Overview

Genetic testing involves examining your DNA, the chemical database that carries instructions for your body's functions. Genetic testing can reveal changes (mutations) in your genes that may cause illness or disease.

Although genetic testing can provide important information for diagnosing, treating and preventing illness, there are limitations. For example, if you're a healthy person, a positive result from genetic testing doesn't always mean you will develop a disease. On the other hand, in some situations, a negative result doesn't guarantee that you won't have a certain disorder.

Talking to your doctor, a medical geneticist or a genetic counselor about what you will do with the results is an important step in the process of genetic testing.

When genetic testing doesn't lead to a diagnosis but a genetic cause is still suspected, some facilities offer genome sequencing a process for analyzing a sample of DNA taken from your blood.

Everyone has a unique genome, made up of the DNA in all of a person's genes. This complex testing can help identify genetic variants that may relate to your health. This testing is usually limited to just looking at the protein-encoding parts of DNA called the exome.

Genetic testing plays a vital role in determining the risk of developing certain diseases as well as screening and sometimes medical treatment. Different types of genetic testing are done for different reasons:

Generally genetic tests have little physical risk. Blood and cheek swab tests have almost no risk. However, prenatal testing such as amniocentesis or chorionic villus sampling has a small risk of pregnancy loss (miscarriage).

Genetic testing can have emotional, social and financial risks as well. Discuss all risks and benefits of genetic testing with your doctor, a medical geneticist or a genetic counselor before you have a genetic test.

Before you have genetic testing, gather as much information as you can about your family's medical history. Then, talk with your doctor or a genetic counselor about your personal and family medical history to better understand your risk. Ask questions and discuss any concerns about genetic testing at that meeting. Also, talk about your options, depending on the test results.

If you're being tested for a genetic disorder that runs in families, you may want to consider discussing your decision to have genetic testing with your family. Having these conversations before testing can give you a sense of how your family might respond to your test results and how it may affect them.

Not all health insurance policies pay for genetic testing. So, before you have a genetic test, check with your insurance provider to see what will be covered.

In the United States, the federal Genetic Information Nondiscrimination Act of 2008 (GINA) helps prevent health insurers or employers from discriminating against you based on test results. Under GINA, employment discrimination based on genetic risk also is illegal. However, this act does not cover life, long-term care or disability insurance. Most states offer additional protection.

Depending on the type of test, a sample of your blood, skin, amniotic fluid or other tissue will be collected and sent to a lab for analysis.

The amount of time it takes for you to receive your genetic test results depends on the type of test and your health care facility. Talk to your doctor, medical geneticist or genetic counselor before the test about when you can expect the results and have a discussion about them.

If the genetic test result is positive, that means the genetic change that was being tested for was detected. The steps you take after you receive a positive result will depend on the reason you had genetic testing.

If the purpose is to:

Talk to your doctor about what a positive result means for you. In some cases, you can make lifestyle changes that may reduce your risk of developing a disease, even if you have a gene that makes you more susceptible to a disorder. Results may also help you make choices related to treatment, family planning, careers and insurance coverage.

In addition, you may choose to participate in research or registries related to your genetic disorder or condition. These options may help you stay updated with new developments in prevention or treatment.

A negative result means a mutated gene was not detected by the test, which can be reassuring, but it's not a 100 percent guarantee that you don't have the disorder. The accuracy of genetic tests to detect mutated genes varies, depending on the condition being tested for and whether or not the gene mutation was previously identified in a family member.

Even if you don't have the mutated gene, that doesn't necessarily mean you'll never get the disease. For example, the majority of people who develop breast cancer don't have a breast cancer gene (BRCA1 or BRCA2). Also, genetic testing may not be able to detect all genetic defects.

In some cases, a genetic test may not provide helpful information about the gene in question. Everyone has variations in the way genes appear, and often these variations don't affect your health. But sometimes it can be difficult to distinguish between a disease-causing gene and a harmless gene variation. These changes are called variants of uncertain significance. In these situations, follow-up testing or periodic reviews of the gene over time may be necessary.

No matter what the results of your genetic testing, talk with your doctor, medical geneticist or genetic counselor about questions or concerns you may have. This will help you understand what the results mean for you and your family.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

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Genetic testing - Mayo Clinic

(UroToday.com)The KEYNOTE-052 trial showed that pembrolizumab monotherapy has durable antitumor activity as first-line therapy in cisplatin-ineligible patients with locally advanced unresectable or metastatic urothelial carcinoma (UC)1. Moreover, pembrolizumab has also shown durable activity as 2nd line therapy in patients with platinum-refractory advanced UC in the KEYNOTE-045 trial2.

Immune gene expression profiling in UC has the potential to identify patients whose tumors are more likely to respond to antiPD-1/PD-L1 treatment3,4. Several factors have been shown to be associated with resistance to antiPD-1/PD-L1 treatment in advanced UC5. These include stromal tumor microenvironment, epithelial to mesenchymal transition (EMT), and transforming growth factor-beta (TGF-) gene expression signatures.

In an exploratory biomarker analysis of KEYNOTE-052, response to pembrolizumab was positively associated with the 18-gene T-cellinflamed gene expression profile (GEP) and negatively associated with a stromal signature (stroma/EMT/TGF-)6,7.

The objective of the presented study was to determine the association of T-cellinflamed GEP and stromal signatures with outcomes in patients treated with pembrolizumab monotherapy in an exploratory analysis of advanced UC patients from the KEYNOTE-045 trial (NCT02256436).

