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.

Theravance Biopharma Announces FDA Approval of Expanded Label for Vibativ (telavancin)

In continuation of my update on telavancin

Theravance Biopharma, Inc. (NASDAQ: TBPH) ("Theravance Biopharma" or the "Company") today announced that the U.S. Food and Drug Administration (FDA) has approved the Company's supplemental New Drug Application (sNDA) for Vibativ (telavancin) to expand the product's label to include data describing the treatment of patients with concurrent Staphylococcus aureus (S. aureus) bacteremia in both of the antibiotic's currently approved indications in the United States. Vibativ is approved in the U.S. for the treatment of adult patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of S. aureus when alternative treatments are not suitable. In addition, Vibativ is approved in the U.S. for the treatment of adult patients with complicated skin & skin structure infections (cSSSI) caused by susceptible isolates of Gram-positive bacteria, including S. aureus, both methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains.

Bacteremia is the presence of bacteria in the bloodstream and can occur spontaneously or in the presence of other infections. Bacteremia continues to represent a significant unmet medical need. Concurrent bacteremia, which in its most serious form is fatal, occurs when bacteria spreads from its initial infection site and enters the bloodstream. As a secondary infection, it introduces significant challenges to the treatment of the primary infection, as well as the concurrent bacteremia itself.

"When patients with cSSSI or HABP/VABP present with concurrent bacteremia, their treatment becomes more difficult for healthcare practitioners. With this action by the FDA, we believe an important advance has been made in addressing the unique challenges in this area. The additional data that are now reflected in the Vibativ label address the use of Vibativ in cSSSI and HABP/VABP with concurrent bacteremia and we are now implementing a strategy to communicate this information to targeted healthcare practitioners," said Frank Pasqualone, Senior Vice President and Global Head, Acute Care Business at Theravance Biopharma. "With the broader medical need for effective bacteremia treatments in mind, we are also conducting a Phase 3 registrational study of telavancin in primary complicated S. aureus bacteremia, which we expect to complete in late 2017 or early 2018. Should we prove successful with this trial and secure approval in this infection type, Vibativ would possess the broadest set of indications of any branded anti-MRSA agent."

The sNDA filing was based on the combined data from Theravance Biopharma's previously conducted pivotal trials of Vibativ in its two approved indications -- cSSSI (ATLAS I and II) and HABP/VABP (ATTAIN I and II). The trials were large, multi-center, multinational, double-blind, randomized Phase 3 clinical studies enrolling and treating 3,370 adult patients, including a portion of patients with concurrent bacteremia. Importantly, these studies involved two of the largest cohorts of patients ever studied in these diseases and included one of the largest cohorts of patients with MRSA infections studied to date.

Expanded Vibativ Label Data

The data added to the Vibativ label describe patients with concurrent S. aureus bacteremia in the Phase 3 ATLAS and ATTAIN trials. These include:

• In the all-treated cSSSI patient population with baseline S. aureus bacteremia in the ATLAS I and II trials, clinical cure rates at test-of-cure were 57.1% for Vibativ-treated patients vs. 54.6% for vancomycin-treated patients.
• In the HABP/VABP patient population with at least one Gram-positive respiratory pathogen at baseline who had concurrent S. aureus bacteremia in the ATTAIN I and II trials, the 28-day all-cause mortality rate was 40.0% for Vibativ-treated patients vs. 39.5% for vancomycin-treated patients.

Separately, Theravance Biopharma is currently conducting a Phase 3 registrational study of telavancin in patients with complicated S. aureus bacteremia. The trial is a multi-center, randomized, open-label study that is enrolling approximately 250 adult patients with confirmed MSSA or MRSA bacteremia at about 70 clinical sites in the U.S. and around the world. Researchers are evaluating telavancin in treating these patients as compared to standard therapies such as vancomycin, daptomycin and anti-staphylococcal penicillins. The trial is expected to be completed in late 2017 or early 2018.

