New class of sleeping pill preserves ability to wake in response to danger signals

https://chem.nlm.nih.gov/chemidplus/rn/1088991-95-0

In a trial of one of the main class of prescription sleeping pills, half the participants slept through a fire alarm as loud as someone vacuuming next to their bed. But a newer alternative preserves the ability to wake in response to danger signals, according to a new research.

Published this week in Frontiers in Behavioral Neuroscience, the study showed that mice given the experimental hypnotic drug DORA-22 wake as quickly when threatened as drug-free sleepers - and then fall back asleep as quickly as ones given standard sleeping pills, once the threat is gone.

Common sleeping pills muffle your sleeping brain's 'intruder alert'

Even during sleep the brain continuously processes sensory information, waking us if it detects a threat. But the most widely prescribed class of sleeping pills, known as benzodiazepines, makes us less likely to rouse in response to sensory input.

"Benzodiazepines stimulate the widespread brain receptor GABA-A, which makes us sleepy but also suppresses off-target brain areas - including the 'gatekeeper' that decides which sensory inputs to process," explains study senior author Professor Tomoyuki Kuwaki of Kagoshima University, Japan.

Over the last decade, researchers have been developing a new class of hypnotic drugs called dual orexin receptor antagonists (DORAs). DORAs more selectively target the brain's sleep/wake pathways, which gives them safety advantages over benzodiazepines. These include a reduced 'hangover effect', with DORAs less likely to affect driving ability the day after use.

Kuwaki and colleagues hypothesized that the selectivity of DORAs could make them a safer alternative during sleep as well - by allowing the brain's sensory gatekeeper to stay vigilant to threats.

DORA-22 allows mice to wake to a threat, but still helps them sleep

The group tested their theory in mice.

The mice were dosed and tested after dark, when they are normally most active. One group was administered DORA-22, another a benzodiazepine called triazolam - and a third group was given placebo as a control.

"DORA-22 and triazolam had similar sleep promoting effects, extending the duration of deep sleep by 30-40% compared to placebo," reports Kuwaki.

One to four hours after dosing, the deep-sleeping mice were presented with a threatening stimulus: the smell of a fox, a high-pitched noise like a dog whistle, or trembling of their cage. The trembling frequency was designed to match that of an earthquake - a serious threat in Kuwaki's native Japan and many other parts of the word.

"As expected, arousal in response to these threatening stimuli was delayed significantly in the triazolam treatment, but not in the DORA-22 treatment, compared to placebo.

Even more promising, the sleep-promoting effect of DORA-22 remained after the rude awakening.

"Even though the DORA-22-treated mice were quickly woken by a threat, they subsequently fell back asleep as quickly as with triazolam, and significantly faster than with placebo."

To help demonstrate that the delay in waking to a threat during triazolam treatment was due specifically to inhibition of sensory gating in the brain, the researchers also tested the sleeping mice with a non-sensory stimulus.

"The three groups woke equally quickly when we suddenly reduced the amount of oxygen in their cage. This suggests that the delay in rousing to threatening stimuli caused by triazolam was not caused by a general inhibition of waking systems in the brain."

Human studies are needed to confirm DORA safety and efficacy

"Although it remains to be seen whether DORAs have the same properties when used in humans, our study provides important and promising insight into the safety of these hypnotics."

Since 2014, another DORA called surovexant has gained regulatory approval in Japan, the USA and Australia. So far, the high cost and limited clinical testing of surovexant have limited its use, amid concerns that doses high enough to significantly improve sleep lead to drowsiness the following day. New DORAs currently in development could overcome this hangover effect if they are cleared more quickly from the body than suvorexant, so that their effects are less likely to last beyond bedtime. Keep your eyes peeled.

Good News, Bad News on Levodopa for Parkinson's Disease

In continuation of my update on L-Dopa

The most potent drug available for Parkinson's disease, levodopa, treats symptoms of the disease but does nothing to either ease or increase its still-mysterious underlying causes, a new clinical trial has concluded.

Doctors often delay prescribing levodopa, or L-dopa, to Parkinson's patients for fear that the drug might have toxic effects that produce jerky involuntary body movements over time.

But patients started on L-dopa nearly a year earlier than a second group did not develop significantly different rates of involuntary movement, results from the new trial show.

"The current study bolsters our confidence that levodopa is safe even in early Parkinson's disease and that patients should not fear it," said Dr. Michael Okun. He's the national medical director of the Parkinson's Foundation and chairman of neurology at the University of Florida in Gainesville.

There's disappointment here as well. While levodopa isn't toxic, it also doesn't appear to provide any protection against progression of Parkinson's in the brain, said Dr. Susan Bressman, co-director of the Mount Sinai Parkinson and Movement Disorders Center in New York City.

"The bottom line is they couldn't show neuroprotection," Bressman said. "Using this very normal dose we normally use, they couldn't show it slows the progression of the disease."

