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Saturday, October 12, 2019

Clovis Rubraca, trailing PARP rivals, nabs England coverage thanks to NICE U-tur

Already behind in the PARP inhibitor race, Clovis Oncology’s Rubraca has won a boost with reserved backing from England’s drug cost watchdog that helps level the playground in the U.K. region.
Rubraca will now be covered under the Cancer Drugs Fund (CDF) as a maintenance treatment to keep tumors from returning in women with relapsed ovarian, fallopian tube or peritoneal cancer that has responded to at least two rounds of platinum-based chemotherapy, the National Institute for Health and Care Excellence (NICE) said Friday.
The support comes after recommendations for the other two PARP inhibitors marketed in ovarian cancer, GlaxoSmtihKline’s Zejula for the same patient group and for AstraZeneca and Merck & Co.’s Lynparza in the limited BRCA-mutated population that has received one line of chemo. Both NICE backings are also through the CDF, which allows patients to apply for coverage before more clinical evidence supports a drug’s routine use on the NHS.
NICE originally rejected Rubraca due to cost-effectiveness concerns. In the Ariel3 trial, Rubraca stalled tumor progression for a median 10.8 months, significantly longer than the 5.4 months in the placebo arm. However, how much longer people live after taking the Clovis drug is not known—at the original data cut-off, 88% of patients were alive.
With that gold-standard survival data still not available, Clovis did what almost every company has done to win over NICE: offer up a discount.
After slashing Rubraca’s price from its list tag of £3,562.00 ($4,510) per 60-tablet pack, NICE now deems the drug worthy of CDF coverage while Clovis collects further data. “If this revised commercial arrangement is supported with long-term overall survival data, [Rubraca] has the potential to be a cost-effective use of NHS resources,” the agency said. It is estimated that around 1,350 patients in England could benefit from this new decision.

Now, small Clovis will need to go up against GSK and AstraZeneca in their home countries—and things are not looking in its favor right now.
All three drugs are eyeing the much larger first-line maintenance market. Lynparza already has that approval, but only in those who carry BRCA mutations. But at the recent European Society for Medical Oncology annual meeting, a pairing of Lynparza and Roche’s Avastin showed it could cut the risk of disease progression by 41% for all patients compared with Avastin alone.
GSK, touting its own data, showed Zejula alone could cut the risk of disease progression or death by 38% over placebo in the broad all-comer ovarian cancer population who’d responded to one round of chemo.
As for Rubraca, it won’t have front-line maintenance results until the phase 3 Athena study reads out in 2021. Industry watchers expressed concerns that the new Zejula and Lynparza data could spell trouble for Rubraca, which already lags in sales.
https://www.fiercepharma.com/marketing/trailing-parp-rivals-clovis-rubraca-nabs-england-coverage-thanks-to-nice-u-turn

