Eisai takes baton from Biogen as next Alzheimer's prospect follows in Aduhelm's footprints

 Eisai made history last year as Biogen’s partner on Aduhelm, the first approved Alzheimer’s treatment in decades. And yes, they know the launch could have gone better.

“Lessons learned? Yes, there were many. We can go on hours about things that we could have done better,” said Ivan Cheung, Eisai’s chairman and global president of the neurology business group. “But that's what it is to be the first.”

Now Eisai will have a chance to be second, too, or at least race Eli Lilly for the honor. The Japanese pharma and Biogen are moving their follow-up treatment, lecanemab, through the rolling submission process, hoping to obtain an accelerated approval just like the predecessor therapy did.

And this time, Eisai is in the driver’s seat. While Biogen took the lead on Aduhelm's clinical development, regulatory interactions with the FDA and commercial rollout, the script has flipped for lecanemab.

Cheung knows his team is heading into challenging terrain with lecanemab, but this is a place Eisai has been before. In 1996, the company launched Aricept, a daily oral treatment for Alzheimer’s, jointly marketed with Pfizer, that was groundbreaking at the time.

When Aricept launched, Alzheimer’s was not very well understood by the general public. Some even questioned whether it was a disease to be treated or just a part of the natural aging process, Cheung said.

Aricept, which is known generically as donepezil, treats symptoms of dementia caused by Alzheimer’s and was eventually approved for all stages of the disease in 2006. But the therapy’s effects are temporary, only lasting as long as the patient takes it. Symptoms are managed while taking Aricept, but the treatment does not affect the underlying cause of disease. That’s what Biogen and Eisai are trying to do with Aduhelm, and soon, lecanemab.

“It was extremely difficult in the beginning days of Aricept, and you can ask me whether the beginning of Aduhelm was more difficult than that of Aricept, I don't know how to compare,” Cheung said. “But we have experiences to tell you it's never easy to be the first, and we knew that.”

Lecanemab is not being set up as a “me too” treatment behind Aduhelm. Cheung has big hopes that the up-and-coming treatment will take over the market just as Aricept did two decades ago.

One thing lecanemab can potentially improve upon is Aduhelm's rate of amyloid-related imaging abnormalities (ARIA), a problem that shows up in MRI imaging that suggests swelling or bleeding in the brain. This is a known side effect associated with amyloid therapies that has cropped up in Aduhelm trials. In November 2021, one trial patient taking Aduhelm reportedly died after an ARIA diagnosis.

With Aduhelm, a pooled analysis of two phase 3 studies found MRI abnormalities in 41% of patients, compared to just 10% of placebo patients. The adverse event was asymptomatic in 76% of cases, and only 0.3% were reported as serious.

Michael Irizarry, M.D., Eisai’s senior VP of clinical research and deputy chief clinical officer of the neurology business group, said that a midstage study of lecanemab showed about a 10% incidence of ARIA, with only 2% reported as symptomatic. With the lessons learned from Aduhelm, Eisai has a monitoring plan in place for any patient identified to have ARIA.

Another way lecanemab is setting itself apart from its predecessor is that the phase 3 clinical trial, called Clarity AD, is geared toward discovering the therapy's clinical benefits. Remember, Aduhelm was controversially approved on the basis of biomarker data—the new Alzheimer’s buzzword—which means the therapy showed it reduced beta amyloid in the brain. Researchers believe beta amyloid builds up in the brain of Alzheimer's patients, causing problems. 

The FDA green light was not based on evidence that Aduhelm is clinically beneficial and mitigates cognitive decline. For that, Biogen and Eisai are working on a phase 4 confirmatory trial to prove clinical benefit and maintain the FDA approval.

This time around with lecanemab, Eisai is shooting to have those data in hand much sooner in the product's life span. The phase 3 trial completed enrollment in March and will try to verify earlier findings that the therapy can reduce amyloid in the brain and therefore have an impact on clinical benefit and that amyloid biomarker.