Parkinson's disease is a progressive nervous system disorder. One of its hallmarks is the loss of neurons that produce a brain chemical called dopamine. Low dopamine levels affect a person's control over their movements, causing tremors, rigid muscles and slowness.

Developed more than 50 years ago, L-dopa eases these muscular and movement symptoms. The brain synthesizes levodopa into dopamine and then puts the neurotransmitter to good use.

"Levodopa remains the most important and effective treatment for Parkinson's disease and its introduction has undoubtedly improved morbidity, mortality and quality of life," said Okun, who wasn't part of the trial.

But side effects in some patients cause concern that the drug might have a toxic effect on the brain, researchers noted.

A clinical trial 14 years ago that aimed to clear up the matter only muddied the waters, Bressman said.

The earlier trial found that people taking L-dopa showed improvement even after they stopped taking it, raising hopes that it might be somehow be stemming the progression of Parkinson's.

But brain scans of those patients showed some evidence that levodopa was causing potentially harmful changes to dopamine receptors in the brain, Bressman said.

"We couldn't really prove one way or the other if it's good or bad for the brain," Bressman said. "But the bottom line -- people need it. We don't have a better drug. It's the most potent drug for the symptoms, so you've got to use it, but you don't use a high dose."

The new clinical trial, led by Dr. Rob de Bie from the University of Amsterdam, hoped to clarify results of the older study.

A group of 445 early Parkinson's patients in the Netherlands were randomly assigned to either start levodopa therapy right away, or wait 40 weeks and then start taking the drug.

"The theory is if you get those extra 40 weeks of exposure to levodopa and it's neuroprotective, the earlier group will be in a better place and the late group will never catch up," Bressman said. "They'll always be a little worse because the first group got more of this neuroprotective effect."

But both groups wound up in the same place by week 80 of the trial, with essentially the same rate of disease progression, the Dutch researchers found. The drug didn't provide people in the earlier group any extra protection.

At the same time, neither group suffered greater rates of jerky movements or levodopa-related fluctuations in motor response, discounting concerns over toxic effects.

"Basically, it confirms what we currently do," said Bressman, co-author of an editorial accompanying the study. Both were published in the Jan. 24 issue of New England Journal of Medicine.

"Most people don't start levodopa at first diagnosis, when they have hardly any symptoms, because they don't need it. We don't think the drug is protecting the brain, so we don't start it right away, because it's not going to change what they're going to look like 10 years down the pike," she noted.

"But as soon as they do start to need it, we start it. We use it. And we're judicious in how we use it," Bressman continued.

Hopes for a drug that will directly treat or perhaps even cure Parkinson's now rest on research being done into suspected causes of the disease, she said.

Experts now think Parkinson's is a related group of diseases, each subtype potentially triggered by a different cause, Bressman said.

Drugs are being developed to target genes that have been implicated in Parkinson's for some patients. Future drugs might target inflammation in the brain or other potential causes.

"I think ultimately between the genetics and other biomarkers we find in the spinal fluid or in the blood, we're going to be able to group patients better and figure out the disease mechanisms," Bressman said.

https://en.wikipedia.org/wiki/L-DOPA

Good News, Bad News on Levodopa for Parkinson's Disease 

Prostate Drug Finasteride Can Safely Lower Cancer Risk, Study Says

In continuation of my update on Finasteride

Finasteride, best known as the enlarged-prostate medicine Proscar, is a safe, effective way to reduce the risk of prostate cancer, according to long-term findings from the Prostate Cancer Prevention Trial (PCPT).

The trial was funded by the U.S. National Cancer Institute and enrolled nearly 19,000 men between 1993 and 1997.

Initially it found that finasteride -- a hormone-blocking drug -- cut the risk of prostate cancer by 25 percent. Those results were published in 2003.

The newly released long-term data show that the reduction of prostate cancer risk has continued and that fewer than 100 men in the trial died from prostate cancer in more than two decades of follow-up, according to a research team led by Dr. Ian Thompson.

The updated results also showed no statistically significant increased risk of death from prostate cancer among men taking finasteride. This removes concerns over early findings of a possible risk of more aggressive cancers among patients who take the drug.

"Finasteride is safe, inexpensive and effective as a preventive strategy for prostate cancer," said Thompson, who is principal investigator of the PCPT for the SWOG Cancer Research Network.

The SWOG Cancer Research Network is an international cancer clinical trials group.

"Doctors should share these results with men who get regular prostate-specific antigen [PSA] tests that screen for the presence of prostate cancer," Thompson said in a SWOG news release. "The drug will have its greatest effect in this group of men."

Thompson is also emeritus professor at the University of Texas Health Science Center. He and his team published their findings Jan. 23 in the New England Journal of Medicine.