The Real Science Behind ‘Anti-Aging’ Beauty Products

The beauty market abounds with high-end creams and serums that claim the use of stem cells to rejuvenate aging skin.
Selling on the internet and at department stores like Nordstrom, these products promise “breakthrough” applications to plump, smooth, and “reverse visible signs of aging,” and at least one product offers to create a “regenerative firming serum, moisturizer, and eye cream” from customers’ own stem cells – for a whopping $1200.
The beauty industry is heavily hyping glimmers of the nascent field of stem cell therapy.
Steeped in clinical-sounding terms like “proteins and peptides from pluripotent stem cells,” the marketing of these products evokes a dramatic restoration of youthfulness based on cutting-edge science. But the beauty industry is heavily hyping glimmers of the nascent field of stem cell therapy.  So what is real and what’s not? And is there in fact a way to harness the potential of stem cells in the service of beauty?
Plant vs. Human Stem Cells
Stem cells do indeed have tremendous promise for treating a wide range of diseases and conditions. The cells come from early-stage embryos or, more commonly, from umbilical cord blood or our own bodies.  Embryonic stem cells are considered the body’s “master” cells because they can develop into any of our several hundred cell types. Adult stem cells, on the other hand, reside in mature tissues and organs like the brain, bone marrow, and skin, and their versatility is more limited. As an internal repair system for many tissue types, they replenish sick, injured, and worn-out cells.
Nowadays, with some sophisticated chemical coaxing, adult stem cells can be returned to an embryonic-like blank state, with the ability to become any cell type that the body might need.
Beauty product manufacturers convey in their advertising that the rejuvenating power of these cells could hold the key to the fountain of youth. But there’s something the manufacturers don’t always tell you: their products do not typically use human stem cells.
“The whole concept of stem cells is intriguing to the public,” says Tamara Griffiths, a consultant dermatologist for the British Skin Foundation. “But what these products contain is plant stem cells and, more commonly, chemicals that have been derived from plant stem cells.”
The plant stem cells are cultured in the lab with special media to get them to produce signaling proteins and peptides, like cytokines and chemokines. These have been shown to be good for reducing inflammation and promoting healthy cell functioning, even if derived from plants. However, according to Griffiths, there are so many active ingredients in these products that it’s hard to say just what role each one of them plays. We do know that their ability to replenish human stem cells is extremely limited, and the effects of plant stem cells on human cells are unproven. 
“…any cosmetic that is advertised to be anti-aging due to plant stem cells at this time is about as effective as all the skin creams without stem cells.”
Whether products containing plant cell-derived ingredients work better than conventional skin products is unknown because these products are not regulated by the U.S. Food and Drug Administration and may rest on dubious, even more or less nonexistent, research. Cosmetics companies have conducted most of the research and the exact formulas they devise are considered proprietary information. They have no incentive to publish their research findings, and they don’t have to meet standards imposed by the FDA unless they start using human cells in their products.
“There are biological limits to what you can do with plant cells in the first place,” says Griffiths. “No plant stem cell is going to morph into a human skin cell no matter what magic medium you immerse it in. Nor is a plant cell likely to stimulate the production of human stem cells if applied to the skin.”
According to Sarah Baucus, a cell biologist, for any type of stem cell to be of any use whatsoever, the cells must be alive. The processing needed to incorporate living cells into any type of cream or serum would inevitably kill them, rendering them useless. The splashy marketing of these products suggests that results may be drastic, but none of these creams is likely to produce the kind of rejuvenating effect that would be on par with a facelift or several other surgical or dermatological procedures.
“Plant stem cell therapy needs to move in the right direction to implement its inherent potential in skin care,” researchers wrote in a 2017 paper in the journal Future Science OA. “This might happen in the next 20 years but any cosmetic that is advertised to be anti-aging due to plant stem cells at this time is about as effective as all the skin creams without stem cells.”
From Beauty Counter to Doctor’s Clinic
Where do you turn if you still want to harness the power of stem cells to reinvigorate the skin? Is there a legitimate treatment using human cells? The answer is possibly, but for that you have to switch from the Nordstrom cosmetics counter to a clinic with a lab, where plastic surgeons work with specialists who culture and manipulate living cells.
Plastic surgeons are experts in wound healing, a process in which stem cells play a prominent role. Doctors have long used the technique of taking fat from the body and injecting it into hollowed-out or depressed areas of the face to fill in injuries, correct wrinkles, and improve the face’s curvature. Lipotransfer, or the harvesting of body fat and injecting it into the face, has been around for many years in traditional plastic surgery clinics. In recent years, some plastic surgeons have started to cull stem cells from fat. One procedure that does just that is called cell-assisted lipotransfer, or CAL.
