Stem Cell Clinic

Next generation cell and gene therapies: fine tuning the promise – Business Weekly

On 19 November, the UK BioBeat19 summit goes to Stevenage to discuss the potential of cell and gene therapy and how to accelerate these transformational medicines.

Victoria Higgins of GSK and Miranda Weston-Smith from BioBeat spoke to two panellists who gave a sneak peek of their remarks and agree wholeheartedly that the discovery side and clinical side work best when they are teamed up.

Sophie Papa, an oncologist at Guys Cancer at Guys and St Thomas NHS Trust, and Aisha Hasan, a clinical development lead at GSK, both recognise the big challenge ahead for cell therapy researchers: to dial up efficacy and dial down toxicity.

Cell and gene therapies, with their remarkable potential to transform medicine, have seen some important but hard-won milestones: it took 20 years of combined academic and industry research to deliver the first gene therapy approval in 2016 and today there are two CAR-Ts approved for haematological malignancies.

Whilst CAR-Ts recognise proteins expressed on the tumour cell surface, making them ideal for targeting blood cancers, more complicated but with greater potential to address solid tumours are the gene modified TCR-T technologies.

These harness the power of T cells to specifically target and destroy tumours even on the inside of cells. TCR-Ts come with an additional level of complexity, but potentially open the door to a range of untreatable cancer types.

Looking at the TCR opportunity is where Sophie Papa sees the inherent trade-off between risk and benefit as an academic clinician whos now evaluating modified T-cell based therapies in clinical trials.

Sophie urges her peers to take courage. It is important to be brave and tolerant of certain toxicities. Academic clinicians and drug researchers need to work closely together to engage the regulators in early discussion, so that we can move cell therapies earlier in treatment schedules as soon as feasible.

Timing is critical to enable patients to be treated when they are physically fit so they can better tolerate these complex and potentially toxic treatments.

From her perspective, this is not an either/or, but an area where discussion and open dialogue will allow us to make the most of the opportunity. By allowing clinical academics to play a lead role in developing guidelines to manage patient safety, we can address legitimate concerns but not let them stand in the way of clinical development, she says.

Aisha brings the perspective of drug discovery and development and starts by asking what is in the realm of the possible from a design perspective.

She says: A superior T-cell therapy will require engineering approaches that enhance efficacy on one-end while also incorporating switches to minimise toxicity.

For example, in a counter-intuitive way, a T-cell with high-killing capacity actually can create dangerous levels of inflammation in the body, due to the rapid death of cancer cells. But the beauty of drug design opens up options:By building a switch within the engineered T-cells, researchers can inactivate the T-cells and prevent harm to the patient, says Aisha.

But this creative problem solving requires open dialogue between clinicians and pharma. Aisha says: The more we talk about clinical need and toxicity benchmarks, the more sophisticated we can be when developing the next generation of enhanced engineered cell therapies.

Theres no doubt that the challenges of delivering cell and gene therapy span the full spectrum of issues related to medicine development. However, the potential for both curative therapy and commercial opportunity is tremendous.

The scientific, clinical, technical, regulatory and commercial challenges are all surmountable when everyone in the ecosystem work together towards a shared goal, united by an unwavering focus on the patient.

Sophie and Aisha are speaking about the translational journey from science to bedside at the BioBeat19 summit.

The BioBeat19 summit on Accelerating cell and gene therapy, 1-6pm, Tuesday 19 November, GSK Stevenage. Guarantee your place by registering at http://www.biobeat19.org

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Next generation cell and gene therapies: fine tuning the promise - Business Weekly

110-year-olds live so long thanks to ‘super’ immune systems: study – New York Post

If you think daily exercise and a healthy diet were the key to a long life, think again.

Scientists say that the secret to living more than 100 years comes down to a hardy immune system, thanks to an abundance of a particular infection-fighting white blood cell.

In a study coordinated by scientists at Japans RIKEN Center for Integrative Medical Sciences (IMS) and Keio University School of Medicine, researchers discovered that supercentenarians those aged over 110 years have an excess of cytotoxic CD4 T-cells.

These super immune system cells, according to the study published in Proceedings of the National Academy of Sciences (PNAS), are more aggressive and known to kill any damaged cell that crosses its path, such as virus-infected or cancer cells.

We believe that this type of cells, which are relatively uncommon in most individuals, even young, are useful for fighting against established tumors, and could be important for immunosurveillance, said Piero Carninci, deputy director of RIKEN, in a statement. This is exciting as it has given us new insights into how people who live very long lives are able to protect themselves from conditions such as infections and cancer.

Scientists noticed that most of Japans supercentenarians had managed to dodge illness most of their lives, leading them to believe their advanced age might have something to do with their extraordinary immune systems.

To find out, they pulled a total of 41,208 immune cell samples from seven supercentenarians, and 19,994 cells from younger individuals ages 50 to 89. They found that while both groups had about the same number of T-cells altogether, the supercentenarians had an excess of the unique cytotoxic CD4 T-cells.

This finding might help explain why so many centenarians will say that drinking booze regularly didnt stop them from reaching 100. Others, though, credit a life without the stress of marriage or children as helping them to outlast their peers.

Amparo Perez, 105, told The Post she doesnt regret never remarrying when her first husband died. No aggravation, she said, [is] the most important thing, not to have aggravation.

Caroline Binns, 101, would agree that husbands were only trouble. She told The Post last year, Id rather be left in peace, not in pieces.

Her friend, 101-year-old Lucille Watson, said dancing and cheesecake inspires her to get out of bed every morning: Lifes pleasures are meant to be enjoyed.

