Cone snail venom could hold key to efficient therapies for diabetes

New research has found that venom extracted from a species of marine cone snail could hold the key to developing 'ultra-fast-acting' insulins, leading to more efficient therapies for diabetes management.

Researchers from Australia and the US have successfully determined the three-dimensional structure of a cone snail venom insulin, revealing how these highly efficient natural proteins called Con-Ins G1 can operate faster than human insulin.

The teams also discovered that Con-Ins G1 was able bind to human insulin receptors, signifying the potential for its translation into a human therapeutic.

Associate Professor Mike Lawrence from Melbourne's Walter and Eliza Hall Institute of Medical Research led a collaborative study between the University of Utah, the Monash Institute of Pharmaceutical Sciences, La Trobe University and Flinders University in Australia.

Associate Professor Lawrence, a specialist in the structure of insulins and their receptors, said the teams utilised the Australian Synchrotron to create and analyse the three-dimensional structure of this cone snail venom insulin protein with exciting results.

"We found that cone snail venom insulins work faster than human insulins by avoiding the structural changes that human insulins undergo in order to function -- they are essentially primed and ready to bind to their receptors, " Associate Professor Lawrence said.

Associate Professor Lawrence said human insulins could be considered 'clunky' by comparison.

"The structure of human insulins contain an extra 'hinge' component that has to open before any 'molecular handshake' or connection between insulin and receptor can take place.

"By studying the three-dimensional structure of this snail venom insulin we've found how to dispense with this 'hinge' entirely, which may accelerate the cell signalling process and thus the speed with which the insulin takes effect." Associate Professor Lawrence said.

Published today in Nature Structural and Molecular Biology, the team's findings build on earlier studies from 2015, when the University of Utah reported that the marine cone snail Conus geographus used an insulin-based venom to trap its prey. Unsuspecting fish prey would swim into the invisible trap and immediately become immobilised in a state of hyperglycaemic shock induced by the venom.

Dr Helena Safavi-Hemami from the University of Utah said it was fascinating to uncover how the cone snail insulin was able to have such a rapid effect on its prey and, furthermore, that the peptide had therapeutic potential in humans. "We were thrilled to find that the principles of cone snail venom insulins could be applied to a human setting," Dr Safavi-Hemami said.

"Our Flinders University colleagues have shown that the cone snail insulin can 'switch on' human insulin cell signalling pathways, meaning the cone snail insulin is able to successfully bind to human receptors," Dr Safavi-Hemami said.

"The next step in our research, which is already underway, is to apply these findings to the design of new and better treatments for diabetes, giving patients access to faster-acting insulins," she said.

Ref : http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3292.html

Study provides insight into how weight-loss drug acts in the brain

In continuation of  my update on lorcaserin

A weight-loss drug dampened the response to food cues in regions of the brain associated with attention and emotion, leading to decreases in caloric intake, weight and body mass index (BMI), a team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) reported. In the first study of the drug lorcaserin in the human brain, the research revealed the mechanism underlying the drug's efficacy and provides insight into which individuals may benefit most from the medication. The paper was published today in the journal Diabetes, the journal of the American Diabetes Association.

"Human feeding behaviors involve areas of the brain responsible for cognitive control and decision-making," said Christos S. Mantzoros, MD, Director of the Human Nutrition Unit in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School. "We wanted to find out if lorcaserin was acting on these brain regions and, if so, where and how. One-third of the U.S. population is obese, and another one-third is overweight. This is a huge burden on individuals and the health care system. In addition, it increases the risk of diabetes, cardiovascular disease and many types of cancer. We need to continue to develop safe and effective therapies to combat this epidemic."

Approved by the FDA in 2012, the generic drug lorcaserin is a medication prescribed for obese or overweight adults who also have weight-related health complications such as diabetes. Several studies have shown the drug helps about half of the people who take it lose more than 5 percent of their body mass within a year, but there's a great deal of variability in individual results, and the mechanism underlying its effect was previously unknown.

To determine how the drug works in the human brain, Mantzoros and colleagues observed 48 obese men and women - half taking the drug, half taking a placebo - over the course of a four-week experiment. Participants came into the clinic on four occasions for blood work, physical exams, measurements and weight-loss counseling with a registered dietician. They were also expected to keep records of the food they ate during the study.

