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

January 26, 2012

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

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


European Medicines Agency (EMA) starts review of aliskiren-containing medicines

January 17, 2012

January 17, 2012 – Recently, the European Medicines Agency (EMA) has announced that it  is reviewing aliskiren-containing medicines, to assess the impact of data coming from the ALTITUDE study on the balance of benefits and risks of these medicines in their approved indication. Aliskiren-containing medicines are approved for the treatment of essential hypertension. ‘Essential’ means that there is no obvious cause for high blood pressure.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) started the review after it was informed on 19 December 2011 by the marketing authorisation holder of the decision to terminate the ALTITUDE study early. This clinical trial included patients with type 2 diabetes and renal impairment and/or cardiovascular disease. In most patients arterial blood pressure was adequately controlled. The patients included in the trial received aliskiren in addition to either an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

Termination of the placebo-controlled phase III trial was recommended by the independent Data Monitoring Committee overseeing the study, because the results showed that there was no benefit with aliskiren and that there were more cases of stroke, renal complications, hyperkalemia and hypotension in patients who received aliskiren compared with patients who received a placebo.

The information available at present is limited. The Committee has asked the company to provide additional analyses to allow the CHMP to assess the impact of the results of the ALTITUDE trial on the overall benefit-risk profile of aliskiren-containing medicines and to determine the need for regulatory action.

Interim advice for doctors and patients

While the review is ongoing the CHMP recommends, as a precautionary measure, that doctors should not prescribe aliskiren-containing medicines to diabetic patients in combination with ACE inhibitors or ARBs.

Doctors should therefore review the treatment of patients taking aliskiren at a routine (non-urgent) appointment, and if patients are diabetic and are also taking ACE inhibitors or ARBs, aliskiren should be stopped and alternative treatments considered.

Patients should not stop any of their treatment before speaking to their doctor, because stopping anti-hypertensive medication without medical supervision can put them at risk. They are advised to discuss their treatment with their doctor at their next scheduled (non-urgent) appointment.

Patients in clinical trials with aliskiren should contact their study site for guidance on their medication.

Further information on the review of aliskiren-containing medicines will be provided when available.

 Additional Notes

  • Eight aliskiren-containing medicines are authorised in the European Union since 2007: Rasilamlo, Rasilez, Rasilez HCT, Rasitrio, Riprazo, Riprazo HCT, Sprimeo, Sprimeo HCT. Some of these medicines (Rasilamlo, Rasilez HCT, Rasitrio, Riprazo HCT and Sprimeo HCT) are combinations of aliskiren with other antihypertensive medicines.
  • The review of aliskiren is conducted in the context of a formal review, initiated at the request of the European Commission under Article 20 of Regulation (EC) No 726/2004.

Drug Safety Communication on Brentuximab Vedotin [Adcetris] – Progressive Multifocal Leukoencephalopathy (PML) and Pulmonary Toxicity

January 17, 2012

January 16, 2012 – The American Food and Drug Administration ( FDA) released on January 13, 2012 the following drug safety communication:

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ISSUE: FDA notified healthcare professionals that two additional cases of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that can result in death, have been reported with the lymphoma drug Adcetris (brentuximab vedotin). Due to the serious nature of PML, a new Boxed Warning highlighting this risk has been added to the drug label.

In addition, a new Contraindication warning was added against use of Adcetris with the cancer drug bleomycin due to increased risk of pulmonary (lung) toxicity.

The signs and symptoms of PML may develop over the course of several weeks or months. They may include changes in mood or usual behavior, confusion, thinking problems, loss of memory, changes in vision, speech, or walking, and decreased strength or weakness on one side of the body.

BACKGROUND: Adcetris (brentuximab vedotin) is used to treat Hodgkin lymphoma and a rare lymphoma known as systemic anaplastic large cell lymphoma. At the time of Adcetris’ approval in August 2011, one case of PML was described in the Warnings and Precautions section of the label.

RECOMMENDATION: Patients who develop any signs and symptoms of PML should notify their healthcare professional immediately. Healthcare professionals should hold Adcetris dosing if PML is suspected and discontinue Adcetris if a diagnosis of PML is confirmed. See the Data Summary in the Drug Safety Communication for additional information.

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.htm1
  • Download form2 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

 More Information as of 01/13/2012 – Drug Safety Communication3 – FDA]


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