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Old 11-30-2012, 08:21 AM
Dross Dross is offline
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Default Clinical trial delivers results in leukemia patients

A tyrosine kinase inhibitor (TKI) is a type of drug which blocks the transfer of phosphate molecules to specific sites in important enzymes which provide signals for cells to grow, spread, divide or perform other cellular properties. TKIs are used in the treatment of many types of cancer but first achieved prominence in CML when Gleevec (imatinib mesylate) was found to block the bcr/abl enzyme which is found in all patients with this disease, thereby killing the CML cells which are dependent on BCR/ABL mediated signaling for survival.

Treatment with orally administered TKIs are the standard initial therapy for patients with all stages of CML. They are highly effective at profoundly reducing the number of CML cells in the body, eliminating all symptoms from the disease and markedly reducing the rate of progression to more aggressive stages of CML. Recent trials have shown that newer, more potent TKS produce more rapid responses than Gleevec, although the overall long term results seem to be similar at this time.

Two researchers from the Huntsman Cancer Institute have published results for a recent clinical trial using the drug ponatinib for the treatment of chronic myelogenous leukemia in patients that were refractory to Gleevec and other standard treatments for Philadelphia chromosome positive hematological neoplasms.

Conducted at five cancer centers, this phase one trial demonstrated that ponatinib was highly active in patients with CML and Ph++ ALL who were resistant to approved tyrosine kinase inhibitors.

"Ponatinib is arguably the most potent and broadest BCR-ABL1 available thus far, covering even the T315I mutant, which is completely resistant against all approved TKIs", says Deininger, a senior author on the study who leads an ongoing ponatinib trial at Huntsman Cancer Institute. "The results of this study as well as preliminary data from a larger phase 2 trial show that ponatinib has remarkable activity in patients with resistant CML and Ph+ ALL, suggesting that this new TKI will expand our therapeutic armamentarium very significantly. It is a poster child for personalized cancer therapy."

Last edited by gdpawel : 03-12-2013 at 08:53 AM. Reason: posted full article on forum board
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Old 11-30-2012, 10:03 AM
gdpawel gdpawel is offline
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Default Not all Tests Can be Companion Diagnostics

In another stumbling block for personalized medicine, MolecularMD has chosen to pull its premarketing approval application to the FDA for its BCR-ABL T315I Mutation Test. The company made this announcement yesterday with Ariad Pharmaceuticals. The test was meant to be a companion diagnostic to be used with Ariad’s BCR-ABL inhibitor, ponatinib, which is under FDA review for the treatment of resistant or intolerant chronic myeloid leukemia and Philadelphia-chromosome positive acute lymphocytic leukemia. But the FDA’s Center for Devices and Radiological Health told MolecularMD recently that the test is not considered a companion diagnostic for ponatinib. FDA guidance states that for a test to be considered as a companion diagnostic test, it must provide information that is essential for the safe and effective use of a therapeutic product.

According to Joshua P. Cohen, Ph.D., Senior Research Fellow, Tufts Center for the Study of Drug Development says while the withdrawal is a minor blow, it will not have major repercussions to the development of personalized medicine.

“Personalized medicine will progress the same way a toddler learns to walk,” he says. “The important thing is companies are collaborating at earlier stages in the drug development process to develop therapeutics and tests in tandem. In this respect, they are following FDA guidance on personalized medicine and co-development of test and therapeutic. Ultimately, the more co-developed product combinations companies launch the better off patients will be. Moreover, it is a win-win situation in that other stakeholders, such as payers, providers, and the pharmaceutical industry stand to benefit as well.”

In July 2011, Dr. Cohen released a study titled “Lack of clinically useful diagnostics hinder growth in personalized medicines.” Among the study findings was the fact that less than 1 percent of currently marketed drugs in U.S. have a companion diagnostic. Lack of clinical usefulness of many companion diagnostics has led payers to deny or restrict reimbursement of tests.