The KEYNOTE-045 trial was an open-label, international, phase 3 trial (N = 542)2 (Figure 1). Patients were randomly assigned 1:1 to receive either pembrolizumab 200 mg every three weeks or the investigator's choice of chemotherapy (paclitaxel, docetaxel, or vinflunine). Association of the signatures as continuous variables with the outcomes was assessed in each treatment arm separately, using univariate analysis, performed using logistic regression (objective response rate [ORR]), and Cox proportional hazards (progression-free survival [PFS], overall survival [OS]) modeling, adjusted for Eastern Cooperative Oncology Group (ECOG) performance status.

Figure 1 KEYNOTE 045 trial:

The results demonstrated that 147 of 266 pembrolizumab-treated patients (55%) and 127 of 255 chemotherapy-treated patients (50%) had available RNA-sequencing data. Key baseline characteristics were similar between the overall study population and the population with available RNA-sequencing data.

The results show that T-cellinflamed GEP, as a continuous variable, was positively associated with ORR to pembrolizumab but not to chemotherapy (Table 1). There was no association with PFS or OS in either the pembrolizumab or chemotherapy group (table 1). Pembrolizumab improved PFS and OS vs. chemotherapy in the T-cellinflamed GEP non-low group (Figure 1). The stromal signature, assessed as a continuous variable, was not associated with favorable outcomes with pembrolizumab (Figures 3 and 4).

Table 1 - Association Between T-CellInflamed GEP/Stromal Signature and Clinical Outcomes in Each Treatment Group:

Figure 1- Clinical Utility of the Prespecified T-CellInflamed GEP Cutoff for objective response rate:

Figure 2 Clinical Utility of the Prespecified T-CellInflamed GEP Cutoff for PFS and OS:

Figure 3 Clinical Utility of the Prespecified Stromal Signature Median for objective response rate:

Figure 4 - Clinical Utility of the Prespecified Stromal Signature Median for PFS for stromal >= median, PFS for stromal < median, OS for stromal >=median, OS for stromal

In conclusion, this exploratory biomarker analysis of patients with advanced UC, T-cellinflamed GEP, as a continuous variable, was positively associated with ORR to pembrolizumab but not chemotherapy. No association with PFS or OS was observed in either the pembrolizumab or chemotherapy group. HR estimates using a prespecified T-cellinflamed GEP cutoff suggested that pembrolizumab improved PFS and OS vs.

Chemotherapy in the T-cellinflamed GEP non-low group.

T-cellinflamed GEP should continue to serve as a useful exploratory gene signature to support the mechanism of action of pembrolizumab in highly inflamed tumors. The stromal signature assessed as a continuous variable was not associated with favorable outcomes with pembrolizumab. HR estimates, using a prespecified stromal median, did not support the hypothesized negative association between increased stromal signature median and response to pembrolizumab previously observed in KEYNOTE-0527.

More analyses are currently exploring differences in the association of the stromal signature with pembrolizumab between KEYNOTE-052 and KEYNOTE-045. It is worth mentioning that patients in KEYNOTE-045 received therapy before enrollment, potentially affecting the tumor microenvironment and limiting the ability of the stromal signature to predict response to pembrolizumab.

Presented by: Dr. Petros Grivas, Associate Professor and the Clinical Director of the Genitourinary Cancers Program at the University of Washington, and an Associate Member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

Written by: Hanan Goldberg, MD, MSc., Assistant Professor of Urology, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHananat the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020

References:

1.Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. The Lancet Oncology 2017; 18(11): 1483-92.2.Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. New England Journal of Medicine 2017; 376(11): 1015-26.3. Ayers M, Lunceford J, Nebozhyn M, et al. IFN--related mRNA profile predicts clinical response to PD-1 blockade. The Journal of clinical investigation 2017; 127(8): 2930-40.4. Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science (New York, NY) 2018; 362(6411).5. Wang L, Saci A, Szabo PM, et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nature Communications 2018; 9(1): 3503.6. O'Donnell PH, Plimack ER, Bellmunt J, et al. Pembrolizumab (Pembro; MK-3475) for advanced urothelial cancer: Results of a phase IB study. Journal of Clinical Oncology 2015; 33(7_suppl): 296-.7. Grivas P, Castellano DE, O'Donnell PH, et al. Association between stromal/TGF-/EMT gene expression signature and response to pembrolizumab monotherapy in cisplatin-ineligible patients with locally advanced (unresectable) or metastatic urothelial carcinoma. Journal of Clinical Oncology 2019; 37(7_suppl): 433-.

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ESMO Virtual Congress 2020: Association Between Gene Expression Signatures and Pembrolizumab Efficacy in Pa... - UroToday

Summary

In a study of people with lung cancer whose tumors contained the mutation targeted by sotorasib, 52 of 59 patients experienced disease control, which means that their tumors stopped growing.

Targeted therapies aim to block the activity of genes that cause cancer, providing a direct attack on tumors while sparing healthy cells. Identifying genes that trigger tumor growth is only the first hurdle to developing targeted drugs just because investigators know a gene may cause cancer doesnt mean they can prevent it from wreaking havoc.

The cancer gene KRAS (pronounced kay-rass) is a case in point. Its been studied for about 40 years and is known to be responsible for many of the most common cancers. This includes about one-quarter of lung cancers and between one-third and one-half of colon and rectal cancers. Until recently, however, the KRAS protein was considered an undruggable target.

