Allergan Receives FDA Approval of Teflaro (ceftaroline fosamil) for Pediatric Patients

Allergan plc, a leading global pharmaceutical company,  announced the U.S. Food and Drug Administration (FDA) has approved the company's supplemental New Drug Application (sNDA) for Teflaro (ceftaroline fosamil), granting new indications for pediatric patients 2 months of age to less than 18 years of age with acute bacterial skin and skin structure infections (ABSSSI), including infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and community-acquired bacterial pneumonia (CABP) caused by Streptococcus pneumoniae and other designated susceptible bacteria.

"The impact of ABSSSI and CABP among children is significant, as these infections often require hospitalization and are met with limited pediatric treatment options, particularly as resistance increases among the pathogens that cause these infections," said David Nicholson, Chief R&D Officer, Allergan. "These new indications are yet another testament to our ongoing research and development in anti-infectives to address the evolving challenges of serious infections. Importantly, it allows us to educate physicians on the data they need to prescribe Teflaro to appropriate pediatric patients in need of an option that is safe and effective against some of the most difficult-to-treat pathogens in ABSSSI and CABP."

ABSSSI and CABP are common causes of healthcare visits and hospitalizations among children. Studies show more than 70,000 hospitalizations for ABSSSI occur among children per year – a rate that has more than doubled over the past 13 years.1 A study conducted by the Centers for Disease Control and Prevention (CDC) also found children younger than 5 years of age accounted for 70 percent of children hospitalized for community-acquired pneumonia.

These new indications were approved based on results from clinical studies evaluating TEFLARO in pediatric patients (2 months to less than 18 years of age), including one active-controlled study in ABSSSI and two active-controlled studies in CABP. In the ABSSSI active-controlled study, the efficacy and safety of Teflaro was compared with vancomycin or cefazolin (each with optional aztreonam). In the CABP studies, Teflaro was compared with ceftriaxone. Use of Teflaro in pediatric patients 2 months to less than 18 years of age is supported by evidence from adequate and well-controlled studies of Teflaro in adults, as well as additional pharmacokinetic and safety data from pediatric trials.

The primary objective of the pediatric ABSSSI and CABP studies was to evaluate the safety and tolerability of Teflaro. These studies were not powered for comparative inferential efficacy analysis, and no efficacy endpoints were identified as primary.

To evaluate the treatment effect of Teflaro in the ABSSSI pediatric trial, an analysis was conducted in 159 patients with ABSSSI in the Modified Intent-to-Treat (MITT) population. This analysis evaluated responder rates based on achieving both cessation of lesion spread and absence of fever on Study Day 3. Patients treated with Teflaro showed a higher response at Study Day 3 versus the comparator group, with clinical response achieved in 80.4 percent (86/107) of patients treated with Teflaro and 75 percent (39/52) of patients in the comparator group, with a treatment difference of 5.4 percent (95 percent Confidence Interval [CI] -7.8, 20.3). Clinical cure rates at the test of cure (TOC) visit (8 to 15 days after the end of therapy) for the ABSSSI pediatric trial were 94.4 percent (101/107) for patients treated with Teflaro and 86.5 percent (45/52) for the comparator, with a treatment difference of 7.9 (95 percent CI -1.2, 20.2).

To evaluate the treatment effect of Teflaro in the CABP trial submitted for this pediatric filing, an analysis was conducted in 143 patients with CABP in the MITT population. This analysis evaluated responder rates at Study Day 4 based on achieving improvement in at least two out of seven symptoms (cough, dyspnea, chest pain, sputum production, chills, feeling of warmth/feverish and exercise intolerance or lethargy), and worsening in none of these symptoms. The clinical response at Study Day 4 was 69.2 percent (74/107) for patients treated with Teflaro and 66.7 percent (24/36) for the comparator, with a treatment difference of 2.5 percent (95 percent CI -13.9, 20.9). Clinical cure rates at TOC were 87.9 percent (94/107) for patients treated with TEFLARO and 88.9 percent (32/36) for the comparator, with a treatment difference of -1.0 (95 percent CI -11.5, 14.1).

Results from the clinical studies in pediatric patients showed that Teflaro demonstrated a safety profile that was compatible with treatment of ABSSSI and CABP at the clinical dosages studied. The safety findings were similar to those seen in the adult studies, and no safety concerns were identified beyond those already known to be cephalosporin class effects.

Teflaro is the first and only cephalosporin indicated in adults and pediatric patients 2 months of age and older for the treatment of ABSSSI and CABP due to designated susceptible pathogens that can be administered by intravenous (IV) infusion in five minutes to one hour.