In CAL, adipose tissue, or fat, is harvested by liposuction, usually from the lower abdomen. Fat contains stem cells that can differentiate into several cell types, including skin, muscle, cartilage, and bone. Fat tissue has an especially stem cell-rich layer. These cells are then mixed with some regular fat, making in effect a very stem cell-rich fat solution, right in the doctor’s office. The process of manipulating the fat cells takes about 90 to 110 minutes, and then the solution is ready to be injected into the skin, to fill in the lips, the cheeks, and the nasolabial folds, or the deep folds around the nose and mouth.
Unlike regular fat, which is often injected into the face, some experts claim that the cell-enriched fat has better, longer-lasting results. The tissue graft grows its own blood vessels, an advantage that may lead to a more long-lasting graft – though the research is mixed, with some studies showing they do and other studies showing the complete opposite.
For almost all stem cell products on the market today in the U.S., it is not yet known whether they are safe or effective, despite how they are marketed.
One of the pioneers in CAL, a plastic surgeon in Brazil named Dr. Aris Sterodimas, says that the stem cells secrete growth factors that rejuvenate the skin — like the plant stem cells that are used in topical creams and serums. Except that these cells are human stem cells and hence have inherently more potential in the human body.
Note that CAL doesn’t actually result in large numbers of fresh, new replacement cells, as might be imagined. It’s simply fat tissue treated to make it richer in stem cells, to have more of the growth-inducing proteins and peptides delivered to the dermis layer of the skin.
Sterodimas works alongside a tissue engineer to provide CAL in his clinic. He uses it as a way to rebuild soft tissues in people disfigured by accidents or diseases, or who are suffering the after-effects of radiation treatments for cancer.
Plastic surgeons get plenty of these patients. But how widespread is CAL for beauty purposes? Sterodimas says that he regularly performs the procedure for Brazilians, and it’s widely available in Europe and Japan. In the U.S., the procedure hasn’t taken off because there is no FDA approval for the various methods used by different doctors and clinics. A few major academic centers in the U.S. offer the treatment on a clinical trials basis and there are several trials ongoing.
But there is a downside to all lipotransfers: the transplanted fat will eventually be absorbed by the body. Even the cell-enriched fat has a limited lifespan before reabsorption. That means if you like the cosmetic results of CAL, you’ll have to repeat the treatment about every two years to maintain the plumping, firming, and smoothing effects on the skin. The results of CAL are “superior to the results of laser treatments and other plastic surgery interventions, though the effect is not as dramatic as a facelift,” says Sterodimas.
Buyer Beware
For almost all stem cell products on the market today in the U.S., it is not yet known whether they are safe or effective, despite how they are marketed. There are around 700 clinics in the U.S. offering stem cell treatments and up to 20,000 people have received these therapies. However, the only FDA-approved stem cell treatments use cells from bone marrow or cord blood to treat cancers of the blood and bone marrow. Safety concerns have prompted the FDA to announce increased oversight of stem cell clinics. 
As for CAL, most of the clinical trials so far have been focused on using it for breast reconstruction after mastectomy, and results are mixed. Experts warn that the procedure has yet to be proven safe as well as effective. It’s important to remember that this newborn science is in the early stages of research.
One question that has also not been definitively settled is whether the transplanted stem cells may give rise to tumors — a risk that is ever-present any time stem cells are used. More research is required to assess the long-term safety and effectiveness of these treatments.
Given the lack of uniform industry standards, one can easily end up at a clinic that overpromises what it can deliver.
In the journal Plastic Reconstruction Surgery in 2014, Adrian McArdle and a team of Stanford University plastic surgeons examined the common claims of CAL’s “stem cell facelifts” being offered by clinics across the world. McArdle and his team write: “…the marketplace is characterized by direct-to-consumer corporate medicine strategies that are characterized by unsubstantiated, and sometimes fraudulent claims, that put our patients at risk.” Given the lack of uniform industry standards, one can easily end up at a clinic that overpromises what it can deliver.
But according to McArdle, further research on CAL, including clinical trials, is proceeding apace. It’s possible that as more research on the potential of stem cells accrues, many of the technical hurdles will be crossed.
If you decide to try CAL in a research or clinical setting, be forewarned. You will be taking part in a young science, with many unknown questions. However, the next time someone offers to sell you stem cells in a jar, you’ll know what you’re paying for.
The Real Science Behind “Anti-Aging” Beauty Products

