Dabrafenib [Tafinalar] and Trametinib [Mekinist] Approved for BRAF V600 Mutated Metastatic Melanoma

May 30, 2013

May 30, 2013 – From a Medscape News Release we learn today that two new drugs have been approved by the US Food and Drug Administration (FDA) for use in certain patients with metastatic or unresectable melanoma, along with a diagnostic test to identify patients who are suitable for treatment.

The new products, Dabrafenib [Tafinalar] and Trametinib [Mekinist], were both developed by GlaxoSmithKline. Both are orally available tablets, but they have slightly different mechanisms of action.

Dabrafenib [Tafinalar]  acts as a BRAF inhibitor and is approved for use in patients with melanoma whose tumors express the BRAF V600E gene mutation. It is seen as being a next-generation product but is in the same class as the first BRAF inhibitor to reach the market, Vemurafenib [Zelboraf] (Genentech).

Trametinib [Mekinist] has a related but slightly different mechanism and acts as a mitogen-activated, extracellular signal-regulated kinase inhibitor (MEK inhibitor). It is the first drug in this class to be approved and is indicated for use in patients with whose tumors express the BRAF V600E or V600K gene mutations.

Approximately half of melanomas arising in the skin have a BRAF gene mutation, the FDA notes in its approval notice. Alongside the new drugs, the agency also approved a genetic test, the THxID BRAF test, a companion diagnostic developed in collaboration with bioMérieux that will help determine wither a patient’s melanoma cells have the V600E or V600K mutation in the BRAF gene.

Melanoma is the leading cause of death from skin disease, the FDA adds. The National Cancer Institute estimates 76,690 Americans will be diagnosed with melanoma and 9480 will die from the disease in 2013.

Clinical Trial Data

Dabrafenib [Tafinalar]  was approved on the basis of data from the BREAK 3 study, conducted in 250 patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. It showed that in such patients, Dabrafenib [Tafinalar]  significantly improved the median progression-free survival compared with chemotherapy with dacarbazine (5.1 vs 2.7 months; P < .0001). These results were published in July 2012 issue of the Lancet (2012;380:358-365).

The FDA notes that the most serious adverse effects reported in patients receiving Dabrafenib [Tafinalar] included an increased risk for cutaneous squamous cell carcinoma, fevers that may be complicated by hypotension, severe rigors, dehydration, kidney failure, and increased blood sugar levels requiring changes in diabetes medication or the need to start medicines to control diabetes.

The most common adverse effects reported in patients receiving Dabrafenib [Tafinalar]  included hyperkeratosis, headache, fever, joint pain, noncancerous skin tumors, hair loss, and hand–foot syndrome.

The pivotal study for Trametinib [Mekinist], the METRIC study, was a little different in that it was conducted in 322 patients who had already tried a prior regimen of chemotherapy. In this study, compared with chemotherapy, Trametinib [Mekinist] significantly improved progression-free survival as well as overall survival. The results were published in the New England Journal of Medicine.

The FDA notes that the most serious adverse effects reported in patients receiving Trametinib [Mekinist]  included heart failure, lung inflammation, skin infections, and loss of vision. Common adverse effects included rash, diarrhea, tissue swelling (peripheral edema), and skin breakouts that resemble acne.

The agency also noted that women of childbearing years should be advised that Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  carry the potential to cause fetal harm. Men and women should also be advised that both drugs also carry the potential to cause infertility.

Being Investigated in Combination

Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  have been approved for use as monotherapy, and not as a combination treatment, the FDA has emphasized. However, there is a lot of interest from clinicians in using both drugs together, and indeed the manufacturer is conducting a clinical trial with the combination.

Preliminary results from a clinical trial with the combination suggest that use of the 2 drugs together resulted in less toxicity, and specifically in fewer secondary skin cancers, than has been seen with  Vemurafenib [Zelboraf]  used alone.

GlaxoSmithKline is now conducting a phase 3 study (known as COMBI-AD) of the combination of Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  in patients with BRAF V600 melanoma that has been completely removed by surgery. Such patients are at high risk for relapse, and the combination of drugs is being tested to see whether it can delay or prevent the recurrence of melanoma, the company noted.

Problem: Responses Are Short-lived

The new Dabrafenib [Tafinalar]  appears to be similar to the already-marketed Vemurafenib [Zelboraf], but there are important differences between the 2 BRAF inhibitors in their toxicity profiles, noted Kim Margolin, MD, from the Seattle Cancer Care Alliance in Washington..