Flamel Technologies Receives FDA Approval of Akovaz (ephedrine sulfate) for Surgical Hypotension

Flamel Technologies (NASDAQ: FLML) announced that the U.S. Food and Drug Administration (FDA) has approved the Company's New Drug Application (NDA) for Akovaz™ (ephedrine sulfate), a drug administered parenterally as a pressor agent to address clinically important hypotension in surgical settings. Flamel obtained NDA approval for Akovaz as scheduled on April 29 and is the first to receive approval from the FDA for ephedrine sulfate. Flamel expects to launch Akovaz during the third quarter 2016 in a strength of 50 mg/mL.

 ephedrine 

"We are very excited to receive FDA approval for Akovaz, the third product from our Éclat portfolio, and in line with the PDUFA date expectations. Revenue expectations associated with this product were included in our previously issued 2016 revenue guidance of $110 - $130 million. Our Éclat portfolio of products, which includes Bloxiverz® and Vaculep®, has produced significant cash flow for Flamel, allowing us to operate independently of partners, fund strategic acquisitions and continue development of our proprietary pipeline products," said Mike Anderson, Chief Executive Officer of Flamel.

Currently, there is one "unapproved marketed" formulation of ephedrine sulfate 50 mg/mL injection sold by Akorn Pharmaceuticals, and according to IMS Health, the market size is over five million vials per year.

About Akovaz

Akovaz is the brand name for the Company's ephedrine sulfate injection, USP, an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent that is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia. Akovaz injection, 50 mg/mL, (equivalent to 38 mg ephedrine base) must be diluted before administration and is injected intravenously as a bolus.

Bevespi Aerosphere Approved by the FDA for Patients with COPD

In continuation of my update on formoterol

AstraZeneca today announced that the US Food and Drug Administration has approved Bevespi Aerosphere (glycopyrrolate and formoterol fumarate) inhalation aerosol indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

glycopyrrolate formoterol 

Sean Bohen, Executive Vice-President, Global Medicines Development and Chief Medical Officer, said: “With the approval of Bevespi Aerosphere we are pleased to provide patients with the first LAMA/LABA in a pressurised metered-dose inhaler, delivered using our unique formulation technology. LAMA/LABAs are emerging as a preferred treatment option for many COPD patients. This class aims to provide maximum bronchodilation, which enables patients to breathe better and may help them be more active.”

Bevespi Aerosphere is a twice-daily, fixed-dose dual bronchodilator combining glycopyrrolate, a long-acting muscarinic antagonist (LAMA), and formoterol fumarate, a long-acting beta-2 agonist (LABA). The FDA approval is based on the PINNACLE trial programme, which demonstrated that Bevespi Aerosphere achieved statistically significant improvement in morning pre-dose forced expiratory volume in 1 second (FEV1) at 24 weeks (p<0.001) versus its mono-components and placebo.

Bevespi Aerosphere is the first product approved using AstraZeneca’s Co-Suspension Technology. This technology enables consistent delivery of one or more different medicines from a single pMDI. The technology is being applied to a range of AstraZeneca respiratory inhaled combination therapies currently in clinical development, such as the fixed-dose triple combination of LAMA/LABA/Inhaled corticosteroid (PT010).

About COPD

COPD (chronic obstructive pulmonary disease) is a progressive disease associated mainly with tobacco smoking, air pollution or occupational exposure, which can cause obstruction of airflow in the lungs resulting in debilitating bouts of breathlessness. It affects an estimated 329 million people worldwide and is predicted to be the third leading cause of death by 2030. Improving lung function and managing daily symptoms such as breathlessness are important to the management of COPD. It is estimated that eight out of 10 patients suffer symptoms at night, such as an irritative cough and difficulty breathing, frequent nocturnal awakenings, which leads to insomnia, worry and anxiety.

FDA Approves Gilotrif (afatinib) for Patients with Squamous Cell Carcinoma of the Lung

I continuation of my update on Afitinib

Boehringer Ingelheim  announced that the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for Gilotrif® (afatinib) tablets for the treatment of patients with advanced squamous cell carcinoma of the lung whose disease has progressed after treatment with platinum-based chemotherapy. The U.S. approval follows the recent marketing authorization of Gilotrif in this patient population by the European Commission. Gilotrif, an oral, once-daily EGFR-directed therapy, is currently approved in the U.S. for the first-line treatment of specific types of EGFR mutation-positive NSCLC.

 afatinib

“We are pleased to bring a proven therapy to patients suffering from advanced squamous cell carcinoma of the lung who have progressed despite chemotherapy,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “This approval is further evidence of Boehringer Ingelheim’s strong commitment to bringing new treatment options to the lung cancer community.”

