Clinically Meaningful Improvements in Physician-Reported Outcomes Maintained Through Week 32
Consistent Efficacy Was Observed at Week 16 in Subgroups of Patients with BSA <5% and BSA >5% in the Phase 3 ADVANCE Trial
Supplemental New Drug Application for Otezla to Treat Adults with Mild-to-Moderate Plaque Psoriasis Currently Under Review by the U.S. Food and Drug Administration
https://finance.yahoo.com/news/otezla-apremilast-significantly-improved-measures-200000032.html
The United States should resume Johnson & Johnson Covid-19 vaccinations, an advisory committee to the Centers for Disease Control and Prevention recommended Friday, after an 11-day pause.
Panel members voted 10 to 4, with one abstention for a conflict of interest, to recommend lifting the pause on the vaccine, but advised adding a warning about the increased risk of very rare but severe blood clots.
"Today's presentations and discussions have convinced me that lifting the pause on J&J's vaccine is in the best public health interest of the U.S. population," said Dr. Henry Bernstein, a professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell in New York.
The group's recommendation is not binding; it will now go to CDC director Dr. Rochelle Walensky who will decide whether to formally accept it. Walensky told the "TODAY" show she expects to "make a decision quickly."
It is unclear when shots will resume. The Food and Drug Administration must also alter the language on the emergency use authorization for the Johnson & Johnson vaccine to reflect the potential risks.
The CDC and the Food and Drug Administration recommended the pause April 13, after receiving six reports of dangerous blood clots in the brain among the more than 7 million people who had received the Johnson & Johnson vaccination.
A day later, the CDC's advisory committee, called the Advisory Committee on Immunization Practices, met to review the available data on the cases and make a recommendation on how to proceed. Ultimately, however, the committee felt it didn't have enough information to make a recommendation at that time, and instead decided to reconvene this week.
Since then, new information has emerged, including reports of an additional nine confirmed cases, for a total of 15, Dr. Tom Shimabukuro, a member of the CDC's Covid-19 Vaccine Task Force, said during the meeting Friday. A handful of other possible cases are under review, he added.
Among the confirmed cases, three patients died, and seven others remain hospitalized.
All cases were in women, and all but two were in women ages 18 to 49. Seven were among women in their 30s, occurring at a rate of 11.8 per million doses of the Johnson & Johnson vaccine administered.
Still, "the last 11 days have been reassuring that we have not identified hundreds more cases despite enhanced awareness," Dr. Grace Lee, a professor of pediatrics at the Stanford University School of Medicine, said during Friday's meeting.
No medical conditions or medications linked the cases, including obesity or use of birth control pills.
While it is true that some birth control pills carry an increased risk for blood clots, Dr. Helen Talbot, an associate professor of medicine at Vanderbilt University in Nashville, Tennessee, pointed out the risks are very different. "My major concern about talking about this is that people are confusing the risks of this adverse event with those of oral contraceptives," adding that the types of clots are very different, as the treatments.
The CDC is calling the extremely rare combination of blood clots and low platelet counts "thrombosis with thrombocytopenia syndrome," or TTS. (Platelets are components in the blood that cause clotting; it's unusual to have blood clots and low platelets at the same time.)
Symptoms generally began at least six days following administration of the Johnson & Johnson vaccine, usually with headaches, chills, fever, nausea, weakness and stomach pain.
As the syndrome progresses, headaches tend to become much worse, sometimes combined with neck pain or stiffness. Others reported difficulty speaking or seeing clearly. Loss of consciousness and seizures were also listed as complications.
During the meeting, Dr. Joanne Waldstreicher, chief medical officer for Johnson & Johnson, shared language from a potential warning label, which reads in part that recipients of the shot "should be instructed to seek immediate medical attention if they develop shortness of breath, chest pain, leg swelling, persistent abdominal pain," as well as neurological symptoms, such as blurred vision or severe and ongoing headaches.
Of particular concern is how the condition must be treated. The standard treatment, a blood thinner called heparin, should not be used for these particular cases.
Rarely, the anticoagulant works in the opposite way, actually triggering platelets to start clotting. That mirrors the clots linked to the Johnson & Johnson vaccine. Doctors suspect heparin could worsen the condition, though none of the women who died had been given heparin.
