Pluristem Therapeutics (NASDAQ:PSTI)slumps 42% premarket in reaction to recommendation letter by the independent Data Monitoring Committee (DMC) of its global Phase III study for the treatment of critical limb ischemia (CLI).
The clinical dataset was reviewed for safety and analysis of the primary endpoint of amputation-free survival, defined as time to occurrence of major amputation of the index leg or death.
Based on the review, the DMC concluded that the CLI study is unlikely to meet the primary endpoint by the time of the final analysis.
Substantial low number of events in the placebo group in the CLI study decreased the statistical power of the study to meet its primary endpoint.
PLX-PAD was well tolerated and no significant safety concerns were raised during the study.
Following the DMC’s recommendation, the Company decided to terminate the CLI study to focus on different therapeutic areas.
Intec Pharma (NASDAQ:NTEC)entered into a feasibility agreement with London-based GW Research to explore using the Accordion Pill (AP) platform for an undisclosed research program.
The complete details of the agreement are undisclosed.
"Through partnerships such as this, we continue to evaluate the utility of our Accordion Pill platform in the development of innovative therapeutics," says Jeffrey A. Meckler, Vice Chairman and Chief Executive Officer of Intec Pharma.
Eli Lilly (NYSE:LLY)announces top-line results from SURPASS-1 monotherapy clinical trial evaluating the efficacy and safety of tirzepatide compared to placebo in adults with type 2 diabetes.
Treatment differences for two estimands – efficacy and treatment-regimen – were evaluated for the three tirzepatide doses (5 mg, 10 mg and 15 mg) compared to placebo.
Using the efficacy estimand, the highest dose of tirzepatide led to an A1C reduction of 2.07% and reduced body weight by 9.5 kg (11.0%).
51.7% of participants in this arm achieved an A1C less than 5.7% – the level seen in non-diabetic people, 87.9% of partticipants achieved A1C <7%.
In 10 and 5mg dose, A1C reduction was of 1.89% and 1.87%, respectively, with weight reduction of 7.8 and 7.0, respectively.
Percent of participants achieving A1C <5.7%: 30.5% (10 mg), 33.9% (5 mg) and 0.9% (placebo).
Percent of participants achieving A1C <7%: 91.5% (10 mg), 86.8% (5 mg) and 19.6% (placebo).
Study participants had a relatively short mean duration of diabetes of 4.7 years, a baseline A1C of 7.9% and a baseline weight of 85.9 kg.
The treatment-regimen estimand also led to statistically significant A1C and body weight reductions:
The overall safety profile of tirzepatide was similar to the GLP-1 receptor agonist class, with gastrointestinal side effects being the most commonly reported adverse events.
Treatment discontinuation rates were less than 7%.
The complete SURPASS-1 study data have not yet been evaluated but will be presented at the American Diabetes Association's 81st Scientific Sessions.
Six months ago, Apple and Google introduced a new smartphone tool designed to notify people who might have been exposed to the coronavirus, without disclosing any personal information. But for the most part, Americans haven't been all that interested.
Fewer than half of U.S. states and territories—18 in total—have made such technology widely available. And according to a data analysis by The Associated Press, the vast majority of Americans in such locations haven't activated the tool.
Data from 16 states, Guam and the District of Columbia shows that 8.1 million people had utilized the technology as of late November. That's about one in 14 of the 110 million residents in those regions.
In theory, such apps could bolster one of the most difficult tasks in pandemic control: Tracing the contacts of people infected with the coronavirus in order to test and isolate them if necessary. In practice, however, widespread COVID-19 misinformation, the complexity of the technology, overwhelmed health workers needed to quickly confirm a diagnosis, and a general lack of awareness have all presented obstacles, experts and users say.
"There's a lot of things working against it," said Jessica Vitak, an associate professor at the University of Maryland's College of Information Studies. "Unfortunately, in the U.S., COVID has been politicized far more than in any other country. I think that's affecting people's willingness to use tools to track it."
Charlotte, North Carolina, lawyer Evan Metaxatos was thrilled to learn in November about his state's tracking app, called SlowCOVIDNC. He immediately downloaded it and got his parents and pregnant wife to follow suit.
But they're still outliers in the state, which launched the app in September with little fanfare. Of roughly 10.5 million state residents, only 482,003 had installed it through the end of November.
"It won't work great until everyone's using it, but it's better than nothing," Metaxatos said.
Apple and Google co-created the primary technology behind such apps, which use Bluetooth wireless signals to anonymously detect when two phones have spent time in close proximity. If an app user tests positive for the virus, that person's phone can trigger a notification to other people they've spent time near—without revealing names, locations, or any other identifying information.