Squamous cell carcinoma (SqCC) of the lung is associated with a poor prognosis, limited survival and symptoms like cough and dyspnea. The median overall survival (OS) after diagnosis of advanced SqCC is around one year.

LUX-Lung 8 clinical trial investigator Shirish Gadgeel, MD, leader of the Thoracic Oncology Multidisciplinary Team at the Karmanos Cancer Center, Detroit, commented: “The overall survival data and significant delay in lung cancer progression seen in the global head-to-head Phase III trial demonstrated that Gilotrif is an effective new treatment option in this patient population.”

The sNDA was based on results of the head-to-head LUX-Lung 8 trial in patients with SqCC of the lung whose tumors progressed after first-line chemotherapy. Gilotrif, compared to erlotinib, demonstrated:

• Significant delay in progression of lung cancer (PFS, progression-free survival, primary endpoint), reducing the risk of cancer progression by 18%
• Significant improvement in overall survival (OS, key secondary endpoint), reducing the risk of death by 19%
• Significantly improved disease control rate (51% vs 40%; P=0.002)

The most common adverse reactions observed with Gilotrif (reported in at least 20% of study patients) were diarrhea (75%), rash or acne (70%), stomatitis (mouth sores) (30%), decreased appetite (25%), and nausea (21%).

LUX-Lung 8 (NCT01523587) is part of the Gilotrif LUX-Lung program – the largest collection of clinical trials of any EGFR tyrosine kinase inhibitor (TKI), with over 3,760 patients across eight studies conducted around the world. The comprehensive LUX-Lung program includes two pivotal studies in the first-line setting for EGFR mutation-positive patients, LUX-Lung 3 and LUX-Lung 6, which compared Gilotrif to chemotherapy regimens. In addition, the program included two head-to-head studies (LUX-Lung 7 and LUX-Lung 8) of Gilotrif versus first-generation EGFR TKIs gefitinib and erlotinib, respectively. The LUX-Lung program has involved over 680 sites in 40 countries, reflecting the strong partnership between Boehringer Ingelheim and the lung cancer specialist community.

New experimental drug may prevent stress damage in the brain

Chronic stress can make us worn-out, anxious, depressed--in fact, it can change the architecture of the brain. New research at The Rockefeller University shows that when mice experience prolonged stress, structural changes occur within a little-studied region of their amygdala, a part of the brain that regulates basic emotions, such as fear and anxiety. These changes are linked to behaviors associated with anxiety and depressive disorders

There is good news, too: an experimental new drug might prevent these changes.

"There have been hints that the amygdala displays a complex response to stress," says lead author Carla Nasca, a postdoc in Bruce S. McEwen's lab. "When we took a closer look at three regions within it, we found that neurons within one, the medial amygdala, retract as a result of chronic stress.

"While this rewiring can contribute to disorders such as anxiety and depression, our experiments with mice showed that the neurological and behavioral effects of stress can be prevented with treatment by a promising potential antidepressant that acts rapidly," Nasca says.

In the research, published May 31 in Molecular Psychiatry, her team found this protective approach increased resilience among mice most at risk for developing anxiety or depression-like behaviors.

The brain's limbic system controls emotions and memory, and it comprises a number of structures, including the amygdala, which is found deep in the brain. Scientists interested in the neurological effects of stress have focused on several structures in the limbic system, but the medial amygdala has thus far received little attention in stress studies.

To see what was going on in this area, as well as two other parts of the amygdala, Nasca and her team first subjected mice to 21 days of periodic confinement within a small space--an unpleasant experience for mice. Afterward, they tested the mice to see if their behaviors had changed--for instance, if they had begun to avoid social interaction and showed other signs of depression. They also analyzed the neurons of these mice within the three regions of the amygdala.