Instead, non-heparin anticoagulants should be used, and in some cases, a therapy called intravenous immunoglobulin, Dr. Michael Streiff, medical director of the Johns Hopkins anticoagulation management service, said in a presentation during the meeting.
He also noted that educating both health care providers and patients that this syndrome exists — and what symptoms to look out for, such as severe headache or severe abdominal pain — can help improve outcomes.
"It's clear that it in some of the cases … they tried to treat their symptoms at home for a number of days before they presented, and when they presented, they were severely ill," he said.
Outside experts said they were pleased the committee recommended resuming the vaccines, even though the initial pause was "totally justified," Dr. Carlos del Rio, executive associate dean of the Emory University School of Medicine in Atlanta, wrote in an email. "When the committee first met on April 14 there were 6 cases, now there are 15. All in women."
Dr. Leana Wen, an emergency physician and former health commissioner for Baltimore, said "I think it makes sense to advise women under the age of 50 that this very rare condition could happen, and that if they are able to receive another vaccine, then they should do so."
But, Wen added, if another vaccine is unavailable, or if the recipient chooses not to get another vaccine, the Johnson & Johnson shot is "still a vaccine for which the extraordinary benefit outweighs the risks."
"For someone who is comfortable and says, 'it's a really low risk, and I'd like a shot that's one and done,' they will have that option," said Dr. Richard Besser, president of the Robert Wood Johnson Foundation and former acting director of the CDC. The Robert Wood Johnson Foundation owns stock in Johnson & Johnson, but operates independently of the company.
Besser added, "from a public health standpoint, maintaining this tool is extremely important."
The COVID-19 vaccine supply is outweighing demand in more than 1,000 U.S. counties, according to recent research from pharmacy discount company GoodRx.
As of April 19, 1,139 counties had COVID-19 vaccine appointments available at local CVS, Rite-Aid or Walmart pharmacies. That is a 30 percent increase compared to the appointment availability GoodRx recorded April 5.
From April 5-19, 415 more counties reported a surplus of COVID-19 vaccine appointments. During the same period, only 122 counties saw all their appointments get booked. Many counties in California, New York and Michigan experienced a surge in vaccine surplus during those two weeks, according to GoodRx.
To effectively curb the spread of the virus in the U.S., about 80 percent of Americans need to get vaccinated against COVID-19. The longer it takes to reach that level, the more likely it is that virus variants will evolve to dodge the immune response elicited by vaccines, according to the report.
https://www.beckershospitalreview.com/pharmacy/covid-19-vaccine-surplus-rose-by-30-in-2-weeks.html
The FDA and HHS are backtracking on previous plans to end regulatory review of 83 mobile health devices after determining the basis for the proposed plan was flawed.
On Jan. 15, HHS published a notice proposing to exempt the mobile health devices from the regulation requirement. The FDA said there is no evidence that HHS consulted with, involved or even notified the FDA before issuing the notice, an April 16 release said.
The January notice said that HHS felt that the lack of adverse events in unclassified medical devices determined regulation requirements were "no longer necessary to assure the safety and effectiveness of those devices."
Upon further review, HHS and the FDA determined the notice was published without scientific support, contained errors and ambiguities and was overall flawed.
HHS did not consult or notify the FDA before publishing the notice.
The FDA said: "It is particularly important that FDA have at least some level of involvement in this type of an action given the expertise needed in evaluating whether a submission under the [regulatory act] is necessary to assure the safety and effectiveness of a device."
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ZYNLONTA addresses an unmet need across a broad population of third-line (3L)+ r/r patients, including patients with DLBCL not otherwise specified, DLBCL arising from low grade lymphoma and high-grade B-cell lymphoma
ZYNLONTA demonstrated 48.3% overall response rate, 24.1% complete response rate and durable responses in heavily pretreated patients in pivotal LOTIS-2 trial
Investor conference call and webcast to be held Friday, April 23rd at 4 p.m. ET
ADC Therapeutics management will host a conference call and live audio webcast on Friday, April 23, 2021 at 4 p.m. ET. To access the live call, please dial (833) 303-1198 (domestic) or +1 914 987 7415 (international) and provide conference ID 6867157. The live webcast will be available under "Events & Presentations" in the Investors section of the ADC Therapeutics website at ir.adctherapeutics.com. The archived webcast will be available for 30 days following the call.
https://finance.yahoo.com/news/adc-therapeutics-announces-fda-approval-183800397.html
Michigan and other states that experienced springtime Covid-19 surges or faced worrisome transmission trends appear to have turned a corner, with drops in new cases in recent days as vaccines reach more people.