Another reason to get cataract surgery: It can make you 48% safer on the road

The ability of cataract surgery to restore sight is well known. People say they’re stunned by the vibrancy of color after surgery and the improvement in night vision. Some can even reduce their reliance on glasses. But can you quantify that improved quality of vision? To find out, researchers in Australia used a driving simulator to test patients’ vision before and after cataract surgery. They found that near misses and crashes decreased by 48 percent after surgery. The researchers present their study today at AAO 2019, the 123rd Annual Meeting of the American Academy of Ophthalmology.
Cataracts are a normal consequence of aging. They happen gradually over years, as the clear lens inside the eye becomes cloudy. The effects of a developing cataract are sometimes hard to distinguish from other age-related vision changes. You may become more nearsighted; colors appear duller and glare from lights make it harder to see at night. By age 80, about half of us will have developed cataracts.
Cataract surgery replaces the cloudy lens with an artificial lens. The surgery is low-risk, fast and effective. But not everyone has surgery right away. The decision is usually based on how much the cataract is interfering with daily life activities. Ophthalmologists typically operate on one eye at a time, starting with the eye with the denser cataract. If surgery is successful and vision improves substantially, sometimes surgery in the second eye is forgone or delayed. However, most people get significant benefit from having surgery on the second eye. Depth perception is improved, vision is crisper, making reading and driving easier.
To better understand the true benefit of cataract surgery to patients’ quality of life, Jonathon Ng, MD, and his colleagues at the University of Western Australia, tested the driving performance of 44 patients before they had cataract surgery. The driving simulator assessed a variety of variables: adjusted speed limits, traffic densities, uncontrolled intersections and pedestrian crossings. Patients were put through the driving simulator again after their first
surgery and then again after their second eye surgery. After the first, near misses and crashes decreased by 35 percent; after the second surgery, the number fell to 48 percent.
While visual acuity – how well one sees the eye chart – is an important method to assess a person’s fitness to drive, it’s an incomplete assessment, Dr. Ng said. Quality of vision is also an important indicator. Improved contrast sensitivity and better night vision improves drivers’ safety on the road.
“In Australia and other countries, people may often wait months to receive government funded surgery after a cataract is diagnosed,” said Dr. Ng. “These results highlight the importance of timely cataract surgery in maintaining safety and continued mobility and independence in older adult drivers.”
Some things to consider, when considering cataract surgery:
  • Can you see to safety do your job and to drive?
  • Do you have problems reading or watching TV?
  • Is it difficult to cook, shop, climb stairs or take medications?
  • Do vision problems affect your independence?
  • Do bright lights make is harder to see?
https://www.eurekalert.org/pub_releases/2019-10/aaoo-art101119.php

