largest bets placed against them by market contrarians.
The Thomson Reuters United States Most Shorted Index rose 6 percent, the biggest percentage rise in its six-year history, as some investors moved to cover bearish bets on the 51 stocks in the index, some of which were at their lowest price in years.
The gain came as the Dow Jones Industrial Average surged more than 1,000 points in a single session for the first time, in a broad stock rebound that pulled the benchmark S&P 500 index back from the brink of a bear market.
“This is a short-covering rally,” said Michael Antonelli, managing director of institutional sales trading at Robert W. Baird in Milwaukee.
“The move you see is just everybody trying to get out of these super, super bearish positions that they have been in, that have been easy to make money in,” he said.
U.S. stocks have been battered this month by fears of slowing economic growth and worries about a potential conflict between the White House and the Federal Reserve, putting the S&P on pace for its worst December since the Great Depression.
“From the day the market opened in December, if you just went short the market every morning, you were making money at the close,” said Antonelli.
Short-sellers aim to profit by selling borrowed shares, hoping to buy them back later at a lower price.
The rally in heavily shorted names exerted pressure on short-sellers to at least partly cover their bets, analysts said.
“The shorts realize that they probably shouldn’t be too greedy here,” said Brett Ewing, chief market strategist at First Franklin Financial Services in Tallahassee, Florida.
Several components of the Thomson Reuters United States Most Shorted Index rose sharply from multi-year lows on Wednesday.
Shares of home furnishing retailer Bed Bath & Beyond Inc (NASDAQ: BBBY), which on Monday fell to a two-decade low, rose 9 percent on Wednesday. Snap Inc (NYSE: SNAP), which dropped to a record low last week, rose 4.6 percent. Shares of California Resources Corp (NYSE: CRC) rebounded 22 percent from their lowest since early March.
Abercrombie & Fitch Co (NYSE: ANF), another component of the index, rose 10.5 percent.

Cardiovascular Systems says patients treated in U.S with OrbusNeich Teleport


Cardiovascular Systems announced that the first patients in the United States were treated using the OrbusNeich Teleport Microcatheter, which recently received U.S. Food and Drug Administration 510 clearance. Microcatheters are used to provide support and safe guidewire exchange during complex cardiovascular procedures. Teleport is a new generation microcatheter designed for deliverability and support, with a unique and robust tip designed to enable access in the most challenging lesions.

Wainwright Bullish On Corbus Therapeutics’ Cystic Fibrosis Opportunity


Corbus Pharmaceuticals Holdings Inc CRBP 6.84% has Phase 3 trials ongoing for its lead compound lenabasum in systemic sclerosis and dermatomyositis, and Phase 2 trials for cystic fibrosis and systemic lupus erythematosus.
With cannabinoid receptor type 2 being a critical component of resolution following inflammation, there could be “significant readthrough from one indication to the next,” according to H.C. Wainwright.

The Analyst

Analyst Andrew Fein initiated coverage of Corbus Pharmaceuticals with a Buy rating and $24 price target.

The Thesis

Although success in systemic sclerosis or dermatomyositis alone may be insufficient to lend upside to Corbus Pharmaceuticals’ shares, there is potential in lenabasum’s ability to address inflammation in cystic fibrosis, Fein said in the Wednesday initiation note.
Cystic fibrosis patients experience chronic inflammation that results in a decline in lung function, and the disease is strongly associated with more frequent pulmonary exacerbations and morbidity.
While Vertex Pharmaceuticals Incorporated VRTX 6.54%‘s triple therapies may make modulator therapy available for nearly 90 percent of those with a CF mutation, modulators of the cystic fibrosis transmembrane conductance regulator are unlikely to fully reverse the structural damage in CF patients, the analyst said.
A need exists for anti-inflammatory therapy in the cystic fibrosis space, Fein said, adding that addressing the resolution phase could offer a new approach. Lenabasum provides “the most advanced agent to target resolution,” he said.

NeuroMetrix Benefits From Alternative Pain Management Trend


NeuroMetrix Inc NURO 3.18% is a commercial-stage health care technology company with two products on the market: Quell, an OTC wearable device relying on neurostimulation technology for chronic pain relief; and DPNCheck, a point-of-care diabetic peripheral neuropathy test.
With $17.1 million in sales in 2017, NeuroMetrix’s market capitalization of approximately $5 million appears low, according to H.C. Wainwright.

The Analyst

Analyst Andrew Fein initiated coverage of NeuroMetrix with a Buy rating and $5 price target.

The Thesis

NeuroMetrix’s stock seems underappreciated, and any positivity from the company could lend upside to its share price, Fein said in the Wednesday initiation note. (See the analyst’s track record here.)
Quell 2.0, which was launched in the U.S. in September, could boost market adoption given that the new device is smarter, half the size of the original Quell device and runs on an improved app, the analyst said. Quell 2.0 is expected to be launched outside the U.S. in 2019 and beyond, he said.
NeuroMetrix is selling Quell 2.0 to the highest-profit margin channels of e-commerce, and the company’s gross margins could expand over the next couple of years, Fein said.
A regulatory environment that seeks to reduce new addictions through opioid use and increase the use of alternative pain management bodes well for Quell’s adoption, in H.C. Wainwright’s view.
NeuroMetrix’s commercial downside and financial risks “are limited by a number of partnerships,” Fein said.