Earlier studies of lecanemab have shown consistent reduction of amyloid and improvements in clinical decline, Cheung said. These data were published in a peer-reviewed journal.

“We as a team are confident in that clinical efficacy from that phase 2b data, but of course, that’s only one study. That’s why we’re doing Clarity AD to prove it one more time,” Cheung said.

The Clarity study, which is expected to read out in the fall, will be much bigger than the midstage test and is being done with “rigor” in terms of recruitment and how it’s conducted, Irizarry added.

Eisai also said Wednesday that enrollment has begun in the phase 2/3 Tau NexGen study being conducted by the Washington University School of Medicine in St. Louis, which will use two of the Japanese pharma's Alzheimer's therapies. Lecanemab will serve as the background anti-amyloid therapy, while an earlier-stage asset, tau antibody E2814, will be the investigational medicine. The study features asymptomatic and symptomatic patients with dominantly inherited Alzheimer’s, a type of the disease that is caused by genetic mutations and is passed down in families.  

Calling back to the Aricept days, Cheung said another thing that’s different this time around is that Alzheimer's patients are identified earlier in the disease course. So new Alzheimer’s treatments can be offered earlier in a patient’s journey to prevent damage that can’t be corrected later.

Explaining the difference between a biomarker and clinical efficacy remains a communication challenge for patients, though. Not to mention the fact that treatments like Aduhelm or lecanemab are meant to address the disease, not necessarily reverse symptoms.

“What it means to receive a so-called disease-modifying therapy versus receiving a symptomatic treatment, I think the majority of the public don't understand that,” Cheung said. “This is about early diagnosis, early treatment, and then you can slow down the progression of the disease. It’s a fairly different concept.”

To help with the public understanding of lecanemab, Eisai is laying all the data out for the world to see.

“We don't believe in any easy path. I think Alzheimer's is challenging, but we are confident and at the end of the day the data speaks for itself,” Cheung said.

https://www.fiercebiotech.com/biotech/eisai-takes-baton-from-biogen-as-next-alzheimer-s-prospect-follows-aduhelm-s-footprints

Stop sugarcoating cancer cells to empower CAR-T therapy in solid tumors

 To repeat the success of CAR-T therapies in blood cancers, a key direction for solid tumor research focuses on enabling the engineered immune cells to better target those tumors. Now, a group of scientists in Italy has proposed a method to do just that.

Sugar-based structures called N-glycans, which are expressed on the surface of pancreatic tumor cells, could protect the cancer from CAR-T cells, scientists at the IRCCS San Raffaele Scientific Institute have found. Disruption of the coating with a sugar analog dubbed 2DG enhanced CAR-T killing in different mouse models of pancreatic tumors and showed promising efficacy against other cancers in lab dishes.

The findings, published in Science Translational Medicine, could pave the way to designing improved CAR-T cell therapy strategies against pancreatic cancer and other solid tumors, the researchers said.

Glycosylation, the process by which sugar-based molecules attach to and modify a protein, plays an important role in cellular processes. Cancer cells display abnormal glycosylation, with the expression of a more diverse glycan coat compared with healthy cells. Among them, an increase in N-glycans is among the most frequent alterations found in cancer.

For their study, the San Raffaele researchers hampered branched N-glycan in pancreatic tumor cells by crippling the MGAT5 gene, which encodes for an enzyme key to the synthesis of the sugar-based coat. They treated the cancer cells with CAR-T cells directed at CD44v6, a heavily glycosylated protein. The CAR-T cells showed markedly enhanced antitumor activity with increased cancer-killing and the production of the proimmune cytokines interferon-gamma and TNF-alpha.

By digging deeper into the mechanism behind the improved efficacy, the researchers found that N-glycans interfered with the formation of immunological synapses. CARs rely on such synapses with tumor cells to activate the T cells and exert their functions.

