Category Archives: Gene Medicine

A girl in New Delhi gets a nasal swab to test for the new coronavirus. A rare Kawasaki diseaselike illness linked to the virus is sickening young people.

By Jennifer Couzin-FrankelMay. 21, 2020 , 4:10 PM

Sciences COVID-19 reporting is supported by the Pulitzer Center.

Three children at one London hospital in mid-April, followed the next day by three at anotherfor Elizabeth Whittaker, a pediatric infectious disease doctor at Imperial College London, those first cases raised an alarm. The youngsters had fevers, rashes, stomach pain, and, in some cases, heart problems, along with blood markers that characterize COVID-19 in adults, including one associated with clotting. But in most, nasal swabs failed to reveal any virus.

I dont understandthey look like they have coronavirus, Whittaker recalls thinking. Doctors nonetheless suspected a link. Within days, a survey turned up 19 additional cases across England, and an alert on 27 April asked doctors to be on the lookout for such symptoms in children. Soon after, dozens more cases surfaced in New York along with smaller clusters elsewhere, bolstering a connection to the pandemic. Reports of children on life support and some deaths put parents on edgeand were especially disheartening after earlier signs that COVID-19 largely spares children from serious illness.

It is another surprise from a virus that hasproffered many, and projects worldwide are gearing up to study it. They are combing the blood and sequencing the genomes of patientsand the virus, if it can be isolated from themto search for clues to what makes some children susceptible and how to head off the worst symptoms. Theres hope that whats learned from young patients might help the many adults in whom COVID-19 also triggers a grievous overreaction of the immune system.

In some respects, Its absolutely not shocking to see this, says Rae Yeung, a rheumatologist and immunologist at the Hospital for Sick Children, whose center treated 20 children over the past 3 weeks with similar symptoms.Many pathogens occasionally trigger a similar hyperactive immune response in children, known as Kawasaki disease. Its symptoms vary but include rash, fever, and inflammation in medium-size blood vessels. Children can suffer heart problems. In rare cases, blood pressure plummets and shock sets in.

Doctors disagree on whether the variant linked to COVID-19 is Kawasaki disease or something new, with some experts calling it multisystem inflammatory syndrome in children. But as with Kawasaki disease, most recover with treatment, including steroids and immunoglobulins, which calm the immune system.

In linking the inflammatory syndrome to COVID-19,Were going on more than just a hunch, says Jesse Papenburg, a pediatric infectious disease specialist at Montreal Childrens Hospital, in a city thats seen about 25 children with the condition. Kawasaki disease is rare, ordinarily affecting just one to three in every 10,000 children in Western countries, though its more common in children with Asian ancestry. The spikes recorded so far, in COVID-19 hot spots like northern Italy and New York City, track the novel coronavirus march around the world. And although a minority of these children test positive for SARS-CoV-2, a studypublished inThe Lancetby a team in Bergamo, Italy, reported that eight of 10 children with the Kawasaki-like illness had antibodies to the virus, indicating they had been infected. Positive antibody tests have been reported in sick children elsewhere, too.

It was obvious that there was a link, says Lorenzo DAntiga, a pediatrician at the Papa Giovanni XXIII Hospital who led the study. The new coronavirus can elicit a powerful immune response, which he thinks may explain why shock and a massive immune reaction called a cytokine storm are more common in the COVID-19linked cases than in textbook Kawasaki disease. And a time lag between infection and the Kawasaki-like illness could explain why many of the affected children show no evidence of the virus. The immune systems overreaction may unfold over weeks, though virus could also be hiding somewhere in the body.

Theres clearly some underlying genetic component that puts a small number of children at risk, says Tom Maniatis, founding director of Columbia Universitys Precision Medicine Initiative. New York state is investigating 157 cases, and Maniatis is also CEO of the New York Genome Center, which is pursuing whole-genome sequencing of affected children and their parents, as well as sequencing the virus found in children, with family consent. Finding genes that heighten risk of the illness or of developing a severe case could point to better treatments or help identify children who may take a sudden turn for the worse.

