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."

Chemical compound eCF506 may be highly effective at blocking growth of breast cancer cells

A drug for breast cancer that is more effective than existing medicines may be a step closer thanks to new research. Scientists have identified a chemical compound that is highly effective at blocking the growth of breast cancer cells in the laboratory.

The compound - called eCF506 - targets a molecule called Src tyrosine kinase that is required for breast cancer cells to grow and spread.

 eCF506

Drugs that target the same molecule are already being tested in clinical trials. Researchers say eCF506 is different because it is more selective and doesn't affect other molecules in the cell.

This may mean it will be more effective and have fewer side effects than the other drugs in development but further studies are needed, researchers say.

The study identified the compound using a pioneering approach that uses imaging techniques to directly visualise the effects of candidate drugs on cells.

The team from the University of Edinburgh says the discovery proves that this approach offers a powerful and cost-effective method of discovering new medicines for cancer and other diseases.

The study, published in the Journal of Medicinal Chemistry, was funded by the Medical Research Council, Wellcome Trust and the commercialisation catalyst Sunergos Innovations.

Dr Asier Unciti-Broceta, who led the study at the University's Cancer Research UK Edinburgh Centre, said: "eCF506 is the first drug candidate of a second generation of Src inhibitors that will not only help to understand the complexity of some cancers but also the development of safer combination therapies."

Professor Neil Carragher, Head of the Edinburgh Cancer Discovery Unit at the University of Edinburgh, who co-led the study, said: "This candidate drug will need to undergo further preclinical testing before it can be taken forward into clinical trials but these early findings are very promising.

"The result provides further support for our new drug discovery approach, which aims to deliver more effective medicines at reduced costs for patients and healthcare providers."

Ref : http://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b00065

Antimuscarinic drugs effective in improving OAB symptoms

In a recent study of patients with overactive bladder (OAB), a 30 mg extended release formulation of propiverine hydrochloride was at least as effective and safe as a 4 mg extended release formulation of tolterodine tartrate. Both medications are called antimuscarinic drugs that block certain cell receptors, but propiverine differs from other antimuscarinics because of a dual mode of action.

Propiverine hydrochloride was more effective than tolterodine tartrate in terms of decreasing patients' voiding frequency per 24 hours and their average number of incontinence episodes per 24 hours.

"More than two-thirds of patients reported an improvement of their OAB symptoms after 2 weeks of treatment increasing to 77.8 and 88.9% of patients after 8 weeks of treatment for tolterodine ER 4 mg and propiverine ER 30 mg, respectively," wrote the authors of the BJU International study.

Antimuscarinic drugs effective in improving OAB symptoms

Taking vitamin D with quetiapine can help avoid new-onset diabetes risk

In continuation of my update on quetiapine

Atypical antipsychotics, though effective for treating disorders like schizophrenia, bipolar disorder, and depression, gives patients a heightened risk of developing new-onset diabetes. A new data mining study, however, has found a way to relieve this side effect. The study, published in Scientific Reports, shows that taking vitamin D ameliorates the risk of developing new-onset diabetes from atypical antipsychotics like quetiapine.

 quetiapine.

The consequences of developing diabetes from taking antipsychotics are dire, as they occasionally cause life-threatening conditions and sometimes even death.

Members of Shuji Kaneko's lab at Kyoto University looked for potential antidotes on the US FDA's Adverse Event Reporting (FAERS) system, which is the largest database of self-reported adverse side effects. "We found that patients who had coincidentally been prescribed vitamin D with quetiapine were less likely to have hyperglycaemia," says Kaneko. "It's unusual for vitamin D to be prescribed with quetiapine because it is typically prescribed to treat osteoporosis; in fact, there were only 1232 cases in the world where vitamin D was prescribed with quetiapine. Data mining proved helpful in locating these cases."

The team confirmed this finding with further tests on mice; the group of mice that was fed vitamin D along with quetiapine had significantly lower levels of blood sugar than those that took only quetiapine.

