The Fast Pace of CAR T-Cell Innovation Caused an Array of Challenges in Treatment – AJMC.com Managed Markets Network

The evidence shows that chimeric antigen receptor (CAR) T-cell therapies are effective, but the price tags on these treatments are high and have raised concerns about how many patients will get treated. During a discussion at The American Journal of Managed Cares Patient-Centered Oncology Care meeting, held Friday in Philadelphia, panelists outlined the efficacy of the 2 FDA-approved therapies, Medicare reimbursement for CAR T-cell therapies, and the pace of innovation in healthcare.

In children, tisagenlecleucel (Kymriah) has successfully treated children and young adults, up to age 25, with relapsed or refractory acute lymphoblastic leukemia, explained Shannon L. Maude, MD, PhD, assistant professor of pediatrics in the Division of Oncology at the Childrens Hospital of Philadelphia, and medical director of the Center for Cellular Immunotherapies at the University of Pennsylvania Perelman School of Medicine.

In the trials that led to FDA approval, patients treated with tisagenlecleucel had a remission rate of 81% after relapsing more than once after the best standard of care. In some of the longer-term data now being seen, patients who went into remission have a relapse-free survival rate of 66%.

The other FDA-approved therapy, axicabtagene ciloleucel (Yescarta), is indicated in adults with diffuse large B-cell lymphoma (DLBCL), which typically affects people in their 60s and 70s, said John W. Sweetenham, MD, FRCP, FACP, FASCO, professor of medicine and associate director of clinical affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. For 15 to 20 years, treatment for disease has be relatively the same: chemotherapy is front line followed by a bone marrow transplant. But if those 2 treatments are unsuccessful, the patients had essentially no other options.

Now, there have been extraordinary responses with CAR T-cell therapy, he said. There are patients who, in the past, he would have anticipated have a bad outcome after relapsing, who have now survived more than a year after treatment.

This treatment is like nothing weve ever seen before in terms of its ability to turn very sick people around, Sweetenham said.

However, since these therapies are so different, there are still plenty of unknowns. There have not been any randomized trials to compare the CAR T-cell therapy treatment with more standard treatments, for instance.

As a result of how successful CAR T-cell therapies have been and the uniqueness of them, they cost upwards of $373,000 per treatmentthe good news, said Erika Miller, JD, senior vice president and counsel at CRD Associates, is that patients only need the treatment one time. The problem is that regulators and legislators are concerned about safeguarding the Medicare trust fund, and these therapies are a big hit, financially.

There is concern that if Medicare pays the full cost, that it is sending a signal to drug makers that the price tag is not a problem and they might even be able to ask for more for the next treatment.

[Regulators and legislators] are concerned about how many patients are going to get this, Miller said. Theyre afraid of a tsunami. And then, this is all happening at the same time that everyone in Washington [DC] is talking about the price of drugs.

She echoed Sweetenham and Maudes comments that everyone is still waiting to see how effective the treatments will be in the long term. In addition, a greater concern is that there are other CAR T-cell therapies in the pipeline, which will only add to the costs.

Medicare doesnt change on a dime, she said. It takes them a long time to change their policy. They have mechanisms for payment that have been in place for a long time that they are reluctant to change.

The pace of innovation has been, perhaps, too fast. It has outpaced changes in payment, but also, in some ways, were ahead of the evidence, Sweetenham said.

We dont want to end up in a situation where patients are potentially missing out on effective treatment because its taking us too long to get the evidence that we really need, he added.

Putting together clinical trials is complicated and expensive, and researchers need a solid partnership with all the stakeholders in terms of getting needed clinical trials moving, Sweetenham said.

Maude added that when trials are set up, they need to be optimized so we can identify which patients will benefit the most from CAR T-cell therapies and, thus, improve the outcomes that are already seen. There is additional cost in setting up those types of trials, but they will be more cost effective in the long run, she said.

Moving forward, improving patient access to these treatments is critical, Miller said. The cost of CAR T-cell therapies is so high that academic medical centers are losing out on more than $100,000 for each patient treated. As a result, there are some centers that are deciding not to offer CAR T-cell therapy.

Maude and Sweetenham also highlighted the access challenges. Since so few centers offer CAR T-cell therapy, patients often have geographic barriers and have to drive long distances in order to get treatment. Patients who have commercial insurance tend to have less trouble getting the treatment approved than patients who are in Medicare.

While the current administration has been reluctant to pay the full price tag for these therapies, it has shown it is very focused on promoting innovation, Miller said. Theres recognition that theres innovation here that cant be choked off, she said. The administration is listening, and there has been some progress with the increased new technology add-on payment, but with an election next year, there could be a new administration in the White House with a different perspective.