One area saw no change with stress. In another, the basolateral amygdala, they saw that neurons' branches became longer and more complex--a healthy sign of flexibility and adaptation, and something that had been shown up in previous work. But in the medial amygdala, they neuronal branches, which form crucial connections to other parts of the brain, appeared to shrink. The loss of connections like these can harm the brain, distorting its ability to adapt to new experiences, leaving it trapped in a state of anxiety or depression.

Protecting neurons

This effect could be prevented. The scientists repeated the stress experiment, and this time they treated mice nearing the end of their 21 days of chronic stress with acetyl carnitine, a molecule Nasca is studying for its potential as a rapid-acting antidepressant. These mice fared better than their untreated counterparts; not only were they more sociable, the neurons of their medial amygdalas also showed more branching.

Stress does not affect everyone the same way. This is true for both humans and mice--some individuals are just more vulnerable. Nasca and her colleagues' experiments included mice at high risk of developing anxiety- and depression-like behaviors in response to stress. Treatment with acetyl carnitine also appeared to protect these mice, suggesting that a similar preventative approach might work for depression-prone people.

Both humans and rodents naturally produce acetyl carnitine under normal conditions and several depression-prone animal models are deficient in acetyl carnitine. In a separate study, Nasca and colleagues are examining whether people with depression have abnormally low levels of the molecule.

"Chronic stress is linked to a number of psychiatric conditions, and this research may offer some new insights on their pathology," McEwen says. "It seems possible that the contrasting responses we see within the amygdala, and the limbic system in general, may contribute to these disorders' differing symptoms, which can range from avoiding social contact to experiencing vivid flashbacks."

Betrixaban scores near miss for extended thromboprophylaxis

enoxaparin

In continuation of my update on enoxaparin

Extended thromboprophylaxis with the direct factor Xa inhibitor betrixaban just fails to show superiority to standard treatment with enoxaparin in acutely ill medical patients.

 betrixaban

Indeed, the randomised trial published in The New England Journal of Medicine shows significant results for the overall cohort, but this was prespecified as only an exploratory analysis in the event of a negative result in patients of primary interest: those with elevated ᴅ-dimer levels.

Among these patients, there was a numerical but not statistically significant difference in the primary outcome of asymptomatic proximal deep-vein thrombosis or symptomatic venous thromboembolism. This occurred at a rate of 6.9% in 1914 patients who received subcutaneous placebo for around 10 days plus oral betrixaban (80 mg/day) for 35 to 42 days, and of 8.5% in 1956 who received subcutaneous enoxaparin (40 mg/day) plus oral placebo.

This gave a nonsignificant relative risk of 0.81 in favour of betrixaban, with a confidence interval of 0.65 to 1.00 and a p value of 0.054.

The researchers, Alexander Cohen (Guy's and St Thomas' Hospitals, London, UK) and colleagues, anticipated the best chance of a significant treatment effect among the highest-risk patients with elevated ᴅ-dimer levels. Because this did not occur, further analyses, although prespecified, were classed as exploratory.

The first of these analyses extended the population to include patients who were aged at least 75 years. Event rates in this cohort were 5.6% in the 2842 patients given betrixaban versus 7.1% in the 2893 given enoxaparin, equating to a significant relative risk of 0.80 (p=0.03).

And in the overall population, which also included patients with neither elevated ᴅ-dimer nor old age, the rates were 5.3% in the 3112 patients given betrixaban versus 7.0% in the 3174 given enoxaparin, again equating to a significant relative risk of 0.76 (p=0.006).

The primary safety endpoint, of major bleeding, was no more common in the betrixaban than enoxaparin groups, at 0.7% versus 0.6% in the overall population, but clinically relevant non-major bleeding was significantly more common, at 2.5% versus 1.0%.

However, Cohen et al say that these safety results set betrixaban apart from other previously tested drugs, which caused significantly increased major bleeding when used for extended thromboprophylaxis. They note that use of preventive treatment "hinges on the safety of the intervention."

The researchers say that their results overall provide "evidence suggesting a benefit for betrixaban."

They comment that the current trend towards shorter hospital stays may lead to patients receiving inadequate duration of thromboprophylaxis and that being able to extend this with oral treatment "would benefit public health."

