Feds propose vaccine requirements if Canada-US border reopens

 Choosing to skip the COVID-19 vaccine could be problematic for those who wish to travel if the Canada-U.S. border reopens on June 21.

According to a proposed system created by an expert advisory panel, Canadians who return from abroad would be divided into four categories: fully vaccinated, partially vaccinated, unvaccinated and exempt.

Anyone who has proof they received one dose of the vaccine would require a negative test within 72-hours of their departure, a negative PCR test when they return and must quarantine at home until they receive a second negative test in seven days.

Unvaccinated travellers would have the same requirement with an automatic 14-day quarantine upon returning to Canada unless they're exempt from border restrictions.

Windsor Regional Hospital CEO David Musyj says only fully vaccinated Canadian's would be able to return home without a quarantine if they pass a PCR test at the border.

"It's not set in stone right now, but everything is leading towards the need to be, at a minimum, partially vaccinated but most likely fully vaccinated to allow for easy travel there or coming home," he says.

Musyj says those hesitating on the vaccine who think they won't need it will likely be in for a surprise.

"They make their decision for whatever reason, but if they want to travel somewhere outside the province and out of Canada, they're probably going to need it," he says.

Musyj says a commitment to discuss a vaccine passport at the upcoming G7 Summit means G7 countries, including Canada, are taking the idea seriously.

"When a prime minister like Boris Johnson mentions he wants an agreement audited on vaccine passport and our government issues a statement saying, yup, we need to have that discussion and have it now," he added.

The proposed plan would require proof vaccination such as a receipt issued by government officials — Ontario residents can receive a copy online if they've misplaced their receipt.

Changes to vaccination status would only take effect 14-days from the date of receiving a dose.

CLICK HERE to find the full proposal.

https://www.iheartradio.ca/am800/news/feds-propose-vaccine-requirements-if-canada-u-s-border-reopens-1.15350039

New insights into skull-based immune cells could inspire treatments for brain disease

 Some immune cells in the brain protect against disease, while others cause inflammation and other problems that can actually lead to disease. Researchers at Washington University School of Medicine in St. Louis are shedding light on the differences between these immune cell populations in two new studies.

The researchers discovered that some immune cells originate in the skull and migrate to the meninges—the tissues that line the brain and spinal cord—without passing through the bloodstream. The sole job of those skull-based immune cells is to shield the brain from disease, they explained in the journal Science.

The discovery could boost drug development for a wide range of brain diseases, the researchers believe.

"There has been this gap in our knowledge that applies to almost every neurological disease: neuro-COVID, Alzheimer's disease, multiple sclerosis, brain injury, you name it," said senior author Jonathan Kipnis, Ph.D., professor of pathology and immunology at Washington University, in a statement. "We knew immune cells were involved in neurological conditions, but where were they coming from? What we've found is that there's a new source that hasn't been described before for these cells."

Kipnis and his team had previously demonstrated that immune cells in the meninges shield the brain from harmful invaders. For one of the two new studies, he and his colleagues focused on “innate” immune cells, which cause inflammation that can heal injuries and defend against disease. But these cells can also cause damage and contribute to diseases like Alzheimer’s.

A second Washington University team zeroed in on “adaptive” immune cells, which can destroy viruses and cancer but sometimes mistakenly attack healthy tissues, causing diseases like multiple sclerosis. The researchers discovered that B cells in the adaptive immune system originate and mature in the skull’s bone marrow.

Those B cells learn how to tell the difference between normal proteins and those that indicate the presence of disease. Because they migrate from the skull to the brain via channels other than blood, they maintain that ability to patrol the central nervous system without attacking normal proteins, the researchers explained.

A separate set of B cells does travel into the meninges from the blood—and these cells are not as good at distinguishing normal from abnormal proteins, according to that team. Meanwhile, Kipnis and his colleagues discovered that innate meningeal myeloid cells, which flood injured brain tissues, are inflammatory when they travel from the blood.

The influence of immune cells in the brain on neurological diseases is an area of intense research, much of which has been focused on microglia, a subset of myeloid cells that remove debris. Last year, for example, researchers at Stanford University spun off a startup, Tranquis Therapeutics, to target dysfunctional microglia in neurologic disorders. Its lead asset is a drug that restores a downregulated metabolic pathway in myeloid cells.