In states such as Colorado, Connecticut, Maryland and Washington, as well as Washington, D.C., iPhone users don't even have to download an app. In fact, Apple prompts users via pop-ups to activate the notification system by adjusting their phone settings.
North Carolina' s cell phone app contact tracing SlowCOVIDNC is shown on Friday, Dec. 4, 2020, in Charlotte, N.C. An analysis shows that few Americans are utilizing contact tracing technology launched in a host of U.S. states and territories. (AP Photo/Chris Carlson)
In these states, adoption rates are notably higher. But even in the most successful state, Connecticut, only about a fifth of all residents have opted into this tracking. On Friday, Washington said that more than 1 million state residents—roughly 13% of its population—had activated the technology in its first four days.
Virginia's COVIDWISE app launched on Aug. 5 and was the first to go live. Since then, fewer than one in ten residents have downloaded it, though the state estimates almost 20% of Virginians between the ages of 18 and 65 with a smartphone have done so. Delaware's app downloads account for about 7% of the state's population.
All other U.S. states analyzed have much lower adoption rates.
New York launched its app on Oct. 1. It recently surpassed 1 million downloads, which amounts to about 5% of the population. New Jersey and Pennsylvania have seen less use, with a 4% download rate.
Adoption is even lower in Wyoming, North Dakota, Michigan, Nevada and Alabama, with users representing only 1% to 3% of their state populations. The apps, which are free, can be found in Apple's app store and the Google Play store for Android devices; they're also typically available on state health-department websites.
Irish app developer NearForm says more than one-quarter of Ireland's population uses its COVID-19 app. It's been harder to get such traction in the four U.S. states where it's built similar apps: New York, New Jersey, Pennsylvania and Delaware.
In Ireland, "all sides of the political divide came together with a consistent message on this is what we need to do," said Larry Breen, NearForm's chief commercial officer. "That debate continues to rage on your side of the pond."
Elsewhere in Europe, the uptake has been mixed. Germany and Britain have penetration rates similar to Ireland's; in Finland the figure is 45%, according to data compiled by MIT Technology Review. In France, however, less than 4% of the population is using the official COVID app, which shuns the Apple-Google approach for a more intrusive data collection system that raised privacy concerns and technical issues.
Security experts praise the Apple-Google system for protecting users' anonymity, but it's been a tough sell for many people. American users say partisanship, privacy concerns and stigma surrounding COVID-19 have kept participation low. A lack of state and federal efforts to boost awareness hasn't helped.
Neither have technological and bureaucratic issues.
Lee McFarland, a loan officer from Grand Forks, North Dakota, was eager to download his state's Care19 Alert app but said he couldn't push a "Notify Others" button after getting the virus in late October.
"If you test positive, a public health official will call and verify your code," said a message on McFarland's app. "This ensures that only verified positive COVID-19 people can send notifications."
McFarland said he forgot to tell the health worker he had the app installed on his phone. He was unsuccessful in following up with the worker to get the needed code, and has since deleted the app.
Even when that process works, however, many North Dakotans don't actually push the button to notify others.
Tim Brookins, CEO of app developer ProudCrowd, said 91 of North Dakota's 14,000 active users had their "Notify Others" button enabled after the state confirmed them as positive. Of the 91 users, only 29 pushed the button, which prompted 50 notifications.
Still, many users say they'll keep the app in hopes others will see its potential benefits.
"You can say that about just about anything that not enough people are doing this or that, but everybody that does something is helping," said David Waechter, a general contractor from Lenoir, North Carolina. "I think that the United States could use a good strong dose of E pluribus unum and stop thinking about self and start thinking about our countrymen."
Three common antihistamine medications have been found in preliminary tests to inhibit infection of cells by the coronavirus that causes COVID-19, University of Florida Health researchers have found.
Their findings, based on laboratory tests of cells and a detailed analysis of nearly a quarter-million California patients' medical records, are published today in the journalBiochemical and Biophysical Research Communications. The data may support the launch of a randomized, controlled clinical trial to determine whether the specific antihistamines can treat or even prevent COVID-19 in humans, the researchers said.
Earlier this year, Leah Reznikov, Ph.D., an assistant professor of physiological sciences in the UF College of Veterinary Medicine and the study's principal investigator on the study, began collaborating with David A. Ostrov, Ph.D., an immunologist and associate professor in the UF College of Medicine's department of pathology, immunology and laboratory medicine. They and other colleagues set out to identify approved drugs that can interfere with the way the SARS-CoV-2 virus binds to cells. Blocking that connection essentially locks a cellular doorway that inhibits the virus's transmission to the respiratory system.
"We discovered epidemiological data showing that the usage of specific drugs was associated with a reduced likelihood of testing positive for SARS-CoV-2, the virus that causes COVID-19. We then found that these specific drugs exhibited direct antiviral activity against SARS-CoV-2 in the lab," Ostrov said.
