Commercial-Stage Pharmaceutical Company Pioneering Novel Cancer Therapies
Sunday, October 9, 2022
Clover Provides Update on 2022 Corporate Milestones
Significant progress made on regulatory submissions to the China NMPA, the EMA, and the WHO for Clover’s lead COVID-19 vaccine candidate, SCB-2019 (CpG 1018/Alum), with completion anticipated in Q4 2022 --
-- New data demonstrating superiority as a heterologous booster compared to inactivated vaccine, robust neutralization of globally dominant Omicron BA.5 strain, and 84% reduction in transmission of SARS-CoV-2 infection to household contacts --
-- Clover poised to become a unique, integrated, vaccine-focused company with established China and global R&D, manufacturing and commercialization capabilities, and an innovative vaccine portfolio --
Merck KGaA says larger-scale acquisitions an option from 2023
German diversified healthcare and chemicals group Merck KGaA said it would begin to look into larger takeover deals next year.
"As of 2023, the Group will once again consider potential larger-scale acquisitions as an option," the company said in a statement ahead of an investor day on Thursday.
Weighted Blankets Promote Melatonin Release, May Improve Sleep
A weighted blanket of approximately 12% body weight used at bedtime prompted the release of higher concentrations of melatonin, as measured in the saliva, compared with a lighter blanket of only about 2.4% of body weight.
This suggests that weighted blankets may help promote sleep in patients suffering from insomnia, according to the results from the small, in-laboratory crossover study.
"Melatonin is produced by the pineal gland and plays an essential role in sleep timing," lead author Elisa Meth, PhD student, Uppsala University, Sweden, and colleagues observe.
"Using a weighted blanket increased melatonin concentration in saliva by about 30%," Meth added in a statement.
"Future studies should investigate whether the stimulatory effect on melatonin secretion remains when using a weighted blanket over more extended periods," the researchers observe, and caution that "it is also unclear whether the observed increase in melatonin is therapeutically relevant."
The study was published online October 3 in the Journal of Sleep Research.
Weighted blankets are commercially available at least in some countries in Scandinavia and Germany, as examples, and in general, they are sold for therapeutic purposes. And at least one study found that weighted blankets were an effective and safe intervention for insomnia in patients with major depressive disorder, bipolar disorder, generalized anxiety disorder, and attention deficit hyperactivity disorder (ADHD) and led to improvements in daytime symptoms and levels of activity.
Study Done in Healthy Volunteers
The study involved a total of 26 healthy volunteers, 15 men and 11 women, none of whom had any sleep issues. "The day before the first testing session, the participants visited the laboratory for an adaptation night," the authors observe. There were two experimental test nights, one in which the weighted blanket was used and the second during which the lighter blanket was used.
On the test nights, lights were dimmed between 9 PM and 11 PM and participants used a weighted blanket covering the extremities, abdomen, and chest 1 hour before and during 8 hours of sleep. As the authors explain, the filling of the weighted blanket consisted of honed glass pearls, combined with polyester wadding, which corresponded to 12.2% of participants' body weight.
"Saliva was collected every 20 minutes between 22:00 and 23:00," Meth and colleagues note. Participants' subjective sleepiness was also assessed every 20 minutes using the Karolinska Sleepiness Scale both before the hour that lights were turned off and the next morning.
"Sleep duration in each experimental night was recorded with the OURA ring," investigators explain.
The OURA ring is a commercial multisensor wearable device that measures physiological variables indicative of sleep. Investigators focused on total sleep duration as the primary outcome measure.
On average, salivary melatonin concentrations rose by about 5.8 pg/mL between 10 PM and 11 PM (P < .001), but the average increase in salivary melatonin concentrations was greater under weighted blanket conditions at 6.6 pg/mL compared with 5.0 pg/mL during the lighter blanket session (P = .011).
Oxytocin in turn rose by about 315 pg/mL initially, but this rise was only transient, and over time, no significant difference in oxytocin levels was observed between the two blanket conditions. There were also no differences in cortisol levels or the activity of the sympathetic nervous system between the weighted and light blanket sessions.
Importantly, as well, no significant differences were seen in the level of sleepiness between participants when either blanket was used nor was there a significant difference in total sleep duration.
"Our study cannot identify the underlying mechanism for the observed stimulatory effects of the weighted blanket on melatonin," the investigators caution.
However, one explanation could be that the pressure exerted by the weighted blanket activates cutaneous sensory afferent nerves, carrying information to the brain. The region where the sensory information is delivered stimulates oxytocinergic neurons that can promote calm and well-being and decrease fear, stress, and pain. In addition, these neurons also connect to the pineal gland to influence the release of melatonin, the authors explain.