"Interestingly, vitamin D on its own doesn't lower diabetes risk, but it certainly defends against the insulin-lowering effects of quetiapine," elaborates lead author Takuya Nagashima. "We clarified the molecular mechanisms of how quetiapine causes hyperglycaemia using datasets in a genomics data repository. Through this we found that quetiapine reduces the amount of a key enzyme called PI3K that gets produced. Vitamin D stops quetiapine from lowering PI3K production."

"Databases like FAERS aren't just for making drug regulations; they have so much potential for side-effect relief using pre-existing drugs," says Kaneko. "There's a lot we can hope for from reverse translational research like this. "

Ref : http://www.kyoto-u.ac.jp/en/research/research_results/2016/160523_2.html

Walnuts may improve your colon health: Eating walnuts changes the gut microbiome and reduces cancer growth, study shows

In continuation of my update on walnuts  

A team of researchers from UConn Health and The Jackson Laboratory for Genomic Medicine found that mice that ate 7-10.5 percent of their total calories as walnuts developed fewer colon cancers. The effect was most pronounced in male mice, which had 2.3 times fewer tumors when fed walnuts as part of a diet similar to the typical American's. That's equivalent to a human eating about an ounce of walnuts a day.

"Our results show for the first time that walnut consumption may reduce colon tumor development," said Principal Investigator Dr. Daniel W. Rosenberg of UConn Health. "There is accumulating evidence that eating walnuts may offer a variety of benefits related to health issues like cancer. This study shows that walnuts may also act as a probiotic to make the colon healthy, which in turn offers protection against colon tumors."

Walnuts are packed with compounds known to be important nutritionally. They have the most polyunsaturated fatty acids of all the commonly eaten tree nuts, as well as the highest ratio of omega-3 to omega-6 fatty acids, and high levels of a form of Vitamin E with anti-cancer properties.

But walnuts are not merely the sum of their chemical parts, and it may be as a whole food that they pack the most significant anti-cancer punch against colon cancer, the third most common cancer in the world. Other studies have shown walnuts have promise warding off diseases connected to diet and lifestyle, including heart disease, diabetes and neurological disorders.

Rosenberg, a cancer researcher and professor of medicine at UConn Health and Dr. Masako Nakanishi, a research associate in the Center for Molecular Medicine at UConn Health tested the cancer prevention qualities of walnuts on mice fed two different diets. One group of mice ate a standard lab mouse chow, while the other group ate a chow that captured the nutritional profile of the typical American diet. Subsets of both groups were supplemented with walnuts.

Interestingly, male mice fed the Western diet fortified with 10.5 percent walnuts showed the greatest decrease in colon tumors compared with mice fed no walnuts.

To figure out why walnuts were beneficial, the UConn Health team collaborated with Dr. George Weinstock and colleagues at The Jackson Laboratory. Weinstock's lab took fecal samples from the mice and analyzed the communities of bacteria living in their digestive tracts. They found that walnut consumption tended to push the gut microbiome toward an ecology that was potentially protective against cancer. It's not clear exactly how this works, but there are clues. For example, previous research has shown that some gut bacteria digest fiber into compounds with anti-inflammatory properties that may reduce tumor initiation. The microbiome analyses also reflected interesting differences between male and female. Males on walnut-free diets tended to have less-diverse gut flora than females. Adding walnuts to the diets of male mice brought their microbiomes closer to those of female mice on either of the diets. Whether this change contributes to the protection seen in male mice remains to be determined.

Because the studies were done only in mice, more testing needs to be done in humans before walnuts can be unequivocally recommended as a cancer-prevention agent. Rosenberg's group is working with a nutritionist and surveying human colonoscopy patients about their diets as part of a longer term study in humans.

However, Rosenberg isn't waiting for the final word. Even right now, he says, "I try to eat walnuts every day."

Topical skin creams effective to treat superficial basal cell carcinoma

In continuation of my update on imiquimod and fluorouracil

Basal cell carcinoma is one of the most common cancers and its incidence is increasing worldwide, putting a significant burden on health services. Topical treatments are available for superficial basal cell carcinoma (BCC) but there has a lack of long-term follow-up data to guide treatment decisions. A three-year randomized controlled clinical trial has found that two topical creams are effective in most primary, low-risk superficial BCC, comparing favorably with photodynamic therapy (PDT), as reported by investigators in the Journal of Investigative Dermatology.