After hovering at stubbornly high levels or increasing over the past two months, average daily cases in Massachusetts, Minnesota, New Jersey, Illinois, and other states in the Midwest and Northeast have started to fall, providing a breath of relief that the communities are past their most recent peaks. Crucially, new infections in Michigan — which experienced the worst of the spring spikes, with some of its highest Covid-19 levels of the entire pandemic occurring in recent weeks — have started declining, with hospitalizations also starting to tick down.
Experts are cautious that the progress has just begun and needs to be sustained if the states want to actually achieve low levels of transmission. But they’re heartened that it appears vaccines are increasingly not just protecting individuals from Covid-19, but are starting to have broader benefits for communities.
“April’s been a bad month,” said Preeti Malani, an infectious disease physician at the University of Michigan. “There are hospitals across the state overwhelmed with patients. And because staff are sick, they’ve been having trouble with staffing their hospitals.” Different parts of the state remain under different levels of pressure, but now, with a big increase in vaccine availability in the past month, Malani said, “I’m optimistic about the direction we’re headed.”
At the national level, the country’s average daily infection count has also started to come down, from more than 70,000 in the middle of April to closer to 60,000 now. But summarizing the U.S. Covid-19 epidemic from that frame obscures how much variability there is. After experiencing a horrific surge over the winter, California now has one of the lowest rates of infections in the country, while cases in Puerto Rico have increased over the past month.
“We remain in a complicated stage,” Rochelle Walensky, the director of the Centers for Disease Control and Prevention, said at a briefing Monday. “On the one hand, more people in the United States are being vaccinated every single day at an accelerated pace. On the other hand, cases and hospitalizations are increasing in some areas of the country, and cases among young people who have not yet been vaccinated are also increasing.”
The progress in the United States stands in stark contrast to most of the rest of the world, which lacks anything close to the vaccine supply this country has. Persistently high cases in Europe and the Americas and huge spikes in Asia have driven global case counts to among the highest levels of the whole pandemic.
Trends can also be moving in the right direction when, in raw numbers, infections are still high. Cases may be coming down in Michigan, but they’re still higher than they were there at just about at any other point in the pandemic. National case counts in the 60,000 range as opposed to the, say, 20,000 range mean that many more people will suffer severe outcomes from the coronavirus. And while death counts have dropped dramatically from the more than 3,000 people taken daily in the United States in stretches of January and February, the progress has been stalled at more than 700 deaths per day. The hope is that if case counts continue to fall over the coming weeks, deaths will follow in turn.
Already, the rollout of vaccines has dramatically changed the dynamics of the U.S. epidemic. Hospitalization and death rates among older adults — the population with the highest immunization coverage — have plummeted, while hospitalizations among younger adults have also started to come down more recently. Whereas for the first year of the pandemic hospitalizations and deaths would follow case counts in predictable patterns, experts now speak of vaccines “decoupling” those metrics because they are so powerfully protective against the worst outcomes of the disease.
But the shots aren’t just protecting individuals. Increasing evidence shows that they take a substantial bite out of transmission once they’re given to a certain swath of the population, as countries like Israel that have vaccinated most of their populations have demonstrated. It’s not a specific threshold — it will vary place to place depending on other factors — but experts are hoping and anticipating that some places in the U.S. could be nearing that point, and drops in case counts could accelerate.
“I think that might be what’s happening in the Upper Midwest,” said infectious disease physician Monica Gandhi of UCSF.
Experts had expected that the vaccine rollout would suppress Covid-19 come this summer, to such low levels that many of the activities we’ve forsaken over the past year could be done relatively safely.
But there was an intermediate hurdle: In some states, cases started rising again this spring, as politicians eased restrictions and individuals grew more relaxed. More transmissible variants of the coronavirus pushed cases up or slowed progress — most notably B.1.1.7, which ignited major outbreaks in the United Kingdom (where it first emerged) and then in other European countries. Some recent transmission in New York and New Jersey also seems to have been driven by another variant, B.1.526.