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110-year-olds live so long thanks to 'super' immune systems: study - New York Post

Halting the progression of multiple sclerosis by blocking harmful B cells – FierceBiotech

The blood-brain barrier in healthy people is a powerful shield that protects neurons from harmful invaders. But in people with multiple sclerosis (MS), that shield malfunctions, allowing B cells from the immune system to pass into the brain and destroy healthy tissues.

Scientists at the University of Montreal Hospital Research Centre (CRCHUM) have identified a new target that they suggest could be exploited to slow down the flow of B cells into the brains of people with MS. They reported the discovery in the journal Science Translational Medicine.

B cells produce a substance called activated leukocyte cell adhesion molecule (ALCAM) that allows them to migrate into the brain via blood vessels, the researchers found. Blocking ALCAM in mouse models of MS reduced the flow of B cells into the brain and slowed the progression of the disease, they reported.

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RELATED: How new gene discoveries could guide precision medicine in multiple sclerosis

B cells are a major culprit in progressive MS, the most severe form of the disease, and there are drugs on the market designed to deplete them, including Roches Ocrevus. Novartis is in phase 3 trials of Arzerra (ofatumumab), a drug that eliminates B cells by binding to the surface protein CD20. Arzerra is approved to treat chronic lymphocytic leukemia, but Novartis has been gunning for a bigger market opportunity. In September, it released new phase 3 data showing that Arzerra reduced MS relapse rates by more than 50% when compared to Sanofis Aubagio.

Meanwhile, several academic teams are looking to genetics as a path to personalized MS treatment strategies. In October, researchers at Johns Hopkins reported that newly discovered variants in the genes C1, CR1 and C1QA are associated with vision loss in progressive MS. They believe further research into these complement genes could lead to the development of new MS therapies.

Blocking ALCAM could also offer a promising strategy for thwarting B cells in MS, said University of Montreal Professor Alexandre Prat, Ph.D., in a statement. "The molecule ALCAM is expressed at higher levels on the B cells of people with multiple sclerosis, he said. By specifically targeting this molecule, we will now be able to explore other therapeutic avenues for the treatment of this disease."

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Halting the progression of multiple sclerosis by blocking harmful B cells - FierceBiotech

Editas Medicine Announces Third Quarter 2019 Results and Update – Yahoo Finance

Amended Celgene collaboration to focus on engineered alpha-beta T cell medicines with a $70 million payment to Editas Medicine

Appointed Judith R. Abrams, M.D., as Chief Medical Officer

EDIT-101 (AGN-151587) for LCA10 first patient dosing expected by early 2020

EDIT-301 for hemoglobinopathies in vivo pre-clinical data to be presented at ASH

CAMBRIDGE, Mass., Nov. 12, 2019 (GLOBE NEWSWIRE) -- Editas Medicine, Inc. (EDIT), a leading genome editing company, today reported business highlights and financial results for the third quarter of 2019.

"Our momentum in 2019 remains strong in advancing our pipeline of in vivo CRISPR and engineered cell medicines," said Cynthia Collins, Chief Executive Officer of Editas Medicine. We announced this morning an amended agreement with Celgene to further expand and accelerate our oncology pipeline. In hemoglobinopathies, we look forward to presenting in vivo pre-clinical data for EDIT-301 at ASH that supports its potential as a best-in-class medicine. Finally, we eagerly anticipate first patient dosing with EDIT-101 for LCA10 in the coming months.

Recent Achievements and OutlookIn VivoCRISPR Medicines

Engineered Cell Medicines

Corporate

Upcoming Events

Editas Medicine will participate in the following investor events:

Editas Medicine will present pre-clinical data for EDIT-301 to address sickle cell disease and beta-thalassemia in at the 61st American Society of Hematology Annual Meeting & Exposition. Details are as follows:

Abstract Number: 4636Title: EDIT-301: An Experimental Autologous Cell Therapy Comprising Cas12a-RNP Modified mPB-CD34+ Cells for the Potential Treatment of SCDPresenter: Edouard De Dreuzy, Ph.D.Session: 801. Gene Therapy and Transfer: Poster III Time: Monday, December 9, 2019: 6:00 PM-8:00 PMLocation: Hall B, Orange County Convention Center, Orlando, FL

Third Quarter 2019 Financial Results

Cash, cash equivalents, and marketable securities at September 30, 2019, were $332.6 million, compared to $369.0 million at December 31, 2018. The $36.4 million decrease was primarily attributable to operating and capital expenses related to our on-going preclinical and clinical activities, patent costs and license fees, and employee-related costs, partially offset by $42.1 million in proceeds from financing activities.

For the three months ended September 30, 2019, net loss was $32.9 million, or $0.66 per share, compared to $15.2 million, or $0.32 per share, for the same period in 2018.

Conference Call

The Editas Medicine management team will host a conference call and webcast today at 8:00 a.m. ET to provide and discuss a corporate update and financial results for the third quarter of 2019. To access the call, please dial 844-348-3801 (domestic) or 213-358-0955 (international) and provide the passcode 6577216. A live webcast of the call will be available on the Investors & Media section of the Editas Medicine website at http://www.editasmedicine.com and a replay will be available approximately two hours after its completion.

About Editas MedicineAs a leading genome editing company, Editas Medicine is focused on translating the power and potential of the CRISPR/Cas9 and CRISPR/Cpf1 (also known as Cas12a) genome editing systems into a robust pipeline of treatments for people living with serious diseases around the world. Editas Medicine aims to discover, develop, manufacture, and commercialize transformative, durable, precision genomic medicines for a broad class of diseases. For the latest information and scientific presentations, please visit http://www.editasmedicine.com.

About EDIT-101 (AGN-151587)EDIT-101 is a CRISPR-based experimental medicine under investigation for the treatment of Leber congenital amaurosis 10 (LCA10). EDIT-101 is administered via a subretinal injection to reach and deliver the gene editing machinery directly to photoreceptor cells.

