FDA Approves Kalydeco (ivacaftor) for Cystic Fibrosis in Children Ages 12..

 Vertex Pharmaceuticals Incorporated  announced the U.S. Food and Drug Administration (FDA) approved Kalydeco (ivacaftor) to include use in children with cystic fibrosis (CF) ages 12 to <24 months who have at least one mutation in their cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to Kalydeco based on clinical and/or in vitro assay data.

“Cystic fibrosis is a chronic, progressive disease that is present at birth, with symptoms often occurring in infancy,” said Reshma Kewalramani, M.D., Executive Vice President and Chief Medical Officer at Vertex. “With today’s approval, parents and physicians now have a medicine to treat the underlying cause of CF in patients as young as one year of age. We are excited about the progress of our portfolio and continue to support additional research on the potential benefit of early intervention with all of our medicines, with the goal of bringing a treatment to all people living with CF.”

This FDA approval is based on data from the ongoing Phase 3 open-label safety study (ARRIVAL) of 25 children with CF aged 12 to <24 months who have one of 10 mutations in the CFTR gene (G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D or R117H). The study demonstrated a safety profile consistent with that observed in previous Phase 3 studies of older children and adults; most adverse events were mild or moderate in severity, and no patient discontinued due to adverse events. Two patients had elevated liver enzymes greater than eight times the upper limit of normal, but continued to receive Kalydeco after a dose interruption. The most common adverse events (≥30%) were cough (74%), pyrexia (37%), elevated aspartate aminotransferase (37%), elevated alanine aminotransferase (32%) and runny nose (32%). Four serious adverse events were observed in two patients.

Mean baseline sweat chloride for the children in this study was 104.1 mmol/L (n=14). Following 24 weeks of treatment with Kalydeco, the mean sweat chloride level was 33.8 mmol/L (n=14). In the 10 subjects with paired sweat chloride samples at baseline and week 24, there was a mean absolute change of -73.5 mmol/L. These data were presented at the 41stEuropean Cystic Fibrosis Society (ECFS) Conference in June 2018 and published in The Lancet Respiratory Medicine (Volume 6, No 7, July 2018).

“I’m very excited about the approval of ivacaftor in children ages 12 to less than 24 months as this is the first regulatory approval of a CFTR modulator in this age group,” said Margaret Rosenfeld, M.D., MPH, Seattle Children’s Research Institute and Department of Pediatrics, University of Washington School of Medicine. “The premise of newborn screening for CF is to intervene very early in the course of disease with the goal of improving long term outcomes, so this is a significant milestone for parents and caregivers of young children with CF.”

Kalydeco was already approved in the U.S. for the treatment of CF in patients ages 2 and older who have one of 38 ivacaftor-responsive mutations in the CFTR gene based on clinical and/or in vitro assay data. Vertex submitted a Marketing Authorization Application for a line extension (ages 12 to <24 months) to the European Medicines Agency with a decision anticipated in the first half of 2019.

https://es.wikipedia.org/wiki/Archivo:Carnosine.png

FDA Approves Diacomit (stiripentol) for Seizures Associated with Dravet Syndrome

   

FDA approved Diacomit (stiripentol) for seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam.

Dravet syndrome is a rare genetic condition that usually appears during the first year of life with prolonged fever-related seizures. Later, other types of seizures typically appear, and additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity, and difficulty relating to others.

The efficacy of Diacomit was established in two multicenter placebo-controlled double-blind randomized studies (Study 1 and Study 2). Patients enrolled in the studies were required to be aged between 3 years and under 18 years with Dravet syndrome that was inadequately controlled with clobazam and valproate, and experiencing at least 4 generalized clonic or tonic-clonic seizures per month.

After a 1-month baseline period where patients continued to receive clobazam and valproate, they were then randomly selected to receive additional treatment with either Diacomit or placebo for a double-blind period of two months.

The primary efficacy endpoint for both studies was the responder rate - a responder being a patient who experienced more than 50% decrease in the frequency of seizures per month during the two month double-blind period compared to the one month baseline period.