On three visits - before receiving any medication (Week 0), after a week of medication (Week 1), and after four weeks of medication (Week 4) - exams were followed by two brain scans: one after the patients had fasted for at least 12 hours, the other after they had eaten a meal. The scans were taken using functional magnetic resonance imaging (fMRI) to measure changes in blood flow in an active brain, which suggests which regions play a role during a given task. During each scan, participants were shown 150 images of foods generally considered highly desirable, such as cake and onion rings; foods generally considered less desirable like vegetables; and nonfood items like rocks and trees.

At Week 1, the fMRI scans in the fasting state revealed that people taking the drug showed decreased brain activity in response to images of highly desirable foods in the attention-related parietal and visual cortices. At Week 4, the lorcaserin group in the fed state showed less activity in the parietal cortex - which is responsible for integrating sensory information - when looking at any of the food images.

The data also revealed that subjects who had the strongest brain responses to food prior to taking lorcaserin saw the most success with the weight-loss medication.

"Decreases in caloric intake, weight, and BMI were linked to strong responses to food cues in the areas of the brain related to emotion, pleasure and attention prior to taking the weight-loss drug, which suggests that lorcaserin could prove to be of particular benefit to 'emotional eaters,' " Mantzoros said.Lorcaserin targets only a very specific serotonin receptor (known as 5-HT2c), shown in animal studies to play a role in abnormal food consumption. A previous generation of weight loss drugs was linked to this receptor, but because their scope was broader, those products also had dire cardiac side effects including pulmonary hypertension and valve problems. Lorcaserin could produce weight loss without these cardiac risks, the authors noted.

"In addition, the different mechanism of action in comparison to other drugs for obesity creates an opportunity for combination drugs for the treatment of obesity," Mantzoros said. "This might create more powerful solutions and is something that remains to be explored."

New drug holds potential for treating advanced mastocytosis

In continuation of my update on Midostaurin 

Most people have never heard of mastocytosis. It's a rare, sometimes deadly, immune disorder. Now new research may help those with advanced mastocytosis and possibly many more people, too. "This is the first drug that's shown to be effective in this very rare disease," says Tracy George, MD, at the University of New Mexico Comprehensive Cancer Center. George was part of the international team that recently published the results of its study on mastocytosis in the New England Journal of Medicine.

"Mast cells are normal cells in the body that mediate the body's allergic and inflammatory responses," says George. "But people with mast cell disease have too many mast cells and they're abnormal." Too many abnormal mast cells can cause allergic reactions and inflammation. Different subtypes of the disease differ in the how serious these responses are.

People with indolent mastocytosis may have mild symptoms and lead normal lives. Others with indolent mastocytosis may have flushing and diarrhea and other symptoms severely enough that they can't hold a job or do things that most people can do. People with other subtypes of the disease can have life-threatening reactions, such as anaphylactic shock and organ damage. And people with advanced mastocytosis — the most deadly subtype is called mast cell leukemia — live less than six months after their diagnosis.

The Food and Drug Administration has approved only one drug, called imatinib, to treat advanced mastocytosis. Imatinib blocks the action of a cellular protein called a tyrosine kinase receptor. But people with a mutation in a gene called D816V KIT do not respond to imatinib. The D816V KIT gene codes for a tyrosine kinase receptor, says George. And, she says, most people with advanced mastocytosis have the D816V KIT mutation.

Research on the new treatment began at Stanford University, where George worked with a colleague, Jason Gotlib, MD, whose patient had mast cell leukemia. They gave that woman a drug called midostaurin under the FDA's compassionate use policy. "Midostaurin is a multi-kinase inhibitor," says George. "Midostaurin was being evaluated in a clinical trial for a different disease, acute myeloid leukemia. And this lady with mast cell leukemia remarkably improved within weeks, within days."

 Midostaurin 

Gotlib and George began a small clinical trial to test midostaurin in people with advanced mastocystosis. That clinical trial expanded into an international clinical trial after Gotlib and George shared their preliminary results at an international conference. George brought the clinical trial to UNM when she joined the Pathology department and the UNM Comprehensive Cancer Center.

The clinical trial included treatment for three subtypes of advanced mastocytosis. Still, it took years to enroll enough people because the disease is so rare. Mastocytosis affects only about one person in 10,000. In comparison, breast cancer affects more than 12 times as many people and prostate cancer affects more than 13 times as many, according to the American Cancer Society. But even though the clinical trial was small, the results were astounding.

People with advanced mastocytosis on the clinical trial lived an average of 28 months longer. This average includes the 40 percent of people who did not respond to midostaurin. The 60 percent who did respond, though, responded within two or three months of starting treatment. Responders had mild side effects like diarrhea, vomiting and nausea, if they had any at all.

