Drug could be promising new option against eczema

In continuation of my update on Upadacitinib

 

 

A pill called upadacitinib, already approved for treating rheumatoid arthritis, might also ease another common immunological condition—eczema.

In two phase 3 clinical trials, patients with moderate to severe eczema showed rapid and significant improvements after taking the drug, said researchers at Mount Sinai in New York City.

The clinical trials were funded by the dug's maker, AbbVie Inc., and included nearly 1,700 patients with the inflammatory skin condition.

"The results of these trials ... were so incredible that by week 16, most patients with moderate to severe atopic dermatitis [eczema] either had a 90% disease clearance, or even 100% disease clearance," study first author Dr. Emma Guttman-Yassky said in a Mount Sinai news release. She's professor and chair of the department of dermatology at Mount Sinai's Icahn School of Medicine, in New York City.

"We achieved extremely high clearance rates that are bringing us closer to the amazing clearance rates that we see in psoriasis," Guttman-Yassky noted.

According to the National Eczema Association, "people with eczema tend to have an over-reactive immune system that when triggered by a substance outside or inside the body, responds by producing inflammation. It is this inflammation that causes the red, itchy and painful skin symptoms common to most types of eczema."

Eczema affects more that 31 million American adults and between 10 to 20% of children, the study authors noted.

The two new clinical trials involved a total of almost 1,700 patients and took place between 2018 and 2020.

Besides the rapid disease clearance noted in patients, "the itch improvements already started to be significant within days from the beginning of the trials, and the maximum clinical efficacy was obtained early, at week 4, and maintained to week 16," Guttman-Yassky said.

The drug was well tolerated by patients who received the two highest doses of the drug—15 milligrams and 30 milligrams—and no significant safety risks were seen, she added.

Upadacitinib is already approved and marketed for use against rheumatoid arthritis under the brand name Rinvoq. It works by blocking what are known as multiple cytokine-signaling pathways—parts of the immune system that can malfunction and cause eczema.

According to Guttman-Yassky, other eczema therapies exist, but most come with certain drawbacks.

While injectable biologic drugs are highly successful in treating eczema patients who don't respond to or can't use topical creams, their use cannot be stopped and restarted at will, because the potential creation of anti-drug antibodies will shorten the half-life of the drugs, she explained.

However, "patients were able to start and restart [upadacitinib] at any time, allowing for flexibility, which cannot be achieved with biologics," Guttman-Yassky, said. "And, biologics, which are injectable agents that target specific lymphocytes that are 'misbehaving' or are up-regulated in atopic dermatitis, do not suppress the entire immune system as other immunosuppressants tend to do."

Dr. Michele Green is a dermatologist at Lenox Hill Hospital in New York City who wasn't involved in the new study.

She called the findings "important."

Upadacitinib is the first drug in its class "to be effectively used for patients with significant improvement of pruritus [itch] within several days of treatment and clearance of their disease within several weeks," Green noted.

"It is also significant since adolescents were included in this study and I believe an oral treatment is much more appealing to treating adolescents than current injectable biologics," she added.

 

 https://pubchem.ncbi.nlm.nih.gov/compound/Upadacitinib#section=2D-Structure

 

Drug commonly used as antidepressant helps fight cancer in mice

A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain's "happiness hormone."

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the immune system attack cancer. Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

"MAOIs had not been linked to the immune system's response to cancer before," said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "What's especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn't as challenging as developing a completely new drug would be."

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies—drugs that boost the immune system's activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA's corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

"For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two," said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. "So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells."

Next, the researchers studied mice that didn't produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells—the immune cells that target cancer cells for destruction—produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system.

In the Science Immunology paper, the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer.

But the drugs also have a second role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

"It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells," Yang said.

Combining MAOIs with existing immunotherapies

Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That's because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules.

Studies in mice showed that any of three existing MAOIs—phenelzine, clorgyline or mocolobemide—either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven't tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers.

Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells' response to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.

"We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits," she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

Drug commonly used as antidepressant helps fight cancer in mice

Cancer drug shows potential against pseudo SARS-CoV-2 in lab tests

In continuation of my update on Lenalidomide

Despite the effectiveness of COVID-19 vaccines, treatments are still needed to combat this disease, which has killed millions of people and still kills thousands each day across the world. Scientists at the UNC School of Medicine conducted lab experiments showing how the cancer drug lenalidomide disrupts a cellular pathway in human cells so that pseudo-viruses derived from SARS-CoV-2—the virus that causes COVID-19—cannot enter cells to cause infection.

The research, published in a letter to the journal Signal Transduction and Targeted Therapy, shows the potential of an existing FDA-approved drug to help doctors treat the sickest COVID-19 patients.