More evidence linking common bladder med to vision-threatening eye condition

A drug widely prescribed for a bladder condition for decades, now appears to be toxic to the retina, the light sensing tissue at the back of the eye that allows us to see. After an initial report last year that Elmiron (pentosan polysulfate sodium) may be associated with retinal damage, three ophthalmologists conducted a review of patients at Kaiser Permanente in Northern California. They found that about one-quarter of patients with significant exposure to Elmiron showed definite signs of eye damage, and that this medication toxicity could masquerade as other known retinal conditions, such as age-related macular degeneration or pattern dystrophy. The research will be presented today at AAO 2019, the 123nd?Annual Meeting of the American Academy of Ophthalmology.
Interstitial cystitis causes chronic pain in the bladder and pelvis area. More than 1 million people in the United States, mostly women, are estimated to have the condition. Elmiron is the only FDA-approved pill to treat it. As a mainstay of treatment for decades, hundreds of thousands of people have likely been exposed to the drug.
Last year, Nieraj Jain, M.D., of Emory Eye Center in Atlanta, Ga., reported that six patients who had been taking Elmiron for about 15 years had developed unusual changes in their macula, the central part of the retina responsible for delivering clear, crisp, central vison. Because nothing in the patients’ medical history or diagnostic tests explained the subtle, but striking pattern of abnormalities, Dr. Jain and his colleagues raised a warning flag that long-term use of Elmiron may damage the retina.
Robin A. Vora, M.D , Amar P. Patel, M.D., and Ronald Melles M.D., ophthalmologists at Kaiser Permanente, heeded that warning and looked at their population of patients. They initially found one woman on long-term treatment who was misdiagnosed as having a retinal dystrophy. This worrisome case prompted them to examine Kaiser’s entire database of 4.3 million patients.
They found 140 patients who had taken an average of 5,000 pills each over the course of 15 years. Of those 140 patients, 91 agreed to come in for an exam. Drs. Vora, Patel, and Melles took detailed images of the back of their eyes and then divided the images into three categories: normal, possible abnormality, definite abnormality. Twenty-two of the 91 patients showed clear signs of drug toxicity. The rate of toxicity rose with the amount of drug consumed, from 11 percent of those taking 500 to 1,000 grams to 42 percent of those taking 1,500 grams or more.
“It’s unfortunate,” said Dr. Vora. “You have a patient with a chronic condition like interstitial cystitis, for which there is no cure and no effective treatment. They get put on these medications because it’s thought to have few side effects and few risks, and no one thinks about it again. And year after year, the number of pills they’re taking goes up and up.”
Because it’s unclear how much medication is too much, Dr. Vora recommends patients who show no signs of toxicity be screened for retina damage at least once a year. For those who do show some signs of damage, he recommends they speak with their urologist or ob/gyn about discontinuing the medication.
Good news is that if identified early, the damage may be mitigated by stopping the medication. In the late-stage, toxicity can mimic late-stage dry atrophic age-related macular degeneration and result in permanent vision loss.
https://www.eurekalert.org/pub_releases/2019-10/aaoo-mel100919.php

SmileDirectClub Has Given Back Most Its IPO-Driven Valuation Gain

Morning Markets: Today in “oh crud, that’s not recurring revenue!”
When SmileDirectClub was going public, things looked great for the at-home, teeth-straightening company. After raising over $400 million while private, SmileDirect’s IPO pricing cycle went terrifically. The company initially set a $19 to $22 per-share IPO price range before selling nearly 60 million shares at $23 apiece.

The new per-share price valued SmileDirectClub at around $8.9 billion. For the Nashville-based company, that new valuation was rich and welcome. By pricing where it did, SmileDirect raised over $1 billion with minimal dilution, at least compared to what it would have cost the firm to raise the same sum at its old valuation.
That prior valuation was a fraction of the firm’s IPO worth. Indeed, when SmileDirectClub last raised known private capital, back in October of 2018 (just one year ago), investors valued it at a smidge under $3.2 billion after counting the value of the $380 million infusion.
Given that the company managed to squeeze a 178 percent gain in value in under a year when it went public, perhaps we should have better forecasted what came next.
Namely this:
SDC Chart
As we reported at the time, SmileDirectClub’s shares were instantly spat out by the public markets, closing at $16.67 on their first day of trading, a 28 percent decline.
Today the company is worth just over $10 per share, off 55.5 percent from their IPO price ahead of trading today. That’s a stunning repudiation, bringing the company to a somewhat embarrassing private-public value inversion. SmileDirect is in danger of seeing its public valuation fall under its final private valuation:
  • Final SmileDirectClub private valuation: $3.18 billion.
  • Current SmileDirectClub public valuation: $3.94 billion.
It’s not there yet, but the value of SmileDirectClub today is a shadow of what it was when its bankers got its IPO put together. (Oddly, this result is an endorsement of sorts for the traditional method of determining the value of a company. If SmileDirect had been valued fairly, it would have raised far less capital in its debut.)
One last thing before we go. If you observe the above chart, there are two lines. The orange line corresponds to the far-right axis. It’s SmileDirect’s trailing price/sales ratio. More simply it gives us a good idea of how investors are valuing the company’s top line.
As you can see, early in its life as a public company, even down from its IPO price, SmileDirectClub was able to garner a double-digit revenue multiple. Calculated on a forward basis that metric would shrink some, but a better question is why the firm was valued at over 10x revenue to begin with?
In retrospect, SmileDirect has all the things that public-market investors seem tired of:
  • Dual-class share structure.
  • Scaling losses as the firm grew.
  • A recent sales and marketing expense boom.
  • Majority non-recurring revenue.
To its credit, SmileDirectClub had rapidly scaling revenue (from $175.1 million in H1 2018 to $373.5 million in H1 2019), and strong gross margins (around 78 percent in H1 2019). Those two highlights weren’t enough to sustain a nearly $9 billion valuation.
We’re keeping an eye on SmileDirect, and will report if it does dip below its final private price. Sadly the company doesn’t report earnings until November 12th, so we still have a while to wait for new numbers.
SmileDirectClub Has Given Back Most Its IPO-Driven Valuation Gain