Sixteen people in the clinical trial had mast cell leukemia. "For those patients who did respond," says George, "their median survival has not been reached. So that means [some are] still living, which is unbelievable."

The clinical trial has spurred more research. Scientists around the world are now studying how midostaurin affects mast cells and how to combine it with other drugs to create an even more potent treatment. Novartis, the maker of midostaurin, and other drug companies are investing in research on multi-kinase inhibitors. Clinical trials to test midostaurin for controlling symptoms in people with indolent mastocytosis have opened. And more research into using midostaurin to treat asthma, skin diseases and allergies is in the planning stages.

George, who is the American expert in mastocytosis pathology, says, "I do think this [mastocytosis] is under-diagnosed. Even though patients with advanced mastocytosis are rare, indolent [mastocytosis] is more common. And there are lots of diseases for which unhappy mast cells are a pathogenesis." Now, with the potential for a treatment, people with unhappy mast cells may feel better.

New drug holds potential for treating advanced mastocytosis

Edible ginger-derived nano-lipids could effectively deliver drugs for treating colon cancer

Edible ginger-derived nano-lipids created from a specific population of ginger nanoparticles show promise for effectively targeting and delivering chemotherapeutic drugs used to treat colon cancer, according to a study by researchers at the Institute for Biomedical Sciences at Georgia State University, the Atlanta Veterans Affairs Medical Center and Wenzhou Medical University and Southwest University in China.

Colorectal cancer is the third most common cancer among men and women in the United States, and the second-leading cause of cancer-related deaths among men and women worldwide. The incidence of colorectal cancer has increased over the last few years, with about one million new cases diagnosed annually. Non-targeted chemotherapy is the most common therapeutic strategy available for colon cancer patients, but this treatment method is unable to distinguish between cancerous and healthy cells, leading to poor therapeutic effects on tumor cells and severe toxic side effects on healthy cells. Enabling chemotherapeutic drugs to target cancer cells would be a major development in the treatment of colon cancer.

In this study, the researchers isolated a specific nanoparticle population from edible ginger (GDNP 2) and reassembled their lipids, naturally occurring molecules that include fats, to form ginger-derived nano-lipids, also known as nanovectors. To achieve accurate targeting of tumor tissues, the researchers modified the nanovectors with folic acid to create FA-modified nanovectors (FA nanovectors). Folic acid shows high-affinity binding to the folate receptors that are highly expressed on many tumors and almost undetectable on non-tumor cells.

The FA nanovectors were tested as a delivery platform for doxorubicin, a chemotherapeutic drug used to treat colon cancer. The researchers found that doxorubicin was efficiently loaded into the FA nanovectors, and the FA nanovectors were efficiently taken up by colon cancer cells, exhibited excellent biocompatibility and successfully inhibited tumor growth. Compared to a commercially available option for delivering doxorubicin, the FA nanovectors released the drug more rapidly in an acidic pH that resembled the tumor environment, suggesting this delivery strategy could decrease the severe side effects of doxorubicin. These findings were published in the journal Molecular Therapy.

"Our results show that FA nanovectors made of edible ginger-derived lipids could shift the current paradigm of drug delivery away from artificially synthesized nanoparticles toward the use of nature-derived nanovectors from edible plants," said Dr. Didier Merlin, a professor in the Institute for Biomedical Sciences at Georgia State and a Research Career Scientist at the VA Medical Center. "Because they are nontoxic and can be produced on a large scale, FA nanovectors derived from edible plants could represent one of the safest targeted therapeutic delivery platforms."

Ref : http://www.nanowerk.com/nanotechnology-news/newsid=44454.php

Vitamin A Compound Might Aid in Colon Cancer Fight

In continuation of my update on Retinoic acid

Retinoic acid, a compound derived in the body from vitamin A, might have a role in suppressing colon cancer, new animal research suggests.

"Retinoic acid has been known for years to be involved in suppressing inflammation in the intestine," said study senior author Dr. Edgar Engleman, professor of pathology and medicine at Stanford University School of Medicine in Palo Alto, Calif.

Meanwhile, the development of colon cancer has been linked to inflammation. For example, inflammatory bowel disease, such as ulcerative colitis, has been associated with colon cancer, he said in a university news release.

"We wanted to connect the dots and learn whether and how retinoic acid levels directly affect cancer development," Engleman added.

When the researchers looked at mice with colon cancer, they saw lower levels of retinoic acid in the intestines of the mice.