The declining case counts in Michigan and other states suggest we may be back on track.
“I’m hopeful for that,” epidemiologist Stephen Kissler of Harvard’s T.H. Chan School of Public Health said about the U.S. dodging the full brunt of B.1.1.7. “I’m cautiously optimistic.”
One reason is that the weather got warmer, which appears to have an impact on transmission both for behavioral reasons (people spend more time outdoors) and perhaps for biological ones (many respiratory viruses lose some of their transmission efficiency in hotter, more humid temperatures). B.1.1.7-fueled spikes in the U.K. and Europe were exacerbated because they occurred over the colder months, for example.
The U.S. also had a big wall of natural immunity blunting just how widely the virus could spread this spring. Experts estimate that more than 100 million people in the country have recovered from an infection — the vast majority of whom remain protected against reinfection for now.
And then, of course, vaccines. More than half of adults in the U.S. have received at least one dose of a vaccine, and a full third of adults are fully vaccinated.
The factors that spur outbreaks or slow them — the weather, the number of susceptible people, the virus itself, the precautions people take — can compound or counteract each other, and the plateaued national case count in recent weeks is a reflection of an almost even tug-of-war. But it appears that the balance in more places appears to be tilting toward declines.
“Our optimism that the country as a whole has reached a clear turning point is further reinforced,” modelers at Children’s Hospital of Philadelphia’s PolicyLab wrote in their latest update on Wednesday. “This is great news for a Covid-weary nation, but we are mindful that the rates of improvement for some areas will be quicker than others.”
For all the progress achieved with vaccines, the U.S. is reaching the point where supply is outpacing demand in a growing number of communities. The average number of daily vaccines administered reached a peak of nearly 3.2 million earlier this month, but has since fallen to 2.8 million, even as all people 16 and up became eligible for the shots. It’s a matter of both access and hesitancy, and health officials at every level will increasingly have to reach people where they are or assuage their concerns to get more shots in arms. The University of Michigan’s Malani, for example, raised the concern that teens and young adults could drive outbreaks if they’re not incentivized to get vaccinated.
Experts still foresee a summer when vacations and barbecues return. The coronavirus won’t be gone from the United States, but at what level it circulates — and how much damage it inflicts — in large part depends on how many people in each area remain unvaccinated. (Most children still won’t be vaccinated this summer, but experts say that high levels of vaccine coverage among adults and lower transmission rates generally will reduce spread among children as well. Children overall are far less vulnerable to severe outcomes from Covid-19 than older adults, and appear to transmit the virus at lower levels.)
One trend experts will be keeping an eye on this summer is if there are echoes of summer 2020. While the warmer weather gives states in the northern part of the country some breathing room, last summer brought large outbreaks in places like Texas and Florida, where summer temperatures drive people into air-conditioned indoors. If there are large pockets of people who remain susceptible to Covid-19 in those places, they could potentially see a repeat increase in cases — if on a significantly smaller scale — this summer.
https://www.statnews.com/2021/04/23/states-springtime-covid-19-surges-turned-corner/
Scars. Like memories, we all have them. When you look at a scar you might see a tumble, a fight, an operation, a reminder of that time you succumbed to youthful stupidity, survived a traumatic incident, cheated death. But these marks aren’t just cosmetic keepsakes. Scar tissue is what happens when skin heals but it doesn’t regenerate. It’s not as strong, it can’t move as well, it can’t grow hair or secrete sweat or sense the environment.
And it has long been thought that scarring, like death and taxes, is an inevitable part of being human.
Now, researchers at Stanford University have decoded the chemical and physical signals that trigger a particular type of skin cell to produce scars. And they have discovered a way to reprogram these cells, transforming them into another cell type capable of regenerating tissues intact. Mice that received this tweak healed from wounds with no scars, scientists reported Thursday in Science. The animals regrew hair, glands, and other critical structures. Their recovery was so complete that an image-classifying algorithm couldn’t tell the healed wound apart from the animals’ healthy, unmaimed skin.