A cheap, reliable prostate cancer prevention drug will have a big impact on public health, Thompson and his colleagues said.

They noted that prostate cancer rates are on the rise and that nearly 165,000 American men were diagnosed with the cancer in 2018, according to the American Cancer Society.

Many cases of prostate cancer are slow-growing and not life-threatening, but are still often treated with surgery and radiation, sometimes resulting in complications such as impotence and incontinence.

"There are significant negative consequences to patients' health and quality of life that can result from prostate cancer treatment, as well as to their finances and their peace of mind," Thompson said.

"If we can save people from surgeries and scores of examinations and tests, and spare them from living for years with fear, we should. The best-case scenario for patients is prevention, and this trial has found an inexpensive medication that gets us there," he concluded.

One prostate specialist unconnected to the research said the new findings come after "many years of debate" on finasteride's role in cancer prevention.

Based on early findings from the PCPT, the U.S. Food and Drug Administration "issued a warning that chronic use of the medication may increase the risk of high-grade or aggressive prostate cancer in a small percentage of men," said Dr. Manish Vira. He helps direct urologic research at Northwell Health's Arthur Smith Institute for Urology in Lake Success, N.Y.

Unfortunately, that warning "effectively nullified the benefits of the medication in the eyes of many patients and their physicians," Vira said.

These later, fuller results should turn that around, he noted.

"Physicians and patients need to be aware of these results, and at least consider again using these medications in the prevention of prostate cancer," Vira said."This may be especially true among men at high risk, such as African-American men and men with a strong family history of prostate cancer," he said.

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

https://www.webmd.com/drugs/2/drug-1548-167/finasteride-oral/finasteride-oral/details

Prostate Drug Finasteride Can Safely Lower Cancer Risk, Study Says 

US FDA Accepts Regulatory Submissions for Review of Tafamidis to Treat Transthyretin Amyloid Cardiomyopathy

In continuation of my update on Tafamidis

Pfizer Inc. (NYSE: PFE) announced today that the US Food and Drug Administration (FDA) accepted for filing the company’s New Drug Applications (NDAs) for tafamidis for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). Pfizer has submitted two NDAs based on two forms of tafamidis: meglumine salt and free acid. Tafamidis is the only product to complete a Phase 3 trial evaluating its efficacy, safety, and tolerability in patients with ATTR-CM, a rare, fatal, and underdiagnosed condition.1,2

The tafamidis meglumine form (20 mg capsule) has been granted Priority Review. The FDA grants Priority Review to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists. The target Prescription Drug User Fee Act (PDUFA) action date for a decision by the FDA is in July 2019.

The tafamidis free acid form (61 mg capsule) will be under Standard Review. This form is bioequivalent to the 80 mg tafamidis meglumine dose, which was administered as four 20 mg capsules in the pivotal trial; it was developed for patient convenience to enable a single capsule for daily administration. The target PDUFA action date for a decision by the FDA is in November 2019.

“The diagnosis of ATTR-CM is often delayed, primarily because disease awareness is low and patients often present with symptoms similar to more common causes of heart failure. In fact, we believe less than one percent of patients living with this disease are currently diagnosed,” said Brenda Cooperstone MD, Senior Vice President and Chief Development Officer, Rare Disease, Pfizer Global Product Development. “The FDA’s filing acceptance is an encouraging step toward our goal of further raising awareness and providing a treatment option for ATTR-CM patients who are in desperate need of an approved pharmacologic therapy. We look forward to working with the FDA to bring the first treatment for this deadly disease to patients.”

The submission is based on findings from the pivotal Phase 3 Transthyretin Amyloid Cardiomyopathy (ATTR-ACT) study, which evaluated the efficacy, safety, and tolerability of tafamidis meglumine compared to placebo for the treatment of patients with ATTR-CM. In the primary analysis of the study, tafamidis met the primary endpoint, demonstrating a significant reduction in the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalizations compared to placebo over a 30-month period in patients with wild-type or hereditary ATTR-CM (P=0.0006). Tafamidis was well tolerated, with an observed safety profile comparable to placebo.3 The primary results were presented in a Hot Line session at the ESC Congress 2018 in Munich, Germany, and simultaneously published online in the New England Journal of Medicine (NEJM) in August 2018. Results from additional sub-group analyses were presented during the Late Breaking Clinical Trials session at the Heart Failure Society of America 22nd Annual Scientific Meeting in Nashville, TN, in September 2018. For more information on the ATTR-ACT trial, go to www.clinicaltrials.gov.