On September 20, 2020, in the New England Journal of Medicine (NEJM), investigators reported results from CodeBreak 100, the first-ever clinical study of a drug that directly targets KRAS. In this international phase 1 trial, researchers found that a drug called sotorasib (AMG 510) slowed or stopped cancer growth in many people with advanced cancer that had a KRAS mutation. The investigators say much more research is needed to determine how to best use this drug, but this trial is a significant first step.

KRAS was one of the first cancer genes discovered and is the most common cancer-causing gene.

Sotorasib is not a cure, but this study is the first to crack KRAS in a clinically meaningful way, says Memorial Sloan Kettering medical oncologist Bob Li, a senior investigator and corresponding author of the study. Its an important step forward, but its not yet a home run.

The challenge in targeting the KRAS gene comes from the uncommon shape of the KRAS protein. Most proteins have a lumpy, irregular shape, with many clefts and pockets where a drug can wedge in. When this happens, a drug can act as a key, locking up a protein and shutting down its activity. By contrast, the KRAS protein is quite round and smooth, Dr. Li explains. Theres no lock-and-key approach.

In 2013, researchers at the University of California, San Francisco, reported there may be a way in: They found a small pocket in a version of the mutant KRAS protein, called KRAS-G12C, and designed a drug to fit into this pocket when it was open.

In 2016, MSK physician-scientists Piro Lito and Neal Rosen published a study that built on this work. They described the trapping mechanism that enables the new class of drugs to shut down the growth of cancer cells driven by the KRAS-G12C mutation.

When one of these drugs goes in the proteins pocket, it traps KRAS-G12C in its off state, says Dr. Lito, who is also a senior author on the new NEJM paper. The protein cant wake up, and the tumor cell cannot grow.

Sotorasib, which was developed by investigators at the biopharmaceutical company Amgen, is an improved and more potent KRAS-G12C inhibitor. Combining their respective strengths in phase 1 clinical trial development and translational science, Drs. Li and Lito partnered with Amgen to bring the first-in-class KRAS-G12C inhibitor sotorasib to patients.

In the trial for sotorasib, 129 people whose tumors had KRAS-G12C received the drug, which is taken as a pill. Fifty-nine of them had non-small cell lung cancer, 42 had colorectal cancer, and 28 had other types of tumors. All of the study participants had disease that spread to other parts of the body; they already had received an average of three previous treatments. The trial included people treated at more than two dozen hospitals around the world.

Among those 59 people with lung cancer, seven patients did not respond and 52 experienced disease control (which means that their tumors either stopped growing or shrank). In that group of 52, 19 patients had their tumors shrink substantially. The average time until the disease got worse was about six months. That level of response is significant for this population of patientsbecause most of them have exhausted other treatment options. Dr. Li explains.

We're already thinking one step ahead about how to use this drug for the greatest benefit of people who need it.

A little more than half of the people in the trial (73 patients) had some side effects, but only 15 of them had significant side effects. All but one patient were able to safely continue the drug when the side effects resolved, and no one died from side effects. Because the drug is selective for this specific KRAS mutation, it was well tolerated by patients, Dr. Lito says. It only binds to and inhibits the mutated form of the protein in cancer cells. This is important because it enables high doses of the drug to be safely administered.

Responses for other types of cancer including colorectal cancer, as well as pancreatic, endometrial (uterine), and appendiceal cancers and melanoma were not as good as they were for lung cancer. But some patients with those other cancers did benefit with substantial tumor shrinkage. The investigators plan to study why sotorasib appears to work better in some types of cancer than it does in others, even when the cancers have the same mutated protein. Additional trials are already underway to continue studying sotorasib, both alone and in combination with other drugs.

Research on how to block KRAS is continuing in the laboratory as well. In January 2020, Dr. Litos lab published a study that looked at new approaches for combining KRAS inhibitors with other drugs. Were taking what weve learned in patients back to the bench to continue developing new treatments, Dr. Lito says. Were already thinking one step ahead about how to use this drug for the greatest benefit of people who need it.

The results from this clinical trial are also being presented at the European Society for Medical Oncology 2020 Virtual Congress.

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Promising Results from the First-Ever Trial of a Drug that Blocks Cancer Gene KRAS - On Cancer - Memorial Sloan Kettering

Last week geneticist Dr Charles Steward shared with us his experiences of searching for a genetic cause for his childrens rare neurological diseases. Here he gives us a deeper look at how genomic medicine is evolving and the barriers that are preventing it from reaching its full potential.

Through his work at the Wellcome Sanger Institute and Congenica, and involvement with the 100,000 Genomes Project, Charlie has been well placed to see the development of genomics over the years and the promises that it will bring to healthcare. However, he says there is always the danger of overpromising the benefits and at the same time, underdelivering.

I saw this, in particular, with the finishing of the human genome, says Charlie. At that time, we thought this would be the holy grail for medicine. Many of the promises we made were not forthcoming, in particular to the pharma industry.

In reality, finishing the human genome was the first step of what is a long journey.

Unsurprisingly, in many respects, the human genome turned out to be a lot more complex than was originally thought.

While there may be just under 20,000 confirmed protein coding genes, it turns out that much of the genome outside of these genes is also important in regulating how the genome is controlled. For example, we know that not all genes are expressed in all tissues and that not all genes are expressed during all developmental stages.

Now, however, the field is changing with respect to genomic medicine.

