New substance prevents vascular calcification

Researchers at ETH Zurich and ETH spin-off Inositec have developed a new substance to prevent vascular calcification, which affects many patients suffering from chronic kidney disease. As their metabolism is impaired, calcium salts may deposit in soft tissues, such as blood vessels or even the heart valves, causing them to stiffen. This often leads to severe, potentially fatal cardiovascular diseases. However, before patients can benefit from the substance further research and tests must be carried out.

"Calcification occurs when calcium phosphate crystals are deposited in tissue," explains Jean-Christophe Leroux, professor of drug formulation and delivery at ETH Zurich. "The compound adheres to calcium phosphate crystals, inhibiting their growth."

Derivative of a natural substance

The new molecule is structurally related to inositol hexakisphosphate, also known as IP6. Occurring naturally in legumes and cereals, IP6 binds phosphate and various minerals, such as calcium, magnesium and iron. The plants use the molecule in their seeds to provide the seedlings with a sufficient supply of these substances.

It has been known for some time that IP6 also has an effect in the human bloodstream. The molecule has to be injected as it cannot be absorbed after oral ingestion. Other scientists are currently conducting clinical trials to study how effectively IP6 prevents vascular calcification.

Screening the collection of molecules

"The problem, though, is that IP6 is not particularly stable and is metabolized by the body very quickly," Antonia Schantl says. A doctoral student in Leroux's group, she is the lead author of the paper that has been published in the journal Nature Communications. In order to overcome this problem, Leroux and his colleagues sought to stabilize the molecule by making specific chemical modifications. They developed a series of related molecules, which ETH then patented. To be able to market one or more of these derivatives as medication in the future, ETH Professor Leroux and others involved founded the spin-off Inositec, which acquired the licence from ETH to use the molecule family.

Leroux's group at ETH subsequently collaborated with Inositec and researchers from other universities to screen this collection of molecules in a project that was co-financed by the Swiss innovation agency Innosuisse. The scientists conducted in vitro experiments to study the molecules' ability to inhibit the growth of calcium phosphate crystals in the blood and check their stability. They also tested their effect in a disease model in rats. The studies singled out one of the molecules in the collection as particularly suitable.

For the next stage, the ETH scientists will work with Inositec and third parties to clarify various issues, such as drug safety and the optimal dosage.

https://www.nature.com/articles/s41467-019-14091-4
https://en.wikipedia.org/wiki/Phytic_acid

Team finds that their cancer-fighting compound fights obesity and diabetes, too

Eric Prossnitz, Ph.D., and his team hope to help 93 million obese Americans fight their fat.

In a paper published in Science Translational Medicine, they reported that G-1, a cancer-fighting compound they discovered some years ago, reduces fat in obese mice. Although G-1 is currently in phase 1 clinical trials for cancer, Prossnitz and his team are planning preclinical studies to use G-1 to fight fat in obese people.

Obesity affects 40% of adults in the United States, resulting in health conditions that include heart disease, high blood pressure, type 2 diabetes and some cancers. According to the U.S. Centers for Disease Control and Prevention, obesity and its related conditions far outweigh other causes of death. Current drugs for obesity don't effectively reduce it or have undesirable side effects.

Prossnitz and his team have been studying GPER, the G protein-coupled estrogen receptor that G-1 activates, because GPER affects certain breast cancer cells. When breast cancer drugs like tamoxifen and fulvestrant block estrogen receptors in a cell's nucleus, they also activate GPER, which is found in cell membranes.

Prossnitz's previous studies showed that GPER may play a role in resistance to tamoxifen and similar drugs, and that led him to wonder how G-1 affects non-cancerous cells when estrogen is lacking.

Estrogen is considered a female hormone, although men produce it at low levels. Low estrogen in women is a hallmark of menopause, and postmenopausal women also have higher rates of heart disease, high blood pressure, obesity and diabetes. So to understand whether G-1 might affect metabolism in postmenopausal women, Prossnitz and his team studied mice with low estrogen levels.

In their studies, low-estrogen female mice gained weight rapidly, even on a normal diet, and quickly became obese and diabetic. When the researchers treated these obese female mice with G-1, the mice lost weight and their diabetes went away.

The researchers determined that the weight loss wasn't due to the mice eating less or moving around more; it resulted from what their bodies did with the calories they ate. Instead of storing calories as fat, the mice used them as fuel.

"Their metabolism changed," Prossnitz says. "The mice showed an increased energy expenditure."

Prossnitz's team also studied male mice, which have naturally low levels of estrogen. The male mice were fed a high-fat diet, which made them obese and diabetic, and then some were treated with G-1. Although the treated mice did not lose weight, they did not gain additional weight either, like the untreated mice. More importantly, their diabetes improved.