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1601747

TSRI scientists develop first drug candidate that neutralizes disease-causing RNA repeats

Top, Venn diagram of substructures in compounds that were found to bind to RNA from the fluorescence screening assay showed in Fig. 1c. Data were compiled by using compounds that had a P value of <0.001 for binding to the RNA hairpins. Bottom, structures of compounds 1 and 2 that were the most avid for binding to AUAU and AAUU RNA hairpins.

In an important new study with implications for the treatment of dozens of incurable diseases, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time created a drug candidate that attacks and neutralizes the RNA structure that causes an incurable progressive, inherited disease involving a gradual loss of control over body movement.

The study, which was published June 1, 2016 in Nature Communications, showed the compound significantly improved several aspects of cells taken directly from patients with spinocerebellar ataxia type 10 (SCA10), a form of spinocerebellar ataxia.

“More than 30 diseases, all of them incurable, are caused by RNA repeats,” said TSRI Professor Matthew Disney, who led the study. “By a thorough basic science investigation, we identified small molecules that target RNA base pairs precisely. We then leveraged this information to design the first drug candidate that binds to disease-causing defects in SCA10. Application of the drug candidate returns certain aspects of those cells to healthy levels—it’s like the defect is not even there.”

SCA10 is caused by what is called a pentanucleotide repeat (a genetic sequence of five nucleotides repeated many more times than normal) affecting the mitochondria, the cell’s energy source. The new drug candidate, known as 2AU-2, targets these repeats by binding to RNA base pairs.

“The potent bioactivity of 2AU-2 to moderate the structurally induced toxicity in SCA10 strongly suggests that base-pair-targeting RNA modules could have broad applicability in our effort to develop other compounds that target different RNAs,” said TSRI Research Associate Wang-Yong Yang, the first author of the study. “More than 70 percent of RNA secondary structure is made up of base pairing.”

The Disney group has developed new tools to identify optimal interactions between RNA structures and drug candidates targeting them. A database of these interactions has already been used to design several small molecule drug candidates.

“We are in the process of developing tools that allow one to design small molecules to target any RNA structural motif in a complex cellular environment. That environment can contain millions of other RNAs. In this study, Wang-Yong has done an exceptional job tackling this previously-thought-to-be-impossible molecular recognition problem,” Disney said.

Pathogenic RNA repeats contribute to disorders including Huntington’s disease, fragile X-associated tremor ataxia syndrome and myotonic dystrophy type 1 and 2.

Ref : http://www.nature.com/ncomms/2016/160601/ncomms11647/full/ncomms11647.html

Ancient anti-inflammatory drug salicylic acid has cancer-fighting properties: Diflunisal -- a cousin of aspirin -- blocks a key protein that causes tumor formation in leukemia

In a study published in eLife, the researchers found that both salicylic acid and diflunisal suppress two key proteins that help control gene expression throughout the body. These sister proteins, p300 and CREB-binding protein (CBP), are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth. By inhibiting p300 and CBP, salicylic acid and diflunisal block the activation of these proteins and prevent cellular damage caused by inflammation. This study provides the first concrete demonstration that both p300 and CBP can be targeted by drugs and may have important clinical implications.

"Salicylic acid is one of the oldest drugs on the planet, dating back to the Egyptians and the Greeks, but we're still discovering new things about it," said senior author Eric Verdin, MD, associate director of the Gladstone Institute of Virology and Immunology. "Uncovering this pathway of inflammation that salicylic acid acts upon opens up a host of new clinical possibilities for these drugs."

Earlier research conducted in the laboratory of co-author Stephen D. Nimer, MD, director of Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and a collaborator of Verdin's, established a link between p300 and the leukemia-promoting protein AML1-ETO. In the current study, scientists at Gladstone and Sylvester worked together to test whether suppressing p300 with diflunisal would suppress leukemia growth in mice. As predicted, diflunisal stopped cancer progression and shrunk the tumors in the mouse model of leukemia.

"The ability to repurpose drugs that are already FDA-approved to be part of novel therapies for cancer patients is incredibly exciting," said Nimer. "We have conducted a clinical trial of salicylic acid in patients with hematologic cancers and found it to be safe. Thus, this collaborative effort to develop novel epigenetic therapies is an important next step in our journey to find more effective treatment for leukemia patients."

