Category Archives: Cell Medicine

Parkinsons disease (PD) is the most common neurodegenerative movement disorder, afflicting more than 10 million people worldwide and more than one million Americans. While there is no cure for PD, current therapies focus on treating motor symptoms and fail to reverse, or even address, the underlying neurological damage. In a new study, researchers at the Medical University of South Carolina (MUSC) have identified a novel role for the regulatory protein Bach1 in PD. Their results, published on Oct. 25 in the Proceedings of the National Academy of Sciences, showed that levels of Bach1 were increased in postmortem PD-affected brains, and that cells without Bach1 were protected from the damages that accumulate in PD. In collaboration with vTv Therapeutics, they identified a potent inhibitor of Bach1, called HPPE, that protected cells from inflammation and the buildup of toxic oxidative stress when administered either before or after the onset of disease symptoms.

This is the first evidence that Bach1 is dysregulated in Parkinsons disease, said Bobby Thomas, Ph.D., professor of Pediatrics in the College of Medicine and the SmartState COEE Endowed Chair in Pediatric Neurotherapeutics.

In PD, brain cells that produce the chemical messenger dopamine begin to die as the disease progresses, resulting in tremors and other disruptions to motor function. Additionally, as we age, neurons accumulate damage through inflammation and the buildup of toxic oxidative stress.

There are many genes that combat these destructive pathways, many of which are controlled by two key proteins: Nrf2 and Bach1. Nrf2 functions to turn on the expression of over 250 genes that are involved in protecting the cell from these stressors. Conversely, Bach1 prevents these genes from being activated.

Thomas lab found that levels of Bach1 are increased in autopsied brains of patients with PD, as well as toxin-based preclinical PD models, suggesting that high levels of Bach1 may contribute to PD pathophysiology. To confirm this, the researchers depleted Bach1 in a PD mouse model and showed that dopamine-producing neurons were protected from some of the destructive stress pathways.

To determine how the loss of Bach1 protected neurons from accumulated stress, they analyzed the entire genome of brains from Bach1-depleted mice and looked at which genes were activated.

What we found was that Bach1 not only represses the expression of protective genes that are under the control of Nrf2, but it also regulates the expression of many other genes not directly regulated by Nrf2, said Thomas. So there are additional advantages to inhibiting Bach1 besides just activating Nrf2. Ideally you would want a drug that inhibits Bach1 and also activates Nrf2.

To that end, Thomas partnered with the North Carolina-based company vTv Therapeutics to develop Bach1 inhibitors. Using its proprietary TTP Translational Technology platform, vTv discovered several potential candidates that were validated by Thomas. The top candidate, HPPE, functioned as a superior Bach1 inhibitor in in vitro models. Importantly, HPPE was also a potent activator of Nrf2.

Therefore, pharmacological intervention using HPPE provided the dual benefit of stabilizing Nrf2 and inhibiting Bach1. But how would HPPE work in a preclinical PD mouse model?

The effectiveness of HPPE was tested in a neurotoxin-based PD mouse model. HPPE alleviated toxin-induced PD symptoms when given either before the induction of disease or after the onset of disease symptoms. Further analyses showed that HPPE protects neurons from destructive pathways by turning on antioxidant genes and turning off pro-inflammatory genes.

Interestingly, HPPE worked better at protecting neurons than current FDA-approved Nrf2 activators, such as Tecfidera (dimethyl fumarate). Current activators function as electrophiles they permanently bind to and modify proteins which can lead to cellular toxicity or activation of the immune system and have many side effects.

The most interesting aspect of the study is that the Bach1 inhibitor is a non-electrophile, so it doesnt work like the FDA-approved Nrf2 activators, said Thomas. As a result of this difference, hopefully, HPPE will not demonstrate as many side effects.

Disruption of Bach1 and the simultaneous activation of Nrf2 clearly provide a strong basis for using HPPE as a potential therapeutic in PD. But several questions remain unanswered. While there were no side effects observed with acute treatment using HPPE in the PD mouse model, one key goal moving forward is to determine what impacts, if any, long-term use of HPPE might have. Another key question centers on the benefits of modulating this pathway in more chronic models of PD, other cell types in the brain and potentially other dementias.

Thispathway may be beneficial whenever you have impairments in anti-inflammatorypathways or mitochondrial dysfunctions, said Thomas. I think any disease thathas these kinds of etiologies would benefit from modulating this pathway.

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Deterioration of brain cells in Parkinson's disease is slowed by blocking the Bach1 protein, preclinical study shows - Medical University of South...

Dr. Michael Kaplitt, a professor of neurological surgery at Weill Cornell Medicine and a longtime leader in developing cutting-edge surgical therapies for movement disorders, leads a team that has been awarded a three-year, $8.9 million grant from the Aligning Science Across Parkinsons (ASAP) initiative. The grant will fund an ambitious and innovative multi-institutional collaborative effort to study how abnormal protein aggregates may spread from the gut to the brain to drive the early stages of Parkinsons disease.

Dr. Michael Kaplitt. Credit: Stephanie Diani

ASAP is a coordinated research initiative to advance targeted basic research for Parkinsons disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources and data sharing. The Michael J. Fox Foundation for Parkinsons Research is ASAPs implementation partner and issued the grant.

I am so grateful to ASAP and The Michael J. Fox Foundation for this exciting opportunity, said Dr. Kaplitt, who is also vice-chair for research in the Department of Neurological Surgery at Weill Cornell Medicine and a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center. Interaction between the body and the brain is a very exciting and important area of research, and it is increasingly clear that, at least in some cases, Parkinsons disease may begin in the gut, with the disease spreading through nerve connections to the brain and eventually throughout the brain.

