Additional Treatments Offer Little Benefit for Pancreatic Cancer: Study

In continuation of my updates on Erlotinib, gemcitabine and capecitabine

Additional treatments for locally advanced pancreatic cancer don't appear to boost survival, a new French study reports.

Researchers looked at the effects of adding a second drug -- erlotinib (Tarceva) -- to the initial round of chemotherapy. They also tested whether adding radiation to a second round of chemotherapy (chemoradiotherapy) would offer any survival benefit.

 erlotinib (Tarceva)

Unfortunately, the addition of the second drug didn't help people live longer, and those on chemoradiotherapy didn't fare any better.

"Chemoradiotherapy was not superior to chemotherapy," said the study's senior author, Dr. Pascal Hammel. Hammel is from the department of gastroenterology-pancreatology at Beaujon Hospital, in Clichy, France.

The study was funded by the pharmaceutical company Roche, the maker of Tarceva, and the French National Institute of Cancer.

More than 53,000 Americans are diagnosed with pancreatic cancer annually, the U.S. National Cancer Institute (NCI) says. About 42,000 Americans die each year from the disease, the NCI reports.

The new study focused on 449 people with pancreatic cancer. Their average age was just over 63.

All received standard four-month chemotherapy with the drug gemcitabine (Gemzar). Gemzar is currently used to treat a range of cancers, including pancreatic, ovarian, breast, and non-small cell lung cancers, the drug's labeling information says. For the study, about half the patients (219) also took Tarceva along with Gemzar.

 gemcitabine (Gemzar).

After completing initial treatment, imaging tests revealed that 269 patients appeared to have tumors that were under control. That meant their cancer was stable and didn't appear to have spread, or metastasized.

But the tumors couldn't be surgically removed because they had developed around the arteries surrounding the pancreas, study authors said.

About half this group of stable patients (136) received two additional months of the same chemotherapy regimen. The other half (133) was treated with a combination of radiation and the chemotherapy drug capecitabine (Xeloda).

 capecitabine (Xeloda)

After three years of follow-up, the researchers found that patients given Gemzar chemotherapy alone survived an average of 13.6 months. Those given the combination of Gemzar and Tarceva had an average survival of 11.9 months, the study found.

Patients treated with chemoradiotherapy lived an average of 15.2 months. Those who got chemotherapy alone lived an average of 16.5 months, the study found.

Hammel said there's still work to be done to improve the results of both chemotherapy and radiotherapy treatments.

But for now, Dr. Deborah Schrag agreed that "the French trial demonstrates that routine addition of chemo-radiation following initial chemotherapy for patients with locally advanced pancreatic cancer does not improve survival compared to continued chemotherapy." Schrag, chief of the Division of Population Sciences, Medical Oncology, at the Dana-Farber Cancer Institute in Boston, wrote an accompanying editorial in the same issue of the journal.

"[And] given the burdens of daily radiation therapy, there is no routine role for the application of this treatment strategy," added Schrag.

Schrag said it's possible there might be a certain group of pancreatic cancer patients who could get some measurable benefit from radiation. "Further evaluation of the tumor samples from the study participants might help to more precisely determine who might benefit from radiation, and such data are eagerly awaited," she said.

Additional Treatments Offer Little Benefit for Pancreatic Cancer: Study  

Eisai Announces FDA Approval of Fycompa (perampanel) Oral Suspension

In continuation of my update on Fycompa

Eisai Inc.  announced that the U.S. Food and Drug Administration (FDA) has approved Fycompa (perampanel) CIII Oral Suspension as adjunctive therapy for the treatment of partial-onset seizures (POS) with or without secondarily generalized seizures, and primary generalized tonic-clonic (PGTC) seizures in patients with epilepsy 12 years of age and older. The oral suspension formulation is a bioequivalent, interchangeable alternative to the Fycompa tablet formulation, and is expected to be available to patients in June 2016.

"We are excited about the approval of Fycompa Oral Suspension, as it gives another option to patients with epilepsy who may have difficulty swallowing tablets or prefer liquids," said Lynn Kramer, M.D., Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai. "The development of this new formulation underscores Eisai's commitment to advancing epilepsy care by making contributions to help address the diversified needs of epilepsy patients and their families."

The approval of Fycompa Oral Suspension was based on a bioequivalence (BE) study that demonstrated BE between a single dose of perampanel oral suspension and a single dose of perampanel tablet, when administered under fasted conditions in healthy subjects.

About Fycompa

Fycompa (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older.

Fycompa is an oral medication and the first and only FDA-approved non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist. The precise mechanism by which Fycompa exerts its antiepileptic effects in humans has not been fully elucidated.