The team then tried blocking N-glycan with the glucose analog 2DG. In two xenograft mouse models of pancreatic cancer, a combination of 2DG and the CAR-T cells showed the best tumor control, significantly prolonging the survival of mice compared with either single treatment alone, the team reported.

What’s more, in mice that also received 2DG, T cells that entered the tumors showed a reduced exhaustion profile with lower expression of several immune inhibitory markers such as TIM-3 and PD-1. Exhaustion of T cells, which could be caused by sustained antigen stimulation and the expression of inhibitory receptors, is a major obstacle to CAR-T cell efficacy against solid tumors.

“These findings suggest that combination with 2DG not only improves tumor clearance but might also enable CAR-T cells to evade immune checkpoint inhibition,” the researchers wrote in the study.

Beyond pancreatic cancer, the addition of 2DG also helped increase the killing of other highly glycosylated tumors that CD44v6 CAR-T alone failed to tackle, including in mice with bladder cancer and ovarian cancer.

CAR-T therapies such as Gilead Sciences’ Yescarta have demonstrated impressive results in blood cancers, and scientists are in hot pursuit of effective solutions to overcome the many barriers that stop the immunotherapy from working in solid tumors.

To tackle the problem of there being a lack of appropriate tumor-specific antigens that a CAR can target, a team at the University of Pennsylvania's Children’s Hospital of Philadelphia designed “peptide-centric” CAR-T cells to hunt down fragments of cancer-related proteins that are revealed to immune cells through antigen-presenting MHC proteins.

Canadian biotech Oncolytics Biotech is working on an oncolytic virus called pelareorep to alter the hostile tumor microenvironment that could suppress T-cell activity. Working with Mayo Clinic, the company previously showed CAR-T cells armed with the virus enhanced antitumor activity in mice with solid tumors.

The San Raffaele team now believes breaking down the sugar barrier around tumor cells represents a promising strategy to overcome solid tumors' resistance to CAR-T therapy by improving CAR-T cell activation and alleviating CAR-T cell exhaustion.

“Our findings point to the therapeutic potential of combining CAR-T cells with 2DG to counteract multiple layers of tumor resistance including the inadequate tumor engagement and the damaging effects of inhibitory pathways,” the researchers said in the study.

https://www.fiercebiotech.com/research/stop-sugarcoating-cancer-cells-to-empower-car-t-therapy-solid-tumors

COVID Lab-Leak Whitewash Has Been 'The Death Of Science' Says Professor Who Found 'Unique Fingerprints'

 University of London professor Angus Dalgleish, who co-authored a paper in summer 2020 after spotting "unique fingerprints" in Covid-19 samples that point to genetic manipulation, says that he's been the victim of a "disgusting whitewash," and that anyone suggesting a non-natural origin for Covid-19 has been silenced by peers.

"This goes back to the days of Copernicus and Galileo - it is the death of science," said the oncologist - who in 1984 discovered how HIV enters and kills cells.

Dalgleish's work was roundly rejected by a string of journalists before it was eventually published in a 'watered-down form,' according to the Express.

In February 2020, the Lancet had published a letter that “strongly condemned conspiracy theories” suggesting that Covid-19 does not have a natural origin. This highly influential letter – subsequently cited in thousands of scientific publications – was signed by 27 experts including Wellcome Trust head and former Sage member Sir Jeremy Farrar.

However, it has since emerged that two weeks before the letter was published, Sir Jeremy stated in private emails that some senior scientists believed a ‘likely explanation’ was that the virus was man-made. -Express

Indeed, Farrar led a February 1, 2020 teleconference (one day after Farrar emailed Anthony Fauci about a Zero Hedge article suggesting Covid may have come from the Wuhan Institute of Virology) - in which one virologist was "80 percent sure this thing had come out of a lab," with others sharing his view.

Dalgleish is the author of a book on Covid which claims the virus has "no credible natural ancestor." He says his team found amino acids within the Covid-19 spike protein with a positive charge - allowing the virus to cling to negative parts of the body.