This is essential information for the pharma industry to know about, says Charlie. If you are developing a drug, for example, for infantile epilepsy, then you need to know if your drug target is expressed in the brain and also during early development.

Likewise, some patients may have a different version of a gene with respect to people on whom a drug has been tested, which means that drug might not work.

While the ability to specifically target the genome for therapy for all patients is not yet a reality, the time will come when it will be.

Already, we know of some types of epilepsy where the underlying genome can inform on specific therapy, says Charlie.

For example, people who have epilepsy caused by mutations in the gene SCN1A should not be prescribed sodium channel blockers, as this can make their epilepsy worse. Another example is pyridoxine-dependent epilepsy, which can result in severe developmental regression, caused by mutations in the gene ALDH7A1. Yet, this can be treated simply by administering a type of vitamin B6.

While it is a very rare form of epilepsy, it is such a cheap and harmless medication that it is often used as a first-line therapy for infants in intensive care who have no genetic diagnosis.

This is where the future of medicine lies where we are able to read a patients genome and then direct care and therapy based upon that.

Genomics also means we will be able to stratify patients, based upon their genomic makeup, to make clinical trials much more efficient and targeted.

Currently, the approach is akin to throwing darts in the dark, where a clinical trial may use the same drug across a whole range of patients, each with a very different genomic makeup, in the hope that a drug will work, says Charlie.

For example, this approach was taken with the International Collaborative Infantile Spasms Study (ICISS) clinical trial that my daughter was on, where therapy was administered to patients with no idea of the underlying genome.

While the clinical trial was successful in stopping seizures in around 72% of patients, which is an amazing result, nearly one third of patients did not respond. This is indicative of patients having different underlying aetiologies.

In such epilepsy studies, where every seizure causes catastrophic brain malfunctioning, time is of the essence to prevent severe and irreversible developmental regression.

Had clinicians known that this cohort was not going to respond to the clinical trial, perhaps because of their genomic makeup, a different treatment pathway could have been chosen, says Charlie.

On one hand, unfortunately this means that many drugs are doomed to failure. On the other hand, many drugs that have been developed so far, but have not made it into the clinic, are worth revisiting, to see if their effectiveness can be improved with better genomic insight.

However, there are still hurdles to overcome to understand completely how a patients genome impacts their health.

Enhancing sequencing

Luckily there have been some encouraging developments in sequencing technology in recent years.

Currently, the most common way of looking at genomes in these settings is by using short-read technology.

The human genome is too long to be sequenced as one continuous string by current technology so short-read sequencing breaks DNA into short fragments that are amplified and then sequenced to produce reads of around 150 nucleotides in length. Bioinformatic techniques are then used to piece together the reads into a continuous genomic sequence by aligning them to the reference human genome.

That works really well most of the time, says Charlie, but if a patient has a region of the genome thats deleted, or expanded, its very difficult for short-read technology to understand that. If you look at a region that is repeated or deleted, by, for example, 10,000 nucleotides in length and youve got a tiny read, you cant match that to the genome with any confidence.

To address these issues, scientists and clinicians are starting to look at long-read sequencing.

These technologies directly sequence single molecules of DNA in real time, often without the need for amplification. This allows for much lengthier reads.

Through this, we are able to more clearly resolve large changes in the genome, says Charlie. Thats going to be really helpful, because we know that large changes in the human genome are responsible for a lot of developmental disorders such as epilepsy and autism.

Most current technology actually focuses on looking at the bits of the genome that produce proteins. As mentioned, this accounts for roughly 1-2% of the genome, so theres 98% that were not actually looking at yet because we dont know what it does.

Its likely to contain what we call control regions parts of the genome that control whether a gene is turned on or off. We need to start finding technologies that help us to understand these regions more fully.

At the same time as trying to understand what those regions do, researchers may also be able to measure to what degree a gene is being expressed.

If you can see that you have a gene thats being massively over-expressed or under-expressed in a patient, with respect to a normal person, it may also be an indicator that theres something wrong, says Charlie.

There are lots of technologies already out there, but we still need to wait for them to be included in general clinical practice. Its still difficult to interpret a lot of these results. From a research point of view, you can make all sorts of guesses and hypotheses, but that cant really apply in a clinical setting.

Clearly, there are still challenges in integrating genomic medicine into everyday healthcare, yet great strides are already being made. For example, we are beginning to see genomic medicine being used to treat disorders caused by a single faulty gene, so the ability to replace the gene (or the affected part of the gene) should help.

One such example uses the adeno-associated virus (AAV), a small non-pathogenic virus that lives in humans (the way gut bacteria do) and travels freely around the body, including crossing the blood-brain barrier unimpeded.

Scientists are removing the virus DNA and replacing it with a normal copy of a faulty gene in the specific genetic nervous system disease.The virus then travels and delivers the normal gene to the cells making them functional again. This has recently led to an approved therapy for spinal muscular atrophy.

Such technologies have immense potential to bring relief to patients with severe genomic disorders, although there remain ethical concerns about how these techniques could be used.

The future will only see more of these technologies being embraced and it is clear that the pharma and genomics industry must start talking to each other again in earnest, Charlie says. We are entering the age where genomic medicine is no longer a pipe dream but actually becoming a reality.

