Category Archives: Gene Medicine

Pfizer aims to be the third big pharma with a significant presence in gene therapy. Its plans to initiate this year three Phase 3 trials targeting mutation-driven blood and muscular diseases would make it a large player in this cutting-edge area of medicine.

The difference between Pfizer and its Swiss rivals Novartis and Roche is that its treatments for muscular dystrophy and hemophilia do not look like they will be the first to market. With hopes that gene therapy could be a one-and-done treatment, arriving second could put Pfizer at a disadvantage if eager patients rush for curative therapies.

Having spun of its off-patent drugs business, the pharma is now trying to talk up the "new Pfizer." Its gene therapies are among seven pipeline projects that it cited Tuesday during its year-end earnings call as critical to its strategy of becoming a more innovation-focused company.

Company executives weren't, however, asked to answer how Pfizer views the emerging gene therapy competition. BioMarin Pharmaceutical looks set to get to the market earlier in hemophilia A than Pfizer, while Uniqure in hemophilia B and Sarepta Therapeutics in Duchenne muscular dystrophy appear ahead.

Pfizer's hemophilia A project, the Sangamo Therapeutics-originated SB-525, is up against BioMarin's valrox, which has been submitted to the Food and Drug Administration for an approval decision later this year.

In hemophilia B, fidanacogene elaparvovec, licensed from Roche subsidiary Spark Therapeutics, is in a neck-and-neck race with UniQure's etranacogene dezaparvovec in Phase 3 testing. Duchenne research, meanwhile, is led by Sarepta, which is launching a Phase 3 trial of its drug this year, putting Pfizer's at a disadvantage.

Other than announcing its intent to launch Phase 3 trials in hemophilia A and Duchenne, Pfizer didn't provide much more detail about these clinical programs. Mikael Dolsten, Pfizer's chief scientific officer, said more could be revealed about the DMD program at an upcoming research & development day.

Progress on that project had been delayed after one patient was hospitalized with kidney complications, but Dolsten said trial investigators had dosed additional patients. The Phase 2 will wrap up this spring, and the new data and longer follow-up will help guide a Phase 3 trial design, the company said.

Dolsten also described the hemophilia A project as having a 'best-in-class profile," even though BioMarin's valrox has impressed hematologists with its ability to increase expression of a key blood-clotting protein.

In addition, he said the company hopes it can bring one new gene therapy into its pipeline per year.

Building its drug development portfolio is one reason why the company has chosen not to buy back shares, said CEO Albert Bourla.

He pointed to the company's need in the past to buy back shares to support their valuation because of revenue declines, but now he said the company is in a different strategic position.

"The company is going to have a best-in-class revenue growth story," he said. "We can use the capital to invest in good Phase 2, Phase 3 assets to grow our pipeline."

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Pfizer lays out gene therapy aspirations - BioPharma Dive

The non-profit science NGO Genetic Literacy Project has released its latest educational initiative, the Global Gene Editing Regulation Tracker and Index.

With the worldwide war on GMOs essentially lost by environmental lawyers, they still continue to hold back Europe but developing nations have seen through the false promises of western activists who have no solutions to poverty and food insecurity, only fear of the future. They are becoming hopeful about the future.

Thanks to CRISPR-Cas9 gene editing, non-chemical solutions to life-impacting developing nation problems such as malaria (dengue, yellow fever) mosquitoes can be developed, and governments will be scrambling to adapt a regulatory structure that meets the 21st century.

In the past, anti-science NGOs were able to successfully frame GMOs as too modern and terrifying. They had to ignore the existence of Mutagenesis, chemical and radiation baths used to create new strains of food and plant products in the lab, because those biotechnology results are considered part of an organic scheme. GMOs were different, they insisted.

So now they have to scramble to claim GMOs are different from mutagenesis and yet the same as CRISPR, even though they all share little in common beyond being ways to improve on nature.

So much information and disinformation can be confusing for the public. The new Genetic Literacy Project program summarizes gene editing regulations in each country's agriculture, medicine and gene efforts, along with what products and therapies are in development.

