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Monday, February 28, 2022

Bayer Beat Expectations in 4Q; Guides for Increased Earnings, Sales in 2022

 Bayer AG on Tuesday posted earnings and sales that beat consensus expectations, and guided for increased earnings and sales in the year ahead.

The German pharmaceutical-and-agricultural company reported net profit of 1.16 billion euros ($1.30 billion) for the last quarter of the year, up from EUR308 million in the same quarter the year prior and beating analysts' expectations of EUR731 million.

Earnings before interest, taxes, depreciation and amortization before special items came in at EUR2.40 billion, also up from the previous year, when it was EUR2.39 billion.

Sales grew to EUR11.12 billion from EUR10 billion the year prior, beating consensus expectations of EUR10.47 billion.

Looking ahead, the company said it expects to significantly increase sales, earnings and free cash flow in 2022. Sales are expected to be about EUR46 billion in the year ahead, while Ebitda before special items should be about EUR12 billion, Bayer said.

Core earnings per share are expected to be about EUR7, while free cash flow is seen at about EUR2 billion to EUR2.5 billion, after deducting settlement payments.

Bayer said it would propose to maintain its dividend unchanged to EUR2.

Glaxo: Daprodustat Drug Gets EU Marketing Authorization

 GlaxoSmithKline PLC said Tuesday that its drug Daprodustat has received marketing authorization by the European Medicines Agency.

The company said its application was accepted for review by the EMA.

The drug Daprodustat, aimed at treating anaemia of chronic kidney disease, is currently approved in Japan, the FTSE 100-listed company said.

AstraZeneca, Neurimmune Sign Exclusive Commercialization Global Deal

 AstraZeneca PLC said Tuesday that its rare disease group Alexion has closed an exclusive global deal and license agreement with Neurimmune AG to commercialize NI006, an investigational antibody in Phase 1b aimed at treating a cardiomyopathy.

The Anglo-Swedish pharma giant said that Alexion has agreed to make an upfront payment to Neurimmune of $30 million, adding that Neurimmune will continue to be responsible to complete the current phase of the trial while Alexion pays certain trial costs.

"Alexion will make additional contingent milestone payments of up to $730 million upon achievement of certain development, regulatory and commercial milestones. It will also pay low-to-mid teen royalties on net sales of any approved medicine resulting from the collaboration," the FTSE 100 listed company said.

Poison Control Centers Warn About Toxic Chemical In At-Home COVID-19 Test Kits

 by Jack Phillips via The Epoch Times (emphasis ours),

Some at-home rapid COVID-19 tests contain a toxic chemical that may be harmful to both children and adults, according to health officials.

A Flowflex COVID-19 Lateral Flow (LFT) self-test kit, containing a SARS-CoV-2 Antigen Rapid Test, arranged for a photograph, in London on Feb. 20, 2022. (Justin Tallis/AFP via Getty Images)

The Cincinnati Drug and Poison Information Center reported an uptick in accidental exposures to a possibly toxic substance in at-home COVID-19 test kits, according to a blog post. Meanwhile, the National Poison Control Center issued a warning about the chemical.

“It is important to know that the extraction vial in many rapid antigen kits includes the chemical sodium azide as a preservative agent,” the center said. “The BinaxNow, BD Veritor, Flowflex, and Celltrion DiaTrust COVID-19 rapid antigen kits all contain this chemical.”

Sodium azide is a colorless, odorless powder that testers dip cotton swabs into. The chemical is found in herbicides, pest control agents, and airbags for cars.

Small doses of sodium azide can lower blood pressure, and larger doses may cause more serious health effects,” an advisory from Health Canada also said. “ProClin is also found in many kits. It contains chemicals that can cause skin and eye irritation, as well as allergic reactions.”

Some hospitals around the United States say they have received a surge in phone calls about exposures to the chemical.

“We started getting our first exposures to these test kits around early November,” said Sheila Goertemoeller, pharmacist and clinical toxicologist for the Cincinnati Children’s Hospital Medical Center. “It was, really, all ages.”

“Mostly, I’ve been very worried about our young children.”

Accidental exposure is occurring among both children and adults, said Dr. Kelly Johnson-Arbor, with the National Capital Poison Center in Washington, told WNEP over the weekend.

“People might mistake them for eye drops. Children might drop it onto their skin. Adults will sometimes mistakenly put them into their eyes,” she said.

“You don’t want to leave it on the skin because it could potentially cause an allergic reaction or a skin rash.

If someone drinks the solution, it’s really important to contact poison control right away. The solutions have different ingredients. Some have non-toxic ingredients and others have more dangerous ingredients.”

Officials told WNEP that there’s no need to throw away the test kits, but people should be mindful when using them.

“Use them properly, dispose of them properly, and it won’t cause an issue,” Dr. Jeffrey Jahre, with St. Luke’s University Health Network, told the outlet.

If you suspect you or someone you know has ingested the chemical, officials recommend not to make the person vomit. For eye exposures, rinse the eyes for 15 to 20 minutes with warm water. For skin exposures, rinse the skin well with tap water. Immediately check the Poison Control Center’s online tool for guidance or call poison control at 1-800-222-1222, the website says.