But it was highly unusual to find so many positive charges in a row because they also repel each other, he said.

“We realised when they released the sequence of the virus it broke the laws of physics for a natural virus meaning it was genetically modified. 

“At the time my position was supported by Sir Richard Dearlove, the former head of MI6 who now chairs the University of London board of trustees.”

However, when they tried to publish their work they were turned down by numerous papers, including the Lancet. 

“My paper was rejected within five hours”, he said. “Normally it takes three weeks before it is even peer reviewed.” -Express

According to Dalgleish, "It was a political decision for this to be suppressed," adding that after the paper was released, "I was ostracised. I was fearful - really frightened at the way I was being treated."

"I was told I was not an expert on coronavirus’ and should just shut up. People tried to push us away. We were told our theory had no rationale and it was a conspiracy theory. I am so angry about this. I have more virus papers cited than most virology experts and they tried to push me aside. 

"They did not even look at the science. It was obvious it was a gain of function escape from a lab and I say escape, but that is generous. We had this data in late February after the sequences were released.

"This has been a whitewash. This whole thing has killed science. Science is meant to look at evidence. It is truly unbelievable."

According to Jacques van Helden, a bioinformatics professor at Aix-Marseille University in France, Peter Daszak's February 2020 Lancet letter effectively shut down debate over the origins of Covid-19.

"By labelling anyone with different views a conspiracy theorist, the Lancet letter was the worst form of bullying in full contravention of the scientific method," said van Helden," adding "To say that something has leaked from a lab does not make it a conspiracy theory."

"Why was that letter signed by so many people? Why can’t we discuss this issue in a scientific journal? I do not want to have to resort to an open exchange on Twitter."

https://www.zerohedge.com/covid-19/covid-lab-leak-whitewash-has-been-death-science-says-professor-who-found-unique

Prior COVID infection more protective than vaccination during Delta surge -U.S. study

 People who had previously been infected with COVID-19 were better protected against the Delta variant than those who were vaccinated alone, suggesting that natural immunity was a more potent shield than vaccines against that variant, California and New York health officials reported on Wednesday.

Protection against Delta was highest, however, among people who were both vaccinated and had survived a previous COVID infection, and lowest among those who had never been infected or vaccinated, the study found.

Nevertheless, vaccination remains the safest strategy against COVID-19, according to the report published in U.S. Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report.

The results do not apply to the Omicron variant of the virus, which now accounts for 99.5% of COVID-19 cases in the United States.

"The evidence in this report does not change our vaccination recommendations," Dr. Ben Silk of the CDC and one of the study's authors told a media briefing.

"We know that vaccination is still the safest way to protect yourself against COVID-19," he said.

For the study https://www.cdc.gov/mmwr/volumes/71/wr/mm7104e1.htm?s_cid=mm7104e1_e&ACSTrackingID=USCDC_921-DM73434&ACSTrackingLabel=MMWR%20Early%20Release%20-%20Vol.%2071%2C%20January%2019%2C%202022&deliveryName=USCDC_921-DM73434, health officials in California and New York gathered data from May through November, which included the period when the Delta variant was dominant.

It showed that people who survived a previous infection had lower rates of COVID-19 than people who were vaccinated alone.

That represented a change from the period when the Alpha variant was dominant, Silk told the briefing.

"Before the Delta variant, COVID-19 vaccination resulted in better protection against a subsequent infection than surviving a previous infection," he said.

In the summer and fall of 2021, however, when Delta became the predominant circulating iteration of the virus in the United States, "surviving a previous infection now provided greater protection against the subsequent infection than vaccination," he said.

But acquiring immunity through natural infection carries significant risks. According to the study, by November 30, 2021, roughly 130,781 residents of California and New York had died from COVID-19.

The analysis did not include information on the severity of initial infection, nor does it account for the full range of illness caused by prior infection.