"This result suggests that G-1 has separate effects on obesity and diabetes," Prossnitz says. "The G-1-treated male mice were metabolically healthier, even though they were still obese."

Finally, the team also fed a high-fat diet to low-estrogen female mice. These mice became obese very quickly, but just like their sisters on a normal mouse diet, they lost weight and their diabetes improved when they were treated with G-1. These results, says Prossnitz, could point to a sex difference in the effects of the drug or in the way GPER signals in the cells of males and females.

To learn about how G-1 increases energy expenditure, the team studied brown fat cells, which generate heat instead of storing excess calories as fat. What they found surprised them: when treated with G-1, the cells expended more energy.

"This fits nicely with what we saw in mice," Prossnitz says, "and suggests that G-1 may reduce obesity by targeting brown fat cells that burn extra calories."

In a future series of experiments, Prossnitz plans to study how signals from GPER induce the cellular changes that cause more energy to be used. He hopes that one day soon G-1 could revolutionize the treatment of metabolic disorders.

In the meantime, he and his team are starting the long path toward clinical trials that will test the ability G-1 to fight obesity and diabetes in people.

https://stm.sciencemag.org/content/12/528/eaau5956/tab-figures-data

Chinese scientists ask for patent on US drug to fight virus

In continuation of my update on Remdesivir

Scientists in the city at the center of China's virus outbreak have applied to patent a drug made by U.S. company Gilead Sciences Inc. to treat the disease, possibly fueling conflict over technology policy that helped trigger Washington's tariff war with Beijing.

The government-run Wuhan Institute of Virology said this week it applied for the patent in January along with a military laboratory. An institute statement acknowledged there are "intellectual property barriers" but said it acted to "protect national interests."

Granting its own scientists a patent might give the Chinese government leverage in negotiations over paying for the drug. But it also might fuel complaints Beijing abuses its regulatory system to pressure foreign companies to hand over valuable technology.

On Thursday, the official Xinhua News Agency said clinical trials of the drug, remdesivir, were due to start.

Gilead, headquartered in Foster City, California, said it applied in 2016 for a Chinese patent on use of remdesivir against coronaviruses and is waiting for a decision. The coronavirus family includes the novel coronavirus, or 2019-nCoV, blamed for the outbreak in Wuhan.

"Gilead has no influence over whether a patent office issues a patent to the Chinese researchers," said a company spokesman, Ryan McKeel. "Their application has been filed more than three years after Gilead's filing and will be considered in view of what is already known about the compound and pending patent applications."

The institute said its application was filed Jan. 21. Two days later, Chinese authorities suspended most access to Wuhan, a city of 11 million people. That lockdown has expanded to surrounding cities and some in other provinces, isolating a total of about 60 million people in the most sweeping anti-disease measures ever imposed.

China has the right under World Trade Organization rules to declare an emergency and compel a company to license a patent to protect the public. It would be required to pay a license fee that is deemed fair market value.

The government might be able to avoid that fee if the patent were granted to the Wuhan institute, part of the elite Chinese Academy of Sciences.

The institute said it applied for a "use patent" that specifies the Wuhan virus as the drug's target. Gilead's patent application, filed before the virus was identified, cites only the overall family of coronaviruses.

The Chinese researchers made their patent application "from the perspective of protecting national interests," said the institute statement.

"If relevant foreign companies plan to contribute to China's epidemic prevention and control, we both agree that if the state needs it, we will not require enforcement of rights given by the patent," it said.

Gillead said last week it was working with U.S. and Chinese health authorities on studying remdesivir. The company said it has provided the drug for emergency use in a small number of patients with the Wuhan virus "in the absence of any approved treatment options."

https://www.bloomberg.com/news/articles/2020-02-03/gilead-drug-to-undergo-human-trials-in-china-to-cure-coronavirus

https://www.med-chemist.com/search?q=remdesivir

Chemical found in drinking water linked to tooth decay in children

Children with higher concentrations of a certain chemical in their blood are more likely to get cavities, according to a new study by West Virginia University School of Dentistry researchers.

Manufactured chemical g roups called perfluoroalkyl and polyfluoroalkyl substances are universal as a result of extensive manufacturing and use. Although manufacturers no longer use PFAS to make nonstick cookware, carpet, cardboard and other products, they persist in the environment. Scientists have linked them to a range of health problems—from heart disease to high cholesterol—but now R. Constance Wiener and Christopher Waters are exploring how they affect dental health.