About Leber Congenital AmaurosisLeber congenital amaurosis, or LCA, is a group of inherited retinal degenerative disorders caused by mutations in at least 18 different genes. It is the most common cause of inherited childhood blindness, with an incidence of two to three per 100,000 live births worldwide. Symptoms of LCA appear within the first years of life, resulting in significant vision loss and potentially blindness. The most common form of the disease, LCA10, is a monogenic disorder caused by mutations in the CEP290 gene and is the cause of disease in approximately 2030 percent of all LCA patients.

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About the Editas Medicine-Allergan AllianceIn March 2017, Editas Medicine and Allergan Pharmaceuticals International Limited (Allergan) entered a strategic alliance and option agreement under which Allergan received exclusive access and the option to license up to five of Editas Medicines genome editing programs for ocular diseases, including EDIT-101 (AGN-151587). Under the terms of the agreement, Allergan is responsible for development and commercialization of optioned products, subject to Editas Medicines option to co-develop and share equally in the profits and losses of two optioned products in the United States. In August 2018, Allergan exercised its option to develop and commercialize EDIT-101 globally for the treatment of LCA10. Additionally, Editas Medicine exercised its option to co-develop and share equally in the profits and losses from EDIT-101 in the United States. Editas Medicine is also eligible to receive development and commercial milestones, as well as royalty payments on a per-program basis. The agreement covers a range of first-in-class ocular programs targeting serious, vision-threatening diseases based on Editas Medicines unparalleled CRISPR genome editing platform, including CRISPR/Cas9 and CRISPR/Cpf1 (also known as Cas12a).

Forward-Looking StatementsThis press release contains forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, target, should, would, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements in this press release include statements regarding the Companys plans with respect to the Brilliance Phase 1/2 clinical trial for EDIT-101 (AGN-151587), including the Companys expectations regarding the timing of dosing a patient by early 2020. The Company may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of pre-clinical studies and clinical trials and clinical development of the Companys product candidates; availability and timing of results from pre-clinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products and availability of funding sufficient for the Companys foreseeable and unforeseeable operating expenses and capital expenditure requirements. These and other risks are described in greater detail under the caption Risk Factors included in the Companys most recent Quarterly Report on Form 10-Q, which is on file with the Securities and Exchange Commission, and in other filings that the Company may make with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.

Investor ContactMark Mullikin(617) 401-9083mark.mullikin@editasmed.com

Media ContactCristi Barnett(617) 401-0113cristi.barnett@editasmed.com

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Editas Medicine Announces Third Quarter 2019 Results and Update - Yahoo Finance

Treatment-Free Remission at Heart of New CML Study – AJMC.com Managed Markets Network

Maggie L. Shaw

Researchers aim to eliminate leukemia stem cells safely.

Its like removing the tree, but leaving the roots that can sprout new shoots, they said in a statement.

Because stem cells are responsible for cell self-renewal and differentiation, Lacorazza and his team set out to better understand the LSC self-renewal process, hoping to pinpoint possible new options to target that activity, prevent relapses, and lead to treatment-free remission. Their results appeared recently in Blood, the official publication of the American Society of Hematology.

Knowing that Krppel-like factor 4 (KLF4) plays an essential part in carcinogenesisalthough it has also been shown to have antitumor activitythe study investigators removed KLF4 to see if it was necessary also for LSCs to survive. The result? Loss of LSC/progenitor cells and increased levels of tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) protein.

According to the authors, A major change in the absence of KLF4 was an increase in the production of kinase DYRK2, an enzyme involved in protein stability, cell cycle control, and apoptosis.

Stabilizing levels of this protein, then, could be a possible solution. To do this, they inhibited ubiquitin E3 ligase SIAH2 by introducing menadione (vitamin K3), as this has been shown to stimulate cell death in human CML stem/progenitor cells and increase levels of DYRK2. The drawback to this approach is that vitamin K3 can be toxic. To remedy this, the authors suggest SIAH2 inhibitors with lower hematological toxicity, evaluating the safety of that inhibition, and developing alternatives to activating DYRK2 in CML LSCs. In other words, stabilize or increase DYRK2 levels to inhibit LSCs.

Having set out to better their understanding of LSC renewal for new inroads to treatment-free survival and relapse prevention, Lacarozza and colleagues did just that. They identified the DYRK2 checkpoint in LSC/progenitor cell survival and self-renewal, showing there are 2 ways to increase its levels: (1) remove the Klf4 gene or (2) inhibit the ubiquitin ligase SIAH2 pharmacologically.

At present, they continue to search for ways to accomplish this that will not harm patients with CML, who today must take TKIs for life. We envision that targeting the bulk of leukemia with tyrosine kinase inhibitors plus a new drug that targets the stem cells might be a future strategy for patients to reach drug-free remission.

Reference

Park CS, Lewis A, Chen T, et al. KLF4 represses DYRK2 inhibition of self-renewal and survival through c-Myc and p53 in leukemia stem/progenitor cells [published online September 12, 2019]. Blood. doi: 10.1182/blood.2018875922.

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Treatment-Free Remission at Heart of New CML Study - AJMC.com Managed Markets Network

The female problem: how male bias in medical trials ruined women’s health – The Guardian

From the earliest days of medicine, women have been considered inferior versions of men. In On the Generation of Animals, the Greek philosopher Aristotle characterised a female as a mutilated male, and this belief has persisted in western medical culture.

For much of documented history, women have been excluded from medical and science knowledge production, so essentially weve ended up with a healthcare system, among other things in society, that has been made by men for men, Dr Kate Young, a public health researcher at Monash University in Australia, tells me.

Youngs research has uncovered how doctors fill knowledge gaps with hysteria narratives. This is particularly prevalent when women keep returning to the doctor, stubbornly refusing to be saved.