When asked to peer into the future, Miller predicted that there would be a payment model for CAR T or cellular therapies being tested. Next year there might be a CAR T-cell therapy for multiple myeloma, which has a large patient base, so there will be more pressure on CMS to create a payment model.

Maude and Sweetenham are both hoping to see more longer-term follow-up data and better predictions about which patients will benefit the most. Sweetenham is also anticipating that these treatments will move more into the outpatient setting and hopes to see patients getting better access to the treatments.

Pessimistically, I havent seen the field really move that far in 5 years, Sweetenham said.

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Government of Ghana Makes Hydroxyurea Available to People With Sickle Cell Disease Through First of Its Kind Public-private Partnership With Global…

Government is already working to accelerate inclusion of the medicine and associated laboratory testing in the National Health Insurance Scheme Novartis has already delivered more than 20 000 treatments1 and is committed to implementing two clinical trials with novel biologic treatment for sickle cell disease Partnership includes establishing national treatment guidelines, newborn screening, and centers of excellence for treatment of sickle cell disease; making accessible treatment options available in line with the global standards of care; and using digital technologies to monitor and evaluate patient registration, report real-time data, and help ensure safe large scale roll-out of medicine 15,000 babies are born with sickle cell disease every year in Ghana

ACCRA, Ghana, Nov. 11 /CSRwire/ - Today, the Government of Ghana announced the availability of hydroxyurea for the treatment of people with sickle cell disease (SCD), marking the official launch of a first of its kind public-private partnership to improve the diagnosis and accelerate treatment for people with SCD. The launch follows the signature of a Memorandum of Understanding in January among the Ministry of Health of Ghana, Ghana Health Service, the Sickle Cell Foundation of Ghana and global medicines company Novartis to create a holistic approach to help manage the disease. Ghana is the first African country to commit to offering the global standard of care for their people with SCD.

I am proud of this bold partnership, and it is my hope that, through this collaboration, we will help ease the pain and improve the lives of people living with sickle cell disease in our country. We are committed to put SCD among the priorities on our national health agenda and to take the necessary steps to make treatment broadly available through our National Health Insurance Scheme, bringing much-needed relief to families struggling to cover the cost of care for their loved ones, said H.E. Alhaji Dr. Mahamudu Bawumia, Vice President of the Republic of Ghana. Our collective goal is to reimagine what the future could look like for people with sickle cell disease: where children do not need to miss out on school or be singled out; where young adults can have equal opportunity for employment; and where families can flourish and continue to be the bedrock of our civil societyin a nutshell, we will make every effort to normalize sickle cell disease within the Ghanaian society.

To date, Novartis has delivered more than 20 000 treatments of hydroxyurea. Initially, the therapy will be made available through 11 trained treatment centers, as well as through private distribution channels, and is expected to cover the needs of patients for up to 12 months. The partners aim to open more treatment centers by the end of the year, and Novartis is committed to delivering a total of 60 000 treatments. Discussions are aleady underway for inclusion of the medicine and associated laboratory testing in the National Health Insurance Scheme, as well as prioritizing SCD as a national program.

Hydroxyurea is a commonly used medicine for patients with SCD in developed countries, and is approved for use in both adults and children. In October 2018, the Ghana FDA granted marketing authorization to Novartis hydroxyurea, making it the first time that hydroxyurea will be available for this indication in Ghana. A recent study, published in the New England Journal of Medicine3indicates that hydroxyurea treatment is effective and safe in children with SCD in sub-Saharan Africa and reduces the incidence of pain events (vaso-occlusive crises), malaria, blood transfusions, and death.

All the traditional names by which SCD is known allude to the episodes of severe pain experienced by people with the disease, said Prof. Kwaku Ohene-Frempong, MD, President of the Sickle Cell Foundation of Ghana and Program Coordinator for the National Newborn Screening Program for Sickle Cell Disease. Hydroxyurea is a drug with proven efficacy in reducing pain episodes and other complications of the disease. Currently, the highest standard of care for people with SCD starts with early diagnosis through newborn screening followed by penicillin prophylaxis to prevent early death from infection, and hydroxyurea therapy to ease the pain, prevent other complications and improve quality of life.

At the same time, Novartis has committed to develop a child-friendly formulation of hydroxyurea and has announced plans to conduct two clinical trials in Ghana and Kenya for its next-generation treatment for SCD, crizanlizumab. Crizanlizumab is a novel targeted biologic therapy that is expected to help reduce pain crises in people with SCD. The trials are expected to start in 2020; this will be the first time that a biologic therapy, which is not a vaccine, enters multicenter clinical trials in sub-Saharan Africa (excluding South Africa)4.

Novartis is deeply committed to reimagining medicine for patients in Ghana and across Africa, said Vas Narasimhan, MD, CEO of Novartis. Building on our long heritage of addressing malaria and leprosy in Africa, were excited to help improve the diagnosis and treatment of people with sickle cell disease here in Ghana. Novartis is proud to join this pioneering partnership, which could accelerate efforts to forge a healthier future for children across the continent.