Melatonin Often Viewed in the Wrong Context
Senior author Christian Benedict, PhD, associate professor of pharmacology, Uppsala University, Sweden, explained that some people think of melatonin in the wrong context.
In point of fact, "it's not a sleep-promoting hormone. It prepares your body and brain for the biological night...[and] sleep coincides with the biological night, but it's not like you take melatonin and you have a very nice uninterrupted slumber — this is not true," he told Medscape Medical News.
He also noted that certain groups respond to melatonin better than others. For example, children with attention deficit hyperactivity disorder (ADHD) may have some benefit from melatonin supplements, as may the elderly who can no longer produce sufficient amounts of melatonin and for whom supplements may help promote the timing of sleep.
However, the bottom line is that, even in those who do respond to melatonin supplements, they likely do so through a placebo effect that meta-analyses have shown plays a powerful role in promoting sleep.
Benedict also stressed that just because the body makes melatonin, itself, does not mean that melatonin supplements are necessarily "safe."
"We know melatonin has some impact on puberty — it may delay the onset of puberty — and we know that it can also impair blood glucose, so when people are eating and have a lot of melatonin on board, the melatonin will tell the pancreas to turn off insulin production, which can give rise to hyperglycemia," he said.
However, Benedict cautioned that weighted blankets don't come cheap. A quick Google search brings up examples that cost upwards of $350. "MDs can say try one if you can afford these blankets, but perhaps people can use several less costly blankets," he said. "But I definitely think if there are cheap options, why not?" he concluded.
Benedict has reported no relevant financial relationships.
J Sleep Res. Published online October, 3, 2022. Full text
Reddit Leads the Way for STD Information Seeking
Where do teens and young adults go to talk about sex, sexual health, and sexually transmitted diseases?
The obvious – routine medical checkups, hanging out with friends or partners – are possibly becoming less common than social media platforms for information and advice. And it appears that researchers and doctors alike are starting to pay close attention by meeting users where they are – both to observe and take part in real-time exchanges around sexual health topics that occur in more leveled, stigma-free playing fields.
For patients and doctors, it's a win-win situation, one that provides a chance to address and prevent the spread of STD misinformation and, at the same time, help to reverse skyrocketing rates of some of these infections in younger people.
Ina Park, MD, an STD doctor and professor of family and community medicine at the University of California, San Francisco, School of Medicine, says that almost all of her and her colleagues' patients – especially within a certain age range – are on social media.
"Many have had negative experiences when they've disclosed their sexual practices to their clinicians, when they felt that they were being judged for how many sexual partners they had, or [felt] that getting an STD meant getting punished for bad behavior" she says.
This is especially true of sexual minority youth (LGBTQ), whose clinical encounters are all too often marred by doctors who lack an understanding of gender identity issues, or by those who aren't comfortable discussing sexual health and STDs with their patients.
Perhaps this explains, at least in part, why platforms like Reddit and its smaller, moderated community forums, known as subreddits, are getting more popular. At last count, there were more than 3.4 million subreddits dedicated to specific topics, including the 'Ask Me Anything (AMA)' STD subreddit (r/STD), which does regular online question-and-answer sessions on sexual health and STDs among a community of 23,000 active users.
Discovering and Leveraging r/STD
In 2019, a group of researchers from the University of California, San Diego, did a small study to find out if people were getting medical diagnoses on social media platforms. They chose STDs as a case study, in part because these infections were getting more common.
"Our goal was to introduce the concept of crowd diagnosis, where you go to obtain a diagnosis on social media for a clinical outcome from your peers," explains John Ayers, PhD, vice chief of innovation in the Division of Infectious Diseases and Global Public Health at UCSD and one of the study's authors.
"When we looked at the data, we saw that 100s of people were going on Reddit and a large plurality were posting pictures, and asking for a diagnosis of sexually transmitted diseases," he says.
The team's findings were published later that year in JAMA and highlighted that 58% of roughly 17,000 posts were requests for a crowd diagnosis, 31% of which also included an image of physical signs of infection. Only 20% of posts asking for a crowd diagnosis were made to obtain a second option after receiving a diagnosis from a doctor.
Ayers says the main takeaway is that many doctors have a "field of dreams" perspective, "you know, if we build it, they will come. But they're not coming, so why don't we go and help them where they already are?"
