Genetic Trigger Discovered For Most Common Form of Mental Disability and Autism

March 08, 1014 – The following article just appeared in PsyBlog and provides highly interesting reading in relation to newly discovered molecular mechanisms in the etiology of (possibly individualized) disease predispositions. Very exciting.

The most common form of intellectual disability is caused by a mechanism which shuts of an associated gene, a new study finds.Scientists at the Weill Cornell Medical College have also shown that a drug can block the silencing mechanism, thereby preventing the most common form of mental disability: fragile X syndrome (Colak et al., 2014).This points the way towards a therapy for fragile X syndrome — a leading genetic cause of autism — and possibly for about 20 other diseases. Fragile X syndrome causes a wide range of emotional, behavioural and physical problems and occurs mostly in boys. For around twenty years scientists have known that the cause of fragile X syndrome is the excess repetition of a sequence of genetic code. The problem was understanding how this code caused the disease.

Now, in a new study, published in the prestigious journal Science, researchers have discovered that this code halts the production of a protein which is crucial to communication within the brain. To find out how to fix this problem, the researchers used human stem cells from embryos that had tested positive for fragile X syndrome to create brain neurons in the lab.

This gave them a model of how the embryonic brain develops in which to test a new drug developed by Dr. Matthew Disney of the Scripps Research Institute. After adding the drug, they found that the gene continued to produce the vital protein, instead of being deactivated as it is in fragile X syndrome.

This points the way towards a treatment for fragile X syndrome. One of the study’s authors, Dr. Samie Jaffrey, explained: The findings have implications for a range of other diseases because of the biological mechanism that has been discovered. Other diseases including Jacobsen syndrome, an intellectual disorder, and Huntington’s disease, a neurodegenerative disorder, involve similar repetitions of DNA sequences and so may be amenable to similar treatments.

The Ethics of Personalized Medicine: A Philosopher’s Perspective

March 1, 2014 – Below please find an article just published in Medscape Oncology News. Since in the age of personalized or individualized medicine, personalization or individualization is so personal or individual to each one of the readers of this blog, I thought it worthwhile to make available to you this philosophers view on the topic. Enjoy reading, and draw your own personal or individual conclusions. (May I add that I copied and pasted the article in its entirety from Medscape site, and are copyrights are entirely with Medscape. I left the list of references, which can be easily found at the site of the original article).

Start of Article

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It is a standard joke that when philosophers are asked to give a perspective on a topic, they first of all ask what it means and make no further progress. When it comes to personalized medicine, however, the question of meaning is very important insofar as our understanding of what is involved informs our understanding of the ethical issues. ^[1] This is critical, especially as the way issues are presented affects the expectations of patients. ‘Personalization’ suggests association with an individualist paradigm in ethics, although it may emerge that what is envisaged is more accurately described, at least in some cases, as stratification of the patient population into, for example, good or poor responders to a particular drug. Alternatively, patients may be divided into groups according to their disease type as more is learned about, for example, cancer subtypes. The prospects of increasing use of whole-genome sequencing (WGS), however, may make personalization a reality in a stronger sense.

The central idea of pharmacogenomics, that information about the variation in genetic make-up between individuals is relevant to prescription of drugs, introduced a specific sense to the concept of ‘personalization’ in which personalization became associated with a person’s genomic information. The ethical argument supporting this was the need to reduce the incidence of mortality and morbidity resulting from adverse drug responses. Personalized prescribing for a patient could be genetically informed, not only in relation to the choice of drug, but also in regards to dosage, thus minimizing the potential harm of inappropriate prescribing for a particular patient. Patients could be subdivided into those who could, and those who could not, tolerate a specific substance.