Sickle cell disease is recognized by the World Health Organization as a public health priority and a neglected health problem in sub-Saharan Africa. Approximately 80% of individuals with

SCD globally are born in sub-Saharan Africa, and there is evidence to suggest that more than half of affected individuals may die before the age of five due to preventable complications. In Ghana, it is estimated that 15 000 babies are born with sickle cell disease every year2.

The five-year partnership aims to improve and extend the lives of people with SCD through a comprehensive approach to screening and diagnosis; treatment and disease management; training and education; and elevating basic and clinical research capabilities. Specifically, the partners aim to collaborate on field testing and implementation of SCD treatment guidelines, the establishment of centers of excellence across regions and the implementation of newborn screening at these centers. In addition, partners plan to employ digital technologies to monitor and evaluate patient registration, report real-time data and help ensure safe large scale roll-out of medicine.

In parallel, Novartis is working with Zipline, a California-based automated logistics company, to make sickle cell treatments widely available, especially in rural areas. Zipline is already operating two distribution centers in Ghana, in Omenako and Asante Mampong, with plans to open two more in the near future.

In addition, in order to help further ensure a sustainable supply of high quality hydroxyurea, Novartis has entered a strategic collaboration with Olon, a manufacturer based in Italy that supplies the active ingredient for the drug. We are proud to collaborate with Novartis and its partners to help make hydroxyurea more broadly available and in a sustainable way, said Paolo Tubertini, CEO of Olon.As a demonstration of our commitment to patients with sickle cell disease and this program, we will also contribute, without cost, the active ingredient to cover approximately 12 000 thousand treatments. Our hope is to continue to meet the needs and challenges of those living with sickle cell disease and their families to improve access to quality health care.

About Sickle Cell Disease

Sickle cell disease is a deblitating, inherited blood disorder. It causes affected red blood cells to become sickle-shaped, stiff and fragile easily breaking apart. Blood vessels and blood cells become sticky due to damage caused by sickle cells and ongoing chronic inflammation5,6. That leads to blood cells sticking to each other and to the blood vessels and causing blockages called vaso-occlusion - which can lead to the acute episodes of pain (known as sickle cell pain crises or vaso-occlusive crises), stroke and other life-threatening complications5,7. It is a lifelong illness that can put an emotional, physical, and financial burden on patients and their families8,9.

SCD is a global health problem, with the highest burden of disease concentrated in sub-Saharan Africa. In countries in West, Central and East Africa, the prevalence of the sickle cell gene is between 10 to 30 percent, while in some areas it is as high as 45%10. It is estimated that approximately 1 000 children in Africa are born with SCD every day and more than half die before they reach five years of age11. This is due primarily to lack of early diagnosis through newborn screening, penicillin prophylaxis, parental education, and comprehensive care. In resource-poor countries, more than 90 percent of children with SCD do not survive to adulthood12. Despite the adoption by the WHO of an SCD strategy for Africa in 2010, the disease is largely absent from the global or national health agenda.

References

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Government of Ghana Makes Hydroxyurea Available to People With Sickle Cell Disease Through First of Its Kind Public-private Partnership With Global...

Exercise found to block chronic inflammation in mice – Harvard Gazette

Scientists at Harvard-affiliated Massachusetts General Hospital (MGH) have identified a previously unknown biological pathway that promotes chronic inflammation and may help explain why sedentary people have an increased risk for heart disease and strokes.

In a study to be published in the November issue ofNature Medicine, MGH scientists and colleagues at several other institutions found that regular exercise blocks this pathway. This discovery could aid the development of new therapies to prevent cardiovascular disease.

Regular exercise protects the cardiovascular system by reducing risk factors such as cholesterol and blood pressure. But we believe there are certain risk factors for cardiovascular disease that are not fully understood, said Matthias Nahrendorf of the Center for Systems Biology at MGH. In particular, Nahrendorf and his team wanted to better understand the role of chronic inflammation, which contributes to the formation of artery-clogging blockages called plaques.

Nahrendorf and colleagues examined how physical activity affects the activity of bone marrow, specifically hematopoietic stem and progenitor cells (HSPCs). HSPCs can turn into any type of blood cell, including white blood cells called leukocytes, which promote inflammation. The body needs leukocytes to defend against infection and remove foreign bodies.

When these [white blood] cells become overzealous, they start inflammation in places where they shouldnt, including the walls of arteries.

Matthias Nahrendorf

But when these cells become overzealous, they start inflammation in places where they shouldnt, including the walls of arteries, said Nahrendorf.