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

US FDA Accepts Regulatory Submissions for Review of Tafamidis to Treat Transthyretin Amyloid Cardiomyopathy

Sprycel (dasatinib) Tablets Now Approved in Combination with Chemotherapy in Certain Pediatric Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

In continuation of my update on Dasatinib

Bristol-Myers Squibb Company (NYSE:BMY)  announced the U.S. Food and Drug Administration (FDA) has expanded the indication for Sprycel ® (dasatinib) tablets to include the treatment of pediatric patients one year of age and older with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination with chemotherapy.1 Sprycel is the only second-generation tyrosine kinase inhibitor approved for this patient population. The approval, which was granted following priority review by the FDA, is based on data from the Phase 2 study, CA180-372 (NCT01460160).

“We recognize the urgency around developing and delivering therapies for children and young adults living with cancer, and today’s approval is an important example of our commitment to pediatric oncology,” said Jeffrey Jackson, Ph.D., development lead, hematology, Bristol-Myers Squibb. “Building on our previous indication for children with Ph+ chronic myeloid leukemia in chronic phase, we’re pleased to bring Sprycel tablets to a second type of pediatric leukemia. This approval will give physicians another treatment option to offer appropriate pediatric patients with Ph+ ALL.”

Sprycel is associated with the following Warnings and Precautions: myelosuppression, bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor lysis syndrome, embryo-fetal toxicity and effects on growth and development in pediatric patients.1 Please see detailed Important Safety Information below.

The efficacy of Sprycel tablets in combination with chemotherapy was evaluated in a single cohort of the Phase 2, multicenter, single-arm CA180-372 study, which included 78 pediatric patients with newly diagnosed B-cell precursor Ph+ ALL.1,2 At three years, the study demonstrated an event-free survival (EFS) binary rate of 64.1% (95% confidence interval [CI]: 52.4 to 74.7).1 Event-free survival is defined as the time from the start of Sprycel to lack of complete response at the end of the third high-risk block, relapse, secondary malignancy or death from any cause.

Of the 81 patients evaluated for safety, fatal adverse reactions occurred in three patients (4%), and eight (10%) experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis and drug hypersensitivity.1 The most common serious adverse reactions (incidence ≥10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain and musculoskeletal pain.1

“As treatments have advanced in recent years, we’ve seen improvements in outcomes for pediatric patients with Ph+ ALL overall, but there remains a need for additional options,”3 said Stephen Hunger, MD, lead study author, chief of the division of oncology and director of the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia. “The Phase 2 CA180-372 trial was particularly informative because it was designed to limit the use of cranial irradiation and stem cell transplant. In the study, Sprycel plus chemotherapy demonstrated a three-year event-free survival benefit. These results show that Sprycel is an effective medication for physicians to consider for children and adolescents with Ph+ ALL.”1,4

Acute lymphoblastic leukemia is characterized by chromosomal abnormalities and genetic alterations involved in the differentiation and proliferation of lymphoid precursor cells.5 The most common childhood cancer in the United States, ALL represents 20% of all cancers diagnosed in persons aged less than 20 years, or more than 3,000 new cases each year.6 Three percent of children who have ALL have the Ph+ subtype, which means they have a chromosome alteration that results in a specific mutation of the BCR-ABL gene.3

“Coping with a pediatric cancer diagnosis, including searching for and identifying the right treatment regimen, can take a physical and emotional toll on patients and their families,” said Vickie Buenger, president of the Coalition Against Childhood Cancer (CAC2). “The availability of another option is a welcome step forward for those affected by this disease.”

In addition to this pediatric approval, Sprycel is approved for use in children one year of age and older with Ph+ chronic myeloid leukemia (CML) in chronic phase (CP).

New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States

Eisai Co., Ltd. (CEO: Haruo Naito, “Eisai”) and Purdue Pharma L.P. (President and CEO: Craig Landau, MD, “Purdue Pharma”) today announced that a new drug application has been submitted to the U.S. Food and Drug Administration (FDA) for lemborexant, an investigational agent for sleep-wake regulation, seeking approval for the treatment of insomnia, a sleep-wake disorder.

This application was based on the results of two pivotal Phase 3 clinical studies in patients with insomnia, SUNRISE 1 (Study 304) and SUNRISE 2 (Study 303), enrolling approximately 2,000 patients, as well as important safety studies, including assessment of postural stability after middle-of-the-night awakening and a next-morning driving study. SUNRISE 1, a one-month, double-blind, placebo-controlled study, included the first ever Phase 3 head-to-head comparison versus zolpidem ER and objectively assessed sleep parameters (time to sleep onset, sleep efficiency, and wake after sleep onset) resulting in the largest (objective) polysomnography dataset collected to date in patients with insomnia. SUNRISE 2 was a 12-month study and subjectively assessed for ability to fall asleep and stay asleep based on patient self reports (sleep diaries).