The researchers say the next step is to try to achieve similar skin regeneration in larger, tighter-skinned animals, like pigs, that more closely resemble humans. They are optimistic that the finding could lead to readily available treatments, and the possibility of a scar-free future. They already have identified a drug candidate that has been on the market for two decades to treat certain eye conditions.
“This is really groundbreaking,” said Radhika Atit, a skin biologist at Case Western Reserve who studies skin development and was not involved in the research. “I had goosebumps reading the paper.”
Every year, an estimated 100 million patients acquire scars from surgery. Millions more suffer burns and minor injuries that also leave scars. So scarless wound healing has long been something of a holy grail for scientists, since it was first discovered in fetal lambs 50 years ago.
But accomplishing it involves meeting three critical requirements. First, you have to give skin back all its appendages. Though it might not look like much, skin has a lot going on beneath the surface — follicles for growing hair, glands for secreting sweat and oil, nerves for sensing pain and pressure. Scar tissue doesn’t have any of these things. “It’s basically a hole that’s been plugged with a plaster of epidermis,” said Atit. “It’s just a living Band-Aid.”
When your skin is split or sliced open, you bleed. But pretty quickly, platelets in your blood grab onto the cut edges of the severed vessels, releasing signals to attract more platelets. The reinforcements glom together into a clot that staunches the flow. Immune cells start arriving to dispatch any bacteria or debris in the area. Cells called keratinocytes close the outermost edges of the wound. Then scraggly cells known as fibroblasts begin to fill it in, laying down thick layers of collagen.
In healthy skin, fibroblasts knit collagen fibers into a sort of disorderly basket-weave. That provides the tissue with structure, but it also lends skin tensile strength. So you can grab it and pull it and it doesn’t just shear open.
“You can think of fibroblasts as construction workers,” said Ryan Driskell, a cell biologist at Washington State University who studies skin regeneration and wound healing. “They create a house in which stem cells live, and stem cells give rise to all the other structures of the skin. The quality of the house will define the health of the stem cell.”
During wound healing, fibroblasts hastily lay down collagen fibers parallel to each other instead of cross-wise. The process builds up tissue quickly, but the bonds holding the fibers together are much weaker, resulting in skin that’s thicker but not as strong or flexible. And it doesn’t leave a lot of room for stem cells. For that, you have evolution to thank.
A hundred thousand years ago, healing slowly wasn’t an option. Early hominids didn’t have sterile solutions, stitches, and antibiotics. If you got cut up, the wound would get infected, making you easy prey for a big cat or other predator. Speed-healing was an evolutionary advantage. It didn’t have to be pretty. As long as you could survive and procreate, it gave you an edge.
Overcoming that legacy of natural selection means recreating the lattice-like structure of healthy skin, and the mechanical properties that come with it — the last two requirements for achieving scar-free wound healing, said Atit. The paper in Science nails all three.
The study represents a culmination of discoveries decades in the making. In 1971, a pediatric surgeon in Chicago discovered that when he operated on fetal lambs, their wounds healed without any scarring. Over the next 20 years, scientists found the same remarkable ability in other animals, including sheep, rats, mice, pigs, and monkeys.
In the early ’90s, Michael Longaker, whose lab at Stanford led the new research, was working as a postdoc under pediatric surgeon Michael Harrison at the University of California, San Francisco. Harrison was doing something no one else in the world was — performing surgeries on the unborn. He’d remove fetuses from their mother’s uterus, and, with the umbilical cord still intact, correct various life-threatening defects — patch a hole in the diaphragm, repair a blocked urinary tract — before returning them to the womb. When the babies were born 8 to 12 weeks later, they’d have a little bit of redness around the site of the surgery, but no scars. He asked Longaker to figure out why that might be. And that’s what he’s spent the last 30 years trying to do.
For much of that time, the field focused almost exclusively on stem cells, the cells that make all the skin’s mini-organs. “Fibroblast” was almost a dirty word back then. “The assumption was they were all the same,” said Driskell. And that all they did was cause scarring. But scientists like he and Atit set out to study them and discovered that not only were there lots of different kinds, but that they sent out signals to tell the stem cells where to make sweat glands and hair follicles. Longaker’s lab took that work and ran with it.