In both studies, the responder rate was significantly greater for Diacomit than for placebo. In Study 1 (N=41), 71% of Diacomit patients (N=21) were responders, compared to 5% of patients taking the placebo (N=20), and 43% of patients reported no generalized clonic or tonic-clonic seizure during the duration of the study. In Study 2 (N=23), 67% of Diacomit patients (N=12) were responders, compared to 9.1% of patients taking the placebo (N=11), and 25% of patients reported no seizures.

The exact mechanism of action by which Diacomit exerts its anticonvulsant effect in humans is unknown, but possible actions include direct effects mediated through GABAA receptors and indirect effects involving inhibition of CYP450 activity.

Common side effects (occurring in at least 10% of Diacomit-treated patients) included somnolence (sleepiness and drowsiness), decreased appetite, agitation, ataxia (impaired coordination and balance), weight decreased, hypotonia (low muscle tone), nausea, tremor, dysarthria (difficulty speaking words; difficulty forming words during speech), and insomnia.

Diacomit will be available as oral capsules and powder for oral suspension, and prescriptions must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. As is true for many other drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression, and panic attacks.

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

FDA Approves Diacomit (stiripentol) for Seizures Associated with Dravet Syndrome

Sun Pharma Announces FDA Approval of Cequa (cyclosporine) Ophthalmic Solution to Treat Dry Eye Disease

Sun Pharmaceutical Industries Ltd, announced that Sun Pharma has received approval for Cequa (cyclosporine ophthalmic solution) 0.09%, from the U.S. Food and Drug Administration (FDA). Cequa is indicated to increase tear production in patients with keratoconjunctivitis sicca (dry eye).

                   

Cequa provides the highest FDA-approved concentration of cyclosporine A (CsA) and is the first and only approved CsA product that incorporates a nanomicellar technology. The innovative nanomicellar formulation allows the CsA molecule to overcome solubility challenges, penetrate the eye’s aqueous layer and prevents the release of the active lipophilic molecule prior to penetration. In the Phase 3 confirmatory trial on Cequa, after 12 weeks of treatment, as compared to vehicle, Cequa showed statistically significant improvement in the primary endpoint, Schirmer’s score (a measurement of tear production) (p<0.01). Improvements in secondary endpoints (i.e. ocular staining assessments) were seen as early as 1 month after initiating treatment. Cequa is dosed twice daily and will be available as a single-use vial.

The nanomicellar formulation technology uses micelles, which are gelatinous aggregates of amphipathic (both hydrophobic and hydrophilic) molecules formed at a well-defined concentration. The small size of the nanomicelles facilitates entry into corneal and conjunctival cells, enabling delivery of high concentrations of CsA.

“Dry Eye Disease represents an area of high unmet medical need, with a significant number of patients who are currently untreated,” said Abhay Gandhi, CEO, North America, Sun Pharma. “The U.S. FDA approval of Cequa represents a long-awaited dry eye treatment option and is an important milestone in the development of Sun’s Ophthalmics business. Cequa, with its novel nanomicellar formulation for a proven dry eye medication, delivers a lipophilic molecule in a clear solution form.”

Additionally, Jodi Luchs, MD, the principal investigator behind the Cequa confirmatory Phase 3 trial, noted: “Dry eye is a complex disease that lacks a ‘one-size-fits-all’ approach. As a clinician treating a high volume of dry eye patients, it’s important to have multiple treatment modalities available at my disposal. Given its strong clinical trial performance, the approval of Cequa is welcomed news, and I look forward to offering my patients this compelling new option.”

Cequa (cyclosporine ophthalmic solution) 0.09%, for topical ophthalmic use will be commercialized in the U.S. by Sun Ophthalmics, the branded ophthalmics division of Sun Pharma’s wholly owned subsidiary.

Sun Pharma Announces FDA Approval of Cequa (cyclosporine) Ophthalmic Solution to Treat Dry Eye Disease

Four cups of coffee a day shown to protect heart muscle

In continuation of my update on coffee

A new study has shown that drinking four cups of coffee a day can protect against heart muscle damage through the effect of caffeine on a protein called p27

Caffeine intake has been associated with a lower risk of several chronic metabolic diseases such as cardiovascular disease (stroke and ischemic heart disease), and type II diabetes.

The current study, which was carried out at Heinrich-Heine-University and the IUF-Leibniz Research Institute for Environmental Medicine in Duesseldorf, Germany, shows that caffeine, at a concentration equivalent to that in four cups of coffee, works to enhance the mitochondrial entry of a protein called p27.