More than 80% of all skin cancers are BCC, arising from the basal cells (i.e., small, round cells found in the lower layer of the epidermis). There are over two million cases a year in the U.S. and the lifetime risk of developing a BCC before the age of 85 years is one in five people. The prognosis is excellent, but it can cause significant disfigurement by invading surrounding tissues.

While most types of BCC require surgery, superficial BCC can be treated topically with noninvasive treatments such as PDT, imiquimod cream, fluorouracil cream, cryosurgery or electrodessication and curettage.

Investigators in the Netherlands report the results of a three-year follow-up of a randomized controlled trial that compared three noninvasive treatments that included imiquimod and fluorouracil cream. "The main advantages of noninvasive treatments are good cosmetic outcome, preservation of surrounding tissue, and potential for home application of either creams," explained lead investigator Marieke Roozeboom of the Department of Dermatology, Maastricht University Medical Center in the Netherlands. "Throughout the last two decades there has been a growing interest in these non-surgical therapies, which offer the possibility of avoiding surgery and reducing demands on busy medical practices."

However, prior to this study there has been a lack of randomized controlled trials with a long-term follow-up that compare the effectiveness of noninvasive treatments. Consequently, there is no consensus in international BCC guidelines on the first choice of noninvasive therapy for superficial BCC.

A total of 601 patients with a superficial BCC participated in this study: 202 patients were treated with methylaminolevulinate photodynamic therapy (MAL-PDT), 198 with imiquimod cream, and 201 with fluorouracil cream. The three study groups had a similar distribution of baseline characteristics, with the exception of tumor size.

Around 80% of patients with superficial BCC were tumor free after imiquimod treatment after three years. The clearance rate was 68% for patients treated with fluorouracil and 58% for individuals receiving PDT.

 imiquimod   fluorouracil

"Based on our findings, both imiquimod and fluorouracil are effective noninvasive treatments in most primary, low-risk superficial BCC, but the data provide no definite evidence for superiority of imiquimod to fluorouracil," commented Dr. Roozeboom. "Both creams have an equal cosmetic outcome and risk of local adverse events. Fluorouracil has the advantage of being less expensive than imiquimod. However, between one- and three-year follow-up, more recurrences were diagnosed in the fluorouracil group compared with the imiquimod group."

Fasnall drug appears to inhibit tumor growth by promoting cancer cell death

A promising new compound appears to impede a process that fuels breast cancer in mice, a discovery that could have implications in the treatment of a host of cancers.

On top of short-circuiting the proliferation of cancer cells, a new agent that the researchers called Fasnall also contributed to the death of existing cancer cells, according to scientists from The Ohio State University and Duke University.

The mice injected with Fasnall survived for an average of 63 days, more than double the lifespan of the mice in the control group. After three weeks, tumors in the mice that received Fasnall were about two-thirds the size of those in the control group, the researchers report in a study published in the journal Cell Chemical Biology.

When researchers tried Fasnall alongside the chemotherapy drug carboplatin, they saw tumors shrink and survival increase more than with either agent by itself.

The study focused on mice with HER2-positive breast cancer, which is responsible for about one in five breast cancer diagnoses in women. But because of the critical role of an enzyme called fatty acid synthase in a variety of cancers, this work could have much broader implications, said Ohio State's Jesse Kwiek, an associate professor of microbiology and microbial infection and immunity.

The discovery, five years in the making, was speedy by drug development standards, he said.

"We started with an idea and got it to work in a mouse in a relatively short amount of time," Kwiek said.

"It's a promising starting point."

He and Duke's Timothy Haystead, a cancer biologist who co-led the study, are seeking a patent.

Fasnall inhibits the normal activity of fatty acid synthase, which regulates cell growth and proliferation.

"Tumor cells are quite dependent on that enzyme as a fuel source for survival," Haystead said. "If you nail this target, you're selectively striking the tumor rather than normal cells. And not only do you starve the tumor cell of its energy source, but also trigger changes that convince the cell to essentially kill itself."