Most importantly for real progress, it also details the efforts by anti-science NGOs to block progress.

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Genetic Literacy Project Releases Global Gene Editing Regulation Tracker and Index - Science 2.0

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Detailed genetic road map will guide research into TB treatments, vaccines

A new study led by Washington University School of Medicine in St. Louis lays out a genetic road map of immune responses to tuberculosis (TB) infection across three species. Pictured is a TB-infected human lung. TB is shown in green, and immune cells surrounding the TB bacteria are shown in red and white.

Tuberculosis (TB) is one of the worlds most vexing public health problems. About 1.5 million people died from this bacterial lung infection in 2018, and the World Health Organization (WHO) estimates that one-quarter of the worlds population some 2 billion people, mostly in developing countries are infected with the bacteria that causes TB.

For decades, scientists have been studying the deadly disease in mice and other animal models to develop drug therapies and vaccines to treat or prevent the infection. But findings in animals with TB dont always translate well to people with the disease, leaving scientists puzzled by the discrepancies.

Now, a new study led by Washington University School of Medicine in St. Louis offers a genetic road map detailing the similarities and differences in immune responses to TB across three species mice, macaques and humans. According to the researchers, the insight into the immune pathways that are activated in diverse models of TB infection will serve as a valuable tool for scientists studying and working to eradicate the disease.

The research, appearing Jan. 29 in the journal Science Translational Medicine, is a collaboration between Washington University; the Texas Biomedical Research Institute in San Antonio; and the University of Cape Town in South Africa.

For many years, scientists have been frustrated by the fact that animal models of TB especially the genetically identical mice so often studied dont really reflect what we see in people with TB infections, said co-senior author Shabaana A. Khader, PhD, a professor of molecular microbiology at Washington University. This study is important because now we show in great detail where these animal models overlap with humans with TB and where they dont.

Unlike many previous mouse studies, the new research involved genetically diverse mice that more closely recapitulate the wide range of TB infection severity in humans: Some infected individuals show no symptoms; others show intermediate degrees of severity; and still others develop extreme inflammation of the lungs.

With co-author Deepak Kaushal, PhD, at the Texas Biomedical Research Institute, the researchers compared the genetic and immune responses to TB infection in these diverse mice with the responses of TB-infected macaques in the Kaushal lab. And with co-author Thomas J. Scriba, PhD, of the University of Cape Town, the research team analyzed blood samples from adolescents in Western Cape, South Africa, who are enrolled in a clinical trial investigating TB infection. The samples from people allowed the researchers to analyze and compare data from the mice and macaques with a range of responses to TB infection in young people.

Past research from this long-running clinical trial identified a group of 16 genes whose activation patterns predicted the onset of TB disease more than a year before diagnosis. These genes called a human TB gene signature differed significantly in their activation patterns between young people who developed symptoms of TB and those who didnt.

In macaques, primates closely related to humans, scientists have long assumed that TB infection closely resembles such infection in people.

Our data demonstrate that 100% of the genes previously identified as a human TB gene signature overlap in macaques and people, said co-senior author Makedonka Mitreva, PhD, a professor of medicine and of genetics at Washington University and a researcher at the universitys McDonnell Genome Institute. Its important to have the definitive data showing it to be true.

There was significant overlap between humans and mice as well, according to the researchers, including co-first authors Mushtaq Ahmed, PhD, an assistant professor of molecular microbiology in Khaders lab; Shyamala Thirunavukkarasu, PhD, a staff scientist in Khaders lab; and Bruce A. Rosa, PhD, an assistant professor of medicine in Mitrevas lab. But they also identified genetic pathways that differed between mice and humans, providing detailed analysis of areas where TB in mice is unlikely to point to meaningful insight into human TB infection.