Parkinsons disease is a progressive neurodegenerative disease that is considered chiefly a movement disorder, although it typically features many other signs and symptoms, from sleep problems and low blood pressure to dementia. Parkinsons affects more than 10 million people worldwide and has no cure.

One clue to the cause of the disorder is the presence of abnormal clumps of protein within brain cells in affected brain regions. These clumps mainly consist of tiny, fiber-like aggregates of the brain-cell protein alpha synuclein. The synuclein fibrils tend to spread through the brain in a characteristic pattern during the course of Parkinsons. There is evidence suggesting that, in many cases, these disease-linked fibrils form initially in nerve cells in the intestines and trigger the classic signs of Parkinsons only after they travel to the brain, via a large gut-to-brain nerve called the vagus nerve.

Dr. Kaplitt and his collaborators will use a recently developed mouse model of this gut-to-brain disease-seeding process to explore in detail how it begins in the intestines, how it relates to early, pre-motor Parkinsons signs including sleep disorders, and whether it differs between maleswho are known to get Parkinsons at a higher rateand pre-menopausal females. Ultimately the researchers will try to develop methods for the early detection of gut alpha-synuclein aggregates and the blocking of their spread to the brain to prevent full-blown Parkinsons. Dr. Kaplitt will draw on his extensive experience in developing and testing experimental gene therapies for Parkinsons.

Bringing our nearly 30 years of experience with gene therapy to this project will allow us to not only understand how this gut-to-brain transmission happens, but also potentially intervene genetically to improve brain function and stop the spread of disease, said Dr. Kaplitt, who is also a professor of neuroscience in the Feil Family Brain and Mind Research Institute, a professor of neurological surgery in neurology and of neurological surgery in otolaryngology at Weill Cornell Medicine.

Dr. Kaplitt will collaborate with co-investigators Dr. Ted Dawson, director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine, and Dr. Per Svenningsson, a professor of neurology at Karolinska Institutet and Karolinska University Hospital in Sweden, on the research. Co-investigator Dr. Roberta Marongiu, assistant professor of neuroscience research in neurological surgery and assistant professor of research in neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, will conduct the research examining sex and menopause effects.

It is exciting to be part this fantastic team of international investigators, said Dr. Dawson. There is a growing amount of evidence of the guts role in Parkinsons disease, and we are developing excellent scientific models to study the diseases progression from the start. Our multidisciplinary approach holds tremendous promise in identifying innovative ways to treat Parkinsons disease.

"It is very stimulating to work on this excellent team to increase our understanding of mechanisms underlying the propagation of alpha-synuclein from the gut to the brainstem,"added Dr. Svenningsson.

We are excited to work with our outstanding international team of leading investigators to address different aspects of this question, said Dr. Kaplitt.

It is extremely exciting to work alongside this outstanding team of investigators, said Dr. Marongiu. My group will study how sex and menopause influence the spread of Parkinsons disease pathology from the gut to the brain in the early stages of the disease. This will help us understand more about the intricate relationship between hormones and onset of Parkinsons and has the potential to identify novel precision medicine approaches for men and women.

Other members of Dr. Kaplitts team include Drs. Chris Schaffer and Nozomi Nishimura, associate professors at the Meinig School of Biomedical Engineering at Cornell University, who will use innovative methods they have developed to image vagus-linked gut neurons, to track the spread and the physiological effects of early synuclein pathology. Dr. Babacar Cisse, assistant professor of neurological surgery at Weill Cornell Medicine, a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center and an expert in immune cells in the brain called microglia, will investigate whether microglia are responsible for some of the patterns of spread once the pathology enters the brain from the gut.

"We are so honored that Dr. Kaplitt and his team have been selected for this grant," said Dr. Philip E. Stieg, chair of neurological surgery at Weill Cornell Medicine and neurosurgeon-in-chief of NewYork-Presbyterian/Weill Cornell Medical Center. "There is no neurosurgeon in the world better qualified than he is to do this work. Dr. Kaplitt has been a pioneer in functional neurosurgery, particularly for movement disorders, for many years now and is a true leader in the field.

Bringing together this international team of the most forward-thinking, most innovative researchers in Parkinson's disease holds so much promise for patients, he added. We all look forward to the discoveries that come from this research, which has the potential to create effective new treatments for this debilitating disease."

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$9M Grant Funds Study of Gut-Brain Connection in Parkinson's Disease - Weill Cornell Medicine Newsroom

News Release

Friday, October 15, 2021

Intravenous immune globulin (IVIG) a common treatment for multisystem inflammatory syndrome in children (MIS-C) likely works by depleting immune cells called neutrophils, according to a recent study funded by the National Institutes of Health (NIH). MIS-C is a rare condition that usually affects school-age children who initially had only mild COVID-19 symptoms or no symptoms at all. The researchers also found that IVIG works in a similar manner for treating Kawasaki disease, another rare inflammatory condition that affects children and shares symptoms with MIS-C. The findings are published in the Journal of Clinical Investigation.

MIS-C is marked by severe inflammation of two or more parts of the body, including the heart, lungs, kidneys, brain, skin, eyes and gastrointestinal organs. Its symptoms overlap with Kawasaki disease, and treatments for MIS-C are guided in part by what is known about treating Kawasaki disease. IVIG, which is made up of antibodies purified from blood products, is a common and effective treatment for heart complications caused by Kawasaki disease. For MIS-C patients, however, IVIG alone does not always resolve symptoms, and healthcare providers may need to prescribe additional anti-inflammatory drugs.