Scientists exploring opportunities to close the doors on cancer growth have known for some time that many solid tumors depend on fatty acid synthase. Most other cells in the body are either less reliant on the enzyme, or don't need it at all, reducing the chances that harmful side effects would overshadow benefits.

All of that makes for an obvious, but thus far tricky, target for cancer fighters in the lab.

"It's always this balance where you try to identify molecules that are more important to the malignancy than to the host," Kwiek said. "You're looking for these little tweaks - little advantages."

In this case, that means interrupting fatty acid synthesis, effectively robbing the cancer of a molecule it needs in order to grow.

"Fasnall inhibits the ability of this enzyme to make palmitic acid, a molecule important for many cellular processes," Kwiek said.

And when the enzyme isn't doing its normal job, it appears to be diverted elsewhere - to a place where it has the added benefit of provoking the programmed death of cancer cells.

Before the mouse study, the research team sifted through a pool of 3,400 molecules looking for one that was efficient at knocking out fatty acid synthase in pig mammary glands without causing much residual harm. They first narrowed the field to about 1,300, then to 13 strong contenders.

Then the researchers examined each of the 13 finalists' activity within a cell. Fasnall rose to the top. Not only did it inhibit the tumor-fueling activity, it didn't take much of the compound for that to happen, which lowered the chances it would be toxic to the mice.

The discovery stemmed from an effort to look for novel treatments for cancer and HIV. Fatty acid synthase, disrupted by Fasnall, plays a role in both. The research team has not yet published results on their HIV work.

"Cancer is uncontrolled cell division, and fatty acid synthase helps make the raw materials that make the cells divide," Kwiek said.

The mice in the study showed no signs of major side effects, such as weight gain or loss or significant changes in liver enzymes, he said.

It appears the dose could be increased from the amount used in this research and that could produce more dramatic results, Kwiek said.

Fasnall needs more testing in animals before it can be employed in human studies, the researchers said. Other fatty acid inhibitors are under review, but thus far none has made it to market and none operates in precisely the way Fasnall does, Kwiek said.

The mechanism by which it works is less likely to run up against drug resistance in the cancer cells than some other approaches, Haystead said.

Its potential as one element of a cancer treatment cocktail is attractive, because it's possible Fasnall would offset the need for high doses of potent treatments that come with serious side effects, Haystead said.

"There are a huge gamut of implications and some may be better than others. Our job now is to sort of move this molecule down the clinical path," he said.

The researchers caution that this is the first, albeit big, step in a process that would take years if all goes well.

"This is just a mouse model of a single cancer," Kwiek said.

Specific commercial red algae could help combat food allergies

 

Seaweed has long been a staple food in many Asian countries and has recently caught on as a snack food in America as a healthful alternative to chips. The edible algae that fall in the category of seaweed are low-calorie and packed with nutrients. In addition, now scientists have found that a type of commercial red algae could help counteract food allergies. They report their findings in mice in ACS' Journal of Agricultural and Food Chemistry.

Food allergies are a major global health issue that can be life threatening in some cases. One 2014 study by researchers at Mount Sinai Hospital estimates that the condition affects about 8 percent of children and 5 percent of adults worldwide. In people who are allergic, certain compounds in food trigger a cascade of immune system reactions that lead to symptoms such as hives, wheezing and dizziness -- and in the worst cases, anaphylactic shock. Previous research has suggested that certain seaweed varieties contain polysaccharides with anti-asthmatic and anti-allergy effects. But no one had investigated whether similar molecules in Gracilaria lemaneiformis, a commercial variety of red algae, might have similar properties. Guang-Ming Liu and colleagues wanted to find out.

The researchers isolated polysaccharides from G. lemaneiformis and fed them to a group of mice sensitive to tropomyosin, a protein that is a major shellfish allergen. Another group of mice, also sensitive to tropomyosin, did not get the polysaccharides. After both groups were given the allergen, allergy symptoms in the treated mice were reduced compared to the untreated animals. Further studying polysaccharides from G. lemaneiformis could help lead to a better understanding of food allergies and their prevention, the researchers say.