The historical hysteria discourse was most often endorsed when discussing difficult women, referring to those for whom treatment was not helpful or who held a perception of their disease alternative to their clinician, Young wrote in a research paper published in the journal Feminism & Psychology.

Rather than acknowledge the limitations of medical knowledge, medicine expected women to take control (with their minds) of their disease (in their body) by accepting their illness, making lifestyle changes and conforming to their gendered social roles of wife and mother. Moralising discourses surround those who rebel; they are represented as irrational and irresponsible, the safety net for medicine when it cannot fulfil its claim to control the body.

In her work, Young has shown how endometriosis patients are often viewed by their treating doctors as reproductive bodies with hysterical tendencies. One gynaecologist said to Young: Do mad people get endo or does endo make you mad? Its probably a bit of both. Another said: Theres a lot of psychology, just as much as there is pathology [in gynaecology].

Nobody suggests that endometriosis is not a real disease, or is somehow imagined, but there is a general feeling in medicine that womens reaction to having endometriosis is somehow hysterical, especially when symptoms prevail after treatment has been offered, which is common. And it is not just endometriosis patients treated this way. One male GP said to me: Ive never had a fibromyalgia patient who wasnt batshit crazy.

Historically, Young says, men have made the medical science about women and their bodies, and there is an abundance of research evidence about the ways in which that knowledge has been constructed to reinforce the hysteria discourse and women as reproductive bodies discourse. One of my favourite examples is that in some of the first sketches of skeletons, male anatomy artists intentionally made womens hips look wider and their craniums look much smaller as a way of saying: Here is our evidence that women are reproductive bodies and they need to stay at home and we cant risk making them infertile by making them too educated, look how tiny their heads are. And we see that again and again.

Not only have doctors, scientists and researchers mostly been men, but most of the cells, animals and humans studied in medical science have also been male: most of the advances we have seen in medicine have come from the study of male biology. Dr Janine Austin Clayton, an associate director for womens health research at the United States National Institutes of Health (NIH), told the New York Times that the result is: We literally know less about every aspect of female biology compared to male biology.

Medicine has always seen women first and foremost as reproductive bodies. Our reproductive organs were the greatest source of difference to men and because they were different, they were mysterious and suspicious. But the fallout of this difference is that for a long time medicine assumed it was the only difference. Because women had reproductive organs, they should reproduce, and all else about them was deemed uninteresting.

In the early 20th century, the endocrine system, which produces hormones, was discovered. To medical minds, this represented another difference between men and women, overtaking the uterus as the primary perpetrator of all womens ills. Still, medicine persisted with the belief that all other organs and functions would operate the same in men and women, so there was no need to study women. Conversely, researchers said that the menstrual cycle, and varied release of hormones throughout the cycle in rodents, introduced too many variables into a study, therefore females could not be studied.

Diseases presenting differently in women are often missed or misdiagnosed, and those affecting mainly women remain largely a mystery: understudied, undertreated and frequently misdiagnosed or undiagnosed. This has major knock-on effects for both medical practice and the health of women.

As Young has argued: Medicine defines the female and male bodies as distinct but not equal; analyses of medical texts throughout history reveals the male body to be constructed as superior and the template against which bodies are judged. Any aspect of the female body that differs from the male or that cannot be given a male comparative (exemplified by the uterus) is viewed as evidence of deviation or fault.

Because women can bear children, medical discourse associated women with the body and men with the mind, a binary division that reinforces and is reinforced by the public-private division ... In addition to restricting womens public contribution, such beliefs provide medicine with an explanatory model of disease and illness in women: to deny ones biological destiny is to incite all manner of diseases, as Plato stated when theorising the wandering womb.

We see this in many predominantly female conditions: women with endometriosis are told that delayed childbearing causes the illness, or that pregnancy will cure it; women with breast cancer were once fed this line until advances in research (which only occurred because women campaigned for better knowledge and treatments) proved otherwise.

During the 80s, a group of female scientists in the US formed a society to campaign for better health research in women, now called the Society for Womens Health Research. They teamed up with some US Congress members to draw attention to the discrepancies in medical research and the effect on womens health.

In 1985, a report by the US Public Health Service Task Force on Womens Health warned that the historical lack of research focus on womens health concerns has compromised the quality of health information available to women as well as the health care they receive.

The campaign drew attention to some of the absurdities that resulted from this male bias, which Maya Dusenbery has summarised in her 2018 book Doing Harm: The Truth About How Bad Medicine and Lazy Science Leave Women Dismissed, Misdiagnosed and Sick. She notes that, in the early 60s: Observing that women tended to have lower rates of heart disease until their oestrogen levels dropped after menopause, researchers conducted the first trial to look at whether supplementation with the hormone was an effective preventive treatment. The study enrolled 8,341 men and no women ... And a National Institutes of Health-supported pilot study from Rockefeller University that looked at how obesity affected breast and uterine cancer didnt enrol a single woman.

And thats not all.

The Baltimore Longitudinal Study of Aging, which began in 1958 and purported to explore normal human ageing, didnt enrol any women for the first 20 years it ran. The Physicians Health Study, which had recently concluded that taking a daily aspirin may reduce the risk of heart disease? Conducted in 22,071 men and zero women. The 1982 Multiple Risk Factor Intervention Trial known, aptly enough, as MRFIT which looked at whether dietary change and exercise could help prevent heart disease: just 13,000 men.

The result of this male bias in research extends beyond clinical practice. Of the 10 prescription drugs taken off the market by the US Food and Drug Administration between 1997 and 2000 due to severe adverse effects, eight caused greater health risks in women. A 2018 study found this was a result of serious male biases in basic, preclinical, and clinical research.