The researchers also found that boosting levels of retinoic acid in the intestines of mice with colon cancer slowed progression of the disease.

In humans, colon cancer patients who had high levels of a protein that degrades retinoic acid in their intestinal tissue tended to have worse outcomes than other patients, the study authors noted.

The findings suggest new ways to prevent or treat colon cancer. However, it's important to note that animal research doesn't always produce the same results in humans.

"The intestine is constantly bombarded by foreign organisms. As a result, its immune system is very complex," Engleman said.

"We found that bacteria, or molecules produced by bacteria, can cause a massive inflammatory reaction in the gut that directly affects retinoic acid metabolism," he said.

He said that retinoic acid levels are normally regulated very tightly.

"Now that we've shown a role for retinoic acid deficiency in colorectal cancer, we'd like to identify the specific microorganisms that initiate these changes in humans. Ultimately we hope to determine whether our findings could be useful for the prevention or treatment of colorectal cancer," he concluded.

The study was published online Aug. 30 in the journal Immunity.

Combo Drug for Childhood Asthma Appears Safe in Study

In continuation of my update on fluticasone 

Lingering safety concerns regarding an asthma drug for children may be put to rest by new clinical trial results showing the widely used medication is safe, according to a new report.

Long-acting beta agonists (LABAs) provide short-term relief of asthma symptoms by relaxing and opening the airways. They're prescribed to child asthma sufferers in combination with an inhaled steroid drug to reduce airway inflammation, said study co-author Dr. Stanley Szefler. He is director of pediatric asthma research for the University of Colorado School of Medicine.

"Together they have a dual purpose, one to reduce inflammation and the other to open up the airways to make it easier to breathe," Szefler said.

But a 2008 analysis by the U.S. Food and Drug Administration questioned the safety of LABAs, noting that some studies had found an increased risk of asthma-related deaths in adults and asthma-related hospitalizations in children.

Based on the analysis, the FDA slapped a "boxed warning" label on the drugs, which calls attention to serious or life-threatening risks. The agency also asked GlaxoSmithKline, the manufacturer of a LABA intended for children, to perform a large-scale safety trial for its product, researchers said in background information.

The clinical trial, conducted by Szefler and his colleagues, found that children using a combination LABA/steroid inhaler -- sold as Glaxo's Advair Diskus-a powder form of fluticasone and salmeterol  ( -- did not have any greater risk of harm than children using an inhaler loaded only with a steroid.

  fluticasone   salmeterol

The results have been forwarded to the FDA, which now will decide whether to lift the black box warning, Szefler said.

"The next step is for the FDA to assemble all the available studies, make their own interpretation and determine how that would affect product labeling," he said.

The LABA/steroid combination drug is a valuable option that asthma doctors often use when inhaled steroids alone don't help kids with chronic asthma, said Dr. Alfin Vicencio, chief of pediatric pulmonology at Mount Sinai Hospital in New York City.

The boxed warning has impeded use of that option, he said.

"Not infrequently, families whose children could benefit from this medication decline on the medication specifically because of that warning," Vicencio said. "This manuscript not only gives physicians a little more reassurance, but parents as well."

In the safety trial, researchers recruited more than 6,200 children between 4 and 11 years old. They were randomly assigned inhalers containing a combination of salmeterol (a LABA) and fluticasone (a steroid), or fluticasone alone.

Of all the patients, 27 in the combination drug group had a serious asthma-related event that required hospitalization, compared with 21 in the steroid-only group. There were no deaths, and no emergencies that required insertion of a breathing tube.

The study results appear in the Sept. 1 issue of the New England Journal of Medicine.

The past safety concerns might have cropped up because patients were using an LABA without also taking a steroid alongside it, Szefler said. LABAs provide only short-term relief, and do nothing to treat the chronic airway inflammation targeted by steroids.

"In asthma, when you're using the long-acting beta agonist it should be combined with a steroid," he said.

Inhaled steroids will remain the front-line option for kids with chronic asthma, but this trial shows the combination drug is "a tool that can be used for those children that require something in addition to steroids for their persistent asthma," said Dr. Marilyn Li. She is an assistant professor of clinical pediatrics at the University of Southern California's Keck School of Medicine.

"There's been widespread fear about that kind of medication because of the long-acting beta agonist component, and unjustly so because, truthfully, for those children who have moderate to severe asthma, there is a serious unmet need," Li said.