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The future of genomic medicine: can it fulfil its promises? - - pharmaphorum

The CDC estimates that sickle cell disease affects well over 100,000 Americans, with the disease occurring most often in African Americans. September has been designated as National Sickle Cell Awareness month designed to focus attention on the ongoing research in this field and the need for new treatments. The sector can certainly point to the significant progress that has taken place during the past few years, with new medicines reaching the market and several novel therapeutics with new mechanisms of action advancing in the pipeline.

Ted Love, president and CEO of Global Blood Therapeutics Inc. (GBT), said 2019 was a landmark year with the FDA approval of two new novel therapies to treat sickle cell disease. He was speaking at the virtual annual Sickle Cell Disease (SCD) Therapeutics Conference this week. His company, together with the Sickle Cell Disease Association of America, was hosting the one-day event featuring discussions on the latest advances and future trends.

Approvals

The key manifestation of the inherited blood disorder is that red blood cells (RBCs) are abnormally shaped (crescent), which restricts their flow in blood vessels and limits oxygen delivery to the bodys tissues, leading to severe pain and organ damage. The condition is also characterized by severe chronic inflammation that results in vaso-occlusive crisis (VOC) where patients experience episodes of extreme pain and organ damage.

Late November, GBT gained accelerated approval for its Oxbryta (voxelotor) tablets for the treatment SCD in adults and pediatric patients 12 and older. The agencys green light came less than two weeks after it gave the go-ahead to Novartis AG for Adakveo (crizanlizumab) to reduce the frequency of VOCs in adult and pediatric patients ages 16 and older with SCD.

According to Love, Oxbryta is a new class of therapy binding to hemoglobin and stabilizing RBCs in an oxygenated state and inhibiting deoxygenated sickle hemoglobin polymerization, making cells less likely to bind together and form the distinctive sickle shape.

The launch of the drug has gone well since it was approved, he said in the companys second-quarter financial report and business update, despite the impact of COVID-19. Net sales in the period reached $31.5 million, well ahead of the Streets expectations. Going forward, the company is planning to expand the potential use of Oxbryta for the treatment of SCD in children as young as 4 years old and also seek marketing authorization in Europe for Oxbryta to treat hemolytic anemia in SCD patients ages 12 and older with a marketing authorization application being submitted to the EMA by the middle of next year.

Pipeline progress

Cambridge, Mass.-based Agios Pharmaceuticals Inc. is working on mitapivat (AG-348), an investigational, oral, small-molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase-R (PKR) enzymes, in patients with SCD. The compound has been shown to decrease 2,3-diphosphoglycerate (2,3-DPG) and increase adenosine triphosphate (ATP), and through that mechanism, it may reduce hemoglobin (Hb) S polymerization and red blood cell sickling. In June, the company reported that clinical proof of concept had been established based on a preliminary analysis in a phase I trial being conducted in collaboration with the U.S. NIH as part of a cooperative research and development agreement.

The ongoing study had enrolled nine patients, with eight completing all planned dose levels of mitapivat. Seven of eight patients who completed all dose levels experienced a Hb increase, with five of eight patients (63%) achieving a hemoglobin increase of 1 g/dL from baseline (range 1-2.7 g/dL). All five patients who achieved a hemoglobin increase of 1 g/dL did so at doses of 50 mg BID or lower. Decreases in 2,3-DPG and increases in ATP levels were observed, consistent with the proposed mechanism of action and comparable to that observed in healthy volunteer studies with mitapivat.

The company said it expects to report data from ACTIVATE and ACTIVATE-T, its two global pivotal trials for mitapivat in adults with pyruvate kinase deficiency, between the end of 2020 and mid-2021.

Watertown, Mass.-based Forma Therapeutics Holdings Inc., which made its public debut this year, also has a selective RBC pyruvate kinase-R activator in its pipeline for treating SCD. FT-4202 is being evaluated in a phase I trial in SCD patients ages 12 and older and has been granted fast track, rare pediatric and orphan drug designations. The compound is a potent activator of pyruvate kinase-R designed to improve RBC metabolism, function and survival by decreasing 2,3 DPG and increasing ATP, potentially resulting in both increased hemoglobin levels and reduced VOCs.

Olinciguat, an oral guanylate cyclase (sGC) stimulator, being developed by Cyclerion Therapeutics Inc., has completed the treatment period in its STRONG-SCD study with a total of 70 patients randomized. The placebo-controlled, dose-ranging study is designed to evaluate safety, tolerability and pharmacokinetics, as well as to explore effects on daily symptoms and biomarkers of disease activity when dosed over a 12-week treatment period. Top-line results are expected this year. Olinciguat is a compound that aims to stimulate sGC production, leading to the production of a signaling molecule called cyclic guanosine monophosphate (cGMP). High levels of cGMP help reduce inflammation in blood vessels, decrease adhesion between RBCs, and allow for improved blood flow by increasing the availability of nitric oxide.

Boston-based Imara Inc. is developing IMR-687, a small-molecule inhibitor of PDE9 that degrades cyclic guanosine monophosphate (cGMP), an active signaling molecule that plays a role in vascular biology. The company said that lower levels of cGMP are often found in people with SCD and beta-thalassemia and are associated with impaired blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide-mediated vasodilation. Blocking PDE9 acts to increase cGMP levels, which are associated with reactivation of fetal hemoglobin.

In August, the company dosed the first patient in its Ardent phase IIb trial of IMR-687 for adult patients with SCD. The planned primary efficacy objective is to evaluate the proportion of all patients with fetal hemoglobin (HbF) response, defined as an increase of 3% in HbF from baseline to week 24, compared to placebo.