The labs of Pengda Liu, Ph.D., and Guochun Jiang, Ph.D., both assistant professors in the UNC Department of Biochemistry and Biophysics, conducted this work. Liu is a member of the UNC Lineberger Comprehensive Cancer Center, and Jiang is a member of the UNC HIV Cure Center.

SARS-CoV-2, a novel coronavirus and the causative agent of COVID-19, has caused a global social and economic disruption, and there are still thousands of cases and death each day in the United States and around the world. Treatments to prevent severe illness and death are still needed.

In this research letter, the UNC team reported that a protein called E3 ligase SPOP recognizes and protects the human cell surface receptor ACE2, which is the protein SARS-CoV-2 latches onto in order to gain entry into cells to cause infection. Another protein called CK1 kinase triggers this recognition and protection of ACE2.

The researchers used the cancer drug lenalidomide to inhibit CK1 kinase activity in cell cultures and showed a substantial reduction in ACE2 protein levels in kidney cancer cells. Researchers used SARS-CoV-2 S protein conditioned pseudoviruses in vitro and found lenalidomide treatment reduced the effect of this infection on kidney-derived cells.

"We hope that our identification and tests for the efficacy of inactivating the SPOP/CKI signaling in reducing ACE2 protein expression to attenuate SARS-CoV-2 infection provides a timely investigation into new therapeutic directions to combat COVID-19," Liu said.

A next step could be to use animal models to see if the drug blocks real SARS-CoV-2.

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

Cancer drug shows potential against pseudo SARS-CoV-2 in lab tests

Melatonin shown to protect kidney damage caused by obesity with diabetes

In continuation of my update on Melatonin

Scientists from the University of Granada (UGR), the Hospital Universitario La Paz (Madrid), and the University of Texas (U.S.) have taken an important step in the fight against kidney damage and its progression toward kidney failure, which is closely related to diabesity (obesity with type 2 diabetes) and its complications.

Specifically, in two new studies recently published in the Journal of Clinical Medicine and Pharmaceuticals, researchers have developed an obese and diabetic rodent model and have shown that melatonin protects from kidney damage caused by diabesity.

The scientists have shown that chronic administration of melatonin at doses (10 mg/kg body weight/day) prevents mitochondrial and endoplasmic reticulum disruption, which play a critical role in the development and pathogenesis of kidney cell (nephron) damage, and its progression to renal failure.

Thus, it has been shown that melatonin prevents the impairment of the function and dynamics of cellular mitochondria, decreasing the increased production of oxygen free radicals (responsible for oxidative stress). It also prevents pathological alteration in the function of the endoplasmic reticulum (another cell cytoplasmic organelle), which, in conditions of abnormally high oxidative stress, is related to an increase in programmed cell death (of the nephron) leading to the loss of renal functionality, as a preliminary step to the development of renal failure and the need for hemodialysis or transplantation.

The studies coordinated by the UGR show the efficacy of melatonin in halting the progression of renal damage mediated by mitochondrial damage and excess endoplasmic reticulum stress.

As the lead author of this study, Ahmad Agil, a researcher at the Department of Pharmacology of the UGR, says, "Kidney damage is caused by metabolic complications of obesity, such as diabetes, hypertension, blood lipid disorders or fatty liver disease. Given that the prevalence of these pathologies (collectively recognized as metabolic syndrome) continues to increase, kidney damage and its progression over time to kidney failure has become a health problem that affects millions of people worldwide, with a great socioeconomic cost, requiring hemodialysis facilities and/or kidney transplant services, with the corresponding compatibility studies required."

The importance of the work lies not only in the efficacy of melatonin in counteracting the two proposed mechanisms of renal damage (based on the alteration of mitochondrial function and dynamics and the function of the endoplasmic reticulum (ER)), but they also propose an alternative preventive treatment that would improve this renal function with a well-studied drug with a very high safety profile such as melatonin, which is a drug that in the EU must be prescribed by a doctor and is already administered in the treatment of insomnia.

The new findings have also been associated with an improvement in glomerular filtration rate and renal damage of the nephron, manifested in a decrease in creatinine clearance levels (the best marker of renal function), proteinuria, and in the improvement of renal structure, observed after histopathological study of the kidney.

These results are in line with those previously published by these researchers in the last 10 years, demonstrating that the pharmacological administration of melatonin constitutes another new strategy in the therapeutic approach to diabesity (central obesity and its type 2 diabetes) and its complications (such as hepatic steatosis, hypertension, lipid alteration, etc.).