Breakthrough gene-editing technology belongs to Harvard, MIT -U.S. tribunal

 A U.S. tribunal overseeing patent disputes ruled on Monday that patents on the breakthrough gene-editing technology known as CRISPR belong to Harvard University and the Massachusetts Institute of Technology.

The U.S. Patent and Trademark Office's decision is a defeat for the University of California, Berkeley; the University of Vienna and Nobel Prize-winning researcher Emmanuelle Charpentier.

Harvard's and MIT's Broad Institute, which obtained the first CRISPR patent in 2014 and later obtained related patents, said the decision confirmed its patents were properly issued.

CRISPR lets scientists edit genes by using biological scissors that can edit DNA.

The technology is being tested in clinical trials to potentially help cure diseases caused by genetic mutations and abnormalities.

Jennifer Doudna of UC Berkeley and Charpentier of the University of Vienna had been first to seek a CRISPR patent in 2012. Eight years later they shared the Nobel Prize in Chemistry for their CRISPR work.

Putin's Disinformation & Opportunity: Weapons Of Mass Destruction

 by David Lasseter via RealClear Defense,

Back in early 2020, when COVID-19 was spreading around the globe and public health professionals were struggling to make sense of the virus, the Russians, like the Chinese, were conducting information operations blaming America for the outbreak. The Russian Federation went so far as to suggest that the Richard Lugar National Center for Disease Control and Public Health in Tbilisi, Georgia, was producing biological weapons and could be responsible for releasing deadly agents, i.e., COVID-19, into former Soviet states. 

At the time, I was the Deputy Assistant Secretary of Defense for Countering Weapons of Mass Destruction (WMD). My Office and our colleagues at the Defense Threat Reduction Agency answered these Russian lies with facts. The Georgian and U.S. governments and public health professionals pushed back on these false and dangerous stories. The truth is that these labs are part of the Department of Defense Cooperative Threat Reduction (CTR) Program which works with international partners to mitigate WMD-related threats to the U.S. homeland, U.S. forces abroad, and U.S. partners and allies. We do this in over 30 countries worldwide because these labs improve the respective countries’ ability to detect, diagnose, and report the spread of especially dangerous pathogens.

But this is what President Putin does – make irresponsible accusations and conduct disinformation campaigns. For years now, Putin’s government has falsely claimed that the CTR labs, specifically the Lugar Center, manufacture biological agents for the United States military. This is not true.

In response to the COVID-19 mistruths, officials at the Lugar Center invited the Russian government to visit the facility. Russia demanded that if they visited, no other international governments or organizations be present. That counteroffer was refused since the Georgians knew it would enable Russia to proliferate obscene amounts of disinformation after an unsupervised visit. It would be an opportunity for Putin to manipulate the Georgian government and any gullible international press.

COVID-19 origin facts aside, Russian government officials reiterated this propaganda in May 2021, stating that “deadly microorganisms” could be released from U.S. sponsored facilities in the region. Then again, earlier this month, through state-owned media, Russia claimed Tbilisi could use the Lugar Center’s research of infectious diseases for bioterrorism in the region. 

In a joint Russia-Chinese statement following a February 4, 2022, meeting between Putin and Chinese President Xi Jinping, Russia claims the U.S. supported labs in Ukraine contain deadly bioweapons saying: “The sides emphasize that domestic and foreign bioweapons activities by the United States and its allies raise serious concerns and questions for the international community regarding their compliance with the BWC [Biological Weapons Convention].”

In a couple of months, the U.S. Department of State will release its annual WMD nonproliferation compliance report. This year’s report is unlikely to differ from the findings in recent iterations, including last year’s report. Namely, regarding chemical weapons, “the United States certifies that Russia is in non-compliance with the Chemical Weapons Convention (CWC)” and with respect to biological weapons, the “United States assesses that Russia maintains an offensive BW program and is in violation of its obligations under Articles I and II of the Biological Weapons Convention (BWC).”  What’s more, the Russian Federation’s blatant disregard for international law and associated norms concerning its nuclear program speaks for itself. While the use of nuclear weapons would have the most devastating and world-altering impact, it is an unlikely course of action at this time.

However, it is Putin's potential use of chemical and biological weapons that we should more fully appreciate. As we know, in 2018, former Russian spy Sergei Skripal and his daughter Yulia were attacked with a previously unknown chemical agent, Novichok, in Salisbury, England. Then, in 2020, yet another unlawful attack via Novichok chemical agent occurred against Putin's political rival, Alexei Navalny. Both attacks were violations of the CWC and reprehensible acts by a government. Additionally, and possibly the most egregious actions by the Russian Federation were those promulgated by the Syrian regime and likely known and condoned by Putin that resulted in asphyxiation, disfigurement, and even death of hundreds of innocent children, women, and men. 