They investigated whether higher concentrations of PFAS were associated with greater tooth decay in children. One of them—perfluorodecanoic acid—was linked to dental cavities. Their findings appear in the Journal of Public Health Dentistry.

"Due to the strong chemical bonds of PFAS, it is difficult for them to breakdown, which makes them more likely to be persistent within the environment, especially in drinking water systems," said Waters, who directs the School of Dentistry's research labs. "A majority of people may not be aware that they are using water and other products that contain PFAS."

The 629 children who participated in the study were 3 to 11 years old and were part of the National Health and Nutrition Examination Survey. Samples of the children's blood were analyzed for PFAS in 2013 and 2014. Their tooth decay and other factors—such as their race, their BMI and how often they brushed their teeth—were assessed.

Of the seven PFAS that Wiener and Waters analyzed, perfluorodecanoic acid was the one that correlated with higher levels of tooth decay.

"Perfluorodecanoic acid, in particular, has a long molecular structure and strong chemical bonds; therefore, it remains in the environment longer. As a result, it is more likely to have negative health consequences such as dental caries," said Dr. Wiener, an associate professor in the Department of Dental Practice and Rural Health.

But how does that influence happen? Wiener and Waters have a hypothesis. According to other research, perfluorodecanoic acid may disrupt the healthy development of enamel, which is what makes teeth hard. That disruption can leave teeth susceptible to decay.

However, when it comes to cavities, scientists haven't parsed perfluorodecanoic acid's mechanism of action yet. The topic warrants further investigation.

"While the findings of this study are important, there are some study limitations, and more work is needed to fully understand how this molecule impacts normal tooth formation," said Fotinos Panagakos, the School of Dentistry's vice dean for administration and research.

"The good news is that, in our study, about half of the children did not have any measurable amount of PFAS. Perhaps this is due to certain PFAS no longer being made in the US," Wiener said.

Another piece of good news is that the study reaffirmed the importance of dental hygiene and checkups. Children who brushed once a day or less frequently had significantly higher tooth decay than those who brushed at least twice daily.

Likewise, children who had not been to the dentist within the previous year were twice as likely to have higher rates of tooth decay than kids who hadn't.

So, even though parents cannot control what is in their children's drinking water, they can still protect their children's teeth by fostering thorough, regular brushing and scheduling dental exams.

The School of Dentistry will hold Give Kids a Smile Day on Friday, Feb. 7, at the Pediatric Dentistry Clinic. Dental students will treat more than 100 children for free that day. Each visit includes an exam, a cleaning, a fluoride treatment and—if appropriate—X-rays.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jphd.12329

https://www.epa.gov/pfas

https://www.epa.gov/pfas/basic-information-pfas

https://www.epa.gov/pfas/basic-information-pfas

Botanical drug is shown to help patients with head and neck cancers

In continuation of my update on Curcumin

In a UCLA-led phase I clinical trial, a new plant-based drug called APG-157 showed signs of helping patients fight oral and oropharyngeal cancers. These cancers are located in the head and the neck.

APG-157  (a botanical drug containing multiple polyphenols, including curcumin see above structure), is made up of multiple compounds produced by plants, including curcumin. UCLA Jonsson Comprehensive Cancer Center researchers found that treatment with this botanical drug resulted in high concentrations of curcumin and its byproducts circulating in the blood and absorbed by tumor tissues within three hours after being taken orally.

APG-157 reduced the concentration of cytokines—proteins involved in inflammation—in the saliva when administered to cancer patients. The therapy also reduced the relative abundance of Bacteroides species, a group of gram-negative bacteria. Gram negative refers to a group of dangerous bacteria that have an outer layer which hides them from the immune system. The relative abundance of gram-negative bacteria compared to the presence of other types of bacteria is correlated with oral cancer.

APG-157 also resulted in the expression of genes that are associated with attracting immune system T cells to the tumor area. This therapy could have a beneficial effect when used in combination with immunotherapy drugs that help immune system T cells recognize and kill tumors.

The treatment did not have any adverse effects on the study's participants.

Cancers of the head and neck account for 4% of all cancers. About 650,000 new cases are reported each year around the world. People with advanced head and neck cancers have a low survival rate and current treatment options such as surgery, radiation and chemotherapy can have adverse effects. Therefore, more effective and less toxic therapies are needed to help improve the quality of life and outcome for those with these cancers.

APG-157 is a botanical drug developed under the FDA's Botanical Drug Guidance, which includes requirements for production of plant-based therapies that are marketed as prescription medications. The drug is made up of botanical compounds including curcumin from the Curcuma longa plant, which is commonly referred to as turmeric and is a member of the ginger family.