Gene therapy/gene editing

Since SCD is a monogenic disease condition, researchers believe that it would be a good candidate for gene therapy therapeutic approaches. For example, significant progress is being made by Cambridge, Mass.-based Bluebird Bio Inc. with lentiglobin, its lentiviral-based gene therapy that inserts an anti-sickling beta-globin variant into CD34-positive cells, progenitors of red blood cells.

At the virtual European Hematology Association (EHA) meeting in June, it reported new data from its ongoing phase I/II study involving adult and adolescent patients with SCD that showed a near-complete reduction of serious VOCs and acute chest syndrome. The company expects to submit a BLA to the FDA for the gene therapy next year.

Crispr Therapeutics AG and Vertex Pharmaceuticals Inc. are progressing CTX-001, an investigational, autologous, CRISPR/Cas9 gene-edited hematopoietic stem cell therapy being evaluated for patients suffering from severe hemoglobinopathies. At EHA, the companies reported that in the phase I/II Climb-121 study, at nine months after CTX-001 infusion, the first treated patient was free of VOCs, was transfusion independent and had total hemoglobin levels of 11.8 g/dL, 46.1% fetal hemoglobin and F-cells (erythrocytes expressing fetal hemoglobin) of 99.7%.

Last month, Cambridge, Mass.-based Editas Medicine Inc., a genome editing company, reported that the FDA had granted rare pediatric disease designation for EDIT-301, an experimental, autologous cell medicine, being developed as a potentially best-in-class, durable medicine for SCD. The company plans to file an investigational new drug application for EDIT-301 by the end of this year. EDIT-301 comprises sickle patient CD34+ cells genetically modified using a hCRISPR/Cas12a (also known as Cpf1) ribonucleoprotein to edit the HBG1/2 promoter region in the beta-globin locus. Red blood cells derived from EDIT-301 CD34+ cells demonstrate a sustained increase in fetal hemoglobin (HbF) production.

In its second-quarter financial report and business update, Beam Therapeutics Inc. announced the nomination of its first two adenine base editing development candidates, BEAM-101, targeting patients with hereditary persistence of fetal hemoglobin, and BEAM-102 (Makassar variant), both aimed at correcting SCD.

New Initiative

The NIH, which reports it spends approximately $100 million on sickle cell disease research, announced that is has launched The Cure Sickle Cell Initiative designed to speed the development of cures for the disease. It will take advantage of the latest genetic discoveries and technological advances to progress the most promising genetic-based curative therapies safely into clinical trials within five to 10 years.

Aided by research partners, the initiative will establish a national data warehouse of genetic therapies for sickle cell disease and conduct comparative analyses of therapeutic approaches to assess both clinical and cost effectiveness. National networks will also be created to make it easier for patients and providers to interact with the research, clinical trials, and other activities.

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New medicines in the pipeline to treat sickle cell disease - BioWorld Online

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that it presented the latest results from three Phase III studies from the Tecentriq (atezolizumab) clinical development program in triple-negative breast cancer (TNBC) at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

While we have made great progress in the treatment of many forms of breast cancer, TNBC remains an aggressive and difficult-to-treat disease, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. We are proud of our work to address challenges and advance scientific understanding of cancer immunotherapy in the context of distinct chemotherapy regimens and in various TNBC treatment settings. Although the IMpassion131 study did not reach its endpoint, we are pleased to bring new treatment options for some TNBC patients, and remain committed to improving the lives of all women with early and advanced stages of this disease.

Results from the Phase III IMpassion031 study, evaluating Tecentriq in combination with chemotherapy (Abraxane [albumin-bound paclitaxel; nab-paclitaxel]; followed by doxorubicin and cyclophosphamide) in comparison to placebo plus chemotherapy (including nab-paclitaxel) demonstrated a statistically significant and clinically meaningful improvement in pathological complete response (pCR) for the treatment of people with early TNBC, regardless of PD-L1 expression. pCR was observed in 57.6% (95% CI: 49.7-65.2) of patients treated with Tecentriq in combination with chemotherapy, an increase of 16.5% from 41.1% (95% CI: 33.6-48.9) in patients treated with placebo plus chemotherapy (one-sided p=0.0044, significance boundary = 0.0184) in the intention-to-treat (ITT) population. The safety profile was consistent with the established profile of the individual medicines and no new safety concerns were identified.

The IMpassion031 study is the second positive Phase III study from Genentech demonstrating the benefit of Tecentriq in TNBC, and the first Tecentriq study to demonstrate benefit in early TNBC. Tecentriq in combination with nab-paclitaxel is currently approved in more than 70 countries worldwide, including the United States and across Europe, for the treatment of adults with unresectable locally advanced or metastatic TNBC in people whose tumors express PD-L1 (IC1%).

The final overall survival (OS) analysis of the Phase III IMpassion130 study, evaluating Tecentriq in combination with nab-paclitaxel compared with placebo plus nab-paclitaxel as a first-line treatment for patients with metastatic TNBC, was consistent with the first and second interim analyses. There was no significant difference in OS between the treatment groups in the ITT population. Clinically meaningful improvements in OS were seen with Tecentriq plus nab-paclitaxel in PD-L1-positive patients. The magnitude of OS improvements with Tecentriq in PD-L1-positive patients remained clinically meaningful, with an increase of 7.5 months in median OS with Tecentriq plus nab-paclitaxel compared with placebo plus nab-paclitaxel (hazard ratio [HR]=0.67 [95% CI: 0.530.86]). However, this result could not be formally tested due to the prespecified statistical testing hierarchy. The cumulative safety of the Tecentriq plus nab-paclitaxel combination remains consistent with the previously reported safety data for this study and the known risks of individual study medicines. No new safety concerns were identified with longer follow-up.