With the advent of WGS, the possibility of ‘tailoring’ medical advice and treatment to the individual throughout a lifetime becomes, at least, an in-principle possibility, although the term ‘tailoring’ was used by the UK Department of Health in 2003, before WGS was on the horizon. ^[2] The use of the tailoring metaphor gives a much stronger sense to personalization: all the multiple variations between individuals could be taken into account. In the clothing industry, there is a distinction between clothes tailored for the individual and those ready to wear for the mass market, and it might be tempting to think that this mirrors the distinction between personalized and blockbuster approaches to pharmaceuticals. However, within tailored clothing there is also a distinction between ‘bespoke’ and ‘made to measure’. Whereas ‘bespoke’ clothes are created without the use of a pre-existing pattern, ‘made to measure’ alters a standard-sized pattern to fit the customer. The move from genetic testing to WGS arguably suggests a move from ‘made to measure’ to ‘bespoke’. There is a caveat here, however, and that is that the word ‘bespoke’ comes from ‘bespeak’, which suggests that the individual is in control of the process. This may be where the analogy between personalized medicine and tailoring breaks down.

It is important not to overlook the fact that, although the ethical argument for personalized medicine was initially made to prevent adverse drug reactions (deeming it uncontroversial from that point of view), once a richer version of tailoring appears, attention also increasingly turns to benefits and to issues of equity in access. ^[3] The questions then are not only ‘how can we prevent harm to this person?’, but ‘how can we maximise the benefit?” and ‘how can we achieve justice in distribution?’ For example, suppose information emerges that, in relation to the prescription of a very expensive drug for cancer, some people may achieve a life extension of only a couple of weeks, while others may benefit with 2 years extra life. ^[4] It is not clear what criteria would be appropriate in such a situation. From one point of view, it might be argued that despite the variation in benefit, each person is entitled to receive the drug. From another, it might be argued that prescribing should be performed in order to maximize benefit.

There are also issues of international distribution to consider. Daar and Singer’s classic piece on pharmacogenomics and genetic ancestry argued eloquently against a situation in which the benefits of personalized medicine not only reinforced an individualistic ’boutique-style’ model of healthcare, but also operated to the disadvantage of less developed countries. ^[5] They argued a case for the possible benefits of ‘drug resuscitation’ in relation to products that had been taken off the market in the west, but which could also be beneficial in settings where the population had relevantly different genetic factors. ^[5]

Issues of equity impact strongly on public perceptions. When a new technology is introduced, there are always questions, not only relating to whether there are any new ethical issues, but also whether there are any public perception issues that might be challenging. This might be the case, for example, where personalization or stratification coincides with other ways of dividing up the population that might, historically, coincide with discrimination, such as racial or ethnic categories.

Some of the worries about personalized medicine arise in connection with its implementation. The rise of companies offering direct-to-consumer tests, for example, has led to criticisms over how the results might be interpreted, conveyed and misused. There are also concerns about what tests are offered, and the time at which tests may be offered. While it may be considered acceptable for an autonomous adult to decide to undertake genetic testing, there are different considerations relating to WGS at birth or even prenatally, for the purposes of personalized predictive medicine. ^[6] There is a view that prenatal genetic testing will become the standard of care. ^[7] However, over the past 15 years or so, the argument for a right not to know genetic information about oneself has been advanced, on the grounds that such knowledge may change one’s whole perception of one’s future life for the worse. ^[8] If widespread sequencing becomes the norm, to remain in ignorance may cease to be an option, and yet we should not necessarily think that knowledge here brings greater autonomy. The person ‘bespeaking’ the test is not identical with the one tested. There are also issues about the extent to which a genetic counseling model can be transferred to the new possibilities, or whether a consumer model is more appropriate.

For those who do want genetic testing and are prepared to pay for it, the price is falling, which may alleviate some of the concerns about access, but there are nevertheless concerns about control of the resulting data.

The promise of personalized medicine offers real exciting possibilities, and the language of personalization is becoming more than a rhetorical device: implementation is more complicated, partly because of the complexity of the mass of information emerging and partly because of concerns about implementation.