Until now, we have studied mouse models to understand TB disease progression, not knowing where the mouse disease translates to human disease and where it doesnt, Khader said. Now, we have shown that many areas do translate but that there are important aspects of TB infection that dont. If you are using mouse models to develop TB vaccines or other therapeutics that target areas that dont overlap, you likely wont succeed.

Added Mitreva, Our study will inform researchers when they may need to move to a different animal model to study their genetic or molecular pathways of interest.

The researchers studied in detail the genes that increase in expression in people who develop severe TB disease. Of 16 such genes identified in people, they were able to study 12 in mice. Four of the genes could not be studied because mice dont have equivalent versions of such genes or, when such genes were eliminated, the mouse embryos died during development.

The scientists found that the 12 genes fall into three categories: those that provide protection against TB infection; those that lead to greater susceptibility to TB infection; and those that had no effect either way. Such information will be useful in seeking future therapeutics that could, for example, boost effects of protective genes or shut down harmful ones.

According to Khader and Mitreva, their team plans to use the new knowledge to better understand TB infections that have become drug-resistant, a growing problem in places where the disease is endemic. In addition, they will harness the information to help understand why the TB vaccine often administered to high-risk groups of people works well in some individuals but not others.

With the studys raw data publicly available, Khader and Mitreva said they are hopeful it will serve as a valuable resource to TB research and immunology communities worldwide.

This work was supported by Washington University in St. Louis; the National Institutes of Health (NIH), grant numbers HL105427, AI111914-02, AI123780, AI134236-02, U19 AI91036 and U19AI106772; the Department of Molecular Microbiology at Washington University; and a Stephen I. Morse Fellowship; the Department of Medicine at the University of Rochester Medical Center.

Scriba is a co-inventor of a patent of the 16-gene signature for TB susceptibility from the Adolescent Cohort Study (ACS).

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Immune responses to tuberculosis mapped across 3 species - Washington University School of Medicine in St. Louis

Eisai and Personal Genome Diagnostics (PGDx) will use liquid biopsy to accelerate Next-Generation drug discovery and development

Japanese firm Eisai Co., Ltd., has entered into a joint research and development agreement with Personal Genome Diagnostics Inc., Maryland, for cancer genetics panel test, and it has initiated the research.

In this joint research and development, Eisai and PGDx will create a kitted cancer gene panel test that enables comprehensive analysis of mutation in more than 500 cancer gene using liquid biopsy with blood samples. Additionally, the kit will be used in our drug discovery and development.

In Eisai's medium term business plan EWAY2025, Eisai is pursuing creating innovation focused in neurology area and oncology area aimed at realizing prediction / prevention and cure. Aiming to acquire next-generation sequencing technology for realizing personalized cancer medicine, Eisai has concluded a joint research and development agreement with PGDx, a US bio-venture with liquid biopsy genomic expertise.

By analyzing the circulating tumor DNA (ctDNA) in the blood using its own created gene panel testing technology, Eisai will investigate the Cancer Evolution, which is a series of process such as developments of cancer cells, recurrence / metastasis and the appearance of acquired drug resistance. Eisai will also identify genetic abnormalities of drug resistance to existing anti-cancer agents that will be the targets of a new drug discovery and use a kitted cancer gene panel test for clinical trials to develop new anticancer drugs. Eisai will continue to work on cancer genome medicine for realizing early detection of cancer, and providing personalized cancer medicine and cures for cancer patients in the future.

In addition to accelerating cancer genome medicine based on the latest liquid biopsy technology, Eisai aims to build an oncology ecosystem, in which a longitudinal trajectory of cancer patients will be monitored, to lead to the creation of cures for cancer patients as well as diagnosis for prediction and prevention of cancer. Eisai will make continuous efforts to meet diversified needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare professionals.

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Eisai and PGDx jointly start R&D of cancer genetics panel test - BSA bureau

A new analysis of available data has convinced a panel genomic experts that nine genes previously believed to be associated with a rare, genetic heart conditionlong QT syndromewere an erroneously linked to the condition, as revealed in a new study funded by the National Human Genome Research Institute (NHGRI), a division of the National Institutes of Health (NIH).