Just 10 percent of currently marketed drugs have pharmacogenomic info on labeling. Of eight drugs reviewed, AstraZeneca’s Iressa presents the highest barriers to developers and payers, followed by Tarceva, Erbitux, and Camptosar. Two widely cited reasons by payers and developers were a lack of evidence supporting efficacy of companion diagnostics and the cost of companion diagnostics. Patients also noted a lack of insurance coverage for companion tests.

“The input provided by the Agency to MolecularMD regarding its T315I mutation test indicates that the T315I mutation test is no longer required as a companion diagnostic test to identify patients with the BCR-ABL T315I mutation who may be treated with ponatinib,” said Harvey J. Berger, M.D. chairman and chief executive officer of Ariad. “We look forward to continuing our longstanding collaboration with MolecularMD, the world leader in BCR-ABL testing, in clinical trials of ponatinib in patients with CML.”

“We are pleased to see ponatinib moving forward in its U.S. regulatory review and look forward to continuing our close involvement with its ongoing and future clinical development as a premier companion diagnostic partner ,” stated Dan Snyder, President, chief operation officer of MolecularMD.

Mia Burns, Associate Editor, Pharmalive.com
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Old 11-30-2012, 10:06 AM
gdpawel gdpawel is offline
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Back in 2010, a report from the Agency for Healthcare Research and Quality (AHRQ) suggested that some mutations of the BCR-ABL gene make the cancer resistant to Gleevec (imatinib), which is designed to block the action of the hyperactive tyrosine kinase receptors in patients with CML.

But they say not to look to any tests currently on the market to determine what they are. The review of 31 studies found that the presence of any BCR-ABL mutation does not appear to predict differential response to treatment in CML patients treated with Gleevec (imatinib), Sprycel (dasatinib) or Nilotinib based regimens.

Indeed, the report said there is "no evidence that presence of any BCR-ABL mutation can differentiate reponse to tyrosine kinase inhibitor therapies." "It is possible that pharmacogenetic (how our inherited genes affect the way we respond to drugs) testing and the subsequent use of targeted therapies will add cost without producing clinically meaningful improvement in patients outcomes," the report said.

There are some challenges in the development and practical use of pharmacogenomics. Many doctors now do not widely practice pharmacogenomics when treating patients since the field is still new.

Pharmacogenetic testing is also expensive, and insurance plans may not cover the costs of available tests. Researchers are working to develop more efficient and less expensive testing methods.

Although federal legislation has been passed that makes it illegal for companies and insurers to discriminate against people based on their genetic information, some ethical, legal, and privacy issues remain unresolved, which may affect the continued development of pharmacogenomics.

[url]http://www.ahrq.gov/
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Old 12-17-2012, 10:46 AM
gdpawel gdpawel is offline
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Default Iclusig (ponatinib) Approved To Treat CML

A new drug used to treat patients with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute leukemia (Ph+ ALL) has just received approval from the U.S. Food and Drug Administration.

The drug, Iclusig (ponatinib), was expected to be approved on March 27, 2013, but as there is no alternative therapy that currently exists for the two rare blood and marrow diseases, the FDA prioritized it's review.

The drug works among leukemia patients who don't respond to treatment from a class of drugs called tyrosine kinase inhibitors (TKIs). It works by blocking proteins that cause cancerous cells to develop. Sometimes the cancerous cells can develop a mutation called T315I which makes them resistant to TKIs, Iclusig is effective at targeting these cells.

According to Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in FDA's Center for Drug Evaluation and Research: "The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options. Iclusig is the third drug approved to treat CML and the second drug approved to treat ALL this year, demonstrating FDA's commitment to approving safe and effective drugs for patients with rare diseases."

449 patients with CML and Ph+ALL participated in the clinical trial to evaluate the effectiveness of the drug. The researchers found that that there was a significant reduction in the number of cancerous cells with the Philadelphia chromosome genetic mutation, achieving major cytogenetic response (MCyR). MCyR was achieved in 70 percent of patients with the T315I mutation and in 54 percent of all patients.