We should learn from the deaths of innocent people and view these previous attacks as test cases. We do not need to query whether they would use them. They have, and they will again. In the Salisbury attack, the world reacted quickly in condemning the action once the forensics were complete; however, the formal penalties or sanctions exacted by the world's powers were rather ineffectual. A mere two and a half years later, Putin ordered another attack on a political rival. While the world recognized the signs of yet another attack, the reaction did little to adjust Putin's use calculus by way of sanctions and diplomatic actions. With Syria, the world has not held Assad to account and has done absolutely nothing to punish the Russian Federation for their support and complicity.

So, with Ukraine, we have a country Putin believes should rightly exist within Russia's sphere of influence if not absolute control. A country with western fealty and NATO ambitions, he wants control and appears willing to garner it at the cost of war. We have already seen Russian officials and state supported media implicate CTR supported labs in Ukraine in any future biological warfare incidents. Recently, Secretary of State Anthony Blinken informed the world that Russia might execute a false flag chemical weapons attack in advance of a Ukraine invasion. While illegal and potentially very deadly, we shouldn't think he would stop there.

Throughout this Russian buildup, the Administration has chosen to selectively release intelligence through its own information operations. While many question the righteousness of doing so, it is the President's prerogative. One nugget recently released is the existence of a Russian “kill list” of Ukrainians following military occupation. If true, these could be prime targets for WMD in the form of biological and chemical weapons.

At this stage, all we can do is speculate based on historical knowledge, known capabilities, and the mindset of a malevolent, authoritarian leader. But the events in Salisbury and Syria, the disinformation operations related to legitimate threat reduction laboratories in former Soviet states, and the assessments provided in the State Department’s annual assessment of WMD programs tell us that Mr. Putin has means, motive, and opportunity. Let's hope and pray he does not use these horrific weapons, but we shouldn’t be surprised when he does.

* * *

David F. Lasseter is the former Deputy Assistant Secretary of Defense for Countering Weapons of Mass Destruction.  He is the Founding Partner at Horizons Global Solutions as well as a Visiting Fellow at the National Security Institute.

Metformin highly effective in targeting diabetes and some cancers but potentially dangerous with others

 Using computer drug simulations, researchers have found that doctors need to be wary of prescribing a particular treatment for all types of cancer and patients.

The drug, called metformin, has traditionally been prescribed for diabetes but has been used in clinical settings as a cancer treatment in recent years.

The researchers say while metformin shows great promise, it also has negative consequences for some types of cancers.

"Metformin is a wonder drug, and we are just beginning to understand all its possible benefits," said Mehrshad Sadria, a PhD candidate in applied mathematics at the University of Waterloo. "Doctors need to examine the value of the drug on a case-by-case basis, because for some cancers and some patient profiles, it may actually have the opposite of the intended effect by protecting tumour cells against stress."

The computer-simulated treatments use models that replicate both the drug and the cancerous cells in a virtual environment. Such models can give clinical trials in humans a considerable head-start and can provide insights to medical practitioners that would take much longer to be discovered in the field.

"In clinical settings, drugs can sometimes be prescribed in a trial and error manner," said Anita Layton, professor of applied mathematics and Canada 150 Research Chair in mathematical biology and medicine at Waterloo. "Our mathematical models help accelerate clinical trials and remove some of the guesswork. What we see with this drug is that it can do a lot of good but needs more study."

The researchers say their work shows the importance of precision medicine when considering the use of metformin for cancer and other diseases. Precision medicine is an approach that assumes each patient requires individualized medical assessment and treatment.

"Diseases and treatments are complicated," Sadria said. "Everything about the patient matters, and even small differences can have a big impact on the effect of a drug, such as age, gender, genetic and epigenetic profiles. All these things are important and can affect a patient's drug outcome. In addition, no one drug works for everyone, so doctors need to take a close look at each patient when considering treatments like metformin."

Sadria, Layton and co-author Deokhwa Seo's paper was published in the journal BioMed Central Cancer.

Story Source:

Materials provided by University of WaterlooNote: Content may be edited for style and length.

Journal Reference:

  1. Mehrshad Sadria, Deokhwa Seo, Anita T. Layton. The mixed blessing of AMPK signaling in Cancer treatmentsBMC Cancer, 2022; 22 (1) DOI: 10.1186/s12885-022-09211-1

Cholesterol-lowering drugs may slow down metastases

 Many people have to take statins to lower their cholesterol levels. But statins may be able to do even more: Researchers report that these drugs inhibit a gene that promotes cancer cell metastasis.

Cancer patients rarely die from the primary tumor but rather from the metastases -- even after successful tumor surgery. This is because cancer cells sometimes spread to other parts of body early in the disease, when the tumor is still very small and may not have even been discovered yet. To do this they must break away from the extracellular matrix and migrate into neighboring lymphatic vessels or blood vessels that transport them to new tissue, where they settle and proliferate.

Understanding the molecular mechanisms of metastasis is therefore a key piece of the puzzle in the fight against cancer. More than ten years ago, Professor Ulrike Stein and her lab at the Experimental and Clinical Research Center (ECRC) were able to discover an important driver of this process in human colorectal cancer: the metastasis-associated in colon cancer 1 (MACC1) gene. The ECRC is a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité -- Universitätsmedizin Berlin.