Curcumin is one of the medicinally active or therapeutic molecules that has been tested as a possible treatment to help fight multiple cancers because it is an antioxidant that reduces swelling and inflammation. However, there is poor absorption into the bloodstream when curcumin is taken orally. In this study, UCLA researchers found that when APG-157 is taken through oral mucosal absorption, patients have high levels of curcumin circulating in their blood and absorbed by cancer tissues.

UCLA researchers conducted the study of APG-157 comparing 12 people who had oral and oropharyngeal cancer with a control group of 13 people who did not have cancer. The reason both the people with cancer and without cancer were part of the study was to show that the drug was not toxic to either people with cancer or those without cancer.

The medication was given each hour for three hours and was delivered as a lozenge that slowly dissolved in the mouth. Blood and saliva samples were collected beforehand—each of the three hours the medication was administered—and 24 hours after the last dosage. The medication was given to 12 people (some who had cancer and some who did not) and a placebo was given to 13 people. Blood and electrocardiogram tests did not show increased toxicity in the people who took the active medication in comparison with the people who took the placebo, regardless of whether they had cancer or not.

For the cancer patients who took the medication, there was a decrease in Bacteroides and an increase in T cells in the tumor tissue as compared to cancer patients who took the placebo. Neither the subjects nor the investigators knew whether the drug or a placebo was given when reviewing the blood and saliva test results of the blinded study.

APG-157 is a botanical drug that has low toxicity. It works effectively to reduce inflammation that contributes to the growth of cancer cells. It also attracts T cells to the tumor micro-environment. When used in combination with immunotherapy drugs, APG-157 might have the ability to make the immune system more effective in attacking head and neck cancers. With potential to inhibit the growth of Bacteroides species, APG-157 could also improve cancer therapy through oral microbial changes.

https://acsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/cncr.32644

Discovery of compound that reverses the fertility clock

                                

Nicotinamide adenine dinucleotide (NAD)     

 Nicotinamide mononucleotide ("NMN", "NAMN", and "β-NMN") 

The reproductive years of a woman are at their peak before the age of 30. Beyond that, fertility starts to decline, and by the age of 40, fertility potential is about half the level it was before 30 years old. Many women experience fertility issues, but now a new study on mice may help reverse the clock on eggs, offering new fertility hope to older women.

A team of scientists at the University of Queensland reports that they have lifted fertility rates in older female mice with the use of a compound, which can reverse the aging process in eggs. The discovery may pave the way for human use in the future, offering hope for some women who are struggling to conceive.

When women reach the age of 40, conceiving is harder and nearly impossible for some women. This loss of fertility is due to poor egg quality, something that becomes a problem in developed countries where women would wait until they're older before they get married and bear children.

Newfound hope

Published in the journal Cell Reports, the study highlights reversing the fertility clock, improving egg quality that's important for pregnancy success. The team found that losing egg quality due to aging was because of the declining levels of a cell molecule that's vital for producing energy.

Taking an oral dose of a precursor compound, which is utilized to create the molecule, can help boost fertility. The molecule called nicotinamide adenine dinucleotide (NAD) and the precursor, nicotinamide mononucleotide (NMN), are key drivers to promote reversal of aging fertility.

To arrive at their findings, the team treated aging female mice with low doses of NMN infused in their drinking water for one month. They found that the mice had restored egg quality and increased live births during a breeding trial.

Assisted reproductive technologies

The new treatment, if applicable to humans, can help maintain and restore egg cell quality during aging. Further, it helps reduce a rate-limiting barrier to pregnancy for older women. With more aging women facing fertility problems, there had been a sharp increase in the demand for assisted reproductive technologies, including In vitro fertilization (IVF).

However, since the study involved mice models, it's essential to conduct further research on humans to determine if the effect of the compound is the same.

"IVF cannot improve egg quality, so the only alternative for older women at present is to use eggs donated by younger women," UQ's Professor Hayden Homer said in a statement.

"Our findings suggest there is an opportunity to restore egg quality and, in turn, female reproductive function using oral administration of NAD-boosting agents – which would be far less invasive than IVF. It is important to stress, however, that although promising, the potential benefits of these agents remains to be tested in clinical trials," he added.

Infertility by the numbers

Infertility is a growing concern among couples who are having a hard time conceiving. The Centers for Disease Control and Prevention (CDC) defines infertility as the inability to get pregnant after one year of unprotected sex; it may be longer for some. For women who are 35 years old and beyond, doctors may begin treatment if they fail to conceive within six months of regular and unprotected sex.

In the United States, about 6 percent of married women between the age of 15 and 44 are having problems conceiving after one year of trying. Moreover, approximately 12 percent of women of the same age group have issues getting pregnant or carrying a pregnancy to term.