During the accelerated and blast phase CML and Ph+ ALL they found that 52 percent of participants with accelerated phase CML experienced no evidence of leukemia (major hematologic response, MaHR) for a median period of 9.5 months. 31 percent of participants with blast phase CML experienced major hematologic response for a median period of 47 months. And 41 percent of participants with Ph+ ALL achieved MaHR for a median period of 3.2 months.

Side effects of the drug include high blood pressure, abdominal pain, headache, dry skin, joint pain, fever and nausea. The drug will also be labeled with a warning alerting patients of the increased risk of developing blood clots and liver toxicity associated with taking the drug.

"Drug Approved To Treat Rare Forms Of Leukemia." Medical News Today. MediLexicon, Intl., 17 Dec. 2012.

[url]http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332252.htm
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Old 02-13-2013, 09:30 AM
gdpawel gdpawel is offline
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Default FDA Approves Ponatinib for CML

(Medscape Oncology) - Ponatinib (Iclusig) was approved today by the US Food and Drug Administration (FDA) for use in patients with 2 leukemias that have stopped responding to other therapies, and offers new hope for these subgroups of patients.

Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) and also Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (Ph+ ALL) who have relapsed or are refractory to other therapies. Many of these patients, but not all, have developed a T3151 mutation, which makes the disease resistant to the standard treatment with tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec).

"The approval of ponatinib is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T3151 mutation who have few therapeutic options," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

Ponatanib was described as a major advance at the annual meeting of the American Society of Hematology by ASH President Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto in Ontario, Canada.

Over the past decade, CML has changed from a fatal disease to a chronic condition that is held in check by targeted therapies such as imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif).

These TKIs have transformed the lives of patients with CML, he explained. However, some patients develop resistance to these drugs, and around 5% to 20% develop the T3151 mutation, which makes them resistant to all the TKIs. "These patients would eventually develop a blast crisis and then die," but ponatinib offers hope of a rescue medication for these patients, Dr. Keating explained.

The approval is based on results from the phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, which were presented at the meeting. The results show that ponatinib works in patients who are resistant to or who cannot tolerate other therapies and confirms the efficacy seen in the recently published phase 1 clinical trial (N Engl J Med. 2012;367:2075-2088), as reported by Medscape Medical News.

"We have simply never had any treatment produce such high rates of durable response in a heavily pretreated group of patients," said lead author Jorges Cortes, MD, professor of medicine and deputy chair of the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston.

The PACE trial was conducted in Europe and the United States in 449 patients with CML or with Ph+ ALL. All patients had been heavily pretreated, with a median of 3 TKIs. Most of the patients (96%) had received imatinib, 84% had received dasatinib, 65% had received nilotinib, and some patients had received the newest agent, bosutinib, Dr. Cortes said.

The median time from diagnosis to enrollment in this study was 6 years (range, 0.3 - 28 years). Almost one third of patients (29%) had the T3151 mutation; a few other mutations were found, but 44% of patients had no mutation.

For patients with chronic-phase CML (270 of 449 participants), the primary end point was a major cytogenetic response within 12 months of treatment (where more than 65% of cells are normal). This was achieved in 55% of patients with chronic-phase CML (50% who had been resistant/intolerant to TKIs and 70% with the T3151 mutation).

These responses are durable, Dr. Cortes reported. It is estimated that the major cytogenetic response will be sustained at 12 months in 91% of patients with chronic-phase CML.

Remarkably, a complete cytogenetic response (no Ph+ cells measured in the body) was achieved in 46% of patients with chronic-phase CML, and even higher response rates were observed in patients who had been exposed to fewer TKIs and had a shorter duration of disease, Dr. Cortes noted.

For patients with accelerated-phase CML (n = 85) or blast-phase CML/Ph+ ALL (n = 94), the primary end point was a major hematologic response (normal white blood cell counts) within 6 months of treatment. This was achieved in 58% of patients with accelerated-phase CML (57% who had been resistant/intolerant and 50% with the T3151 mutation) and in 34% of those with blast-phase CML/Ph+ ALL (35% who had been resistant/intolerant and 33% with the T3151 mutation).