Drug screening identified statins

When cancer cells express MACC1, their ability to proliferate, move around the body, and invade other tissues is enhanced. "Many types of cancers spread only in patients with high MACC1 expression," Stein explains. MACC1's role as a key factor and biomarker of tumor growth and metastasis -- not only in colorectal cancer, but in more than 20 solid tumors such as gastric, liver and breast cancer -- has since been studied by many other researchers worldwide and confirmed in more than 300 publications. Now together with Dr. Robert Preißner of Charité, Stein has discovered what could disrupt metastatic progression in such cases: Statins, which are prescribed as cholesterol-lowering drugs, inhibit MACC1 expression in tumor cells. The scientists are presenting their findings in the journal Clinical and Translational Medicine.

In their search for MACC1 inhibitors, the researchers conducted high-throughput drug screening with colleagues at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. They independently hit upon statins. They tested this discovery on various tumor cell lines, with favorable results: All seven drugs tested reduced MACC1 expression in the cells but to varying degrees. The scientists then administered the cholesterol inhibitors to genetically modified mice with increased MACC1 expression. This almost completely suppressed the formation of tumors and metastases in the animals. "What is particularly remarkable is that the benefits continued in the animals even after we reduced the dose relative to the amount that humans normally ingest," Stein says.

Statins have one big advantage: they are already approved

Robert Preißner and scientists at the University of Virginia also examined data from a total of 300,000 patients who had been prescribed statins. This analysis found a correlation: "Patients taking statins had only half the incidence of cancer compared to the general population," Preißner explains.

Stein advises against taking statins as a preventive measure without consulting a doctor and having their lipid levels checked, so as to ensure no serious side effects occur. "We are still at the very beginning," the scientist stresses. "Cell lines and mice are not human beings, so we cannot directly transfer the results." The experimental studies and retrospective data analysis will now be followed up by a clinical trial, she says. Only after that will it be possible to say with certainty whether statins actually prevent or reduce metastasis in patients with high MACC1 expression.

Story Source:

Materials provided by Max Delbrück Center for Molecular Medicine in the Helmholtz Association. Original written by Jana Ehrhardt-Joswig. Note: Content may be edited for style and length.

Journal Reference:

  1. Bjoern‐O Gohlke, Fabian Zincke, Andreas Eckert, Dennis Kobelt, Saskia Preissner, Juliane Maria Liebeskind, Nikolas Gunkel, Kerstin Putzker, Joe Lewis, Sally Preissner, Benedikt Kortüm, Wolfgang Walther, Cameron Mura, Philip E. Bourne, Ulrike Stein, Robert Preissner. Real‐world evidence for preventive effects of statins on cancer incidence: A trans‐Atlantic analysisClinical and Translational Medicine, 2022; 12 (2) DOI: 10.1002/ctm2.726

New data analysis tool uncovers important COVID-19 clues

 A new data analysis tool developed by Yale researchers has revealed the specific immune cell types associated with increased risk of death from COVID-19, they report Feb. 28 in the journal Nature Biotechnology.

Immune system cells such as T cells and antibody-producing B cells are known to provide broad protection against pathogens such as SARS-CoV-2, the virus that causes COVID-19. And large-scale data analyses of millions of cells have given scientists a broad overview of the immune system response to this particular virus. However, they have also found that some immune cell responses -- including by cell types that are usually protective -- can occasionally trigger deadly inflammation and death in patients.

Other data analysis tools that allow for examination down to the level of single cells have given scientists some clues about culprits in severe COVID cases. But such focused views often lack the context of particular cell groupings that might cause better or poorer outcomes.

The Multiscale PHATE tool, a machine learning tool developed at Yale, allows researchers to pass through all resolutions of data, from millions of cells to a single cell, within minutes. The technology builds on an algorithm called PHATE, created in the lab of Smita Krishnaswamy, associate professor of genetics and computer science, which overcomes many of the shortcomings of existing data visualization tools.

"Machine learning algorithms typically focus on a single resolution view of the data, ignoring information that can be found in other more focused views," said Manik Kuchroo, a doctoral candidate at Yale School of Medicine who helped develop the technology and is co-lead author of the paper. "For this reason, we created Multiscale PHATE which allows users to zoom in and focus on specific subsets of their data to perform more detailed analysis."

Kuchroo, who works in Krishnaswamy's lab, used the new tool to analyze 55 million blood cells taken from 163 patients admitted to Yale New Haven Hospital with severe cases of COVID-19. Looking broadly, they found that high levels T cells seem to be protective against poor outcomes while high levels of two white blood cell types known as granulocytes and monocytes were associated with higher levels of mortality.

However, when the researchers drilled down to a more granular level they discovered that TH17, a helper T cell, was also associated with higher mortality when clustered with the immune system cells IL-17 and IFNG.

By measuring quantities of these cells in the blood, they could predict whether the patient lived or died with 83% accuracy, the researchers report.

"We were able to rank order risk factors of mortality to show which are the most dangerous," Krishnaswamy said.

In theory, the new data analytical tool could be used to fine tune risk assessment in a host of diseases, she said.