Nahrendorf and his colleagues studied a group of laboratory mice that were housed in cages with treadmills. Some of the mice ran as much as six miles a night on the spinning wheels. Mice in a second group were housed in cages without treadmills. After six weeks, the running mice had significantly reduced HSPC activity and lower levels of inflammatory leukocytes than the mice that simply sat around their cages all day.

Nahrendorf explains that exercising caused the mice to produce less leptin, a hormone made by fat tissue that helps control appetite, but also signaled HSPCs to become more active and increase production of leukocytes. In two large studies, the team detected high levels of leptin and leukocytes in sedentary humans who have cardiovascular disease linked to chronic inflammation.

This study identifies a new molecular connection between exercise and inflammation that takes place in the bone marrow and highlights a previously unappreciated role of leptin in exercise-mediated cardiovascular protection, said Michelle Olive, program officer at the National Heart, Lung, and Blood Institute Division of Cardiovascular Sciences. This work adds a new piece to the puzzle of how sedentary lifestyles affect cardiovascular health and underscores the importance of following physical-activity guidelines.

Reassuringly, the study found that lowering leukocyte levels by exercising didnt make the running mice vulnerable to infection. This study underscores the importance of regular physical activity, but further focus on how exercise dampens inflammation could lead to novel strategies for preventing heart attacks and strokes. We hope this research will give rise to new therapeutics that approach cardiovascular disease from a completely new angle, said Nahrendorf.

The primary authors of theNature Medicinepaper are Nahrendorf, who is also a professor of radiology at Harvard Medical School; Vanessa Frodermann, a former postdoctoral fellow at MGH who is now a senior scientist at Novo Nordisk; David Rohde, a research fellow in the Department of Radiology at MGH; and Filip K. Swirski, an investigator in the Department of Radiology at MGH.

The work was funded bygrantsHL142494 andHL139598from the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

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Introduction to Cell Therapy – Clinical OMICs News

Sponsored content brought to you byCell Therapy Overview

CAR-T therapies have quickly shifted the direction of treatments for aggressive diseases, such as blood cancers, where previous treatments were limited. There are currently over 1000 cell and gene therapy trials and two approved cell therapies, axicabtagene ciloleucel and tisagenlecleucel, but determining cellular fitness is still a top need in moving the next generation of cell therapy treatments forward.

Both autologous and allogeneic options are among the cutting-edge therapies of today, which also comprise T cells, NK cells, and more, while using technologies like CRISPR and TALEN to address blood cancers and solid tumor. CRISPR, for example, has paved the way for new possibilities in the cell therapy space, including providing a way for researchers to develop a renewable source of NK cells to be optimized for cell therapies,1 as well as enabling more specific and targeted edits to cells in general.

Because cell therapy relies on immune cells from patients, or healthy donors in the case of allogeneic therapies, development and production is more complicated. To ensure that these cell products are potent and effective, knowing how to engineer potency and durability throughout the development and bioprocessing stages is crucial.

Knowledge of the powerful functional T cell drivers can give complex engineered immune cell therapies the edge that they need in this competitive and fast-paced environment. Legacy technologies, such as bulk ELISA or flow cytometry, can give estimates of a samples cytokine secretions, but miss the highly functional cell subsets that correlate to in vivo response. Bulk analysis is unable to analyze single cell function or identify which cells are secreting specific cytokines. Flow cytometry involves fixing and permeabilizing cells and can only provide estimates of cellular function. RNA-Seq can estimate function as well, but only shows a 0.4 correlation from RNA to protein.2 These limitations from legacy technologies remain challenges in determining function of cell products.

To address this challenge and need, IsoPlexis functional T cell biology is rooted in the ability to directly identify what each T cell secretes in a highly multiplexed manner, for the first time. High multiplexing of simultaneous true cytokines reveals most consistently intense and potent T cells. The IsoPlexis system can discover true function in single cell subsets, or highly polyfunctional cells, which correlates to response and reveals highly differentiated T cell insights.

In the initial phase of approved cell therapies, researchers published data using IsoPlexis single-cell functional cytokine detection system to demonstrate the enhanced ability to detect underlying cell therapy product heterogeneity. IsoPlexis single-cell cytokine based PCA visualizations (Figure 1) of the CAR-T product, published in JITC,3 revealed the potential to visualize donor differences.

Figure 1. Visualizing CAR-T cell functional groups and donor differences.

In an additional study, researchers used the IsoPlexis single-cell platform to correlate pre-infusion cell product data, using a metric termed Polyfunctional Strength Index (PSITM), with objective response in vivo for the first time. Importantly, existing technologies like flow cytometry and bulk ELISA did not correlate with response (Figure 2), as published in Blood.4 In contrast to flow-based systems, where cells must be fixed and permeabilized, halting biological function and trapping cytokines within the cells, IsoPlexis single-cell cytokine system measures true secretions of the full range of functional cytokines, which recruit other immune cells, destroying the tumor.