Fycompa is supplied as 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg film-coated tablets, and now in an oral suspension formulation. Fycompa has been designated by the U.S. Drug Enforcement Administration as a federally-controlled substance (CIII).

Fycompa, approved in 43 countries, was discovered and developed by Eisai. Over 60,000 patients globally have been treated with Fycompa.

Eisai Announces FDA Approval of Fycompa (perampanel) Oral Suspension

Brintellix (vortioxetine) Renamed Trintellix (vortioxetine) in U.S. to Avoid Name Confusion

In continuation of my update on vortioxetine

Takeda Pharmaceuticals U.S.A., Inc., a wholly-owned subsidiary of Takeda Pharmaceutical Company Limited (TSE:4502) (collectively “Takeda”), and Lundbeck announced today that Brintellix(vortioxetine) will be marketed in the United States under the new name Trintellix(vortioxetine) starting in June of 2016. The vortioxetine product is a prescription medicine approved to treat Major Depressive Disorder (MDD) in adults. The formulation, indication and dosages of Trintellix remain the same as that of Brintellix.

This name change comes after receiving reports of name confusion in the marketplace between Brintellix and the anti-blood clotting therapy Brilinta® (ticagrelor). In response, Takeda and Lundbeck, in coordination with the U.S. Food and Drug Administration (FDA), determined that a name change would be the best way to minimize future product name confusion by patients and providers.

“Though the original name was fully screened prior to launch, after learning about name confusion issues with Brintellix and Brilinta, we quickly took action to educate healthcare professionals and pharmacies about the potential for name confusion,” said Thomas Harris, Vice President Global Regulatory Affairs at Takeda. “Takeda and Lundbeck then proactively worked with the FDA and decided to change the name of our product as we believe this action will help minimize future risk of patients inadvertently receiving the incorrect medication.”

“Even though the name of the product is changing, together with Takeda, we will work to ensure providers and patients are aware that the vortioxetine product itself has not changed. It’s still the same medication, dosing and expected outcomes,” said Gregg Pratt, Vice President, U.S. Regulatory Affairs at Lundbeck.

“Patient safety is our utmost priority at Takeda and Lundbeck,” said Ramona Sequeira, President, U.S. Business Unit at Takeda. “Together, with our partners at Lundbeck, we will initiate a robust communication campaign and actively work to ensure that patients, healthcare professionals and pharmacies have uninterrupted access to this important medication. We believe these actions speak to our goals of building our business around patients, trust and reputation.”

During the transition period this summer, healthcare providers can still prescribe, and patients will still have access to, the product under its current brand name. The newly named Trintellix will be available in June 2016. Additionally, markings on the Trintellix tablets will be identical to the markings on tablets prior to the name change. Trintellix will have new National Drug Code (NDC) numbers associated with the product. Individuals and healthcare professionals who have questions about Brintellix, Trintellix and/or the name change, should contact Takeda at 1-877-TAKEDA-7.

Errors involving Brintellix/Trintellix or any other products should be reported to the FDA MedWatch program online at www.fda.gov/medwatch.

About Brintellix (vortioxetine), now known as Trintellix (vortioxetine), in the United States

Brintellix (vortioxetine) Renamed Trintellix (vortioxetine) in U.S. to Avoid Name Confusion

New drug against nerve agents in sight

A model of how sarin and HI-6 are positioned in the protein acetylcholinesterase just before HI-6 removes sarin and restores the function of the protein. The model was developed by a combination of X-ray crystallography and quantum chemical calculations. Sarin in magenta, HI6 in green, oxygen in red, phosphorus in orange and nitrogen in blue. 

The nerve agent sarin causes a deadly overstimulation of the nervous system that can be stopped if treated with an antidote within minutes of poisoning. Today, a ground-breaking study has been published in PNAS, which in detail describes how such a drug works. Researchers at the Swedish Defence Research Agency, Umeå University and in Germany are behind the study.

Sarin is a colourless, odourless liquid fatal even at very low concentrations. Serious sarin poisoning causes visual disturbance, vomiting, breathing difficulties and, finally, death.

"Nerve agents are dreadful weapons, and our hope is for these results to lead to improved drugs against them," says Anders Allgardsson, Biochemist at the Swedish Defence Research Agency (FOI).

Nerve agents destroy the function of a very important protein in the nervous system called acetylcholinesterase. As long as the nerve agent is bound to the protein, the breakdown of an important signal substance is prevented. The antidote HI-6 removes the nerve agent and restores the function of the nervous system. Drugs against nerve agent poisoning have been used for a long time, still it has been unclear how they actually work.

