As Russia stacked troops on Ukraine's border, Karuna's trial partners got ready

 When Russia began to stack troops along Ukraine's border—up to 190,000 of them—Karuna Therapeutics' partners began to prepare clinical trial participants for the company's schizophrenia treatment in psychiatric hospitals across the country.

That, combined with additional contingency plans, is why CEO Steven Paul, M.D., is confident there won't be much, if any, delay to the initial phase 3 readout for KarXT, despite earlier concerns that the timing would be pushed out. 

Karuna’s partners in Ukraine were enrolling “quite recently,” but the trial was paused when the invasion began, according to Paul. Ultimately, a “substantial number of patients” were enrolled prior to the invasion, and data was collected on many of them prior to the start of the conflict. 

“That data is all collected, it’s all protected, we have it and we will use it in the trial,” he said. 

Paul’s efforts to assuage concerns come after the company disclosed last week in a Securities and Exchange Commission filing that the projected timeline for the data was being withdrawn. The disclosure also noted that the company were unsure of when data would in fact be available. Karuna hadoriginally reported during fourth-quarter earnings that the ETA for top-line data from the EMERGENT-3 phase 3 trial was the second half of this year. 

Even though 10 of the company's 19 clinical trial sites for the late-stage study are in Ukraine, Paul said the disclosure was "a tempest in the teapot." 

“I think we spooked people,” he said. “There are many, many companies, both drug companies and other companies, that are doing business in Ukraine that will be disrupted to a much, much, greater extent than we will because we were far along.” 

Karuna CEO Steven Paul (Karuna Therapeutics)

Contributing to Paul’s bullish projection is that the company’s concurrent phase 3 trial, EMERGENT-2, is recruiting only in the U.S. Karuna has estimated that data from that trial will be available in the middle of this year. Paul also said Karuna could shift recruiting for EMERGENT-3 to be mainly in the U.S. 

“We’ve always had the possibility of just using those sites to enroll the remainder of the patients,” he said. 

As for the company’s EMERGENT-4 trial, which is looking at the long-term effects of KarXT among patients enrolled in either EMERGENT-2 or EMERGENT-3, Paul is likewise confident the war won’t hinder data, given the company’s ability to rely on U.S. recruitment. Right now, five out of 32 sites listed for that trial are in Ukraine.

The impact of the war on clinical trials has been felt across the pharmaceutical and biotech industry, one of the many economic implications occurring in the backdrop of a conflict that’s now cost thousands of lives.

Ascendis Pharma A/S reported Wednesday that the war could impact the readout for a phase 3 trial of an adult growth hormone deficiency treatment. Tricidia on Thursday delayed a readout for a late-stage study in chronic kidney disease from the third quarter to the fourth quarter. The company said that 15% of enrolled randomized patients were based in Ukraine.   

Russia’s decision to invade has brought condemnation from across the biotech industry. Business leaders issued a letter last week calling for “complete economic disengagement” with the country and called the war a “criminal act deliberately committed by Russia.” 

The tumult comes as Karuna is trying to keep its head above water in a market that's pummeled biotechs in the last year. Karuna's stock has jumped more than $10 per share since disclosing the potential delay, from $99.19 on Feb. 24 to $109.25 on March 1. Paul said that even amid the choppy financial waters facing the industry, the company has fared well. 

"Now, of course, like many biotech companies we've settled back, but we're still doing quite well, relatively speaking, [in] this biotech market which as you know has been a tough one of late," he said. 

The company’s hopes are primarily pinned to the schizophrenia treatment, KarXT, which was shown to be both tolerable and, on average, improved patients' symptoms of the mental disorder in a phase 2 trial. The treatment acts as a control panel for muscarinic acetylcholine receptors in the brain, turning them on in the central nervous system as treatment and turning them off in peripheral tissues to avoid side effects. 

Paul said he discovered the original compounds of the drug by accident while working at Eli Lilly looking into treatments for dementia-related psychosis. He retired from the company in 2010 after a 17-year stint, leaving as executive vice president of science and technology and as president of Lilly Research Laboratories. 

The ongoing phase 3 trials for Karuna were initiated after the FDA advised the company in a end-of-phase 2 meeting in 2020 that one more trial was needed to demonstrate efficacy. Although Paul set out to clarify the timeline for top-line data, he wouldn’t divulge when the company is likely to apply for a new drug application with federal regulators, saying the company will apply when ready. 

https://www.fiercebiotech.com/biotech/karuna-ceo-invasion-ukraine-unlikely-significantly-delay-data-phase-3-trial

Transcript : Stereotaxis, Inc., Q4 2021 Earnings Call, Mar 03, 2022

 https://www.marketscreener.com/quote/stock/STEREOTAXIS-INC-65289611/news/Transcript-Stereotaxis-Inc-Q4-2021-Earnings-Call-Mar-03-2022-39657676/

Biogen Makes Layoffs Amid Stalled Aduhelm Launch

 Biogen Inc. made layoffs to its work force on Wednesday, the company said in a statement to Dow Jones Newswires.