The campaign had an effect in the US: in 1993, the FDA and the NIH mandated the inclusion of women in clinical trials. Between the 70s and 90s, these organisations and many other national and international regulators had a policy that ruled out women of so-called childbearing potential from early-stage drug trials.

The reasoning went like this: since women are born with all the eggs they will ever produce, they should be excluded from drug trials in case the drug proves toxic and impedes their ability to reproduce in the future.

The result was that all women were excluded from trials, regardless of their age, gender status, sexual orientation or wish or ability to bear children. Men, on the other hand, constantly reproduce their sperm, meaning they represent a reduced risk. It sounds like a sensible policy, except it treats all women like walking wombs and has introduced a huge bias into the health of the human race.

In their 1994 book Outrageous Practices, Leslie Laurence and Beth Weinhouse wrote: It defies logic for researchers to acknowledge gender difference by claiming womens hormones can affect study results for instance, by affecting drug metabolism but then to ignore these differences, study only men and extrapolate the results to women.

Since the 90s, more women have been included in clinical trials but researchers have not always analysed results by sex and/or gender. And though clinical studies have changed substantially, preclinical studies remained focused on male cell lines and male animals.

A 2010 study by Annaliese Beery and Irving Zucker reviewed sex bias in research on mammals in 10 biological fields during 2009 and their historical precedents. It found: Male bias was evident in eight disciplines and most prominent in neuroscience, with single-sex studies of male animals outnumbering those of females 5.5 to 1. In the past half-century, male bias in non-human studies has increased while declining in human studies. Studies of both sexes frequently fail to analyse results by sex. Under-representation of females in animal models of disease is also commonplace, and our understanding of female biology is compromised by these deficiencies.

The study also found the justification that researchers gave for excluding female animals that it introduced too much variability in results to be without foundation.

It took until 2014 for the NIH to begin to acknowledge the problem of male bias in preclinical trials, and until 2016 for it to mandate that any research money it granted must include female animals.

These policies and practices have often been framed as paternalistic, designed to protect women against the harmful effects of medical research. But history belies this notion. The practice of brutal experimentation of medical treatments on women throughout history makes medicines unwillingness to include women in scientific studies seem a lot less like magnanimous paternalism. Rather, we are left with the impression that women are not interesting enough for scientific endeavour but good enough for practice.

This is an edited extract from Pain and Prejudice by Gabrielle Jackson, published by Little, Brown (14.99 rrp). To order a copy for 11.24 with free UK p&p, go to guardianbookshop.com or call 020-3176 3837

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The female problem: how male bias in medical trials ruined women's health - The Guardian

Sodium Selenite Improves The Therapeutic Effect Of BMSCs Via Promoting | OTT – Dove Medical Press

Dongmei Yan,1,* Botao Tang,2,* Lixin Yan,3 Lei Zhang,1 Meijuan Miao,1 Xi Chen,4 Guangyi Sui,5 Qi Zhang,1 Daoyuan Liu,1 Hui Wang1

1Department of Blood Transfusion, The Second Affiliated Hospital of Harbin Medical University, Harbin, Peoples Republic of China; 2Department of Cardiology, Heilongjiang Red Cross Hospital, Harbin, Peoples Republic of China; 3Department of Laboratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Peoples Republic of China; 4Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Peoples Republic of China; 5Ethics Committee, The Tumor Hospital Affiliated to Harbin Medical University, Harbin, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Hui WangDepartment of Blood Transfusion, The Second Affiliated Hospital, Harbin Medical University, Xuefu Road No. 246, Nangang District, Harbin, Heilongjiang Province, Peoples Republic of ChinaTel +86-451-86605134Email wanghui@hrbmu.edu.cn

Purpose: Sodium selenite (Na2SeO3) has been known to restore the antioxidant capacity of bone marrow mesenchymal stem cells (BMSCs), reduce the production of reactive oxygen species (ROS) in the cells, and promote cell proliferation and inhibit cell apoptosis. However, it is still not clear whether selenium can mediate the differentiation and inhibit the induced hemagglutination of BMSCs. In this study, we attempted to explore the effect of Na2SeO3 on these aspects of BMSCs.Methods: We evaluated the fate of the MSCs isolated from the bone marrow of mice by studying their differentiation and proliferation after treatment with Na2SeO3. We also simultaneously evaluated the coagulation reaction induced by Na2SeO3-treated BMSCs in vitro.Results: While the mice-derived BMSCs expressed CD44, CD73, CD90, and CD105, they did not express CD45. The morphology of the derived cells was homogeneously elongated. These results showed that the isolated cells are indeed BMSCs. We found that 0.1 M and 1 M of Na2SeO3 promoted the proliferation and apoptosis of BMSCs, respectively. This showed that Na2SeO3 can be toxic and exert certain side effects on the BMSCs. The results of the osteogenic and adipogenic assay showed that 0.1 M Na2SeO3 could significantly promote the osteogenic and adipogenic differentiation of BMSCs by upregulating the lipid factors (LPL and PPRAG) and osteogenic factors, RUNX2, COL1, and BGP, in a concentration-dependent manner. Coagulation experiments in animals (mice and rats) revealed that Na2SeO3 can reduce the coagulation time of BMSCs in a concentration-dependent manner, which is related to the high expression of hematopoietic factors (SDF-1, GM-CSF, IL-7, IL-8, IL-11, and SCF).Conclusion: Na2SeO3 promotes the proliferation and differentiation as well as reduces the coagulation time of BMSCs, and this effect might enhance the therapeutic effect of BMSCs.