Lemborexant, which acts on the orexin neurotransmitter system and is believed to regulate sleep and wake by dampening wakefulness without impeding the ability to awaken to external stimuli, is being jointly developed by Eisai and Purdue Pharma for the treatment of multiple sleep-wake disorders, including insomnia disorder. In addition to the treatment of insomnia disorder, a Phase 2 clinical study of lemborexant in patients with irregular sleep-wake rhythm disorder and mild to moderate Alzheimer's dementia is underway. Information about ongoing clinical studies is available at clinicaltrials.gov.

Eisai and Purdue Pharma are striving to address new unmet medical needs and to improve the lives of patients and their families.

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such an investigational agent will successfully complete clinical development or gain health authority approval.

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







New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States

FDA Advisory Committee Votes on Zynquista (sotagliflozin) as Treatment for Adults with Type 1 Diabetes

In continuation of my update on sotagliflozin

The Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) today voted eight to eight on the question of whether the overall benefits of Zynquista™* (sotagliflozin) outweighed the risks to support approval. Sotagliflozin is an investigational oral dual SGLT1 and SGLT2 inhibitor under regulatory review as an adjunct to insulin for the treatment of adults with type 1 diabetes (T1D). While the FDA is not required to follow the committee’s vote, the agency considers the committee’s recommendations when making its decision, which is anticipated by March 22, 2019.

Sotagliflozin, developed by Sanofi and Lexicon, has the potential to be the first oral antidiabetic drug approved in the United States together with insulin therapy to improve glycemic (blood sugar) control in adults with T1D.

“We believe in the overall benefit-risk profile of sotagliflozin for adults with type 1 diabetes who lack adequate glycemic control using insulin alone,” said Rachele Berria, MD, PhD, Global Vice President and Head of Diabetes Medical Affairs, Sanofi. “We will continue to work with the FDA through its review process to hopefully bring to patients a new treatment that can help people living with type 1 diabetes control their blood sugar and address some of the challenges of insulin-only therapy.”

Sotagliflozin is an investigational oral dual inhibitor of two proteins responsible for glucose regulation known as sodium-dependent glucose co-transporter types 1 and 2 (SGLT1 and SGLT2). SGLT1 is responsible for glucose absorption in the gastrointestinal tract, and SGLT2 is responsible for glucose reabsorption by the kidney. About 1.3 million Americans have T1D and an estimated 40,000 people will be newly diagnosed each year in the U.S., according to the American Diabetes Association.

“In clinical trials, when used in combination with insulin therapy, sotagliflozin significantly improved glycemic control without increasing hypoglycemia,” said Pablo Lapuerta, MD, Executive Vice President and Chief Medical Officer, Lexicon. “These results could not be achieved with insulin alone. Diabetic ketoacidosis is an inherent risk of type 1 diabetes and an increase was seen with sotagliflozin compared to insulin alone. We believe this can potentially be addressed with proper education and monitoring.” 

The New Drug Application for sotagliflozin included data from the inTandem clinical trial program, which included three Phase 3 clinical trials assessing the safety and efficacy of sotagliflozin in approximately 3,000 adults with inadequately controlled T1D. The safety and efficacy data have not yet been fully evaluated by any regulatory authority.

Sanofi also submitted a regulatory application to the European Medicines Agency (EMA) in 2018. An EMA approval decision is expected in the first half of 2019.

https://www.drugbank.ca/drugs/DB12713

https://pubchem.ncbi.nlm.nih.gov/compound/lx-4211#section=2D-Structure

FDA Advisory Committee Votes on Zynquista (sotagliflozin) as Treatment for Adults with Type 1 Diabetes

Exelixis Announces U.S. FDA Approval of Cabometyx (cabozantinib) Tablets for Previously Treated Hepatocellular Carcinoma

In continuation of my update on Cabometyx (cabozantinib)

Exelixis, Inc. announced that the U.S. Food and Drug Administration (FDA) approved Cabometyx (cabozantinib) tablets for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. HCC is the most common form of liver cancer and the fastest-rising cause of cancer-related death in the U.S. 

“This new indication for Cabometyx is an important treatment advance for patients with this aggressive form of liver cancer, a community in need of new therapeutic options,” said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. “This approval is an important milestone as we continue to explore how Cabometyx may benefit people with difficult-to-treat-cancers beyond renal cell carcinoma. We would like to thank the patients and clinicians who participated in CELESTIAL and to acknowledge the team at the FDA for their continued collaboration during the review of our application.”

The FDA’s approval of Cabometyx was based on results from the CELESTIAL phase 3 pivotal trial of Cabometyx for patients with advanced HCC who received prior sorafenib. Cabometyx demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. On November 15, 2018, Exelixis’ partner Ipsen received approval from the European Commission for Cabometyx tablets as a monotherapy for HCC in adults who have previously been treated with sorafenib.

“Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib,” said Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL. “Physicians are eager for new options for these patients, and the results of the CELESTIAL trial demonstrate that Cabometyx has the efficacy and safety profile to become an important new therapy in our efforts to slow disease progression and improve treatment outcomes.”