The scientists are now pursuing a clinical trial that will test the ability of salicylic acid to treat patients with leukemia as part of novel combination therapies. Other possible clinical applications for salicylic acid include other forms of cancer, type 2 diabetes, inflammatory diseases, and even neurodegenerative disorders, such as Alzheimer's disease. Prior Gladstone research showed that another drug containing salicylic acid prevented the accumulation of tau in neurons and protected against cognitive decline in a mouse model of dementia.

First buprenorphine implant for opioid dependence treatment gets FDA approval

The U.S. Food and Drug Administration today approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for six months in patients who are already stable on low-to-moderate doses of other forms of buprenorphine, as part of a complete treatment program.

Until today, buprenorphine for the treatment of opioid dependence was only approved as a pill or a film placed under the tongue or on the inside of a person's cheek until it dissolved. While effective, a pill or film may be lost, forgotten or stolen. However, as an implant, Probuphine provides a new treatment option for people in recovery who may value the unique benefits of a six-month implant compared to other forms of buprenorphine, such as the possibility of improved patient convenience from not needing to take medication on a daily basis. An independent FDA advisory committee supported the approval of Probuphine in a meeting held earlier this year.

"Opioid abuse and addiction have taken a devastating toll on American families. We must do everything we can to make new, innovative treatment options available that can help patients regain control over their lives," said FDA Commissioner Robert M. Califf, M.D. "Today's approval provides the first-ever implantable option to support patients' efforts to maintain treatment as part of their overall recovery program."

Expanding the use and availability of medication-assisted treatment (MAT) options like buprenorphine is an important component of the FDA's opioid action plan and one of three top priorities for the U.S. Department of Health and Human Services' Opioid Initiative aimed at reducing prescription opioid and heroin related overdose, death and dependence.

Opioid dependence is the diagnostic term used for the more common concept, "addiction," in the Probuphine clinical trials. Addiction is defined as a cluster of behavioral, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use, persisting in drug use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, as well as the possibility of the development of tolerance or development of physical dependence. Physical dependence is not the same as addiction. Newer diagnostic terminology uses the term "opioid use disorder," which includes both milder forms of problematic opioid use as well as addiction.

MAT is a comprehensive approach that combines approved medications (currently, methadone, buprenorphine or naltrexone) with counseling and other behavioral therapies to treat patients with opioid use disorder. Regular adherence to MAT with buprenorphine reduces opioid withdrawal symptoms and the desire to use, without causing the cycle of highs and lows associated with opioid misuse or abuse. At sufficient doses, it also decreases the pleasurable effects of other opioids, making continued opioid abuse less attractive. According to the Substance Abuse and Mental Health Services Administration, patients receiving MAT for their opioid use disorder cut their risk of death from all causes in half.

"Scientific evidence suggests that maintenance treatment with these medications in the context of behavioral treatment and recovery support are more effective in the treatment of opioid use disorder than short-term detoxification programs aimed at abstinence," said Nora Volkow, M.D., director of the National Institute on Drug Abuse at the National Institutes of Health. "This product will expand the treatment alternatives available to people suffering from an opioid use disorder."

Probuphine should be used as part of a complete treatment program that includes counseling and psychosocial support. Probuphine consists of four, one-inch-long rods that are implanted under the skin on the inside of the upper arm and provide treatment for six months. Administering Probuphine requires specific training because it must be surgically inserted and removed. Only a health care provider who has completed the training and become certified through a restricted program called the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program should insert and remove the implants. If further treatment is needed, new implants may be inserted in the opposite arm for one additional course of treatment. The FDA is requiring postmarketing studies to establish the safety and feasibility of placing the Probuphine implants for additional courses of treatment.

The safety and efficacy of Probuphine were demonstrated in a randomized clinical trial of adults who met the clinical criteria for opioid dependence and were considered stable after prior buprenorphine treatment. A response to MAT was measured by urine screening and self-reporting of illicit opioid use during the six month treatment period. Sixty-three percent of Probuphine-treated patients had no evidence of illicit opioid use throughout the six months of treatment – similar to the 64 percent of those who responded to sublingual (under the tongue) buprenorphine alone.