Figure 2. Polyfunctional Strength Index (PSITM) is uniquely predictive to patient response.

IsoPlexis correlative CAR-T cellular fitness metrics are defined by their ability to capture truly released cytokine function of each cell. This knowledge is being applied in advanced bioprocessing with cell product biomarkers (Figure 3) and in donor selection in allogeneic cell therapies by leaders in the cell therapy field.

Figure 3. Novel finding: CAR T cell polyfunctionality associated with outcomes.

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Approach to Personalizing Treatment of Triple-Negative Breast Cancer Shows Promise in Cell Lines – Michigan Medicine

Next, the team tested 78 approved or investigational cancer drugs against each of the cell lines, selecting the compounds based on their effectiveness in other solid-tumor cancers. After a series of initial experiments to gauge their effectiveness, 12 of the drugs were prioritized for deeper analysis.

Among these, the research group found six drugs that showed promising results against tumors with particular molecular features suggesting the approach is a solid first step toward developing robust biomarkers of drug response in triple-negative breast cancer.

Many other breast cancer subtypes are defined by the pathways that you would use to target them for example, youd treat HER2-positive breast cancer with a HER-2 inhibitor, says senior study author Sofia Merajver, M.D., Ph.D., a professor of internal medicine and epidemiology at the U-M. Triple-negative breast cancer is defined by its lack of hormone receptors and HER2 expression, which makes it much more difficult to target. We needed to do better.

Since cancer often quickly develops resistances against individual drugs, the researchers also wanted to use their multi-omic approach to look for ideal combinations of drugs.

The idea is that if we find a marker that is particularly high in drug-resistant cells, we might be able to make the cells more responsive to treatment by adding a drug that also targets that marker, says senior study author Matthew Soellner, Ph.D., an assistant professor of internal medicine and chemistry at U-M, and an affiliate faculty member of the U-M Life Sciences Institute. Ultimately, we found we could make most of the cell lines more sensitive to our target drug it worked better than we had hoped for.

The research was supported by the National Institutes of Health (1R21CA218498), the Breast Cancer Research Foundation, Tempting Tables, The Rose Run, and the Kathy Bruk Pearce Research Fund of the U-M Rogel Cancer Center.

Additional authors include Eric J. Lachacz, Nathalie M. Vandecan, Peter J. Ulintz, Liwei Bao, John P. Lloyd, Joel A. Yates and Aki Morikawa, all of U-M.

Paper cited: Molecular determinants of drug response in TNBC cell lines, Breast Cancer Research and Treatment. DOI: 10.1007/s10549-019-05473-9

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Approach to Personalizing Treatment of Triple-Negative Breast Cancer Shows Promise in Cell Lines - Michigan Medicine

miR-1305 Inhibits The Progression Of Non-Small Cell Lung Cancer By Reg | CMAR – Dove Medical Press

Yuxing Cai,1 Yi Hao,2 HaiFeng Ren,3 ZhiGuo Dang,3 Hui Xu,1 Xiangfei Xue,1 Yan Gao3

1Department of Respiratory Medicine, Baoji Central Hospital, Baoji, 721008, Peoples Republic of China; 2Department of Pediatric Surgery, Baoji Maternal and Child Health Hospital, Baoji, 721008, Peoples Republic of China; 3Department of Respiratory Medicine, People Hospital BaoJi City, Baoji, 721001, Peoples Republic of China

Correspondence: Yan GaoDepartment of Respiratory Medicine, People Hospital BaoJi City, No. 24 Xinhua Street, Weibin District, Baoji City, Shanxi Province 721001, Peoples Republic of ChinaEmail zhungao703730393@126.com

Background: Increasing evidence has suggested the critical implication of microRNAs (miRNAs) in the initiation and progression of non-small cell lung cancer (NSCLC). Previous studies have shown the tumor-suppressive function of miR-1305 in cancer; however, the role of miR-1305 in NSCLC has not been fully understood.Methods: The expression of miR-1305 in NSCLC was detected by RT-qPCR. The influence of miR-1305 on the growth of NSCLC cells was determined via Cell Counting Kit 8 (CCK-8), colony formation and FACS analysis. The targets of miR-1305 were predicted with the miRDB database. Luciferase reporter assay was performed to investigate the binding between miR-1305 and 3-UTR of MDM2. Western blot was applied to check the expression of MDM2 with miR-1305.Results: Here, we found that miR-1305 was down-regulated in NSCLC tissues and cell lines. Decreased miR-1305 was significantly correlated with the metastasis and poor prognostics of NSCLC patients. Overexpression of miR-1305 inhibited the proliferation and migration and promoted the apoptosis of NSCLC cells. Bioinformatics and luciferase assay uncovered that the mouse/murine double minute 2 (MDM2) was a target of miR-1305. miR-1305 bound the 3-untranslated region (UTR) of MDM2 and decreased the expression of MDM2 in NSCLC cells. As MDM2 was a negative regulator of p53, decreased MDM2 by miR-1305 up-regulated the abundance of p53 in NSCLC cells. Restoration of MDM2 markedly attenuated the suppressive role of miR-1305 in the proliferation and migration of NSCLC cells.Conclusion: The findings provided novel mechanism of miR-1305/MDM2 signaling in regulating the progression of NSCLC, suggesting miR-1305 as a promising target for the treatment of NSCLC.