While there is an association between the medications and infection rates, the researchers stressed there is much more to be learned and no cause and effect has been formally established.
"The fact that these drugs actually inhibit the virus in the lab does not necessarily mean that they will inhibit it actively in people—but they might," Ostrov said.
To establish their findings, the collaborators focused on angiotensin-converting enzyme-2, or ACE2, a "gateway" protein the virus uses to invade human cells. Working with a colleague at the University of California San Francisco, they analyzed medical records of nearly a quarter million California patients. People age 61 and older who had used certain antihistamines were less likely to test positive for the SARS-CoV-2 virus than those who did not take the medications, the researchers found.
Next, the researchers tested this group of antihistamines for their ability to inhibit the coronavirus in a combination of human and primate cells. Three of the drugs—hydroxyzine, diphenhydramine and azelastine—showed direct, statistically significant antiviral effects on the SARS-CoV-2 virus.
Hydroxyzine, sold as Atarax, and the nasal spray azelastine are prescription medications while diphenhydramine is sold over-the-counter as Benadryl, a treatment for cold and allergy symptoms.
The drugs were tested at different concentrations to measure how much is required to inhibit the virus.
While the findings are encouraging, Ostrov cautions against self-medicating with antihistamines as a COVID-19 prevention or treatment. So-called "off-label" use of medications should only take place after a detailed consultation with a physician, he said.
Among the three medications, azelastine was found to inhibit the SARS-CoV-2 virus at a dose that was smaller than the amount prescribed as a nasal spray. The other two antihistamines required higher drug concentrations than currently recommended dosing levels to achieve antiviral activity in cells. That doesn't make diphenhydramine any less of a potential COVID-19 therapy for now, especially considering its ubiquity and over-the-counter status, Ostrov said. Clinical trials will be necessary to establish the drugs' effectiveness in prevention, early treatment and as a secondary therapy for severe COVID-19.
Reznikov said the data suggest these three antihistamines may work by either disrupting the virus's interactions with ACE2 or by binding with another protein that may interfere with viral replication. The protein, known as a sigma receptor, is part of a cell's communications network.
Reznikov approached Ostrov in March with a hypothesis and an idea: Drugs that bind ACE2 could change disease outcomes, so she asked Ostrov to develop a list of small-molecule drug candidates.
She then pursued a strategy to screen the drugs against virus isolates of SARS-CoV-2 with Michael Norris, Ph.D., an assistant research professor of medical geography in the department of geography and the UF Emerging Pathogens Institute. In May, Reznikov was included in the UF Clinical and Translational Science Institute's Rapid-Response Translational Research Funding initiative to facilitate this project.
Although the findings are intriguing, Reznikov and Ostrov note there is still much to be learned about the mechanisms of how antihistamines interact with the SARS-CoV-2 virus.
Because of the urgency of the COVID-19 pandemic, Ostrov said there is a possibility that the antihistamine candidates could go directly to human clinical trials without first being tested in animal models. That is the case with famotidine, an antihistamine and antacid that is undergoing clinical trials elsewhere as a therapy for severely ill COVID-19 patients.
More information:Leah R. Reznikov et al. Identification of antiviral antihistamines for COVID-19 repurposing,Biochemical and Biophysical Research Communications(2020).DOI: 10.1016/j.bbrc.2020.11.095
Melanie Ott co-led a study with researchers from Gladstone, the Chan Zuckerberg Biohub, UC San Francisco, and Synthego Corporation that points toward ways to treat not only COVID-19, but future coronaviruses that might emerge. Credit: Gladstone Institutes
When a coronavirus—including SARS-CoV-2, which causes COVID-19—infects someone, it hijacks the person's cells, co-opting their molecular machinery for its own survival and spread. Researchers at Gladstone Institutes and the Chan Zuckerberg Biohub, in collaboration with scientists at UC San Francisco (UCSF) and Synthego Corporation, have identified critical molecular processes in human cells that coronaviruses use to survive.
They report, in a study published in the journal Cell, that targeting these processes with drugs may treat not only COVID-19 infections, but other existing and future coronaviruses.
"What is unique about our study is that we didn't just look at SARS-CoV-2, but other coronaviruses at the same time," says one of the leaders of the study, Melanie Ott, MD, Ph.D., director of the Gladstone Institute of Virology. "This gives us a good idea of drug targets that could broadly suppress many coronaviruses."
A large family of viruses, coronaviruses include common cold viruses as well as more severe viruses. The SARS-CoV virus that caused a deadly SARS epidemic in 2002 was a coronavirus, as is the MERS virus, which has caused outbreaks in the Middle East.