The most common side effects from treatment with Probuphine include implant-site pain, itching, and redness, as well as headache, depression, constipation, nausea, vomiting, back pain, toothache and oropharyngeal pain. The safety and efficacy of Probuphine have not been established in children or adolescents less than 16 years of age. Clinical studies of Probuphine did not include participants over the age of 65.

Probuphine has a boxed warning that provides important safety information for health care professionals, including a warning that insertion and removal of Probuphine are associated with the risk of implant migration, protrusion, expulsion and nerve damage resulting from the procedure. Probuphine must be prescribed and dispensed according to the Probuphine REMS program because of the risks of surgical complications and because of the risks of accidental overdose, misuse and abuse if an implant comes out or protrudes from the skin. As part of this program, Probuphine can only be prescribed and dispensed by health care providers who are certified with the REMS program and have completed live training, among other requirements.

Probuphine implants contain a significant amount of drug that can potentially be expelled or removed, resulting in the potential for accidental exposure or intentional misuse and abuse if the implant comes out of the skin. Patients should be seen during the first week after insertion and a visit schedule of no less than once-monthly is recommended for continued counseling and psychosocial support.

First buprenorphine implant for opioid dependence treatment gets FDA approval: The U.S. Food and Drug Administration today approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. Probuphine is designed to provide a constant, low-level dose of buprenorphine for six months in patients who are already stable on low-to-moderate doses of other forms of buprenorphine, as part of a complete treatment program.

Study identifies potential new treatment for subset of gastric cancer patients

Testing cancers for 'addiction' to a gene that boosts cell growth can pick out patients who may respond to a targeted drug under development, a major new study reports.

By measuring the number of copies of just one gene from cancer DNA circulating in the bloodstream, scientists were able to identify the patients with stomach cancer who were most likely to respond to treatment.

Stomach cancers with many copies of the FGFR2 gene were found to be particularly susceptible to the experimental drug, an FGFR inhibitor, because the tumours had become reliant on, or 'addicted' to, the gene in order to grow.

The new test, described in the prestigious journal Cancer Discovery this week, could be used in future to direct treatment, by identifying a subset of patients who could benefit from an FGFR2 inhibitor.

A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust assessed the potency of the FGFR inhibitor AZD4547 in patients with stomach and breast cancer in a phase II clinical trial that screened 341 patients.

The study was funded by Cancer Research UK and AstraZeneca, with some additional funding from the charity Breast Cancer Now and the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR).

Initially using tumour biopsies, researchers found many copies of the FGFR2 gene in 9 per cent of cancers among the 135 stomach cancer patients on the trial. Cancer cells often undergo changes in their DNA that can result in multiple copies of genes that help cancers grow and spread.

Tumours with multiple copies of the gene FGFR2 responded well to the treatment, with three out of nine patients having a response to treatment, and in those patients the drug worked for an average of 6.6 months.

Some 18 per cent of breast cancers were found to have multiple copies of a sister gene, known as FGFR1, and not FGFR2 - but tumours with multiple FGFR1 genes did not have the same susceptibility to the drug.

Interrogating the reason for their observations, the researchers took samples back to the laboratory to pick apart the reasons why the drug worked well in FGFR2 tumours and not in other FGFR genes.

Through painstaking experiments, they found that FGFR2 hijacks molecular pathways that help cancer grow and spread, and some stomach tumours become addicted to high levels of the gene's protein product.

This phenomenon is known as cancer gene 'addiction', and is a weakness that can be exploited by modern targeted therapies.

Study co-leader Dr Nicholas Turner, Team Leader in Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"Our study has identified a potential new treatment for a subset of patients with gastric cancer, and has explained why some gastric cancers were responding to treatment while others did not. We were able to design a blood test to screen for patients who were most likely to benefit from an FGFR2 inhibitor, helping us to target drug therapy at those patients who were most likely to benefit.

"The research helps shed light on how tumours can become addicted to certain cancer genes, and shows how we can treat the disease effectively by taking advantage of these weak points in cancer's armoury."