Skin toxicities, particularly the emergence of low-grade squamous cancers and keratoacanthomas, which occurred in a substantial number of patients taking Vemurafenib [Zelboraf], appear to be quite unusual with Dabrafenib [Tafinalar], Dr. Margolin noted. However, a systemic “pyrexia reaction,” which is almost never seen with Vemurafenib [Zelboraf], has been seen in a substantial percentage of patients taking Dabrafenib [Tafinalar]. “We don’t know yet about the off-target mechanisms of these differences and how much may be due to the vehicle or the formulation for each of these oral agents,” she added.

However, the biggest problem with the BRAF inhibitors in the treatment of melanoma has been the lack of durable response: These drugs “tend to work for an average of 5 to 6 months,” Dr. Margolin noted. What to do when patients fail on these drugs remains a challenge, she added.

Ultimately, combination therapy with a BRAF inhibitor (such as Vemurafenib [Zelboraf]  or Dabrafenib [Tafinalar]) plus a MEK inhibitor (such as Trametinib [Mekinist]) is “likely to be most valuable for improved and lasting results,” according to Dr. Margolin. Firstclinical results along these lines have been published in the New England Journal of Medicine at the end of last year.

New Breast Cancer HER2 Diagnostic Tests Approved by FDA

June 13, 2012
June 12, 2012 — Two diagnostic tests to identify HER2-positive breast cancer have been approved by the US Food and Drug Administration (FDA) for use as companion diagnostics for the new targeted therapy Pertuzumab [Perjeta].
The tests — HercepTest and HER2 FISH pharmDx Kit — are both manufactured by Dako in Glostrup, Denmark. The tests serve as diagnostic tools to identify patients with HER2-positive metastatic breast cancer who might be eligible for treatment with HER2-positive targeted therapies. The latest of these —Pertuzumab [Perjeta]— was approved  just days ago by the American Food and Drug Administration (FDA) for use in combination with Trastuzumab [Herceptin] and chemotherapy in patients with HER2-positivemetastatic breast cancer who have not been treated with either trastuzumab or chemotherapy.
“The role of HER2 in diagnosis and clinical decision making continues to evolve with the recent approval of Pertuzumab [Perjeta]”, said David Hicks, MD, director of surgical pathology at the University of Rochester Medical Center in New York. “It is clear that optimal patient care depends now more than ever on the accurate, reliable, and reproducible assessment of HER2 status for the full benefit of pertuzumab to be derived by the appropriate patient population,” he noted in a Dako press release. Dako reported that it had been collaborating with Genentech on a parallel FDA approval process for the 2 tests and the new drug.

FDA Approves Crizotinib [Xalkori] with Companion Diagnostic Test for Non-Small Cell Lung Cancers (NSCLC) Positive for the Anaplastic Lymphoma Kinase (ALK) Gene

August 28, 2011

August 26, 2011 – Today, the  American Food and Drug Administration (FDA) has approved Crizotinib [Xalkori] to treat the patient subgroup with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) whos cancers express (i.e., test positive for the presence of) the abnormal anaplastic lymphoma kinase (ALK) gene.

The abnormal anaplastic lymphoma kinase (ALK) gene causes cancer cell development and growth. About 1 percent to 7 percent of the patients with NSCLC have the ALK gene abnormality. Patients with this form of lung cancer are typically non-smokers. Crizotinib [Xalkori] works by blocking certain proteins called kinases, including the protein produced by the abnormal ALK gene. Xalkori is a pill taken twice a day as a single-agent treatment.

Crizotinib [Xalkori] has been approved together with a companion diagnostic test that will help determine if a patient’s tumor expresses the abnormal ALK gene. This genetic test is called the Vysis ALK Break Apart FISH Probe Kit. The application of this specific test allows the selection of only those  patients for treatment with Crizotinib [Xalkori] who are most likely to respond to the drug. Targeted therapies such as this one invoving Crizotinib [Xalkori] are considered important options for sucessfully treating patients with this disease.