Allergan Announces FDA Approval of Byvalson (nebivolol and valsartan) for Hypertension

In continuation of my update on nebivolol and valsartan

Allergan plc (NYSE: AGN), a leading global pharmaceutical company,  announced the approval of Byvalson (nebivolol and valsartan) 5 mg/ 80 mg tablets, by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension to lower blood pressure. Byvalson is the first and only fixed-dose combination (FDC) of a beta blocker (BB) and angiotensin II receptor blocker (ARB) available in the U.S.

 nebivolol  Valsartan

"Achieving blood pressure control is critical to reducing the risk of serious and life-threatening cardiovascular events. There remains a need for new therapies, as observed by the nearly half of patients in the U.S. who remain uncontrolled," said David Nicholson, Chief R&D Officer at Allergan. "We are pleased with the FDA approval of Byvalson, which will provide physicians a new fixed dose combination therapy treatment option for patients affected by hypertension."

Hypertension represents a significant public health problem with high prevalence in the U.S. Hypertension often has no warning signs or symptoms and has been associated with serious cardiovascular (CV) risks, such as stroke, heart failure, and myocardial infarction. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the beta-blocker class to which nebivolol principally belongs and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Byvalson.

"The majority of patients with hypertension require two or more medications to achieve their blood pressure goals," said William B White, MD Professor of Medicine and Chief of the Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center at UConn Health in Farmington and immediate past president of the American Society of Hypertension. "Nebivolol and valsartan are used widely in the management of hypertension and are effective drugs. The new fixed-dose combination Byvalson, that includes these 2 therapies, offers reduction of blood pressure through multiple mechanisms of action."

The FDA approval of Byvalson was based on a Phase 3, double-blind, placebo-controlled, dose-escalating, 8-week efficacy and safety study, published in The Lancet, which randomized approximately 4,100 patients with Stage 1 or 2 hypertension. In this pivotal efficacy and safety study, treatment with the FDC of nebivolol and valsartan for 4 weeks demonstrated statistically significant reductions from baseline in diastolic and systolic blood pressure versus either nebivolol alone or valsartan alone. The overall rate of adverse events was similar across treatment groups and placebo during this 4 week period.

Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease

In continuation of my update on dimethylfumarate 

The metabolite of a drug that is helping patients battle multiple sclerosis appears to significantly slow the onset of Parkinson's disease, researchers say.

The oral drug, dimethylfumarate, or DMF, and its metabolite, monomethylfumarate, or MMF, both increase activity of Nrf2, a protein that helps protect the body from oxidative stress and inflammation, hallmarks of both diseases, said Dr. Bobby Thomas, neuroscientist in the Department of Pharmacology and Toxicology at the Medical College of Georgia at Augusta University.

 dimethylfumarate  monomethylfumarate, 

But the new study provides the first evidence that the metabolite, which is essentially the active portion of the parent drug, more directly targets Nrf2, potentially reducing known side effects of the parent drug that include flushing, diarrhea, nausea, vomiting, abdominal pain and the brain infection encephalopathy, said Thomas, corresponding author of the study in The Journal of Neuroscience.

Particularly, the gastrointestinal side effects can exacerbate some problems patients with Parkinson's already experience, said Dr. John Morgan, neurologist, neuroscientist and Parkinson's disease specialist in the MCG Department of Neurology. In addition to destroying neurons in the brain that produce dopamine, a neurotransmitter that enables movement and learning, Parkinson's causes nerve cell death in the gastrointestinal tract and related problems such as severe constipation.

"Nrf2 is a natural protective mechanism we have for oxidative stress," Thomas said. The fact that multiple sclerosis and Parkinson's have in common evidence of declining activity of the Nrf2 pathway has generated interest in the drug for Parkinson's and other neurodegenerative diseases.

DMF was approved for multiple sclerosis three years ago by the Food and Drug Administration. While its metabolite MMF is not quite as potent as the parent drug in increasing Nrf2 activity, the new study indicates that its action is sufficient to dramatically slow the loss of dopamine-producing neurons as well as the parent drug, in an animal model of Parkinson's.

In their model, mice given the neurotoxin MPTP experience a dramatic loss of dopamine-producing neurons, losing about half within a handful of days, and rapidly develop Parkinson's-like symptoms. Patients, on the other hand, slowly develop symptoms over many years. By the time they seek medical care, patients may have lost 30-50 percent of their dopaminergic neurons, said Morgan, a study coauthor. "Presentation is after the disease is kind of out of the gate."

To accommodate the very compressed timeline in their model and the fact that several daily doses are needed before the drug starts to work, the researchers first gave the mice either the drug or metabolite the day before they started the toxin.