Keywords: NSCLC, miR-1305, MDM2, p53

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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Genentech’s Gazyva (obinutuzumab), in Combination With Standard of Care, More Than Doubles the Percentage of Lupus Nephritis Patients Achieving…

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced data from the Phase II NOBILITY study, investigating the safety and efficacy of Gazyva (obinutuzumab) for adults with proliferative lupus nephritis. The study met the primary endpoint with Gazyva, in combination with standard of care (mycophenolate mofetil or mycophenolic acid and corticosteroids), demonstrating superiority compared to placebo plus standard of care. Patients treated with Gazyva showed increasing rates of complete renal response (CRR) from week 52 to week 76, with 40% of patients in the Gazyva group achieving CRR, compared to 18% of patients in the placebo group at week 76 (p=0.007). Gazyva additionally met key secondary efficacy endpoints showing improved overall renal response (complete or partial renal responses) and serologic markers of disease activity as compared to placebo. No new safety signals were observed with Gazyva in the study at the time of this analysis. Through week 76, serious adverse events (24% vs. 29% in placebo group) and serious infections (6% vs.18% in placebo group) were not increased with Gazyva. These data will be presented at the 2019 American College of Rheumatology (ACR) Annual Meeting in Atlanta, Georgia, on November 10, 2019 (Abstract 939).

We are very encouraged by the positive results from the NOBILITY study, which suggest that Gazyva may provide a clinically meaningful benefit for adults with proliferative lupus nephritis; a condition for which there is a strong need for more effective and targeted treatment options, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. These results support the continued development of Gazyva for people with lupus nephritis and underscore our longstanding commitment to pursue new treatment options that may benefit the lupus community.

Lupus nephritis is a severe and potentially life-threatening manifestation of systemic lupus erythematosus resulting from inflammation of the kidneys, with proliferative lupus nephritis being the most severe form and associated with high-risk of end-stage renal disease and death. In September 2019, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to Gazyva for adults with lupus nephritis based on the Phase II NOBILITY study data. Genentech will initiate a Phase III study for Gazyva in lupus nephritis in 2020.

Phase II data from the NOBILITY study was also presented as a late-breaking oral presentation at the American Society of Nephrologys (ASN) Kidney Week 2019 in Washington, DC, on November 8, 2019 (Abstract FR-OR136).

An audio webcast for analysts and investors on the Phase II NOBILITY study data will be held on Tuesday, November 12, 2019 from 4:30-5:30 p.m. CET / 10:30-11:30 a.m. ET. Further details are available here.

Lupus nephritis overwhelmingly impacts women, particularly young women of color. About 90% of those diagnosed with lupus are women, and African American, Hispanic, Native American and Asian American women are two to three times more likely than Caucasian women to get lupus. Genentech is committed to addressing barriers to clinical trial participation and advancing inclusive research to create new standards for clinical studies. Genentech is taking action to recruit a broader, more diverse population of participants into clinical trials, including diseases such as lupus nephritis, to ensure clinical trial participants more closely reflect those impacted by the disease for which a medicine is being studied. To learn more about Genentechs efforts in this area, please visit https://www.gene.com/inclusiveresearch.

About the NOBILITY Study

The Phase II, randomized, double-blind, placebo-controlled, multi-center study, NOBILITY (NCT02550652), compared the safety and efficacy of Gazyva, combined with mycophenolate mofetil (MMF) or mycophenolic acid (MPA) and corticosteroids, to placebo, combined with MMF or MPA and corticosteroids, in adult patients with ISN/RPS 2003 class III or IV proliferative lupus nephritis. The study enrolled 125 people who were randomized to receive Gazyva or placebo infusions on days 1, 15, 168, and 182. The primary endpoint was the proportion of participants who achieved a protocol-defined complete renal response (CRR) at 52 weeks. Key secondary endpoints included overall renal responses (complete or partial renal response) and serologic markers of disease activity, as compared to placebo. Patients were followed in a blinded fashion through week 104, and patients with persistent B-cell depletion are being followed for safety and continued B-cell measurements.