Keywords: sodium selenite, BMSCs, proliferation, differentiation, coagulation factors, clotting time

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Sodium Selenite Improves The Therapeutic Effect Of BMSCs Via Promoting | OTT - Dove Medical Press

US FDA Grants BeiGene’s BRUKINSA (zanubrutinib) Accelerated Approval to Treat Adult Patients with Mantle Cell Lymphoma Who Received at Least One Prior…

CAMBRIDGE, Mass. and BEIJING, China, Nov. 14, 2019 (GLOBE NEWSWIRE) -- BeiGene Co.,Ltd (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, today announced that BRUKINSA (zanubrutinib) has received accelerated approval from the United States Food and Drug Administration (FDA) as a treatment for mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy.1 BRUKINSA is the first BeiGene-discovered product to be approved, an important milestone toward the companys goal of transforming treatment for cancer patients around the world.

This accelerated approval is based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

We are working to improve outcomes for people with cancer worldwide and this approval brings us closer to realizing our mission of bringing the highest quality therapies to patients globally, said John V. Oyler, Chairman, Co-Founder, and CEO of BeiGene. Todays FDA approval of BRUKINSA, following the previously granted Breakthrough Therapy designation in this indication, validates it as an important treatment option for people with relapsed or refractory MCL. We hope this is the first of many approvals for BRUKINSA as we continue to evaluate its potential in other hematologic cancers.

BRUKINSA is a BTK inhibitor that was designed to maximize target occupancy and minimize off-target binding. It entered the clinic in 2014 and since that time our broad development program has enrolled more than 1,600 patients globally, said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. Todays accelerated approval is the culmination of many years of effort by the BeiGene team, the dedicated investigators involved in these trials and, most importantly, the patients who participated by enrolling in the clinical trials. We are humbled by the opportunity to develop this therapy and launch it as our first internally discovered and approved cancer treatment.

BTK inhibition is an established mode of treatment for patients with MCL, but many patients treated with previously approved BTK inhibitors do not fully respond to BTK therapy or are forced to discontinue treatment early due to side effects. Today we have a new option for our adult patients who have received one prior systemic or targeted therapy and are living with MCL, an aggressive blood cancer thats often diagnosed at a more advanced stage, said Luhua (Michael) Wang, M.D., Professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, and clinical trial investigator.

The approval of BRUKINSA as a second line therapy represents an important advancement for the treatment of mantle cell lymphoma, said Meghan Gutierrez, Chief Executive Officer for the Lymphoma Research Foundation. Expanded treatment options can transform the patient experience and provide hope to people living with a mantle cell diagnosis.

The FDAs approval of BRUKINSA is based on efficacy results from two single-arm clinical trials, with independent review committee (IRC)-assessed ORR per 2014 Lugano Classification as the primary endpoint. Across both trials, BRUKINSA achieved an ORR, which is the sum of complete responses and partial responses, of 84%.

In the multicenter Phase 2 trial of zanubrutinib in patients with relapsed or refractory (R/R) MCL BGB-3111-206 (NCT03206970), the ORR was 84% (95% CI: 74%, 91%), including 59% complete response (FDG-PET scan required) and 24% partial response. In this study, the median duration of response (DOR) was 19.5 months (95%CI: 16.6, NE) and median follow-up time on study was 18.4 months. In the global Phase 1/2 trial BGB-3111-AU-003 (NCT02343120), the ORR was 84% (95% CI: 67%, 95%), including 22% complete response (FDG-PET scan not required) and 62% partial response. In this study, the median DOR was 18.5 months1 (95% CI:12.6, NE) and median follow-up time on study was 18.8 months.

The most common adverse reactions (> 10%) with BRUKINSA were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, cough, musculoskeletal pain, pneumonia, urinary tract infection, blood in the urine (hematuria), fatigue, constipation, and hemorrhage. The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Of the 118 patients with MCL treated with BRUKINSA, eight (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

The recommended dose of BRUKINSA is 320 mg, taken orally 160 mg twice daily or 320 mg once daily with or without food. The dose may be adjusted for adverse reactions, and reduced for patients with severe hepatic impairment and certain drug interactions.1

BRUKINSA is expected to be available to people in the United States in the coming weeks.

myBeiGene Patient Support Program

BeiGene is committed to ensuring that people have access to the medicine and the support needed to have the best possible outcomes and experiences. Coinciding with todays approval, BeiGene is launching myBeiGene in the United States to support patients, caregivers, and healthcare providers with access to BRUKINSA. The myBeiGene program goes beyond financial assistance support to provide patients and caregivers with education about their disease and treatment with BRUKINSA, as well provide practical and emotional support by connecting them to third-party resources that can address their individual unique needs. For more information on myBeiGene, please call 1-833-234-4363 or visit BRUKINSA.com.

About Mantle Cell Lymphoma (MCL)

Lymphoma is a diverse group of cancers that originate from B-, T- or NK- cells. MCL is typically an aggressive form of non-Hodgkins lymphoma (NHL) that arises from B-cells originating in the mantle zone.2 Inthe United States, about 74,200 people will be diagnosed with NHLin 2019,3 with MCL representing about six percent (about 4,452 cases) of all new cases ofNHL.2 MCL usually has a poor prognosis, with a median survival of three to four years,4 and it often diagnosed at a later stage of disease.

About BRUKINSA (zanubrutinib)

BRUKINSA is a small molecule inhibitor of Brutons tyrosine kinase (BTK), discovered by BeiGene scientists, that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. BRUKINSA was approved by the U.S. FDA to treat adult patients with MCL who have received at least one prior therapy on November 14, 2019.

New Drug Applications (NDAs) in China for relapsed refractory (R/R) MCL and R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been accepted by the China National Medical Products Administration (NMPA) and granted priority review and are pending approval.

BRUKINSA is not approved for use outside the United States.