Dopamine-producing neurons are located in a darker-pigmented central portion of the brain called the substantia nigra. Even in the absence of disease, making dopamine is a stressful job for these neurons that makes them generally more fragile and actually results in oxidative stress even in a healthy scenario, Morgan said. To make a difficult situation worse, increased oxidative stress can make dopamine toxic to neurons, he said.

To increase Nrf2 activity, the parent drug DMF also appears to first make bad matters worse. DMF increases oxidative stress by depleting the natural antioxidant, glutathione, and reduces the power of cell powerhouses, called mitochondria, by limiting their ability to use oxygen and glucose to make energy leading to reduced viability of dopamine-producing cells, Thomas said.

The metabolite MMF appears to more directly activate Nrf2, and actually increases glutathione and improves mitochondrial function, brain cell studies showed. While the parent drug ultimately produces a higher Nrf2 activation, the researchers found the MMF effect was sufficient to stop the dramatic neuron loss in the animal model.

Both DMF and MMF slowed neuron loss to a more normal level, and the neurons that survived continued to make dopamine. Inflammation and oxidative stress levels also were significantly reduced, the researchers said.

As a next step, they are working toward a clinical trial of MMF in patients with early Parkinson's disease. Although the metabolite could be easily formulated for humans, it has not yet been done, Thomas notes.

"If we can catch them early enough, maybe we can slow the disease," Morgan said. "If it can help give five to eight more years of improved quality of life that would be great for our patients."

Clinical studies of the drug in Parkinson's are being planned in the United Kingdom and additional analogues of its metabolite, which could be used clinically and which the researchers think ultimately will be the best option for patients, are under development.

Oxidative stress is a byproduct of the body's use of oxygen. Free radicals, generated by oxygen use, are unstable molecules that can interfere with usual cell function and are believed to contribute to a wide range of conditions from normal aging to Alzheimer's disease. Simply giving antioxidants, such as vitamin E, which work more like scavengers to scarf up free radicals, has not worked in combating neurodegenerative disease, Thomas said. He's optimistic that directly targeting Nrf2 will be effective in at least slowing the disease, but there remains a need for clinically safe Nrf2 activators.

Activity of the Nrf2 pathway tends to slowly decline with age. Exercise upregulates Nrf2, and Morgan regularly encourages his patients to be as active as possible. A small group of patients with Parkinson's in Europe has a concentrated activation of Nrf2 that at least delays their disease onset. Parkinson's tends to be diagnosed in the mid-to-late 50s and early 60s and is more common in men.

One concern with chronically elevating anti-oxidant and anti-inflammatory molecules with drugs like DMF and MMF is creating some of the same problems that immunosuppressive drugs given to organ transplant patients create. Chronic suppression of the immune response makes patients more susceptible to invaders like cancers and infections.

Ref : http://www.jneurosci.org/content/36/23/6332.short?sid=e7a934c5-6996-4fff-bfa9-f2c600507e1f

Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease

Researchers identify promising new compound for targeting triple-negative breast cancer

Researchers at the University of Michigan have identified a promising new compound for targeting one of the most aggressive types of breast cancer.

The compound, currently called UM-164, goes after a kinase known to play a role in the growth and spread of triple-negative breast cancer. UM-164 blocks the kinase c-Src and inhibits another pathway, p38, involved in this subtype. The researchers also found that the compound had very few side effects in mice.

"Triple-negative breast cancer is in dire need of new drugs. The treatments that have dramatically improved breast cancer outcomes don't apply to patients with this type of disease," says senior study author Sofia Merajver, M.D., Ph.D., scientific director of the breast oncology program at the University of Michigan Comprehensive Cancer Center.

Triple-negative breast cancer is more aggressive than other types of breast cancer. Patients are much more likely to see their cancer recur and spread. Currently there are no approved targeted therapies for triple-negative breast cancer, which represents about 20 percent of breast cancer diagnoses.

Triple-negative breast cancer is so-called because it is negative for two hormone receptors and the HER2 protein - the three markers that current treatments have successfully targeted. That leaves chemotherapy as the only treatment option for this type of cancer.

"We are gaining a better understanding of the biology of triple-negative breast cancer, which is essential to developing targeted therapies," says study first author Rabia A. Gilani, Ph.D., a post-doctoral research fellow at U-M.

Scientists have been interested in c-Src because of its role in breast cancer progression and metastasis. But drugs designed to target c-Src have proven mostly ineffective.

The U-M team took a different approach. While other c-Src inhibitors merely try to block the kinase, UM-164 binds to it and forces the kinase to turn off. Results of their study are published in Clinical Cancer Research.