He also explains that it's not enough to simply discover that a phenomenon exists (people going online to get a diagnosis), but that by discovering or revealing a problem (possible misinformation), doctors have a chance to intervene.
That is exactly what the American Sexual Health Association (ASHA) aimed to explore when it when it hopped onto an r/STD AMA forum armed with two experts – Park and a sexologist – and hosted a discussion about STDs. Their goal was to learn what types of information people were seeking, and ultimately drive sexually active people to seek testing through its Yes Means Test public awareness campaign.
The session generated 254 comments, and Park and her co-host addressed 42 questions, most commonly on STD transmission (24%) and STD testing (22%). Other common questions focused on sexual difficulties (15%) and sexuality (15%), although the AMA also included posts discussing contraception, partner communication, research, prevention, and treatment.
If scores and click-throughs indicate outcomes, then The ASHA AMA resulted in the best possible results. The session received a 5 out of 5 Reddit AMA score (the benchmark is 4), three community awards, and a click-through rate back to the ASHA site (and its STD testing campaign) of 45% (which surpassed the 10% Reddit benchmark).
Not All That Glitters Is Gold
Reddit AMAs don't come without risk, and it's best for those who want STD information to be aware of the pitfalls and red flags.
"One of the things to think about is that an approach like the subreddit adds to the false narrative that STDs in particular have to be symptomatic to be problematic, which we know is not the case," explains Dennis Li, an assistant professor of psychiatry and behavioral sciences, and sexual and gender minority health and well-being, at Northwestern Feinberg School of Medicine in Chicago.
"We also have to be careful not to misdiagnose and potentially cause harm," he says, emphasizing that many young people – especially those with equity issues – don't have experience in navigating health systems or reputable websites for information.
Ayers concurs.
"One of the outcomes in our study was people saying that they had a positive HIV test and were asked to come back and get a confirmatory test," he explains. "But then someone in the community said don't worry about it; you're OK."
So, "it's OK to seek out advice but look for confirmation of that advice," he says. "Make sure to follow [up] with a physician or go to a forum where you can actually engage with a physician."
Although she took part in the ASHA AMA session, Park has strong words of caution for people seeking advice on social platforms, especially when it comes to Reddit, which carries with it the baggage of hosting a lot of trolls.
"Reddit has the highest risk in terms of accepting advice because oftentimes, the person responding back to you is anonymous. They can say that their credentials are x, y, and z, but you really don't have any way of proving that" Park says.
"You don't know who's answering your question."
Personally, she says that she uses her real name, on the few Reddit forums she's taken part in as well as on her Instagram page, where she shares STD information.
Park also cautions users to avoid someone trying to sell something, as the information is, by nature, likely to be somewhat biased. Like Ayers, she recommends taking the information and verifying it before making health decisions.
Health Experts Call for New Prevention Strategies
In September, the CDC held the 2022 STD Prevention Conference, resulting in an Associated Press news report that warned of an out-of-control "STD situation" in the U.S. In addition to dire news about rising infection rates for STDs such as gonorrhea, the CDC also reported that 2021 syphilis cases reached a high not seen since 1948 and that HIV cases were likewise on the rise.
The key takeaway from this conference was that prevention is key, especially among at-risk populations like young people, men who have sex with men, Black and Hispanic Americans, Indigenous Americans, and women.
According to Li, testing should be the best outcome.
"What online resources can really help with is reducing stigma around testing, getting people comfortable asking questions to a medical or health care provider, and helping to bolster trust in the medical system – not just trusting that people are doing the right thing, but trust that you'll be taken care of in a way that respects you as a person," he says.
Li sees sites like Reddit as bridging the gap between doing things on one's own and knowing when to go to a qualified health professional.
But there may be a need for doctors to take the leap onto social media, if only to start following user accounts and learning what people are talking about.
By doing so, "we can minimize the harm," says Ayers.
Sources
Children: "LGBTQ+ Youth Health: An Unmet Need in Pediatrics."
Renolon: "How Many Subreddits Are There 2022? (Subreddit Statistics)."
Reddit: "'Ask Me Anything' series."
John Ayers, PhD, epidemiologist; vice chief of innovation, Division of Infectious Diseases and Global Public Health, associate professor of medicine, and affiliate scientist, Qualcomm Institute, University of California, San Diego.
JAMA: "Requests for Diagnoses of Sexually Transmitted Diseases on a Social Media Platform."
Ina Park, MD, associate professor, family and community medicine, University of California, San Francisco.
Dennis Li, assistant professor, psychiatry and behavioral sciences, Northwestern University Feinberg School of Medicine.