"There have now been multiple coronavirus outbreaks, so it's clear this virus family has high pandemic potential," says Andreas Puschnik, Ph.D., a principal investigator at the Chan Zuckerberg Biohub and the other leader of the study. "COVID-19 is not the last coronavirus infection we'll be dealing with."
Comparing and Contrasting Coronaviruses
Like all viruses, coronaviruses can only grow inside host cells; they rely on the host cell's molecules to multiply. Because of this, the team of researchers want to target human molecules that the viruses use to survive, rather than components of viruses themselves.
In the new study, they infected human cells with either SARS-CoV-2 or two other coronaviruses that cause common colds—and all three viruses killed the cells. Next, the team of researchers mutated the cells using CRISPR-Cas9 gene-editing technology and studied which mutations made the cells less vulnerable to the coronaviruses.
"We reasoned that the few cells that could survive these infections presumably had mutations in host molecules that the viruses use to infect them or to multiply," explains Puschnik.
Some results were not surprising. For instance, the human ACE2 receptor is known to be required by SARS-CoV-2 to enter human cells. So, cells with a mutation in the ACE2 gene were no longer infected or killed by SARS-CoV2.
But other findings were less expected. The researchers found that certain genetic mutations prevented all three coronaviruses from successfully infecting and killing the cells. These were mutations in genes known to control the balance of two types of lipid molecules in human cells, namely cholesterol and phosphatidylinositol phosphate (PIP).
Cholesterol is needed for some viruses to enter cells, but it hadn't been studied in the context of coronaviruses when this study started. Similarly, PIP is known to play a role in forming the small vesicles that viruses often use to travel into and around cells, but it had not been directly linked to SARS-CoV-2 before.
A Pathway toward Therapeutics
To verify the importance of the cholesterol and PIP genes for coronavirus infection, the researchers engineered human cells that lack these genes completely and infected them with the virus. Cells lacking the genes were protected from infection by all three coronaviruses. Similarly, when the team used existing compounds to disrupt the balance of PIP or cholesterol, the cells were less susceptible to infection by any of the viruses.
These results suggest that targeting cholesterol or PIP could be a promising strategy to combat multiple coronaviruses.
"For viruses, the traditional view has been that we design drugs against unique viral targets, and that means it takes time to develop a drug each time there's a new virus," says Ott, who is also a professor in the Department of Medicine at UCSF. "If we could develop a few broader antiviral drugs that target host cells' molecules, that would go a long way toward making us better prepared for future pandemic viruses."
Not all results were the same between the three studied viruses, however. Some human molecules required for SARS-CoV-2 infection weren't needed by the two common cold coronaviruses, and vice versa. These findings could help explain what makes SARS-CoV-2 more deadly than the other two viruses.
More work is needed to test the effectiveness of drugs targeting PIP and cholesterol, and whether they can effectively stop viral growth without causing dangerous side effects. The team would also like to repeat the screens using other coronaviruses—including the first SARS-CoV and MERS viruses—to determine just how universal the new targets they pinpointed are.
Ott and Puschnik agree that the current study was made possible by researchers from many labs coming together without hesitation. Puschnik has expertise in studying viral host factors, but didn't have access to a Biosafety Level 3 (BSL-3) lab required to work with SARS-CoV-2. Ott was spearheading Gladstone's effort to open such a lab earlier this year and offered to collaborate. Scientists at Synthego provided the engineered cells needed to study the viruses, and Gladstone Senior Investigator Nevan Krogan, Ph.D., helped analyze the results of the CRISPR-Cas9 screen.
"Everybody was completely willing to roll up their sleeves, pool resources, and work together to help contribute to better understanding COVID-19," says Puschnik.
The paper "Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses," was published online by the journal Cell on December 8, 2020.
Ultragenyx Pharmaceutical Inc. (RARE), announcing the data from the Phase 1/2 study of GTX-102 in Angelman syndrome, says the additional data, including EEG findings, support prior initial indications of activity with no new adverse events.
In August 2019, Ultragenyx partnered with GeneTx Biotherapeutics to develop GTX-102, with an exclusive option to acquire GeneTx.
“We better understand the serious adverse events reported with GTX-102 at higher doses and we see a way forward to redose patients and to enroll new patients into the clinical trial,” commented Scott Stromatt, M.D., Chief Medical Officer of GeneTx.
The study is currently on hold, and with the receipt of guidance and approval from the FDA, the companies intend to resume the enrollment and dosing as soon as possible.
Angelman syndrome, a rare neurogenetic disorder due to loss-of-function of the maternally inherited allele of the UBE3A gene, affects 1 in 12,000 to 1 in 20,000 people globally, with no approved therapies.
GTX-102, an investigational antisense oligonucleotide designed to target and inhibit the expression of UBE3A-AS, has won the Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation by the FDA.