"The reason our compound works is that we have a novel mechanism for binding the kinase. It has a response similar to removing the protein entirely from the cell, as opposed to only inhibiting the activity," says senior study author Matthew B. Soellner, Ph.D., assistant professor of medicinal chemistry at the University of Michigan.

In addition to blocking c-Src, the researchers found that UM-164 inhibited p38, another kinase pathway implicated in triple-negative breast cancer. By testing an existing c-Src inhibitor individually and then combining it with an existing p38 inhibitor, they found the combination was more effective. This work was done in cells.

"They're much better together than they are individually," Soellner says. "And with our compound, the outcomes were even stronger than with the existing drugs. We weren't trying to target p38, but it turns out to be a promising target in this disease."

The researchers also found that they could administer the drug to mice at a dose that was effective against the cancer but that caused few side effects. Much more laboratory testing is needed to understand the safety profile of UM-164 before any clinical trials could be considered. The researchers plan to do additional safety testing in specialized mouse models based on tissue from patients.

Ref: http://clincancerres.aacrjournals.org/content/early/2016/05/06/1078-0432.CCR-15-2158.abstract#aff-2

Researchers identify promising new compound for targeting triple-negative breast cancer

Drug candidate delivered by plant-virus-based carrier shows promise for triple-negative breast cancer

In continuation of my update on phenanthriplatin

In a pair of firsts, researchers at Case Western Reserve University and Massachusetts Institute of Technology have shown that the drug candidate phenanthriplatin can be more effective than an approved drug in vivo, and that a plant-virus-based carrier successfully delivers a drug in vivo. 

phenanthriplatin

Triple-negative breast cancer tumors of mice treated with the phenanthriplatin -carrying nanoparticles were four times smaller than those treated either with cisplatin, a common and related chemotherapy drug, or free phenanthriplatin injected intravenously into circulation.

The scientists believe the work, reported in the journal ACS Nano, is a promising step toward clinical trials.

"We may have found the perfect carrier for this particular drug candidate," said Nicole Steinmetz, an assistant professor of biomedical engineering at Case Western Reserve, who has spent 10 years studying the use of plant viruses for medical purposes.

She teamed with Stephen J. Lippard, Arthur Amos Noyes Professor of chemistry at MIT, and an expert in biological interactions involving platinum-based chemotherapies.

Platinum-based drugs are used to treat more than half of cancer patients receiving chemotherapy. Two of the most commonly used drugs are cisplatin and carboplatin. They form bifunctional cross-links with DNA in cancer cells, which block the DNA from transcribing genes and result in cell death, Lippard explained.

Despite widespread use, cisplatin has been shown to cure only testicular cancer, and many cancers have or develop immunity to the drug.

Lippard's lab altered cisplatin by replacing a chloride ion with phenanthridine and found that the new molecule also binds to DNA. Instead of forming cross-links, however, phenanthriplatin binds to a single site but still blocks transcription.

In fact, his lab found that phenanthriplatin is up to 40 times more potent than traditional platins when tested directly against cancer cells of lung, breast, bone and other tissues. The molecule also appears to avoid defense mechanisms that convey resistance.

But when injected into mouse models of cancer, the drug candidate performed no better than standard platins.

Lippard realized phenanthriplatin wasn't reaching its target. He had a drug delivery problem.

He found a potential solution while visiting Case Western Reserve's campus and heard Steinmetz explain her work investigating tobacco mosaic virus (TMV) for drug delivery more than a year ago.

"I envisioned that TMV would be the perfect vehicle," Lippard said. "So we had a beer and formed a collaboration."

The long, thin tobacco mosaic virus nanoparticles are naturals for delivering the drug candidate into tumors, said Steinmetz, who was appointed by the Case Western Reserve School of Medicine.

The virus particles, which won't infect humans, are hollow. A central tube about 4 nanometers in diameter runs the length of the shell and the lining carries a negative charge.

Phenanthriplatin is about 1 nanometer across and, when treated with silver nitrate, has a strong positive charge. It readily enters and binds to the central lining.

The elongated shape of the nanoparticle causes it to tumble along the margins of blood vessels, remain unnoticed by immune cells and pass through the leaky vasculature of tumors and accumulate inside. Little healthy tissue is exposed to the toxic drug.

Inside tumors, the nanoparticles gather inside the lysosomal compartments of cancer cells, where they are, in essence, digested. The pH is much lower than in the circulating blood, Steinmetz explained. The shell deteriorates and releases phenanthriplatin.