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End of Article

The deletion variant of the ADRA2B gene and the genetic predisposition to focus on the negative

October 17, 2013 – This morning, while commuting (a one and a half hour train ride) not only was I noticing all those stoned and negatively charged early morning faces of my fellow commuters but also I stumbled upon the following fantastic little article on PsyBlog, which explains it all. And yes, I am definitively not a carrier of the deletion variant of ADRA2B. I just imagined how a homozygote individual (i.e. ADRA2Bdel / ADRA2B del) would possibly cope with the world early in the morning. Go on reading the article below (in italics):

Some people are genetically predisposed to spot negative events automatically, according to a new study published in Psychological Science (Todd et al., 2013). A gene called ADRA2B seems to cause people to take particular note of negative emotional events. The study’s lead author, Professor Rebecca Todd explained:

“This is the first study to find that this genetic variation can significantly affect how people see and experience the world. The findings suggest people experience emotional aspects of the world partly through gene-coloured glasses — and that biological variations at the genetic level can play a significant role in individual differences in perception.”

The study used a phenomenon called ‘attentional blink‘ and involved participants looking at a series of positive, negative and neutral emotional words. Those who had the ADRA2b gene variant were more likely to perceive the negative emotional words than those without it. 

Positive emotion words, though, were perceived by those with and without the gene to the same degree.

Of course, we all need to spot very strong emotional stimuli around us–like a loved one in pain or anger and aggression in others–but paying too much attention to negative events can obviously make us unhappy. Not only is the gene linked to differences between people in their attention, but also to memory. People with the gene likely also find negative events are enhanced in their memories.

It may mean that people with the gene are more likely to suffer from uncomfortable flashbacks to negative memories or even posttraumatic stress disorder. Statistically, around 50% of Caucasians have the ADRA2Bdel gene variant, but the rates are much lower in other ethnicities.

As with many genes, though, they interact with the environment: their effect on our individual psychology is partly determined by our upbringing, those around us and how we choose to think and act. Just because there is a gene that influences our starting point, that doesn’t stop us having some control over where we end up.

Can We Identify Risk for Drug Toxicity?

October 10, 2013 – Very recently, David Kerr, Professor of Cancer Medicine at University of Oxford, in the United Kingdom, and past President of the European Society for Medical Oncology, talked on Medscape (see the video here) about risk-benefit analyses for novel, inventive cancer treatments. See here in italics his statement:

 When we talk about precision medicine and personalized medicine, it occurs to me that most of the discussion has been about benefits and seeing what we can do to better understand the cancer and the molecular biology of the tumor. Through that understanding, we would try to come up with biomarkers that allow us to select patient populations that are likely to receive added benefit.

 As Francis Collins has said, those of us who are in the cancer field are probably standard-bearers for the whole broad field of personalized medicine because of the steps that we have made in terms of linking molecular genotypes to phenotypes and identifying the people who respond better to drugs.

 However, a risk-benefit ratio implies 2 sides of the coin. It seems to me that perhaps we have been missing out in terms of considering the toxicology, the pattern of side effects. These will be determined not by the somatic tumor mutations that we use to identify biomarkers for benefit, but within the germline. How do we metabolize the drug? How do we excrete it? The absorption, distribution, and metabolism components become important. I believe that one way of improving the risk-benefit ratio is to reduce risk. If we had tools, if we had assays, if we had biomarkers to identify patients most at risk for toxicity, most at risk perhaps even for lethal toxicity, then we as an oncology community would adapt our therapy accordingly, possibly even omitting some drugs if the hazard ratio for death or lethality were very high, but more likely modulating the dose of the drug to see if we could obviate the need for inducing life-threatening grade 4 toxicities.

 There is an interesting play here. If we look at most modern, well-designed, phase 3 cancer treatment trials, sometimes including a couple of thousand patients, we are starting to get the statistics that may allow us to do some genome-wide association studies looking for patterns of genetic change in the germline — not in the tumor, but the germline. That may give us an idea about which patients are most at risk for certain adverse effects and tell us, as practicing physicians, to adjust the dose accordingly.

 It is a new science. I am going to call it tox-nostics. There you are. You have heard it here first. I am going to trademark the term. We need to do more concerted research to see if we can improve risk-benefit, but through the portal of reducing risk rather than focusing only on benefit. I think modern, well-designed trials in which germline DNA — ie, blood — has been collected, gives us a way of doing this.