IMPORTANT SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%) and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Drug Interactions

CYP3A Inhibitors:When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers:Avoid coadministration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

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

Please see fullPrescribing Information at beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at beigene.com/PDF/BRUKINSAUSPPI.pdf

About the Zanubrutinib Clinical Trial Program

Clinical trials of zanubrutinib include:

About BeiGene

BeiGene is a global, commercial-stage, research-based biotechnology company focused on molecularly-targeted and immuno-oncology cancer therapeutics. With a team of over 3,000 employees in the United States, China, Australia, and Europe; BeiGene is advancing a pipeline consisting of novel oral small molecules and monoclonal antibodies for cancer. BeiGene is also working to create combination solutions aimed to have both a meaningful and lasting impact on cancer patients. In the United States, BeiGene markets and distributes BRUKINSA (zanubrutinib) and in China, the Company markets ABRAXANE (nanoparticle albuminbound paclitaxel), REVLIMID (lenalidomide), and VIDAZA (azacitidine) under a license from Celgene Corporation.5

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding BeiGenes plans and expectations for the commercialization of BRUKINSA, the potential implications of clinical data for patients, BeiGenes further advancement of, and anticipated clinical development, regulatory milestones and commercialization of BRUKINSA. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeiGene's ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; BeiGene's ability to achieve commercial success for its marketed products and drug candidates, if approved; BeiGene's ability to obtain and maintain protection of intellectual property for its technology and drugs; BeiGene's reliance on third parties to conduct drug development, manufacturing and other services; BeiGenes limited operating history and BeiGene's ability to obtain additional funding for operations and to complete the development and commercialization of its drug candidates, as well as those risks more fully discussed in the section entitled Risk Factors in BeiGenes most recent quarterly report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in BeiGene's subsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeiGene undertakes no duty to update such information unless required by law.

Investor Contact

Craig West

+1 857-302-5189

ir@beigene.com

Media Contact

Liza Heapes or Vivian Ni

+1 857-302-5663 or +1 857-302-7596

media@beigene.com

_________________________________________

1 BRUKINSA (zanubrutinib) Prescribing Information. beigene.com/PDF/BRUKINSAUSPI.pdf. BeiGene, Ltd; November 14, 2019.

2 https://www.lls.org/sites/default/files/file_assets/FS4_MCL_Facts_2018-final.pdf

3 https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html

4 Philip J. Bierman,James O. Armitage, in Goldman'sCecil Medicine(Twenty Fourth Edition), 2012.

5 ABRAXANE, REVLIMID and VIDAZA are registered trademarks of Celgene Corporation.

Photos accompanying this announcement are available at:

https://www.globenewswire.com/NewsRoom/AttachmentNg/f728ceea-0c2b-4042-a937-e6b1638b4323

https://www.globenewswire.com/NewsRoom/AttachmentNg/5e5fe145-2754-4389-b9b9-b23a3731d03e

PDFsaccompanying this announcement are available at:

http://ml.globenewswire.com/Resource/Download/aca04555-626d-4c35-821b-957abaab640c

http://ml.globenewswire.com/Resource/Download/c47ea153-ba25-4dd1-8155-937b64fdf4b7

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US FDA Grants BeiGene's BRUKINSA (zanubrutinib) Accelerated Approval to Treat Adult Patients with Mantle Cell Lymphoma Who Received at Least One Prior...

CRISPR’s unwanted anniversary – Science Magazine

PHOTO: BARBARA RIES FOR UCSF

There are key moments in the history of every disruptive technology that can make or break its public perception and acceptance. For CRISPR-based genome editing, such a moment occurred 1 year agoan unsettling push into an era that will test how society decides to use this revolutionary technology.

In November 2018, at the Second International Summit on Human Genome Editing in Hong Kong, scientist He Jiankui announced that he had broken the basic medical mantra of do no harm by using CRISPR-Cas9 to edit the genomes of two human embryos in the hope of protecting the twin girls from HIV. His risky and medically unnecessary work stunned the world and defied prior calls by my colleagues and me, and by the U.S. National Academies of Sciences and of Medicine, for an effective moratorium on human germline editing. It was a shocking reminder of the scientific and ethical challenges raised by this powerful technology. Once the details of He's work were revealed, it became clear that although human embryo editing is relatively easy to achieve, it is difficult to do well and with responsibility for lifelong health outcomes.

It is encouraging that scientists around the globe responded by opening a deeper public conversation about how to establish stronger safeguards and build a viable path toward transparency and responsible use of CRISPR technology. In the year since He's announcement, some scientists have called for a global but temporary moratorium on heritable human genome editing. However, I believe that moratoria are no longer strong enough countermeasures and instead, stakeholders must engage in thoughtfully crafting regulations of the technology without stifling it. In this vein, the World Health Organization (WHO) is pushing government regulators to engage, lead, and act. In July, WHO issued a statement requesting that regulatory agencies in all countries disallow any human germline editing experiments in the clinic and in August, announced the first steps in establishing a registry for future such studies. These directives from a global health authority now make it difficult for anyone to claim that they did not know or were somehow operating within published guidelines. On the heels of WHO, an International Commission on the Clinical Use of Human Germline Genome Editing convened its first meeting to identify the scientific, medical, and ethical requirements to consider when assessing potential clinical applications of human germline genome editing. The U.S. National Academy of Medicine, the U.S. National Academy of Sciences, and the Royal Society of the United Kingdom lead this commission, with the participation of science and medical academies from around the world. Already this week, the commission held a follow-up meeting, reflecting the urgent nature of their mission.

Where is CRISPR technology headed? Since 2012, it has transformed basic research, drug development, diagnostics, agriculture, and synthetic biology. Future CRISPR-based discoveries will depend on increased knowledge of genomes and safe and effective methods of CRISPR delivery into cells. There needs to be more discussion about prioritizing where the technology will have the most impact as well as equitable, affordable access to its products. As for medical breakthroughs, clinical trials using CRISPR are already underway for patients with cancer, sickle cell disease, and eye diseases. These and many other future uses of genome editing will involve somatic changes in individuals, not heritable changes that are transmissible. But the rapidly advancing genome editing toolbox will soon make it possible to introduce virtually any change to any genome with precision, and the temptation to tinker with the human germ line is not going away.