The shell is broken down into proteins and cleared through metabolic or natural cellular processes within a day while the drug candidate starts blocking transcription, leading to greater amounts of cell death through apoptosis than cross-linking platins.

The researchers say delivery of the phenanthriplatin into the tumor led to its improved performance over cisplatin or free phenanthriplatin.

Lippard and Steinmetz continue to collaborate, investigating use of this system to deliver other drugs or drug candidates, use in other types of cancers, the addition of agents on the exterior of the shell to increase accumulation inside tumors and more.

One-third of osteoporotic women taking oral bisphosphonates have elevated risk for bone fracture

Chemical structure of pyrophosphate (A, above) and bisphosphonates (B, below). P = phosphorus, O = oxygen, H = hydrogen, C = carbon, R = side chain. In bisphosphonates, the central oxygen atom is replaced with a carbon atom. All bisphosphonates share a common phosphorus-carbon-phosphorus motif with two side chains (R1 and R2 in the figure). The R2 side chain determines the chemical properties of the drug, and distinguishes individual types of bisphosphonates. This chemical structure affords a high affinity for calcium hydroxyapatite, allowing for rapid and specific skeletal targeting.

More than 53 million Americans age 50 and older, primarily women, have osteoporosis or are at high risk for the condition due to low bone density. A recent study of oral bisphosphonates, the most commonly prescribed osteoporosis treatment, found that approximately a third of women prescribed these drugs continue to be at elevated risk for bone fracture, an outcome that may have several origins.

Oral bisphosphonates are a pillar of preventive treatment for patients with osteoporosis and have been shown to be effective in reducing the risk of disabling bone fractures. It is known from clinical trials that no medication completely eliminates the risk of fracture. Additionally, medication effectiveness may be different in clinical practice compared to well-controlled research trials.

Research from the Regenstrief Institute-Merck (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.) collaboration suggests that many women still have indicators consistent with higher risk of fracture while taking these medications. The cross-sectional population health study was based on a retrospective database analysis of 7,435 women age 50 and older taking bisphosphonates for at least two years during the 2000-2012 time period. The analysis was published in the peer-reviewed journal Bone.

"While we found that a substantial proportion of patients who took oral bisphosphonates remain at risk for hip, spine, and other major fractures, this class of drug does improve bone density in the majority of patients and should remain a mainstay of osteoporosis management," said Erik Imel, M.D., the Indiana University School of Medicine endocrinologist and Regenstrief Institute-affiliated scientist who led the study.

"We limited our study to patients who were considered to be compliant with taking their medication, based on drug dispensing days covered, with the presumption being that those who filled prescriptions took the medication properly. We would expect even less benefit if patients fail to take their medication properly. To increase treatment effectiveness, patients and their doctors should be vigilant that the drug is taken reliably and properly. However, osteoporosis drugs are not enough. Physicians and their patients are well advised to discuss additional important modifications to decrease fall risk and fracture risk. These include exercise, smoking cessation, use of assistive devices such as canes or walkers, modifying the home to avoid obstacles that might lead to falls, and taking appropriate amounts of vitamin D and calcium."

Conducted under the auspices of a Regenstrief Institute-Merck collaboration, the retrospective cohort study utilized anonymized data from the Indiana Network for Patient Care, a health information exchange founded by the Regenstrief Institute. The study authors note that the data they used reflects real-life medical practice and patient behavior from a wide range of physicians and patient backgrounds. Adherence to bisphosphonate therapy was determined by prescription fulfillment records. Clinical data included information on bone density and fractures.

"We know that taking bisphosphonates decrease fracture risk compared to those not taking these drugs," Dr. Imel said. "But what about those women who weren't getting the anticipated benefit and are not improving bone density or even are losing bone density? What predicted that? The purpose of this study was to focus attention on those not doing well, in order to begin to decrease the odds of future fractures in this large group of vulnerable patients.

"Not everyone responds the same way to oral bisphosphonates or any drug. Various factors could convey continued risk of fracture in spite of bisphosphonate therapy, including other medical problems and risk factors for falling. Since we know that such a high percentage of women continue to have elevated fracture risk we -- doctors and patients -- need to focus on these factors," Dr. Imel said. "For example, we found that women who had other medical conditions in addition to low bone density--a frequent occurrence in this older population--had higher fracture risk. Taking some medications in combination with bisphosphonates seemed to increase fracture risk. However, having more medical conditions and taking more drugs are most likely markers of heightened risk rather than causative factors."

Neurologic problems, often linked to heightened risk of falls, as well as inflammatory and other chronic joint conditions including arthritis were found to be associated with higher odds of having a fracture among those taking bisphosphonates.