The Washington University researchers believe their discoveries about the origins of immune cells in the brain could be used to design new therapies for inflammatory brain disorders. "The location of these cells in the skull makes them relatively accessible, and opens up the possibility of designing therapies to alter the behavior of these cells and treat neuro-immune conditions," Kipnis said.

https://www.fiercebiotech.com/research/how-new-insights-into-skull-based-immune-cells-could-inspire-new-treatments-for-brain

ASCO: Amgen deals 'knockdown punch' with Lumakras approval, but decades of work ahead

 You’d think Amgen would still be celebrating in the halls after scoring an FDA approval for the KRAS inhibitor Lumakras just one week ago, but there’s just too much to do.

The Thousand Oaks, California-based biotechnology company is instead looking to a new cohort from the drug's pivotal trial, which is beginning to reveal the patients most likely to benefit from the drug, formerly known as sotorasib. 

The new data, revealed Friday at the virtual American Society of Clinical Oncology meeting, could help Amgen move Lumakras up in the line of treatment for non-small cell lung cancer patients, a goal the company is actively working towards in other clinical trials.

Lumakras’ journey from “a twinkle in our eyes” to an approved product took only eight years, Amgen told Fierce Biotech last week. The FDA’s approval came months before the August action date, surprising pharmaceutical industry watchers and patients who were eagerly awaiting the decision.

“If you zoom out, the review wasn't just lightning fast, the entire program was lightning fast,” said Greg Friberg, Amgen VP and Therapeutic Area Head, Oncology, in an interview following the approval. “It's fantastic to be sitting here just under three years from the first patient being dosed and having that drug be available on the market for patients.”

Amgen intends to move fast to get the drug out to patients, too. The company had already built up a supply of product to ship out and Friberg estimates the first patients in the post-approval environment will receive doses within weeks.

“We've been moving at the fastest pace possible and the last thing we wanted was to have supply be a bottleneck. We're ready to go,” Friberg said. With the FDA approval in hand, Amgen is awaiting regulatory decisions around the world as well.

Meanwhile, at ASCO, the University of Texas MD Anderson Cancer Center’s Ferdinandos Skoulidis, M.D., Ph.D., is presenting findings from the phase 2 CodeBreaK 100 study that showed treatment with Lumakras induced a 37% objective response rate in patients and 12.5 months of median overall survival. These patients had KRAS G12C-mutated non-small cell lung cancer (NSCLC) and had previously received at least one or more rounds of treatment. Friberg said this study formed the “backbone” of the FDA application.

Skoulidis, assistant professor of Thoracic/Head & Neck Medical Oncology at MD Anderson, is thrilled that Lumakras is now approved and can be rolled out to patients, but he, like Amgen, says there’s still work to be done.

“If I were to use a boxing analogy, I would say that we have dealt KRAS a knockdown blow … [but] the fight is not over,” Skoulidis said in an interview.

Friberg estimates that with the approval in hand, the company and medical investigators like Skoulidis still “have a decade of work ahead of us” sorting through CodeBreaK and other studies involving the therapy.

“We're very early days,” Friberg said. “This is going to be a rich data set. We'll be using this data for some time to come.”

Amgen also plans to follow the patients in the trial for further long-term survival data, and Friberg hopes to see some long-term survivors coming back year after year.

The ASCO data did two things for Amgen: it began to reveal a picture of what is working and what isn’t in patients who receive the KRAS inhibitor. Or, in Friberg’s terms, what told a story and what did not tell a story. Amgen is now looking at the most granular data to ask why certain subsets of patients might have responded better, or why some did not.

“No story is a permanent negative, right? We ask the questions with the scientific method because we want to add anchor points,” Friberg said.

They found that patients with STK11 co-mutations did well on Lumakras, experiencing a 50% objective response, 11-month median progression-free survival and median overall survival of 15.3 months. Tumors with an STK11 mutation tend to have a poor response to standard-of-care therapies.

“A story is evolving here,” Friberg said. “It's important that we understand, particularly in cases where we know patients are in a very poor prognosis: Is this a drug that might be quite helpful for them and might be helpful earlier in their treatment?”

This co-mutation data is what Skoulidis found most interesting. He said the clinical activity seen in this subgroup of patients is “unprecedented and may suggest a clear avenue towards the further clinical development of sotorasib in the first-line disease setting.”