"Our main challenge is the application of melatonin and other strategies such as intermittent fasting in the field of medicine, especially to address the possibility of a treatment perspective for the aforementioned pathologies (diabesity and its complications) that involve an increase in oxidative stress, and mitochondrial damage and associated meta-inflammation (inflammation of metabolic origin)," Agil says.

According to the results, melatonin could help treat kidney damage, which establishes the need to develop new clinical trials to test its effectiveness in humans. The next step is to investigate how it helps in the maintenance of mitochondrial and endoplasmic reticulum homeostasis, and to a greater extent, if melatonin therapy would allow delaying or stopping progressive renal damage by promoting its chronic pharmacological use in kidney repair and regeneration.

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

Melatonin shown to protect kidney damage caused by obesity with diabetes

FDA Approves Roszet (rosuvastatin and ezetimibe) to Reduce LDL-C in Hyperlipidemia and Homozygous Familial Hypercholesterolemia

Althera Pharmaceuticals, a company focused on heart health, announced the FDA approval of Roszet (rosuvastatin and ezetimibe) tablets, as an adjunct to diet, for treatment of elevated low-density lipoprotein cholesterol (LDL-C) in adult patients with primary non-familial hyperlipidemia and in adult patients with homozygous familial hypercholesterolemia. Roszet contains rosuvastatin, a powerful statin for LDL-C reduction, and ezetimibe, an efficacious cholesterol absorption inhibitor. The two components work through distinct but complimentary mechanisms to give Roszet the power to significantly lower LDL-C.

  

“The optimal LDL-C levels in guidelines across the world have been shifting lower and now many patients need to get their LDL-C below 70 mg/dL,” said Dr. Christie Ballantyne, Chief of Cardiology and Cardiovascular Research at Baylor College of Medicine. “These levels can be quite difficult to achieve with just a statin on top of diet and exercise. Rosuvastatin and ezetimibe have been extensively studied in combination therapy and have been shown to significantly reduce LDL cholesterol beyond the statin alone. Combination therapy has been widely used in hypertension to achieve lower blood pressure targets. This new therapy provides a high efficacy statin plus ezetimibe in a single once daily pill which is a powerful new option to help get patients to the desirable LDL goal without increasing pill burden or requiring addition of injectable therapies”

"With Roszet’s approval in the U.S., we reaffirm our commitment to improving cholesterol treatment options for physicians and patients," said Sanjeev Agarwal, CEO of Althera Pharmaceuticals. "We are on a mission to positively impact patients’ health. By making this highly effective medicine available and affordable, we hope to improve the long-term health of patients, including those with prior cardiovascular disease.”

While a patient's out-of-pocket costs will vary depending on insurance status, the Roszet Savings Program aims to reduce co-pays to as little as $20 per month for eligible patients with commercial insurance coverage. Althera is continuing to work with all stakeholders to ensure that Roszet is affordable and accessible to all. Please visit http://www.roszet.com for more information and updates about the Roszet Savings Program and eligibility.

Availability

Roszet will be available in pharmacies in June 2021.

Roszet Indications, Dosage and Other Select Information

Roszet is indicated, as an adjunct to diet, in adults with primary non-familial hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C), and alone or as an adjunct to other LDL-C lowering therapies in adults with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C.

Roszet is available as a once-daily tablet with rosuvastatin/ezetimibe dosages of 5 mg/10 mg, 10 mg/10 mg, 20 mg/10 mg and 40 mg/10 mg.

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

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

FDA Approves Qelbree (viloxazine) for the Treatment of ADHD

Supernus Pharmaceuticals, Inc., a biopharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases,  announced that the U.S. Food and Drug Administration (FDA) has approved Qelbree (viloxazine extended-release capsules) for the treatment of attention-deficit hyperactivity disorder (ADHD) in pediatric patients 6 to 17 years of age.

“Based on the efficacy demonstrated in the clinical program, we believe Qelbree offers a unique new alternative for the treatment of ADHD,” said Jack A. Khattar, President and Chief Executive Officer of Supernus Pharmaceuticals. “Qelbree provides prescribing physicians and patients living with ADHD a therapy that is not a controlled substance with proven efficacy and a tolerable safety profile. We are grateful to the patients, families and their care givers who participated in and supported our research.”

“ADHD is one of the most common mental health issues in the U.S.,” said Andrew J. Cutler, M.D., Clinical Associate Professor of Psychiatry at SUNY Upstate Medical University, and Chief Medical Officer, Neuroscience Education Institute. “The right treatment is key for children and adolescents, as they grow and navigate school and social relationships. This approval offers a novel once a day sprinkleable non-stimulant that can be a great option for children and adolescents with ADHD.”