"I always tell my osteoporosis patients, 'Don't fall,'" said Dr. Imel. "They usually chuckle, and then we talk about things they can do to decrease the risk of falling, including proper footwear and assistive devices. Many patients are reluctant to use a cane or a walker. I try to get them to understand the importance of using any tool that decreases the chance of falling."

Maintenance lenalidomide treatment improves overall survival in multiple myeloma patients

In continuation of my update on lenalidomide 

 lenalidomide 

While several clinical trials have demonstrated that maintenance therapy with lenalidomide reduces the risk of disease progression in patients with multiple myeloma, there have been no definitive results regarding overall survival. While some previous studies found that maintenance lenalidomide after autologous hematopoietic stem cell transplant improved overall survival for newly diagnosed multiple myeloma patients, others showed no benefit to this approach. Philip McCarthy, MD, Director of Blood & Marrow Transplant at Roswell Park Cancer Institute (RPCI), will present the findings of an international team of researchers at the American Society of Clinical Oncology (ASCO) 52nd Annual Meeting in Chicago.

The new study is a meta-analysis of three randomized controlled trials conducted by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B) (CALGB) with support from the NCI, Intergroupe Francophone du Myélome (IFM), and the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA). It involved more than 1,200 participants. For this analysis, 605 patients with newly diagnosed multiple myeloma and treated with continuous lenalidomide (brand name Revlimid) following autologous stem cell transplant were compared to 604 patients who were treated with placebo or no maintenance. At seven years, 62% of those treated with maintenance lenalidomide had survived, compared to 50% of those in the control group. The benefit in overall survival was consistent across subgroups.

"Lenalidomide maintenance following autologous stem cell transplant can now be considered a standard of care for people with multiple myeloma," says Dr. McCarthy, senior author on the meta-analysis and Principal Investigator of the U.S. study, CALGB (Alliance) 100104. "The improvements over the last decade in terms of both survival and quality of life for patients with this disease are striking, and very encouraging."

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

The targeted therapy rucaparib, which has demonstrated robust clinical activity in ovarian cancer patients with a BRCA mutation, also showed promise in previously treated pancreatic cancer patients with the mutation, according to results from a phase II clinical study presented by Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania, at the American Society of Clinical Oncology (ASCO) Annual Meeting. (Abstract # 4110).

rucaparib

Overall, a clinical benefit was observed in 32 percent of patients (6 of 19) treated with rucaparib. Of the 19 pancreatic patients, one had a complete response and two had partial responses, while four patients had stable disease. The objective response rate, the primary endpoint for the study, was 16 percent (3 of 19).

"These results are encouraging and further demonstrate the clinical significance of the BRCA cancer genes outside of breast and ovarian, and not just in women," Domchek said. "Importantly, it points us to a potential new treatment avenue for pancreatic cancer, an aggressive disease that's often caught in the later stages. Though smaller in number, some patients with advanced disease and carrying a BRCA mutation may benefit from the same targeted therapy being used today in the clinic to successfully treat some ovarian cancer patients."

Given the poor prognosis and limited treatment options in pancreatic cancer, new therapies to combat the disease are desperately needed: Earlier this year, the American Cancer Society reported that it is estimated that in 2016, nearly 42,000 people will die from the disease, surpassing the number of deaths from breast cancer by more than 1,000.

Recent studies have shown that rucaparib, a PARP inhibitor, effectively treats patients with platinum-sensitive, relapsed, high-grade ovarian cancer harboring a BRCA mutation. In a study presented at ASCO in 2015, researchers showed that treatment resulted in a 69 percent RECIST response rate in these patients. In April 2015, it received a U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation. The FDA's designation, created in 2012, is intended to expedite the development and review of new medicines - both drugs and biologic agents - that treat serious or life-threatening conditions, if the therapy has demonstrated substantial improvement over available therapies.

The success in ovarian patients prompted a clinical study in pancreatic patients with the same mutation--about nine percent of pancreatic patients are BRCA1/BRCA2 positive.

The team enrolled participants with measurable, relapsed disease who received one to three prior rounds of chemotherapy for locally advanced or metastatic cancer. The trial included 11 male and eight female patients, with a median age of 57. Twenty-one percent of the patients tested positive for the BRCA1 mutation, while 79 percent tested positive for BRCA2.

The disease control rate (defined as partial response or stable disease for more than 12 weeks) for all patients was 32 percent (6 of the 19 patients) and 50 percent (three of six patients) in patients who received one prior line of chemotherapy. Four patients had stable disease, nine patients had progressive disease, and three were not evaluable for response. One patient was on the drug for 72 weeks and is continuing to receive the drug. The drug had an acceptable safety profile. Common treatment-emergent side effects included nausea (63 percent) and anemia (47 percent).