Newer Epilepsy Drugs May Be Safer During Pregnancy

In continuation of my update on  levetiracetam and topiramate 

  Topiramate    Levetiracetam 

Women who take the new epilepsy drugs levetiracetam and topiramate during pregnancy don't run the risk of harming their infant's mental development, British researchers report.

But the commonly prescribed anti-seizure drug valproate was linked with lower IQs in children, especially when taken at higher doses, researchers say.

"The treatment of epilepsy in women who are considering a pregnancy or are pregnant involves optimizing the health of the mother as well as keeping the risk to the fetus as low as possible," said lead researcher Rebecca Bromley, a research fellow at the Institute for Human Development at the University of Manchester.

In the study, children exposed to levetiracetam (Keppra) or topiramate (Topamax) in the womb did not differ from children not exposed to these drugs. And they had better outcomes than the children exposed to valproate (Depakote) in terms of their IQ, thinking and language skills, Bromley said.

"These data can be used by doctors and women to help them make their decisions about which medication is best for them," she added.

For the study, Bromley and her colleagues used the U.K. Epilepsy and Pregnancy Register to identify 171 women with epilepsy who had a child between 5 and 9 years old. During their pregnancy, 42 of the women took levetiracetam, 27 took topiramate, and 47 took valproate, the researchers said.

Bromley's team compared the women with epilepsy with 55 women who did not take epilepsy drugs during pregnancy. The children had their IQ measured and took tests on verbal and nonverbal comprehension and how fast they could process visual information.

The researchers found that children of women who took levetiracetam or topiramate did not have lower IQs or other thinking-skill problems, compared with kids of mothers who did not take these drugs, no matter what dose of these drugs were taken.

Children whose mothers took valproate, however, had the lowest IQs of the study, Bromley said. These kids scored, on average, 11 points lower on the IQ test.

Among children whose mothers took valproate, 19 percent had IQs lower than the average score of 100, compared with 6 percent among kids whose mothers did not take any epilepsy drugs during pregnancy, the researchers found.

Because the registry the researchers used does not include all women with epilepsy, the findings might not apply to all women with the conditions, Bromley noted. She also said that topiramate, one of the newer drugs, has been associated with an increased risk of birth defects, such as cleft lip and palate.

The study was funded by Epilepsy Research U.K. and the report was published online Aug. 31 in the journalNeurology.

Dr. Ian Miller is a pediatric neurologist and medical director of the comprehensive epilepsy program at Nicklaus Children's Hospital in Miami. "This study means that we have a little bit more information for women who become pregnant while taking epilepsy medicines," he said.

The exact risks of taking any medicine during pregnancy are very difficult to know, he added.

"As a result, many questions remain," Miller said. "But this study gives doctors a reason to choose topiramate or levetiracetam, which did not show a measurable effect on the child's development, rather than valproate, which did."

Women who are on valproate because they already tried other medications and "moved on because those medications were less effective, will face some difficult decisions," he said.

"Any woman of childbearing potential should discuss this aspect of their medical management with their doctor, especially in light of these new findings," Miller added.

Researchers identify promising new drug treatment for cocaine addiction

A team of researchers led by Cardiff University has discovered a promising new drug treatment for cocaine addiction.

The experimental therapy, which involves administering a drug currently used in cancer therapy trials, treats cocaine addiction by inhibiting memories responsible for cravings.

Professor Riccardo Brambilla from Cardiff University's School of Biosciences said: "We have demonstrated that a single administration of a trial drug from the pharmacompany Pfizer can completely obliterate cocaine associated memories and significantly accelerate the end of drug seeking behaviour in animals. With this drug currently being used in cancer trials, it could be easily repositioned for treatment of cocaine addiction and other drugs of abuse."

Cocaine produces its addictive effects partially by acting on the brain's limbic system - a set of interconnected regions that regulate pleasure and motivation. When a person uses cocaine, memories of the intense pleasure felt and the things associated with it are newly created. It is these long lasting memories and drug-associated cues, key to the transition from recreational drug taking to compulsive drug use, which the new treatment inhibited when tested on mice.

Dr Stefania Fasano from Cardiff University added, "With drug use recently on the rise, new treatments for breaking addiction are much needed. The availability of a powerful drug from Pfizer, already validated in humans, could speed up the clinical development of our findings."

The research is published in the journal eLife.

This was an experimental study in mice, which allows for conclusions to be made about cause and effect in this species. To learn about the effect of this treatment in people experimental trials with humans will be necessary.