Biogen is struggling with the disappointing launch of its Alzheimer's disease drug Aduhelm, and said in December that it would seek to cut costs by $500 million annually, but not all of the savings will come from layoffs, the company said Thursday.

"The cost-savings initiative is not based on headcount reductions alone, and we have prioritized not filling some open positions in addition to other measures," Biogen said.

Biogen's job cuts on Wednesday totaled more than 100, a person familiar with the matter tells Dow Jones. Biogen had 9,610 employees globally at the end of 2021, about 59% of which were in the U.S., according to Biogen SEC filings.

https://www.marketscreener.com/quote/stock/BIOGEN-INC-4853/news/Biogen-Makes-Layoffs-Amid-Stalled-Aduhelm-Launch-39656869/

Over 90% of U.S. population can ditch facemasks under CDC Covid guidance

 More than 90% of the U.S. population lives in area where they no longer need to wear facemasks, the Centers for Disease Control and Prevention said on Thursday.

The CDC issued new guidance last week that focuses on severe disease from Covid and hospitalizations when making recommendations on whether or not facemasks are needed.

The guidance is broken into three color-coded levels. People in green and yellow counties, with low and medium Covid levels respectively, do not need to wear masks. However, people in yellow counties who are at high risk of severe illness from Covid should consult with their physician about whether they should wear a mask or take other precautions.

Everyone is still required by federal law to wear facemasks and planes, trains and other forms of public transportation. The facemask requirement for planes expires on March 18. CDC officials have said they are reviewing whether or not the requirement is still necessary.

People in red counties with high Covid levels are recommended to wear masks indoors in public places regardless of vaccination status. Less than 10% of the U.S. population now lives in such counties, according to the CDC. You can check the status of your county by visiting the CDC’s website.

The omicron Covid variant upended the U.S. in December and January, causing an unprecedented level of infection. However, new infections have plummeted and are now down more than 90% from a pandemic record in January. The U.S. reported an average of nearly 58,000 new infections on Wednesday, compared the peak of more than 802,000 on Jan. 15, according to a CNBC analysis of data from Johns Hopkins University.

Hospitalizations are down 77% from the peak level during the omicron wave. More than nearly 35,000 people were hospitalized with Covid on Thursday, down from nearly 153,000 on Jan. 20, according to data from the Health and Human Services Department.

President Joe Biden, in his State of the Union speech on Tuesday, said it was safe for most Americans to return to work in person.

“With 75% of adult Americans fully vaccinated and hospitalizations down by 77%, most Americans can remove their masks, return to work, stay in the classroom, and move forward safely,” the president said.  

https://www.cnbc.com/2022/03/03/more-than-90percent-of-us-population-can-ditch-facemasks-under-cdc-covid-guidance.html

Don't seek conflict with Russia but ready for it,: U.S.

 NATO will defend all its allies and territory against a Russian attack, U.S. Secretary of State Antony Blinken said on Friday, as he arrived for a meeting of the alliance's foreign ministers in Brussels.

"Ours is a defensive alliance. We seek no conflict. But if conflict comes to us we are ready for it and we will defend every inch of NATO territory," he told reporters, while condemning what he called Russian attacks on civilians in Ukraine.

"And overnight, we've also seen reports about the attack against a nuclear power plant. This just demonstrates the recklessness of this war and the importance of ending it and the importance of Russia withdrawing all its troops and engaging in good faith in diplomatic efforts." 

https://finance.yahoo.com/news/dont-seek-conflict-russia-ready-083529512.html

'Drug factory' implants eliminate ovarian, colorectal cancer in mice

 Rice University bioengineers have shown they can eradicate advanced-stage ovarian and colorectal cancer in mice in as little as six days with a treatment that could be ready for human clinical trials later this year.

The researchers used implantable "drug factories" the size of a pinhead to deliver continuous, high doses of interleukin-2, a natural compound that activates white blood cells to fight cancer. The drug-producing beads can be implanted with minimally invasive surgery. Each contains cells engineered to produce interleukin-2 that are encased in a protective shell.

The treatment and animal test results are described online today in a Science Advances study co-authored by Omid Veiseh, Amanda Nash and colleagues from Rice, the University of Texas MD Anderson Cancer Center, the University of Virginia and others.