 We know that some tests out there are moderately well used for 5-FU, for irinotecan.[1] I think we can improve on these. I think we can improve test performance, utility, availability. We just need a few clinical champions, a few good tests, to really make the difference.

 Thanks for listening. As always, we will be very happy to take any comments that you may care to make or to post. Medscapers, ahoy! Thank you.

 This is a very notable statement, not only for Medscapers. I would like to comment it on two accounts. First, I am not so sure whether the world has waited for the new term “tox-nostics” and whether a “trade marking” of it will be necessary and would successfully serve its purpose, namely to promote the concepts of targeted efficacy and safety of patient’s therapies. For one, “tox-“ (or any mentioning of toxicity) in the field of drug development and marketing is very negatively looked at and basically considered a “non do”.  Extensive and start-up company terminating (TheraSTrat AG to be precise (you may still search the net for it)) past experience of the author of this Blog would indicate that neither the phamaceutical industry, nor investors and financial markets, nor regulators and patients would like to hear anything near to toxicity in connection with their product and/or therapy.  On the other hand, we (and others), in the early years of the last decade, have coined the term “theragenomics” to embrace the concept of targeted efficacy and safety of patient’s therapies by applying genomic and individualized genetic knowledge to drug therapy.

 Secondly, on a far more positive note, the recently FDA-approved anti-melanoma drug Zelboraf (Vemurafinib) would be one of several good example in case for Prof. Kerr’s proposal/statement. Zelboraf (Vemurafinib) is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved companion genetic test. Zelboraf (Vemurafinib) is not indicated for treatment of patients with wild-type BRAF melanoma. That means in the clear that before treatment, patients need to be tested for this mutation (i.e. allelic variant of the tumor BRAF gene) by a companion gene test. Only those patients who test positive for the BRAF V600E variant are eligible for and will profit from a  treatment with Zelboraf (Vemurafinib).

 In the “Warnings and Precautions”-section of Zelboraf’s FDA-approved drug label, the following potential serious, if not fatal, adverse effects of Zelboraf are listed: New Primary Cutaneous Malignancies; New Non-Cutaneous Squamous Cell Carcinoma; Other Malignancies; Tumor Promotion in BRAF Wild-Type Melanoma; Serious Hypersensitivity Reactions; Severe Dermatologic Reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN); QT Prolongation; Hepatotoxicity; Photosensitivity; Serious Ophthalmologic Reactions; Embryo-Fetal Toxicity. Here (at FDA) and here (at DailyMed), you will find the drug label on Zelboraf (Vemurafinib).

 The other listed severe drug effects not withstanding, at least for “Severe Dermatologic Reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)” we know from many other drug which are associated with this adverse effect, that there seems to exist a genetic predisposition of patients to develop SJS and TEN. For example, patients carrying the HLA-B*5701 allele have a very high risk for developing SJS and TEN when treated with Ziagen (Abacavir). Likewise, patients carrying the HLA-B*1501 allele have a very high risk for developing SJS and TEN when treated with Carbamazepine-containing medications such as Tegretol, Equetro, Carbatrol, and generics thereof. For more information on SJS and TEN, you might want to consult the link here to get started.

 Here, with Zelboraf (Vemurafinib) it might be worthwhile to see, if one the HLA-alleles already associated with SJS or TEN also dispose individuals treated with Zelboraf (Vemurafinib) to SJS or TEN or if in this case, genome wide analysis (GWA) would be necessary to identify new (HLA) alleles predisposing according patients to SJS or TEN. In any case, using such procedures, clinicians might in already today be in the position to provide highly effective targeted therapies combined with targeted avoidance of severe, treatments limiting and/or fatal drug toxicities to at least some patients, all of which would be in line with Prof. Kerr’s statement.

FDA approves new treatment for a type of late-stage lung cancer. Companion test also approved to identify appropriate patients

July 18, 2013 – The U.S. Food and Drug Administration (FDA) very recently approved Gilotrif (afatinib) for patients with late stage (metastatic) non-small cell lung cancer (NSCLC) whose tumors express specific types of epidermal growth factor receptor (EGFR) gene mutations, as detected by an FDA-approved test.