Genetics may also help explain a puzzle: why the illness hasnt been reported in Asian countries, even though Kawasaki disease is far more common in children with Asian ancestry. The virus own genetics may be important; an analysis last month indicatedthe predominant viral variant in New York was brought by travelers from Europe. Its also possible that the Kawasaki-like illness is so rare that it only shows up in COVID-19 hotbeds. The areas that have been hardest hit by coronavirus are the areas reporting this syndrome now, says Alan Schroeder, a critical care physician at Lucile Packard Childrens Hospital at Stanford University, which has seen one potentially affected child, a6-month-old baby, who healed quickly.

Yeung is pursuing ways to flag children with COVID-19 who are at risk of this complication. She co-leads an international consortium thats banking blood from affected children both before and after treatment and screening for various markers, including the cytokine molecules that indicate a revved-up immune system. They are also searching for gene variants known to predict poor outcomes in Kawasaki disease. Theres also core COVID stuff that needs to be measured, Yeung says, such as markers of heart function and levels of D-dimer, a protein fragment in the blood that indicates a tendency toward clotting and that surges in many sick adults.

Another project, called DIAMONDSand originally designed to improve diagnostics of pathogens based on patterns of immune response in children with fevers,is recruiting children across Europe with the Kawasaki-like complication, along with those who have run of the mill COVID-19 symptoms. Scientists will study blood for pathogensnot just SARS-CoV-2and the behavior of immune cells such as T cells and B cells.

We have to do a deep dive into the immunology of those patients, says Elie Haddad, a pediatric immunologist and scientist at the St. Justine University Hospital Center who,with Yeung and Susanne Benseler at Alberta Childrens Hospital, is leading Canadian research efforts on the new syndrome. These deep dives may also clarify the immune system chaos seen in many sick adults. Children are cleaner, Haddad points outtheyre less likely to have other health burdens, such as diabetes or high blood pressure, that can make it harder to tease out the virus impact on the immune system.

Its possible, too, that the illness affects adults as well but is harder to tease out from their other symptoms. A global effort studying COVID-19 in adults, called the International Severe Acute Respiratory and Emerging Infection Consortium, will look at adults clinical data and blood samples,Whittaker says, to see, is this a uniquely pediatric problem?

Eager as they are to understand this new face of the pandemic, doctors want to avoid overstating the hazards. We need to identify early and we need to intervene early in treating these children, Yeung says. But she also urges calm. The kids were seeing so far, she stresses, they respond to the treatments were giving.

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Doctors race to understand rare inflammatory condition associated with coronavirus in young people - Science Magazine

May 22, 2020 |A pair of studies demonstrate antibody responses to COVID-19 in primates. Researchers are applying artificial intelligence to lung images of COVID-19 patients. An accurate, easy-to-use, fully disposable, rapid and handheld test that consumers and healthcare providers in clinics can use to detect active SARS-CoV-2. We round up the weeks research and industry news for COVID-19.

Literature Updates

A pair of studies led by researchers at Beth Israel Deaconess Medical Center(BIDMC) were published in the journal Science. In the first study, the team demonstrated that six candidate DNA vaccines induced neutralizing antibody responsesand protected against SARS-CoV-2 in rhesus macaques. DOI: 10.1126/science.abc6284. In the second study, the team demonstrated that macaques that recovered from COVID-19 developed natural protective immunity against re-infection. Upon second exposure, the animals demonstrated near-complete protection against the virus. These data suggest natural protective immunity against COVID-19 in this model. DOI: 10.1126/science.abc4776.

Insilico Medicinehas co-authored a preprint paper with Nanome.aidescribing 10 potential small molecule inhibitors targeting the SARS-CoV-2 main protease that were generated by artificial intelligence (AI). The approach taken, called AI imagination, involves teaching a computer what the target protein looks like, letting it sniff out the binding pockets, and then imagine molecules with certain features having to do with the likelihood that a molecule will fit inside, and stay inside, a binding pocket. The AI-generated molecules are some of the first non-covalent drug candidates for COVID-19; non-covalent inhibitors are safer and more selective than covalent inhibitors. DOI: 10.13140/RG.2.2.13846.98881.