Jessie Huang in the Yale Department of Computer Science and Patrick Wong in the Department of Immunobiology are co-lead authors of the paper. Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology, is co-corresponding author.

Story Source:

Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

Journal Reference:

  1. Manik Kuchroo, Jessie Huang, Patrick Wong, Jean-Christophe Grenier, Dennis Shung, Alexander Tong, Carolina Lucas, Jon Klein, Daniel B. Burkhardt, Scott Gigante, Abhinav Godavarthi, Bastian Rieck, Benjamin Israelow, Michael Simonov, Tianyang Mao, Ji Eun Oh, Julio Silva, Takehiro Takahashi, Camila D. Odio, Arnau Casanovas-Massana, John Fournier, Abeer Obaid, Adam Moore, Alice Lu-Culligan, Allison Nelson, Anderson Brito, Angela Nunez, Anjelica Martin, Anne L. Wyllie, Annie Watkins, Annsea Park, Arvind Venkataraman, Bertie Geng, Chaney Kalinich, Chantal B. F. Vogels, Christina Harden, Codruta Todeasa, Cole Jensen, Daniel Kim, David McDonald, Denise Shepard, Edward Courchaine, Elizabeth B. White, Eric Song, Erin Silva, Eriko Kudo, Giuseppe DeIuliis, Haowei Wang, Harold Rahming, Hong-Jai Park, Irene Matos, Isabel M. Ott, Jessica Nouws, Jordan Valdez, Joseph Fauver, Joseph Lim, Kadi-Ann Rose, Kelly Anastasio, Kristina Brower, Laura Glick, Lokesh Sharma, Lorenzo Sewanan, Lynda Knaggs, Maksym Minasyan, Maria Batsu, Maria Tokuyama, M. Cate Muenker, Mary Petrone, Maxine Kuang, Maura Nakahata, Melissa Campbell, Melissa Linehan, Michael H. Askenase, Michael Simonov, Mikhail Smolgovsky, Nathan D. Grubaugh, Nicole Sonnert, Nida Naushad, Pavithra Vijayakumar, Peiwen Lu, Rebecca Earnest, Rick Martinello, Roy Herbst, Rupak Datta, Ryan Handoko, Santos Bermejo, Sarah Lapidus, Sarah Prophet, Sean Bickerton, Sofia Velazquez, Subhasis Mohanty, Tara Alpert, Tyler Rice, Wade Schulz, William Khoury-Hanold, Xiaohua Peng, Yexin Yang, Yiyun Cao, Yvette Strong, Shelli Farhadian, Charles S. Dela Cruz, Albert I. Ko, Matthew J. Hirn, F. Perry Wilson, Julie G. Hussin, Guy Wolf, Akiko Iwasaki, Smita Krishnaswamy. Multiscale PHATE identifies multimodal signatures of COVID-19Nature Biotechnology, 2022; DOI: 10.1038/s41587-021-01186-x

Biotech leaders call on industry to cut ties with Russia amid Ukraine invasion

 CEOs at dozens of biotechs and investors from the industry's leading venture firms urged their global business counterparts to "disengage from Russian industry" over the weekend. 

The executives called on biopharma and other industries to "cease investment in Russian companies," halt plans to funnel money within the borders of Russia, reject new funds from Russia, nix collaboration and service agreements with companies in the country and halt trade in goods, except for food and medicines.

Chief executives at Nkarta, BioMarin, Rubius, atai Life Sciences, Blueprint Medicines, Ovid, Global Blood Therapeutics and dozens of others signed the letter, dated Feb. 26. CEOs, who have been called on to speak out more over injustices in the past two years, especially in the U.S., were joined by dozens of other industry leaders bearing titles across the C-suite.

The letter, written in multiple languages, called Russia's war on Ukraine a "barbaric act." The business leaders rejected President Putin's actions and "those who enable and embolden him," including scions of Russian industry. 

"We cannot look back in the future wondering whether we could have taken stronger measures. This justifies the strongest possible economic disengagement now," the letter reads in part. 

Aside from drug developers, venture capital firms and other investment shops were also represented in the letter's signatories. Among them, industry heavyweights like RA Capital, Atlas Venture and Third Rock Ventures. 

As of Friday, February 25, 2022

Russia's invasion of Ukraine is likely to impact millions of people, not just in the Eastern European nation but around the world as drug developers might face delays in clinical trials conducted in Kyiv and elsewhere.

One biotech, in particular, called out the geopolitical tensions as possible cause for concern. Karuna Therapeutics warned Thursday that timelines for its second phase 3 study in schizophrenia, dubbed EMERGENT-3, are uncertain because 10 of the 19 trial sites are in Ukraine. In a further statement issued late Thursday evening, Karuna said the company's priority is the safety of its clinical trial partners and patients. 

"We want to reiterate that our hearts are with the people of Ukraine during this unimaginably difficult time," a spokesperson for the Boston-based biotech said. "We are closely monitoring the evolving geopolitical situation between Ukraine and Russia and remain in contact with our investigators and clinical trial sites. As the situation is still unfolding, we will continue to assess the impact on the ongoing program and will provide updates as appropriate."

