Search This Blog

Sunday, January 20, 2019

Stress fracture? Your foot hitting pavement wasn’t the main problem


It starts as a persistent and irritating pain in the foot or lower leg, then it gets more intense, maybe with swelling, and soon a runner knows she’s being sidelined by one of the most common running injuries: a stress fracture. These tiny cracks in the bone can halt training for months or even end a sports season.
A segment of the multibillion-dollar wearables industry aims to save potential victims from this fate, but a Vanderbilt University engineering professor found a major problem: the devices are measuring the wrong thing.
Working with a local running club, an orthopedic specialist who advises the NFL Players Association and a team of Vanderbilt engineers, Assistant Professor of Mechanical Engineering Karl Zelik discovered that sensors only measuring the impact of the foot hitting pavement — which is what virtually all of them do — tell users little about the forces on bones that lead to stress fractures.
His research confirmed that the vast majority of force on the bone is actually from muscles contracting, not from the foot’s impact on the ground, a finding widely overlooked by both the wearables industry and many scientific studies.
Zelik’s research, appearing today in the peer-reviewed journal PLOS One and titled “Ground reaction force metrics are not strongly correlated with tibial bone load when running across speeds and slopes: Implications for science, sport and wearable tech,” offers the most clear and simple demonstration of the problems underlying the existing tools and prevailing methods for assessing bone stress and injury risk.
“We looked through the recent scientific literature, and we found that more than 50 scientific publications each year report or interpret their results based on this incorrect assumption that ground reaction force is representative of internal structure loading — the stress on bones and muscles inside the body,” said Zelik, a former college track and field standout. “Measuring ground reaction force may be convenient, but it’s the wrong signal.”
Wearable accelerometer and pressure sensors already on the market may help monitor bone stress injury risks, but only if they combine information about the ground reaction force and the force from muscles pulling against the bone. In general, you cannot assume that increases in ground reaction force indicate increases in bone stress, said Emily Matijevich, a mechanical engineering Ph.D. student in Zelik’s lab and herself an avid runner.
Matijevich performed the lab work that the study outlines, testing 10 runners over a range of speeds and slopes.
“We used high-speed, motion-capture cameras to track runners’ movement and a special force-measuring treadmill to record the ground reaction force under their feet,” she said. “We then combined these signals using biomechanical algorithms to estimate the compressive force experienced by the tibia bone in the shank, a common place for stress fractures to occur. In nearly all cases, we found that the ground reaction forces were not strongly correlated with tibial bone loading.”
In several cases, lower ground reaction forces actually meant more stress on the tibia, a finding opposite of what most athletes believe and counter to how most existing wearables work.
This research began two years ago, when Vanderbilt University Assistant Professor of Orthopaedics Leon Scott, who serves on the NFL Players Association’s health and safety committees, asked Zelik a simple question: Could wearable sensors be used effectively to prevent the stress fractures Scott saw in his clinic every day?
Matijevich, Zelik and Scott are now exploring new ways to monitor bone stress non-invasively, and recently filed a patent application for a system that fuses data from multiple wearable sensors to estimate tibia loading from both muscle contractions and ground reaction forces. They’re seeking commercial partners to develop this new wearable tech and explore applications to recreational runners, military cadets and elite athletes.
Scott said the combination of wearable sensors and new algorithms the team is developing gives a far better picture of bone stress, with the potential to help runners lower their chance of injuries.
“There’s only so much you can do when the game is going, because those are high-speed injuries, but we can do something about stress fractures during training and conditioning,” Scott said. “Right now, we don’t have great tools to tell us what’s happening to the bones other than experience and anecdote and these are, unfortunately, failing quite a few people.”
Story Source:
Materials provided by Vanderbilt University. Original written by Heidi Hall. Note: Content may be edited for style and length.
Posted by at No comments:

Brain cells that make pain unpleasant


If you step on a tack, neurons in your brain will register two things: that there’s a piercing physical sensation in your foot, and that it’s not pleasant. Now, a team of scientists at Stanford University has identified a bundle of brain cells in mice responsible for the latter — that is, the negative emotions of pain.
Pain research has traditionally focused on the neurons and molecules at the front line of pain perception — the cells in nerves that process stings, cuts, burns and the like — and ultimately convey a physical threat message. What Grégory Scherrer, PhD, assistant professor of anesthesiology and of neurosurgery, and Mark Schnitzer, PhD, associate professor of biology and of applied physics, are studying goes one step further. “We’re looking at what the brain makes of that information,” Scherrer said. “While painful stimuli are detected by nerves, this information doesn’t mean anything emotionally until it reaches the brain, so we set out to find the cells in the brain that are behind the unpleasantness of pain.”
Backed by animal-brain imaging and molecular testing, the researchers have found an ensemble of cells in the amygdala, a region of the brain classically associated with emotion and fear, that seems to specifically function as an on-off switch for pain aversion. And although the finding was made in mice, there’s reason to think it could one day serve as a therapeutic target for human pain, since the mouse and human amygdala aren’t so different in function. Researching this group of cells could reveal a potential treatment for chronic pain, the scientists hope.
The idea is that patients suffer from the emotional unpleasantness of pain, rather than pain sensation itself. If there’s a way to dull the emotional hurt, rather than the physical sensation of pain, that could be big for chronic pain patients.
A paper describing the results of the study will be published Jan. 18 in Science. Scherrer and Schnitzer, who is also a Howard Hughes Medical Institute investigator, share senior authorship. Postdoctoral scholar Gregory Corder, PhD and former postdoctoral scholar Biafra Ahanonu, PhD, are the co-lead authors.
Peeping at pain neurons
The amygdala seemed to the researchers a logical place to start, since it’s a well-established hub for emotion in the brain. Within the amygdala, they narrowed their search by looking for neurons in mice that were active during brief pain stimulation — such as a drop of hot, but not scalding, water applied to a paw. Neurons that are active express more of a specific gene called c-Fos, and indeed, a sea of c-Fos-expressing neurons flared after this stimulus.
“But that really only tells you that those neurons were active at some point, and it’s not specific enough,” Scherrer said. “What we wanted was to look at the neurons of freely moving animals.”
To observe the deep-seated wiring of a mouse’s brain, Scherrer partnered with Schnitzer, who had developed a “miniscope” — a microscope about the length of a small paper clip, which could be affixed to a mouse’s head to record activity in its brain. They positioned the device strategically to visualize the amygdala. The mouse, alive and well, could stroll as it pleased, while the miniscope recorded calcium flux in the neurons, a proxy for cell activity.
The scientists monitored the mouse brains with the microscope, watched the mice detect something uncomfortable, observed the aversive reactions and then checked which neurons were active. “With this setup, we identified a set of neurons in the amygdala that selectively encodes signals related to the emotional aspects of a painful experience,” Schnitzer said.
When the mice touched a drop of uncomfortably hot or cold water (neither of which were severe enough to injure the mice) they withdrew, signaling to the scientists that the rodents were not pleased. Upon this withdrawal, the microscope’s recording showed a bundle of neurons firing in the amygdala — specifically in the basolateral region — suggesting that these neurons were specifically responsible for the emotion of pain.
It was, however, still possible that this basolateral ensemble was simply firing to relay general emotion, rather than specifically the unpleasantness of pain. So, the researchers fed the mice sugar water — a sweet treat known to bring joy to any mouse — and kept an eye on the collection of neurons suspected to relay displeasure. As expected, those neurons stayed silent.
“There’s also a difference between experiencing pain and experiencing something annoying, so we further wanted to test if the amygdala neurons active during pain were also associated with overall negative emotion, rather than pain particularly,” Scherrer said.
What miffs a mouse? The same things that might bother a sibling: tiny puffs of air to the face, an unappetizingly bitter taste or a very bad smell. While bothering the mice, the researchers again monitored the basolateral amygdala pain ensemble, and here, too, the neurons remained subdued.
Tracking the perception of pain
“After all of that, we concluded that this ensemble of neurons selectively responds during pain,” Scherrer said. “But it still didn’t fully demonstrate that they underpinned the emotional response.”
To investigate that question more deeply, the researchers set up a walking track with three invisible lanes: On the far left was a cold strip, on the right, a hot one; and in between the two was a temperate middle ground. (For context, walking in the two outer lanes was comparable to briefly walking barefoot on pavement in the midst of winter or summer, respectively — uncomfortable, but not permanently damaging.)
Normal mice that walked on the track gradually learned that the middle lane was tolerable, while the outer two were unpleasant. But in a select group of mice, the researchers temporarily disabled the bundle of amygdala pain neurons thought to relay feelings of physical discomfort. These mice — free of pain-incited unpleasantness — skittered around the outer regions, undeterred by the extreme temperatures.
What’s intriguing about this, Scherrer said, was that these mice weren’t bereft of physical feeling. “Pain was just no longer unpleasant for them,” he said. The rodents could still feel and respond to physical sensations, but the stimuli they once perceived as unpleasant (hot or cold drops of water) were no longer bothersome. When exposed to a drop of hot water, for example, the mice with a muted basolateral neural ensemble would move their paw away from the dropper, signaling that they felt the stimulus — but they would move their paw back to its original position, something that normal mice did not do. This is a crucial part of harnessing the ensemble as a tool in pain therapy, Scherrer said, as an animal, or human, without the ability to physically feel anything at all leaves them vulnerable to injury.
Long term, Scherrer aims to confirm that the function of the basolateral ensemble in mice is the same as it is in people, and then down the line, find a safe and effective way to silence the ensemble’s function without interfering with other neurons.
“There’s really no good treatment for chronic pain in humans, and that’s a major driver of the opioid epidemic,” Scherrer said. “But you’ll notice, patients who take opioids for pain report that they can still feel the sensation of pain but say it’s less bothersome — the emotions of pain are different. Our big future hope is that the cells in the basolateral ensemble could be a tactic to curb the ailment of pain without causing addiction and thus, ideally, act as a possible substitute for opioid treatment.”
Other Stanford authors of the study are former Stanford postdoctoral scholar Benjamin Grewe, PhD; and research scientist Dong Wang, PhD.
The study was funded by the National Institutes of Health (grants R00DA031777, R01NS106301, K99DA043609, F32DA041029 and T32DA35165), the New York Stem Cell Foundation, the Rita Allen Foundation, the American Pain Society, the National Science Foundation, the Howard Hughes Medical Institute, the Bill and Melinda Gates Foundation and the Swiss National Science Foundation.
Story Source:
Materials provided by Stanford Medicine. Original written by Hanae Armitage. Note: Content may be edited for style and length.
Journal Reference:
  1. Gregory Corder, Biafra Ahanonu, Benjamin F. Grewe, Dong Wang, Mark J. Schnitzer, Grégory Scherrer. An amygdalar neural ensemble that encodes the unpleasantness of pain. Science, 2019 DOI: 10.1126/science.aap8586
Posted by at No comments:

Home-based hypertension program produces ‘striking’ results


Hypertension, or high blood pressure, is a widespread clinical problem affecting nearly half of all adults. Despite the serious consequences that can result from hypertension, which puts patients at increased risk for heart attacks, strokes and other cardiovascular events, elevated blood pressures often remain untreated or undertreated for years, and the control rate for hypertension hovers at just 50 percent. Seeing opportunities for improvement, innovators and clinicians at Brigham and Women’s Hospital have developed a new home-based, care-delivery program aimed to improve hypertension control rates quickly and at significantly lower cost than traditional, office-based blood pressure programs. The new approach, piloted among 130 participants, helped 81 percent of patients bring their blood pressures under control in, on average, just seven weeks. The results of the pilot study are published this week in Clinical Cardiology.
“This is a striking result, especially given the very short time frame in which control was reached: an average of seven weeks,” said corresponding author Naomi Fisher, MD, director of the Hypertension Service and Hypertension Specialty Clinic at the Brigham. “There are a few notable health care systems that have matched or exceeded this control rate, but most clinical practices do not approach this rate of success.”
To overcome some of the challenges that clinical practices face, Fisher and colleagues combined several innovative strategies to create their program. Enrolled participants each received a Bluetooth-enabled blood pressure device that could automatically transmit the blood pressure measurements patients took at home into their electronic medical records. Patients had easy and frequent access to “patient navigators” — non-physicians who had been trained to use a clinical algorithm developed by hypertension specialists. The program enabled rapid assessment and medication dosage adjustments for the patients.
The pilot was conducted as a prospective cohort study. The team enrolled 130 patients whose blood pressure was uncontrolled (greater than 140/90 mmHg). Patients were recruited from two clinics to test efficacy in two settings: a Brigham primary care clinic (800 Huntington Ave.), and the Brigham’s Watkins Cardiovascular Clinic. All adults were eligible except pregnant women and those with advanced kidney disease. Enrolled patients were given a Bluetooth-enabled blood pressure device and taught how to use it. Patients were instructed to measure their blood pressure at home twice daily in duplicate. Medication adjustments were made every two weeks until home blood pressure was controlled at <135/85 mmHg.
The team’s next step will be to scale up the program to test its generalizability and sustainability. With this approach, the team anticipates significant cost effectiveness and cost savings, in addition to the prevention of cardiovascular events and death from treating hypertension more intensively in men and women.
“The time-honored model of treating hypertension via traditional visits to the doctor is neither effective nor sustainable,” said Fisher. “Development of innovative solutions to manage hypertension effectively and efficiently, and thus reduce the cardiovascular risk burden in larger populations, is critical. Organizations can and should develop and adopt innovative technologies to create sustainable solutions for the control of hypertension.”
Story Source:
Materials provided by Brigham and Women’s Hospital. Note: Content may be edited for style and length.
Journal Reference:
  1. Naomi D.L. Fisher, Liliana E. Fera, Jacqueline R. Dunning, Sonali Desai, Lina Matta, Victoria Liquori, Jaclyn Pagliaro, Erika Pabo, Mary Merriam, Calum A. MacRae, Benjamin M. Scirica. Development of an entirely remote, non-physician led hypertension management program. Clinical Cardiology, 2019; DOI: 10.1002/clc.23141
Posted by at No comments:

How common virus reactivates after transplantation


A new study in Science challenges long-held theories of why a common virus — cytomegalovirus, or CMV — can reactivate and become a life-threatening infection in people with a compromised immune system, including blood cancer patients undergoing bone marrow transplantation.
The discovery, to be published in Science‘s Jan. 18 issue, used a newly developed mouse model and could pave the way for cheaper, safer therapies to protect patients from CMV.
“This is a big deal for the bone marrow transplantation field,” said Dr. Geoffrey Hill, the paper’s senior co-author and director of Hematopoietic Stem Cell Transplantation at Fred Hutchinson Cancer Research Center. “Our study shows for the first time that antibodies can play a dominant role in controlling CMV reactivation. This is turning dogma on its head.”
Previous research on CMV reactivation has focused on T cells, the celebrated disease fighters of the immune system. There had been occasional hints that antibodies produced by immune system B cells played some role against CMV, but it seemed to be a supporting role. Clinical trials using antibodies to fight the virus were disappointing, Hill said.
But Hill and his research team found that strain-specific antibodies made from B cells are responsible for keeping CMV suppressed in mice, without the need for any other immune cells.
A future therapy could work by collecting the CMV-thwarting antibodies from patients who have been exposed to the virus and who are undergoing bone marrow transplant. The antibodies would be purified and multiplied in the lab, then returned to the patient after transplant.
At Fred Hutch, Hill and colleagues are now pursuing clinical studies to test the approach.
“Most people don’t see any symptoms of the virus because their healthy immune systems keep CMV in check,” Hill said. “But it can roar back to life in anyone with a compromised immune system, and the results can be life-threatening.”
BACKGROUND
CMV, a type of herpes virus, infects at least half of adults by age 40. The virus can cause life-threatening complications such as pneumonia, hepatitis and gastroenteritis and has plagued allogenic transplant patients for decades. CMV infection is the most common complication of bone marrow transplantation. Just over 8,000 people in the United States received allogenic transplants in 2017 for blood cancers, including leukemias and lymphomas, and other blood disorders, according to the Center for International Blood & Marrow Transplant Research.
“Just having been exposed to the virus in the past predicts a worse outcome, despite new antiviral medications. It’s a major problem,” said Hill, who cares for patients at Seattle Cancer Care Alliance, the Hutch’s clinical care partner.
To find out the fuller story, Hill, who worked at the QIMR Berghofer Medical Research Institute until 2018, and Mariapia Degli-Esposti at the Lions Eye Institute in Perth, Australia, created the first animal model of CMV reactivation. They infected mice with CMV so that the animals experienced the primary infection followed by virus dormancy, as a person would. Three months later, the researchers gave the mice a bone marrow transplant, effectively wiping away their immune systems and replacing them with new donor marrow.
In a series of experiments looking at the roles of different types of immune cells, the team found that B cells played a critical role in controlling CMV. That is, transplanted mice that had no pre-existing B cells and thus lacked antibodies saw CMV spring back to life within 10 days of the transplant.
The group then looked into different strains of the virus, since CMV exists in many related but differing forms and can change over the course of infection. The researchers used eight different strains of CMV and found mice given the antibody from the same strain of the virus that they were exposed to previously were protected completely from CMV coming back.
Since earlier clinical trials had used antibodies from pooled sources, the strain-specific CMV protection had been hidden.
The National Health and Medical Council of Australia funded the study.
In addition to Hill and Degli-Esposti, co-authors of the paper are Jose Paulo Martins, Christopher E. Andoniou, Peter Fleming, Rachel D. Kuns, Iona S. Schuster, Valentina Voigt, Sheridan Daly, Antiopi Varelias and Siok-Keen Tey. The scientists involved in the discoveries could benefit financially from this work in the future.
Story Source:
Materials provided by Fred Hutchinson Cancer Research Center. Note: Content may be edited for style and length.
Journal Reference:
  1. Jose Paulo Martins, Christopher E. Andoniou, Peter Fleming, Rachel D. Kuns, Iona S. Schuster, Valentina Voigt, Sheridan Daly, Antiopi Varelias, Siok-Keen Tey, Mariapia A. Degli-Esposti, Geoffrey R. Hill. Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation. Science, 2019; 363 (6424): 288 DOI: 10.1126/science.aat0066
Posted by at No comments:

Merck And The Future of Immuno-Oncology: EVP Perlmutter


Cancer immunotherapy is, in a word, tantalizing. It might save the life of someone at death’s door and keep the cancer at bay for years. Or it might not work at all. There’s no telling what a patient will experience.
“There’s a real poverty of understanding of how the machine that is us works,” says Roger Perlmutter, the executive vice president of pharmaceutical giant Merck (NYSE: MRK) and the head of its research division, Merck Research Laboratories.
Perlmutter (pictured) lives this dilemma. He and his team shape Merck’s immunotherapy strategy and its sprawling network of trials, and pick which drugs to pair with the company’s flagship pembrolizumab (Keytruda). More than half of the 900 or so ongoing trials involving pembrolizumab combine the Merck drug with another treatment.
Since he left Amgen (NASDAQ: AMGN) to return to Merck in 2013, Perlmutter has seen pembrolizumab come to market and become the most lucrative cancer immunotherapy in the world. It is on track to generate more than $6 billion in sales in 2018, thanks to approvals in 10 different types of cancer, and has surpassed a rival drug from Bristol-Myers Squibb (NYSE: BMY) to become the standard of care, alongside chemotherapy, for a majority of people with advanced lung cancer. “The impact that it’s having on patients with advanced malignant diseases is remarkable,” Perlmutter says.
But Perlmutter is dealing with the same problem as the biopharma industry writ large. Immunotherapy, for all of its promise, works for only 20 to 30 percent of patients whose immune systems are revved up enough to wipe out their cancers. Merck is racing Bristol, Roche/Genentech, and others to learn why most patients don’t respond, and to boost their results by pairing the right drugs and technologies with immunotherapies like pembrolizumab.
The race has had its share of critics. In interviews with Xconomy, many oncologists have chided companies for moving too fast, running redundant studies, and launching trials of combination therapies with inadequate grasp of the effects the combinations might have in the body. Some high-profile failures have ensued, most notably last year’s Phase 3 flop in melanoma, which combined pembrolizumab and a so-called IDO inhibitor, epacadostat, from Incyte (NASDAQ: INCY). The ripple effects are still being felt.
To hear what might be next for the field and for Merck, Xconomy caught up with Perlmutter at the J.P. Morgan Healthcare Conference in San Francisco last week. The following conversation has been edited and condensed.
Xconomy: Why don’t most people respond to immunotherapy, and what is Merck doing to boost those response rates?
Roger Perlmutter: There are three explanations. The first is a cancer that no immune system can see, period. In that circumstance, you’re going to have to try alkylating agents [a type of chemotherapy] or other things to change the nature of the cancer so that it becomes more recognizable to the immune system.
The second is the tumor is recognizable by an immune system, just not the patient’s immune system. In that case, immunization might be helpful. We’ve embarked upon a strategy that says, what can we immunize with, and how can we identify patients who have those characteristics?
The third is a patient’s immune system can see the tumor, but for one reason or another, just [one type of immunotherapy] isn’t enough. There’s something else you need. A lot of focus has gone into that.
Xconomy: Given all the potential options, how do you focus?
RP: Anything that is pro-inflammatory is beneficial alongside Keytruda. That includes a lot of things that you wouldn’t think of, ordinarily, as being pro-inflammatory. Radiation therapy is pro-inflammatory, and you can see it work in combination. Traditional platinum-based cytotoxic chemotherapy is pro-inflammatory. While most people said, ‘Oh, you shouldn’t be giving these things together, because you’re going to suppress the immune system,’ the reality is the pro-inflammatory character wins out. I had a lot of people who said, ‘Why are you doing these chemo combos?’ Yet look at the results.
Surgery is also a pro-inflammatory stimulus, and that’s one reason the neo-adjuvant approach [as in, giving a patient Keytruda before surgery] has worked. I think we’ve made enormous progress in pursuing these different paths.
Xconomy: Several oncologists believe there isn’t enough basic research and too much spaghetti-against-the-wall when it comes to clinical trials for combinations. What is your response?
RP: The philosophical underpinnings of our approach have integrity. It’s not like we do everything. To those who are concerned that we’re just saying, “Oh, what the hell, let’s try anything, orange juice, mineral oil, whatever”—we are thinking this through very carefully. Among the literally hundreds of things we could do, we select just a few. Although we have more than 450 combination studies ongoing, it’s the product of a very thoughtful, precise selection.
Xconomy: What would help produce a more rationalized, refined approach?
RP: There are big gaps in our understanding of how Keytruda works. I would like a much more thorough molecular, cellular description of what happens in a cancer patient who responds to Keytruda. What are the T cells doing that are responsible for this good work? An understanding of those cells could be enormously helpful in getting better combinations with Keytruda. Thus far it’s an embarrassment to say—and I’m embarrassed for the entire scientific community—none of us have been able to achieve this.