Researchers from the La Jolla Institute for Immunologyhave published the first cellular immunology data to help guide social distancing recommendations. Published in Cell, the study documents a robust antiviral immune response to SARS-CoV-2 in a group of 20 adults who had recovered from COVID-19. The findings show that the body's immune system is able to recognize SARS-CoV-2 in many ways, dispelling fears that the virus may elude ongoing efforts to create an effective vaccine. DOI: 10.1016/j.cell.2020.05.015.

Previous data from COVID-19 patients suggests that cigarette smokers are more likely to have health complications. One possible reason, researchers report in Developmental Cell, is that smoking increases the gene expression of ACE2the protein that binds SARS-CoV-2which may promote COVID-19 infection. The study suggests that prolonged smoking could cause an increase of the ACE2 protein in the lungs, possibly resulting in a higher rate of morbidity in patients. ACE2, or Angiotensin Converting Enzyme 2, is a regulatory protein that has been linked to vulnerability to the 2003 SARS (2003) virus. DOI: 10.1016/j.devcel.2020.05.

Researchers from the University of Trentohave published a novel fully-annotated dataset of lung ultrasonography (LUS) imagesfrom COVID-19 patients collected from several Italian hospitals, with labels indicating the degree of disease severity at a frame-level, video-level, and pixel-level (segmentation masks). Leveraging these data, they introduce a novel deep network, derived from Spatial Transformer Networks, which simultaneously predicts the disease severity score associated to an input frame and provides localization of pathological artefacts in a weakly-supervised way. They also benchmark state of the art deep models for estimating pixel-level segmentations of COVID-19 imaging biomarkers. Results were published in IEEE Transactions on Medical Imaging(Early Access). DOI: 10.1109/TMI.2020.2994459.

Leading immunologists in Japan reviewed two recent studies by Zhou et al. and Hoffmann et al. in order to understand their implications for finding effective therapeutic strategies for ARDSin COVID-19 patients. Based on their review, they are proposing a possible molecular mechanism that causes the massive release of proinflammatory cytokines, or a cytokine storm, that leads to acute respiratory distress syndrome (ARDS) in COVID-19 patients. Their suggestions are published in the journal Immunity. DOI: 10.1016/j.immuni.2020.04.003.

Mount Sinairesearchers are also applying artificial intelligence to lung images of COVID-19 patients. The Mount Sinai team has developed an algorithm that can rapidly detect COVID-19 based on how lung disease looks in computed tomography (CT scans) of the chest, in combination with patient information including symptoms, age, bloodwork, and possible contact with someone infected with the virus. This study, published in Nature Medicine, could help hospitals across the world quickly detect the virus, isolate patients, and prevent it from spreading during this pandemic. DOI: 10.1038/s41591-020-0931-3.

Patients infected with either severe acute respiratory syndrome coronavirus (SARS-CoV) or SARS-CoV-2 produce antibodies that bind to the other coronavirus, but the cross-reactive antibodies are not cross protective, at least in cell-culture experiments, researchers report in Cell Reports. Researchers analyzed blood samples collected from 15 SARS-CoV-2-infected patients in Hong Kong between 2 and 22 days after the onset of symptoms. Compared to blood samples from healthy controls, the five samples collected from patients 11 days after symptom onset or later had antibodies capable of binding to the RBD and other parts of the S protein on both SARS-CoV-2 and SARS-CoV. The researchers also analyzed blood samples collected from seven patients 3 to 6 months after infection with SARS-CoV. Compared to blood samples from healthy controls, those collected from patients had antibodies capable of binding to the RBD and other parts of the S protein on SARS-CoV-2. It remains unclear whether such antibodies offer cross protection in the human body or potentiate disease. DOI: 10.1016/j.celrep.2020.