The approval of Qelbree is supported by data from an extensive development program consisting of four Phase III clinical trials that studied more than 1000 pediatric patients from the age of 6 to 17 years. In December 2020, the Company announced positive results from a Phase III trial in adult patients with ADHD and plans to submit a supplemental New Drug Application to the FDA for Qelbree in adults in the second half of 2021.

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

Eating Mushrooms Lowers Cancer Risk

In continuation of my update on the benefits of mushrooms

 

Edible mushrooms are good for health. Now, a new study revealed that consuming mushrooms on a daily basis can lower your risk of developing cancer.

Next time you make a salad, you might want to consider adding mushrooms to it. The new Penn State study was published in Advances in Nutrition.

The systematic review and meta-analysis examined 17 cancer studies published from 1966 to 2020. Analyzing data from more than 19,500 cancer patients, researchers explored the relationship between mushroom consumption and cancer risk.

Benefits of Mushrooms

Mushrooms are rich in vitamins, nutrients and antioxidants.

The team's findings show that these super foods may also help guard against cancer.

Even though shiitake, oyster, maitake and king oyster mushrooms have higher amounts of the amino acid ergothioneine than white button, cremini and portabello mushrooms, the researchers found that people who incorporated any variety of mushrooms into their daily diets had a lower risk of cancer.

According to the findings, individuals who ate 18 grams of mushrooms daily had a 45% lower risk of cancer compared to those who did not eat mushrooms.

"Mushrooms are the highest dietary source of ergothioneine, which is a unique and potent antioxidant and cellular protector," said Djibril M. Ba, a graduate student in epidemiology at Penn State College of Medicine. 

Fight Cancer with Mushrooms

When specific cancers were examined, the researchers noted the strongest associations for breast cancer as individuals who regularly ate mushrooms had a significantly lower risk of breast cancer.

Ba explained that this could be because most of the studies did not include other forms of cancer. Moving forward, this research could be helpful in further exploring the protective effects that mushrooms have and helping to establish healthier diets that prevent cancer.

"Overall, these findings provide important evidence for the protective effects of mushrooms against cancer," said coauthor John Richie, a Penn State Cancer Institute researcher and professor of public health sciences and pharmacology.

"Future studies are needed to better pinpoint the mechanisms involved and specific cancers that may be impacted."

Eating Mushrooms Lowers Cancer Risk

FDA Approves Nextstellis (drospirenone and estetrol) Oral Contraceptive for Birth Control

In continuation of my update on drospirenone

"When speaking with patients about their contraceptive options, one of the most common concerns is side effects," said Mitchell Creinin, Professor and Director of Family Planning at the University of California, Davis. "Nextstellis is an innovative contraceptive that has been shown to be not only safe and effective, but also well tolerated in clinical trials with a desirable bleeding profile and minimal impact on triglycerides, cholesterol, and glucose, as well as weight and endocrine markers."

Nearly 10 million American women use short-acting combination contraceptives (estrogen and progestin). Of these contraceptives, more than 99% contain ethinyl estradiol (EE), a synthetic estrogen that binds widely to all estrogen receptors in the body.
Nextstellis is the only oral contraceptive to contain E4; E4 acts differently than other estrogens and is the first estrogen to be described as a NEST:  A Native Estrogen with Selective actions in Tissues. It has more selective activity in tissues, focusing on those needed to support contraceptive efficacy, cycle control and other beneficial effects of estrogen. Nextstellis pairs E4, which has a long half-life (24-28 hours), with the proven progestin drospirenone, specifically chosen due to its long half-life (~30 hours) and its anti-androgenic and anti-mineralocorticoid properties.

"The approval of Nextstellis represents an important milestone in providing women with another choice for their reproductive health," said Scott Richards, CEO of Mayne Pharma. "We are delighted to be introducing a new estrogen and bringing to market this novel, safe and effective option for women to consider with their healthcare providers."

The comprehensive Nextstellis clinical study program included a diverse patient population with women both starting and switching birth control as well as patients with a body mass index (BMI) of up to 35 kg/m2. According to phase 3 study findings, Nextstellis demonstrated contraceptive efficacy across all subgroups by age, BMI and prior hormonal contraception use. Nextstellis was also associated with a favorable bleeding profile and low rates of breakthrough bleeding, including in cycle 1.

Nextstellis was developed by Mayne Pharma's development and manufacturing partner, Mithra Pharmaceuticals, SA. The company anticipates the commercial launch of Nextstellis by the end of June 2021.

Mayne Pharma announced today that the U.S. Food and Drug Administration (FDA) has approved Nextstellis (3 mg drospirenone [DRSP] and 14.2 mg estetrol [E4] tablets) for the prevention of pregnancy. Nextstellis is the first and only contraceptive pill containing E4, a naturally occurring estrogen, now produced from a plant source, with a unique mechanism of action that offers potential advantages over other estrogens.