In the pivotal CELESTIAL trial, median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92; p=0.0049). Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001). Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of patients in the cabozantinib group compared with 33 percent of patients in the placebo group.

Adverse events in CELESTIAL were consistent with the known safety profile of cabozantinib. The most common (≥10 percent) grade 3 or 4 adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17 percent vs. 0 percent), hypertension (16 percent vs. 2 percent), increased aspartate aminotransferase (12 percent vs. 7 percent), fatigue (10 percent vs. 4 percent) and diarrhea (10 percent vs. 2 percent). Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.

“While we’ve seen some progress in the treatment of primary liver cancer in recent years, the patient community still needs new and better options,” said Andrea Wilson, President and Founder of Blue Faery: The Adrienne Wilson Liver Cancer Association. “The approval of Cabometyx has been eagerly anticipated, making this an important day for patients diagnosed with this devastating disease.”

In December 2018, Exelixis and its partner Ipsen announced the initiation of COSMIC-312, a phase 3 pivotal trial of cabozantinib in combination with atezolizumab versus sorafenib in previously untreated advanced HCC. The trial will also explore single-agent activity of cabozantinib in the first-line setting. For more information about the trial, visit ClinicalTrials.gov.

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



Exelixis Announces U.S. FDA Approval of Cabometyx (cabozantinib) Tablets for Previously Treated Hepatocellular Carcinoma

FDA Approves Tosymra (sumatriptan) Nasal Spray for Acute Treatment of Migraine

In continuation of my update on Tosymra (sumatriptan)

Dr. Reddy’s Laboratories Ltd. and its subsidiary, Promius Pharma, LLC today announced the approval of Tosymra (previously known as DFN-02) by the U.S. Food and Drug Administration (FDA). Tosymra is indicated for the acute treatment of migraine with or without aura in adults. Tosymra is the latest product to join the Promius Pharma acute migraine treatment portfolio. The company is working toward commercialization of this product.

“We are excited about the approval of Tosymra. This approval affirms our ability to develop well-differentiated products to meet the unmet needs of patients with migraine and HCPs treating them,” said G.V. Prasad, Co-Chairman and CEO, Dr. Reddy’s Laboratories.

According to Dr. Anil Namboodiripad, PhD, President, Promius Pharma, “Tosymra nasal spray is formulated using a proprietary novel excipient known as Intravail [®] to achieve blood levels similar to a 4-mg sumatriptan subcutaneous injection, resulting in rapid onset of action. Independent research shows that 26% to 40% of migraine patients are not optimally controlled with their current treatment.  For patients who suffer from the debilitating and disruptive effects of migraine, there continues to be a need for reliable and efficacious treatment options. At Promius, we are committed to developing new ways of improving patient experiences. Tosymra is a mist-like nasal spray that acts rapidly and is well tolerated.”

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

FDA Approves Tosymra (sumatriptan) Nasal Spray for Acute Treatment of Migraine

FDA Approves Imbruvica (ibrutinib) Plus Obinutuzumab as First Non-Chemotherapy Combination Regimen for Treatment-Naïve Patients with Chronic Lymphocytic Leukemia

In continuation of my update on  ibrutinib

The Janssen Pharmaceutical Companies of Johnson & Johnson announced  the U.S. Food and Drug Administration (FDA) approval of Imbruvica (ibrutinib) in combination with obinutuzumab in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the most common form of leukemia in adults.1 This is the first approval for a non-chemotherapy combination regimen for treatment-naïve patients with CLL/SLL, and marks the tenth FDA approval for Imbruvica since its U.S. launch in November 2013. The approval expands the label for Imbruvica in frontline CLL/SLL beyond its use as a monotherapy to include combination use with obinutuzumab. Imbruvica, a Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.

"In just a few years, Imbruvica has become an important treatment for chronic lymphocytic leukemia. Imbruvica as a single agent – and now as a combination with obinutuzumab – provides patients with CLL with an alternative to frontline treatment with chemoimmunotherapy," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and lead investigator of the iLLUMINATE study.

This approval is based on results from the Phase 3 iLLUMINATE study (PCYC-1130). At a median follow-up of 31 months, Imbruvica plus obinutuzumab showed a significant improvement in Independent Review Committee (IRC)-evaluated progression-free survival compared with chlorambucil plus obinutuzumab (median not evaluable [NE] vs. 19 months; hazard ratio [HR] 0.23; 95 percent confidence interval [CI]: 0.15-0.37; P<0.0001), with a 77 percent reduction in risk of progression or death. Patients with high-risk disease (17p deletion/TP53 mutation, 11q deletion, or unmutated IGHV) treated with Imbruvica plus obinutuzumab experienced an 85 percent reduction in risk of progression or death (HR 0.15; 95 percent CI: 0.09-0.27). The IRC-evaluated overall response rate was 89 percent in the Imbruvica plus obinutuzumab arm versus 73 percent in the chlorambucil plus obinutuzumab arm. The data were recently presented in an oral session at the 2018 American Society of Hematology (ASH) Annual Meeting and simultaneously published in The Lancet Oncology.