The Associated Press: "'Out of control' STD situation prompts call for changes."
Stdpreventionconference.com: "Virtually Possible: New Horizons in Sexual Health."
Long COVID could be linked to a totally different (and common) virus
A number of factors may increase the risk of someone developing long COVID, aside from catching COVID itself. They include having asthma, Type 2 diabetes, or autoimmune conditions, and being female.
Now researchers think prior exposure to another coronavirus—one that causes a common cold—may play a role in some patients.
In the new study by Harvard University–affiliated scientists, published Sept. 26 to Yale University–affiliated preprint server medRxiv, authors tested the blood of 43 patients who had arthritis or a similar condition before the pandemic.
Such patients who later developed long COVID showed evidence of an underwhelming antibody response to COVID—and of an overwhelming antibody response to OC43, one of several circulating coronaviruses that cause common colds.
The patients were likely infected with the cold at some point in their lives before they were infected with COVID, the authors theorize. When their bodies’ immune systems were exposed to the coronavirus SARS-CoV-2, which causes COVID, they responded with OC43 antibodies that, while similar, were less than ideal, leading to chronic inflammation and other long COVID symptoms.
Dr. Eric Topol, a professor of molecular medicine at Scripps Research and founder and director of the Scripps Research Translational Institute, said the new findings come in a “very interesting report that adds to the possible underpinnings of long COVID.”
Researchers have looked at prior infection with Epstein-Barr virus, a form of herpes that can cause mono, and other viruses as potentially contributing to the development of long COVID, Topol tweeted Sept. 26. But the new study is the first to look at the role a common cold might play.
There are thought to be multiple categories of long COVID with, perhaps, different triggers for each, aside from COVID. While prior infection with this common cold may play a role in arthritis patients with long COVID, it may or may not play a role in other categories of patients, the authors wrote.
But for arthritis patients in particular, the discovery could serve as a way to identify long COVID and potentially develop a treatment for it, they added.
Nearly 20% of American adults who’ve had COVID—an estimated 50 million Americans—report having long COVID symptoms after their infection resolves, according to data collected by the U.S. Census Bureau this summer.
Long COVID is roughly defined as symptoms that persist or appear long after the initial COVID infection is gone, but a consensus definition has not yet been broadly accepted.
Many experts contend that long COVID is best defined as a chronic-fatigue-syndrome-like condition that develops after COVID illness, similar to other post-viral syndromes like those that can occur after infection with herpes, Lyme disease, and even Ebola. Other post-COVID complications, like organ damage and post-intensive-care syndrome, should not be defined as long COVID, they say.
Coronaviruses, named for their crown-like appearance under a microscope, were discovered in the 1960s. Four types, including OC43, commonly circulate among humans, usually causing colds. Three additional coronaviruses involve more serious symptoms: MERS (Middle Eastern respiratory syndrome), which caused an epidemic in 2012; SARS (severe acute respiratory syndrome), which caused an epidemic in the early 2000s; and COVID.
Bold Effort to Cure HIV—Using Crispr
IN JULY, AN HIV-positive man became the first volunteer in a clinical trial aimed at using Crispr gene editing to snip the AIDS-causing virus out of his cells. For an hour, he was hooked up to an IV bag that pumped the experimental treatment directly into his bloodstream. The one-time infusion is designed to carry the gene-editing tools to the man’s infected cells to clear the virus.
Later this month, the volunteer will stop taking the antiretroviral drugs he’s been on to keep the virus at undetectable levels. Then, investigators will wait 12 weeks to see if the virus rebounds. If not, they’ll consider the experiment a success. “What we’re trying to do is return the cell to a near-normal state,” says Daniel Dornbusch, CEO of Excision BioTherapeutics, the San Francisco-based biotech company that’s running the trial.
HIV attacks immune cells in the body called CD4 cells and hijacks their machinery to make copies of itself. But some HIV-infected cells can go dormant—sometimes for years—and not actively produce new virus copies. These so-called reservoirs are a major barrier to curing HIV.
“HIV is a tough foe to fight because it’s able to insert itself into our own DNA, and it’s also able to become silent and reactivate at different points in a person’s life,” says Jonathan Li, a physician at Brigham and Women’s Hospital and HIV researcher at Harvard University who’s not involved with the Crispr trial. Figuring out how to target these reservoirs—and doing it without harming vital CD4 cells—has proven challenging, Li says.
While antiretroviral drugs can halt viral replication and clear the virus from the blood, they can’t reach these reservoirs, so people have to take medication every day for the rest of their lives. But Excision BioTherapeutics is hoping that Crispr will remove HIV for good.