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

FDA Approves Fotivda (tivozanib) for the Treatment of Adult Patients with Relapsed or Refractory Advanced Renal Cell Carcinoma

In continuation of my update on Tivozanib

AVEO Oncology (Nasdaq: AVEO)   announced  the U.S. Food and Drug Administration (FDA)   approval of  Fotivda (tivozanib) for the treatment of adults with relapsed or refractory advanced renal cell carcinoma (RCC) who have received two or more prior systemic therapies. Fotivda is an oral, next-generation vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI).

“Today’s approval of Fotivda provides a new tool for treating patients with kidney cancer who have relapsed or become refractory to two or more prior systemic therapies,” said Brian Rini, MD, Chief of Clinical Trials at Vanderbilt Ingram Cancer Center and principal investigator of the TIVO-3 trial. “With advances in RCC treatment, patients are living longer, increasing the need for proven, well tolerated treatment options in the relapsed or refractory setting. The TIVO-3 study is the first positive Phase 3 study in RCC patients who received two or more prior systemic therapies, and also the first Phase 3 RCC study to include a predefined population of patients who have received prior immunotherapy, the current standard of care in earlier-line treatment. With this approval, I believe Fotivda represents an attractive intervention, and expect it to play a meaningful role in the evolving RCC treatment landscape.”

“We believe in Fotivda’s potential to provide a differentiated treatment option for the growing number of individuals in the U.S. with relapsed or refractory RCC, and today marks the culmination of many years of hard work and determination of many individuals to bring this therapy to patients,” said Michael Bailey, president and chief executive officer of AVEO. “With today’s approval, AVEO begins its journey as a commercial-stage company, a noteworthy accomplishment in our industry. On behalf of the entire AVEO team, I would like to thank all the patients, their families, and caregivers whose tireless efforts made this day possible.”

“Relapsed or refractory RCC is a devastating disease for which patient outcomes can be limited due to the tradeoff between tolerability and efficacy,” said Dena Battle, president of KCCure. “The FDA approval of Fotivda represents an exciting, meaningful advancement by providing a new treatment option for this patient population.”

AVEO plans to make Fotivda available to patients in the U.S. by March 31, 2021.

The approval of Fotivda is based on AVEO’s pivotal Phase 3 study, TIVO-3, comparing Fotivda to sorafenib in relapsed or refractory advanced RCC following two or more prior systemic therapies. The application is also supported by three additional trials in RCC and includes safety data from over 1,000 clinical trial subjects.

Patients (n=350) enrolled in the TIVO-3 study were randomized 1:1 to receive either Fotivda or sorafenib. The main efficacy outcome measure was progression-free survival (PFS), assessed by a blinded independent radiology review committee. Other efficacy endpoints were overall survival (OS) and objective response rate (ORR).

Median PFS was 5.6 months (95% CI: 4.8, 7.3) in the Fotivda arm (n=175) compared with 3.9 months (95% CI: 3.7, 5.6) for those treated with sorafenib (HR 0.73; 95% CI: 0.56, 0.95; p=0.016). Median OS was 16.4 (95% CI: 13.4, 21.9) and 19.2 months (95% CI: 14.9, 24.2), for the Fotivda and sorafenib arms, respectively (HR 0.97; 95% CI: 0.75, 1.24). The ORR was 18% (95% CI: 12%, 24%) for the Fotivda arm and 8% (95% CI: 4%, 13%) for the sorafenib arm.

The most common (≥20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis. The most common grade 3 or 4 laboratory abnormalities (≥5%) were decreased sodium, increased lipase, and decreased phosphate.

The recommended tivozanib dose is 1.34 mg once daily with or without food for 21 days every 28 days on treatment followed by 7 days off treatment (28 day cycle) until disease progression or unacceptable toxicity.

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

FDA Approves Kimyrsa (oritavancin) for the Treatment of Adult Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

Melinta Therapeutics, LLC (Melinta), a commercial-stage company focused on the development and commercialization of novel antibiotics, today announced that the U.S. Food and Drug Administration (FDA) has approved Kimyrsa (oritavancin)  for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of designated Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). Kimyrsa is a lipoglycopeptide antibiotic that delivers a complete course of therapy for ABSSSI in a single, one hour 1,200 mg infusion.