X: What’s holding this back? A lack of available technologies?
RP: A little bit. But the clinical studies are hard to do. They’re prospective studies with multiple biopsies. Not every cancer patient is appropriate for that, and not everyone will give informed consent. Of course, you would like to compare [immunotherapy] to other therapies. But these days everybody says, ‘I’ll take the [immunotherapy], thank you very much.’ So it’s very hard to do a randomized study.
X: One of the most high-profile combination failures so far was the Phase 3 test of Keytruda and Incyte’s IDO inhibitor epacadostat in melanoma. What happened?
RP: IDO was pretty speculative to begin with. We did single-arm studies with our colleagues at Incyte, and if we squinted really hard, it looked like, gosh, those responses seemed a little bit broader and a little bit deeper [than with Keytruda alone]. Not changing night into day, but a little bit better. So we said, OK, let’s do a randomized, controlled clinical trial.
Incyte was so convinced they were going to see something, they wanted to do five [Phase 3 trials]. We said, let’s start with one. In essence, we found that the glimmer of hope [in the single-arm studies] was just a play of chance, which is so often the case. The IDO inhibitor really doesn’t have an effect. It was an important test to do, but I always had reservations, and that’s the reason I wasn’t willing to pile into six Phase 3 studies. After the first one, we changed another to a Phase 2 study and got rid of the others.
[Editor’s note: Incyte didn’t respond to requests for comment.]
X: Several of your peers have made big bets on CAR-T cell therapy [a cutting edge form of immunotherapy that uses live T cells, modified to find and kill cancer]. Bristol, for instance, just agreed to buy Celgene in part to bet on the future of CAR-T. Why hasn’t Merck jumped in?
RP: I love the CAR-T data in hematological malignancies. People’s lives have been saved, so that’s great. But to make this work, you’re going to have to treat solid tumors. And if you’re going to do solid tumors, you have to find a tumor-specific antigen to wipe out. Guess what? People have been looking for tumor-specific antigens for the last 50 years. We don’t have any.
The second problem is the industrialization of the process. Right now, with autologous transplant—we remove a blood sample from you, engineer it to kill your tumor cells, and in 14 days return the sample to you—the chain-of-custody issue becomes a big deal. Anybody who’s practiced medicine knows how often blood transfusions are mismatched. I hate to bet against American engineers, or any engineers for that matter, but the full-scale throughput for CAR-T is very small.
David Chang, who developed Yescarta [one of two FDA-approved CAR-T therapies] at Kite Pharma, and who used to work for me at Amgen, spent a lot of time talking to me about this. When Kite was acquired by Gilead [Sciences], the maximum throughput in their new facility was six patients a week. I’m not interested in treating six patients a week. I need to treat 100,000 patients. How am I going to do that?
The future for those kinds of therapies is tumor-specific antigens and allogeneic [‘off the shelf’] treatments, so you’ve got something in a bottle.
[Editors note: A Gilead spokeseman told Xconomy that its El Segundo, CA, manufacturing facility currently has the capacity, at full operation, to produce up to 4,000 CAR-T treatments per year, which would equate to as many as 77 per week.]
X: Are you waiting for some type of proof-of-concept from the allogeneic players before jumping into that business?
RP: Or for the improvement in bi-specific [antibodies], which we and others are doing. Those are good, too. The bi-specifics, in principle, could do everything that the cell-based therapies can do.
X: By comparison, you were in on mRNA technology early through a relationship with Moderna. [Messenger RNA, or mRNA, is an unproven drug-making method that aims to coax the body into producing its own disease-fighting proteins.] How do you think it will help you?
RP: We’ve known Moderna since before they started. Shortly after I returned to Merck in 2013, they said they’d found something surprising—in principle they could make any vaccine component just from the mRNA. We have a very big vaccine business, and I’m interested in improving it. Maybe we could use this to get at some things that are otherwise extremely hard to engineer—a common flu vaccine, for example, so you don’t have to make a new one every year based on what shows up in Hong Kong. Or a vaccine for respiratory syncytial virus, for which we’ve never been able to develop a satisfactory immunization regimen.
Also, it became clear that mRNA seemed like a natural way of immunizing patients [who might otherwise not respond to immunotherapy]. Keytruda doesn’t prime the immune system; mRNA would prime it.
X: Where do you see cancer care going in the near-term?
RP: You’re not going to see much monotherapy anymore, except perhaps in an adjuvant setting. In first-line [treatment of] lung cancer, which is obviously the biggest market, 70 percent of patients are [eligible for] Keytruda plus chemo, and it’ll be more later. My expectation is that Keytruda will be foundational in the treatment of the majority of malignancies, and the question will be Keytruda plus what? It’s going to be Keytruda plus X, where X is going to be a large set of different things, and it will be much more personalized, depending on the tumor type.
Posted by at No comments:

Data Back Benefits of Abbott Spinal Cord Stimulation for Chronic Pain


Abbott today announced positive results from a new multicenter study of the company’s BurstDR™ stimulation which showed that lower-energy, intermittent doses of BurstDR stimulation – known as ‘microdosing’ – can provide pain relief that is just as effective as standard doses of BurstDR stimulation in people with chronic intractable pain.
The BurstDR micrOdosing stimuLation in De-novo patients (BOLD) study, presented at the 22nd Annual North American Neuromodulation Society (NANS) meeting, shows a potential way to prolong the battery life of a patient’s spinal cord stimulation (SCS) device while offering optimal pain relief. The research may also provide a path toward ensuring lower-maintenance recharge-free SCS devices offer similar battery longevity as rechargeable SCS systems, which carry a higher burden for patients.
In a separate study called BURST(able), also presented at NANS 2019, data showed that patients who no longer received effective pain relief from their SCS therapy experienced restored pain control and reduced opioid dependency when they switched to an Abbott device offering the BurstDR waveform. Loss of pain relief is the most common cause for patients seeking an explant of their SCS system, and combatting this loss of efficacy addresses one of the key problems seen in long-term SCS therapy.
‘BurstDR stimulation has been used clinically now for many years and these latest data indicate that we’ve just scratched the surface of what’s possible,’ said Allen W. Burton, M.D., medical director of Abbott’s Chronic Pain Therapies. ‘Our goal is to continue studying BurstDR stimulation to maximize its potential, even at extremely low doses, and allow people with chronic pain to live their best lives without the burden of recharging their devices and the fear of losing efficacy over time.’
Approximately 1.5 billion people around the world are affected by chronic pain. SCS delivers a low-voltage electrical current through the spine to block the sensation of pain and offers an important alternative to opioid therapy. While traditional SCS systems produce therapeutic waveforms that are delivered at a consistent frequency and charge, Abbott’s unique BurstDR stimulation works differently from other stimulation devices, utilizing proprietary technology to produce intermittent pulses – or bursts – designed to mimic the body’s natural nerve impulse patterns. Abbott is the only company approved to offer BurstDR stimulation to patients in the U.S. and international markets.
Posted by at No comments:

Intuitive Surgical Is Likely to Post Another Strong Earnings Report


Shares of Intuitive Surgical (NASDAQ:ISRG) performed notably in 2018, even with the late-year market downturn. After being up more than 50% at one point, the stock ended the year sporting a 31% gain — a far cry from the S&P 500‘s 6% decline. This is testament to the company’s strong underlying performance.
The maker of the minimally invasive da Vinci Surgical System will have another opportunity to impress investors in the coming week, as Intuitive Surgical is scheduled to report its fourth-quarter and year-end results on Thursday, Jan. 24, after the market close. Let’s dive into the company’s recent results to find insight into what investors can expect.

Underlying performance was strong

For the third quarter, Intuitive generated revenue of $921 million, up 14% year over year, while adjusted earnings per share of $2.83 were up just 2%.
These numbers require context, however. The prior-year revenue got a boost of $21 million from deferred revenue related to trade-ins. Adjusting for that one-time event, revenue grew by 17%. Changes in the tax law resulted in a one-time benefit to prior-year earnings as well. Adjusting for these anomalies would have resulted in profitability that grew by 33%.
Additionally, the number of operating leases tripled. Revenue from the sale of a system is recorded immediately, while revenue from operating leases is recognized over the duration of the lease. Revenue growth appears lower over the short term, as a large part of the transaction is realized in future periods.
On the operational side, da Vinci procedures increased by 20% worldwide year over year, while system shipments hit 231, up 37%.

Preliminary earnings results

Intuitive released preliminary results for the fourth quarter last week, so there shouldn’t be too many surprises. The company reported estimated revenue of $1.047 billion, an increase of 17% year over year. The company didn’t provide profit metrics in its release.
Procedures increased by 19% year over year in the fourth quarter, and topped 1 million annually for the first time in 2018. And 290 da Vinci Surgical Systems were shipped during the quarter, up 34% versus the prior-year quarter.

Beyond the numbers

In September, the company submitted a pre-market notification to the Food and Drug Administration (FDA) for the Ion endoluminal system, its new flexible, robotic-assisted, catheter-based platform. The system is designed to navigate through very small passageways in the lungs to reach peripheral nodules for biopsies.
By submitting this notification, Intuitive is signaling that the device is “at least as safe and effective, that is, substantially equivalent, to a legally marketed device,” according to the FDA. This is a much less stringent process that applies to products using technology that has previously been approved in another device.
The Ion helps doctors more effectively diagnose lung cancer, by getting to areas of the lungs that were previously inaccessible. This will open up a whole new market for Intuitive Surgical, which is good news for investors.
The company also said that it obtained clearance from regulators in China for the da Vinci Xi Surgical System, and was advised that the China National Health Commission announced a new quota of 154 surgical robots through 2020, which includes the da Vinci.

What the market expects

While investors shouldn’t place too much emphasis on expectations, it can be a good way to gauge Wall Street’s overall feeling for a company. Analysts were expecting $1.03 billion in revenue, up 15.8% year over year, and adjusted EPS of $3.06, an increase of 20%. Intuitive’s preliminary revenue estimate already exceeds those expectations, which likely bodes well for the company.
Intuitive Surgical doesn’t provide quarterly guidance, and the release of the preliminary results removes much of the mystery. That said, the fourth quarter is typically a seasonally strong one for the company, and the numbers it provided in the preliminary release were likely conservative. There may still be some upside when it reports on Jan. 24.
Posted by at No comments:
Subscribe to: Posts (Atom)