Results Support Further Exploration of Therapeutic Potential of Lomecel-B to Slow Cognitive Decline, Improve Quality of Life for Alzheimer’s Patients
Phase 2 Trial Recently Launched With First Patient Treated
https://finance.yahoo.com/news/longeveron-publishes-peer-reviewed-study-120000534.html
Y-mAbs Therapeutics, Inc. (the “Company” or “Y-mAbs”) (Nasdaq: YMAB) a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, today announced that on March 31, 2022, the Company completed the resubmission of its Biologics License Application (“BLA”) for 131I-omburtamab (“omburtamab”) to the FDA.
Omburtamab is an investigational, monoclonal antibody that targets B7-H3, an immune checkpoint molecule that is widely expressed in tumor cells of several cancer types. The omburtamab BLA is for the treatment of pediatric patients with CNS/leptomeningeal metastasis from neuroblastoma. The submission is based on the safety and efficacy results of the pivotal Phase 2 studies 101 and 03-133, which the Company expects to publish later this year.
Eli Lilly and Company (NYSE: LLY) today announced updated data from the Phase 1/2 LIBRETTO-001 trial of Retevmo® (selpercatinib 40 mg & 80 mg capsules) in patients with RET fusion-positive non-small cell lung cancer (NSCLC). Retevmo (marketed as Retsevmo® outside of the U.S.) is a selective and potent RET kinase inhibitor that is approved in multiple countries including the United States for treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive NSCLC, and the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, or advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). These data were presented at the European Lung Cancer (ELCC) 2022 (poster 27p).
"The LIBRETTO trial provides the largest set of clinical data for a RET inhibitor and these results continue to demonstrate evidence of meaningful clinical outcomes for patients with metastatic RET fusion-positive NSCLC treated with Retevmo, including those with difficult-to-treat brain metastases," said David Hyman, M.D. chief medical officer, oncology at Lilly. "We are continuing to build on the robust body of evidence supporting Retevmo, including through an ongoing randomized Phase 3 confirmatory study, with a planned readout in 2023."
The updated analysis utilized a June 15, 2021, data cut-off and included 355 patients who were eligible for efficacy analysis, 247 of which were previously treated with at least one line of platinum chemotherapy and 69 of which were treatment-naïve. Patients who were previously treated with at least one line of platinum chemotherapy received a median of two prior treatment regimens (range: 1-15), with 58% having received anti-PD-1 or anti-PD-L1 therapy. Responses are based on independent review committee (IRC) assessment.
The Red Cross and Ukrainian Deputy Prime Minister Iryna Vereshchuk said that efforts are underway to evacuate civilians from the Ukrainian city of Mariupol as officials heed the humanitarian organization’s warnings, which have underscored the necessity to get Ukrainians out of the besieged city.
Vereshchuk and the International Committee of the Red Cross (ICRC) said that 45 buses were in transit to the city, with evacuations slated to begin on Friday, The Guardian reported.
The ICRC Ukraine posted a video on Twitter on Friday with a woman from the organization saying they were in transit to Mariupol “in order to ensure safe passage for the civilians who desperately want to flee the city.”
A safe corridor had been agreed to by Russia, the ICRC and Vereshchuk confirmed, but the ICRC signaled that the exact terms may not be fully agreed upon and urged both sides to come to a mutual accord on it, Reuters reported.
Mariupol has seen some of the worst devastation since Russia began its invasion into the neighboring country weeks ago, and the ICRC warned that the evacuation of its civilians was “hugely important.”
“Time is running out to help these people. This evacuation is hugely important,” Alyona Synenko, a spokesperson for the ICRC, said, according to The Guardian. “It is essential we get concrete and precise agreements from both sides on times and routes tomorrow. These instructions need to be conveyed to military units on the ground and they must be respected.”
The ICRC said last month that unless life-saving aid and evacuation routes are agreed upon, Mariupol residents could see a “worse-case scenario.”
“Hundreds of thousands of the city’s residents are now facing extreme or total shortages of basic necessities like food, water and medicine,” the ICRC said in a statement.