Skoulidis also pointed to a separate study to be presented at ASCO that discusses patient-reported outcomes on Lumakras, which is a once-daily oral medication. Treatment-related adverse events were mostly mild and manageable with care.

“This means that patients can enjoy an active life,” he said.

Going forward, Skoulidis wants to see more research on the molecular drivers of response to Lumakras and possible combination therapies that might prevent resistance.

Amgen has all that and more already going on in the clinic, but the data are still young. A first-line treatment trial is expected to kick off in the second half of the year.

Skoulidis and MD Anderson will continue to be involved in clinical trials for the therapy, including on the CodeBreaK 200 study that compares Lumakras with standard of care chemotherapy docetaxel. He’s also working on another clinical trial comparing the drug with other targeted therapies including checkpoint inhibitors.

https://www.fiercebiotech.com/biotech/amgen-deals-knockdown-punch-lumakras-approval-but-decades-work-lay-ahead

ASCO: Novartis radiotherapy ambition hit as Lutathera relegated to 'clinically relevant' survival edge

 Radiopharmaceuticals, along with cell and gene therapy, is one of the advanced drug platforms Novartis has pegged for long-term growth. But that ambition has hit a small setback.

Lutathera, the first radioligand therapy Novartis introduced to the market, failed to significantly prolong the lives of patients with midgut neuroendocrine tumors, according to data unveiled at the American Society of Clinical Oncology.

When used alongside Novartis’ own Sandostatin LAR in the phase 3 Netter-1 trial, Lutathera reduced the risk of death by 16% compared with solo Sandostatin LAR. But the improvement didn’t clear the statistical significance bar.

But Jonanthan Strosberg, M.D., principal investigator of the trial, was quick to note that adding Lutathera to the mix extended the median time patients lived by nearly a year; patients treated with the Lutathera regimen lived a median 48 months, versus 36.3 months for the control group.

“While not statistically significant, I consider this difference to be clinically relevant for these patients,” Strosberg said in a statement.

Multiple factors may have hurt Lutathera’s survival stats, Novartis said. A large number of patients in the control arm—about 36%—actually crossed over to receive Lutathera, Strosberg noted. Patients in the Netter-1 trial were allowed to receive other anti-cancer treatments after disease progression on their randomized treatment or upon finishing an 18-month treatment period.

Lutathera earned its initial FDA go-ahead in early 2018 for gastroenteropancreatic neuroendocrine tumors, after Netter-1 showed it could reduce the risk of disease progression or death by a whopping 79%. At that time, a planned interim analysis pointed to an estimated 48% reduction in the risk of death for Lutathera.

For a rare cancer type, Lutathera brought in sales of $445 million in 2020, in line with the prior year. The drug has so far been administered to more than 9,000 patients in Europe and U.S., according to Novartis Chief Medical Officer John Tsai.

“We believe in the potential of targeted radioligand therapy and are investing in new discovery and expansion of this important platform, including exploration of new radioisotopes and combinations with complementary mechanisms of action, such as immunotherapy and inhibitors of DNA damage response,” Tsai said in a statement Thursday.

Lutathera came to Novartis by way of its acquisition of Advanced Accelerator Applications. Netter-1 tested it in patients with well-differentiated, or G1, tumors. Novartis is now testing the drug in newly diagnosed patients with moderately- or poorly differentiated G2 and G3 tumors.

Also at ASCO, Novartis reported a phase 3 win for another radiotherapy dubbed 177Lu-PSMA-617, which it scored via the $2.1 billion buyout of Endocyte. The drug reduced the risk of death by 38% in patients with metastatic castration-resistant prostate cancer.

In addition to AAA and Endocyte, the Swiss drugmaker recently licensed rights to radioligand treatments targeting fibroblast activation protein, or FAP, from iTheranostics.

https://www.fiercepharma.com/pharma/novartis-radiotherapy-ambition-takes-small-hit-as-lutathera-relegated-to-clinically-relevant

After breakout year, Moderna on track to generate $15B+ in 2022 thanks to more demand, higher prices

 Moderna is hard at work ramping up production of its mRNA COVID-19 vaccine, which is projected to reap over $19 billion for the company by year’s end. But given that the pandemic is easing in parts of the world, what’s less certain is how 2022 will play out.