All patients who responded received only one prior line of chemotherapy therapy, suggesting that the drug may be an option earlier in the treatment course.

Targeted therapy rucaparib shows promise in treating pancreatic cancer patients with BRCA mutation

Metformin along with chemotherapy/radiation improves outcomes in head and neck cancer patients

In continuation of my update on metformin

Researchers at the University of Cincinnati (UC) College of Medicine have found that adding increasing doses of an approved Type 2 diabetes drug, metformin, to a chemotherapy and radiation treatment regimen in head and neck cancer patients is not well tolerated if escalated too quickly, but allowing slower escalation could be beneficial.

These findings are being presented via poster June 4 at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting: Collective Wisdom, being held June 3-7 in Chicago.

Trisha Wise-Draper, MD, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine, a member of both the Cincinnati Cancer Center and UC Cancer Institute and principal investigator on this study, says retrospective studies have shown improved outcomes in tumors treated with chemotherapy and radiation if they were also on metformin for diabetes.

"In head and neck squamous cell carcinoma, which develops in the mucous membranes of the mouth, nose and throat, diabetic patients taking a medication called metformin had better overall survival compared to those not on metformin when also treated with chemotherapy and radiation," she says. "Additionally, pancreatic cancer patients treated with chemotherapy and metformin required higher doses of metformin--1,000 milligrams twice a day--to experience positive results.

"In basic science studies, metformin has been shown to stop mTOR, a molecular pathway present and active in this type of head and neck cancer, and pretreatment with metformin resulted in a decrease in the occurrence of oral cavity tumors in animal models. In this study, we wanted to see if the combination of escalating doses of metformin with the chemotherapy agent cisplatin and radiation for head and neck cancer tumors in non-diabetic patients would be effective."

Wise-Draper says that metformin, which is an approved Type 2 diabetes medication, was provided by their investigational pharmacy. Metformin was administered orally in escalating doses for 7 to 14 days prior to starting the cisplatin and radiation and continued throughout standard treatment. Blood samples were collected before and after metformin treatment as well as during chemotherapy. Flow cytometry, a technique used to count cells, was used to detect the percent of circulating immune activated cells, and clinical laboratory tests including glucose, B12 and C-peptide (an amino acid that is important for controlling insulin) were performed.

"This is part of an ongoing clinical trial," says Wise-Draper. "We found that eight patients with advanced head and neck cancer have been enrolled so far; we plan to have 30 total. Due to the relatively quick escalation of metformin, the patients' tolerance was poor with higher doses of metformin when initiated 7 days prior to their chemotherapy and radiation therapy regimen.
"Therefore, the protocol was modified to allow slower escalation over 14 days. The most common toxicities observed included nausea (71 percent of patients) and vomiting (43 percent of patients), increase in creatinine (57 percent of patients), decreased white blood cell count (43 percent of patients) and pain when swallowing (43 percent of patients) with only nausea being directly attributed to metformin and the rest attributed to cisplatin and radiation."

She adds that there wasn't a substantial change in T cell or glucose levels with administration of metformin in the small sample of patients but that there were increased C-peptide levels in response to metformin administration.

"These results show that the combination of metformin and cisplatin and radiation was poorly tolerated when metformin was escalated quickly. However, there has been no significant increase in side effects thus far with the addition of metformin," Wise-Draper says. "The trial is continuing with escalation of metformin over a longer period of time to provide more data; we will also try to increase our sample size."

Cobimetinib combined with vemurafenib shows added benefit for melanoma with BRAF V600 mutation

In continuation of my update on Cobimetinib   and Vemurafenib

Cobimetinib (trade name: Cotellic) has been approved since November 2015 in combination with vemurafenib for the treatment of adults with advanced, i.e. metastatic or unresectable, melanoma with a BRAF V600 mutation. In a dossier assessment from March 2016, the German Institute for Quality and Efficiency in Health Care (IQWiG) found both advantages and disadvantages of cobimetinib in combination with vemurafenib in comparison with the appropriate comparator therapy vemurafenib alone. This resulted in an indication of a minor added benefit.

 Cobimetinib 

In the subsequent commenting procedure, the drug manufacturer presented further data analyses, which were now included in the assessment in a so-called addendum. This increased the extent of the added benefit: There is now an indication of a considerable added benefit of cobimetinib plus vemurafenib in comparison with vemurafenib .

  vemurafenib 

Third data cut-off of the approval study decisive

The manufacturer dossier was based on the study coBRIM, which was decisive for the approval. In this study, cobimetinib in combination with vemurafenib was directly compared with vemurafenib. Besides advantages, particularly in overall survival, several disadvantages also resulted from the data.