Ref : http://pubs.acs.org/doi/abs/10.1021/acs.jafc.6b01086

FDA Expands Indication of Invokamet (canagliflozin/metformin HCl) to Include First-Line Treatment of Type 2 Diabetes

In continuation of my updates on INVOKANA® (canagliflozin) and metformin hydrochloride,

Janssen Pharmaceuticals, Inc. (Janssen), announced the U.S. Food and Drug Administration (FDA) has approved Invokamet, a fixed-dose combination therapy of INVOKANA® (canagliflozin) and metformin hydrochloride, for first-line treatment of adults with type 2 diabetes. With this new approval, Invokamet may now be prescribed in adults with type 2 diabetes who are not already being treated with canagliflozin or metformin and may benefit from dual therapy.

 metformin    canagliflozin

Invokamet, the first combination of a sodium glucose co–transporter 2 (SGLT2) inhibitor and metformin available in the United States, was previously approved by the FDA in August 2014 as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes not adequately controlled by either canagliflozin or metformin, or who are already being treated with both medications separately.

“Physicians increasingly try to achieve greater initial blood sugar control by using dual therapy at the outset, versus single-agent therapy alone, especially for patients with higher A1C levels,” said John Anderson, M.D.*, Frist Clinic, Nashville, Tenn. “Invokamet combines two effective, complementary medicines—canagliflozin and metformin—into one convenient pill, to lower A1C significantly more than metformin alone.”

A1C is a measure of average blood glucose over the past two to three months; the American Diabetes Association recommends most adults with type 2 diabetes maintain A1C levels of 7 percent or less.[2]

The new Invokamet indication aligns with recent type 2 diabetes treatment guidelines, which recommend dual therapy for patients with higher A1C levels. Specifically, guidelines recommend dual therapy for patients who have an initial A1C level of 7.5 percent or higher;[3] and for those who have an initial level below 7.5 percent and do not achieve an A1C treatment goal after about three months on single therapy, often metformin.3,[4] In addition, dual or triple therapy is recommended as first-line therapy in asymptomatic patients with an initial A1C level above 9 percent.3

Studies have demonstrated that administration of Invokamet results in the same levels and effects of canagliflozin and metformin in the body as co-administration of corresponding doses of both drugs as individual tablets. Canagliflozin works with the kidneys to help adults with type 2 diabetes lose some sugar through the process of urination, and metformin decreases the production of glucose in the liver and improves the body's response to insulin. Invokamet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.1

Invokamet is available in four dose strengths, in tablets containing canagliflozin 50 milligrams (mg) or 150 mg, and metformin 500 mg or 1000 mg. The recommended dosing is twice daily. The prescribing information for Invokamet also contains a boxed warning for lactic acidosis, a rare, but serious complication that can occur due to metformin accumulation.1

“The available doses of Invokamet allow physicians to tailor therapy for individual patient needs and offer an alternative for people living with type 2 diabetes who may be able to reduce the number of pills they take each day,” said Paul Burton, M.D., Ph.D., Vice President, Medical Affairs, Janssen. “This expansion marks an important milestone as we continue to study Invokamet and INVOKANA®—the number-one prescribed SGLT2 inhibitor with more than 8 million prescriptions to date—for the treatment of type 2 diabetes.”

Phase 3 Study Supports Expanded Indication

The expanded indication for Invokamet was based largely on a 26-week, double-blind, active-controlled, multicenter Phase 3 study in 1,186 adults with type 2 diabetes inadequately controlled with diet and exercise, and who had not been treated previously with any glucose-lowering medications. The participants were assigned randomly to one of five treatment groups: metformin hydrochloride extended release (MET), canagliflozin 100 mg (CANA100), canagliflozin 300 mg (CANA300), canagliflozin 100 mg + MET (CANA100/MET), or canagliflozin 300 mg + MET (CANA300/MET). The mean baseline A1C across all groups was 8.8 percent. The primary endpoint was the change in A1C. A report on the study findings was published in Diabetes Care in March 2016.[5]

