Can We Identify Risk for Drug Toxicity?

October 10, 2013

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

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

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 16, 2013

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.


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

August 28, 2011

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

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

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

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

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

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

See the FDA Press Release here.


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

August 20, 2011

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

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

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

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

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


Could a biomarker rescue Lumiracoxib [Joicela], formerly known as [Prexige]? A genome-wide study identifies a strong assossiation of the HLA allele DQA1*0102 with Lumiracoxib [Joicela]-related serious liver injury

April 25, 2011

April 23, 2011 – In the history of flawed and/or market-withdrawn drugs, Lumiracoxib [Joicela], formely known as [Prexige], may only be a footnote, hardly comparable to the attention received by the high flying but ill-fated Rofecoxib [Vioxx], Troglitazone [Rezulin], and more recently Rosiglitazone [Avandia].

However, Lumiracoxib [Prexige] may make a mark after all in the history of pharma beyond its missed revenue opportunity or beneficial impact on patients. The drug is a selective COX-2 inhibitor, indicated for symptomatic relief of pain from osteoarthritis. COX-2s inhibitors, such as the infamous Rofecoxib [Vioxx], seem all but off the market in the US because of their cardiovascular side effects. Lumiracoxib [Prexige] seems to bind to a different site on the COX-2 receptor, which may give it advantages that lift it from under the Rofecoxib [Vioxx] shadow: minimal cardiovascular side effects, high selectivity, rapid clearing from the circulation and absorption into the inflamed joint.

Lumiracoxib [Prexige] received European marketing authorization in November 2006 and was launched in parts of Europe the following year. Because of its own safety shortcomings such as rare but potentially fatal liver injury at higher doses, from 2007 onwards, Lumiracoxib [Prexige] was withdrawn from most European markets, as well as from the Australian and Canadian markets. Lumiracoxib was never approved by the American Food and Drug Administration (FDA), mostly for safety reasons.

Could the biomarker DQA1*0102 rescue Lumiracoxib?

In a recent study by Singer et al., published in 2010 in Nature Genetics 42, pages 711-714, a case-control genome-wide association study was performed on 41 Lumiracoxib-treated patients with liver injury (cases) and 176 matched Lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 x10 to -10). These findings were replicated in an independent set of 98 Lumiracoxib-treated cases and 405 matched Lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 x 10 to -12). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501 -HLA-DQB1*0602 -HLA-DRB5*0101 -HLA-DQA1*0102, most significant allele P = 6.8 x 10 to -25, allelic Odds ratio = 5.0, 95% CI 3.6 – 7.0).

In princip, these results offer the potential to improve the safety profile of Lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from Lumiracoxib treatment. In fact, Novartis Pharma, the makers of Lumiracoxib, applied with the European Medicines Agency (EMEA) for a centralized marketing authorisation for Lumiracoxib [Joicela], in December 2009. According to this application, Lumiracoxib [Joicela] was intended, in a 100 mg film-coated tablet form, to be used for symptomatic relief in the treatment of osteoarthritis of the knee and hip in patients who are non-carriers of the DQA1*0102 allele. In essence, patients who test negative for the DQA1*0102 allele are expected to have a low risk for the development of serious liver side effects and could therefore safely take the drug. Those patients who test positive for the DQA1*0102 allele, however, should not get the drug.

This approach would constitute the first example throughout the pharmaceutical industry where a biomarker strategy rescued a drug, previously withdrawn from the markets because serious adverse effects (i.e., liver injury).  For the pharmaceutical industry, such a strategy for rescuing drugs previously flawed by serious drug adverse effects may hold tremendous appeal (cases such as Exanta, Galvus, etc., come to mind), even if the ultimate market for such rescued drugs may be nowhere near the original projections.

Lumiracoxib [Joicela] and its companion test: Not quite there yet

As we learned by mid-April 2011 from an announcement by the European Medicines Agency (EMEA), the application of the marketing authorisation for Lumiracoxib [Joicela] was withdrawn by Novartis. At the time of the withdrawal it was under review by the Agency’s Committee for Medicinal Products for Human Use (CHMP).

In its official letter, the company stated that its decision to withdraw the application was based on its inability to address the CHMPs request to provide additional data within the time frame allowed in the centralised registation procedure. We should take note here that withdrawal of an application does not prejudice the possibility for the company to make a new application at a later stage. In any case, more information about Lumiracoxib [Joicela] and the state of the scientific assessment at the time of withdrawal will be made available in a question-and-answer document. This document, together with the withdrawal letter from the company, will be published on the Agency’s website after the next CHMP meeting on 16 to19 May 2011.


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