About 12 to 13 of 100 couples have trouble becoming pregnant in the country, while ten in 100 or 6.1 million women have problems getting pregnant. Fertility issues in women cause one-third of all infertility cases.

Worldwide, one in every four couples in developing countries are experiencing infertility, but the exact rates are hard to determine. The latest data were responses from women in Demographic and Health Surveys in 2004. However, in a 2010 study by the WHO, it shows that the rates in 190 countries remained similar to the estimated numbers between 1990 and 2010.

https://www.sciencedirect.com/science/article/pii/S2211124720300838?via%3Dihub

https://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide

https://en.wikipedia.org/wiki/Nicotinamide_mononucleotide

FDA Approves Ukoniq (umbralisib) for Marginal Zone Lymphoma and Follicular Lymphoma

TG Therapeutics, Inc,   announced the U.S. Food and Drug Administration (FDA) approval of  Ukoniq (umbralisib), for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20 based regimen and adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.


Ukoniq is the first and only, oral, once daily, inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. Accelerated approval was granted for these indications based on overall response rate (ORR) data from the Phase 2 UNITY-NHL Trial (NCT02793583). Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. This application was granted priority review for the MZL indication. In addition, Ukoniq was granted Breakthrough Therapy Designation (BTD) for the treatment of MZL and orphan drug designation (ODD) for the treatment of MZL and FL.
Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics stated, “Today’s approval of Ukoniq marks a historic day for our Company with this being our first approval and we are extremely pleased to be able to bring our novel inhibitor of PI3K-delta and CK1-epsilon to patients with relapsed/refractory MZL and FL. We have built a commercial team with significant experience who will immediately start to engage our customers to educate them on Ukoniq and how to access the product for patients in need and expect to make Ukoniq available to US distributors in the next few days.” Mr. Weiss continued, “We want to thank the patients, physicians, nurses and clinical coordinators for their support and participation in our clinical trials, and the FDA for their collaboration throughout this process. We remain dedicated to patients with B-cell diseases and our mission of developing treatment options for those in need.”
“Despite treatment advances, MZL and FL remain incurable diseases with limited treatment options for patients who relapse after prior therapy and no defined standard of care. With the approval of umbralisib we now have a targeted, oral, once-daily option, offering a needed treatment alternative for patients,” stated Dr. Nathan Fowler, Professor of Medicine at The University of Texas MD Anderson Cancer Center and the Study Chair of the UNITY-NHL MZL &FL cohorts.
“The approval of umbralisib for the treatment of relapsed/refractory marginal zone lymphoma and follicular lymphoma offers patients a new treatment option, and new hope in the fight against these diseases,” stated Meghan Gutierrez, Chief Executive Officer of the Lymphoma Research Foundation.
The safety of Ukoniq monotherapy was based on a pooled population from the 221 adults with MZL and FL in three single arm, open label trials and one open label extension trial. Patients received Ukoniq 800 mg orally once daily. Serious adverse reactions occurred in 18% of patients who received Ukoniq. Serious adverse reactions that occurred in ≥2% of patients were diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (>15%), including laboratory abnormalities, were increased creatinine (79%), diarrhea-colitis (58%, 2%), fatigue (41%), nausea (38%), neutropenia (33%), ALT increase (33%), AST increase (32%), musculoskeletal pain (27%), anemia (27%), thrombocytopenia (26%), upper respiratory tract infection (21%), vomiting (21%), abdominal pain (19%), decreased appetite (19%), and rash (18%).

EFFICACY & SAFETY DATA IN RELAPSED/REFRACTORY MZL AND FL

The efficacy of Ukoniq monotherapy was evaluated in two single-arm cohorts, within the Phase 2 UNITY-NHL clinical trial, in 69 patients with MZL who received at least 1 prior therapy, including an anti-CD20 regimen, and in 117 patients with FL who received at least 2 prior systemic therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. The UNITY-NHL Phase 2 trial is an open-label, multi-center, multi-cohort study with patients receiving Ukoniq 800 mg once daily. The primary endpoint was independent review committee (IRC) assessed overall response rate (ORR) according to the Revised International Working Group Criteria.

https://en.wikipedia.org/wiki/Umbralisib

Cabotegravir Injection Can Protect Women From HIV for Two Months

An experimental injection drug works better than daily pills to protect women from getting HIV from an infected sex partner, researchers say.

The drug cabotegravir is given every two months. It was 89 percent more effective at preventing HIV infection than Truvada pills, but both reduced the risk, the Associated Press reported. The study, which took place in Africa, was stopped early due to the promising results. The new findings echo those announced earlier this year from a study that compared the shots against the daily pills in gay men, the AP reported.