The study might not be needed for Karuna to file the drug, KarXT, for approval, according to RBC Capital Markets analysts. But, if the first phase 3 trial, EMERGENT-2, fails to meet its primary endpoint and produce safety data, Karuna could be in trouble. EMERGENT-3 is a "backup option," RBC wrote in a Thursday note.

"While our clinical trial sites in the Ukraine continue to actively recruit and treat patients, if political or civil conditions require it, our sites may need to delay or suspend clinical trial activities," Karuna said in a regulatory filing Thursday. "Our clinical trial sites have contingency plans in place as part of their standard quality management practices for circumstances such as these and are prepared to initiate such plans when and if necessary."

Ukraine is home to about 2,500 public medical facilities that have experience running international trials, and there are about 500 ongoing trials each year, according to clinical research organization Global Clinical Trials. The affect of the conflict on clinical trials could be far reaching. The biopharma industry is actively testing 251 drugs and devices in clinical trials that have at least one Ukraine site, according to the FDA's clinical trials database. 

This includes 11 of 195 study locations for Merck's phase 3 trial of Keytruda in combination with Lenvima in patients with endometrial carcinoma. Regeneron also has studies in Ukraine, where it's testing Libtayo in combination with doublet chemotherapy in a phase 3 study in patients with non-small cell lung cancer. Six of that study's 143 locations are in Ukraine. 

RBC said the overall impact on biotech should be "manageable" as sales and manufacturing activities in Ukraine and Russia are limited. But clinical trial sites in Ukraine are unlikely to be able to remain operational given the conflict. Sites in Russia may also be impacted by sanctions or data security issues, the firm predicted. 

Pharma response

Ukraine and Russia represent about 1% of Merck's business, a spokesperson said, and the U.S. pharma does not have any manufacturing sites in either country. 

"At this point, all our colleagues are safe and accounted for, and we continue to monitor the situation closely to provide whatever support we can to them and to their families," Merck's spokesperson said. "In line with our mission, we are also doing everything we can to ensure access to our medicines for patients."

GlaxoSmithKline could also be affected. The British Big Pharma has 27 Ukrainian sites, out of 235, in its phase 3 study of otilimab in patients with rheumatoid arthritis. GSK previously culled work on otilimab in COVID-19 in October 2021.

A spokesperson for GSK confirmed the company has local pharma and consumer health care teams in Ukraine but no manufacturing operations. 

"The situation is evolving and we are monitoring it carefully. Our absolute priorities are the safety of our people and maintaining access to our medicines, vaccines and consumer healthcare products," GSK said in a statement to Fierce Biotech. 

AstraZeneca, which has up to 20 active trials in Ukraine, similarly said it's working to protect local employees. 

"The safety and wellbeing of AstraZeneca employees remains our top priority and we have taken steps to support colleagues. Furthermore, a team has been established which will do the utmost to ensure continued supply of our medicines to patients," said a company spokesperson in a statement. 

Sanofi, which has at least two studies underway in Ukraine for the Regeneron-partnered med Dupixent, confirmed the company is monitoring the situation. 

"Our key priority at Sanofi remains to ensure the safety of our people and continuity for the patients we serve," the spokesperson said. "All of our employees based in Ukraine have been asked to stay home and we are monitoring the developing situation very closely."

Takeda said the "situation is fluid," but the Japanese pharma is "doing everything we can to protect our employees and their families and to continue to supply patients with their much-needed treatments.”

Roche is working to ensure patients continue to access to the company's medicines in the region, according to a spokesperson. The Swiss pharma has processes and measures in place for crisis situations to protect employees and their families. 

"We have business continuity plans in place, which are constantly updated given the situation," according to the statement. "At Roche, our utmost priority is to keep our employees and their families safe."

Ongoing trials

Other companies with clinical trials operating in the region include Biogen, Incyte, Gilead, Galapagos, PTC Therapeutics and Sarepta, according to RBC. These could experience delays or data integrity issues. But the firm noted that an individual trial site does not necessarily correlate to a guaranteed pool of patients. Biotechs can likely manage the disruption by moving to other countries or reallocating resources. 

Intra-Cellular Therapies, like Karuna, has clinical trials operating in Ukraine and Russia, RBC said. The company has about 36% of sites for the bipolar depression med Caplyta in Ukraine and Russia. The therapy is being tested in borderline personality disorder and major depressive disorder. RBC said the timeline could be pushed out for the trials, which is slated for a readout in December. 

Biogen, meanwhile, has a couple trials located in Russia for an ALS med, cerebral edema therapy as well as Alzheimer's treatment lecanemab, which is being developed with Eisai. Incyte has "heavy exposure" for its oral PD-L1 program in solid tumors, as 70% of the sites are in Ukraine. A phase 3 study for retifanlimab in non-small cell lung cancer has 23% of its sites in Ukraine. 

Behind pharmaceutical companies' clinical trials are CROs that manage the on-the-ground logistics. Parexel confirmed in a statement to Fierce Biotech that the CRO operates clinical trials in the impacted regions. 