To better understand how IVIG works and to improve treatments for children with MIS-C, researchers led by Ben A. Croker, Ph.D., and Jane C. Burns, M.D., from the University of California San Diego School of Medicine, profiled immune cells from patients with MIS-C or Kawasaki disease. The team sampled cells before treatment began as well as 2 to 6 weeks after patients received IVIG. The researchers found that neutrophils from these patients were highly activated and a major source of interleukin 1 beta (IL-1), which is one driver of inflammation in the body. After IVIG treatment, these activated neutrophils were significantly depleted in patients with MIS-C or Kawasaki disease.

According to the study authors, their findings are the first to explain why IVIG is effective for both conditions. However, more work is needed to understand how IVIG causes cell death in these activated neutrophils and why certain patients with MIS-C require additional anti-inflammatory treatments. Overall, the research will help healthcare providers as they determine the most effective methods to treat patients with MIS-C.

The study is funded by NIHs Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of General Medical Sciences (NIGMS). The work is supported by NIHs CARING for Children with COVID, PreVAIL kIds and RADxSM-rad research programs.

Rohan Hazra, M.D., acting director of NICHDs Division of Extramural Research, is available for comment.

Zu YP et al., Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C. JCI DOI: 10.1172/JCI147076 (2021)

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visit https://www.nichd.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Antibody treatment for MIS-C works by depleting inflammatory immune cells - National Institutes of Health

Harry Paul Erba, MD, PhD, discusses the evolution of treatment in mantle cell lymphoma.

Harry Paul Erba, MD, PhD, instructor, clinical investigator, Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, member, Duke Cancer Institute, director, Leukemia Program and Phase I Development in Hematologic Malignancies, Duke Health, discusses the evolution of treatment in mantle cell lymphoma (MCL).

Similar to acute myeloid leukemia, the goal of therapy in MCL should be the key focus from treatment initiation. For example, a younger patient with limited comorbidities should be considered for curative-intent therapy or treatment with a time-limited regimen to elicit deep responses and prolonged progression-free survival, Erba says.

High-dose cytarabine-based therapies, such as the Nordic regimen known as maxi-CHOP, and autologous stem cell transplant could be considered for patients with MCL, Erba explains. Oral therapies, including BTK inhibitors, are also available options for patients with relapsed/refractory MCL or older patients who cannot tolerate intensive chemotherapy, Erba concludes.

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Dr. Erba on the Evolution of Treatment in MCL - OncLive

Brad S. Kahl, MD, discusses the potential utility of frontline CAR T-cell therapy in mantle cell lymphoma.

Brad S. Kahl, MD, professor of medicine, Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in St. Louis, discusses the potential utility of frontline CAR T-cell therapy in mantle cell lymphoma (MCL).

CAR T-cell therapy has the potential to move into earlier lines of treatment, including the frontline setting, in MCL; however, longer follow-up is needed with CAR T-cell therapy in the relapsed/refractory setting before frontline clinical trials can be explored, Kahl says. Currently, CAR T-cell therapy is demonstrating high response rates at 12 and 18 months of follow-up in the relapsed/refractory setting, but it is unknown whether these responses will remain durable at 3 or 5 years.

Positive 3-year data in the relapsed/refractory setting could provide the clinical rationale to evaluate CAR T-cell therapy in the frontline setting, Kahl says. Pending these results, CAR T-cell therapy could replace autologous stem cell transplant as consolidative therapy or offer a standard option for patients with high-risk biologic features, such as TP53 mutations, Kahl concludes.

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Dr. Kahl on the Potential Utility of Frontline CAR T-Cell Therapy in MCL - OncLive

CAMBRIDGE, Mass., Oct. 15, 2021 (GLOBE NEWSWIRE) -- Generation Bio Co. (Nasdaq: GBIO), a biotechnology company innovating genetic medicines for people living with rare and prevalent diseases, today announced an oral presentation at the European Society of Gene and Cell Therapy (ESGCT) Annual Virtual Congress taking place October 19-22. The presentation will highlight preclinical advances from the companys retina therapeutic area.

We are excited to share our preclinical data demonstrating broad access to key cell types with our lipid nanoparticle developed for the retina, said Matthew Stanton, Ph.D., chief scientific officer of Generation Bio. Many inherited retinal diseases remain out of reach for viral-based gene therapies due to limited cargo capacity. We believe our non-viral delivery technology could overcome this barrier and expand the potential of our genetic medicine platform to treat more diseases.

The presentation will be streamed online for registered attendees on October 22, and a recording of the presentation will be made available for attendees for 30 days following the event.

Generation Bio will present:

About Generation BioGeneration Bio is innovating genetic medicines to provide durable, redosable treatments for people living with rare and prevalent diseases. The companys non-viral genetic medicine platform incorporates a novel DNA construct called closed-ended DNA, or ceDNA; a unique cell-targeted lipid nanoparticle delivery system, or ctLNP; and a highly scalable capsid-free manufacturing process that uses proprietary cell-free rapid enzymatic synthesis, or RES, to produce ceDNA. The platform is designed to enable multi-year durability from a single dose, to deliver large genetic payloads, including multiple genes, to specific tissues, and to allow titration and redosing to adjust or extend expression levels in each patient. RES has the potential to expand Generation Bios manufacturing scale to hundreds of millions of doses to support its mission to extend the reach of genetic medicine to more people, living with more diseases, around the world.

Story continues

For more information, please visit http://www.generationbio.com.

Contacts:

InvestorsMaren KillackeyGeneration Bio541-646-2420mkillackey@generationbio.com

MediaAlicia WebbGeneration Bio847-254-4275awebb@generationbio.com

Lisa RaffenspergerTen Bridge Communications617-903-8783lisa@tenbridgecommunications.com

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Generation Bio to Present at European Society of Gene and Cell Therapy 2021 Annual Virtual Congress - Yahoo Finance

In my mind, the question is not who should get chemotherapy, but who can avoid chemotherapy in this day and age.