"This is a major, major advance," according to Anthony Fauci, M.D., the top infectious disease doctor at the U.S. National Institutes of Health. "I don't think we can overemphasize the importance of this study."

Young women may be two times more likely than men to get HIV in some areas of the world, said one of the study leaders, Sinead Delany-Moretlwe, M.B.B.Ch., Ph.D., of the University of the Witwatersrand in Johannesburg, South Africa, the AP reported.

https://en.wikipedia.org/wiki/Cabotegravir

Cabotegravir Injection Can Protect Women From HIV for Two Months - Drugs.com MedNews

FDA Approves Tepmetko (tepotinib) as the First and Only Once-daily Oral MET Inhibitor for Patients with Metastatic NSCLC with METex14 Skipping Alterations

EMD Serono, the healthcare business sector of Merck KGaA, Darmstadt, Germany in the US and Canada,  announced that the US Food and Drug Administration (FDA) has approved Tepmetko (tepotinib) following Priority Review for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

The approval is based on results from the pivotal Phase II VISION study evaluating Tepmetko as monotherapy in patients with advanced NSCLC with METex14 skipping alterations.

"METex14 skipping occurs in approximately 3% to 4% of NSCLC cases, and patients with this aggressive lung cancer are often elderly and face a poor clinical prognosis," said Paul K. Paik, M.D., VISION primary investigator and Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center. "There is a pressing need for targeted treatments that have the potential to generate durable anti-tumor activity and improve the lives of patients with this challenging disease. Tepmetko offers an important and welcome new therapeutic option for patients with metastatic NSCLC harboring these genetic mutations."

"In recent years, the treatment of lung cancer has seen powerful progress in the understanding of the genetic mutations that lead to tumor growth, resistance and progression," said Andrea Ferris, President and CEO of LUNGevity. "The availability of a new precision medicine for NSCLC with METex14 skipping alterations advances patient access to targeted treatment and underscores the importance of routine comprehensive biomarker testing for patients with this challenging cancer."

Tepmetko is the first and only FDA approved MET inhibitor that offers once-daily oral dosing and is administered as two 225 mg tablets (450 mg). Patients with metastatic NSCLC should be selected for treatment with Tepmetko based on the presence of MET exon 14 skipping alterations.

"This approval of Tepmetko by the FDA is an important milestone on our mission to significantly improve the treatment of cancer where MET plays a driving role," said Danny Bar-Zohar, M.D., Global Head of Development for the Healthcare business of Merck KGaA, Darmstadt, Germany. "Our focus now is to ensure Tepmetko is accessible to patients in the United States and fully integrated into clinical practice given the important advance it represents for indicated patients as an oral once-a-day precision medicine."

EMD Serono, the healthcare business of Merck KGaA, Darmstadt, Germany in the US and Canada, is committed to providing patient access and reimbursement support for eligible Tepmetko patients through its Oncology Navigation Center™ (ONC) program in the US. ONC provides a spectrum of patient access and reimbursement support services intended to help US patients receive appropriate treatment access. ONC may be reached at 1-844-662-3631 (844-ONC-EMD1) between 8am-8pm Eastern Time, Monday through Friday, or by visiting OncNavigationCenter.com.

Tepmetko was the first oral MET inhibitor to receive a regulatory approval anywhere in the world for the treatment of advanced NSCLC harboring MET gene alterations, with its approval in Japan in March 2020. The FDA completed its review of Tepmetko under its Real-Time Oncology Review pilot program after previously granting the medicine Breakthrough Therapy Designation. The FDA also recently granted Tepmetko Orphan Drug Designation (ODD).

A Marketing Authorization Application for tepotinib for a similar indication was validated by the European Medicines Agency in November 2020. Applications have also been submitted in Australia, Switzerland, and Canada under the FDA's Project Orbis initiative, which provides a framework for concurrent submission and review of oncology medicines among international partners.1

VISION Study Pivotal Trial Results

VISION (NCT02864992) is an ongoing pivotal Phase II, multicenter, multi-cohort, single-arm, non-randomized, open-label study investigating tepotinib as monotherapy in 152 patients with a median age of 73 years with advanced or metastatic non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations. Eligible patients were required to have advanced or metastatic NSCLC harboring METex14 skipping alterations, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. Patients received Tepmetko 450 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure is overall response rate (ORR) according to RECIST version 1.1 as assessed by a blinded independent review committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC. Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the study. Data from the primary analysis of the VISION study were previously published online in The New England Journal of Medicine.2 