The CRISPR babies saga should motivate active discussion and debate about human germline editing. With a new such study under consideration in Russia, appropriate regulation is urgently needed. Consequences for defying established restrictions should include, at a minimum, loss of funding and publication privileges. Ensuring responsible use of genome editing will enable CRISPR technology to improve the well-being of millions of people and fulfill its revolutionary potential.

* J.D. is a cofounder of Caribou Biosciences, Editas Medicine, Scribe Therapeutics, and Mammoth Biosciences; scientific advisory board member of Caribou Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics, Mammoth Biosciences, Synthego, and Inari; and director at Johnson & Johnson. Her lab has research projects sponsored by Biogen and Pfizer.

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CRISPR's unwanted anniversary - Science Magazine

Vertex Confirms Wales Offer Accepted for Access to All Licensed Cystic Fibrosis Medicines – Business Wire

LONDON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today confirms that NHS Wales has accepted an offer for all currently licensed Vertex cystic fibrosis (CF) medicines and any future indications of these medicines under the same terms as the recently announced agreement with NHS England.

This means that once the contract is finalized, patients with CF in Wales ages 2 years and older who have two copies of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can access ORKAMBI (lumacaftor/ivacaftor) and CF patients ages 12 years and older who either have two copies of the F508del mutation or one copy of the F508del mutation and a copy of one of the other 14 licensed mutations can access SYMKEVI (tezacaftor/ivacaftor) in combination with ivacaftor in the coming weeks.

The agreement also offers expanded access to KALYDECO (ivacaftor) to include those patients ages 12 months and older who have one of the nine licensed gating mutations.

Todays announcement is good news for the approximately 270 eligible cystic fibrosis patients in Wales who will soon have access to CFTR modulators to treat the underlying cause of their disease, said Ludovic Fenaux, Senior Vice President, Vertex International. We thank the authorities in Wales for their collaboration in accepting this offer under the same terms as were recently announced in England.

About CF in the UKOver 10,000 people in the UK have CF the second highest number in the world. Over 430 people in Wales have CF. CF is a debilitating, life-shortening inherited condition that causes progressive damage to organs across the body from birth. Currently, there is no cure for CF and half of people in the UK with CF die before they are 32. The daily impact of treatment is significant. It can take up to four or more hours, involving nebulizers, physiotherapy and up to 70 tablets a day. CF accounts for 9,500 hospital admissions and over 100,000 hospital bed days a year. A third of these are used by children under 15.

About ORKAMBI (lumacaftor/ivacaftor) and the F508del mutationIn people with two copies of the F508del mutation, the CFTR protein is not processed and trafficked normally within the cell, resulting in little-to-no CFTR protein at the cell surface. Patients with two copies of the F508del mutation are easily identified by a simple genetic test.

Lumacaftor/ivacaftor is a combination of lumacaftor, which is designed to increase the amount of mature protein at the cell surface by targeting the processing and trafficking defect of the F508del-CFTR protein, and ivacaftor, which is designed to enhance the function of the CFTR protein once it reaches the cell surface.

For complete product information, please see the Summary of Product Characteristics that can be found on http://www.ema.europa.eu.

About SYMKEVI (tezacaftor/ivacaftor) in combination with ivacaftorSome mutations result in CFTR protein that is not processed or folded normally within the cell, and that generally does not reach the cell surface. Tezacaftor is designed to address the trafficking and processing defect of the CFTR protein to enable it to reach the cell surface and ivacaftor is designed to enhance the function of the CFTR protein once it reaches the cell surface.

SYMKEVI is indicated for people with CF ages 12 and older who either have two copies of the F508del mutation or one copy of the F508del mutation and have one of the following 14 mutations in which the CFTR protein shows residual function: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3AG, S945L, S977F, R1070W, D1152H, 2789+5GA, 3272-26AG, or 3849+10kbCT.

For complete product information, please see the Summary of Product Characteristics that can be found on http://www.ema.europa.eu.

About KALYDECO (ivacaftor)KALYDECO (ivacaftor) is the first medicine to treat the underlying cause of CF in people with specific mutations in the CFTR gene. Known as a CFTR potentiator, ivacaftor is an oral medicine designed to keep CFTR proteins at the cell surface open longer to improve the transport of salt and water across the cell membrane, which helps hydrate and clear mucus from the airways.

KALYDECO is indicated in people ages 12 months and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R. KALYDECO is also indicated for the treatment of patients with CF ages 18 years and older who have an R117H mutation in the CFTR gene.

For complete product information, please see the Summary of Product Characteristics that can be found on http://www.ema.europa.eu.

About VertexVertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has four approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational medicines in other serious diseases where it has deep insight into causal human biology, such as sickle cell disease, beta thalassemia, pain, alpha-1 antitrypsin deficiency, Duchenne muscular dystrophy and APOL1-mediated kidney diseases.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London, UK. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 10 consecutive years on Science magazine's Top Employers list and top five on the 2019 Best Employers for Diversity list by Forbes.

Special Note Regarding Forward-looking StatementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, the statements by Mr. Fenaux in the fourth paragraph of this press release, statements regarding our expectations for the patient populations that will be able to access Vertexs medicines and the timing of such access, and statements about our expectations regarding a formal agreement in Northern Ireland. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under Risk Factors in Vertex's annual report and subsequent quarterly reports filed with the Securities and Exchange Commission and available through the company's website at http://www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

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Vertex Confirms Wales Offer Accepted for Access to All Licensed Cystic Fibrosis Medicines - Business Wire