Crizotinib [Xalkori]’s effectiveness was established in two multi-center, single-arm studies enrolling a total of 255 patients with late-stage ALK-positive NSCLC. A sample of a patient’s lung cancer tissue was collected and tested for the ALK gene abnormality prior to study enrollment. The studies were designed to measure objective response rate, the percentage of patients who experienced complete or partial cancer shrinkage. Most patients in the studies had received prior chemotherapy. In one study, the objective response rate was 50 percent with a median response duration of 42 weeks. In another study, the objective response rate was 61 percent with a median response duration of 48 weeks.

Based on these favorable efficacy data, Crizotinib [Xalkori] has been approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious  and life-threatening disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients. The program is designed to provide patients with earlier access to promising new drugs, followed by further studies to confirm the drug’s clinical benefit.

The most common side effects reported in patients receiving Crizotinib [Xalkori] included vision disorders, nausea, diarrhea, vomiting, swelling (edema), and constipation. Vision disorders included visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects. Xalkori use has also been associated with inflammation of the lung tissue (pneumonitis), which can be life-threatening. Patients with treatment-related pneumonitis should permanently stop treatment with Crizotinib [Xalkori]. Moreover, the drug should not be used in pregnant women. In the context of the clinical safety of Crizotinib [Xalkori], we should be aware that the companion test (Vysis ALK Break Apart FISH Probe Kit) does not identify patients with either a predisposition for any of the unwanted drug side effects, or irregularities in drug disposition (e.g., poor or ultrarapid metabolizers). We will also need many more patients treated with Crizotinib [Xalkori] in order to more completely understand the clinical safety profile of Crizotinib [Xalkori].

See the FDA Press Release here.

Vemurafenib [Zelboraf] Approved Together with a Companion Diagnostic Test by FDA for Advanced Melanoma in BRAF V600E Positive Patients

August 20, 2011

August 17, 2011 — The US Food and Drug Administration (FDA) has just approved the oral targeted therapy Vemurafenib [Zelboraf] for the first-line treatment of both metastatic and unresectable melanomas. The drug is specifically indicated for patients with melanoma whose tumors have V600E mutations in the BRAF gene. An estimated 50% of patients with melanoma have this type of BRAF mutation, which does not occur in normal cells. The drug is not indicated for use in melanoma patients negative for the BRAF V600E mutation. Vemurafenib [Zelboraf] is a BRAF inhibitor that blocks the function of the V600E-mutated BRAF protein.

Vemurafenib [Zelboraf] has been approved with a companion diagnostic test that will help determine whether a patient’s melanoma cells have the BRAF V600E mutation. The first-of-a-kind test is known as the cobas 4800 BRAF V600 Mutation Test (by Roche Molecular Systems).

The approval of Vemurafenib [Zelboraf] and the cobas test is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health. The FDA’s approval of the cobas 4800 BRAF V600 Mutation Test was based on data from the same study that evaluated the safety and effectiveness of Vemurafenib [Zelboraf].

Vemurafenib [Zelboraf] was reviewed under the FDA’s priority review program that provides for an expedited 6-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists, says the agency.

“This has been an important year for patients with late-stage melanoma. Vemurafenib [Zelboraf] is the second new cancer drug approved that demonstrates an improvement in overall survival,” said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in a press statement. “In March, we approved Ipilimumab [Yervoy], another new treatment for late-stage melanoma that also showed patients live longer after receiving the drug.”

Thalidomide may fight blood vessel disorder: Nosebleeds eased with once-maligned drug

April 5, 2010

April 05, 2010 – A very recent article by msnbc.com indicates that thalidomide, a drug that caused birth defects when it was launched as a morning sickness pill half a century ago, may be useful for treating a hereditary condition that affects blood vessels.

In a study in the journal Nature Medicine, French researchers found giving thalidomide to patients with a disorder called hereditary hemorrhagic telangiectasia (HHT) reduced the severity and frequency of nosebleeds, one of the main symptoms.

Franck Lebrin, who led the study with colleagues from the National Institute for Health and Medical Research in Paris, said experiments on mice with HHT showed thalidomide treatment was able to repair blood vessel wall defects through a mechanism involving proteins involved in cell growth. “Biopsies of the nasal surface tissue from patients with HHT showed that similar mechanisms may explain the effects of thalidomide treatment in humans,” he wrote in the study.

HHT affects about one in 5,000 people. Many patients develop recurrent, difficult-to-treat nosebleeds which can significantly harm their quality of life.