After 26 weeks, participants in the CANA100/MET and CANA300/MET groups had significantly greater decreases in A1C compared to those in the CANA100, CANA300 and MET groups: 1.77 percent and 1.78 percent vs. 1.37 percent, 1.42 percent and 1.3 percent, respectively (p-values for all differences between the combination therapies vs. individual therapies less than 0.001). Additionally, significantly more participants in the CANA100/MET and CANA300/MET groups compared to the MET group achieved the goal of reducing A1C to less than 7 percent: 47 percent and 51 percent vs. 38 percent, respectively (p less than 0.05 for both combination groups vs. MET).1

Other Phase 3 Studies of Canagliflozin-Metformin Therapy

The co-administration of canagliflozin—INVOKANA®—and metformin has been evaluated in six other Phase 3 clinical studies that enrolled 4,732 patients with type 2 diabetes and who were already taking glucose-lowering medications. The studies showed that the combination of INVOKANA® and metformin lowered blood sugar and, in pre-specified secondary endpoints, was associated with significant reductions in body weight and systolic blood pressure.

In two studies comparing INVOKANA® plus metformin to current standard treatments plus metformin—one studying sitagliptin and the other studying glimepiride—INVOKANA® dosed at 300 mg provided greater reductions in A1C levels and body weight than either comparator. The overall incidence of adverse events was similar with INVOKANA® and the comparators.

Results from the Phase 3 studies showed that INVOKANA® was generally well tolerated, and the most common adverse events include genital yeast infections, urinary tract infections, and changes in urination. The most common adverse reactions due to initiation of metformin, as noted in the prescribing information for that medication, are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use. INVOKANA® can increase the risk of hypoglycemia when combined with insulin or a medication that increases insulin levels (e.g., a sulfonylurea). Therefore, a lower dose of insulin or insulin-raising medication may be required to minimize the risk of hypoglycemia when used in combination with Invokamet.

About Type 2 Diabetes

Of the approximately 29 million people who have diabetes in the United States, 90 to 95 percent of them have type 2 diabetes, which is chronic and affects the body's ability to metabolize sugar (glucose), and is characterized by the inability of pancreatic beta cell function to keep up with the body's demand for insulin

FDA Grants Accelerated Approval to Ocaliva (obeticholic acid) for Primary Biliary Cholangitis

Intercept Pharmaceuticals, Inc.   a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat non-viral, progressive liver diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis, previously known as primary biliary cirrhosis (PBC), in combination with ursodeoxycholic acid(UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. Ocaliva is an agonist of the farnesoid X receptor (FXR), a nuclear receptor expressed in the liver and intestine and a key regulator of bile acid, inflammatory, fibrotic and metabolic pathways.

"Intercept was founded on the belief that targeting FXR would benefit patients with liver diseases for which there are limited or no treatment options, and Ocaliva's approval marks the culmination of more than a decade of work," said Mark Pruzanski, M.D., Chief Executive Officer and President of Intercept. "We are very pleased that the FDA has approved Ocaliva for PBC and would like to thank all the patients and investigators around the world who participated in our clinical trials to make this possible."

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

"Ocaliva fills an important unmet need for the many patients with PBC who have an inadequate response to or are intolerant of UDCA, which until now has been the only approved treatment," said John Vierling, M.D., F.A.C.P., F.A.A.S.L.D., Professor of Medicine and Surgery at Baylor College of Medicine and Past President of the American Association for the Study of Liver Diseases (AASLD). "Ocaliva has demonstrated a clinically meaningful improvement in lowering ALP, a liver enzyme and biomarker that is used to track disease progression in patients with PBC. Importantly, Ocaliva maintained durable ALP reductions, which is critical for treatment of a chronic disease like PBC."

In Intercept's Phase 3 POISE trial, Ocaliva administration in combination with UDCA (or as monotherapy in UDCA-intolerant patients) met the primary composite endpoint in 46% of patients in the titration group, as compared to 10% of those receiving placebo added to UDCA (p<0.0001). Pruritus (itching), a common symptom of PBC that is unrelated to disease stage or outcomes, was the most common side effect observed in Ocaliva-treated patients. However, pruritus associated with Ocaliva treatment was generally less in patients who were on the dose titration regimen (5 mg once-daily increasing to 10 mg once-daily); one patient (1%) in the titration group discontinued from the study due to pruritus. Additional side effects observed during the trial included fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality and eczema.