Geneticists and heart specialists around the world had previously reported 17 genes to cause long QT syndrome. However, the Clinical Genome Resources (ClinGen) expert panel has critically reevaluated the scientific evidence for all 17 reported genes, and has concluded at least nine of the genes cannot be linked to the disease, and only three of the genes can be definitively associated with the most common form of the disease.

Long QT syndrome is caused by mutations in genes that regulate the hearts electrical activity. These mutations can cause the heart to have sudden, irregular heart rhythms, or arrhythmias. People with long QT syndrome can have arrythmias that are both unprovoked or as a result of stress and exercise. These arrythmias can be fatal.

Many people with long QT syndrome may be unaware they have the condition, unless they get an unrelated electrocardiogram, know their family history, and have undergone genetic testing.

Ever since the syndrome was described in 1957, researchers have engaged in a genetic race to identify the genes associated with it, which currently includes the 17 genes. By using such a standardized, evidence-based framework, the international ClinGen panel experts on long QT syndrome were able to classify the 17 genes into specific groups.

Three genes, KCNQ1, KCNH2 and SCN5A, had sufficient evidence to be implicated as definitive genetic causes for typical long QT syndrome. Four other genes had strong or definitive evidence supporting their role in causing atypical forms of long QT syndrome, particularly if they presented in the newborn period with associated heart block, seizures or delays in development.

The remaining ten genes were deemed to not have sufficient evidence to support a causal role in the syndrome. In fact, nine of these 10 remaining genes were placed in the limited or disputed category. The study authors suggest that these genes not be routinely tested in clinical settings when evaluating patients and families with long QT syndrome, because they lack sufficient scientific evidence as a cause for the condition.

This removal of genes from the testing list impacts genetic testing providers, who use research papers to determine which genes to include in their testing panels for diagnostic reporting to physicians. Published papers reporting gene-disease associations vary widely in their study design and strength of evidence to support their conclusions. Until recently, standard guidelines that can differentiate between genes found with strong and valid scientific approaches versus those with insufficient evidence did not exist. Clearly, this is a problematic approach, and led to several studies drawing early conclusions.

ClinGens expert panels include researchers, clinicians, and genetic counselors who apply an evidence-based framework in evaluating the available data from research papers to place gene-disease relationships into definitive, strong, moderate, limited, disputed, or refuted categories.

ClinGen is an impressive community effort. With over 1,000 researchers and clinicians from 30 countries volunteering their time and expertise, ClinGen is providing much needed clarity for the clinical genomics community regarding which gene-disease pairs have sufficient evidence to be used clinically, said Erin Ramos, Ph.D., project scientist for ClinGen and program director in the Division of Genomic Medicine at NHGRI.

Our study highlights the need to take a step back and to critically evaluate the level of evidence for all reported gene-disease associations, especially when applying genetic testing for diagnostic purposes in our patients. Testing genes with insufficient evidence to support disease causation only creates a risk of inappropriately interpreting the genetic information and leading to patient harm, says Michael Gollob, M.D., senior author of the paper and researcher at the Toronto General Hospital Research Institute.

Moreover, testing for genes not definitively associated with long QT syndrome can result in inappropriate and costly medical interventions such as implanting of a cardioverter-defibrillator.

This is not the first time a team at ClinGen has clarified published research for clinicians. The same team of researchers published a similar study in 2018, covering another heart condition called Brugada syndrome. In 2019, the American Society of Human Genetics considered the paper as one of the top 10 advances in genomic medicine.

ClinGen is an NHGRI-funded resource created to define the clinical relevance and validity of genes associated with various genetic disorders. It comprises more than 20 expert panels working on a variety of genetically influenced diseases, ensuring the reliability of gene-disease linkage. This work is also instrumental in determining which specific genes should be targeted for further study in precision medicine and research.