After years of hard work, chemists from FOI and Umeå University are now presenting a three-dimensional structure that depicts the HI-6 moments before the bond between the nerve agent and the protein is broken. The structure gives a high-resolution image that, in detail, describes the individual positions of atoms and provides an understanding of how the bond breaks.

The scientific breakthrough was enabled by combining three-dimensional structural depictions with advanced calculations and biochemical experiments.

"With the help of X-ray crystallography, we could see weak traces of the signal we were looking for. As the signal was weak, we decided to integrate the data with quantum chemical methods. After demanding calculations on the supercomputer at the High Performance Computing Center North (HPC2N) at Umeå University, we finally succeeded," says Anna Linusson, Professor at the Department of Chemistry at Umeå University.

The calculations supported the theory that the weak signal in the X-ray crystallography data actually came from HI-6 and sarin. Important knowledge also fell into place after experiments where the system was disturbed by mutating the protein or by introducing isotopes.

"After seven years of work using many different techniques, we have finally been able to bring this to a successful close and can show a uniform picture of how HI-6 approaches sarin. It opens up for new opportunities in finding antidotes to sarin and other nerve agents by structure-based molecular design," says Anders Allgardsson.

Ref : http://www.pnas.org/content/early/2016/04/28/1523362113

New drug against nerve agents in sight 

Experimental Alzheimer's drug reverses genetic changes thought to spur the disease

After treatment with riluzole, the brains of old rats showed more of a transporter molecule that removes excess glutamate, (green fluorescence, right) as compared to untreated rats (left).

Aging takes its toll on the brain, and the cells of the hippocampus--a brain region with circuitry crucial to learning and memory--are particularly vulnerable to changes that can lead to Alzheimer's disease or cognitive decline. With the hope of counteracting the changes that can lead to these two conditions, researchers at Rockefeller University and their colleagues have begun examining the effects of a drug known to affect this circuitry.

In new research described recently in Molecular Psychiatry, a team led by Ana Pereira, Instructor in Clinical Medicine in Bruce McEwen's laboratory found that the drug, riluzole, is capable of reversing key genetic changes associated with these conditions.

 riluzole

"In aging and Alzheimer's, the chemical signal glutamate can accumulate between neurons, damaging the circuitry," Pereira says. "When we treated rats with riluzole, we saw a suite of changes. Perhaps most significantly, expression of molecules responsible for clearing excess glutamate returned to more youthful levels."

Previous work in McEwen's lab by Pereira has shown that the drug prompted structural changes in rats' neurons that prevent the memory loss often seen in old animals. Pereira is currently testing riluzole for the first time in Alzheimer's patients in a clinical trial at the Rockefeller University Hospital.

Glutamate clean up

Generally, glutamate is released to excite other neurons and doesn't linger in the spaces between them. As we age, though, the system gets a little leaky and glutamate can build up in these intercellular spaces. This happens in part when neurons make less and less of the transporter molecule responsible for removing excess glutamate. When it accumulates, this essential neurotransmitter can cause big problems, damaging or killing neurons and so contributing to Alzheimer's disease, and other disorders.

Pereira and co-first author Jason Gray, a postdoc in the lab sought to better understand the molecular vulnerabilities of an aging glutamate system and riluzole's effect on it.

"The essence is we used a drug known to modulate glutamate, and when we gave it to old rats, we saw it reversed many of the changes that begin in middle age in the hippocampus," Gray says. "We saw a similar pattern when we compared the riluzole-induced changes to data from Alzheimer's patients--in a number of key pathways in the hippocampus, the drug produced an effect opposing that of the disease."

The drug, it turns out, modifies the activity of certain genes in an aged animal to resemble that of a younger rat. For example, the researchers found that the expression of a gene called EAAT2, which has been linked to Alzheimer's and is known to play a role in removing excess glutamate from nerve fibers, declines as the animals age. However, in rats treated with riluzole this gene's activity was brought back to its youthful levels.

New targets for treatments?

In addition to its potential ability to allay memory loss and cognitive decline, riluzole is attractive as a potential treatment for Alzheimer's. The drug is already being used to treat another neurological disease, amyotrophic lateral sclerosis, and is therefore considered relatively safe. In Pereira's ongoing clinical trial, patients with Alzheimer's disease have thus far been treated with either the drug or a placebo, and have been undergoing tests to help determine whether their brain functions have been improved.