An antibody called S309, first identified in a blood sample from a patient who recovered from Severe Acute Respiratory Syndrome in 2003, inhibits related coronaviruses, including SARS-CoV-2. The findings have been accepted for publication in Natureand the antibody is now on a fast-track development and testing path at Vir Biotechnology. It has not yet been shown to be protective in living systems. The S309 antibody is particularly potent at targeting and disabling the spike protein that promotes the coronavirus entry into cells. It was able to neutralize SARS CoV-2 by engaging with a section of the spike protein nearby the attachment site to the host cell. DOI: 10.1038/s41586-020-2349-y.

Industry Updates

Illuminaand the Illumina Corporate Foundation have committed more than $10M to COVID-19-related research and support. To support public health efforts associated with SARS-CoV-2 surveillance, sequencing and monitoring, Illumina is providing in kind donations valued at approximately $5M dollars for instruments and consumables. In addition, we dedicated more than $2M to COVID-19-related research efforts. To advance scientific research, Illumina, Inc. recently released the SARS-CoV-2 Data Toolkit, making it easier for researchers to detect and identify the viral sequence in their samples and contribute their findings to critical public databases. The toolkit is freely accessible on BaseSpace Sequence Hub until October 2020. Finally, the Illumina Foundation has awarded more than $3M in philanthropic donations, of which $1M has gone to the CDC Foundation COVID Emergency Response Fund, and $2M to local community-based initiatives in the areas where we operate. Press release.

Mammoth Biosciences and GSK Consumer Healthcareare collaborating to develop an accurate, easy-to-use, fully disposable, rapid and handheld testthat consumers and healthcare providers in clinics can use to detect active SARS-CoV-2. The collaboration will use Mammoth Biosciences CRISPR-based DETECTR platform that can identify and signal the presence of viral RNA strands obtained through a simple nasal swab. The test, which has the potential to deliver point-of-use results in less than 20 minutes, will be available first in the clinical setting and ultimately by consumers at home. Press release.

iSpecimenis partnering with myOnsite HealthCareto offer mobile phlebotomysupport that will bring convenient, at-home sample collection to patients and donors interested in advancing research who would otherwise have limited ability to participate. The mobile service extends iSpecimens ongoing mission to advance medical research by efficiently connecting researchers with patients, biospecimens, and the data they need to perform their important work. It also expands the companys recent initiatives to identify, collect, aggregate, manage, and ship specimens from COVID-19 patients. Press release.

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AI Applications for COVID-19 Research and Other News - Bio-IT World

If youve ever been a newlywed, you know the tingly euphoria of saying I do and starting a life with your spouse. This is romantic love, Western style. We often chalk it up to chemistry, an ill-defined connection of hearts and minds. Groundbreaking research at UC Santa Barbara finds we were closer than we knew.

For the first time, researchers have explored the neural and genetic connections to romantic love in newlyweds. By using functional magnetic resonance imaging (fMRI) and genetic analysis of 19 first-time newlyweds, Bianca Acevedo and her collaborators showed that romantic love maintenance is part of a broad mammalian strategy for reproduction and long-term attachment that is influenced by basic reward circuitry, complex cognitive processes and genetic factors.

In short, were hard-wired to sustain romantic love to maintain a successful marriage and the family unit, thanks to neurotransmitters like dopamine and a suite of genetic mutations.

This is the first study to examine the neural and genetic correlates of romantic love maintenance, said Acevedo, a research scientist at UC Santa Barbaras Department of Psychological & Brain Sciences and the lead author of After the Honeymoon: Neural and Genetic Correlates of Romantic Love in Newlywed Marriages in the journal Frontiers in Psychology.

The study showed that the maintenance of love is not only associated with activation of subcortical regions but also higher order centers of the brain, she said. Also, for the first time we provide evidence that the propensity to sustain romantic love may be affected by genetic variability. Specifically, the genes we examined are associated with pair-bonding behaviors including fidelity and sexual behaviors; and social behaviors such as trust, eye-gazing and attachment.

To test their hypothesis that romantic love is a developed form of the mammalian drive to find and keep mates, the researchers performed fMRI scans of the brains of the members of the study group 11 women and eight men. Participants were shown alternating images of their partners and a neutral acquaintance they knew well.