“The approval of Kimyrsa demonstrates Melinta’s commitment to provide innovative therapies to patients with acute and life-threatening illnesses,” said Christine Ann Miller, President and Chief Executive Officer of Melinta. “We have responded to the requests of the medical community to provide an oritavancin product with a shorter infusion time.  We believe that with the approval of Kimyrsa and product availability this summer, physicians and patients will now have a compelling new one-dose alternative to the current standard of multi-dose regimens for ABSSSI.”

ABSSSI affect approximately 14 million patients in the U.S. each year, are responsible for over 3 million visits to the Emergency Room annually and represent the 8th most common cause of Emergency Department hospital admissions1,2. ABSSSI cost U.S. hospitals $4 billion each year, with a 4.1-day average length of stay for hospitalized ABSSSI patients.2

“Kimyrsa is an important new treatment option that will provide clinicians with additional flexibility to treat ABSSSI patients in multiple care settings, without the need for hospitalization,” said Andrew Dold, D.O., member of a private infectious disease practice covering the Greater Atlanta Region. “Single-dose, long-acting antibiotics, such as Kimyrsa, may be especially beneficial for patients who lack the support or resources to adhere to multiple intravenous administrations.”

The efficacy and safety of Kimyrsa were established in the SOLO clinical trials with another oritavancin product, Orbactiv. The SOLO trials were randomized, double-blind, multicenter studies that evaluated a single 1,200 mg IV dose of oritavancin against twice-daily vancomycin for the treatment of ABSSSI in 1,987 adult patients and assessed one of the largest subsets of documented MRSA infection (405 patients). These trials demonstrated that 1,200 mg one-dose IV oritavancin infusion was as effective as 7-to-10 days of twice-daily vancomycin (1 g or 15 mg/kg) for the primary and secondary endpoints.  Kimyrsa approval is based on the results of an open-label, multi-center, pharmacokinetics study, which compared Kimyrsa administered over 1 hour (N=50) to Orbactiv administered over 3 hours (N=52) for the treatment of adult patients with ABSSSI.

Michael Waters, M.D. and lead investigator in the PK clinical trial stated, “Kimyrsa was shown to be comparable to Orbactiv with a favorable safety profile.  I’m pleased that these outcomes support the approval of Kimyrsa to provide oritavancin with a shorter infusion time and lower infusion volume.  With these features, Kimyrsa can further enhance the treatment experience for the patient and efficiency of administration in clinical practice.”

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

Acid reflux drug may be a promising therapy to reduce preterm birth

In continuation of my update on Lansoprazole

Lansoprazole, an over-the-counter acid reflux drug that is often taken by pregnant women, may be a promising therapy to reduce preterm birth, according to a computational drug repurposing study that also tested several of the drugs in mice.

The study also identified 12 other FDA-approved drugs that are deemed safe in pregnancy. While the drugs encompass a variety of modalities, the scientists said they all appear to act on biological pathways that affect the immune response, which is implicated in preterm birth.

"Inflammation clearly plays a role in initiating labor and preterm birth," said Marina Sirota, PhD, assistant professor of pediatrics, a member of the Bakar Computational Health Sciences Institute at UCSF, and the senior author of the study, published Feb. 13, 2020, in JCI Insight. "Immune pathways are very significantly dysregulated in women who end up delivering preterm, and they're also dysregulated in babies who are born early. However, we have seen from our previous work that there is an interaction between the maternal and fetal immune systems and a breakdown in maternal-fetal tolerance."

To identify candidate drugs that might be effective in preventing preterm birth, the scientists first looked at which genes were up- or down-regulated in the blood cells of women who experienced spontaneous preterm birth to identify a gene expression "signature." Then they looked for the opposite signature in cells that had been exposed to 1,309 different drugs, reasoning that if a drug could correct the effects that preterm birth had on the women's blood cells, the drugs might also prevent preterm birth itself.

The scientists identified 83 drug candidates, but when they excluded those found to have pregnancy risks in animal or human studies, they wound up with 13 drugs, ranked according to their "reversal score," a measure of the extent to which they were able to reverse the gene expression signature of preterm birth.

The other drugs identified by the computational screen included progesterone, which is already used to treat recurrent spontaneous preterm birth, folic acid, which is given to women during pregnancy to prevent birth defects, three antibiotics, an antifungal, an antidepressant, an anti-diabetic, and a blood pressure medication.

The fact that predictable drugs like progesterone came up in the screen gave the scientists confidence that the drugs they identified may turn out to be effective once they are tested in pregnant women. Three of the other drugs that came up in the screen--folic acid, clotrimazole and metformin--have also been shown in previous studies to be effective against preterm birth.

Finding progesterone on the list was a promising validating step. Four of the drugs on our list have seen effectiveness in past studies that were either experimental or retrospective. This leads us to believe in the biology behind the identification of these drugs."