Thalidomide was used to treat nausea during pregnancy in the 1960s. The drug was taken off the market after severe teratogenic congenital defects appeared in the newborns of mothers who had taken it (referred to as “contergan scandal” in germany).

More recently, thalidomide – which has powerful anti-cancer properties – experienced a revival and is now being used to treat certain forms of cancer such as multiple myeloma, and the drug is on the market in the US as Thalidomide [Thalomed]. U.S. drugmaker Celgene has developed a successor drug to thalidomide, called Lenalidomide [Revlimid], which is also approved to treat multiple myeloma.

Emergency Use of Investigational Antiviral Drug Peramivir to Treat H1N1

January 6, 2010
January 06, 2010 – Recently, FDA has authorized the emergency use of the investigational antiviral drug Peramivir for certain adults and children hospitalized with confirmed or suspected 2009 H1N1 influenza. This includes patients who have an influenza A virus that is non-subtypeable and is suspected to be 2009 H1N1 based on cases in the community.

Peramivir, which is administered intravenously, is in the same drug class as Tamiflu and Relenza. Peramivir is authorized only under certain circumstances: when the patient is not responding to either oral or inhaled antiviral therapy, when other routes of drug administration are not expected to be dependable or feasible, or, in the case of adult patients, when the clinician judges that IV therapy is appropriate for other reasons.

Peramivir is not authorized to prevent influenza, to treat seasonal influenza, or to treat acute, uncomplicated 2009 H1N1 infection. Also, it should not be used in patients with severe allergies to Tamiflu (Oseltamivir phosphate) or Relenza (Zanamivir), or those who have shown resistance to Tamiflu.

Only CDC is authorized to distribute Peramivir. Physicians who want to use it must apply through CDC’s Peramivir IV Electronic Request System. Once the decision is made to ship the drug, it may take up to 24 hours to reach the hospital.

Because Peramivir is an unapproved drug with limited safety data, health care providers or their designees are required to report certain adverse events and all medication errors associated with Peramivir to FDA’s MedWatch program. This must be done within 7 calendar days of the onset of the adverse event.

Additional Information:

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European Medicines Agency (EMEA) Pandemic Influenza (H1N1) Portal: Celvapan Approved

November 7, 2009

November 7, 2007 – According to the Pandemic Influenza (H1N1) Portal by the European Medicines Agency (EMEA), Celvapan has recently been approved.

Celvapan is a vaccine that is given by injection into the shoulder muscle in two doses, at least three weeks apart. It contains influenza (flu) viruses that have been inactivated (killed). Celvapan contains a flu strain called A/California/07/2009 (H1N1)v. Celvapan is intended to protect against ‘pandemic’ flu. It should only be used for the influenza A (H1N1) pandemic that was officially declared by the World Health Organization on 11 June 2009. A flu pandemic happens when a new strain of flu virus appears that can spread easily from person to person because people have no immunity (protection) against it. A pandemic can affect most countries and regions around the world. Celvapan is given according to official recommendations. The vaccine can only be obtained with a prescription.

As a vaccine, Celvapan works by ‘teaching’ the immune system (the body’s natural defences) how to defend itself against a disease. Celvapan contains a virus called A(H1N1)v that is causing the current pandemic. The virus has been inactivated so that it does not cause any disease. When a person is given the vaccine, the immune system recognises the inactivated virus as ‘foreign’ and makes antibodies against it. The immune system will then be able to produce antibodies more quickly when it is exposed to the virus again. This helps to protect against the disease. The viruses used in Celvapan are grown in mammal cells (‘vero cells’), unlike those in some other flu vaccines, which are grown in hen’s eggs.

Celvapan was first developed as a ‘mock-up’ vaccine that contained an H5N1 strain of the flu virus called A/Vietnam/1203/2004. The company studied the ability of this mock-up vaccine to trigger the production of antibodies (‘immunogenicity’) against this strain of flu virus in advance of the pandemic. Following the start of the current pandemic, the company replaced the virus strain in Celvapan with the H1N1 strain causing the pandemic, and presented data relating to this change to the Committee for Medicinal Products for Human Use (CHMP).

The mock-up vaccine was shown to bring about protective levels of antibodies in at least 70% of the people in which it was studied. In line with the criteria laid down by the CHMP, this demonstrated that the vaccine brought about an appropriate level of protection. The CHMP was also satisfied that the change of strain to the H1N1 strain did not affect the characteristics of the vaccine.

