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

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.

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.

New Breast Cancer HER2 Diagnostic Tests Approved by FDA

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.

Ivacaftor [Kalydeco] approved by FDA to treat the rare G551D mutant positive form of cystic fibrosis

February 03, 2012 – From a press release by the FDA, we just learn about e new success of the principle of personalized medicine. Please read the original article below:

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The U.S. Food and Drug Administration today approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene.

CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations (defects) in a gene that encodes for a protein called CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation.

“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Margaret A. Hamburg, M.D. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.”

The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.

Kalydeco was approved ahead of the drug’s April 18, 2012 prescription user fee goal date and is designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States.

In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

“Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.

Kalydeco is effective only in patients with CF who have the G551D mutation. It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene, which is the most common mutation that results in CF. If a patient’s mutation status is not known, an FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present.

The most common side effects of Kalydeco include upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.

EMA: Public consultation open on concept paper on pharmacogenomics in evaluation of authorised medicines

January 26, 2012 – I am relaying the information below by the EMA to the readers of this blog. It might be interessting to dwell into this concept paper (as a scientist, a treating physician, or an informed patient) for informations only or even for commenting.

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 The European Medicines Agency (EMA) has released a concept paper on the development of a guideline on the evaluation of pharmacogenomic methodologies in the evaluation of authorised medicines for public consultation.

The concept paper on key aspects for the use of pharmacogenomic methodologies in the pharmacovigilance evaluation of medicinal products explains that a proportion of the variability in response to medicines is due to genetic differences between individuals. Identifying individuals at risk of side effects, unexpected complications or lack of efficacy may help the development of strategies to optimise the use of medicines.

The concept paper sets out a number of issues that a future guideline could cover. These include the systematic consideration of the effects of genetic variability in safety monitoring of medicines, the use of biomarkers, the timing of the monitoring of genomic data and the information that should be provided in medicines’ product information.

The concept paper is open for comments until 15 March 2012. Comments should be sent to pgwpsecretariat@ema.europa.eu using the form for submission of comments.

Patients on Vemurafenib [Zelboraf] Need Testing for RAS Mutations: Secondary Cancers a Major Concern

January 26, 2012 – A January 20, 2012 article in Medscape Medical New illustrates how personalized medicine can be tricky. The case is Vemurafenib [Zelboraf], which was introduced to the market together with an companion genetic test mid 2011 for the treatment of advanced melanoma in suitable BRAF mutation (V600E) positive patients only. In these patients, while melanoma therapy response rates are impressive, a new problem seems to arise, namely secondary tumours. Please read the article published  by Medscape Medical News on this topic.

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Patients with advanced melanoma who are treated with Vemurafenib [Zelboraf ]  should be tested for RAS mutations, according to an editorial published in the January 19 issue of the New England Journal of Medicine.

A study that accompanies the editorial reports that RAS mutations frequently occur in secondary skin tumors that develop in vemurafenib-treated patients.

The testing is necessary because there is “potential for secondary tumor development” that arises from treatment with vemurafenib and other BRAF inhibitors, writes Ashani T. Weeraratna, PhD, from the molecular and cellular oncogenesis program at The Wistar Institute in Philadelphia, Pennsylvania, in her editorial. These secondary skin tumors — namely, cutaneous squamous cell carcinomas and keratoacanthomas — are relatively benign, compared with melanoma, and are no reason to discontinue vemurafenib, said Dr. Weeraratna. However, testing will alert clinicians to which patients have RAS-driven secondary tumors.

The testing is important because patients with RAS mutations could also develop secondary cancers in organs beyond the skin, advised Dr. Weeraratna. “If patients have RAS mutations they should be monitored closely for any development of cutaneous squamous cell carcinomas in all organs,” she told Medscape Medical News.

“Although cutaneous squamous cell carcinomas are not deadly, these lesions can be life-threatening when they occur in other organs,” Dr. Weeraratna writes in her editorial. She discussed other potentially affected organs. “Squamous cell carcinomas can potentially arise in any organ with a squamous epithelium, essentially a layer of flattened epithelial cells that line the basement membranes of organs. A squamous epithelium is found most often in organs where rapid filtration and diffusion is necessary, such as the alveolar lining of the lungs and the glomerulus (kidney). Thus, squamous cell carcinomas can be found in organs such as the lungs, cervix, and esophagus, and also account for a large proportion of head and neck cancers,” Dr. Weeraratna explained.

Importantly, there is no evidence that vemurafenib triggers tumors in other organs. “It is as yet unclear whether the generation of squamous cell carcinomas in these organs, upon BRAF inhibitor therapy, occurs, but these data certainly alert us to that potential risk,” she said.

MEK Inhibitors May Help

In this study of melanoma patients, the investigators sought to characterize the molecular mechanism behind the development of secondary skin cancers in patients treated with vemurafenib.

They admit that a skin cancer drug that causes other skin cancers is unexpected. The development of cutaneous squamous cell carcinomas and keratoacanthomas “is the opposite of what would be expected from a targeted oncogene inhibitor,” write the study authors, led by Fei Su, PhD, from Hoffman-La Roche Pharmaceuticals in Nutley, New Jersey. In their search to understand this toxicity, the investigators analyzed the DNA of a sampling of these tumors and found a high rate of RAS mutations (21 of 35 tumors; 60%). “Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib,” write the authors.

“This study points out that BRAF inhibitors should only be used in patients who have cancers driven by BRAF mutations, and it raises the concern that cancers driven by RAS mutations (KRAS, HRAS, or NRAS) can be paradoxically activated instead of inhibited with this class of drugs,” said coauthor Antoni Ribas, MD, PhD, in email correspondence with Medscape Medical News. He is from the division of hematology–oncology at the UCLA Medical Center in Los Angeles, California.

Why patients treated with vemurafenib have such a high rate of RAS mutations in these secondary cancers is not known. However, the investigators performed animal-model studies that suggest that the development of RAS-mutation-driven secondary tumors might be prevented with a MEK inhibitor, another class of drugs. There might be “usefulness of combining a BRAF inhibitor with a MEK inhibitor to prevent this toxic effect” of secondary cancers, write the authors.

There has already been clinical investigation of this concept — a phase 2 study of the combination of the MEK inhibitor GSK1120212 and the RAF inhibitor GSK2118436 in metastatic melanoma. That study, which was presented at the 2011 annual meeting of the American Society of Clinical Oncology, and reported at that time by Medscape Medical News, showed that the toxicity of the combination seemed to be lower than that of either agent used alone.

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NEJM: Study

NEJM: Editoral

Medscape Medical News: Article