As more and more targeted therapy options emerge in the cancer space, investigators continue to see positive impacts on long-term outcomes. However, this wider, advanced, individualized range of treatment options that may be offered to patients requires more sophisticated molecular testing techniques.

In an interview with ONCOLOGY, Charu Aggarwal, MD, MPH, discussed this topic as it relates to her ongoing research, as well as how it may carry to other areas of oncology care outside of her area of expertise in the lung cancer space. She is the Leslye M. Heisler Associate Professor for Lung Cancer Excellence in the Department of Medicine at the University of Pennsylvanias Perelman School of Medicine in Philadelphia as well as co-chair for the 6th Annual International Congress on Immunotherapies in Cancer, hosted by Physicians Education Resource, LLC (PER).

Aggarwal spoke about how liquid biopsies, rather than invasive procedures, can help determine treatment prognosis. She also detailed how immunotherapy has evolved as a mainstay of treatment and how clinicians are now looking at adverse effects (AEs) as a positive sign of treatment efficacy.

A: Molecular genotyping is becoming extremely important in nonsmall cell lung cancer. At least 9 biomarkers1 must now be tested at initial diagnosis, and the gold standard for testing has been to use tissue-based testing. [However], its often a problem to get tissue because these biopsies are small and sometimes not enough tissue or not enough DNA [is present] on these samples. [So then] we asked, Could we complement our ability to test for these mutations using tissue alone by adding in plasma-based sequencing? We conducted a follow-up trial with about 300 patients here [at the University of Pennsylvania] and found that by adding plasma-based approaches, using 2 tubes of blood, we could get [results] relatively easier compared with tissue-based sequencing.2 We were able to increase our detection of molecular alterations from about 20% to about 36%a significant increase. This means that more patients were able to get targeted therapy, receive a drug based on their molecular profile, and have significant benefit. Patients were able to avoid chemotherapy or immunotherapy.

We are currently doing much more with liquid biopsies [and are] really looking at the dynamics of circulating tumor DNA [ctDNA], to guide whether patients are responding to treatment. If the ctDNA goes down, that gives us a sense, an indicator, that the therapy is working, [possibly] before we get a radiographic response, before I even get the CT scan. [Liquid biopsy] is an active area of research that I think will be extremely interesting.

A: Exactly. Thats the point: We can [check progress] in a minimally invasive way.

A: Lung cancer is among the leading cancer subtypes where liquid biopsies are being used. Thats because a significant amount of ctDNA is shed into the bloodstream in patients with advanced disease. [Also], lung cancer has so many different [molecular, actionable] subtypes that now have targetable drugs. We can say [to a patient], You have an EGFR mutation or You have a MET exon 14 [skipping] mutationIm going to give you a pill. There is more actionability in lung cancer than in other diseases. However, breast cancer, gastrointestinal cancer, and genitourinary cancer are all now [using] liquid biopsies and expanding the space to utilize it in the clinical setting.

A: I think we are getting there. Were not completely there, because we still need a few things from tissue samples. We can never characterize the cell type or the architecture of a tumor, which are still very necessary, with a liquid biopsy. Looking at tissue is still extremely important, no matter what. I think plasma or liquid biopsies will be essential to give us information about the rest of the tumor. In fact, it sometimes gives us a clearer picture of the heterogeneous nature of the tumor, so we can get a sense of the cells that may have more metastatic potential and may have a slightly different mutational profile. We can gather that [information] much better than we can with a single small biopsy.

A: The most obvious indication that [a treatment is working is] less tumor. However, were also looking at other things like methylation signatures, RNA sequencing, and changes in mutational profile over time that may help us eventually [determine how treatment is going].

A: We have learned a great deal about when to use targeted therapy in lung cancer. We need to know a patients molecular subtype. One way we [learn] that is by using both tissue and plasma sequencing, which is a must. Once we know the molecular subtype, the next question is how we utilize the information to guide therapy. In my mind, the question is not who should get chemotherapy, but who can avoid chemotherapy in this day and age. I feel that with the explosion of immunotherapy, we can now deliver immunotherapy safely with a survival benefit for most of our patients. There will always be a subset who dont get immunotherapy, but the vast majority of our patients can, and we use PD-L1 testing to determine which patients can get immunotherapy alone. Again, thats only for a small subset of patients; for [the rest, were still] using a combination of chemotherapy and immunotherapy.

A: The premise of immunotherapy is reactivating the immune system and harnessing the power of T cells during cancer treatment. We know that our T cells as well as our bodies are inherently programmed to fight cancer. However, cancer cells may express inhibitory molecules; these can then be inhibited using PD-L1 inhibitors, potentially creating the immune response again. Thats the premise: the immune activation thats inherent in the immune system to fight cancer.