Dr. Cortes reported that the responses were similar in patients with and without the T3151 mutation, which confirms previous observations. It shows that ponatinib works across a wide range of TKI resistance, whether or not a mutation is present, he explained.

Ponatinib is generally well tolerated. The most common adverse events reported were rash, abdominal pain, headache, dry skin, constipation, fatigue, pyrexia, nausea, arthralgia, and hypertension. There were also some cases of pancreatitis (6% of all patients), some elevation of pancreatic enzymes (lipase in 19%, amylase 7%), and some myelosuppression (thrombocytopenia in 42%, neutropenia in 34%, and anemia in 20%).

Ponatinib was approved with a boxed warning alerting patients and healthcare professionals that the drug can cause blood clots and liver toxicity.

"Ponatinib may be an important new treatment for CML and Ph+ ALL resistant or intolerant to previous TKIs," Dr. Cortes concluded.

"This therapy may be able to transform highly fatal forms of leukemia into a curable disease," he said in a statement.
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Old 11-11-2013, 03:19 PM
gdpawel gdpawel is offline
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Default Market Removal of Ponatinib

The marketing and commercial distribution of the leukemia drug ponatinib (Iclusig, Ariad Pharmaceuticals) has been temporarily suspended, less than a year after it received accelerated approval. The reason cited is safety concerns because of high rates of cardiovascular toxicity associated with the agent.

Ponatinib is indicated for chronic-phase, accelerated-phase, and blast-phase chronic myeloid leukemia (CML), and for Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) in patients who do not benefit from other therapies.

The story of ponatinib reveals many things about the current state of cancer treatments and their approval. It exemplifies the emphasis placed on targeted agents after promising early-stage trial results, the speedy review process that can leave risks only partially revealed and ideal patients undefined, and the incomplete ways cardiac toxicity is classified and monitored in oncology trials.

In October, the US Food and Drug Administration (FDA) requested that Ariad Pharmaceuticals temporarily withdraw ponatinib from the market because of the increased frequency of serious adverse vascular events that emerged since the drug was approved in December 2012, as reported by Medscape Medical News.

The FDA announcement was not entirely unexpected. The agency had been investigating an increase in life-threatening blood clots and blood vessel narrowing in patients taking ponatinib.

"I do think it was prudent for the FDA take the action that it did, given the number of side effects and problems that have cropped up since it gained approval," said Peter Emanuel, MD, director of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock.

Dr. Emanuel was approached by Medscape Medical News for independent comment. He is chair of the American Society of Hematology (ASH) committee on communications, and has not been involved in any ponatinib studies.

"There is really only one very, very small subset of patients that ponatinib was exclusive for," he said. "That's patients with the T315I mutation. For them, it could very well be that the benefit will outweigh the risk."

Currently, 3 tyrosine kinase inhibitors (TKIs) have been approved for the front-line treatment of CML: imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna). Another TKI, bosutinib (Bosulif), has been approved for patients with resistance or intolerance to previous therapy.

Dr. Emanuel pointed out that the FDA recently granted accelerated approval to omacetaxine mepesuccinate (Synribo), a non-TKI indicated for patients with CML that is resistant and/or intolerant to 2 or more TKIs.

"For younger patients, there is still the option of a stem cell transplant," Dr. Emanuel said. "It has kind of fallen off the map with the advent of TKIs. It is a curative therapy, although much more toxic than TKIs. But there are alternatives out there for most CML patients."

It might be that physicians will have to determine that a patient has the T315I mutation to gain access to ponatinib, he said. "As they sort this out, that might be a reasonable compromise."

Unmet Need Trumped Serious Adverse Events, At First

Ponatinib is a potent oral TKI that is active against unmutated and mutated BCR-ABL, including the threonine-to-isoleucine mutation at position 315 (T315I), which is present in up to 20% of patients who exhibit TKI resistance. It was approved on the basis of the PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial, which was conducted in Europe and the United States in 449 heavily pretreated patients with CML or Ph-positive ALL.