"We hope to use a medication to break the cycle of toxicity by which glutamate can damage the neurons that use it as a neurotransmitter, and our studies so far suggest that riluzole may be able to accomplish this," Pereira says. "We found that in addition to recovering the expression of EAAT2, the drug restored genes critical for neural communication and plasticity, both of which decline with aging and even more significantly in Alzheimer's disease."

The findings also help to lay the groundwork for further study of glutamate transporters as potential targets for treating both conditions.

Ref : http://newswire.rockefeller.edu/2016/05/02/an-experimental-alzheimers-drug-reverses-genetic-changes-thought-to-spur-the-disease/

Ref : http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201633a.html

Experimental Alzheimer's drug reverses genetic changes thought to spur the disease  

Screening method uncovers drugs that may combat deadly antibiotic-resistant bacteria

In recent years, hospitals have reported dramatic increases in the number of cases of the highly contagious, difficult-to-treat, and often deadly antibiotic-resistant bacteria carbapenem-resistant Enterobacteriaceae (CRE). Now, investigators at Beth Israel Deaconess Medical Center (BIDMC) have developed a promising method of identifying new antimicrobials that target these organisms. The research is published in April issue of the journal ASSAY and Drug Development Technologies.

CRE are Gram-negative bacteria that frequently express a gene that codes for carbapenemase--an enzyme that breaks down carbapenem and other antibiotics--and that is located on "mobile genetic elements" called plasmids, which can jump from one bacterium to another. The two most common types of CRE are carbapenem-resistant Klebsiella species and carbapenem-resistant Escherichia coli. Patients who become infected with these bacteria have few antibiotic treatment options.

"The US Centers for Disease Control and Prevention recently classified these carbapenem-resistant organisms in their highest, most urgent antimicrobial resistance threat level," said James Kirby, MD, Director of the Clinical Microbiology Laboratory at BIDMC and an Associate Professor of Pathology at Harvard Medical School. "Unfortunately, often either no effective or only toxic antimicrobial options remain for CRE treatment. Moreover, CRE are particularly frightening as they are now increasing in prevalence across the United States and the world."

While there is a critical need for new antimicrobial agents against CRE and other emerging antibiotic-resistant bacteria, the number of new antibiotics that have been developed and approved has steadily decreased in recent decades. To identify new or existing drugs that can destroy multidrug-resistant CRE, Kirby and postdoctoral fellow Kenneth Smith, PhD examined approximately 10,000 compounds with known activity--so called known bioactive molecules--including most previously FDA-approved drugs, veterinary drugs and inhibitors of various cellular processes not currently used as therapeutics.

Through a process called high throughput screening, the investigators looked to see whether any of these compounds could either directly inhibit the growth of CRE or restore the effectiveness of carbapenem against these organisms.

From these screening experiments, 79 compounds were found to inhibit CRE. Of these, three had already been approved for human and veterinary use: azidothymidine (also known as AZT, a therapy for HIV infection), spectinomycin (a treatment for gonorrhea infection) and apramycin (a veterinary antimicrobial). When tested against a large number of CRE strains, the three compounds were broadly active against the strains.

azidothymidine, Spectinomycin

 Apramycin

"These antimicrobials currently have other intended uses and are not currently considered as treatments for CRE, however our findings suggest they could potentially be repurposed for CRE treatment," said Smith. Apramycin and spectinomycin are of particular interest because they have minimal side effects, making them potentially ideal new therapeutic options for CRE infection.

Smith added that while these drugs might be used by themselves to treat CRE infection, they could also be used as starting points for further drug development. "Specifically, these antibiotics could be structurally modified to further increase their activity and prevent resistance from developing against them," he explained.

The next step in this line of research is to examine the potency of the identified drugs in an animal model of CRE infection. "We are also using the same high throughput screening technology to investigate a collection of more than 200,000 completely novel compounds with as yet uncharacterized biological activity in the hopes of identifying new classes of compounds with potent activity against CRE and other multi-drug resistant pathogens," Kirby said.

Ref : http://online.liebertpub.com/doi/10.1089/adt.2016.701

Screening method uncovers drugs that may combat deadly antibiotic-resistant bacteria 

New drug more effective in treating atrial fibrillation

Vernakalant, a new drug for treating recent-onset atrial fibrillation, has proved to be considerably more effective than Ibutilide, an established drug in this indication. It was able to normalize patients' heart rhythm more rapidly and with fewer side-effects ocurring. This was revealed by a study conducted at the Department of Emergency Medicine at Medical University of Vienna/General Hospital that has recently been published in Europace, a journal of the European Society of Cardiology.