A: Many guidelines now help us with managing irAEs in a stepwise fashion, including guidelines from the National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the American Society of Clinical Oncology. Id [like to] add that recent evidence suggests that the presence of irAEs in patients who receive immunotherapy may be related to better outcomes, depending on the grade of AEs. Preliminary data, at least, suggest that grade 2 and 3 AEs may be better in terms of predicting for an improved outcome to immunotherapy, which I think is very interesting. Its reminiscent of the old days when we used to look at things like rash from EGFR inhibitors [to] tell us that the drug is working, [and] also that they are more likely to see a response.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

1. NCCN. Clinical Practice Guidelines in Oncology. Nonsmall cell lung cancer, version 5.2021. Accessed September 2, 2021. https://bit.ly/3DGrtPb

2. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic nonsmall cell lung cancer.JAMA Oncol. 2019;5(2):173-180. doi:10.1001/jamaoncol.2018.4305

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Modern Treatment Standards Require State-of-the-Art Molecular Profiling - Cancer Network

SUMMIT, N.J., Oct. 14, 2021 /PRNewswire/ -- Seqirus, a global leader in influenza prevention, and a business of CSL Limited (ASX:CSL), today announced that The New England Journal of Medicine has published absolute efficacy data on the company's cell-based quadrivalent influenza vaccine (QIVc) from a randomized controlled trial (RCT) which met its primary endpoint.1 The study indicates that the seasonal influenza vaccine was effective and produced a sufficient immune response against influenza in children and adolescents 2 to <18 years of age over three influenza seasons in theSouthern (2017) and Northern (2017/18 and 2018/19) Hemispheres, compared to a non-influenza comparator.1 This represents the first absolute efficacy study of a cell-based influenza vaccine in children as young as two years of age.

"In this study, QIVc demonstrates absolute efficacy in children and adolescents, showing consistent benefit across three seasons and eight countries.1 This is particularly impactful giventhe disease burden in children as young as two years of age," said Jonathan Edelman, MD, Vice President, Clinical Development at Seqirus and study author. "These data add to a growing body of evidence supporting the fact that our differentiated, cell-based seasonal influenza vaccine can help provide effective protection against flu."

QIVc utilizes a cell-based influenza vaccine manufacturing process, an alternative to traditional egg-based manufacturing.2 Traditional egg-based vaccine production can cause the strain to mutate at several steps throughout the manufacturing process, which may lead to an antigenic mismatch between the circulating strains and the inactivated influenza strains contained within the seasonal influenza vaccine.2

Cell-based influenza vaccines are designed to produce an exact match to the World Health Organization (WHO)-selected influenza virus strains by avoiding egg-adapted changes, and therefore have the potential for greater vaccine effectiveness.2,3 Cell-based influenza vaccine technology may offer additional advantages over the standard influenza manufacturing process, including increased scalability and production speed in the event of an influenza pandemic.2

"Young children are at a higher risk than adults for serious influenza-related complications.4 We're particularly pleased with the results of this study because it supports the use of our differentiated, cell-based influenza vaccine technology as an effective means of influenza protection in children as young as two years old," said Gregg Sylvester, MD, Chief Medical Officer at Seqirus.

The results of this study supported the recent U.S. Food and Drug Administration (FDA) approval for an expanded age indication for use of QIVc in children 2 years of age.5 QIVc is marketed in the U.S. as FLUCELVAX QUADRIVALENT (Influenza Vaccine) and is currently under review by the FDA for an expanded age indication for children as young as six months of age.5

The Centers for Disease Control and Prevention (CDC) recommends annual seasonal influenza vaccination for everyone six months of age and older without contraindications as the best way to prevent seasonal influenza.6 It is estimated that more than 52,000 hospitalizations occurred in children younger than 18 years of age during the 2019/20 U.S. influenza season, and there were approximately over 434 influenza-related deaths in this age group.7

In the U.S., Seqirus operates a state-of-the-art cell-based manufacturing facility in Holly Springs, North Carolina, purpose-built in partnership with the Biomedical Advanced Research and Development Authority (BARDA) to increase cell-based vaccine manufacturing capacity and combat pandemic influenza threats.8 Last year, Seqirus announced plans to build a new, world-class cell-based manufacturing facility in Australia, which will be the only cell-based influenza vaccine manufacturing facility in the Southern Hemisphere.9

About the Study

This phase III/IV multi-center, randomized, observer-blind study was conducted across eight countries (Australia, Philippines, Thailand, Estonia, Finland, Lithuania, Poland, and Spain) over three influenza seasons Southern Hemisphere (2017) and Northern Hemisphere (2017/18 and 2018/19).1

The study was designed to demonstrate the efficacy and safety of QIVc in children 2 to <18 years of age, compared to a non-influenza comparator.1 A total of 4514 subjects (n= 2258 QIVc, n=2256 comparator (Menveo, meningococcal [Serogroup ACYW-135] conjugate vaccine)) were enrolled.1 The primary endpoint was the first occurrence of laboratory-confirmed influenza illness (by RT-PCR or viral culture) occurring between >14 days after last vaccination and the end of the influenza season.1 The influenza attack rate in the QIVc group was 175/2257 (7.8%; 6.5% to 10.2% over three seasons), compared with 364/2252 (16.2%; 15.2% to 17.4% over three seasons) cases in the control group.1

The efficacy of QIVc in children and adolescents against laboratory-confirmed influenza illness was 54.6% (95% CI 45.7 to 62.1), meeting the pre-specified endpoint for success and showing benefit across three seasons and eight countries.1

The safety profile of QIVc was comparable to the non-influenza comparator.1

About Seasonal Influenza

Influenza is a common, contagious seasonal respiratory disease that may cause severe illness and life- threatening complications in some people.10 Influenza can lead to clinical symptoms varying from mild to moderate respiratory illness to severe complications, hospitalization and in some cases, death.10 Because transmission of influenza viruses to others may occur one day before symptoms develop and up to 5 to 7 days after becoming sick, the disease can be easily transmitted to others.10 Estimates from the CDC report that during the 2019/20 influenza season, there were an estimated 405,000 influenza-related hospitalizations in the U.S.7 The CDC recommends annual vaccination for individuals aged 6 months and older, who do not have any contraindications.6 Since it takes about two weeks after vaccination for antibodies to develop in the body that help protect against influenza virus infection, it is recommended that people get vaccinated before influenza begins spreading in their community.6 The CDC recommends that people get vaccinated by the end of October.6 For non-pregnant adults, getting vaccinated too early (for example, in July or August), should be avoided, unless there is concern that later vaccination may not be possible, as it can be associated with reduced protection against influenza infection later in the flu season.6

About Seqirus

Seqirus is part of CSL Limited (ASX: CSL). As one of the largest influenza vaccine providers in the world, Seqirus is a major contributor to the prevention of influenza globally and a transcontinental partner in pandemic preparedness. With state-of-the-art production facilities in the U.S., the U.K. and Australia, and leading R&D capabilities, Seqirus utilizes egg, cell and adjuvant technologies to offer a broad portfolio of differentiated influenza vaccines in more than 20 countries around the world.