P27 is protein that promotes effective mitochondrial function. It protects the cells of the heart and blood vessels against damage. The study was recently published in the open access journal PLOS Biology.

Prior research by the same scientists revealed that caffeine improves the function of endothelial cells that line the cardiovascular system. This was seen to occur at normal, safe doses and was related to mitochondria.

Following the study, the scientists focused on the p27 protein, known better as a cell cycle inhibitor, and found that it was present within the mitochondria of all major cell-types in the heart.

The p27 protein prevents cell death in cardiac muscle cells, encourages endothelial cells to migrate, and promotes the maturation of fibroblasts into contractile cells. These processes are vital components of cardiac muscle repair following a heart attack.

Caffeine promotes this repair by facilitating the first step, namely, the entry of p27 protein into the mitochondria, at physiologic levels. This protective effect against heart damage is present in elderly, obese and prediabetic mice.

Our results indicate a new mode of action for caffeine, one that promotes protection and repair of heart muscle through the action of mitochondrial p27. These results should lead to better strategies for protecting heart muscle from damage, including consideration of coffee consumption or caffeine as an additional dietary factor in the elderly population.”

Dr. Judith Haendeler, Heinrich-Heine-University

Ref : https://www.eurekalert.org/pub_releases/2018-06/p-cff061418.php

FDA approves new marijuana-based drug to treat rare and severe forms of epilepsy

In continuation of my update on Cannabidiol

The U.S. Food and Drug Administration today approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome.

CBD is a chemical component of the Cannabis sativa plant, more commonly known as marijuana. However, CBD does not cause intoxication or euphoria (the "high") that comes from tetrahydrocannabinol (THC).

It is THC (and not CBD) that is the primary psychoactive component of marijuana.

"This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies. And, the FDA is committed to this kind of careful scientific research and drug development," said FDA Commissioner Scott Gottlieb, M.D. "Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA's drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients. Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug's uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes. We'll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products. But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims. Marketing unapproved products, with uncertain dosages and formulations can keep patients from accessing appropriate, recognized therapies to treat serious and even fatal diseases."

Dravet syndrome is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms). Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others.

Lennox-Gastaut syndrome begins in childhood. It is characterized by multiple types of seizures. People with Lennox-Gastaut syndrome begin having frequent seizures in early childhood, usually between ages 3 and 5. More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with Lennox-Gastaut syndrome develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with Lennox-Gastaut syndrome require help with usual activities of daily living.

"The difficult-to-control seizures that patients with Dravet syndrome and Lennox-Gastaut syndrome experience have a profound impact on these patients' quality of life," said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. "In addition to another important treatment option for Lennox-Gastaut patients, this first-ever approval of a drug specifically for Dravet patients will provide a significant and needed improvement in the therapeutic approach to caring for people with this condition."

Epidiolex's effectiveness was studied in three randomized, double-blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex, taken along with other medications, was shown to be effective in reducing the frequency of seizures when compared with placebo.

The most common side effects that occurred in Epidiolex-treated patients in the clinical trials were: sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections.

Epidiolex must be dispensed with a patient Medication Guide that describes important information about the drug's uses and risks. As is true for all drugs that treat epilepsy, the most serious risks include thoughts about suicide, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression and panic attacks. Epidiolex also caused liver injury, generally mild, but raising the possibility of rare, but more severe injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine.

Under the Controlled Substances Act (CSA), CBD is currently a Schedule I substance because it is a chemical component of the cannabis plant. In support of this application, the company conducted nonclinical and clinical studies to assess the abuse potential of CBD.

The FDA prepares and transmits, through the U.S. Department of Health and Human Services, a medical and scientific analysis of substances subject to scheduling, like CBD, and provides recommendations to the Drug Enforcement Administration (DEA) regarding controls under the CSA. DEA is required to make a scheduling determination.

The FDA granted Priority Review designation for this application. Fast-Track designation was granted for Dravet syndrome. Orphan Drug designation was granted for both the Dravet syndrome and Lennox-Gastaut syndrome indications.