Lung cancer is the leading cause of cancer-related death among men and women. According to the National Cancer Institute, an estimated 228,190 Americans will be diagnosed with lung cancer, and 159,480 will die from the disease this year. About 85 percent of lung cancers are NSCLC, making it the most common type of lung cancer. EGFR gene mutations are present in about 10 percent of NSCLC, with the majority of these gene mutations expressing EGFR exon 19 deletions or exon 21 L858R substitution.

Gilotrif is a tyrosine kinase inhibitor that blocks proteins that promote the development of cancerous cells. It is intended for patients whose tumors express the EGFR exon 19 deletions or exon 21 L858R substitution gene mutations. Gilotrif is being approved concurrently with the therascreen EGFR RGQ PCR Kit, a companion diagnostic that helps determine if a patient’s lung cancer cells express the EGFR mutations.

“Today’s approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Gilotrif is the second drug approved this year for patients with untreated metastatic NSCLC whose tumors have the EGFR exon 19 deletions or exon 21 L858R substitution mutations.”

In May, the FDA approved Tarceva (erlotinib) for first-line treatment of patients with NSCLC. Tarceva’s new indication was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic to identify patients with tumors having the EGFR gene mutations.

“The approval of companion diagnostic tests and drugs are important developments in oncology, as they help us bring safe and effective treatments to patients who need them,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.

The FDA’s approval of the therascreen EGFR RGQ PCR Kit is based on data from the clinical study used to support Gilotrif’s approval. Tumor samples from NSCLC participants in the clinical trial helped to validate the test’s use for detecting EGFR mutations in this patient population.

Gilotrif’s safety and effectiveness were established in a clinical study of 345 participants with metastatic NSCLC whose tumors harbored EGFR mutations. Participants were randomly assigned to receive Gilotrif or up to six cycles of the chemotherapy drugs pemetrexed and cisplatin.

Participants receiving Gilotrif had a delay in tumor growth (progression-free survival) that was 4.2 months later than those receiving chemotherapy. There was no statistically significant difference in overall survival.

Common side effects of Gilotrif include diarrhea, skin breakouts that resemble acne, dry skin, itching (pruritus), inflammation of the mouth, skin infection around the nails (paronychia), decreased appetite, decreased weight, inflammation of the bladder (cystitis), nose bleed, runny nose, fever, eye inflammation and low potassium levels in the blood (hypokalemia). Serious side effects include diarrhea that can result in kidney failure and severe dehydration, severe rash, lung inflammation and liver toxicity.

The FDA reviewed Gilotrif under its priority review program, which provides an expedited review for drugs that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products.

Gilotrif is marketed by Ridgefield, Conn.-based Boehringer Ingelheim Pharmaceuticals, Inc. The therascreen EGFR RGQ PCR Kit is manufactured by QIAGEN Manchester Ltd., based in the United Kingdom. The cobas EGFR Mutation Test is manufactured by the Roche Molecular Systems in Pleasanton, Calif., and Tarceva is co-marketed by California-based Genentech, a member of the Roche Group, and OSI Pharmaceuticals of Farmingdale, N.Y.

For more information:
FDA: Office of Hematology and Oncology Products
FDA: CDRH Office of In Vitro Diagnostics and Radiological Health
FDA: Approved Drugs: Questions and Answers
FDA: Drug Innovation

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Hydroxyethyl Starch Solutions: FDA Safety Communication – Boxed Warning on Increased Mortality and Severe Renal Injury and Risk of Bleeding

June 26, 2013 – The American Food and Drug Administration (FDA) has just released (June 06 2013) the following important information concerning patients who receive hydroxyethyl Starch (HES) solutions in the course of their treatment.