“People of all ages, including our staff, are sheltering in unheated basements, risking their lives to make short runs outside for food and water. Dead bodies, of civilians and combatants, remain trapped under the rubble or lying in the open where they fell.”
https://thehill.com/news/3256090-ukraine-rushing-to-evacuate-mariupol-after-red-cross-warnings/
Additional Exploratory Patient Subgroup and Virology Data from MOVe-OUT Presented at ECCMID
Among Patients With Infectious Virus at Baseline, No Patients Who Received LAGEVRIO Had Infectious Virus at Days 3, 5 or 10
https://finance.yahoo.com/news/merck-ridgeback-present-data-demonstrating-104000870.html
Hybrid immunity from a COVID-19 infection plus a vaccine provided an immune boost against symptomatic disease, as well as severe outcomes, Brazilian researchers found.
Among people who survived a COVID infection from Feb. 24, 2020 to Nov. 11, 2021, vaccine effectiveness against symptomatic disease at least 14 days after series completion was 44.0% (95% CI 31.5-54.2) for Johnson & Johnson's vaccine and 64.8% (95% CI 54.9-72.4) after two doses of Pfizer's vaccine, reported Julio Croda, MD, PhD, of Universidade Federal de Mato Grosso do Sul in Brazil, and colleagues.
Moreover, vaccine effectiveness against COVID-related hospitalization or death was 57.7% (95% CI -2.6 to 82.5) for Johnson & Johnson's vaccine, and 89.7% (95% CI 54.3-97.7) for Pfizer's, the authors wrote in Lancet Infectious Diseases.
While four COVID vaccines in total were evaluated (including AstraZeneca's vaccine and CoronaVac), only Johnson & Johnson's and Pfizer's are authorized for use in the U.S.
"There has been ongoing public debate about whether previously infected individuals need to be vaccinated," said Croda in a statement. "Our results suggest that vaccine benefits far outweigh any potential risk and support the case for vaccination, including the full vaccine series, among individuals with prior SARS-CoV-2 infection."
However, the authors noted that this analysis was done prior to the emergence of the Omicron variant.
Using national data, Croda and team identified 30,910 people (5.4% of the total 213,457 individuals who tested positive for COVID at least 90 days after the start of the vaccination program) who had a subsequent positive test "consistent with reinfection"; 22,566 were matched with 68,426 controls who tested negative.
Median age of the matched population was 36, and about 60% were women. Median time between first infection and a subsequent positive test was 216 to 223 days. About 65% of cases and 57% of controls were unvaccinated. Overall, 39,717 people were vaccinated -- about 80% were vaccinated with either AstraZeneca's vaccine or CoronaVac, 15% were vaccinated with Pfizer's vaccine, and 2% with Johnson & Johnson's.
Of the four examined vaccines, only Pfizer's vaccine showed a significant increase in effectiveness against symptomatic disease when given 180 days after the first infection versus 91 to 180 days (70.7% vs 35.3%, P=0.011).
An accompanying editorial by Pramod Kumar Garg, MBBS, MD, and Ramachandran Thiruvengadam, MD, of the Translational Health Science and Technology Institute in Faridabad, India, noted that the vaccine effectiveness estimates in this study are "generally lower than those in naive populations reported earlier," but added that these "estimates were for additional protection provided by vaccination over and above that offered by immunity resulting from natural infection."
This study "challenges the concept of population-level herd immunity through natural infection alone" and suggests that "vaccinating individuals who were previously infected provides further protection, particularly against severe disease," they noted.
"Understanding the duration and effectiveness of immunity for those vaccinated with a previous COVID-19 diagnosis becomes increasingly important as ... surges in new cases ... occur as a result of more transmissible variants," Croda said in a statement. "Further research on the need for vaccination for those with a previous COVID-19 infection is a vital step to pandemic policy intervention."
Even Sweden Finds Hybrid Immunity Is Best
A second study in Lancet Infectious Diseases found the lowest number of reinfections and hospitalizations among those with hybrid immunity.