About Lupus Nephritis

Lupus nephritis is a severe and potentially life-threatening disorder of the kidneys. Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus (SLE), an autoimmune disease where a person's own immune system attacks healthy cells and organs, including, in the case of lupus nephritis, the kidneys. This causes kidney inflammation and may lead to blood and/or protein in the urine, high blood pressure, poor kidney function, or kidney failure. An estimated 1.5 million Americans are affected by lupus, with approximately 70% of cases representing SLE. Up to 60% of people with SLE will develop lupus nephritis, and up to 25% of people with the condition develop end-stage renal disease. Lupus overwhelmingly impacts women, particularly young women of color. About 90% of those diagnosed with lupus are women, and African American, Hispanic, Native American and Asian American women are two to three times more likely than Caucasian women to get lupus. Currently, there is no cure for lupus or lupus nephritis.

About Gazyva

Gazyva is an engineered monoclonal antibody designed to attach to CD20, a protein found only on certain types of B-cells. It is thought to work by attacking targeted cells both directly and together with the body's immune system. Gazyva is part of a collaboration between Genentech and Biogen. Combination studies investigating Gazyva with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

Gazyva Indications

Gazyva (obinutuzumab) is a prescription medicine used:

Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that can become serious or life-threatening, including:

Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must tell their healthcare provider if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that may become severe or life threatening, including:

The most common side effects of Gazyva in CLL were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

The safety of Gazyva was evaluated based on 392 patients with relapsed or refractory NHL, including FL (81%), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (a disease for which Gazyva is not indicated), who did not respond to or progressed within six months of treatment with rituximab product or a rituximab product-containing regimen. In patients with follicular lymphoma, the profile of side effects that were seen were consistent with the overall population who had NHL. The most common side effects of Gazyva were infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness and urinary tract infection.

A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of Gazyva as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%). The most common side effects of Gazyva were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please visit http://www.Gazyva.com for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Genentech

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

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Genentech's Gazyva (obinutuzumab), in Combination With Standard of Care, More Than Doubles the Percentage of Lupus Nephritis Patients Achieving...

New Data Uncover Deeper Insight into Tebentafusp (IMCgp100) Clinical Activity in Patients with Advanced Melanoma, Including Uveal – Business Wire

OXFORDSHIRE, England & CONSHOHOCKEN, Pa. & ROCKVILLE, Md.--(BUSINESS WIRE)--Immunocore Limited, a leading T cell receptor (TCR) biotechnology company, presented new findings from its Phase 1/2 tebentafusp (IMCgp100) clinical trial programme demonstrating a correlation between treatment-induced immune response and improvement in overall survival and tumour shrinkage, in patients with advanced uveal and cutaneous melanoma. The new analyses from two clinical trials (IMCgp100-101, IMCgp100-102) were presented at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, Maryland.

We are gaining valuable insights from our clinical data to further our understanding of the mechanism of action of our bispecific, soluble TCR, said Bahija Jallal, Chief Executive Officer of Immunocore. Advancing the science underlying TCR recognition of antigens supports our efforts to further develop our platform and maximize its value on behalf of patients.

Tebentafusp is an investigational novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. It is engineered to specifically target gp100, a lineage antigen expressed in melanocytes and melanoma, and is the first molecule developed using Immunocores ImmTAC technology platform designed to redirect and activate T cells to recognise and kill tumour cells. Pivotal tebentafusp clinical trials are currently underway in metastatic uveal melanoma (UM), a rare form of eye cancer.

When using a therapy designed to induce an immune response, its not unexpected to see inflammatory events like rash or cytokine response syndrome, said Alexander N. Shoushtari, M.D., study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center in New York. While these were general low-grade events that resolved with treatment and time, it was interesting to see their potential connection to overall survival and other clinical outcomes. These findings are encouraging and will help to inform future research and treatment protocols.

SITC Presentation Highlights:

Induction of serum CXCL10 by tebentafusp, a gp100-CD3 bispecific fusion protein, was associated with survival in uveal melanoma in a Phase 1/2 study

The goal of this analysis was to increase understanding of the biological effects of tebentafusp and association between rash seen with treatment, CXCL10 and clinical outcomes in UM. Researchers focused on the initial 42 patient cohort enrolled in IMCgp100-102, a Phase 1/2 study in patients with HLA-A2+ positive advanced UM. Patients were treated using a weekly intra-patient dose-escalation regimen and the occurrence of rash within 21 days following treatment initiation was evaluated as a predictor of overall survival.

The findings showed a transient increase in peripheral cytokines after treatment with tebentafusp, reaching maximal changes at 8-24 hours post treatment, with CXCL10 having the greatest increment between 12-24 hours. Patients treated with tebentafusp experienced induced type 1/2 IFN pathways and neutrophil, eosinophil signatures and reduced CD4, CD8 and NK cell signatures in the blood. Tebentafusp-treated patients with rash and those with a greater increase in serum CXCL10 following the first treatment dose appeared to be associated with improved overall survival. In a multivariate Cox proportional hazards model, both rash (p<0.001) and CXCL10 induction (p=0.01) were independent predictors of survival.

