FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

In continuation of my update on lenvatinib

Woodcliff Lake, NJ and Kenilworth, announced today that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor Lenvima (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT (Study 304), where Lenvima demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

“Unresectable hepatocellular carcinoma is an extremely difficult-to-treat cancer, with no new first-line systemic therapy options for more than a decade,” said Dr. Ghassan Abou-Alfa, medical oncologist, Memorial Sloan Kettering Cancer Center. “REFLECT is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC. The efficacy and safety data from REFLECT are important findings for oncologists and others in the multidisciplinary teams who treat liver cancer, as well as for our patients who are affected by it.”

Adverse reactions, some of which can be serious or fatal, may occur with Lenvima, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the severity of the adverse reaction, Lenvima should be monitored, withheld or discontinued. Based on its mechanism of action and data from animal reproduction studies, Lenvima can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see “Important Safety Information” below.

REFLECT showed that Lenvima achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with Lenvima experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted when 351 events had occurred in the Lenvima arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, Lenvima showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

• Median PFS was doubled with Lenvima compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with Lenvima versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77) per RECIST 1.1.
• Lenvima showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with Lenvima versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
  • Per mRECIST: Treatment with Lenvima resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with Lenvima resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
  • Per RECIST 1.1: Treatment with Lenvima resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with Lenvima resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib

In addition, median time to progression (TTP) was doubled with Lenvima compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with Lenvima versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

In REFLECT, the most common adverse reactions (≥20%) observed in patients treated with Lenvima were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism and nausea. The most common serious adverse reactions (≥2%) reported in patients treated with Lenvima were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%).

The most common adverse reactions (≥20%) observed in patients who received sorafenib were palmar-plantar erythrodysesthesia syndrome, diarrhea, fatigue, hypertension, abdominal pain, decreased appetite, rash, decreased weight and arthralgia/myalgia. The most common serious adverse reactions (≥2%) reported in patients who received sorafenib were ascites (2%) and abdominal pain (2%).

It is also important to note that the dose for Lenvima for patients with unresectable HCC is based on the patient’s weight (12 mg for patients weighing 60 kilograms or more, 8 mg for patients weighing less than 60 kilograms); the recommended dosage and dose adjustments are described in the full prescribing information.

“Eisai strives to be a leading global R&D-based pharmaceutical company, driven by our human health care (hhc) mission to improve the lives of patients and their loved ones,” said Shaji Procida, President and Chief Operating Officer, Eisai Inc., and Commercial Head of the Oncology Business Group, Americas at Eisai. “That purpose is what has propelled us toward this win for patients with unresectable hepatocellular carcinoma. Our goal is to bring monumental solutions to patients and health care providers, changing expectations for the oncology landscape, and we look forward to continuing this work in our ongoing collaboration with Merck.”

“We are pleased by the FDA approval of Lenvima as it marks an important advancement in the treatment of unresectable hepatocellular carcinoma,” said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. “With our shared mission to find solutions for difficult-to-treat cancers, we look forward to working with Eisai to help bring this needed option to patients and physicians.”

Lenvima, a kinase inhibitor, was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In May 2016, Lenvima was approved in the U.S. in combination with everolimus, for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Under the collaboration, Eisai and Merck initiated co-commercialization activities for Lenvima in the U.S. in June 2018. Since the initial launch, more than 10,000 patients were treated with Lenvima, which is approved in more than 50 countries worldwide.

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FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

FDA Approves Oxervate (cenegermin) for Neurotrophic Keratitis

The U.S. Food and Drug Administration approved the first drug, Oxervate (cenegermin), for the treatment of neurotrophic keratitis, a rare disease affecting the cornea (the clear layer that covers the colored portion of the front of the eye).

“While the prevalence of neurotrophic keratitis is low, the impact of this serious condition on an individual patient can be devastating,” said Wiley Chambers, M.D., an ophthalmologist in the FDA’s Center for Drug Evaluation and Research. “In the past, it has often been necessary to turn to surgical interventions; these treatments are usually only palliative in this disease. Today’s approval provides a novel topical treatment and a major advance that offers complete corneal healing for many of these patients.”

Neurotrophic keratitis is a degenerative disease resulting from a loss of corneal sensation. The loss of corneal sensation impairs corneal health causing progressive damage to the top layer of the cornea, including corneal thinning, ulceration, and perforation in severe cases. The prevalence of neurotrophic keratitis has been estimated to be less than five in 10,000 individuals.

The safety and efficacy of Oxervate, a topical eye drop containing cenegermin, was studied in a total of 151 patients with neurotrophic keratitis in two, eight-week, randomized controlled multi-center, double-masked studies. In the first study, patients were randomized into three different groups. One group received Oxervate, a second group received an eye drop with a different concentration of cenegermin, and the third group received an eye drop without cenegermin. In the second study, patients were randomized into two groups. One group was treated with Oxervate eye drops and the other group was treated with an eye drop without cenegermin. All eye drops in both studies were given six times daily in the affected eye(s) for eight weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second study, patients with the disease in both eyes were treated in both eyes (bilaterally). Across both studies, complete corneal healing in eight weeks was demonstrated in 70 percent of patients treated with Oxervate compared to 28 percent of patients treated without cenegermin (the active ingredient in Oxervate).

The most common adverse reactions in patients taking Oxervate are eye pain, ocular hyperemia (enlarged blood vessels in the white of the eyes), eye inflammation and increased lacrimation (watery eyes).

Oxervate was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious condition. Oxervate also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Ref : https://www.drugs.com/history/oxervate.html

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FDA Approves Oxervate (cenegermin) for Neurotrophic Keratitis

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