Two-dose vaccination plus prior immunity resulted in a 66% lower risk of COVID reinfection versus infection alone (adjusted HR 0.34, 95% CI 0.31-0.39, P<0.001), with a non-significant trend towards attenuation after 9 months (P=0.07), reported Peter Nordström, MD, PhD, of Umeå University in Sweden, and colleagues.
In addition, two-dose hybrid immunity was linked with a significantly lower risk of COVID hospitalization compared with infection alone (aHR 0.10, 95% CI 0.04-0.22, P<0.001).
One dose of vaccine had similar results, albeit on a smaller scale. Hybrid immunity with one-dose vaccination resulted in a 58% lower risk of reinfection (aHR 0.42, 95% CI 0.38-0.47, P<0.001), with significant attenuation after 9 months. One-dose hybrid immunity also resulted in a lower risk of hospitalization (aHR 0.06, 95% CI 0.03-0.12, P<0.001).
Nordström and team examined data from Swedish nationwide registries, looking at infections from March 20, 2020 to Oct. 4, 2021, and hospitalizations with COVID from March 30, 2020 to Sept. 5, 2021. Cohort 1 included 2,039,106 unvaccinated individuals with prior infection who were matched with unvaccinated individuals without prior infection. Cohort 2 included 2,962,318 individuals with prior infection and one vaccine dose and cohort 3 included 567,810 individuals with prior infection and two vaccine doses, both matched to individuals with "natural immunity." Median age in all cohorts was 38 to 40.
Compared with unvaccinated individuals without infection, prior infection was associated with a 95% lower risk of reinfection at 3 months and a 87% lower risk of COVID hospitalization for up to 20 months of follow-up, the authors said.
During a mean follow-up of 66 days, 438 people with two-dose hybrid immunity were reinfected with COVID versus 808 with natural immunity. After a median follow-up of 52 days, there were 639 reinfections among those with one-dose hybrid immunity versus 1,662 reinfections in those with natural immunity.
Due to Omicron plus varying recommendations for boosters, hybrid immunity may result from "vaccination followed by infection," rather than vice-versa, noted Hyon-Xhi Tan, PhD, and Jennifer A. Juno, PhD, of the University of Melbourne in Australia, in an accompanying editorial.
However, they cited research that indicated that regardless of the order of infection and vaccination, "the quantity, quality, and breadth of the humoral immune response were vastly improved."
"This finding further supports the notion that infection histories should be an important consideration in determining whether individuals are protected against SARS-CoV-2," Tan and Juno wrote.
Disclosures
Cerqueira-Silva and colleagues were supported by the Brazilian National Research Council, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Oswaldo Cruz Foundation, JBS, Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Generalitat de Catalunya.
Co-authors disclosed support from the Fazer o Bem Faz Bem programme from JBS, Bristol Myers Squibb, Regeneron, Serimmune, and Tata Medical Devices.
Croda and several co-authors are employees of Fiocruz, a federal public institution, which manufactures Vaxzevria (ChAdOx1 nCoV-19 vaccine) in Brazil through a full technology transfer agreement with AstraZeneca.
Garg and Thiruvengadam disclosed no conflicts of interest.
Nordström and colleagues disclosed no conflicts of interest.
Tan and Juno disclosed no conflicts of interest.
Primary Source
The Lancet Infectious Diseases
Secondary Source
The Lancet Infectious Diseases
Source Reference: Garg PK, Ramachandran T "Effectiveness of SARS-CoV-2 vaccines in the post-natural infection world" Lancet Infect Dis 2022; DOI: 10.1016/S1473-3099(22)00207-9.
Additional Source
The Lancet Infectious Diseases
New research released today suggested that an over-stimulated immune system -- possibly triggered by ongoing vascular injury and repair -- may be behind persistent post-COVID cognitive changes.
In preliminary work that will be presented at the American Academy of Neurology annual meeting, researchers led by Joanna Hellmuth, MD, MHS, of the University of California San Francisco, found an "inflammatory signature" in the cerebrospinal fluid of 13 people who had lingering cognitive problems 10 months after they had their first COVID symptoms.