The preliminary phase 2 results were presented last year at the ASH annual meeting. They confirmed the efficacy seen in a phase 1 clinical trial (N Engl J Med. 2012;367:2075-2088).

At that time, praise came quickly for the then-experimental agent. Ponatinib results were highlighted as "a major advance" by ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto, at a premeeting press briefing.

The final results from the phase 2 PACE trial were published in the November 7 issue of the New England Journal of Medicine, coinciding with the suspension of the drug.

The risk for serious cardiovascular events was acknowledged during the accelerated approval process, but it was a question of balancing risk with a potential lifesaving benefit. In the FDA medical review that preceded approval, reviewer R. Angelo de Claro, MD, medical officer of the division of hematology products in the FDA Center for Drug Evaluation and Research, noted that "the proposed indication is a life-threatening condition and represents an unmet medical need."

"The efficacy of ponatinib in patients with T315I-mutant CML and Ph-positive ALL supports the recommendation for accelerated approval as there are no drugs approved for the treatment of T315I-mutant CML or Ph-positive ALL," he wrote.

The data suggest that these risks intensified over time. "The 120-day safety update submission (data cut-off date July 23, 2012) was notable for the following: increase in frequency of arterial thromboembolic events compared with the original submission, and 2 cases of fatal acute hepatic failure," Dr. de Claro reported.

He also stated that the cardiovascular safety profile for this agent "is notable for arterial ischemic events and hypertension. At the cut-off date, 8% of patients experienced serious ischemic events."

Because the serious safety issues with ponatinib were not seen with other TKIs approved for this indication, Dr. de Claro recommended that safety data from the ongoing randomized phase 3 trial comparing ponatinib with imatinib in patients with newly diagnosed chronic-phase CML (EPIC trial), in addition to the 24-month follow-up data from the PACE trial, be a "requirement for conversion to regular approval."

Ponatinib was also approved with a boxed warning alerting patients and healthcare professionals that the drug can cause arterial thrombotic events. The EPIC trial was discontinued shortly before the FDA suspended sales of ponatinib because of the arterial thrombotic events observed.

Escalation Over Time

In the phase 2 PACE trial, led by Jorge Cortes, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, arterial thrombotic events (including cardiovascular, cerebrovascular, and peripheral vascular events) were seen in only 8.9% of the patients who received ponatinib (treatment-related events, 2.9%). Rates initially reported in the prescribing information in December 2012 were 7.6% for serious adverse events and 11.4% for all adverse events (median duration of exposure, 11 months for all patients).

Data on an additional 13 months of exposure in the PACE trial, which became available after the manuscript was accepted for publication, showed that the cumulative incidence of serious arterial thrombotic events was 11.8% and the incidence of all arterial thrombotic events, serious or not, was 17.1%.

There was also a high rate of pre-existing cardiovascular comorbidity in the cohort. In the PACE trial, 55% of patients who had an event had a history of ischemic disease at study enrollment, and 95% had 1 or more risk factors (hypertension, diabetes, hypercholesterolemia, or obesity) with or without a history of ischemic disease, nonischemic cardiac disease, or venous thromboembolism.

However, it appears that the rate of serious and life-threatening adverse events escalates over time, as observed in the FDA medical review.

When ponatinib was approved in December 2012, "14% of patients, or about 1 in 7, experienced these events," said press officer Stephanie Yao, from the FDA Office of Media Affairs. "However, 2 of the company's clinical trials are now showing much higher rates: 24% in the phase 2 trial and 48% in the phase 1 trial."

"The company and the FDA recently recommended stopping the phase 3 trial because of these events in patients with newly diagnosed CML treated with ponatinib," she added. "The increased rates of adverse events were found as a result of continued close monitoring by the company and the FDA."