"PBC affects people in the prime of their lives and, for some, the potential need for a liver transplant is a constant concern during these important years," said Linie Moore, a PBC patient and President of the PBCers Organization, the leading PBC patient support group in the U.S. "After nearly two decades with only one approved treatment, we are thrilled to welcome this important new medicine for people living with PBC."

Ocaliva is expected to be available to PBC patients in the U.S. within 7-10 days and will be distributed through a specialty pharmacy network. Intercept is dedicated to helping ensure that people with PBC can access Ocaliva and has launched Interconnect™, a comprehensive and personalized patient support services program. Through Interconnect, dedicated Care Coordinators will guide patients through disease education, treatment support and, for eligible patients, financial assistance options, which may include reimbursement support, co-pay assistance or access to Ocaliva at no cost. For more information about Interconnect Support Services and U.S. Distribution, call 1-844-622-4278 or visit www.Interconnectsupport.com.

About Primary Biliary Cholangitis, Formerly Known as Primary Biliary Cirrhosis

Primary biliary cholangitis (PBC) is a rare, autoimmune cholestatic liver disease that puts patients at risk for life-threatening complications. PBC is primarily a disease of women, afflicting approximately one in 1,000 women over the age of 40. If left untreated, survival of PBC patients is significantly worse than the general population.

About the Phase 3 POISE Trial

The POISE trial studied the safety and efficacy of once-daily treatment with Ocaliva in PBC patients with an inadequate therapeutic response to, or who are unable to tolerate, UDCA. The POISE data showed that Ocaliva, at both a 10 mg dose and a 5 mg dose titrated to 10 mg, met the trial's primary endpoint of achieving a reduction in serum ALP to below a threshold of 1.67 times the upper limit of normal, with a minimum of 15% reduction in ALP level from baseline, and a normal bilirubin level after 12 months of therapy. Pruritus was the most frequently reported adverse event associated with Ocaliva treatment. In a group of patients who initiated Ocaliva at a 5 mg once-daily dose and titrated up to 10 mg once daily, only one patient (1%) discontinued from the study due to pruritus as compared to seven patients (10%) in the 10 mg dose group and after 12 months of treatment, efficacy was essentially equivalent to those patients who started the study at the 10 mg dose. Based on these results, a 5 mg to 10 mg titration regimen is recommended for Ocaliva dosing in PBC. Decreases in HDL-C were observed during treatment.

FDA Approves Lenvima (lenvatinib) for the Treatment of Patients with Advanced Renal Cell Carcinoma

In continuation of my update on Lenvatinib

 Lenvatinib

Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) approved Lenvima (lenvatinib), the company's multiple receptor tyrosine kinase inhibitor, in combination with everolimus for the treatment of patients with advanced renal cell carcinoma(aRCC) who were previously treated with an anti-angiogenic therapy. This approval was based on the impressive results of the registration study (Study 205), in which the once daily combination of 18 mg Lenvima and 5 mg everolimus demonstrated a substantial improvement in progression-free survival (PFS), powerful objective response rate (ORR) and clinically meaningful overall survival (OS) when compared with everolimus alone, a standard of care for patients with aRCC who have received prior anti-angiogenic therapy.

"Lenvatinib plus everolimus is the first and only FDA-approved regimen that successfully combines treatments that employ tyrosine kinase and mTOR inhibition, the primary targets of advanced RCC treatment for the past decade," said Robert Motzer, M.D., Memorial Sloan Kettering Cancer Center, New York, and the principal investigator of the study. "This combination regimen led to enhanced efficacy and helped patients with advanced RCC live longer without disease progression or death than those treated with everolimus alone. These noteworthy findings advance the treatment paradigm for this patient population."

Lenvima was granted Breakthrough Therapy designation by the FDA for this indication, and the application received Priority Review, which is assigned to drugs the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition.