At the start of each session, the subjects were instructed to recall non-sexual events with the person whose face was displayed. While still in the scanner, participants rated their moods to verify that the evoked emotions corresponded to the target image.

The participants were tested around the time of marriage and a year later.

In addition, they provided saliva samples for testing of vasopressin, oxytocin and dopamine genes implicated in pair bonding in non-human mammals, such as voles.

Our findings showed robust evidence of the dopamine reward systems involvement in romantic love, Acevedo said. This system is interesting because it is implicated in motivation, energy, working for rewards, and is associated with corresponding emotions such as excitement, euphoria and energy, as well as frustration if the drive is thwarted.

Acevedos current research builds on her work on empathy and altruism and its correlates in the brain.

Empathy has its roots in social bonding, she explained. In our previous work we showed that although humans express sentiments such as empathy and altruism towards strangers and non-close others, brain responses to partners are stronger. Thus, there is specificity. Romantic love is somewhat different in that it may or may not include empathy or altruism, but in healthy partnerships it does.

For some romantics, it might seem a tad clinical to chalk up our feelings of love and commitment to biochemistry. Acevedo, however, said gene mutations and brain activity are only components of romance and belonging.

Humans are creative and clever, she said. Romantic love inspires people to know how to put a smile on their partners face. By making our partners happy we not only keep our relationships stable, but we also derive joy from such events.

In the brain, Acevedo continued, this is shown as increased reward activation when people are shown images of a partner smiling and they are told that something wonderful has happened to the partner. People know this intuitively. They know that romance goes a long way in finding and keeping a preferred mate. Thats why there is multibillion-dollar industry built on it from dating sites, to lingerie to Hallmark cards, chocolate and diamond rings.

And besides, our chemical impulses dont buy flowers or cook dinner.

Love is basic but complex, Acevedo said. We are wired to love, but it takes work to find and keep love alive."

Nancy L. Collins, a professor in UC Santa Barbaras Psychological and Brain Sciences, was a co-author of After the Honeymoon. She is also director of the UC Santa Barbara Close Relationship Lab. Other authors are Michael J. Poulin of the University of Buffalo and Lucy L. Brown of the Albert Einstein College of Medicine in New York.

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Are we wired for romance? - University of California

TOKYO & BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZenecas ENHERTU (fam-trastuzumab deruxtecan-nxki) has been granted Orphan Drug Designation (ODD) in the U.S. for the treatment of patients with gastric cancer, including gastroesophageal junction cancer.

The U.S. Food and Drug Administration (FDA) grants ODD to medicines intended for the treatment, diagnosis or prevention of rare diseases of disorders that affect fewer than 200,000 people in the U.S.

An estimated 27,600 new cases of gastric cancer will be diagnosed this year, and the disease could lead to more than 11,000 deaths in the U.S. in 2020.1

The phase 2 DESTINY-Gastric01 trial demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of objective response rate (ORR) and the secondary endpoint of overall survival (OS) for patients with HER2 positive metastatic gastric or gastroesophageal cancer treated with ENHERTU, a HER2 directed antibody drug conjugate (ADC), versus physicians choice of chemotherapy (irinotecan or paclitaxel monotherapy).

The overall safety and tolerability profile of ENHERTU in DESTINY-Gastric01 was consistent with that seen in the phase 1 gastric cancer trial in which the most common adverse events (30%, any grade) were hematologic and gastrointestinal including neutrophil count decrease, anemia, nausea and decreased appetite. There were cases of drug-related interstitial lung disease (ILD) and pneumonitis, the majority of which were grade 1 and 2 with two grade 3 and one grade 4. No ILD-related deaths (grade 5) occurred in patients with gastric cancer in the phase 1 trial or in the DESTINY-Gastric01 trial.

The research results of DESTINY-Gastric01 will be presented at the 2020 American Society of Clinical Oncology (ASCO20) Virtual Scientific Program.