"This label update builds upon the established efficacy and safety of Imbruvica in the frontline treatment of patients with CLL/SLL, as a monotherapy or in combination with other treatments," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Janssen Research & Development, LLC. "This milestone represents our continued commitment to develop Imbruvica-based, non-chemotherapy regimens to address the clinical needs of patients living with CLL/SLL."

The FDA also updated the Imbruvica label to include additional long-term efficacy data supporting its use as a monotherapy in CLL/SLL, with approximately five years of follow-up from the Phase 3 RESONATE™ (PCYC-1112) and RESONATE™-2 (PCYC-1115, PCYC-1116) international studies.

Warnings and Precautions include hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity. The most common adverse reactions (occurring in 20 percent or more of patients) of all grades in patients treated with Imbruvica plus obinutuzumab in the iLLUMINATE study were neutropenia (48 percent), thrombocytopenia (36 percent), rash (36 percent), diarrhea (34 percent), musculoskeletal pain (33 percent), bruising (32 percent), cough (27 percent), infusion related reaction (25 percent), hemorrhage (25 percent), and arthralgia (22 percent).

The recommended dose of Imbruvica for CLL/SLL is 420 mg orally once daily until disease progression or unacceptable toxicity as a single agent or in combination with obinutuzumab or bendamustine and rituximab (BR). When administering Imbruvica in combination with rituximab or obinutuzumab, doctors should consider administering Imbruvica prior to rituximab or obinutuzumab when given on the same day.

------------------------------------------------------------------------------------------------------------------------

FDA Approves Imbruvica (ibrutinib) Plus Obinutuzumab as First Non-Chemotherapy Combination  Regimen for Treatment-Naïve Patients with Chronic Lymphocytic Leukemia

FDA Approves Osphena (ospemifene) for Moderate to Severe Vaginal Dryness Due to Menopause

Duchesnay Inc., a pharmaceutical company specializing in women’s health, announced   that the FDA has approved its supplemental New Drug Application (sNDA) seeking to add moderate to severe vaginal dryness, a symptom of vulvar and vaginal atrophy (VVA), due to menopause, to the indication of Osphena (ospemifene).

The sNDA was based on new safety and efficacy data acquired through a confirmatory phase 3 randomized, double blind, placebo-controlled multicenter study evaluating the efficacy and safety of ospemifene in patients with moderate to severe vaginal dryness. Osphena is non-hormonal and helps improve specific vaginal tissues by increasing superficial cells, decreasing parabasal cells and reducing vaginal pH.

Prior to this approval, Osphena was indicated only for the treatment of moderate to severe dyspareunia (painful intercourse), also a symptom of VVA, due to menopause.

“Many menopausal women are not aware that vaginal dryness is one of the two most common and most bothersome symptoms (MBS) of vulvovaginal atrophy due to menopause. FDA’s approval of this additional indication affirms Osphena’s safety and effectiveness for treating moderate to severe vaginal dryness, broadening its benefits to a larger number of menopausal women,” affirmed Dr. James A. Simon, Clinical Professor of Obstetrics and Gynecology at George Washington University.

Before menopause, estrogen helps maintain the thickness, elasticity and lubrication of vaginal tissues. However, as women age, estrogen levels drop, causing changes in these tissues, which can lead to dryness, itching, burning and painful intercourse.

“With the addition of moderate to severe vaginal dryness to Osphena’s indication, Duchesnay USA can now help postmenopausal women suffering from this symptom of VVA”, explained Dean Hopkins, General Manager of Duchesnay USA. “With this new indication, Osphena now provides an oral option for women who prefer a non-hormonal treatment alternative.”

---------------------------------------------------------------------------------------------------------------------

FDA Approves Osphena (ospemifene) for Moderate to Severe Vaginal Dryness Due to Menopause

New One-Dose Flu Drug Shows Promise

An experimental single-dose flu drug shows promise as a new way to alleviate the misery of influenza, researchers say. 

The drug  called baloxavir (structre)  worked better than no treatment in one phase of a new study. The study also found it as effective as the current standard drug, oseltamivir (Tamiflu), at controlling symptoms such as coughing, sore throat, headache, fever, muscle and joint pain, and fatigue.

Moreover, in light of concerns about flu-drug resistance, most patients treated with baloxavir responded as expected, the study authors said.

"There are few approved influenza antivirals, and current treatments have limitations," said study lead author Dr. Frederick Hayden, of the University of Virginia School of Medicine.

"For example, currently circulating influenza viruses are resistant to the older class of antivirals," he said. These include the drugs amantadine (brand name Symmetrel) and rimantadine (Flumadine).