Veiseh, an assistant professor of bioengineering whose lab produced the treatment, said human clinical trials could begin as soon as this fall because one of his team's key design criteria was helping cancer patients as quickly as possible. The team chose only components that had previously proven safe for use in humans, and it has demonstrated the safety of the new treatment in multiple tests.

"We just administer once, but the drug factories keep making the dose every day, where it's needed until the cancer is eliminated," Veiseh said. "Once we determined the correct dose -- how many factories we needed -- we were able to eradicate tumors in 100% of animals with ovarian cancer and in seven of eight animals with colorectal cancer."

In the newly published study, researchers placed drug-producing beads beside tumors and within the peritoneum, a sac-like lining that supports intestines, ovaries and other abdominal organs. Placement within this cavity concentrated interleukin-2 within tumors and limited exposure elsewhere.

"A major challenge in the field of immunotherapy is to increase tumor inflammation and anti-tumor immunity while avoiding systemic side effects of cytokines and other pro-inflammatory drugs," said study co-author Dr. Amir Jazaeri, professor of gynecologic oncology and reproductive medicine at MD Anderson. "In this study, we demonstrated that the 'drug factories' allow regulatable local administration of interleukin-2 and eradication of tumor in several mouse models, which is very exciting. This provides a strong rationale for clinical testing."

Interleukin-2 is a cytokine, a protein the immune system uses to recognize and fight disease. It is an FDA-approved cancer treatment, but Nash, a graduate student in Veiseh's group and the study's lead author, said the drug factories provoke a stronger immune response than existing interleukin-2 treatment regimens because the beads deliver higher concentrations of the protein directly to tumors.

"If you gave the same concentration of the protein through an IV pump, it would be extremely toxic," Nash said. "With the drug factories, the concentration we see elsewhere in the body, away from the tumor site, is actually lower than what patients have to tolerate with IV treatments. The high concentration is only at the tumor site."

Nash said the same general approach used in the study could be applied to treat cancers of the pancreas, liver, lungs and other organs. The drug factories could be placed next to tumors and within the linings that surround those organs and most others, she said. And if a different cytokine is needed to target a specific form of cancer, the beads can be loaded with engineered cells that make that immunotherapeutic compound.

The bead's outer shell shields its cytokine-producing cells from immune attacks. The shells are made of materials the immune system recognizes as foreign objects but not as immediate threats, and Veiseh's lab leveraged that in its design.

"We found foreign body reactions safely and robustly turned off the flow of cytokine from the capsules within 30 days," he said. "We also showed we could safely administer a second course of treatment should it become necessary in the clinic."

Avenge Bio, a Massachusetts-based startup co-founded by Veiseh, has licensed the cytokine-factory technology from Rice.

Additional co-authors include Maria Jarvis, Samira Aghlara-Fotovat, Sudip Mukherjee, Andrea Hernandez, Andrew Hecht, Yufei Cui, Shirin Nouraein, Jared Lee, David Zhang and Oleg Igoshin of Rice; Peter Rios, Sofia Ghani, Ira Joshi and Douglas Isa of CellTrans Inc.; Chunyu Xu and Weiyi Peng of the University of Houston; Rahul Sheth of MD Anderson; and José Oberholzer of both CellTrans Inc. and the University of Virginia.

The research was funded by the Cancer Prevention Research Institute of Texas (RR160047), Avenge Bio, the Emerson Collective, the Welch Foundation, the Rice University Academy of Fellows, the National Science Foundation (1842494) and the National Institutes of Health (R01DK120459).

Jazaeri receives compensation as a consultant on Avenge Bio's scientific advisory board and has disclosed the relationship to MD Anderson in accordance with its conflict-of-interest policy. Nash, Jarvis, Aghlara-Fotovat, Mukherjee, Hecht, Igoshin, Zhang and Veiseh declared interests via patents filed by Rice on the cytokine factories. Igoshin, Veiseh and Oberholzer are paid consultants for Avenge Bio. Nash, Zhang, Sheth, Oberholzer, Jazaeri and Veiseh hold equity in Avenge Bio.

Video: https://youtu.be/8HegA8q807o

---

Story Source:

Materials provided by Rice University. Original written by Jade Boyd. Note: Content may be edited for style and length.