Brian Le, PhD, postdoctoral scholar in the UCSF Department of Pediatrics and the Bakar Computational Health Sciences Institute, and the first author of the study

The scientists chose lansoprazole for further testing because, in addition to its high reversal score, it is available over the counter, and they know from their previous work that it affects a stress-response protein, heme oxygenase-1, that has been linked with pregnancy disorders. Lansoprazole, which is a proton-pump inhibitor marketed as Prevacid, had the second-highest reversal score of the 13 drugs identified as being safe and effective. Progesterone was further down the list.

The scientists tested lansoprazole in pregnant mice that had been given a bacterial component to induce inflammation, which causes some fetuses to die in utero, where they are reabsorbed. When these mice were given lansoprazole, they had more viable fetuses. Lansoprazole also worked better in these mice than progesterone.

Although it is a good measure of how inflammation affects pregnancy in mice, the scientists said the fetal resorption mouse model is not an adequate model of human preterm birth. They said more work, including studies in people, would need to be done before lansoprazole or any of the dozen other drugs they identified could be proven effective in pregnant women at risk for preterm birth. But the computational study provides leads for a condition that currently has few treatment options.

"This, basically, is a proof of concept that this drug has anti-inflammatory properties, which are not the properties the drug was designed for," said David K. Stevenson, MD, a professor of pediatrics at Stanford University and an author of the study. "This is a short way to get to new therapeutics for known diseases."

https://www.ucsf.edu/news/2020/02/416631/acid-reflux-drug-surprising-candidate-curb-preterm-birth

Newly discovered antibiotics kill bacteria differently

Antibiotic resistance is a growing public health problem across the globe, with many diseases becoming harder to treat. Now, a newly discovered antibiotic group shows promise in the fight against superbugs as it has a unique way of killing bacteria.

A team of scientists at McMaster University has found a new group of antibiotics that can fight infections in a new and unique way. These antibiotics fight infections in a way researchers have never seen before, according to the findings of the study described in the journal Nature.

'Holy grail' of antibiotics

The newly found group of antibiotics, consisting of corbomycin and complestatin, can kill bacteria by blocking the function of the bacterial cell wall. These drugs come from a family of antibiotics known as glycopeptides, which are produced by soil bacteria.

The two antibiotics attack peptidoglycan, the main component of the bacterial cell wall that is vital to the growth and survival of almost all bacteria. They inhibit the action of autolysins, which are important for cell division and growth.

Other antibiotics, such as penicillin, work by preventing the bacteria from building its wall, which is the source of its strength. In killing the bacteria, removing its wall will make it vulnerable and easier to kill.

These new antibiotics work by doing the opposite. Instead of preventing building the wall, it halts the wall ll from being broken down. As a result, blocking the breakdown of the wall would make it impossible for them to divide and expand – just like being trapped in prison.

Unique bacteria killer

The two new antibiotics are known as glycopeptides. The team studied the genes of the group to see if they lack resistance mechanisms. The team believes that if the genes that made these drugs different, perhaps the way they kill will also be different.

In collaboration with scientists from the Université de Montréal, including Yves Brun, they found that the drugs act on the bacterial cell wall to prevent it from dividing and proliferating.  

"Knowing the detailed structure at the atomic level of this connection between the surface layer and the surface of the cell offers enormous potential to then develop molecules that can target this attachment and make the cell more sensitive to antibacterials," Yves Brun, study co-author, said.

"Combined with the discovery of the new mode of action of two antibiotics, this development opens up prospects for weakening the action of bacteria and making them more vulnerable," he added.

The researchers believe the group of drugs is a promising clinical candidate in the hopes of stemming bacteria from becoming resistant to antibiotics.

Fight against antibiotic resistance

Antibiotic resistance is one of the greatest threats to global health, according to the World Health Organization (WHO). Though it happens naturally, the misuse of antibiotics is hastening the process, making it easy to treat infections in the past harder to curb now.

Further, antibiotic resistance increase hospital stays and medical costs. For instance, diseases in the past that were responsive to certain antibiotics may become resistant and difficult to stem, such as tuberculosis, pneumonia, gonorrhea, and other infections. Now, as the diseases become stronger and more resilient, outbreaks may become inevitable, unless new drugs are discovered.

In the United States alone, at least 2.8 million people become infected with antibiotic-resistant bacteria each year, while more than 35,000 people die.

https://www.nature.com/articles/s41586-020-1990-9

Newly discovered antibiotics kill bacteria differently

Novel drug combination discovered to induce high rates of human beta cell proliferation

Harmine

Researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that, together, cause the highest rate of proliferation ever observed in adult human beta cells- the cells in the pancreas that produce insulin- without harming most other cells in the body. The result is an important step toward a diabetes treatment that restores the body's ability to produce insulin.