About CSL

CSL (ASX:CSL) is a leading global biotechnology company with a dynamic portfolio of life-saving medicines, including those that treat hemophilia and immune deficiencies, as well as vaccines to prevent influenza. Since our start in 1916, we have been driven by our promise to save lives using the latest technologies. Today, CSL including our two businesses, CSL Behring and Seqirus provides life- saving products to more than 100 countries and employs more than 27,000 people. Our unique combination of commercial strength, R&D focus and operational excellence enables us to identify, develop and deliver innovations so our patients can live life to the fullest. For more information about CSL Limited, visit http://www.csl.com.

For more information visit http://www.seqirus.com and http://www.csl.com.

Intended Audience

This press release is issued from Seqirus USA Inc. in Summit, New Jersey, USA and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved Seqirus products may vary from country to country. Please consult your local regulatory authority on the approval status of Seqirus products.

Forward-Looking Statements

This press release may contain forward-looking statements, including statements regarding future results, performance or achievements. These statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future results, performances or achievements expressed or implied by the forward-looking statements. These statements reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements.

FLUCELVAX QUADRIVALENT (Influenza Vaccine)IMPORTANT SAFETY INFORMATION

What is FLUCELVAX QUADRIVALENT (Influenza Vaccine)?

FLUCELVAX QUADRIVALENT is a vaccine that helps protect people aged 2 and older from the flu. Vaccination with FLUCELVAX QUADRIVALENT may not protect all people who receive the vaccine.

Who should not get FLUCELVAX QUADRIVALENT?

You should not get FLUCELVAX QUADRIVALENT if you have had a severe allergic reaction to any of the ingredients in the vaccine.

Before receiving FLUCELVAX QUADRIVALENT, tell your healthcare provider about all medical conditions, including if you:

What are the most common side effects of FLUCELVAX QUADRIVALENT?

Additional side effects seen in children include:

These are not all of the possible side effects of FLUCELVAX QUADRIVALENT. You can ask your healthcare provider for more information and for advice about any side effects that concern you.

To report SUSPECTED ADVERSE REACTIONS, contact Seqirus at 1855358-8966 or VAERS at 18008227967 or http://www.vaers.hhs.gov.

You are also encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1800FDA1088.

Before receiving this vaccine, please see the full US Prescribing Information for FLUCELVAX QUADRIVALENT. The information provided here does not include all that is known about FLUCELVAX QUADRIVALENT. To learn more, talk with your healthcare provider or pharmacist.

FLUCELVAX QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates.

All other trademarks referenced herein are the property of their respective owners.

USA-QIVc-21-0085

MEDIA CONTACTMaria Tortoreto+1 (201) 248-5208[emailprotected]

REFERENCES

1 Nolan T, Fortanier AC, Leav B, et al. Efficacy of a Cell-CultureDerived Quadrivalent Influenza Vaccine in Children. N Engl J Med. DOI: 10.1056/NEJMoa2024848.

2 Centers for Disease Control and Prevention (CDC). (2021). Cell-Based Flu Vaccines. Retrieved from: https://www.cdc.gov/flu/prevent/cell-based.htm. Accessed September 2021.

3 Rajaram, S., Boikos, C., Gelone, et al. (2020). Influenza Vaccines: The Potential Benefits of Cell-Culture Isolation and Manufacturing. Therapeutic Advances in Vaccines and Immunotherapy. DOI: 10.1177/2515135520908121.

4 CDC. (2021). Flu & Young Children. Retrieved from: https://www.cdc.gov/flu/highrisk/children.htm. Accessed September 2021.

5 FLUCELVAX QUADRIVALENT (Influenza Vaccine) [package insert]. Holly Springs, NC: Seqirus Inc; 2021.

6 CDC. (2021). Who Needs a Flu Vaccine and When. Retrieved from: https://www.cdc.gov/flu/prevent/vaccinations.htm. Accessed September 2021.

7 CDC. (2021). Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths in the United States 20192020 Influenza Season. Retrieved from: https://www.cdc.gov/flu/about/burden/2019- 2020.html. Accessed September 2021.

8 This project has been funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract numbers HHSO10020060001F2C, HHSO100200700030C, HHSO100200900101C and HHSO100201200003I.

9 Data on file. (2020). Seqirus USA Inc.

10 CDC. (2021). Key Facts about Influenza (Flu). Retrieved from: https://www.cdc.gov/flu/about/keyfacts.htm. Accessed September 2021.

SOURCE Seqirus

https://www.seqirus.com/

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The New England Journal of Medicine Publishes First-of-its-Kind Study on Cell-Based Quadrivalent Seasonal Influenza Vaccine (QIVc) Efficacy in...