Resistance is also growing to the class of drugs including widely used Tamiflu and Relenza (zanamivir), Hayden said. "Consequently, there are medical needs for new anti-influenza agents with different mechanisms of action and greater potency," he added.

Hayden, professor emeritus of clinical virology and medicine, said the new study indicates that baloxavir resolves flu symptoms as quickly, effectively and safely as current options, without yet raising concerns about resistance. It also demonstrated "significantly greater antiviral effects," he added.

Also, while Tamiflu must be taken twice a day for five days, baloxavir requires just one dose.

The investigation was funded by the drug company Shionogi, Inc., which developed and manufactures baloxavir.

Baloxavir is approved for use in Japan. In the United States, it remains an "investigational drug," with the U.S. Food and Drug Administration expected to decide on approval by the end of this year.

The new study, which was published Sept. 6 in the New England Journal of Medicine, unfolded in two trials, both involving otherwise healthy flu patients at low risk for influenza complications.

One trial was conducted during the 2015-2016 flu season. About 400 patients, aged 20 to 64, received one of three doses of baloxavir (ranging from 10 to 40 milligrams) or a placebo. Flu symptoms eased notably faster among all three baloxavir groups, compared with placebo (untreated) patients, the findings showed.

The following flu season, nearly 1,100 patients, aged 12 to 64, were treated with baloxavir or Tamiflu. The drugs relieved symptoms in roughly the same time period, with similar side-effect risk.

However, about 10 percent of the baloxavir patients had a less than robust response to the drug. Hayden acknowledged that "the clinical and public health implications of reduced susceptibility to baloxavir are not fully understood."

Dr. Timothy Uyeki, author of an accompanying journal editorial, heads the influenza division at the U.S. Centers for Disease Control and Prevention's National Center for Immunization and Respiratory Diseases.

"There is a need for antiviral drugs with new mechanisms of action," he agreed.Uyeki highlighted the benefit of baloxavir's single-dose regimen. Besides its convenience, it "avoids concerns about compliance with a five-day treatment course of oseltamivir," he said.

But he also stressed the need for further testing.

It remains unclear what benefits might accrue from combining baloxavir with Tamiflu, Uyeki noted.

Also, he cautioned, the current research only included otherwise healthy people aged 12 to 64 who were not at high risk for flu complications. Whether baloxavir will benefit high-risk groups -- young children, the elderly, pregnant women and others with underlying chronic medical conditions -- remains unknown, Uyeki said.

"A lot more studies are needed of the clinical benefit of baloxavir treatment of influenza in high-risk outpatients," he added.

FDA Approves New Indication for Envarsus XR (tacrolimus extended-release tablets)

In continuation of my update on Tacrolimus

Veloxis Pharmaceuticals announced today that the U.S. Food & Drug Administration (FDA) approved a new indication for Envarsus XR (tacrolimus extended-release tablets) to prevent organ rejection in de novo kidney transplant patients in combination with other immunosuppressants. This indication is commonly referred to as the de novo indication.

Envarsus XR was approved for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in 2015 and has already been used in the conversion setting in more than 90% of the transplant centers in the U.S.  The approval for de novo use provides an important new treatment option for kidney transplant patients and providers, where significant unmet need currently exists.

"Today marks the beginning of an exciting new chapter in immunosuppression.  Kidney transplant patients will now be able to receive a refined and simplified gold standard treatment regimen from the beginning of the kidney transplant journey," said Ulf Meier-Kriesche, M.D. Chief Scientific Officer at Veloxis Pharmaceuticals, Inc.

The FDA's approval is based on the Phase 3 clinical development program which was a randomized, double-blind, double-dummy, Phase III study in 543 de novo kidney transplant patients that demonstrated comparable efficacy and safety compared to twice-daily tacrolimus (Prograf®).

The primary endpoint of the study was a composite endpoint of treatment failure (biopsy-proven acute rejection or BPAR, graft failure, loss to follow up or death) that was evaluated after a 12-month treatment period to demonstrate the non-inferiority of Envarsus® compared to Prograf®. The treatment failure rate for Envarsus® was 18.3% compared to 19.6% for Prograf®.    

"There are approximately 200,000 patients living with a kidney transplant today and we have seen a significant number of them convert to Envarsus XR since our launch in December 2015.  With the addition of the de novo indication, the roughly 16,000 adult patients who receive a kidney transplant each year will now have access to Envarsus XR following surgery. This approval is another example of Veloxis's commitment to transplant and the patients, donors and providers that make it all possible," said Craig A. Collard, Chief Executive Officer of Veloxis Pharmaceuticals A/S.

--------------------------------------------------------------------------------------------------------------------

FDA Approves New Indication for Envarsus XR (tacrolimus extended-release tablets)