In the commenting procedure conducted by the Federal Joint Committee (G-BA) after IQWiG's dossier assessment, the manufacturer now in particular presented more informative analyses on symptoms and health-related quality of life from the third data cut-off, as well as further results for the fourth and fifth data cut-off. The third data cut-off was decisive for the benefit assessment because the recording of symptoms and health-related quality of life was discontinued shortly afterwards. It was investigated whether the data from the later cut-off dates raised doubts about the overall conclusion on the added benefit - which was not the case.

Additional positive effects in symptoms and quality of life

Study finds no added benefit of empagliflozin alone or in combination for type 2 diabetes

In continuation of my update on Empagliflozin

Empagliflozin (trade name: Jardiance) has been approved since May 2014 for adults with type 2 diabetes mellitus in whom diet and exercise alone do not provide adequate glycaemic control. In 2014, the German Institute for Quality and Efficiency in Health Care (IQWiG) concluded in its dossier assessment that an added benefit of the drug in comparison with the appropriate comparator therapies was not proven. Partly, the drug manufacturer had presented no relevant data; partly not only the drugs, but also the therapeutic strategies differed; in addition, the indirect comparisons were based on studies unsuitable for the assessment.

The manufacturer now requested a new benefit assessment due to "new scientific findings", and submitted two dossiers: one for empagliflozin alone, and one for empagliflozin in combination with metformin. IQWiG determined in both early benefit assessments that the dossiers still contained no data and analyses relevant or suitable for the research questions. Hence an added benefit of empagliflozin alone or in combination with metformin in comparison with the appropriate comparator therapies is still not proven. The analyses of the large study EMPA-REG-Outcome additionally submitted were unsuitable for an assessment of the added benefit in Germany.

Same studies, same problems

Both the single agent and the combination of empagliflozin with metformin are approved alone or in combination with other blood-glucose lowering drugs including insulin. According to the Federal Joint Committee (G-BA), this resulted in three and four research questions respectively. The manufacturer again presented no relevant data for five of these seven research questions so that an added benefit is not proven. One study of direct comparison as well as several studies for indirect comparisons, all of which had already been cited in the dossier or in the commenting procedure in 2014, were available for the other two research questions.

The assessment of the data from the indirect comparison was incomplete with regard to content, although it had been known to the manufacturer since the first dossier assessment which patient-relevant outcomes were important. In particular, there was no information on specific adverse events for which a disadvantage of empagliflozin versus the comparator therapy was shown. The information provided on one of the indirect comparisons had the same deficiency; furthermore, there were contradictions to the clinical study reports. The second indirect comparison was not evaluable because the studies compared were not sufficiently similar and because therapeutic strategies instead of drugs were compared with one another again.

Hence there was no hint of an added benefit of empagliflozin in comparison with the appropriate comparator therapies for the single agent or for the fixed combination.

Study EMPA-REG-Outcome unsuitable for the assessment of the added benefit

Both dossiers additionally contained a description of the EMPA-REG-Outcome study used by the manufacturer to answer a question posed by the manufacturer itself, i.e. whether empagliflozin (alone or with metformin) in addition to standard treatment offers an added benefit for patients at high cardiovascular risk in comparison with standard treatment alone plus placebo.

The antidiabetic therapy in this study cannot be considered standard treatment, however: The blood-glucose lowering treatment was not escalated appropriately and the upper threshold values mentioned in guidelines were not consistently respected. And even if treatment was escalated, this was mostly done as emergency treatment, but not as part of a planned treatment expansion.

Effects in favour of empagliflozin mainly in Latin America and Asia

Moreover, marked regional differences were notable: Effects in favour of empagliflozin mainly occurred in study centres in Latin America and Asia, whereas in Europe, partly advantages and partly disadvantages of empagliflozin were shown. Finally, the study addressed neither the G-BA's research questions nor the appropriate comparator therapies specified there.

Thomas Kaiser, Head of the IQWiG Drug Assessment Department, commented on this attempt by the manufacturer to prove an added benefit for at least certain patients: "This is a wasted opportunity. It should be welcomed that studies of this size and this duration, which are therefore potentially informative, are conducted. But it was conducted with obvious deficiencies. Experts had pinned high hopes on this study, particularly as, in contrast to other large outcome studies, it appeared to produce positive results at first glance. A thorough analysis of the study and the results in European participants did not confirm this impression, however."