One important limitation to the study was that it ended before administration of vaccine booster doses was widespread.

Dr. Erica Pan, state epidemiologist for the California Department of Public Health, said in an email that the study "clearly shows" that vaccines provide the safest protection against COVID-19 and they offer added protection for those with prior infections.

"Outside of this study, recent data on the highly contagious Omicron variant shows that getting a booster provides significant additional protection against infection, hospitalization and death,” Pan said.

Silk said the CDC is studying the impact of vaccination, boosters and prior infection during the Omicron surge and expects to issue further reports when that data becomes available.

https://www.marketscreener.com/quote/stock/MODERNA-INC-47437573/news/Prior-COVID-infection-more-protective-than-vaccination-during-Delta-surge-U-S-study-37590078/

Japanese airlines resume U.S. Boeing 777 flights after 5G rollout

 

Two major Japanese airlines said Wednesday they will restore flights to the United States after the deployment of 5G mobile in the United States had prompted some foreign carriers to cancel numerous U.S. bound flights.

A decision by AT&T and Verizon Communications to delay switching on the powerful new telecom masts near key airports, following protests from airlines about possible interference, came too late to avoid a ripple of cancellations on Wednesday.

Japan Airlines and All Nippon Airways said Wednesday they would resume Boeing 777 service to the United States on Thursday after announcing cancellations earlier based on guidance from Boeing.

Both airlines said they had been told by the Federal Aviation Administration (FAA) there is no safety issue after the reduced wireless deployment.

United Airlines said Wednesday it forecast only "minor disruptions at some airports due to the remaining 5G restrictions" and praised the Biden administration's deal with AT&T and Verizon "to avoid mass cancellations across the aviation industry."

Airlines across Asia and several in the Middle East and Europe had said they were cancelling some flights or switching models, with much of the initial disruption hitting the Boeing 777, for decades a workhorse of long-distance air travel.

Dubai's Emirates, the largest user of the Boeing mini-jumbo, kicked off a slew of industry cancellations or aircraft changes late on Tuesday, saying it would suspend nine U.S. routes.

The airline's veteran president Tim Clark told CNN the carrier had not been aware of the extent of the problem until Tuesday and called it "one of the most delinquent, utterly irresponsible" episodes he had seen, a CNN reporter tweeted.

The disruption caps a weeks-long dispute between airlines and telecom companies over the speed of deployment of 5G mobile services in the United States, mirrored by tensions between regulators of the economically sensitive industries.

U.S. airlines and the FAA have warned that the frequencies and transmission strength being deployed in the United States could interfere with the precise height readings needed for bad-weather landings on some jetliners.

European regulators say no risks have been found elsewhere.

The U.S. wireless carriers agreed on Tuesday to delay turning on 5G near key airports but are pressing ahead with the wider U.S. deployment on Wednesday of services designed to serve tens of millions of people.

Late on Tuesday, the FAA began updating guidance on which airports and aircraft models would be affected, in a move expected to dramatically lessen the impact of the nearly 1,500 notices of 5G restrictions previously issued by the regulator.

Even so, dozens of flights had to be cancelled or modified, pushing shares in European long-haul carriers down about 2%.

"The last-minute postponement happened too late to stop the crews being sent out for today's (return) flight. It just made it a nightmare," said a pilot with a major European airline.

OFF SEASON

Analysts said a slump in long-haul flying caused by pandemic border restrictions would limit the immediate impact, however.

"It's the off season, so in January or February airlines will be losing money and that's not counting the impact of the pandemic. At the moment they are fighting for survival," said James Halstead, managing partner at UK-based Aviation Strategy.

"Where it might hurt is that some airlines are using the same long-haul aircraft to carry freight," he added.

Korean Air Lines said it had switched planes on six U.S. passenger and cargo flights, Taiwan's China Airlines rescheduled some flights and Hong Kong's Cathay Pacific said it would change aircraft types if needed.