Earlier this month, ENHERTU received two Breakthrough Therapy Designations from the FDA for the treatment of patients with HER2 positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab, and for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

ENHERTU also received SAKIGAKE designation in March 2018 from Japans Ministry of Health, Labour and Welfare (MHLW) for potential use in HER2 positive gastric cancer, and a supplemental New Drug Application was recently submitted to the Japan MHLW.

About HER2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers. In some tumors, HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis.1

About Gastric Cancer

Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality; there were approximately one million new cases reported in 2018 and 783,000 deaths.2 In the U.S., it is estimated that 27,600 new cases of stomach cancer will be diagnosed in 2020 and more than 11,000 people will die from the disease.1

Approximately one in five gastric cancers are HER2 positive.3 Gastric cancer is usually diagnosed in the advanced stage in the U.S., but even when diagnosed in earlier stages of the disease the survival rate remains modest.4 Recommended first-line treatment for HER2 positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve outcomes when added to chemotherapy.5 For gastric cancer that progresses on first-line treatment, trastuzumab has not shown any further benefit and there are no other approved HER2 targeted medicines.6

DESTINY-Gastric01

DESTINY-Gastric01 is a phase 2, open-label, multi-center trial assessing the safety and efficacy of ENHERTU in a primary cohort of 188 patients from Japan and South Korea with HER2 expressing advanced gastric or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two or more prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy and trastuzumab. Patients were randomized 2:1 to receive ENHERTU or investigators choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with ENHERTU 6.4 mg/kg once every three weeks or chemotherapy. The primary endpoint of the study is ORR as assessed by an independent review committee. Secondary endpoints include OS, progression-free survival, duration of response, disease control rate and time to treatment failure as well as pharmacokinetic and safety endpoints.

About ENHERTU

ENHERTU (fam-trastuzumab deruxtecan-nxki in the U.S. only; trastuzumab deruxtecan outside the U.S.) is a HER2 directed ADC and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZenecas ADC Scientific platform.

ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (payload) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyos proprietary DXd ADC technology, ENHERTU is comprised of a HER2 monoclonal antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker.

ENHERTU (5.4 mg/kg) is approved in the U.S. and Japan for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens based on the DESTINY-Breast01 trial.

ENHERTU has been approved for use only in the U.S. and Japan. ENHERTU has not been approved in the EU, or countries outside of Japan and the United States, for any indication. It is an investigational agent globally for various indications. Safety and effectiveness have not been established for the subject proposed use.

About the ENHERTU Clinical Development Program

A comprehensive development program for ENHERTU is underway globally with six pivotal trials evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

About the Collaboration between Daiichi Sankyo and AstraZeneca

In March 2019, Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for the manufacturing and supply.

U.S. FDA-Approved Indication for ENHERTU

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Contraindications

None.

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in 28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 0.5 mg/kg prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.

Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3C or a sustained temperature of 38C for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Adverse Reactions

The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common adverse reactions (frequency 20%) were nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (29%), diarrhea (29%), leukopenia (22%), cough (20%), and thrombocytopenia (20%).

Use in Specific Populations

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNING, and Medication Guide.

About Daiichi Sankyo

Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical therapies to improve standards of care and address diversified, unmet medical needs of people globally by leveraging our world-class science and technology. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 15,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for cardiovascular diseases, under the Groups 2025 Vision to become a Global Pharma Innovator with Competitive Advantage in Oncology, Daiichi Sankyo is primarily focused on providing novel therapies in oncology, as well as other research areas centered around rare diseases and immune disorders. For more information, please visit: http://www.daiichisankyo.com

References:

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Washington, DC, May 20, 2020 (GLOBE NEWSWIRE) -- via NEWMEDIAWIRE -- The Alliance for Regenerative Medicine (ARM), the international advocacy organization for the cell and gene therapy and broader regenerative medicine sector, announced that it will be holding its annual Legislative Fly-In today. This event, which has been remodeled to take place virtually, enables ARM members to advocate on Capitol Hill for legislative support of gene and cellular therapies and other regenerative medicines.