BOSTON--(BUSINESS WIRE)--Ensoma, a gene therapy company advancing the future of medicine through precision in vivo engineering of blood and immune cells, today announced the appointment of Emile Nuwaysir, Ph.D., as president, chief executive officer and member of the companys board of directors. In conjunction with the CEO appointment, Paula Soteropoulos, executive chairman of Ensoma, will transition to the role of chairman of the board, and Kush M. Parmar, M.D., Ph.D., managing partner of 5AM ventures, will continue to serve as a member of the board.

Since launching Ensoma earlier this year, we have assembled a talented and diverse group of academic, scientific and clinical experts, initiated a strategic partnership with Takeda and have made significant progress on our platform and initial programs. Now, we are thrilled to welcome Emile to lead the team as we advance our platform and expand our strategic focus across multiple therapeutic areas ranging from rare genetic diseases to complex diseases of the immune system, such as oncology and autoimmunity disorders, said Ms. Soteropoulos. With more than 20 years of industry experience, a deep understanding of the gene and cell therapy landscape and as an entrepreneur with a track record for building successful life science companies from the ground up, Emile will be a tremendous asset to Ensoma as we seek to fully realize the power and promise of our platform to precisely edit and modify a patients own specific cells with a one-time in vivo curative medicine. We look forward to beginning our next chapter under Emiles leadership.

Dr. Nuwaysir is currently the chairman of the Alliance for Regenerative Medicine, an international advocacy organization comprised of 400+ member companies dedicated to advancing cell and gene medicines. He joins Ensoma from BlueRock Therapeutics, an independently operated subsidiary of Bayer Pharmaceuticals, where he was CEO and continues to serve as chairman of the companys board of directors. As the CEO of BlueRock from inception, he helped build a platform company at the intersection of cellular and genetic medicine, develop a pipeline of first-in-class therapeutic programs, and managed the companys acquisition and operation with Bayer. Prior to BlueRock, Dr. Nuwaysir served as president and chief operating officer of Cellular Dynamics International (CDI), A Fujifilm Company. He played a leading role in growing CDI and its stem cell therapy efforts from its inception, including its early efforts as a pre-revenue startup, to its successful IPO on Nasdaq and ultimate acquisition by Fujifilm. He was also president of Opsis Therapeutics Inc., CDI's retinal cell therapy subsidiary. Before CDI, Dr. Nuwaysir was the first employee of NimbleGen Systems, serving as a member of the senior management team that built a successful company and orchestrated a dual-track IPO process leading to the company's acquisition by Roche Diagnostics. After the acquisition of NimbleGen, Dr. Nuwaysir served as chief technical officer of the Roche NimbleGen subsidiary. Dr. Nuwaysir is also currently vice chairman of Invenra Inc., a multi-specifics antibody platform company he co-founded in 2011. He has held postdoctoral fellowships at the National Institutes of Health and the University of North Carolina at Chapel Hill. He holds a B.A. from the University of Delaware and a Ph.D. in molecular toxicology with a focus on oncology from the University of Wisconsin-Madison.

I am simply thrilled to join Ensoma. The company is poised to deliver on the full promise of genetic medicine, with the ability to precisely engineer the cells of the hematopoietic system through a single, simple, in vivo process, said Dr. Nuwaysir. The elegance of the platform, combined with its unprecedented payload capacity, will enable applications of genetic medicine that are simply undreamed of today. We will create an entire new class of smart immune cells with the power to provide cures for hundreds of genetic diseases, as well as complex diseases like cancer and autoimmunity. I look forward to joining the team and to the possibility of a brighter future for patients in need. I want to thank Paula and Kush for their vision and important commitment in launching the company and look forward to working with them in their continuing board roles.

About EnsomaEnsoma believes the future of medicine lies within us. Our Engenious gene therapy platform is the first to precisely engineer any or all hematopoietic and immune cells with a one-time, off-the-shelf in vivo treatment. Engenious therapies have an unmatched capacity to deliver all modern genetic modification tools and set a new standard for versatile cell programming and control across a range of complex diseases. Ensoma is supported by top-tier investors, a strategic collaboration with Takeda and a passionate team committed to a bold, global vision for gene therapy. Ensoma is based in Boston. For more information, visit http://www.ensoma.com.

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Ensoma Appoints Cell and Gene Therapy Pioneer Emile Nuwaysir, Ph.D., as Chief Executive Officer - Business Wire

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has approved Tecentriq (atezolizumab) as adjuvant treatment following surgery and platinum-based chemotherapy for adults with Stage II-IIIA non-small cell lung cancer (NSCLC) whose tumors express PD-L11%, as determined by an FDA-approved test.

Tecentriq is now the first and only cancer immunotherapy available for adjuvant treatment of NSCLC, introducing a new era where people diagnosed with early lung cancer may have the opportunity to receive immunotherapy to increase their chances for cure, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. Todays landmark approval gives physicians and patients a new way to treat early lung cancer that has the potential to significantly reduce risk of cancer recurrence, after more than a decade with limited treatment advances in this setting.

Too many patients with early-stage lung cancer experience disease recurrence following surgery. Now, the availability of immunotherapy following surgery and chemotherapy offers many patients new hope and a powerful new tool to reduce their risk of cancer relapse, said Bonnie Addario, Co-founder and Chair, GO2 Foundation for Lung Cancer. With this approval, it is more important than ever to screen for lung cancer early and test for PD-L1 at diagnosis to help bring this advance to the people who can benefit.

The approval is based on results from an interim analysis of the Phase III IMpower010 study that showed treatment with Tecentriq following surgery and platinum-based chemotherapy reduced the risk of disease recurrence or death by 34% (hazard ratio [HR]=0.66, 95% CI: 0.50-0.88) in people with Stage II-IIIA (UICC/AJCC 7th edition) NSCLC whose tumors express PD-L11%, compared with best supportive care (BSC). Safety data for Tecentriq were consistent with its known safety profile and no new safety signals were identified. Fatal and serious adverse reactions occurred in 1.8% and 18%, respectively, of patients receiving Tecentriq. The most frequent serious adverse reactions (>1%) were pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%).