Professor David Cunningham, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Honorary Professor of Cancer Medicine at The Institute of Cancer Research, London, who was Chief Investigator of the clinical trial associated with the study, said:

"This is a great example of a faster, smarter treatment being delivered to a relatively small but important group of patients with gastric cancer, made possible through the support of our NIHR Biomedical Research Centre."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"This is an important study, which shows how new targeted treatments can exploit cancer's genetic addictions, and acts as a proof of principle that cancer DNA detected in the bloodstream can be used to guide treatment.

"This is a perfect example of not just bench to bedside but back again - showing the value in taking clinical findings and scrutinising them back in the lab."

Dr Emma Smith, Cancer Research UK's science information manager, said:

"Developing ways to identify people who are most likely to benefit from drugs targeting particular genetic faults is vital to help ensure each patient gets the most effective treatment. The next steps will be larger clinical trials to see if testing for this genetic abnormality can spot people whose stomach cancer will respond well to this treatment."

Dr Carl Barrett, VP Translational Science, Oncology iMed, Innovative Medicines & Early Development, AstraZeneca, said:

"This collaboration illustrates the importance of carefully analysing patient tissue samples to develop an understanding of markers of sensitivity and resistance. This knowledge will help future development of FGFR inhibitors and the understanding of the genomic response to treatment. The development of a blood-based biomarker assay, which will detect circulating tumour DNA, will help identify patients whose tumour is addicted to FGFR2 gene amplification events. AstraZeneca already uses this approach for several targeted therapies across our oncology portfolio."

Vismodegib drug shows no addded benefit in advanced or symptomatic metastatic BCC patients

  

Vismodegib (trade name: Erivedge) has already been approved since 2013 for the treatment of patients with locally advanced basal cell carcinoma (BCC) or symptomatic metastatic BCC and has already undergone an early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G-BA) limited its decision in February 2014 to two years, which is why the drug manufacturer now submitted a new dossier.

In its second early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) came to the same conclusion as in the first one: The data presented on the drug showed no superiority in comparison with the appropriate comparator therapy. Hence an added benefit of vismodegib is still not proven.

No better data two years later

The appropriate comparator therapy was best supportive care (BSC), i.e. an individual combination of the best possible supportive treatments. According to the G-BA, this can also include surgery or radiotherapy for patients with symptomatic metastatic BCC, which is not the case in locally advanced BCC.

As already in the first dossier, the manufacturer presented no data from randomized or non-randomized comparative studies that would be suitable for the assessment of an added benefit of vismodegib for patients with symptomatic metastatic BCC or with locally advanced BCC. In the newly submitted data from four one-arm intervention studies, patients with symptomatic metastatic BCC cannot be differentiated from study participants with metastases, but without symptoms (metastatic BCC), for example. Furthermore, study results on the outcome "objective response rate" were not presented adequately for locally advanced BCC patients; there was no information on size, number and location of skin lesions, for example. Hence the manufacturer did not implement one of the conditions of the G-BA's Limitation.

Manufacturer's assumptions on BSC not justified

Moreover, a simplified search conducted by IQWiG showed that the study pool on locally advanced BCC in the dossier was incomplete. The manufacturer stated that it had found no studies on BSC, for example. Besides two further potentially relevant studies, IQWiG identified one study (Horn 2003), however.

This study runs counter to the manufacturer's assumptions that no studies on BSC in patients with locally advanced BCC existed and that it could be assumed that patients with locally advanced BCC do not respond to BSC:In the study, 75 per cent of the patients with locally advanced BCC responded completely after three months; after 24 months, these were still at least 50 per cent. Furthermore, the manufacturer claimed that nothing was known on the occurrence of adverse events in BSC. The study Horn 2003 actually addressed this outcome, however: No serious adverse events were reported.

Overall, there was no hint of an added benefit of vismodegib in comparison with the appropriate comparator therapy for any of the two research questions.

Vismodegib drug shows no addded benefit in advanced or symptomatic metastatic BCC patients: Vismodegib (trade name: Erivedge) has already been approved since 2013 for the treatment of patients with locally advanced basal cell carcinoma (BCC) or symptomatic metastatic BCC and has already undergone an early benefit assessment according to the Act on the Reform of the Market for Medicinal Products.