Seniors’ Antidepressant Use Soars, Depression Rates Unchanged

The number of adults aged 65 years or older who take antidepressants more than doubled during the past 2 decades, despite little change in the number of seniors diagnosed with depression, new research shows.
With an increase in the use of antidepressants, it was hoped that the prevalence of depression would decline significantly, “but we haven’t observed that in our study,” lead author Antony Arthur, PhD, University of East Anglia, Norwich, United Kingdom, told Medscape Medical News.
The study was published online October 7 in the British Journal of Psychiatry.

Appropriate Prescribing?

Data for the analysis came from the Cognitive Function and Ageing Studies, conducted between 1991 and 1993 and between 2008 and 2011.
Researchers interviewed more than 15,000 adults aged 65 years or older in England and Wales to see whether the prevalence of depression and antidepressant use had changed.
They used a standardized interview process to determine the presence or absence of symptoms of depression and then applied diagnostic criteria to determine whether the participant had “case level” depression ― a level of depression more severe than that characterized by minor mood symptoms, such as loss of energy, interest, or enjoyment.
Between the two comparable groups of persons interviewed 20 years apart, the prevalence of depression fell only slightly ― from 7.9% in the earlier period to 6.8% in the later period. However, the proportion of adults taking antidepressants jumped from 4.2% in the early period to 10.7% 2 decades later.
The researchers say it is unclear whether the observed increases in treatment reflect overdiagnosis, better recognition and prescribing, or the prescribing of antidepressant medication for conditions other than depression.
Most of those who took antidepressants did not have a diagnosis of depression, and there are several possible explanations for this, Arthur said.
“Sometimes treatment is given for mild depression which falls outside of our definition of depression ― much of the evidence for the effectiveness of antidepressants is for people with moderate or severe depression. Antidepressants are also used to treat other conditions, for example, neuropathic pain and sleep disorders,” he said.
Owing to the nature of the study design ― cross-sectional analysis of two cohorts aged 65+ 20 years apart ― “we can’t infer that older patients are prescribed antidepressants unnecessarily,” Arthur said.
“But we shouldn’t be complacent,” he added. “Regular review is key to ensure that opportunities to deprescribe where it is safe and sensible to do so are not overlooked.”
On the other hand, some patients have depression but are not taking antidepressants.
“Health providers need to be vigilant with this group to discern whether it’s unrecognized depression that would be responsive to treatment,” said Arthur.

Questions Raised

“This study raises a number of questions that are not easy to answer due to the study design and lack of information about the past history of clinical depression,” Ramin Mojtabai, MD, PhD, MPH, professor in the Department of Mental Health at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, told Medscape Medical News.
His own research suggests that the prevalence of mood and anxiety disorders and symptoms has not decreased, despite substantial increases in the provision of treatment, particularly antidepressants.
That study, published in World Psychiatry in 2017, was based on depression prevalence and antidepressant use data from 1990 to 2015 in Australia, Canada, England, and the United States.
“The quality of antidepressant treatment in community settings remains problematic,” said Mojtabai. “Many patients continue on the same medication regimen, although they could benefit from medication adjustment (eg, dose increase, augmentation, switching to other mediations),” he commented.
The study was funded by grants from the Medical Research Council, the UK Department of Health, the Alzheimer’s Society, the National Institute for Health Research Clinical Research Network in West Anglia and Trent, and the Dementias and Neurodegenerative Disease Research Network in Newcastle. Arthur and Mojtabai have disclosed no relevant financial relationships.
Br J Psychiatry. Published online October 7, 2019. Abstract
https://www.medscape.com/viewarticle/919774

Can Anticoagulants Prevent Alzheimer’s?