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Genes Previously Linked to Heart Condition Disputed - Clinical OMICs News

Precision medicine promises a new paradigm in oncology where every patient receives truly personalized treatment. This approach to disease diagnosis, treatment and prevention utilizes a holistic view of the patientfrom their genes and their environment to their lifestyleto make more accurate decisions.

Growing at a rate of 10.7 percent, the precision medicine market is expected to exceed $96 billion by 2024.1 Bioinformatics represent a significant share of the market, as bioinformatics tools enable the data mining necessary for rapid identification of new drug targets and repurposing of existing treatments for new indications.1 (Reuters) The oncology segment of the precision market is expected to experience an 11.1 percent compounded annual growth rate (CAGR) leading up to 2024 due to the success of recent targeted therapies and subsequent high demand.

Still, precision medicine is in its infancy, and making personalized treatment a reality for all patients requires a transformation in how novel therapies are developed and delivered. New regulatory, technical, clinical and economic frameworks are needed to ensure that the right patients are able to access the right therapy at the right time. In this article, we review the current state of precision medicine in oncology and explore some of the challenges that must be addressed for precision medicine to reach its full potential.

Great strides toward precision medicine are being made in the area of cancer immunotherapy, which is designed to boost a patients own immunity to combat tumor cells. The introduction of immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 inhibitors) revolutionized treatment for certain hematologic malignancies and solid tumors. To date, immune checkpoint inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for more than 15 cancer indications, but their widespread use has been hampered by unpredictable response rates and immune-related adverse events.

The approvals of the first chimeric antigen receptor (CAR)-T cell (CAR-T) therapies in 2017 were the next leap forward in precision medicine. These immunotherapies demonstrated that it was possible to take out a patients own T-cells, genetically modify them, and then put them back in to target cancer cells. With complete remission rates as high as 83 percent within three months of treatment, CAR-T therapies represent a seismic shift in our approach to cancer, bringing the elusive possibility of a cure one step closer. However, longer-term follow-up has shown that these remissions may not be durable2 and prevention of relapse must still be studied.

Ultimately, the goal of cancer immunotherapy is to stimulate the suppressed immune system of a patient with cancer so that it can launch a sustained attack against tumor cells.3 This is complicated, as the interactions between tumors and immune systemsometimes called the Cancer-Immunity Cycle (see Figure 1 in the slider above)4are complex and dynamic. The Cancer-Immunity Cycle manages the delicate balance between the immune systems ability to recognize non-self and the development of autoimmunity.

In some cases, the immune system may fail to recognize tumor cells as non-self and may develop a tolerance to them. Moreover, tumors have an armamentarium of methods for evading the immune system. Given this elaborate interplay between cancer and immunity, there is a wide range of potential cancer immunotherapy approaches:

The immune response to cancer involves a series of carefully regulated events that are optimally addressed as a group, rather than individually.4 The complexity of the immune response to cancer provides a strong rationale for combination therapies, for instance:

Increasingly, the development and deployment of immunotherapy relies on harnessing genomic data to identify the patients most likely to respond to immunotherapy and to customize immunotherapy for a given patient.6 Thus, molecular profiling technologies, such as next-generation sequencing, have become integral to drug development and patient selection. At the same time, researchers are focusing on identifying molecular alterations in tumors that may be linked to response.7 The molecular fingerprints of a tumor can be quite complex and heterogeneous, not only across tumors, but also within a single patient. Consequently, molecular tumor characterization requires both multidimensional data from laboratory and imaging tests and advanced software and computational methods for analyzing these data.8 This emergence of computational precision oncology is associated with both opportunities and challenges, from validation and translation to regulatory oversight and reimbursement.

The regulatory landscape is evolving to keep pace with technological advances in cell engineering and gene editing. Since 2013, the FDA has published four guidance documents on cellular and gene therapy products, as well as two guidance documents providing recommendations on regenerative medicine advanced therapies (RMATs). Specifically, their Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, published in November 2017, provides guidance on the expedited development and review of regenerative medicine therapies for serious or life-threatening diseases and conditions. This document also provides information on the use of the accelerated approval pathway for therapies that have been granted the RMAT designation.9

In the EU, the European Medicines Agency (EMA) published a draft revision of its Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells in July 2018.10 This draft revision includes current thinking on the requirements for nonclinical and clinical studies, as well as specific sections on the scientific principles and clinical aspects of CAR-T products.