The review of this application was conducted under the FDAs Project Orbis initiative, which provides a framework for concurrent submission and review of oncology medicines among international partners. According to the FDA, collaboration among international regulators may allow patients with cancer to receive earlier access to products in other countries where there may be significant delays in regulatory submissions. Simultaneous applications were submitted to regulators in the United States, Switzerland, the United Kingdom, Canada, Brazil and Australia under Project Orbis. Additionally, the FDA reviewed and approved the supplemental application under its Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.

Tecentriq has previously shown clinically meaningful benefit in various types of lung cancer, with six currently approved indications in the U.S. In addition to becoming the first approved cancer immunotherapy for adjuvant NSCLC, Tecentriq was also the first approved cancer immunotherapy for front-line treatment of adults with extensive-stage small cell lung cancer (SCLC) in combination with carboplatin and etoposide (chemotherapy). Tecentriq also has four approved indications in advanced NSCLC as either a single agent or in combination with targeted therapies and/or chemotherapies. Tecentriq is available in three dosing options, providing the flexibility to choose administration every two, three or four weeks.

Genentech has an extensive development program for Tecentriq, including multiple ongoing and planned Phase III studies across different lung, genitourinary, skin, breast, gastrointestinal, gynecological, and head and neck cancers. This includes studies evaluating Tecentriq both alone and in combination with other medicines, as well as studies in metastatic, adjuvant and neoadjuvant settings across various tumor types.

About the IMpower010 study

IMpower010 is a Phase III, global, multicenter, open-label, randomized study evaluating the efficacy and safety of Tecentriq compared with BSC, in participants with Stage IB-IIIA NSCLC (UICC/AJCC 7th edition), following surgical resection and up to 4 cycles of adjuvant cisplatin-based chemotherapy. The study randomized 1,005 people with a ratio of 1:1 to receive either Tecentriq for 1 year (16 cycles), unless disease recurrence or unacceptable toxicity occurred, or BSC. The primary endpoint is investigator-determined DFS in the PD-L1-positive Stage II-IIIA, all randomized Stage II-IIIA and intent-to-treat (ITT) Stage IB-IIIA populations. Key secondary endpoints include overall survival (OS) in the overall study population, ITT Stage IB-IIIA NSCLC.

About lung cancer

According to the American Cancer Society, it is estimated that more than 235,000 Americans will be diagnosed with lung cancer in 2021. NSCLC accounts for 80-85% of all lung cancers and approximately 50% of patients diagnosed with NSCLC are diagnosed with early-stage (Stages I and II) or locally advanced (Stage III) disease. Today, about half of all people with early lung cancer still experience a cancer recurrence following surgery. Treating lung cancer early, before it has spread, may help prevent the disease from returning and provide people with the best opportunity for a cure.

About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

Tecentriq U.S. Indications

Tecentriq is a prescription medicine used to treat adults with:

A type of lung cancer called non-small cell lung cancer (NSCLC).

A type of lung cancer called small cell lung cancer (SCLC).

It is not known if Tecentriq is safe and effective in children.

Important Safety Information

What is the most important information about Tecentriq?

Tecentriq can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These problems can sometimes become severe or life threatening and can lead to death. Patients can have more than one of these problems at the same time. These problems may happen anytime during their treatment or even after their treatment has ended.

Patients should call or see their healthcare provider right away if they develop any new or worse signs or symptoms, including:

Lung problems

Intestinal problems

Liver problems

Hormone gland problems

Kidney problems

Skin problems

Problems can also happen in other organs.

These are not all of the signs and symptoms of immune system problems that can happen with Tecentriq. Patients should call or see their healthcare provider right away for any new or worse signs or symptoms, including:

Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if patients undergo transplantation either before or after being treated with Tecentriq. A healthcare provider will monitor for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider will check patients for these problems during their treatment with Tecentriq. A healthcare provider may treat patients with corticosteroid or hormone replacement medicines. A healthcare provider may also need to delay or completely stop treatment with Tecentriq if patients have severe side effects.

Before receiving Tecentriq, patients should tell their healthcare provider about all of their medical conditions, including if they:

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Tecentriq when used alone include:

The most common side effects of Tecentriq when used in lung cancer with other anti-cancer medicines include:

Tecentriq may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information about the benefits and side effects of Tecentriq.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Report side effects to Genentech at 1-888-835-2555.

Please see http://www.Tecentriq.com for full Prescribing Information and additional Important Safety Information.

About Genentech in cancer immunotherapy

Genentech has been developing medicines to redefine treatment in oncology for more than 35 years, and today, realizing the full potential of cancer immunotherapy is a major area of focus. With more than 20 immunotherapy molecules in development, Genentech is investigating the potential benefits of immunotherapy alone, and in combination with various chemotherapies, targeted therapies and other immunotherapies with the goal of providing each person with a treatment tailored to harness their own unique immune system.

In addition to Genentechs approved PD-L1 checkpoint inhibitor, the companys broad cancer immunotherapy pipeline includes other checkpoint inhibitors, individualized neoantigen therapies and T cell bispecific antibodies. For more information visit http://www.gene.com/cancer-immunotherapy.

About Genentech in lung cancer

Lung cancer is a major area of focus and investment for Genentech, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have five approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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FDA Approves Genentech's Tecentriq as Adjuvant Treatment for Certain People With Early Non-Small Cell Lung Cancer - Business Wire