Radio altimeters give precise readings of the height above the ground on approach and help with automated landings, as well as verifying a jet has landed before allowing reverse thrust.

Boeing said it was working with all parties on a "data-driven solution for the long-term that ensures all commercial airplane models can operate safely as 5G is deployed."

The 777 last year was the second-most used widebody plane on flights to and from U.S. airports with around 210,000 flights, behind the older 767, according to data from FlightRadar24.

In other disruption, Germany's Lufthansa said it had cancelled one flight and was switching aircraft on others.

Air India said its four U.S. flights would be curtailed or face changes in aircraft type starting from Wednesday.

Singapore Airlines said it had switched the aircraft used on select U.S. routes.

British Airways switched its daily flight to Los Angeles to an Airbus A380 from the usual Boeing 777 service and cancelled or modified other U.S. flights.

Cargo airlines AeroLogic and Polar diverted away from Cincinnati to Atlanta, according to web tracker FlightRadar24 which said Atlanta was not subject to 5G related restrictions.

Not all 777 flights have been hit. Emirates said it would keep flying the 777 to Washington, which is not so far affected.

Qatar Airways and Air France said U.S. routes were operating as scheduled and Israel's El Al and Abu Dhabi's Etihad Airways said their services had not been affected. Kenya Airways said it was taking precautions outlined by Boeing and the FAA.

https://www.marketscreener.com/news/latest/Japanese-airlines-resume-U-S-Boeing-777-flights-after-5G-rollout--37580348/

Unilever ADRs Bounce Back After Co. Commits to Financial Discipline

 Unilever PLC's U.S. stock rebounded Wednesday after the consumer-goods company said it won't increase its 50 billion pounds ($67.98) bid for GlaxoSmithKline PLC's majority-owned consumer healthcare division.

In midday trading, the American depositary receipts were 9.4% higher at $50.82.

The ADRs dropped 14% Tuesday, touching a 52-week low during the session, on the first day of trading after Unilever over the weekend said it had approached Glaxo and Pfizer Inc. about buying the business in an effort push further into health, beauty and hygiene products. The healthcare business is 68% owned by Glaxo, which said it rejected Unilever's approaches on the basis they undervalued the business, and 32% by Pfizer.

Unilever said it is committed to maintaining strict financial discipline to ensure acquisitions create value for its shareholders.

https://www.marketscreener.com/quote/stock/UNILEVER-PLC-9590186/news/Unilever-ADRs-Bounce-Back-After-Co-Commits-to-Financial-Discipline-37589782/

Petros Pharmaceuticals Extend Fall After Study News

 Petros Pharmaceuticals Inc. shares were down 17% to $1.92 Wednesday, one day after the company said it has begun two self-selection studies for its erectile dysfunction drug, Stendra avanafil.

The stock closed Tuesday's session down 11%.

The company said the results of these studies will be part of a more comprehensive data package it plans to submit to the U.S. Food and Drug Administration to potentially achieve over-the-counter status for Stendra.

Petros said a self-selection study ensures that consumers can make appropriate decisions based on their own personal health circumstances about whether to use a particular drug product. The initiation of these self-selection studies follows encouraging topline pivotal label comprehension results.

In the self-selection non-clinical studies, individuals who are interested in utilizing an over-the-counter ED product are recruited to review the draft over-the-counter labelling and to determine whether the product is, or isn't, appropriate for them to use without the intervention of a healthcare professional, the company said.

Results from these two self-selection studies, one conducted in the general population and the other specific to nitrate medicine users, will be shared with the FDA for input and alignment for the company's OTC development plan.

Petros said it expects to review the results with the FDA during a pre-IND interaction it anticipates having during the first half of 2022.

https://www.marketscreener.com/quote/stock/PETROS-PHARMACEUTICALS-I-116081118/news/Petros-Pharmaceuticals-Extend-Fall-After-Study-News-37589794/