Crispr is being used in several other studies to treat a handful of conditions that arise from genetic mutations. In those cases, scientists are using Crispr to edit peoples’ own cells. But for the HIV trial, Excision researchers are turning the gene-editing tool against the virus. The Crispr infusion contains gene-editing molecules that target two regions in the HIV genome important for viral replication. The virus can only reproduce if it’s fully intact, so Crispr disrupts that process by cutting out chunks of the genome.
In 2019, researchers at Temple University and the University of Nebraska found that using Crispr to delete those regions eliminated HIV from the genomes of rats and mice. A year later, the Temple group also showed that the approach safely removed viral DNA from macaques with SIV, the monkey version of HIV.
That was an important step toward testing the treatment in people, says Kamel Khalili, a professor of microbiology at Temple University who led the work and is a cofounder of Excision Biotherapeutics. “You don’t want to eliminate the viral genome but at the same time cause any disruption in another part of the human genome and then create another set of problems for the patients,” he says. “We had to make sure that we identified a region within HIV that did not overlap with the human genome.”
Dornbusch thinks this strategy will spare patients from serious side effects and “off-target” edits—unintentional cuts elsewhere in the genome that could cause problems such as cancer.
The regions targeted by the company’s Crispr therapy are also in a part of the genome that tends to stay the same even when HIV evolves. That’s important because the virus mutates rapidly, and the researchers don’t want a moving target.
This isn’t the first time scientists have tried to use gene editing in the hope of curing people with HIV, but other efforts have focused on a protective mutation in a gene called CCR5. In the 1990s, scientists found that people with this naturally occurring mutation didn’t get HIV when exposed to it. The mutation—known as delta 32—thwarts the virus’s ability to get inside immune cells. In 2009, California-based Sangamo Therapeutics used an older editing technology called zinc finger nucleases to add that protective mutation into patients’ T cells—an important part of the immune system. Those trials have had limited success.
In 2017, Chinese scientists combined Crispr with a bone marrow transplant in an attempt to cure a patient with HIV and leukemia. In a typical transplant, donor stem cells are transferred to a recipient to replace their cancerous blood cells. These cells go on to form new, healthy blood cells. To also address the patient’s HIV, researchers edited the donor stem cells with Crispr to disable CCR5. But after the transplant, only a small percentage of the patient’s bone marrow cells ended up with the desired edit.
Then in 2018, Chinese scientist He Jiankui used Crispr to edit the CCR5 mutation into the genomes of twin baby girls to make them resistant to HIV. Fraught with ethical violations, the experiment was widely condemned by scientists. He’s research was suspended by the Chinese government, and he served a three-year prison sentence. While the twins were born healthy, only some of their cells were successfully edited, meaning the girls might in fact not be immune to HIV.
As of 2022, two people have now been cured of HIV after receiving bone marrow transplants from donors with the CCR5. Known as the Berlin patient and the London patient, both had cancer and received transplants to treat their disease. But these transplants aren’t a viable option for most people—they’re highly risky, and donors with the delta 32 mutation are scarce. But a third person was declared cured of HIV earlier this year after she received a new type of transplant involving umbilical cord blood.
The Excision trial will eventually enroll nine participants and test three dosage amounts to determine which is most effective. Investigators will measure each person’s viral load and CD4 count before receiving the therapy and after they stop taking antiretroviral drugs. The ultimate goal is to get viral loads down to an undetectable level—that is, less than 200 copies of HIV per milliliter of blood. At this level, HIV can’t be passed on through sex.
The challenge for Excision will be getting Crispr to enough cells to bring HIV down to undetectable levels. The company is using an engineered virus to shuttle the gene-editing components to patients’ HIV-infected CD4 cells. But so far, there’s little human data on how well Crispr works when it’s delivered directly to the body. “It’s possible that you get the virus to such low levels that if a person’s immune system were intact, they might be able to keep the virus at bay such that they don’t have to take antiretroviral therapy anymore,” says Rowena Johnston, vice president and director of research for amfAR, the Foundation for AIDS Research.
And even though these drugs are very effective, Johnston says, many people would rather be completely free of the virus. A single Crispr infusion—if it works—would eliminate the need for daily pills. “People with HIV still live with a lot of stigma and internalized shame,” she says. “I think a cure is something that addresses that much better than lifelong therapy, regardless of how easy that therapy becomes.”
https://www.wired.com/story/a-bold-effort-to-cure-hiv-using-crispr/
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