"While we will not disclose the specific number of colleagues, customers or vendors impacted, like the rest of the world, we have been and continue to monitor the situation closely and are committed to supporting the continuity of trials in progress," the company said. "As always, the safety and wellbeing of our patients and colleagues remains our top priority."

Of the 45 biopharmas Jefferies analysts cover, nine of them have trial sites in Ukraine, according to a note. Karuna is one of those. Another, Veru, is expected to "appropriately react and maintain timelines" on its study of breast cancer treatment enobosarm because the trial is just starting, the analysts wrote in a note. 

TG Therapeutics, another company covered by Jefferies, should not experience "meaningful impact" because the biotech has already asked the FDA to approve its drug ublituximab in patients with relapsing multiple sclerosis. A decision is slated for Sept. 28, 2022. A phase 3 extension study is ongoing with 20 of 85 trial sites in Ukraine.  

"Broadly speaking, we do not believe that the emerging conflict in Ukraine will meaningfully impact ongoing trials in our coverage," Jefferies analysts wrote Thursday.

Intellia now has the data for No. 1 unanswered gene editing question: Does it last?

 Intellia Therapeutics proved last year that gene editing can work in humans. But a lingering question was, for how long? Now, the biotech has the data to begin to answer that question. 

In a hotly anticipated readout, Intellia is presenting additional data from the phase 1 trial for NTLA-2001 in transthyretin, or ATTR, amyloidosis during an investor event today. The company is filling in some pieces that were missing when initial data in June 2021 showed the CRISPR gene editing therapy significantly reduced a known biomarker of the disease. 

Intellia has confirmed in interim data that the reduction in serum levels of transthyretin, or TTR, was maintained in patients after follow-up that ranged from two months to 12 months post-treatment. The company also said NTLA-2001 spurred a greater reduction in serum with a higher dose. Both are key pieces of data investors were eagerly awaiting. Plus, all this was achieved without any new concerning safety signals. 

“What we show is that pretty much what you get on Day 28 is what you're going to have thereafter,” Intellia CEO John Leonard, M.D., said in an interview with Fierce Biotech. 

NTLA-2001 works by deploying lipid nanoparticles to the liver to drop off a two-part genome editing system. The first part is a guide RNA specific to the disease-causing gene, and the second part is a messenger RNA—the tech made famous by COVID-19 vaccines—to encode the Cas9 protein and carry out precision editing.

Intellia CEO John Leonard headshot
John Leonard, M.D. (Intellia Therapeutics)

ATTR amyloidosis is a rare and fatal disease that occurs in people born with TTR gene mutations, which cause the liver to produce abnormal, often misfolded TTR proteins. The damaged proteins, which in a healthy form help carry thyroid hormone and vitamin A in the blood, build up in the body, causing a host of problems in the nervous system, heart and other organs.

The latest data show that the serum reduction seen at the initial Day 28 observation was sustained through the last check-in with each of the six patients who received a dose of 1.0 mg/kg. These patients experienced reductions higher than 80% and 90%, Intellia said. The initial data release last year showed a reduction of 87%. 

Intellia has also settled on a dosing regimen for NTLA-2001 aimed at simplfying treatment going forward, Leonard said. Instead of weight-based dosing, the company will advance a fixed dose of 80 mg for all patients. 

“You can simplify the regimen so you don’t have to worry about the pharmacy mixing up something incorrectly or a weight that's wrong; it tends to just take a lot of complexity out,” Leonard said of the fixed-dosing regimen. 

Intellia has found that while patients receiving the lower doses in the trial did have reduced serum levels, the effect was greater in the higher dose arms of the study.

As for the safety data, Leonard said one dose-limiting toxicity was observed in a single patient that experienced vomiting, which was rated as a grade 3 adverse event. This patient had prior medical history of vomiting due to gastroparesis, a common problem with ATTR amyloidosis in which the digestive system can’t clear food properly. The patient has since recovered, Leonard said. 

Intellia NTLA-2001 graphic

With some data now added to the durability question, Intellia could have itself a one-time treatment option for patients. ATTR amyloidosis is currently treated with one of three available treatments: Alnylam’s Onpattro, Ionis’ Tegsedi or Pfizer's Vyndaqel. But Leonard said the company is more focused on the simple efficacy question along with whether this CRISPR therapy will benefit patients. 

“The appeal is not one-and-done. That's a nice secondary aspect of this thing. This is, first and foremost, an efficacy argument,” he said. “The idea being, from an amyloidosis point of view, you want to make the offending protein go as low as you possibly can.”

Intellia’s current studies are not geared to detect efficacy or patient benefit—that will come in more advanced testing later on—but TTR serum reduction is a known biomarker of the disease that signals a benefit. The actual benefits, i.e., relief from the symptoms of the disease, will not be immediate after treatment with NTLA-2001, Leonard said. 

“What will a patient feel on Day 1? Nothing,” Leonard said, adding that that’s the goal: to kick off serum reduction without any adverse events. 

But with the protein no longer getting deposited into the tissues, the hope is that the body’s natural processes will begin to clear out the buildup, he explained. Those natural processes are not fully understood. 