In the study, Tepmetko demonstrated an overall response rate of 43% (95% CI, 32–56) in treatment-naïve patients (n=69) and 43% (95% CI, 33-55) in previously treated patients (n=83). Median duration of response (DOR) was 10.8 months (95% CI, 6.9-NE) and 11.1 months (95% CI, 9.5-18.5) among treatment-naïve and previously treated patients, respectively. Duration of response of six months or more occurred among 67% of treatment-naïve patients and 75% of previously treated patients, and duration of response of nine months or more occurred among 30% of treatment-naïve patients and 50% of previously treated patients.3

The safety population included 255 patients with NSCLC positive for METex14 skipping alterations, who received Tepmetko in the VISION study. Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload. Serious adverse reactions occurred in 45% of patients who received Tepmetko. Serious adverse reactions occurring in >2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). The most common adverse reactions (≥20%) in patients who received Tepmetko were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.

https://en.wikipedia.org/wiki/Tepotinib

FDA Approves Cosela (trilaciclib) to Decrease the Incidence of Chemotherapy-Induced Myelosuppression

G1 Therapeutics, Inc. (Nasdaq: GTHX), a commercial-stage oncology company, announced   the U.S. Food and Drug Administration (FDA)   approval of  Cosela (trilaciclib) for injection to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). It is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy. Cosela is expected to be commercially available through G1’s specialty distributor partner network in early March.

“The approval of trilaciclib (Cosela) is an important advance in the treatment of patients with extensive-stage small cell lung cancer receiving chemotherapy,” said Dr. Jeffrey Crawford, Geller Professor for Research in Cancer in the Department of Medicine and Duke Cancer Institute. “The most serious and life-threatening side effect of chemotherapy is myelosuppression, or damage to the bone marrow, resulting in reduced white blood cells, red blood cells and platelets. Chemotherapy-induced myelosuppression may lead to increased risks of infection, severe anemia, and/or bleeding. These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays. To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy. In clinical trials, the addition of trilaciclib to extensive-stage small cell lung cancer chemotherapy treatment regimens reduced myelosuppression and improved clinical outcomes. The good news is that these benefits of trilaciclib will now be available for our patients in clinical practice.”

Chemotherapy is an effective and important weapon against cancer. However, chemotherapy does not differentiate between healthy cells and cancer cells. It kills both, including important hematopoietic stem and progenitor cells (HSPCs) in the bone marrow that produce white blood cells (immune cells that help fight infection), red blood cells (cells that carry oxygen from the lungs to the tissues), and platelets (cells that prevent bleeding from cancer, surgeries, chronic diseases, and injuries). This chemotherapy-induced bone marrow damage, known as myelosuppression, can lead to increased risk of infection, anemia, thrombocytopenia, and other complications. Myeloprotection is a novel approach of protecting HSPCs in the bone marrow from chemotherapy-induced damage. This approach can help reduce some chemotherapy-related toxicity, making chemotherapy safer and more tolerable, while also reducing the need for reactive rescue interventions.

“Chemotherapy is the most effective and widely used approach to treating people diagnosed with extensive-stage small cell lung cancer; however, standard of care chemotherapy regimens are highly myelosuppressive and can lead to costly hospitalizations and rescue interventions,” said Jack Bailey, Chief Executive Officer at G1 Therapeutics. “Cosela will help change the chemotherapy experience for people who are battling ES-SCLC. G1 is proud to deliver Cosela to patients and their families as the first and only therapy to help protect against chemotherapy-induced myelosuppression.”

Cosela is administered intravenously as a 30-minute infusion within four hours prior to the start of chemotherapy and is the first FDA-approved therapy that helps provide proactive, multilineage protection from chemotherapy-induced myelosuppression. The approval of Cosela is based on data from three randomized, placebo-controlled trials that showed patients receiving Cosela prior to the start of chemotherapy had clinically meaningful and statistically significant reduction in the duration and severity of neutropenia. Data also showed a positive impact on red blood cell transfusions and other myeloprotective measures. The trials evaluated Cosela in combination with carboplatin/etoposide (+/- the immunotherapy atezolizumab) and topotecan chemotherapy regimens. Approximately 90% of all patients with ES-SCLC will receive at least one of these regimens during the course of their treatment.

The majority of adverse reactions reported with Cosela were mild to moderate in severity. The most common adverse reactions (≥10%) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia. Serious adverse reactions occurred in 30% of patients receiving Cosela. Serious adverse reactions reported in >3% of patients who received Cosela included respiratory failure, hemorrhage, and thrombosis. Grade 3/4 hematological adverse reactions occurring in patients treated with Cosela and placebo included neutropenia (32% and 69%), febrile neutropenia (3% and 9%), anemia (16% and 34%), thrombocytopenia (18% and 33%), and leukopenia (4% and 17%), respectively.