According to the FDA, median treatment duration was 2.7 years in the phase 1 trial and 1.3 years in the phase 2 trial. Events included fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow. In some patients, these fatal and serious adverse events occurred as early as 2 weeks into therapy.

The FDA stated that these adverse events occurred in patients with and without cardiovascular risk factors, and included patients in their 20s. High blood pressure was also observed in 67% of patients treated.
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Old 11-11-2013, 03:22 PM
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Exact Nature of Cardiovascular Disease Unknown

The situation with ponatinib has helped raise concerns about the cardiovascular safety of the newer TKIs, especially because they are being increasingly used as first-line therapy.

In a perspective accompanying the phase 2 PACE study, John D. Groarke, MB, BCh, from the Dana–Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School in Boston, and colleagues point out that the medical community is now left with more questions than answers.

"Many of these questions pertain to the methods of monitoring the cardiovascular safety of novel cancer therapies and the way in which adverse cardiovascular events are evaluated in clinical trials in oncology," they write.

Details regarding the nature of the vascular events is lacking from "official announcements," they note, and the ability to define the exact nature of these events is "critical for developing strategies" that might reduce this risk or even prevent it from occurring.

"It is important to note that vascular disease comes in different shapes and forms, such as atherosclerosis, thrombosis, and vasospasm," Dr. Groarke told Medscape Medical News. "The specific vascular pathophysiology associated with ponatinib is unclear. Knowing this will be helpful because it will allow one to find ways to prevent and manage these complications."

The essential cornerstones of any risk-modifying strategies will be to identify and optimize the management of underlying cardiovascular comorbidities at the onset of cancer treatment. "This is an excellent opportunity for cardiologists and oncologists to work together, learn from the lessons of the PACE trial, and determine how to safely move forward" with the development of ponatinib and other cancer drugs, he said.

This is an excellent opportunity for cardiologists and oncologists to work together.

Another issue is that the criteria for reporting adverse cardiovascular events in oncology trials are markedly different from the methodology used in trials evaluating cardiovascular drugs.

"The PACE trial provides an excellent catalyst for discussion between cardiologists and oncologists on cardiovascular safety surveillance during clinical trials of cancer treatments," explained Dr. Groarke. "At present, the methods used to screen for and categorize adverse cardiovascular events in clinical trails of anticancer drugs are not standardized, and differ from approaches employed in clinical trials of cardiovascular drugs."

This compromises the reliable quantification of cardiovascular risks associated with newer cancer treatments and limits intertrial comparisons of cardiovascular safety data. "The time profile for occurrence of cardiovascular toxicities is variable," he said. "Toxicities can occur in the first year of treatment, as seen with ponatinib, or might not manifest for many years, as is seen with anthracycline-associated cardiomyopathy. This variability emphasizes the need for clinical trials to extend follow-up to ensure that delayed cardiovascular toxicities are identified."

The cardiac safety profile itself varies among the TKIs. When prescribing these agents, physicians need to be cognizant of the risk for complications and the patient's history and risk factors. "Every TKI differs in terms of its molecular profile," said Dr. Groarke. "In the case of ponatinib, it is both an ABL inhibitor and a VEGFR2 inhibitor, which may explain some of its vascular toxicity effects."

The selection of any such agent will need to take a patient's baseline cardiovascular risk into account. "If it is confirmed that such cardiovascular comorbidities predispose patients to the adverse cardiovascular effects of BCR-ABL TKIs, agents with more favorable cardiovascular safety profiles may be preferred for patients stratified into higher cardiovascular risk categories," he said. "Alternatively, strategies that reduce the risk of adverse cardiovascular events, such as empiric prophylactic antithrombotic or antiplatelet therapies, may need to be considered if agents with higher cardiovascular toxicities are deemed necessary for these patients."

Ultimately, cardiologists and oncologists need to work together to ensure that the most effective anticancer agent is used and that cardiovascular risk is minimized, Dr. Groarke added.