“It's, we think, in the realm of possibility that patients can actually improve relative to their baseline. That will take time,” Leonard said. “It's not like the protein goes away, people get up and start playing tennis or something like that. You've got to let the process play out.”

Intellia plans to continue tracking the patients for the rest of their lives to record the durability data, so someday, we may have a more concrete understanding of the science behind ATTR amyloidosis.

As for next steps, Leonard and the team laid out the plan during Intellia’s fourth-quarter earnings Feb. 24 and during a presentation at the J.P. Morgan Healthcare conference in January. The company has initially targeted the polyneuropathy subtype of the disease, which shows up as nerve damage, in the study. But, now, a new patient group will be added to the early-stage study including those with the cardiomyopathy manifestation. 

Intellia about ATTR Amyloidosis graphic

Even before seeing the updated data, RBC analyst Luca Issi, Ph.D., pointed to Intellia’s recent decision to build a new manufacturing facility as a vote of confidence for the therapy. Issi said Intellia’s therapy is likely to be more effective and convenient than the available silencer treatments like Tegsedi and Onpattro that have set the standard with serum reductions in the range of 70 to 80%. 

Issi also pointed to early mouse data that showed gene editing was preserved when a portion of the liver was removed and allowed to grow back. Leonard said today's results seem to confirm that preclinical testing. 

Another thing that’s been confirmed for Leonard is the company’s approach with its broader pipeline, specifically treatments that belong in the in vivo category like NTLA-2001. One is NTLA-2002 in hereditary angioedema, which is in a phase 1 trial that has begun dosing patients, the CEO said. Data for that study will be presented later this year. 

“The read-through should be very direct and quite immediate” on the pipeline, Leonard said of the latest results. Intellia has shown the lipid nanoparticles are getting to where they need to be in the liver, and that mechanism is the same across the in vivo program. 

Intellia also has ex vivo candidates, which should be buoyed as well by the latest ATTR amyloidosis data, but to a lesser extent, Leonard said.

Sanofi chases fourth Dupixent nod after late-stage eosinophilic esophagitis trial win

 Sanofi’s plan to build Big Pharma’s “strongest franchise in immunology” hinges on lead product Dupixent, the company’s chief financial officer, Jean-Baptiste Chasseloup de Chatillon, recently said. Now, the French drugmaker is touting the med’s potential to snag a fourth indication for a chronic inflammatory disease that makes eating and drinking a struggle.

Sanofi and Regeneron's Dupixent, also known as dupilumab, notched a win in a phase 3 study of patients with eosinophilic esophagitis (EoE), Sanofi said in a late-breaking abstract debuted Saturday at the 2022 annual meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI). 

At the study’s 24-week mark, a 300 mg dose of weekly Dupixent “significantly” trumped placebo when it came to improving the signs and symptoms of EoE, Sanofi said in a release. The study looked at the monoclonal antibody in 159 EoE patients ages 12 and older. 

Eighty patients in the study received Dupixent, while 79 were assigned placebo. Among those on Sanofi’s monoclonal antibody, 64% saw a reduction in disease symptoms from baseline versus 41% in the control arm. Specifically, patients on Dupixent saw a 23.78 point improvement on the Dysphagia Symptom Questionnaire—a patient reported measure of difficulty swallowing—versus a 13.86 improvement in the placebo cohort. 

Meanwhile, nearly 10 times as many patients on Dupixent hit histological disease remission at 59%, versus just 6% in the placebo group. Sanofi said it will roll out detailed results on a two-week dosing regimen at an upcoming medical meeting. 

With a winning readout in hand, Sanofi has submitted its Dupixent EoE data to the U.S. FDA. The company says it plans to file for approval in other countries later this year. 

“Eosinophilic esophagitis can greatly impact a person’s ability to eat normally, and physicians have to rely on invasive medical procedures to monitor and, in more serious cases, stretch the esophagus,” Evan Dellon, M.D., M.P.H., a professor of gastroenterology and hepatology and co-principal investigator of the Dupixent EoE trial, said in a statement. “Currently, there are no FDA-approved treatment options that address the underlying drivers of this disease.”

Sanofi estimates there are about 160,000 EoE patients in the U.S. who are currently being treated, of whom some 48,000 have failed multiple treatments.

EoE is a chronic, progressive type 2 inflammatory disease that damages the esophagus and keeps it from working correctly. For patients with the disease, “swallowing the smallest amount of food or taking a sip of water can be a painful and worrisome choking experience,” Sanofi noted. The disease can cause the esophagus to narrow, too, which may need to be treated by physically expanding the organ, which is often painful. 

Dupixent in 2020 scored an FDA breakthrough therapy tag in EoE. It won orphan drug designation for potential treatment of the disease back in 2017. 

Last year, Dupixent garnered full-year sales of 5.25 billion euros (around $6 billion), Sanofi said in its annual report published earlier this month.

Thanks to its strong Dupixent momentum in 2021, Sanofi has set the goal to "build the strongest franchise in immunology among big pharma," CFO Chasseloup de Chatillon said in January at the 2022 J.P. Morgan Healthcare Conference. The company aims to generate €10 billion or more from the drug at peak.