ISSUE: FDA has analyzed recent data that indicate an increased risk of (i) mortality and renal injury requiring renal replacement therapy in critically ill adult patients, including patients with sepsis and those admitted to the ICU; and (ii) excess bleeding particularly in patients undergoing open heart surgery in association with cardiopulmonary bypass. Refer to the FDA Safety Communication for more details about the data analysis.

FDA has concluded that HES solutions should not be used in critically ill adult patients, including patients with sepsis and those admitted to the ICU, and a Boxed Warning to include the risk of mortality and severe renal injury is warranted. In addition, FDA has reviewed a meta-analysis of studies conducted in patients undergoing open heart surgery in association with cardiopulmonary bypass and has determined that an additional warning about excessive bleeding is needed in the Warnings and Precautions Section of the package insert.

BACKGROUND: Hydroxyethyl starch (HES) solutions are used for the treatment of hypovolemia (low blood volume) when plasma volume expansion is desired. Recent data have associated the use of these products with an increased risk of severe adverse events when used in certain patient populations.

RECOMMENDATION: Patients should be aware of the risks associated with the use of HES solutions and discuss these risks with their healthcare provider (refer to the FDA Safety Communication for detailed recommendations for patients).

Recommendations for Health Professionals include the following:

– Do not use HES solutions in critically ill adult patients including those with sepsis, and those admitted to the ICU.
– Avoid use in patients with pre-existing renal dysfunction.
– Discontinue use of HES at the first sign of renal injury.
– Need for renal replacement therapy has been reported up to 90 days after HES administration. Continue to monitor renal function for at least 90 days in all patients.
– Avoid use in patients undergoing open heart surgery in association with cardiopulmonary bypass due to excess bleeding.
– Discontinue use of HES at the first sign of coagulopathy.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
[06/24/2013 – FDA Safety Communication – FDA]

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

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.

FDA Approves Companion Genetic Diagnostic Test for Erlotinib [Tarceva] in NSCLC

May 14, 2013 – The US Food and Drug Administration (FDA) today announced the approval of the cobas EGFR Mutation Test, a companion diagnostic for the cancer drug Erlotinib (Tarceva). This is the first FDA-approved companion diagnostic that can detect epidermal growth factor receptor (EGFR) gene mutations, which are present in approximately 10% of non-small cell lung cancers (NSCLCs).

The approval of this test comes at the same time as an expanded indication for Erlotinib (Tarceva). The FDA has also announced a labeling change for Erlotinib (Tarceva), and the drug is now indicated for first-line use in patients with metastasized NSCLC that tests positive for EGRF mutations. Until now, the official indication was second- or third-line use in advanced NSCLC.

“The approval of the cobas EGFR Mutation Test will allow physicians to identify non-small cell lung cancer patients who are candidates for receiving Erlotinib (Tarceva) as first-line therapy,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health, in a statement. “Companion diagnostics play an important role in determining which therapies are the safest and most effective for a particular patient.”

The safety and effectiveness of the cobas EGFR Mutation Test was established with clinical data showing progression-free survival in NSCLC patients with specific types of EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) for 10.4 months when they received Erlotinib (Tarceva) treatment, compared with 5.4 months for those who received standard therapy.

In the United States, Erlotinib (Tarceva) is currently the only drug available for use in EGFR-positive NSCLC, although elsewhere in the world, another similar drug is widely used: Gefitinib (Iressa). A third drug in this class of EGFR tyrosine kinase inhibitors (TKIs), Afatinib (Tomtovok, by Boehringer Ingelheim), is close to approval, with an FDA decision expected in July 2013. Afatinib will also have its own companion diagnostic test (Therascreen EGFR PCR Kit, from Qiagen).

Using an EGFR TKI in the first-line treatment of EGFR-mutated NSCLC is recommended by several clinical guidelines, including the American Society of Clinical Oncology.

Patient outcomes are significantly better when compared with chemotherapy, so much so that it “would be a tragedy not to use” an EGFR inhibitor in EGFR-positive patients, according to one expert in the field, Edward Kim, MD, PhD, assistant professor of medicine and director of clinical operations at the University of Texas MD Anderson Cancer Center, in Houston. To not know whether the tumor is mutation-positive is not acceptable anymore, he added.