Cytokine release syndrome following treatment with tebentafusp, a novel bispecific TCR-anti-CD3 directed against gp100, in patients with advanced melanoma

The goal of this analysis was to better understand the incidence, severity and resolution of cytokine release syndrome (CRS) following tebentafusp treatment, an adverse event commonly associated with CD3-bispecifics, and its association with clinical outcomes in advanced melanoma. Researchers analysed data from IMCgp100-101, a Phase 1 first-in-human clinical trial assessing the safety and tolerability of tebentafusp in 84 HLA-A2+ patients with metastatic melanoma (n=61 cutaneous, n=19 uveal, n=4 other) resistant to standard treatment regimens or for which no standard treatments exist. This post-hoc analysis evaluated adverse events, serious adverse events, vital signs, and concomitant medications reported by investigators to identify episodes of CRS.

The findings show that patients treated with tebentafusp experienced a low incidence of severe CRS. Despite no corticosteroid pre-treatment, CRS occurrence was generally low grade, reversible with standard management (i.e., IVF and short course corticosteroids), decreased in frequency and severity after the initial doses, and infrequently led to the discontinuation of treatment. The most frequent CRS adverse events were mild-to-moderate fever, fatigue, nausea, hypotension and headache. Patients with a < 1C increase in body temperature eight hours following treatment were less likely to develop subsequent moderate or higher-grade CRS. Consistent with tebentafusps hypothesized mode of action, transient increases in peripheral cytokines occurred within hours of treatment administration, and tended to be greater in patients with higher grade CRS. The incidence of CRS following the first dose of tebentafusp appeared to be associated with the greatest reductions in tumour size.

- Ends -

About ImmTAC MoleculesImmunocores proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilising monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognise and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognise intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumours, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumours, regardless of mutational burden or immune infiltration, including immune cold low mutation rate tumours.

About TebentafuspTebentafusp is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. Tebentafusp specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma, and is the first molecule developed using Immunocores ImmTAC technology platform designed to redirect and activate T cells to recognise and kill tumour cells. Tebentafusp has Fast Track Designation and Orphan Drug Designation in the US and Promising Innovative Medicine designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma. For more information about enrolling tebentafusp clinical trials for metastatic uveal melanoma, please visit ClinicalTrials.gov (NCT03070392).

About Uveal MelanomaUveal melanoma is a rare and aggressive form of melanoma, which affects the eye. Metastatic uveal melanoma typically has a poor prognosis and has no currently accepted optimal management or treatment.1,2 Although it is the most common primary intraocular malignancy in adults, the diagnosis is rare, with approximately 8,000 new patients diagnosed globally each year (1,600-2,000 cases/year in the US).3,4,5 Up to 50% of people with uveal melanoma will eventually develop metastatic disease.1,2 When the cancer spreads beyond the eye, only approximately half of patients will survive for one year.6

About Immunocore

Immunocore is a leading T cell receptor (TCR) biotechnology company working to create first-in-class biological therapies to address unmet patient needs in oncology as well as infectious and autoimmune diseases. Immunocore has a pipeline of proprietary and partnered programmes in development. Collaboration partners include Genentech, GlaxoSmithKline, AstraZeneca, Lilly, and the Bill and Melinda Gates Foundation. Immunocore is headquartered in Oxfordshire, UK, with offices in Conshohocken, PA and Rockville, MD, US. The Company is privately held by a broad international investor base. For more information, please visit http://www.immunocore.com.

Dr. Shoushtari serves on Immunocores scientific advisory board.

1 Damato BE, Dukes J, Goodall H, Carvajal RD. Tebentafusp: T cell redirection for the treatment of metastatic uveal melanoma. Cancers. 2019;11(7):971.

2 Carvajal, RD, Schwartz, GK, Tezel, T, et al., 2017. Metastatic disease from uveal melanoma: treatment options and future prospects. British Journal of Ophthalmology, 101(1), 38-44.

3 Pandiani C, Branger GE, Leclerc J, Ballotti R, Bertolotto C. Focus on cutaneous and uveal melanoma specificities. Genes Dev. 2017;31(8):724-743.

4 Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, Vlajkovic S, Cekic S, Stefanovic V. Ocular melanoma: an overview of the current status. Int J Clin Exp Pathol. 2013;6(7):1230-1244.

5 About ocular melanoma. Ocular Melanoma Foundation website. http://www.ocularmelanoma.org/about-om.htm. Accessed September 2019.

6 Rantala ES, Hernberg M, Kivel TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res 2019

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New Data Uncover Deeper Insight into Tebentafusp (IMCgp100) Clinical Activity in Patients with Advanced Melanoma, Including Uveal - Business Wire