“Quite often, people diagnosed with extensive-stage small cell lung cancer rely on chemotherapy to not only extend their lives, but also to acutely alleviate their symptoms,” said Bonnie J. Addario, lung cancer survivor, co-founder and board chair of the Go2 Foundation for Lung Cancer. “Unfortunately, the vast majority will experience chemotherapy-induced side effects, resulting in dose delays and reductions, and increased utilization of healthcare services. G1 shares our organization’s goal to improve the quality of life of those diagnosed with lung cancer and to transform survivorship among people living with this insidious disease. We are thrilled to see new advancements that can help improve the lives of those living with small cell lung cancer.”

Approximately 30,000 small cell lung cancer patients are treated in the United States annually. G1 is committed to helping patients with extensive-stage small cell lung cancer in the U.S. gain access to treatment with Cosela. For more information on access and affordability programs, patients and providers should call the G1toOne support center at 833-G1toONE (833-418-6663) from 8:00 a.m. to 8:00 p.m. Eastern time.

G1 received Breakthrough Therapy Designation from the FDA in 2019 based on positive data in small cell lung cancer patients from three randomized Phase 2 clinical trials. As is common with breakthrough-designated products that receive priority review, G1 will conduct certain post-marketing activities, including in vitro drug-drug interaction and metabolism studies, and a clinical trial to assess impact of trilaciclib on disease progression or survival in patients with ES-SCLC with chemotherapy-induced myelosuppression treated with a platinum/etoposide-containing or topotecan-containing regimen with at least a two year follow up. G1 intends to initiate the post-approval clinical trial in 2022.

Cosela (trilaciclib) Co-Promotion Agreement with Boehringer Ingelheim

In June 2020, G1 announced a three-year co-promotion agreement with Boehringer Ingelheim for Cosela in small cell lung cancer in the U.S. and Puerto Rico. G1 will lead marketing, market access and medical engagement initiatives for Cosela. The Boehringer Ingelheim oncology commercial team, well-established in lung cancer, will lead sales force engagement initiatives. G1 will book revenue and retain development and commercialization rights to Cosela and pay Boehringer Ingelheim a promotional fee based on net sales. The three-year agreement does not extend to additional indications that G1 is evaluating for trilaciclib. Press release details of the G1/ Boehringer Ingelheim agreement can be found here.

Ref : https://en.wikipedia.org/wiki/Trilaciclib

FDA Approves Amondys 45 (casimersen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 45

In continuation of my update on antisense oligonucleotides 

Sarepta Therapeutics, Inc. the leader in precision genetic medicine for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved Amondys 45 (casimersen). Amondys 45 is an antisense oligonucleotide from Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 45 skipping. This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Amondys 45, which is reasonably likely to predict clinical benefit for those patients who are exon 45 amenable. Consistent with the accelerated approval pathway, the continued approval of Amondys 45 may be contingent on confirmation of a clinical benefit in confirmatory trials.

The ESSENCE trial – a placebo-controlled confirmatory trial to support the Amondys 45 approval – is ongoing and expected to conclude in 2024.

Although kidney toxicity was not observed in the clinical studies with Amondys 45, kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking Amondys 45. In the clinical trial, the most common adverse reactions observed in at least 20% of patients treated with Amondys 45 and at least 5% more frequently than in placebo were (Amondys 45, placebo): upper respiratory tract infections (65%, 55%), cough (33%, 26%), fever (33%, 23%), headache (32%, 19%), joint pain (21%, 10%), and pain in mouth and throat (21%, 7%).

“This is an important day for Sarepta and, far more importantly, for the patients that we serve. After years of scientific commitment, investment and development, the approval of Amondys 45, Sarepta’s third approved RNA therapy, offers treatment to the 8% of the DMD community who have a confirmed exon 45 amenable mutation,” said Doug Ingram, president and chief executive officer, Sarepta. “Along with our other approved RNA therapies, we can now offer treatment options for nearly 30% of Duchenne patients in the U.S. And our commitment to bring therapies to the greatest percentage of the DMD community as soon as possible continues.”

“Decades of research and commitment have fueled and now accelerate our progress towards new treatments for Duchenne,” said Marissa Penrod, founder of Team Joseph and parent of an 18-year old with Duchenne. “The extraordinary diligence and persistence of the Duchenne community – patients and families, clinicians and researchers – have led us to today’s approval, where we now have exon-skipping treatments for almost a third of those with Duchenne.”