In 2015, his team at Stanford amassed an inventory of the different types of fibroblasts living in the skin of a mouse’s back. They found that only one subset of fibroblasts — dubbed EPFs, because they expressed a protein called engrailed-1 — was responsible for the formation of most scar tissue. When they knocked this cell line out, those mice recovered more slowly, with less scarring. The next thing to do was to figure out how those EPFs worked. If they could turn them off with a drug, they might be able to stop scarring in humans, too. For the last three and a half years, that’s what Longaker and his colleagues have been doing.
First, the researchers used fluorescent markers to trace where EPFs come from. They learned that the scar-producing cells actually arise from another population of fibroblasts that don’t produce engrailed-1, and instead regenerate healthy skin. It’s only when the animal gets wounded that the gene flips on. Longaker, a pediatric plastic surgeon who directs the program in regenerative medicine at Stanford, said the group hypothesized that the trigger might be mechanical — the force of the skin splitting apart.
“If I make an incision in a bowl of jello, it doesn’t gape open,” he said. Humans, on the other hand, are tight-skinned animals. Gashes and incisions leave flesh flapping — at least, once we leave the womb. In utero, our skin is gelatinous. It can secrete things and absorb things; it’s not yet watertight. “That fact pointed to mechanics,” said Longaker.
So the group studied how fibroblasts responded to a variety of different mechanical cues. When they were grown in soft substrates they didn’t flip on engrailed-1. The researchers also messed with the tension of wounds in mice and found the same thing. And they noticed that as they applied more tension, the fibroblasts produced more of a protein called YAP. They wondered if maybe it was the key chemical signal for kicking off scarring.
To test that, they blocked YAP a few different ways: first, by genetically modifying mice to not express it in their fibroblasts, and then, with a YAP-disrupting chemical called verteporfin. In both cases, the cells that flooded into each mouse’s wound weren’t the scar-producing EPFs, but the other kind of fibroblast, the one that tells the skin to regenerate, not just repair. “Discovering that YAP starts the fibrotic response, that was the last piece of the puzzle,” said Longaker.
Mice treated with the YAP-blocker not only grew back hair follicles and glands within 30 days, their new skin also recovered normal collagen structure. And when tested for mechanical breaking strength, it was comparable to normal skin.
Washington State’s Driskell sees the discovery as more of a beginning than the end. “If we want to get to full regeneration we have to understand how all these sub-populations of fibroblasts work together to rebuild the tissues properly,” he said. While Longaker’s group catalogued the return of some skin structures, it wasn’t a complete list. More work will need to be done to see if YAP-blockers can turn on all the signals needed to regrow everything healthy skin needs to function, such as temperature- and pressure-sensing nerves. “There’s always more to it,” said Driskell. “But I think it’s definitely worthwhile to move to the next step and try some clinical trials.”
Over the last decade, several companies have sought to commercialize wound-healing therapies — spray-on skins and living sheets of stem cells. But none has yet achieved scar-free healing. Verteporfin, if it works in humans, would be the first. It’s already on the market, sold under its brand name Visudyne. The U.S. Food and Drug Administration approved it in 2000 for treating age-related macular degeneration. That should make it easier to move from testing it in pigs to human trials.
Longaker envisions a time when doctors will be able to inject a bit of verteporfin around a laceration or incision as they stitch it up, encouraging the wound to repair itself slowly, carefully, and completely. That’s scar prevention. But Longaker said the drug might be able to erase old scars too. It would require some minor surgery to cut the damaged tissue out and inject the verteporfin in. But for particularly disfiguring or painful scars that limit people’s mobility, the procedure might be an attractive option.
It’s this future that got Atit so excited she began bombarding her children with fibroblast chat over breakfast this week. “I told them, ‘Guys, this means you will not have scars in your lifetime,’” she said.
Scars are more than just disfiguring. You lose sweat glands and nerves and other critical ways of sensing and responding to the world around you. “Right now the best we can offer people is little bits of skin, but there’s nothing in it — no hair follicles, no blood vessels, no nerve endings,” said Atit. “To be able to give people the ability to regenerate their own skin, which is where this is heading, it’s really just beyond exciting.”
https://www.statnews.com/2021/04/22/scientists-unlock-key-to-scar-free-skin-healing/