After a breakout year, Moderna sees strong reason to believe 2021 won't be a one-off boom year. That's thanks to the predicted need for booster shots and additional supply deals coupled with stronger pricing power, Jefferies analysts wrote to clients Thursday following a conversation with CEO Stéphane Bancel. 

The Jefferies team thinks Moderna could drive $15 billion in 2022 revenues, with an upper limit of $30 billion. Where the company lands will depend on how the pandemic progresses, fear of infection and whether the company can produce future products, like a combo shot against COVID and the flu. 

Plus, it’s possible that Moderna could start charging more per dose given its high efficacy, reliable manufacturing and absence of serious side effects that have plagued other vaccine developers, the analysts said. 

Moderna has said it can churn out between 800 million to 1 billion doses this year, and about 3 billion by 2022. The company has been ramping up supply lines with CDMO heavyweights and is planning a massive expansion at its own U.S.-based facilities to meet its lofty supply expectations. 

With more doses coming down the line, Moderna is already engaging with countries who weren’t able to secure supply this year, as well as with those that previously ordered adenovirus shots, Jefferies analysts wrote.

And discussions are ongoing with nations that already have supply deals, given that many have yet to begin inoculating children. The company’s shot has been used in people ages 18 and older, although the company is working to expand its use to those as young as 12, including in the U.S. 

The Cambridge, Massachusetts-based biotech is also developing three potential booster shots to target troublesome virus variants, including a lower dose of its original vaccine, one developed to target the variant first found in South Africa, and a combination of the two. 

It’s thought that some countries will “want to ensure there are adequate orders” for booster shots as early as six months to a year after the first vaccines were administered, the Jefferies team said. 

Pandemic shots aren’t the only sales prospects Moderna has in its back pocket, Jefferies said. The mRNA developer is also working on a shot for seasonal influenza, with initial results anticipated by the end of the year. 

https://www.fiercepharma.com/pharma/optimistic-about-future-need-for-covid-19-vaccines-moderna-could-bring-about-15b-2022-sales

Early Alzheimer's Trajectories May Vary Widely

 Early Alzheimer's disease progressed with high variability and this may influence whether treatment effects truly are detected in clinical trials, a simulation study suggested.

Individual trajectories on commonly used cognitive measures -- the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale Cognitive (ADAS-cog) -- differed greatly among individuals with prodromal and mild Alzheimer's, even among seemingly homogenous groups, reported Roos Jutten, PhD, of Amsterdam UMC in the Netherlands, and co-authors.

As a result, the 95% range of group differences observed on cognitive measures over 18 months was broad, spanning from 0.35 points improvement to 0.35 points decline on the CDR-SB, for example, they wrote in Neurology.

"Alzheimer's disease patients show substantial variation in how fast or slow their cognitive functions decline over time," Jutten told MedPage Today. "This heterogeneity in disease progression is a problem for clinical trials, which want to show that a drug or treatment can slow or halt cognitive decline."

"We investigated how natural variability in disease progression may lead to significant group differences that are not due to the therapy administered, but instead reflect patient differences in their rate of decline," she said.

"We also studied ways to reduce variability in rates of decline, by looking only at subgroups that had increased risk for fast progression, such as APOE4 carriers," Jutten continued. "An unexpected outcome of our study is it is even more difficult to find treatment effects in these high-risk groups, because they show more within-group variability in decline instead of less."

The findings highlight an important challenge of trial design, noted Rachel Buckley, PhD, of Massachusetts General Hospital in Boston, and David Knopman, MD, of Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

"In the absence of a widely accepted therapeutic success threshold to serve as a starting point, what is a minimal therapeutic benefit that is clinically meaningful?" Buckley and Knopman asked.

"Clinical meaningfulness has been an elusive concept in the world of Alzheimer's disease therapeutics," they added. "The description by Jutten et al. of the 95% confidence interval for random variation in slope of several widely used outcome measures provides a rational estimate of a floor for what clinically meaningful therapeutic benefit should look like."

In their study, Jutten and co-authors identified 302 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline MMSE score of 24 or higher, global Clinical Dementia Rating score of 0.5, and at least one follow-up cognitive assessment. These were the baseline characteristics of the aducanumab EMERGE and ENGAGE trials, they noted.

Mean age of the sample was 73, 44% were women, mean education was 16.1 years, and 69% were APOE4 carriers.