Finally, results from the Phase III IMpassion131 study, evaluating Tecentriq in combination with paclitaxel compared with placebo plus paclitaxel as a first-line treatment for patients with metastatic TNBC, did not show significant improvement for progression-free survival (PFS) in the PD-L1-positive population (HR=0.82 [95% CI: 0.60-1.12]). The OS data showed a negative trend; however, the study was not powered for the secondary endpoint of OS, and OS data were immature at the time of analysis (initial HR=1.55 [95% CI: 0.86-2.80] in the PD-L1-positive population, based on 21% of patients with an event; updated HR=1.12 [95% CI: 0.76-1.65], updated analysis based on 41% of patients with an event). The safety profile of Tecentriq plus paclitaxel was consistent with the established safety profile of the individual study medicines and no new safety concerns were identified.

Genentech has an extensive development program for Tecentriq, including multiple ongoing and planned Phase III studies across several types of lung, genitourinary, skin, breast, gastrointestinal, gynecological, and head and neck cancers. This includes studies evaluating Tecentriq both alone and in combination with other medicines.

About the IMpassion031 study

The IMpassion031 study is a Phase III, multi-center, randomized, double-blind study evaluating the efficacy and safety of Tecentriq (atezolizumab) in combination with chemotherapy (Abraxane [albumin-bound paclitaxel; nab-paclitaxel]; followed by doxorubicin and cyclophosphamide) in comparison to placebo plus chemotherapy, in people with previously untreated, early TNBC. The primary endpoint is pCR using the American Joint Committee on Cancer (AJCC) staging system in the intention-to-treat (ITT) population and in the PD-L1-positive population. Secondary endpoints include overall survival (OS), event-free survival, disease-free survival and quality of life measures.

About the IMpassion130 study

The IMpassion130 study is a Phase III, multicenter, randomized, double-blind study evaluating the efficacy, safety and pharmacokinetics of Tecentriq plus nab-paclitaxel compared with placebo plus nab-paclitaxel in people with unresectable locally advanced or metastatic TNBC who have not received prior systemic therapy for metastatic breast cancer. The study enrolled 902 people who were randomized equally (1:1). The co-primary endpoints are PFS per investigator assessment (RECIST 1.1), and OS in the ITT population and PD-L1-positive population. Secondary endpoints include objective response rate and duration of response.

About the IMpassion131 study

The IMpassion131 study is a Phase III, multi-center, randomized, double-blind study evaluating the efficacy and safety of Tecentriq in combination with paclitaxel, in comparison to placebo plus paclitaxel, in people with previously untreated, inoperable, locally advanced or metastatic TNBC. The study enrolled 651 people who were randomized in a 2:1 ratio to receive Tecentriq or placebo plus paclitaxel. The primary endpoint is PFS per investigator assessment (RECIST 1.1) in the PD-L1-positive population, followed by intention-to-treat (ITT) population. Secondary endpoints include OS, objective response rate, and duration of response in the PD-L1-positive and ITT populations.

About triple-negative breast cancer

Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, close to 280,000 people in the United States will be diagnosed with invasive breast cancer, and more than 42,000 will die from the disease in 2020. Breast cancer is not one, but many diseases based on the biology of each tumor. In triple-negative breast cancer, tumor cells lack hormone receptors and do not have excess HER2 protein. Approximately 15 percent of breast cancers are triple-negative based on the results of diagnostic tests. It is an aggressive form of the disease with few treatment options.

About Tecentriq (atezolizumab)

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

Tecentriq U.S. Indications (pronounced t-SEN-trik)

Tecentriq is a prescription medicine used to treat adults with:

A type of bladder and urinary tract cancer called urothelial carcinoma.

Tecentriq may be used in patients with urothelial carcinoma if their bladder cancer has spread or cannot be removed by surgery, and if they have any one of the following conditions:

The approval of Tecentriq in these patients is based on a study that measured the amount of time until patients disease worsened. Continued approval for this use may depend on the results of an ongoing study to confirm benefit.

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

Tecentriq may be used alone as the first treatment in patients with lung cancer if:

Tecentriq may be used with the medicines bevacizumab, paclitaxel, and carboplatin as the first treatment in patients with lung cancer if:

Tecentriq may be used with the medicines paclitaxel protein-bound and carboplatin as the first treatment in patients with lung cancer if:

Tecentriq may be used alone in patients with lung cancer if:

A type of breast cancer called triple-negative breast cancer (TNBC).

Tecentriq may be used with the medicine paclitaxel protein-bound in patients with TNBC when their breast cancer:

The approval of Tecentriq in these patients is based on a study that measured the amount of time until patients disease worsened. Continued approval for this use may depend on the results of an ongoing study to confirm benefit.

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

A type of liver cancer called hepatocellular carcinoma (HCC).

Tecentriq may be used with the medicine bevacizumab when a patients liver cancer:

A type of skin cancer called melanoma.

Tecentriq may be used with the medicines cobimetinib and vemurafenib when a patients melanoma:

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

Important Safety Information

The most important information about Tecentriq is:

Tecentriq can cause the immune system to attack normal organs and tissues and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.