In Study 205, a Phase 2 trial, Lenvima and everolimus (LEN+EVE) resulted in a median PFS nearly three times that of everolimus alone. The median PFS, or the length of time from randomization until disease progression or death, in patients treated with the combination (n=51) was 14.6 months (95% CI: 5.9–20.1) compared with 5.5 months (95% CI: 3.5–7.1) for those treated with everolimus alone (n=50) (HR 0.37; 95% CI: 0.22–0.62). The combination regimen resulted in a 63% reduction in the risk of disease progression or death compared with everolimus alone. The treatment effect of the combination on PFS was supported by a retrospective independent review.

The objective response rate was 37% (95% CI: 24–52) in patients treated with the combination regimen (35% partial response + 2% complete response) compared to 6% (all partial response, 95% CI: 1–17) in patients treated with everolimus alone.

The patients who received LEN+EVE experienced a 10.1-month increase in median OS compared with those who received everolimus monotherapy (25.5 months [95% CI: 16.4–32.1] versus 15.4 months [95% CI: 11.8–20.6]; HR 0.67; 95% CI: 0.42–1.08). This OS analysis was conducted when 63% of deaths had occurred in the combination arm and 74% of deaths had occurred in the everolimus arm.

The safety of this combination regimen was also examined in Study 205. Serious risks from treatment with the combination of Lenvima and everolimus may include hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid-stimulating hormone suppression/thyroid dysfunction, and embryofetal toxicity. The most common adverse reactions observed in study patients treated with Lenvima and everolimus (greater than 30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events and proteinuria. The most common serious adverse reactions (greater than or equal to 5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%) and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients receiving Lenvima and everolimus and 54% in patients receiving everolimus. The most common adverse reactions (greater than or equal to 5%) resulting in dose reductions in patients treated with Lenvima and everolimus were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%) and proteinuria (5%).

Treating physicians are likely to be familiar with many of the adverse reactions observed for this combination regimen based on their prior experience with these types of drugs. Prescribers may be able to manage certain adverse reactions (such as nausea, vomiting, diarrhea and hypertension) with a proactive plan that includes concomitant medications and/or dose reductions, interruptions and/or discontinuations.

"Rates of renal cell carcinoma have been on the rise over the past several decades, and unfortunately, advanced RCC remains an incurable disease. Since the VEGF pathway is known to be involved in the growth of renal cell tumors, it is important to have a diverse offering of therapeutic options, including treatments that continue to target VEGF inhibition," said Sumanta Kumar Pal, M.D., Assistant Professor, Department of Medical Oncology & Therapeutics Research and Co-Director, Kidney Cancer Program at City of Hope in Duarte, Calif. "The combination regimen of lenvatinib and everolimus provides a new treatment for patients with advanced RCC whose disease continues to progress despite prior treatment with an anti-angiogenic therapy."

Lenvima was first approved in the U.S. on February 13, 2015, for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

"By bringing this breakthrough treatment to patients with advanced RCC, Eisai now offers an efficacious option in a second difficult-to-treat tumor type, just 15 months after its initial approval, and we look forward to continued exploration of LENVIMA in additional malignancies," said Alton Kremer, M.D., Ph.D., Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "This also marks the second time in four months that one of Eisai's oncology treatments has been granted a new indication following Priority Review from the FDA. These milestones, as well as the ongoing development of innovative agents in our pipeline, underscore our steadfast commitment to Eisai's human health care (hhc) mission of identifying and addressing the unmet needs of people living with cancer."

About Study 205

Study 205, the Phase 2 study, was a multicenter, randomized trial in patients (n=153) with unresectable advanced or metastatic RCC who were previously treated with an anti-angiogenic therapy and randomized 1:1:1 to receive a combination of 18 mg LENVIMA plus 5 mg everolimus once a day, LENVIMA only (24 mg once a day) or everolimus only (10 mg once a day) administered orally in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary efficacy endpoint of this study was investigator-assessed PFS. Other endpoints of the study included ORR, OS and safety.

The results of this study were published online in The Lancet Oncology in October 2015, following an oral presentation at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.