Ref : https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm

Fluconazole Use Doesn't Up Risk of Stillbirth, Neonatal Death

In continuation of my update on Fluconazole

Fluconazole use in pregnancy seems not to be associated with significantly increased risks of stillbirth or neonatal death, according to a research letter published in the June 12 issue of the Journal of the American Medical Association.

Björn Pasternak, M.D., Ph.D., from the Karolinska Institutet in Stockholm, and colleagues examined whether fluconazole use during pregnancy is associated with stillbirth and neonatal death. The authors used nationwide register data to identify all pregnancies with singleton live births and stillbirths in Sweden and Norway. A total of 10,669 exposed and 106,690 unexposed pregnancies from a cohort of 1,485,316 pregnancies were included in the matched analysis of stillbirth, and 10,640 exposed and 106,387 unexposed pregnancies were included in the matched analysis of neonatal death.

The researchers found that there were 2.7 and 3.6 stillbirths per 1,000 exposed and unexposed pregnancies, respectively (hazard ratio, 0.76; 95 percent confidence interval, 0.52 to 1.1) and 1.2 and 1.7 neonatal deaths per 1,000 exposed and unexposed pregnancies, respectively (risk ratio, 0.73; 95 percent confidence interval, 0.42 to 1.29). Similar results were seen for doses of 300 mg or less and more than 300 mg.

"Although the data on fluconazole use in pregnancy suggest no increased risk of stillbirth, additional studies should be conducted and the collective body of data scrutinized by drug authorities before recommendations to guide clinical decision making are made, and weighed against the benefits of therapy," the authors write.

FDA Approves Moxidectin for the Treatment of River Blindness

Medicines Development for Global Health (MDGH) and the World Health Organisation Special Programme for Research and Training in Tropical Diseases (TDR) announced today that the United States (U.S.) Food and Drug Administration (FDA) approved moxidectin 8 mg oral for the treatment of river blindness (onchocerciasis) in patients aged 12 years and older1. The FDA has also awarded MDGH a priority review voucher (PRV).

River blindness is caused by a parasitic worm, Onchocerca volvulus. The disease manifests as severe itching, disfiguring skin conditions and visual impairment, including permanent blindness, caused by the worm’s larvae (microfilariae). The approval of moxidectin was based on data from two randomized, double blind, active controlled clinical studies2,3. Each study met its respective primary endpoints, showing a statistically significant superiority of moxidectin over the current standard of care, ivermectin, in suppressing the presence of the microfilariae in skin. Full results from the Phase III study were published in the Lancet in January 20183 and a safety summary is provided below.

“FDA approval is a momentous achievement for any biopharmaceutical company, but it is a particularly rare and exciting event in the neglected diseases setting” said Mark Sullivan, Founder and Managing Director of MDGH. “It takes a broad community to develop a new medicine. FDA approval represents decades of work by thousands of scientists, disease control specialists, expert advisors, community health workers, funders and study participants. We particularly acknowledge the US$13 million investment from the Global Health Investment Fund (GHIF) as well as the extraordinary persistence and dedication of the team at TDR, without whom this would not have happened.”

TDR (the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases) was instrumental in the development of moxidectin. “We are delighted about the FDA’s decision,” says TDR Director John Reeder. “It is a milestone toward the river blindness endgame and our objective to enable African countries to integrate moxidectin into their elimination strategies.”

This approval is the result of a paradigm-changing approach to the development of new medicines for neglected diseases, enabled by the PRV program. “As neglected tropical diseases are endemic in low and middle-income countries, there are limited markets for medicines. Therefore, finding investors willing to support development in these diseases is extremely difficult” added Mark Sullivan. “However, the introduction of the FDA’s neglected diseases PRV program has created a market around neglected diseases.“

The PRV legislation was designed to encourage development of new drug and biological products for neglected diseases. The PRV, a saleable item, permits the holder to accelerate the review of a new drug application (NDA) from the standard 10 months to 6 months. This time saving has significant value to the pharmaceutical industry, thus creating an indirect market for neglected disease treatments.

Dr. Reeder added, “This voucher to MDGH exemplifies the original spirit of the programme – to create incentives for research and development in neglected diseases.”