However, testing for mutations is not yet routine, and there are difficulties with obtaining lung cancer samples of sufficient size and quality, as well as disagreement over which is the best method for obtaining such samples, as recently reported by Medscape Medical News. In addition, there are issues with the costs of such testing, as outlined in a comment from a surgeon is response to that article.

The cobas EGFR Mutation Test is manufactured by the Roche Molecular Systems. Erlotinib is comarketed by California-based Genentech, a member of the Roche Group and OSI Pharmaceuticals.

Incretin Mimetic Drugs for Type 2 Diabetes: Early Communication – Reports of Possible Increased Risk of Pancreatitis and Pre-cancerous Findings of the Pancreas

May 09, 2013 – We have just stumbled upon a recent press release to the public by the American Food and Drug Administration (FDA) on a looming drug safety problem of incretin mimetic drugs related to the pancreas. Find here the unedited press releaase in full:

[Posted 03/14/2013]

AUDIENCE: Gastroenterology, Endocrinology, Oncology, Patient

ISSUE: FDA is evaluating unpublished new findings by a group of academic researchers that suggest an increased risk of pancreatitis and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. FDA has asked the researchers to provide the methodology used to collect and study these specimens and to provide the tissue samples so the Agency can further investigate potential pancreatic toxicity associated with the incretin mimetics.

BACKGROUND: Drugs in the incretin mimetic class include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto). These drugs work by mimicking the incretin hormones that the body usually produces naturally to stimulate the release of insulin in response to a meal. They are used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.

RECOMMENDATIONS: FDA has not reached any new conclusions about safety risks with incretin mimetic drugs. This early communication is intended only to inform the public and health care professionals that the Agency intends to obtain and evaluate this new information. FDA will participate in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Cancer Institute’s (NCI) Workshop on Pancreatitis-Diabetes-Pancreatic Cancer in June 2013 to gather and share additional information. FDA will communicate its final conclusions and recommendations when its review is complete or when the Agency has additional information to report.

The Warnings and Precautions section of drug labels and patient Medication Guides for incretin mimetics contain warnings about the risk of acute pancreatitis. FDA has not previously communicated about the potential risk of pre-cancerous findings  of the pancreas with incretin mimetics. FDA has not concluded these drugs may cause or contribute to the development of pancreatic cancer.

At this time, patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:

Complete and submit the report Online: http://www.fda.gov/MedWatch/report.htm
Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

EMA: Recommendation to suspend tetrazepam-containing medicines

May 09, 2013 – This is from the News and Press Release Archive of the European Medicines Agency (EMA) as of April 29, 2013.  Find here the unedited release in full:

29/04/2013

Recommendation to suspend tetrazepam-containing medicines endorsed by CMDh

Following the recent recommendation by the Pharmacovigilance Risk Assessment Committee (PRAC), the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) has endorsed by majority the PRAC recommendation to suspend the marketing authorisations of tetrazepam-containing medicines across the European Union (EU). The CMDh, a body representing EU Member States, is responsible for ensuring harmonised safety standards for medicines authorised via national marketing authorisation procedures across the EU.

Tetrazepam, a medicine of the benzodiazepine class, is used in several EU Member States to treat painful contractures (such as in low back pain and neck pain) and spasticity (excessive stiffness of muscles).

The CMDh position will now be sent to the European Commission, which will take a legally binding decision throughout the EU.

The review of tetrazepam was triggered by the French National Agency for the Safety of Medicine and Health Products (ANSM), following reports of serious skin reactions with this medicine in France. Having assessed all available data on the risk of skin reactions, including post-marketing data in the EU and the published literature, the PRAC concluded that tetrazepam is associated with a low but increased risk of serious skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome) compared with other benzodiazepines. The Committee also noted that, in the light of the risks identified, the available data on the effectiveness of tetrazepam were not sufficiently robust to support its use in the authorised indications.

The CMDh agreed with the PRAC conclusion that the benefits of these medicines do not outweigh their risks, and adopted a final position that the marketing authorisations should be suspended throughout the EU.