The researchers simulated a clinical trial by randomly assigning individuals to "placebo" and "treatment" groups (even though no treatment was actually given), using longitudinal cognitive data to estimate change from baseline over 18 months. This gave them the variability in effect sizes between a placebo and treatment group if heterogeneity in progression wasn't accounted for. They repeated this simulation 10,000 times to determine the 95% range of effect sizes.

They compared this to effect sizes that have been reported for recent trials of several anti-amyloid drugs with similar inclusion criteria and found that, with the exception of the aducanumab EMERGE trial, the treatment effects fell within the 95% boundaries -- in other words, within the range that could be expected if there were no treatment effect.

"This suggests that, even though within some trials, differences between placebo and treatment groups were statistically significant, the possibility cannot be excluded that those differences were actually due to oversampling of fast decliners in the placebo group or oversampling of slow decliners in the treated group," Jutten and co-authors wrote.

We further showed that, when repeating our simulation for separate risk factors associated with disease progression, a positive APOE4 status and baseline abnormal total tau levels were associated with steeper cognitive decline at a group level, but also with greater variability in progression," they added. "This resulted in even broader ranges of effect sizes in these high-risk groups on all outcome measures (e.g., ±0.70 points for the CDR-SB in those with baseline abnormal tau)."

A run-in period that captures an individual's cognitive trajectory, using biomarkers as primary endpoints, or larger sample sizes may solve the problem, but these solutions have limitations.

"Overly large sample sizes invite the prospect of detecting therapeutic effects that are statistically significant but clinically trivial," Buckley and Knopman noted. "While designing a better outcome measure using criteria to exclude persons who are not likely to decline or using other strategies to minimize measurement error, therapeutics with larger effect sizes are what the field ultimately needs."

The study had several limitations, Jutten and colleagues acknowledged. The simulation was based on ADNI participants, a relatively highly educated sample with little racial and ethnic diversity. Some participants in ADNI had 6-month follow-up data, which may have led to less decline and less variability in change over time. Selection criteria and follow-up timeframe were based on the aducanumab EMERGE and ENGAGE studies, and there may be small differences with criteria used in other trials.

Disclosures

Alzheimer Center Amsterdam, Amsterdam UMC is supported by Alzheimer Nederland and Stichting VUmc funds.

Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI), which receives support from the National Institutes of Health and Department of Defense.

The researchers reported no disclosures relevant to this manuscript.

Buckley reported no disclosures relevant to the manuscript. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network study. He also serves on a Data Safety Monitoring Board for Biogen but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He serves as a consultant for Roche, Samus Therapeutics, Third Rock, and Alzeca Biosciences but receives no personal compensation.

Primary Source

Neurology

Source Reference: Jutten RJ, et al "Finding treatment effects in Alzheimer trials in the face of disease progression heterogeneity" Neurology 2021; DOI: 10.1212/WNL.0000000000012022.

Secondary Source

Neurology

Source Reference: Buckley RF, Knopman DS "Cognitive heterogeneity in Alzheimer clinical trials: harnessing noise to achieve meaningfulness" Neurology 2021; DOI: 10.1212/WNL.0000000000012027.

https://www.medpagetoday.com/neurology/alzheimersdisease/92934

Argentina expects mass production of Russian vaccine in July

 Argentinean Ambassador to Russia Eduardo Zuain said on Friday that his country is keeping its plans to start large-scale production of the Sputnik V vaccine in July.

The Nikolai Gamaleya National Research Center, the developer of the vaccine, confirmed on Tuesday the high quality of the batch prepared by the Argentinean laboratory as a test and sent for review in Russia.

The Argentinean representative in Moscow told Sputnik news agency at the International Economic Forum in Saint Petersburg (Spief 2021) that the next stage will be the import of antigens, a step to be taken in the near future.

Zuain stressed that despite the pandemic, Argentina and Russia are now experiencing 'an excellent time in bilateral relations' and highly valued the cooperation between the two states in the fight against Covid-19.

In this regard, he underscored the supply of the Sputnik V vaccine to Argentina, as well as the transfer of Russian technology for its manufacture.

Zuain recalled that he is not only interested in manufacturing the Russian vaccine for its use in Argentina, but also to export it to Latin America.

https://www.plenglish.com/index.php?o=rn&id=68088&SEO=argentina-expects-mass-production-of-russian-vaccine-in-july