MDGH is the first not-for-profit company to register a medicine through the tropical disease PRV program. “This is exactly what we had in mind when we proposed the PRV program,” said Duke University’s Professor David Ridley, an author of the 2006 paper on which the voucher scheme is based. “The voucher incentive helped Medicines Development for Global Health attract funding to complete testing and registration for a drug that had been on the shelf. I’m delighted that the voucher program is playing a role in treating patients with river blindness, and one day eliminating the disease.”

“Achieving FDA approval is a critically important milestone for moxidectin, but our work to bring this medicine to those who need it most continues in earnest,” concluded Mr. Sullivan. “MDGH plans to provide the community with additional data, including data in younger children. We are here for the full journey – we have committed our skills and resources to play our part in ridding the world of this disabling disease.”

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

Want to Avoid Type 2 Diabetes? Eat More Whole Grains

It may seem counter intuitive, but eating bread, pasta and cereal may actually help prevent type 2 diabetes, as long as those foods are made from whole grains, new research suggests.

The study found that each serving of whole-grain foods per day was linked to as much as an 11 percent drop in the risk of type 2 diabetes.

"Whole grains appear to play an important role in the prevention of type 2 diabetes, and choosing whole grains over refined grains is highly recommended," said study author Cecilie Kyro. She is a post-doctoral researcher at the Danish Cancer Society Research Center in Copenhagen.

Kyro added that, in addition to preventing type 2 diabetes, there is evidence that whole grains can help prevent heart disease and colon cancer.

More than 30 million Americans have diabetes, and most have type 2 diabetes, according to the American Diabetes Association (ADA). People with type 2 diabetes don't use the hormone insulin efficiently.

Insulin normally ushers blood sugar into cells to be used as energy. But some people are resistant to the effects of insulin, and then more and more insulin is needed to do the same job. Eventually, the insulin-producing cells in the pancreas can't keep up with the demand, and blood sugar levels rise, resulting in type 2 diabetes, according to the ADA.

Lifestyle factors, such as diet and exercise, are known to play a role in type 2 diabetes. In the latest study, researchers wanted to see what role specific whole grains played in type 2 diabetes.

To do this, they reviewed diet information from more than 55,000 people, aged 50 to 65, in Denmark. On average, the group was slightly overweight.

Overall, about 7,400 people were diagnosed with type 2 diabetes during the study's average 15-year follow-up.

The study volunteers completed food diaries. From these food diaries, the researchers calculated how many grams of whole grains each person ate daily.

The investigators found that for every serving of whole-grain food, the risk of type 2 diabetes dropped by 11 percent for men and 7 percent for women.

In women, only wheat and oats seemed to reduce the risk of diabetes. But for men, all whole grains -- wheat, rye and oats -- were linked to a lower risk of the blood sugar disorder. Kyro said this difference may just be a statistical anomaly because fewer women developed diabetes.

She added that all whole-grain products can be recommended for preventing type 2 diabetes in both men and women.

Exactly how whole grains help prevent type 2 diabetes isn't clear from this study. Because it's an observational study, it isn't designed to prove a cause-and-effect relationship.

Still, the scientists suspect that there may be several reasons why whole grains could be protective, including reduced blood sugar secretion after a meal.

Registered dietician Samantha Heller said the findings fall in line with previous research.

"People who consume whole grains have lower risks of type 2 diabetes, as well as inflammation, coronary heart disease and cancer," she said. In addition, a diet including whole grains also helps with weight management and may improve digestive health.

"Whole grains contain fiber, vitamins, minerals, protein and phytonutrients, all of which play important roles in maintaining a healthy body. Dietary fiber decreases insulin resistance, after-meal blood sugar spikes and decreases inflammation, all of which may contribute to its beneficial effects on type 2 diabetes," Heller explained. (Phytonutrients are nutrients from plant sources.)

Kyro said one serving of whole grain contained 16 grams of whole grain. That can vary depending on the type or brand of a product, but 16 grams is approximately one slice of whole-grain bread, she said.

Heller said that U.S. dietary guidelines recommend three to four servings of whole grains a day. A serving is one slice of bread, one-cup of ready-to-eat cereal or 1/2-cup cooked rice, pasta or cereal. She said those recommendations are for people who are sedentary. If you're more active, you may need more grains each day.

Findings from the study were published in the September issue of The Journal of Nutrition.