Ref : https://elifesciences.org/content/5/e17111

Combination drug therapy safe, effective in treating asthma patients

In continuation of my update formoterol and  budesonide

A post-marketing safety study mandated by the U.S. Food and Drug Administration has shown that a combination drug therapy for the treatment of asthma is safe and effective.

The therapy tested consisted of a long-acting beta agonist, formoterol, added to an inhaled glucocorticoid, budesonide.

 Formoterol     Budesonide 

"Our study showed no significant increase in serious adverse events in the combination therapy," said Stephen Peters, M.D., Ph.D., professor of pulmonary, critical care, allergy and immunologic diseases at Wake Forest Baptist Medical Center and lead author of the study.

"A large number of studies have shown that this type of combination therapy really helps asthma control and decreases symptoms. Our findings, in combination with results from another FDA-mandated safety study, are very reassuring to those of us who treat asthmatic patients."

The study is published in the Sept. 1 issue of the New England Journal of Medicine.

In this multicenter, double-blind, 26-week study, the scientists evaluated whether the addition of formoterol to budesonide maintenance therapy increased the risk of serious asthma-related events in patients with moderate to severe asthma. Study participants were age 12 or older, had persistent asthma, received daily asthma medication and had one to four exacerbations in the previous year.

Of the 11,693 patients enrolled in the study, an asthma-related event occurred in 43 patients who received the combination therapy of budesonide and formoterol and in 40 patients who received only budesonide. Two asthma-related deaths were reported in the combination arm of the study and none in the single-therapy group, which is not statistically significant.

In addition, a secondary finding showed a 16.5 percent decrease in asthma exacerbations in the combination therapy group as compared to the group receiving budesonide.

Overall, the researchers found that treatment with budesonide-formoterol was associated with a lower risk of asthma exacerbations than budesonide and a similar risk of serious asthma-related events.

Added benefit still not proven for epilepsy drug

In continuation of my updates Briviact

Brivaracetam (trade name: Briviact) has been approved since January 2016 as add-on therapy for adults and adolescents from 16 years of age with epileptic seizures. The German Institute for Quality and Efficiency in Health Care (IQWiG) had already examined the drug in an early benefit assessment published in May. For several reasons, the indirect comparisons presented by the drug manufacturer were unsuitable to assess an added benefit in comparison with the appropriate comparator therapy. Among other things, the manufacturer had not analysed all relevant outcomes. In the commenting procedure, the manufacturer presented a further indirect comparison.

In the addendum thereupon commissioned to IQWiG by the Federal Joint Committee (G-BA), the Institute has now concluded that this new indirect comparison is methodologically better. Among other things, the manufacturer has now analysed the missing outcomes. However, this indirect comparison submitted subsequently still fails to show an added benefit of brivaracetam over the appropriate comparator therapy.

New analyses only partly rectify the deficits

In its dossier assessment in May, IQWiG criticized that not all brivaracetam studies presented by the manufacturer were relevant for the benefit assessment, that the studies were insufficiently similar for informative indirect comparisons, that the manufacturer had not presented analyses of all relevant outcomes, and that the comparator therapies had not been recognizably customized for the individual patient, as demanded by the G-BA.

The new indirect comparison submitted subsequently by the manufacturer addresses the first 3 points of criticism. The brivaracetam study is relevant for the research question, the studies used for the comparison are sufficiently similar to this study, and further patient-relevant outcomes are addressed. However, the problem remains unsolved that treatment in the control arms was not customized for the individual patient and thus does not correspond to the appropriate comparator therapy.

Non-inferiority of brivaracetam questionable

Independent of the question as to whether the appropriate comparator therapy specified by the G-BA was implemented, in the overall consideration, the indirect comparison shows no advantage of brivaracetam over lacosamide. Neither advantages nor disadvantages of brivaracetam were shown in the outcome categories "mortality" and "health-related quality of life" in comparison with lacosamide.

In the category "side effects", significant effects were shown in favour of brivaracetam (for serious adverse events and some specific adverse events, such as dizziness or eye disorders). However, the available data on the morbidity outcomes "seizure frequency", "50% responder rate" and "freedom of seizure", raise doubts that brivaracetam is at least equally effective as lacosamide. For seizure frequency, the one lacosamide study fails to show a clear advantage or disadvantage of brivaracetam, while the other shows a statistically significant disadvantage of the new drug compared with lacosamide. Both lacosamide studies also deliver heterogeneous results for the two other outcomes, which, however, do not lead to statistically significant advantages or disadvantages.

Overall, the indirect comparison therefore does not show an advantage of brivaracetam over the comparator therapy.