 Vernakalant   Ibutilide 

Atrial fibrillation, the most common cardiac arrhythmia, accounts for many medical consultations, hospitalisations and is associated with a high economical burden. Atrial fibrillation affects 2% of the population and its prevalence increases significantly with age (to more than 10% in those over 80). Typical symptoms are sensation of a rapid and irregular heartbeat, dizziness and shortness of breath. In recent onset atrial fibrillation the aim is to restore a normal, regular heartbeat (sinus rhythm) as quickly as possible. This can be achieved either by electrical therapy or by drugs, so called antiarrhythmics.

Two potent antiarrhythmic drugs, Vernakalant (Brinavess) and Ibutilide (Corvert), which is particularly suitable for treating atrial flutter, were compared in a randomized trial at the Department of Emergency Medicine at Medical University of Vienna.

Vernakalant was found to have significant advantages: it achieved conversion to a normal sinus rhythm within an average of 10 minutes, compared to Ibutilide with an average of 26 minutes. 90 minutes after treatment start, 69% of Vernakalant treated patients were in sinus rhythm, compared to 43% of patients treated with Ibutilide.

Consequently, electrical cardioversion under brief anesthesia was less often required to restore sinus rhythm in the Vernakalant group. "Furthermore, in Vernakalant pretreated patients sinus rhythm could be restored easier, necessitating a lower number of shocks," explains study author Alexander Spiel.

Therefore, Ibutilide remains first choice for treating patients with atrial flutter. However, the results of this trial show that in patients with recent onset atrial fibrillation and with no or moderate structural heart disease Vernakalant has several advantages. "In this trial, none of the patients from either group experienced any serious adverse side effects," emphasizes study author Hans Domanovits.

Ref : http://europace.oxfordjournals.org/content/early/2016/03/21/europace.euw052

 New drug more effective in treating atrial fibrillation  

Expand prescribing of buprenorphine for opioid abuse? Experts weigh pros and cons....

In continuation of my update on Buprenorphine

Buprenorphine is a critical part of treatment for the growing epidemic of opioid abuse--but also carries the potential for misuse and diversion. The debate over whether 'to expand or not to expand' prescribing of buprenorphine for opioid abuse is discussed in an expert review in the Journal of Psychiatric Practice, published by Wolters Kluwer.

Based on the strong evidence of effectiveness, "We should not limit or impede the use and expansion of buprenorphine therapy," write Drs. Xiaofan Li, Daryl Shorter, and Thomas Kosten, of the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. They propose specific strategies to promote buprenorphine use while ensuring quality of care and reducing the risk of diversion and abuse.

Focus on Expanding Buprenorphine Use 'Safely and Effectively'

A "partial agonist" of the μ-opioid receptor in the brain, buprenorphine has similar actions to other opioids, but with less potential for abuse and a more favorable safety profile. Because it reduces demand for opioids, buprenorphine therapy is an effective deterrence strategy to combat opioid abuse. The authors cite studies suggesting that access to buprenorphine therapy can sharply reduce heroin mortality--including reductions of more than 50 percent in France and 37 percent in Baltimore.

Compared to methadone--long the standard for treating opioid and heroin addiction--buprenorphine poses lower risks related to diversion and non-medical use. The most commonly prescribed form of buprenorphine includes the opioid antagonist (blocker) naloxone, decreasing the potential for intravenous abuse.

But there are strict controls on prescribing of buprenorphine, which is classified as a Schedule III controlled substance in the United States. To prescribe buprenorphine in office-based settings, physicians must receive a Drug Enforcement Agency (DEA) waiver, complete special training, and comply with limits on the number of treated patients.

While medical use of buprenorphine has skyrocketed over the past decade, most prescribers are located in urban areas. It is estimated that 53 percent of US counties do not have any physician with a DEA waiver to prescribe buprenorphine.

Measures to make buprenorphine treatment more accessible have been proposed, such as allowing prescribing by qualified advanced nurse practitioners and physician assistants and loosening limits on number of patients treated. But these measures have been controversial, reflecting legitimate concerns about increased potential for diversion and abuse. Data show that, as use of buprenorphine to treat opioid use disorder has increased, so have the rates of misuse and diversion.

Drs. Li, Shorter, and Kosten raise special concern about the recent emergence of intravenous buprenorphine abuse. They write, "This real-world, almost paradoxical, phenomenon demonstrates the complexity inherent in the treatment of addictive disorders--a medication intended to treat substance use disorder that has its own abuse potential, upon gaining popularity and increased availability, will inevitably be explored by drug abusers for reward and reinforcement purposes."