People with persistent cognitive problems after mild COVID-19 had higher levels of two inflammatory markers in their spinal fluid -- C-reactive protein and serum amyloid A -- compared with those who had COVID and no cognitive symptoms, Hellmuth and co-authors reported. Vascular endothelial growth factor markers were also higher in these people, with some measures specific to people who experienced cognitive changes soon after being infected.
"This is an important observation," said Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke at the NIH, who wasn't involved with the study. "It suggests vascular injury and repair in the brain may set up the inflammation," he told MedPage Today.
"Many millions of people experience persistent cognitive issues after SARS-CoV-2 infection, which can impact even young, healthy adults who had a mild case of COVID," Hellmuth noted. "However, there are not yet effective laboratory tests or treatments for COVID-associated cognitive changes, in part because we do not understand the underlying biology."
This is a very small study, Hellmuth acknowledged, but the findings, if true, imply that inflammation within the brain may contribute to cognitive changes after COVID, and COVID infection could trigger immunovascular dysregulation through endothelial activation and dysfunction.
Changes in the Brain
Earlier research found damage caused by thinning and leaky blood vessels in brain tissue samples of people who died with COVID, but did not link those changes and resulting inflammation with post-COVID cognition.
Other studies established that post-COVID cognitive changes were similar to symptoms seen after other viral infections like HIV or Ebola, or after chemotherapy.
"The symptoms of cognitive impairment after COVID-19 infection -- impaired attention, concentration, memory, speed of information processing, and executive function -- bear striking clinical similarities to the symptoms of cancer therapy-related cognitive impairment," Stanford University researcher Michelle Monje, MD, PhD, told MedPage Today. "Given these clinical similarities between 'chemo-fog' and 'COVID-fog,' we asked if there were also neurobiological similarities."
In preprint research awaiting journal publication, Monje and co-authors found parallels between the type of cell dysregulation that happens after chemotherapy and mild COVID-19. "We found the same pattern of white matter-predominant microglial reactivity in the brains of people with COVID-19 that we found in the people after chemotherapy," Monje said.
Recent research has shown that people with mild COVID had a greater decline in executive function -- notably in their ability to perform complex tasks -- that dovetailed with brain changes seen before and after COVID on MRI. In a U.K. Biobank study, 401 COVID patients showed a greater loss of gray matter volume and more brain tissue damage an average of 4.5 months after infection compared with people who never were infected.
"The U.K. Biobank study shows the first truly compelling data of a measurable change in the brain structure in people with COVID-19," said Serena Spudich, MD, a Yale University neurologist specializing in nervous system infections, who wasn't involved with the research.
"A key aspect of this study is its focus on people with mild COVID-19," Spudich told MedPage Today. "Only 4% of patients were hospitalized during their bout of acute COVID-19, so the findings come from a population that parallels the experience of most people worldwide who've been infected."
What Drives Cognitive Symptoms?
What drives post-COVID cognitive changes is still a mystery. "The mechanisms have not been very well studied," Nath said. "The indications are that there's at least a subset of persistent immune activation. Now the question is, what type of immune activation are we seeing?"
"My guess is that we're seeing largely macrophage activation, or what I call markers of innate immune response," he added. "What we see in the brain at autopsy is activation of microglia. Once those cells get turned on, they're very hard to turn off. Persistent symptoms are likely to come from that kind of immune activation."
A clinical trial could help move treatment forward while shedding light on what causes post-COVID brain changes, Nath suggested. "We have a lot of drugs that affect the immune system in various ways," he said. "We may be able to figure out what part of the immune system is really impaired and what is not, what is responding to treatment and what is not, and how that is corresponding to recovery."
The NIH plans to start a treatment trial of people with post-COVID cognitive problems, testing intravenous high-dose corticosteroids, intravenous immunoglobulin, and placebo soon, he noted.
"People say you need to know the mechanism behind this," Nath said. "And I would say, yes, that's absolutely true: you don't want to rush because you don't want to cause harm."
"But an argument I would make is that with COVID, you're dealing with a very different beast," he pointed out. "You've got billions of people infected. It takes years to figure out mechanisms. Can we really afford to wait that long?"
https://www.medpagetoday.com/neurology/generalneurology/97981