Precision medicines such as CAR-T therapies require manufacturers to transform a complex, individualized treatment into a commercial product. In conventional manufacturing, the entire manufacturing process occurs within the confines of the manufacturing facility. With cell therapies, however, the process begins with the collection of cells from the patient and ends with administration of the final product (see Figure 2 in the slider above). In between, the cells are handed off multiple times for the process of genetic modification, creating a complex supply chain that blends manufacturing and administration.11

Moreover, in contrast to traditional manufacturing where the starting materials are standardized or well-defined, the starting materials for cell therapies are derived from patients and, thus, highly variable.

As evidenced by the manufacturing challenges that plagued the launch of Kymriah (tisagenlecleucel), even pharmaceutical giants have struggled with meeting label specifications for commercial use.13 To help address its manufacturing hurdles, Novartis acquired CellforCure, a contract development manufacturing organization, and plans to transform by focusing on data and digital technologies.14,15 What this means for sponsors is that robust, scalable manufacturing must be incorporated into clinical developing planning at its earliest stages.

The high price tags associated with CAR-T therapies illustrate how expensive targeted therapies are in comparison to their traditional counterparts.16 Existing health insurance models have not been structured to reimburse for costly treatments that offer the potential for long-term benefit or even cure. The pricing model for CAR-T therapies may be especially challenging for private insurance companies, which have higher turnover and shorter coverage windows than national health insurance programs. For sponsors of precision medicine therapies, one way to address the challenge of reimbursement is to create innovative, value- or outcomes-based pricing models, rather than focusing on sales volume. The success of these new pricing models will rely on patient selection. To demonstrate value and optimizing outcomes, sponsors will need to develop profiles of patients who are most likely to respond and provide tools for identifying these patients.8

Of note, on August 7, 2019, the Centers for Medicare & Medicaid Services (CMS) finalized the decision to cover FDA-approved CAR-T therapies when provided in healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS) for FDA-approved indications. Medicare will also cover FDA-approved CAR-T treatments for off-label uses that are recommended by CMS-approved compendia.17

Beyond the pharmaceutical companies that are working to develop personalized treatments, the precision medicine ecosystem has a number of other key stakeholdersregulators, payers, diagnostic companies, healthcare technology companies, healthcare providers and, of course, patients. Pharmaceutical companies need to engage with each of these stakeholders by providing education or developing partnerships that help demonstrate the need for high-quality data collection, the value of precision medicine, and the process for identifying the right patients.

Sponsors may also benefit from engaging with patient advocacy groups as these groups play a critical role in connecting patients and caregivers with scientific and healthcare experts to learn about how new immunotherapy breakthroughs are changing the standard of care.

Empowered patients pushing for the latest innovations are propelling precision medicine forward, but we still have a way to go before the full potential of precision medicine is realized. In its maturity, precision medicine will not only enable the personalization of treatments for individual patients, but also inform public health at a population level as insights from the genetic and molecular data collected are used to advance our understanding of disease. Robust data collection and analysis, along with standardization, are required for building this foundation of precision medicine, and multi-stakeholder buy-in is necessary for addressing issues around data integration and privacy.

While significant challenges remain, the opportunity to transform patient outcomes and population health with precision medicine is tantalizing. Increasingly, we are seeing advanced technologiessuch as artificial intelligence and machine learningbeing incorporated into the drug discovery and development process. This underscores the critical need for a multidisciplinary approach to precision medicine, from discovery at the bench all the way through to delivery at the bedside, to help ensure that more patients can access the right therapy at the right time, and the right price.

References

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Realizing The Full Potential Of Precision Medicine In Oncology - Contract Pharma