The suspension of the marketing authorisations can be lifted if the companies that market these medicines provide data identifying a specific group of patients for whom the benefits of tetrazepam-containing medicines outweigh the risks.

Information to patients

• Tetrazepam is a muscle relaxant used in painful conditions such as low back pain and neck pain as well as spasticity (excessive stiffness of muscles).
• As a result of the risk of unpredictable, serious skin reactions identified, the CMDh position is that tetrazepam-containing medicines should no longer be used in the EU.
• If you are taking a tetrazepam-containing medicine, you should not suddenly stop taking tetrazepam without your doctor’s advice. You should make an appointment with your treating doctor to discuss your treatment. Your doctor may also consider an appropriate alternative treatment for you.

Information to healthcare professionals

• In light of the unfavourable benefit-risk balance, doctors should review their patients’ treatment at their next appointment, and may consider an appropriate alternative treatment.
• Pharmacists should refer patients on a new or repeat prescription for tetrazepam to their treating physician.

The CMDh position is based on the PRAC review of all available data on the risk of skin reactions with tetrazepam, including post-marketing data in the EU and the published literature, and the available information on efficacy in licensed indications:

• The review found that half of the reported reactions with tetrazepam are skin disorders, which are sometimes serious, life-threatening or fatal. Serious skin reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. They are unpredictable and can occur at any stage during treatment, including after short-term treatment, and at recommended doses.
• In the pharmacovigilance database of the originator product, Myolastan, a total of 513 cutaneous (or allergic) reactions were identified. 65 cases of SJS and TEN were reported. Although the majority of cases occurred in patients taking concomitant medications, the causal link with tetrazepam was strong in a high number of cases.
• The risk of skin reaction is higher with tetrazepam than with other benzodiazepines. This is possibly explained by a structural difference between tetrazepam and other benzodiazepines (i.e. the substituted cyclohexenyl ring of tetrazepam).
• Regarding its efficacy, four studies showed no difference between tetrazepam and other active medicines when used for spasticity. The efficacy of tetrazepam for painful contractures is supported mainly by two small double-blind placebo-controlled clinical trials showing limited efficacy.

In view of the serious, potentially fatal, skin reactions and the limited efficacy of tetrazepam, the benefit-risk balance of tetrazepam-containing medicines is considered no longer favourable.

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More about the medicine

Tetrazepam belongs to a group of medicines called benzodiazepines. It is taken by mouth to treat painful contractures (sustained shortening of muscle tissue), and spasticity (excessive stiffness of muscles).

Tetrazepam-containing medicines have been approved since the 1960s via national procedures in several EU Member States (Austria, Belgium, Bulgaria, Czech Republic, France, Germany, Latvia, Lithuania, Luxembourg, Poland, Romania, Slovakia and Spain), and are available on prescription under various trade names, including Epsipam, Miozepam, Musapam, Musaril, Myolastan, Myopam, Panos, Relaxam, Spasmorelax, Tetra-saar, Tetramdura and Tetraratio. The full list is available in Annex I on the EMA website.

Benzodiazepines work by attaching to certain receptors in the brain, thereby increasing the activity of a substance called gamma-amino butyric acid (GABA). GABA decreases the excitability of many brain cells. By increasing GABA activity, benzodiazepines have a calming effect on various functions of the brain. In particular, tetrazepam is used for its muscle relaxant effects.

More about the procedure

The review of tetrazepam-containing medicines was initiated in January 2013 at the request of France, under Article 107i of Directive 2001/83/EC, also known as the urgent Union procedure.

The review was first conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. As tetrazepam-containing medicines are all authorised nationally, the PRAC recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a final position. The CMDh is composed of representatives of all EU Member States. Its main responsibility is to resolve disagreements between Member States involved in mutual recognition or decentralised procedures, to ensure that patients have the same level of protection, no matter where they are in the EU.

As the CMDh position was adopted by majority vote, the CMDh position will now be sent to the European Commission, which will take an EU-wide legally binding decision.