Earlier this year, President Obama announced an initiative to increase access to effective medications for treating opioid addiction--specifically, buprenorphine and naloxone. Drs. Li, Shorter, and Kosten outline strategies to expand effective treatment with buprenorphine while reducing the risks of diversion and abuse, including:

• Additional support for physicians with high caseloads and other measures to help prescribers comply with guidelines.
• Continuing medical education targeting improvements in office-based therapy for opioid abuse.
• Policies and regulations promoting safe practice.
• Financial incentives coupled with mandatory enforcement of essential components of safe practice.
• More active pharmacy involvement, including supervised dispensing.
• Identification of groups at high risk of intravenous buprenorphine abuse.

"The question is not whether or not to expand buprenorphine prescribing," the authors add. "It is how to expand buprenorphine prescribing safely and effectively."

Ref :1. http://journals.lww.com/practicalpsychiatry/pages/articleviewer.aspx?year=2016&issue=05000&article=00004&type=abstract

 http://dx.doi.org/10.1097/PRA.0000000000000154

Expand prescribing of buprenorphine for opioid abuse? Experts weigh pros and cons 

Ibrutinib: Indication of added benefit in one of three therapeutic indications...

In continuation of my update on Ibrutinib

Ibrutinib is a drug for the treatment of rare diseases. It has been approved for the treatment of adults with chronic lymphocytic leukemia (CLL) or with relapsed or refractory mantle cell lymphoma (MCL) since 2014, and since 2015 also for the treatment of adults with Waldenström macroglobulinaemia. Regarding the treatment of patients with CLL or MCL, the Federal Joint Committee (G-BA) already conducted a benefit assessment and made a decision in 2015.

On request of the G-BA, the drug manufacturer now submitted a new dossier because the turnover of the drug in the statutory health insurance exceeded 50 million euros in the preceding 12 months. The German Institute for Quality and Efficiency in Health Care (IQWiG) therefore examined in an early benefit assessment whether the drug offers an added benefit for patients with these diseases in comparison with the respective appropriate comparator therapies.

According to the findings, there is no hint of an added benefit in CLL and Waldenström macroglobulinaemia. In relapsed or refractory mantle cell lymphoma, there is an indication of major added benefit of ibrutinib for patients for whom temsirolimus is the individually optimized treatment option. An added benefit is not proven for patients for whom temsirolimus is no or only a secondary option.

Chronic lymphocytic leukemia

The G-BA differentiated between pretreated and treatment-naive patients within the therapeutic indication of CLL. Pretreated patients were separated into two subpopulations, resulting in three research questions.

Pretreated patients for whom chemotherapy is indicated were to be treated with individually optimized chemotherapy in the comparator arm. The manufacturer presented no relevant data for these patients in its dossier: The direct comparison and the indirect comparisons conducted by the manufacturer were unsuitable for the derivation of an added benefit of ibrutinib.

Pretreated patients for whom such chemotherapy is not an option were to be treated with idelalisib or best supportive care in the comparator arm. A non-quantifiable advantage in the outcome "mortality," but also potentially lesser benefit of ibrutinib in morbidity and health-related quality of life as well as potentially greater harm in severe and serious side effects resulted from the study data presented. In the consideration of the beneficial and harmful effects, an added benefit is therefore not proven for these patients either.

Idelalisib or best supportive care constituted the appropriate comparator therapy also for treatment-naive patients for whom chemo-immunotherapy is unsuitable due to mutations. The manufacturer presented only one study irrelevant for the research question so that an added benefit is not proven for this patient group either.

Waldenström macroglobulinaemia

Pretreated and treatment-naive patients were to be considered separately also in the therapeutic indication Waldenström macroglobulinaemia. In both cases, the appropriate comparator therapy was individually optimized treatment specified by the physician.

The manufacturer presented no data on first-line treatment so that an added benefit of ibrutinib for treatment-naive patients is not proven.

Regarding patients who have received at least one treatment, the manufacturer submitted a historical comparison based on uncontrolled studies because there were no randomized controlled trials. Due to the selective choice of data, among other reasons, this comparison was unsuitable for drawing conclusions on the added benefit. Hence there was no hint of an added benefit in this case either.

Relapsed or refractory mantle cell lymphoma

Two subpopulations have to be differentiated also in relapsed or refractory MCL: patients for whom temsirolimus is the individually optimized treatment, and patients for whom this is not the case.

Due to a lack of data, an added benefit of ibrutinib is not proven for patients for whom temsirolimus is no or only a secondary treatment Option.