The finding involved one type of drug that is known to cause beta cells to proliferate and another that is already in widespread use in people with diabetes. Together, they caused the cells to proliferate at a rate of 5 to 6 percent per day. The study was published today in Science Translational Medicine online.

We are very excited about this new drug combination because for the first time ever, we are able to see rates of human beta cell replication that are sufficient to replenish beta cell mass in humans with diabetes."

Andrew Stewart, MD, Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study

Diabetes occurs when there are not enough beta cells in the pancreas, or when those beta cells secrete too little insulin, the hormone required to keep blood sugar levels in the normal range. Approximately 30 million people in the United States have diabetes and nearly 50 to 80 million more are living with prediabetes (also called "metabolic syndrome"). Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness, and limb amputation.

In type 1 diabetes, the immune system mistakenly attacks and destroys beta cells. A deficiency of functioning beta cells is also an important contributor to type 2 diabetes, the most common type of diabetes. Thus, developing drugs that can increase the number of healthy beta cells is a major priority in diabetes research.

According to Dr. Stewart, none of the diabetes drugs currently on the market can induce beta cell regeneration in people with diabetes. In parallel with the Mount Sinai work, other researchers are studying pancreatic transplantation, beta cell transplantation, and stem cell replacement of beta cells for people with diabetes, but none of these approaches is in widespread use.

"This is a very exciting discovery in the field of diabetes and is a key next step in drug development for this disease," said Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai. "This important work truly holds promise for so many people."

In 2015, Dr. Stewart and his team published a paper in Nature Medicine that showed that harmine, a drug that inhibits the enzyme dual specificity tyrosine-regulated kinase 1A (DYRK1A), induced multiplication of adult human beta cells. In that study, his team also discovered that harmine treatment led to normal control of blood sugar and proliferation in human beta cells in diabetic mice whose beta cells had been replaced with small numbers of transplanted human beta cells. While this was a major advance, the proliferation rate was lower than needed to rapidly expand beta cells in people with diabetes.

This current paper builds upon a study that Dr. Stewart and his team published in Cell Metabolism in December 2018 where they discovered that DYRK1A inhibitors combined with another drug that inhibits transforming growth factor beta superfamily members (TGFβSF), also known as a family of proteins with various biological processes such as growth, development, tissue homeostasis and immune system, could cause beta cells to proliferate at a rate of 5 to 8 percent per day. However, according to Dr. Stewart, TGFβSF's would likely have side effects on other organs in the body that would prevent clinical use.

The next challenge was developing ways to target regenerative drugs to the beta cells while avoiding other cells and organs in the body where they may elicit adverse effects.

In the study published today, titled "GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human beta cell regeneration," Dr. Stewart and his team combined DYRK1A inhibitors like harmine with a class of beta cell-targeting drugs, also known as GLP1R agonists, which are already in widespread use in people with type 2 diabetes. They showed-;in beta cells from normal people and people with type 2 diabetes, both in the tissue culture dishes and in human beta cells transplanted into mice-;that combining harmine (or any other DYRK1A inhibitor) with any of the many GLP1R agonist drugs currently on the market for diabetes yields high rates of human beta cell replication, and does so in a way that is highly selective for the beta cell.

The project arose from the PhD thesis of an Icahn School of Medicine graduate student, Courtney Ackeifi, now a postdoctoral fellow in Dr. Stewart's lab and first author of the paper, who explored a broad spectrum of potential drug partners that could enhance the beta cell regenerative efficacy and selectivity of harmine.

Said Dr. Ackeifi of the discovery, "The beauty here is that the combination of DYRK1A inhibitors with GLP1R agonists achieves the highest rate of human beta cell replication possible, and does so in a highly specific way. This is an important advance in the field of diabetes because we may have found a way to convert a widely used class of diabetes drugs into a potent human beta cell regenerative treatment for all forms of diabetes."

"We know that a critical pathway to drive a cure for type 1 diabetes includes transplanting insulin-producing beta cells into people or enticing their existing beta cells to start multiplying," explains Francis Martin, PhD, JDRF Director of Research. "It is exciting to learn from the work of Dr. Stewart and his team that GLP1R agonists could increase the effect of the recently discovered agents that promote multiplication. Using GLP1R offers a means to boost the effect while also improving the safety of this type of drug."

The next goals of the project are to perform long-term studies in animals transplanted with human beta cells, and to determine if any cells or organs in the body other than beta cells are affected by the new drug combination.

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

https://en.wikipedia.org/wiki/Glucagon-like_peptide-1_receptor_agonist