"Livesaving" Drug Never Shown to Improve Survival

The FDA instituted its Accelerated Approval Program to allow the early approval of drugs that treat serious conditions and fill an unmet medical need. Although accelerated approvals bring drugs to market more quickly, the practice is not without controversy because questions remain about drug safety and efficacy.

A recent study assessed new drugs approved by the FDA in 2008, and found that those that received expedited approval had data on considerably fewer patients before approval (JAMA Intern Med. Published online October 28, 2013). In addition, of the 85 postmarketing study commitments, 50 remained unfulfilled as of January 2013.

In that study, Thomas J. Moore, AB, from the Institute for Safe Medication Practices in Alexandria, Virginia, and Curt D. Furberg, MD, PhD, from the Wake Forest School of Medicine in Winston-Salem, North Carolina, point out the shift in the testing of new drugs.

In the past, most testing was conducted before initial approval, whereas now, innovative drugs are rapidly approved after a small trial in a limited patient population, and extensive testing is conducted after approval. These findings "suggest that the shift has made it more difficult to balance the benefits and risks of new drugs," they write.

In an accompanying commentary, Daniel Carpenter, PhD, from Harvard University, notes that the "current system of accelerated drug approval in the United States can be described as a growing hodgepodge of exceptions to the rule of rigorous premarket review."

In addition to accelerated approval, there is now priority review, orphan drug designation, separate standards for drugs for AIDS and cancers, and possibly now alternative pathways and "enriched" trials, Dr. Carpenter explains.

"If the critical phrase 'serious or life-threatening conditions that would address an unmet medical need' is defined broadly enough (and there are lobbying efforts to define it as broadly as possible), the future of evidence for pharmaceuticals in the United States will look more like 100 patients for efficacy trials instead of 500 patients," he writes.

In their study, Moore and Furberg point out that there is "no substitute for testing a drug in clinical trials of sufficient size and duration to provide scientific evidence that it has benefits that outweigh its risks, and that adequate information exists to permit its safe use."

For ponatinib, "that testing certainly did not occur," Moore told Medscape Medical News. "As a result, patients suffered severe injury and death.

The only study comparing ponatinib with another CML treatment had to be stopped for safety.

There is no scientific evidence showing that ponatinib is "a lifesaving drug" because there have been no studies measuring survival. "The only study comparing ponatinib with another CML treatment had to be stopped for safety," he said. "The follow-up data from uncontrolled studies showed that the longer patients were exposed to the drug, the higher the risk for serious injury."

Patients can still receive ponatinib under an emergency Investigational New Drug Application, if it is deemed appropriate, according to the FDA. But it is difficult for patients to get the full picture of an agent and make an informed decision until the drug is properly tested and its properties are known. "We need an objective and independent FDA to require sufficient testing to create meaningful choice based on scientific evidence," Moore said.

Ponatinib was given accelerated approval to allow patients access while studies were conducted to confirm safety and efficacy. "In situations of serious and life-threatening diseases with unmet medical need, such as cancer, patients and healthcare professionals have expressed a willingness to accept greater uncertainty about risk in order to have access to improved treatment options," according to FDA press officer Yao.

Dr. Emanuel supports accelerated approval for indications that are life threatening, but not for nonlife-threatening diseases. "We certainly have to be more careful," he said.

What it comes down to, especially for T315I patients, is whether the risks outweigh the benefits.

"Ponatinib needs to be fully investigated. Clearly, patients who are not responding should not be receiving the drug," he added. "What it comes down to, especially for T315I patients, is whether the risks outweigh the benefits."

Dr. Groarke emphasized that there is now a "need and opportunity for cardiologists and oncologists to combine their expertise in an effort to improve cardiovascular safety surveillance during clinical trials of cancer drugs."

"The goal of accelerated approval of cancer drugs — to minimize delays in delivering effective treatments to target patients — is very important, and must continue to be accompanied by rigorous prospective vigilance for adverse events and regular safety analyses as updated data become available," he said.

Citation: Market Removal of Ponatinib Raises Questions, Concerns. Medscape. Nov 08, 2013.
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