For the other patient group, in contrast, the manufacturer presented data from the study MCL3001, in which ibrutinib was compared with temsirolimus. There was no statistically significant difference between the study arms regarding overall survival. Ibrutinib had positive effects in the outcomes "health status" and "side effects," which were not offset by negative effects in other outcomes. Overall, there is therefore an indication of major added benefit for patients for whom temsirolimus constitutes the individually optimized treatment.

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

Ibrutinib: Indication of added benefit in one of three therapeutic indications

Current cancer drug discovery method flawed, study suggests: Researchers develop new approach to assess drug sensitivity in cells ..

The primary method used to test compounds for anti-cancer activity in cells is flawed, Vanderbilt University researchers report May 2 in Nature Methods. The findings cast doubt on methods used by the entire scientific enterprise and pharmaceutical industry to discover new cancer drugs.

"More than 90 percent of candidate cancer drugs fail in late stage clinical trials, costing hundreds of millions of dollars," said Vito Quaranta, M.D., director of the Quantitative Systems Biology Center at Vanderbilt. "The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact."

Quaranta and his colleagues have developed a new metric to evaluate a compound's effect on cell proliferation -- called the DIP (drug-induced proliferation) rate -- that overcomes the flawed bias in the traditional method.

For more than 30 years, scientists have evaluated the ability of a compound to kill cells by adding the compound to cells and counting how many cells are alive after 72 hours. But these "proliferation assays" that measure cell number at a single time point don't take into account the bias introduced by exponential cell proliferation, even in the presence of the drug, said Darren Tyson, Ph.D., co-author and research assistant professor of Cancer Biology.

"Cells are not uniform; they all proliferate exponentially, but at different rates," said Quaranta, professor of Cancer Biology. "At 72 hours, some cells will have doubled three times and others will not have doubled at all."

In addition, he noted, drugs don't all behave the same way on every cell line -- for example, a drug might have an immediate effect on one cell line and a delayed effect on another.

In a close collaboration with computational biologist Carlos Lopez, assistant professor of Cancer Biology, Quaranta's team used a systems biology approach -- a mixture of experimentation and mathematical modeling -- to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

"Systems biology is what really makes the difference here," Quaranta said. "It's about understanding cells -- and life -- as dynamic systems."

Tyson, an experimentalist, conceived the method with Leonard Harris, Ph.D., a systems biology postdoctoral fellow and co-first author Peter Frick, Ph.D., a recent Vanderbilt graduate.

The findings have particular importance in light of recent international efforts to generate data sets that include the responses of "thousands of cell lines to hundreds of compounds," Quaranta said. The Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases include drug response data along with genomic and proteomic data that detail each cell line's molecular makeup.

"The idea is to look for statistical correlations -- these particular cell lines with this particular makeup are sensitive to these types of compounds -- to use these large databases as discovery tools for new therapeutic targets in cancer," Quaranta said. "If the metric by which you've evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good." The researchers evaluated the responses of four different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric -- used for the CCLE and GDSC databases -- and with the DIP rate. In one cell line, they found a stark disagreement between the two metrics.

"The static metric says that the cell line is very sensitive to vemurafenib. However, our analysis shows this is not the case," Harris said. "A brief period of drug sensitivity, quickly followed by rebound, fools the static metric, but not the DIP rate."

The findings "suggest we should expect melanoma tumors treated with this drug to come back, and that's what has happened, puzzling investigators," Quaranta said. "DIP rate analyses may help solve this conundrum, leading to better treatment strategies."

The DIP rate metric offers another advantage -- it can reveal which drugs are truly cytotoxic (cell-killing), rather than merely cytostatic (cell growth-inhibiting). Although cytostatic drugs may initially have promising therapeutic effects, they may leave tumor cells alive that then have the potential to cause the cancer to recur.

Quaranta noted that using the DIP rate is possible because of advances in automation, robotics, microscopy and image processing.

His team has developed a software package that will be available to other researchers through a hyperlink in the Nature Methods paper. Quaranta is working with the Vanderbilt Center for Technology Transfer and 

Current cancer drug discovery method flawed, study suggests: Researchers develop new approach to assess drug sensitivity in cells  

FDA Approves Bayer's Gadavist (gadobutrol) Injection for use with Magnetic Resonance Angiography of Supra-Aortic Arteries

Bayer announced  that the U.S. Food and Drug Administration (FDA) has approved Gadavist (gadobutrol) injection for use with magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates).1 The FDA approval is based on the results of two, multi-center, Phase 3, open-label clinical studies – the GEMSAV study of patients with known, or suspected vascular disease, of the supra-aortic arteries and the GRAMS study of patients with known or suspected renal artery disease. 