6 Valuable Pipeline Drugs With Upcoming Catalysts


Heading into December, biotech stocks held up fairly well in 2018. Evaluate Pharma, a firm specializing in data-driven news and analysis in biotech, compiled a list of blockbuster drugs in the works with catalytic events expected sometime in 2019. Let’s dig in.

VX-659, Tezacaftor, Ivacaftor Triple Combo

Sponsor Company: Vertex Pharmaceuticals Incorporated VRTX 6.54%
Indication: Cystic fibrosis patients with one F508del mutation and one minimal function mutation, as well as patients with two F508del mutations.
Net Present Value: $14.4 billion
Current Status: data from two late-stage studies of this triple combo regimen released Nov. 27 showed improvement in lung function.
Catalyst: Potential NDA filing no later than mid-2019.
Vertex is also evaluating another triple combo regimen, namely VX-445, Tezacaftor and Ivacaftor, and said it will use the data readout from this combo due in Q1 and the results for the VX-659, Tezacaftor and Ivacaftor combo to decide which regimen should be submitted for potential regulatory approval.

Liso-cell/JCAR017

Sponsor Company: Celgene Corporation CELG 5.54%
Indication: A CD-19 protein-targeting CAR T-cell therapy developed for B-cell lymphoma and leukemia.
Net Present Value: $8.5 billion.
Current Status: Preliminary results of a Phase 1/2 study dubbed TRANSCEND CLL 004 that evaluated JCAR017 in heavily pretreated CLL/SLL patients were presented at the ASH 2018 meeting in December. The results showed an 81-percent response rate and “undetectable” minimal residual disease in patients with both high-and standard-risk disease who had previously received Imbruvica.
Catalyst: The trial moves to Phase 2 portion in 2019.

Semaglutide Oral

Sponsor Company: Novo Nordisk A/S NVO 2.41%
Indication: Oral GLP-1 agonist for type 2 diabetes.
Net Present Value: $7.6 billion
Current Status: Headline results from the last global Phase 3a trial, dubbed PIONEER 6, released Nov. 23 demonstrated cardiovascular safety as well as a significant reduction in both CV and all-cause mortality in people with Type 2 diabetes who are at high cardiovascular risk.
Catalyst: regulatory filing in the U.S. and EU in the first half of 2019.

Aducanumab

Sponsor Company: Biogen Inc BIIB 5.99%
Indication: mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease.
Net Present Value: $7.4 billion.
Current Status: the drug is being evaluated in two separate Phase 3 trials dubbed ENGAGE and EMERGE.
Catalyst: Phase 3 data due in late 2019/early 2020.
Aducanumab is an anti-beta-amyloid monoclonal antibody. Thirty six- and 48-month data from the ongoing long-term extension Phase 1b trial presented at a conference in late October showed the results were consistent with previously reported analysis of the study.

Efgartigimod/ARGX-113

Sponsor Company: argenx SE – ADR ARGX 5.2%
Indication: AGRX-113, or efgartigimod, is a first-in-class antibody fragment used to treat patients with severe autoimmune diseases associated with high level of pathogenic immunoglobin G antibodies. It is being evaluated for several indications such as multiple sclerosis, immune thrombocytopenia, myasthenia gravis, pemphigus vulgaris and chronic inflammatory demyelinating polyneuropathy.
Net Present Value: $6.5 billion.
Current Status: Detailed Phase 2 data for efgartigimod in patients with immune thrombocytopenia presented at the ASH 2018 conference in early December showed clinically meaningful improvements in platelet counts.
Catalyst: The immune thrombocytopenia program is likely to be advanced to a Phase 3 trial in 2019, and efgartigimod with a subcutaneous mode of administration is to be tested in a Phase 2 trial in 2019.

NKTR-214

Sponsor Company: Nektar Therapeutics NKTR 7.72%
Indication: Along with Bristol-Myers Squibb Co BMY 2.53%‘s Opdivo or Opdivo/Yervoy, NKTR-214, Nektar’s lead candidate, is evaluated in more than 20 indications across nine tumor types.
Net Present Value: $6.2 billion.
Current Status: New data from the PIVOT-02 Phase 1/2 presented at the 2018 Society for Immunotherapy of Cancer Annual Meeting showed NKTR-214 has the potential to lead to tumor clearance and tumor specific immunologic memory when combined with therapies with complementary mechanisms of action.
Catalyst: Further data from the PIVOT-02 study is expected in 2019.
NKTR-214 binds to the CD122 receptor on the surface of cancer-fighting immune cells in order to stimulate their proliferation.