Patients should call or see their healthcare provider right away if they get any symptoms of the following problems or these symptoms get worse.

Tecentriq can cause serious side effects, including:

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

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

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

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

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

The most common side effects of Tecentriq when used in TNBC with paclitaxel protein-bound include:

The most common side effects of Tecentriq when used in hepatocellular carcinoma with bevacizumab include:

The most common side effects of Tecentriq when used in melanoma with cobimetinib and vemurafenib include:

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

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information. Patients should call their doctor for medical advice about side effects of Tecentriq.

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.Tecentriq.com for the full Tecentriq Prescribing Information for additional Important Safety Information.

About Genentech in cancer immunotherapy

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

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

About Genentech

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 Presents New Data From Multiple Phase III Studies of Tecentriq in Triple-Negative Breast Cancer at ESMO Virtual Congress 2020 - Business...

(UroToday.com)Dr. Juergen Gschwend summarized the three important abstracts in the setting of metastatic urothelial carcinoma (mUC) that were presented at the European Society of Medical Oncology (ESMO) 2020 Virtual Congress:

Dr. Gschwend began his talk stating that mUC is not a curable disease in most cases, and patients rarely survive beyond five years. Treatment of this disease is associated with a high therapy burden and has significant treatment-related adverse events (TRAEs) with increasing costs.

The evolution of the treatment options is shown in Figure 1, showing many new treatment options that are becoming available.

IMvigor130 was the first abstract discussed (figure 2). This was a positive randomized controlled trial, meeting the primary endpoint of progression-free survival (PFS), showing a . The analysis of overall survival (OS) is still pending. Atezolizumab + platinum-based chemotherapy was well-tolerated with no relevant toxicity added resulting from the addition of atezolizumab to chemotherapy.

IMvigor130 also provided an analysis of quality of life and patient-reported outcomes (PROs), which, according to Dr. Gschwend, provide an overall benefit. There was no significant difference in function and quality of life domains in both treatment arms. The PROs were not compromised by the addition of atezolizumab to the standard platinum-based chemotherapy.

Figure 1 Evolution of systemic treatment options in metastatic urothelial carcinoma:

Figure 2 Imvigor 130 trial NCT02807636 design:

Next, Dr. Gschwend discussed the JAVELIN bladder 100 phase three trial comparing the best standard of care (BSC) to Avelumab maintenance + BSC in mUC patients previously treated with platinum-based chemotherapy (figure 3).

Figure 3 JAVELIN bladder 100 trial design:

Dr. Gschwend continued and congratulated the authors of this study due to the very impressive biomarker analyses that were conducted in this study. However, it is still not clear if the work done with the suggested biomarkers will influence clinical decision making. The study shows that the impact of PD-L1 in the JAVELIN bladder 100 trial is questionable because both treatment arms did better in patients with positive PD-L1.

When assessing the impact of the tumor mutational burden (TMB) as a potential biomarker, it showed no clear prediction in this trial. In a similar manner, there was no clear prediction by either TMB or PD-L1 in the IMvigor 130 study. The other biomarkers that were identified and analyzed in the trial, including gene expression signatures, were shown to be potentially predictive, but they were more hypothesis-generating than clinically relevant. None of these potential biomarkers were shown to be predictive in the outcome of overall survival (OS) in the JAVELIN bladder 100 trial and IMvigor 130 trial.

An important limitation to remember is that the backbone of a biomarker test is the tumor tissue itself. However, it is not clear which tissue should be utilized whether tissue should be collected from the primary tumor or from a metastasis. The timing of tissue sampling is also not clear, and tumor heterogeneity within the same tumor also raises concern.

The last abstract discussed was the TROPHY-U-01 trial (figure 4), assessing the role of Sacituzumab Govitecan (SC), which is an anti-Trop-2 antibody-drug conjugate. This trial was compared to the EV-201 trial assessing the role of enfortumab Vedotin (EV), another antibody-drug conjugate, in the same patient population1. Both trials had similar results, as shown in figure 5.

The TROPHY-U-01 showed that SC has promising activity with an objective response rate of 27% compared to 44% for EV. There was a high median OS with 10.5 months for SG and 11.7 months for EV. There are currently ongoing phase three trials assessing the role of SG.

Figure 4 TROPHY-U-01 trial NCT03547973design:

Figure 5 Comparison of results from the TROPHY-U-01 trial and the EV-201 trial:

Dr. Gschwend ended his talk showing the currently available options for first-line treatment of mUC patients in 2020 and beyond (Figure 6).

Figure 6 First-line treatment options for metastatic urothelial carcinoma in 2020 and beyond:

Presented by: Prof. Dr. Jrgen Gschwend, PhD, Department of Urology, TUM School of Medicine, Munich, Germany

Written by: Hanan Goldberg, MD, MSc., Assistant Professor of Urology, SUNY Upstate Medical University, Syracuse, NY, USA, @GoldbergHananat the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.

References:

1. Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2019; 37(29): 2592-600.

Related Content:ASCO 2020: JAVELIN Bladder 100 Phase III Results: Maintenance Avelumab + Best Supportive Case vs BSC Alone After Platinum-Based First-Line Chemotherapy in Advanced Urothelial CarcinomaJAVELIN Bladder 100: Avelumab for Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma - Thomas PowlesThe Dynamic Advancements in Personalized Treatments for Metastatic Urothelial Cancer - Andrea Apolo

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