Side effects

The most common side effect with Celvapan (seen in more than 1 people vaccinated in 10) is pain at the site of the injection. For the full list of all side effects reported with Celvapan, see the Package Leaflet. Celvapan should not be given to people who have had an anaphylactic reaction (severe allergic reaction) to any of the components of the vaccine, or to any of the substances found at trace (very low) levels in the vaccine, such as formaldehyde, benzonase or sucrose.

However, it may be appropriate to give the vaccine to these patients during a pandemic, as long as facilities for resuscitation are available.

Why has Celvapan been approved

The CHMP decided that, based on the information obtained with the mock-up vaccine and the information provided on the strain change, the benefits of Celvapan are greater than its risks for the prophylaxis of influenza in the officially declared H1N1 pandemic situation. The Committee recommended that Celvapan be given marketing authorisation.

Celvapan has been authorised under ‘Exceptional Circumstances’. This means that it has not yet been possible to obtain full information about the pandemic vaccine. Every year, the European Medicines Agency will review any new information that may become available and this summary will be updated as necessary.

What information is still awaited for Celvapan

The company that makes Celvapan will collect information on the safety and effectiveness of the vaccine, and submit this to the CHMP for evaluation. The company that makes Celvapan will collect information on the safety of the vaccine while it is being used. This will include information on its side effects and its safety in children, the elderly, pregnant women, patients with severe conditions and people who have problems with their immune systems.

Other information about Celvapan

The European Commission granted a marketing authorisation valid throughout the EU for the H5N1 mock-up vaccine for Celvapan on 4 March 2009. The change to the marketing authorisation for the H1N1 virus was authorised by the European Commission on 6 October 2009. The full assessment report will be published shortly.

Please contact the Pandemic Influenza (H1N1) Portal by EMEA on similar information for two other vaccines approved: Focetria and Pandemrix.

Bristol-Myers gets approval for its diabetes drug Saxagliptin [Onglyza] in the European Union (EU)

October 14, 2009

October 14, 2009 – On October 5, 2009, drug maker Bristol-Myers Squibb Co. announced that its new diabetes drug, Saxagliptin [Onglyza], has been approved for sale in the European Union’s (EU) 27 countries.

Saxagliptin [Onglyza] is the first diabetes drug to be launched in Europe by a partnership of New York-based Bristol-Myers and British drugmaker AstraZeneca PLC to develop drugs for type 2 diabetes. It was approved for use with three other standard diabetes drugs, based on six late-stage studies including more than 4,100 patients. Saxagliptin [Onglyza] and Merck & Co.’s Sitagliptin [Januvia] both are in a newer class of diabetes medicines called DPP-4 inhibitors. They work by increasing insulin production and lowering the production of glucose

Saxagliptin [Onglyza] will compete with Merck & Co.’s blockbuster diabetes drug Sitagliptin [Januvia] both in the EU and in the United States, where the Bristol Myers drug was approved on July 31, 2009. Whitehouse Station, N.J.-based Merck’s Sitagliptin [Januvia] and a related drug called Janumet, which includes metformin, constitute Merck’s fastest-growing product line, third in overall sales with a total of $1.75 billion in revenue last year. Saxagliptin [Onglyza] is to be launched in the European Union by year’s end; it’s already on sale in the U.S. Analysts have forecast that Saxagliptin [Onglyza] sales could hit as high as $1 billion a year, given the alarming increase in the number of people in developed countries with diabetes. The U.S. market for diabetes medicines alone already exceeds $5 billion annually.

Meanwhile, Bristol and AstraZeneca are in late-stage testing of another potential diabetes drug, dapagliflozin, that works by helping the kidneys eliminate excess glucose. Saxagliptin [Onglyza] was approved to be used with metformin or another drug from one of two different classes that are often prescribed, along with diet and exercise, when patients are first diagnosed with type 2 diabetes. People with the disorder, most often caused by obesity and inadequate exercise, do not use the insulin made by their body efficiently and may eventually need injected insulin as well as pills to control the disease.

Also Monday, Bristol and AstraZeneca released results of a new study showing that Saxagliptin [Onglyza] with metformin works roughly the same as Sitagliptin [Januvia] with metformin, reducing a key measure of long-term blood sugar level by 0.52 percent, compared with a 0.62 percent reduction for the patients in the Januvia group.

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