---

Journal Reference:

1. Amanda M. Nash, Maria I. Jarvis, Samira Aghlara-Fotovat, Sudip Mukherjee, Andrea Hernandez, Andrew D. Hecht, Peter D. Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Yufei Cui, Shirin Nouraein, Jared Z. Lee, Chunyu Xu, David Y. Zhang, Rahul A. Sheth, Weiyi Peng, Jose Oberholzer, Oleg A. Igoshin, Amir A. Jazaeri, Omid Veiseh. Clinically translatable cytokine delivery platform for eradication of intraperitoneal tumors. Science Advances, 2022; 8 (9) DOI: 10.1126/sciadv.abm1032

https://www.sciencedaily.com/releases/2022/03/220302150351.htm

Daily walking steps needed for longevity benefit

 A meta-analysis of 15 studies involving nearly 50,000 people from four continents offers new insights into identifying the amount of daily walking steps that will optimally improve adults' health and longevity -- and whether the number of steps is different for people of different ages.

The analysis represents an effort to develop an evidence-based public health message about the benefits of physical activity. The oft-repeated 10,000-steps-a-day mantra grew out of a decades-old marketing campaign for a Japanese pedometer, with no science to back up the impact on health.

Led by University of Massachusetts Amherst physical activity epidemiologist Amanda Paluch, an international group of scientists who formed the Steps for Health Collaborative found that taking more steps a day helps lower the risk of premature death. The findings are reported in a paper published March 2 in Lancet Public Health.

More specifically, for adults 60 and older, the risk of premature death leveled off at about 6,000-8,000 steps per day, meaning that more steps than that provided no additional benefit for longevity. Adults younger than 60 saw the risk of premature death stabilize at about 8,000-10,000 steps per day.

"So, what we saw was this incremental reduction in risk as steps increase, until it levels off," Paluch says. "And the leveling occurred at different step values for older versus younger adults."

Interestingly, the research found no definitive association with walking speed, beyond the total number of steps per day, Paluch notes. Getting in your steps -- regardless of the pace at which you walked them -- was the link to a lower risk of death.

The new research supports and expands findings from another study led by Paluch, published last September in JAMA Network Open, which found that walking at least 7,000 steps a day reduced middle-aged people's risk of premature death.

The Physical Activity Guidelines for Americans, updated in 2018, recommends adults get at least 150 minutes of moderate-intensity aerobic physical activity each week. Paluch is among the researchers seeking to help establish the evidence base to guide recommendations for simple, accessible physical activity, such as walking.

"Steps are very simple to track, and there is a rapid growth of fitness tracking devices," Paluch says. "It's such a clear communication tool for public health messaging."

The research group combined the evidence from 15 studies that investigated the effect of daily steps on all-cause mortality among adults age 18 and older. They grouped the nearly 50,000 participants into four comparative groups according to average steps per day. The lowest step group averaged 3,500 steps; the second, 5,800; the third, 7,800; and the fourth, 10,900 steps per day.

Among the three higher active groups who got more steps a day, there was a 40-53% lower risk of death, compared to the lowest quartile group who walked fewer steps, according to the meta-analysis.

"The major takeaway is there's a lot of evidence suggesting that moving even a little more is beneficial, particularly for those who are doing very little activity," Paluch says. "More steps per day are better for your health. And the benefit in terms of mortality risk levels off around 6,000 to 8,000 for older adults and 8,000 to 10,000 for younger adults."

Story Source:

Materials provided by University of Massachusetts Amherst. Note: Content may be edited for style and length.

---

Journal Reference:

1. Amanda E Paluch, Shivangi Bajpai, David R Bassett, Mercedes R Carnethon, Ulf Ekelund, Kelly R Evenson, Deborah A Galuska, Barbara J Jefferis, William E Kraus, I-Min Lee, Charles E Matthews, John D Omura, Alpa V Patel, Carl F Pieper, Erika Rees-Punia, Dhayana Dallmeier, Jochen Klenk, Peter H Whincup, Erin E Dooley, Kelley Pettee Gabriel, Priya Palta, Lisa A Pompeii, Ariel Chernofsky, Martin G Larson, Ramachandran S Vasan, Nicole Spartano, Marcel Ballin, Peter Nordström, Anna Nordström, Sigmund A Anderssen, Bjørge H Hansen, Jennifer A Cochrane, Terence Dwyer, Jing Wang, Luigi Ferrucci, Fangyu Liu, Jennifer Schrack, Jacek Urbanek, Pedro F Saint-Maurice, Naofumi Yamamoto, Yutaka Yoshitake, Robert L Newton, Shengping Yang, Eric J Shiroma, Janet E Fulton. Daily steps and all-cause mortality: a meta-analysis of 15 international cohorts. The Lancet Public Health, 2022; 7 (3): e219 DOI: 10.1016/S2468-2667(21)00302-9

https://www.sciencedaily.com/releases/2022/03/220303112207.htm