Treatment with an oral anticoagulant delays memory decline and the conversion to Alzheimer disease (AD) in mice. The finding should spark future studies to see whether use of direct oral anticoagulants has therapeutic value in AD, investigators say.
Prior studies have shown that patients with AD tend to have poor cerebral circulation, and there is increasing evidence that AD is associated with a chronic procoagulant state.
In the new study, long-term anticoagulation therapy with dabigatran (Pradaxa, Boehringer Ingelheim) inhibited thrombin and abnormal deposition of fibrin in a mouse model of AD.
After receiving dabigatran for 1 year, the mice had no memory loss, and there was no reduction in cerebral circulation. Dabigatran also reduced typical AD symptoms, including cerebral inflammation, blood vessel injury, and amyloid protein plaques.
“Dr Alois Alzheimer already more than a century ago said that this disease was a disease of the blood vessels of the brain, and this was forgotten over many years,” co–senior investigator Valentin Fuster, MD, PhD, director of Mount Sinai Heart in New York City, told Medscape Medical News. “We began to study this with the most modern technology in a mouse model of Alzheimer’s that is very similar to humans.”
The study was published online October 7 in the Journal of the American College of Cardiology.

“Fascinating Finding”

Fuster’s co–senior investigator is Marta Cortes-Canteli, PhD, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Together with colleagues at the Rockefeller University in New York City and other centers, they tested the effects of dabigatran (60 mg/kg body weight over 24 hours on average) vs placebo on AD pathogenesis in a transgenic mouse model of AD (TgCRND8 AD mice) and their wild-type litter mates. The mice received dabigatran in their chow.
Treatment with dabigatran for 12 months prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the mice.
Dabigatran treatment also significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and the infiltration of T cells by 24%, 52%, 31%, and 32%, respectively. The drug also had beneficial effects on blood-brain barrier integrity.
“Frankly, it’s a very fascinating finding” and may help “redirect” research into the vascular aspect of AD, said Fuster.
“Therapeutics aimed at normalizing the prothrombotic environment present in AD, in combination with other disease-modifying compounds, might be instrumental in improving AD pathogenesis,” the researchers write.
“Of course, there is a significant distance between an animal model and a human, but the disease appears to be the same,” Fuster said. “The next step is to begin to understand this in humans through all the new technology that we have to assess the vessels of the brain and maybe to begin already to do some studies with anticoagulation in humans. We are meeting already to discuss it,” he added.

Many Unanswered Questions

Commenting on the findings for Medscape Medical News, Maria Carrillo, PhD, chief science officer for the Alzheimer’s Association, said there are many unanswered questions about the use of anticoagulants as a treatment for AD and that “it has possibilities and should be explored further.
“In the bigger picture, it is exciting to see a wide variety of new avenues for Alzheimer’s treatment being investigated more thoroughly,” Carrillo said.
One of the limitations of the use of anticoagulation for treating AD is the increased incidence of intracranial bleeding, which the authors acknowledge, Carrillo said. “While not evident in this study, not all anticoagulant drugs are the same. Plus, we know very little about the effect of long-term anticoagulation in a frail, aging, Alzheimer’s population,” she noted.
“At the same time, repurposing an already-approved drug like the one tested in this study ― where we already know something about safe doses and side effects ― can mean that it moves more quickly through the testing and approval process,” said Carrillo.
The study was funded in part by a proof-of-concept award from the Robertson Therapeutic Development Fund of the Rockefeller University and through grants from the National Institutes of Health. The authors and Carillo have disclosed no relevant financial relationships.
J Am Coll Cardiol. Published online October 7, 2019. Full text
https://www.medscape.com/viewarticle/919772