More than 120 ARM members are participating in the event, making this year ARMs largest Fly-In to date. Participants will form 24 state delegations to meet with Members of Congress via video calls and teleconferencing systems. The meetings will focus onthe immense near-term potential of gene and cell therapies and the need for legislation that supports patient access to these life-saving treatments.

Specifically, Fly-In participants will be asking Members of Congress to remove legislative barriers to the adoption of value-based payment models for gene and cell therapies. These therapies, which can provide a durable and potentially curative therapeutic effect, often with only a single administration, provide a profound benefit to patients and may result incost-savings to the healthcare systemin the medium to long term. However, existing reimbursement mechanisms have difficulty absorbing the upfront cost of these therapies.

To address these challenges, ARM works with its members and policymakers to promote the adoption of innovative payment models for regenerative medicines. These models include annuities, which would allow payors to amortize the cost of therapies over a longer period of time, as well as performance-based models, which tie the payment for therapies to predetermined health outcomes.

For more information on the event or ARMs legislative goals, please contact Kaitlyn (Donaldson) Dupont atkdonaldson@alliancerm.org.

About The Alliance for Regenerative Medicine

The Alliance for Regenerative Medicine (ARM) is an international multi-stakeholder advocacy organization that promotes legislative, regulatory, and reimbursement initiatives necessary to facilitate access to life-giving advances in regenerative medicine worldwide. ARM also works to increase public understanding of the field and its potential to transform human healthcare, providing business development and investor outreach services to support the growth of its member companies and research organizations. Prior to the formation of ARM in 2009, there was no advocacy organization operating in Washington, D.C. to specifically represent the interests of the companies, research institutions, investors, and patient groups that comprise the entire regenerative medicine community. Today, ARM has more than 350 members and is the leading global advocacy organization in this field. To learn more about ARM or to become a member, visithttp://www.alliancerm.org.

Kaitlyn (Donaldson) Dupont8037278346kdonaldson@alliancerm.org

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The Alliance for Regenerative Medicine Announces 2020 Virtual Fly-In, Connecting Sector Stakeholders with Congressional Representatives Amidst the...

FILE PHOTO: The logo of Swiss drugmaker Novartis is pictured at the French company's headquarters in Rueil-Malmaison near Paris, France, April 22, 2020. REUTERS/Charles Platiau

ZURICH (Reuters) - Novartis won European approval for its gene therapy Zolgensma for the hereditary disease spinal muscular atrophy (SMA), the Swiss drugmaker said on Tuesday, adding it is in talks over price with countries in hopes of a quick launch.

The European Commission gave conditional approval to the therapy, whose U.S. price is $2.1 million, for patients with a clinical diagnosis of SMA Type 1, the most severe form of the disease, or SMA patients with up to three copies of a specific gene that helps doctors predict how severe the disease will be.

The EU approval covers babies and young children with SMA up to 21 kilograms. The medicine also has approval in Japan.

Novartis got Zolgensma with its $8.7 billion takeover of U.S.-based AveXis in 2018 and has forecast more than $1 billion in sales for the treatment, which in trials has been shown to significantly improve survival and motor function of babies with SMA, in particular those treated before symptoms develop.

Novartis said it is in talks with nations over what it calls its Day One access program, which the Basel-based drugmaker said is aimed at speeding up treatment by dealing with payment issues up front, even before national pricing and reimbursement agreements with individual countries are in place.

The Day One access program ensures the cost of patients treated before national pricing and reimbursement agreements are in place align with the value-based prices negotiated following clinical and economic assessments, Novartis said, adding the medicine will be immediately available in France.

Drug pricing in Europe varies from country to country, often relying on individual negotiations with regulators and pricing watchdogs that can slow down access, including in instances where officials conclude companies are seeking too much money for their medicines relative to the value they bring.

Reporting by John Miller; editing by Thomas Seythal and Brenna Hughes Neghaiwi

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Novartis wins conditional EU approval for gene therapy Zolgensma - Reuters