"Until now, no contrast agents were FDA approved for use with MRA of the supra-aortic arteries," said Dr. Elias Melhem, M.D., Chair, Department of Diagnostic Radiology & Nuclear Medicine, University of Maryland, and principal investigator for the GEMSAV study. "With FDA's action, radiologists now have an approved MRA contrast agent to help visualize supra-aortic arteries in patients with known or suspected supra-aortic arterial disease, including conditions such as prior stroke or transient ischemic attack (TIA)."

In the GEMSAV and GRAMS studies, gadobutrol met the primary objective of superior assessability (ability to see more vessel segments) and non-inferior sensitivity and specificity as compared to non-contrast MRA. Gadobutrol-enhanced MRA demonstrated statistically significant higher assessability (visualization) versus non-contrast MRA images.

"Bayer is delighted to obtain FDA approval for the use of Gadavist for MRA to evaluate known or suspected supra-aortic or renal artery disease," said Dennis Durmis, Vice President of Radiology Commercial Operations – Region Americas. "As an industry leader in contrast media, this is the third expansion of the Gadavist label in the past 24 months based on a robust clinical development program."

Collegium Receives FDA Approval for Xtampza ER, an Analgesic with Abuse-Deterrent Properties

In continuation of my update on oxycodone

Collegium Pharmaceutical, Inc.   announced that the U.S. Food and Drug Administration (FDA) approved Xtampza ER (oxycodone) extended-release (ER) capsules CII, a twice-daily, oxycodone medication for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Xtampza ER is Collegium’s first product utilizing its proprietary DETERx® technology platform, and is designed to provide adequate pain control while maintaining its drug release profile after being subjected to common methods of manipulation including chewing and crushing the product prior to administration. The Xtampza ER label contains information supporting the administration of the product by sprinkling the capsule contents on soft foods or into a cup, and then directly into the mouth, or through a gastrostomy or nasogastric feeding tube.

“The FDA approval of Xtampza ER is a major milestone for Collegium. Our DETERx technology platform was developed internally and our lead product completed an extensive battery of abuse-deterrent testing consistent with the FDA Guidance on Abuse-Deterrent Opioids. Collegium is committed to supporting responsible, appropriate prescribing for only those patients suffering from chronic pain who don’t have alternative non-opioid treatment options. Xtampza ER will provide clinicians with another treatment option for these patients,” said Michael Heffernan, CEO of Collegium.

Exelixis Announces FDA Approval of Cabometyx (cabozantinib) for Patients with Advanced Renal Cell Carcinoma

In continuation of my update on  cabozantinib

Exelixis, Inc.   announced that the U.S. Food and Drug Administration (FDA) has approved Cabometyx (cabozantinib) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. RCC is the most common form of kidney cancer in adults. Cabometyx, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first therapy to demonstrate in a phase 3 trial for patients with advanced RCC, robust and clinically meaningful improvements in all three key efficacy parameters — overall survival, progression-free survival and objective response rate.

“With  this announcement, patients with previously treated advanced kidney cancer now have a new option, the first and only approved product demonstrated to help patients live longer while also delaying the progression of their cancer,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “We are proud to bring new hope to this community, who are looking for more therapies that can help extend lives. Exelixis is committed to making Cabometyx available to patients in need within the next couple weeks.”

“The efficacy profile demonstrated by Cabometyx in the METEOR trial, now complemented by the overall survival benefit, is highly compelling,” said Toni Choueiri, MD, Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “Cabometyx is distinct from other approved treatment options, as it targets multiple tyrosine kinases involved in the development of RCC, including MET, AXL and three VEGF receptors. At the same time, physicians are very familiar with this class of drug and how to use dose adjustments to balance safety and efficacy. The approval of Cabometyx is wonderful news for physicians who are looking for a new option for their previously treated patients with advanced kidney cancer.”

The approval of Cabometyx is based on results of the phase 3 METEOR trial, which met its primary endpoint of improving progression-free survival. Compared with everolimus, a standard of care therapy for second-line RCC, Cabometyx was associated with a 42 percent reduction in the rate of disease progression or death. Median progression-free survival for cabozantinib was 7.4 months versus 3.8 months for everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). Cabometyx also significantly improved the objective response rate compared with everolimus. These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.

As announced in February 2016, Cabometyx also demonstrated a statistically significant and clinically meaningful increase in overall survival in the METEOR trial. Compared with everolimus, Cabometyx was associated with a 34 percent reduction in the rate of death. Median overall survival was 21.4 months for patients receiving Cabometyx versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).