Cox-2 woes hound celecoxib
The storm of safety issues clouding cyclooxygenase-2 (Cox-2) inhibitors following the withdrawal of rofecoxib (Vioxx) from the market now blows toward Pfizer's way, after similar safety concerns were aired over celecoxib (Celebrex) and valdecoxib (Bextra).
On December 17, the United States National Cancer Institute (NCI) and Pfizer halted a clinical trial investigating the use of Celebrex to prevent colon polyps "because of an increased risk of cardiovascular (CV) events (composite end point of cardiovascular death, acute myocardial infarction, and stroke) in patients taking Celebrex versus those taking a placebo."
The NCI said patients in the clinical trial taking 400 mg of Celebrex twice daily had 3.4 times greater risk of CV events compared to those on placebo. Those taking 200 mg twice daily had 2.5 times greater risk. The three-year study called Adenoma Prevention with Celecoxib (APC) was expected to be completed middle of 2005.
Two other studies--Prevention of Spontaneous Adenomatous Polyps Trials and Alzheimer's Disease Antiinflammatory Prevention Trial--similar in size and duration to APC, have been evaluated by data monitoring committees and are continuing because increased risk of CV events was not observed.
"While we have not seen all available data on Celebrex, these findings are similar to recent results from a study of Vioxx, another drug in the same class as Celebrex," said the US Food and Drug Administration (FDA).
The FDA advised physicians to "consider this evolving information in evaluating the risks and benefits of Celebrex in individual patients," and to reduce or try alternative therapy if necessary.
Bextra, also a Cox-2 inhibitor, has also shown an increased risk for CV events in patients after heart surgery, according to the FDA, prompting revision of its label to warn doctors and patients of the risk. The new label, approved by the FDA on December 9, includes a boxed warning about the risk of life-threatening skin reactions and a new bolder warning contraindicating the use of Bextra in patients undergoing coronary artery bypass graft.
The warning states that patients taking Bextra have reported serious, potentially fatal skin reactions, including Steven-Johnson Syndrome and toxic epidermal necrolysis. The label advises doctors that Bextra should be discontinued at the first appearance of a skin rash, mucosal lesions (such as sores on the inside of the mouth), or any other sign of allergic reactions.
In a statement released from its New York headquarters, Pfizer said: "Within [the] accumulated body of data, there were certain studies in which there was an increased percentage of specific cardiovascular events for patients taking Celebrex; in other studies, there was a decreased percentage of specific cardiovascular events. The investigators of those studies determined at the time that the differences were not meaningful and did not establish an increased or decreased cardiovascular risk for Celebrex."
Hank McKinnell, Pfizer chief executive officer, said Pfizer was "leaving Celebrex on the market because it is an appropriate option for many, many patients."
In an editorial on December 18, the New York Times stopped short of asking the FDA to order Celebrex's market withdrawal. Said the editorial: "Pfizer said it would not pull Celebrex off the shelves, a stance that is not surprising given the profits generated by the drug, and the widespread belief in the industry that Merck only compounded its legal and financial problems by withdrawing Vioxx. But if Vioxx was risky enough for Merck to remove from the market, one wonders why Celebrex should not be yanked as well."
It asked the FDA to "step in to reduce the dangers."
The fate of Celebrex and Bextra may finally be decided on February 16 and 18 when the FDA advisory panel holds marathon meetings to evaluate their risks, as well as those of other widely used painkillers. Also up for review is naproxen, a nonselective nonsteroidal antiinflammatory drug associated with increased CV risk in a recent long-term clinical trial.
WHO reinstates two AIDS drugs
GENEVA
The World Health Organization has reinstated two generic AIDS drugs that had been withdrawn from an international list for failing to meet safety standards.
WHO officials hoped that the reinstatement of lamivudine and lamivudine-plus-zidovudine by Cipla would encourage other producers to speed up their retesting of 16 other delisted drugs.
The Indian pharmaceutical giant Cipla had been forced to retest lamivudine and lamivudine-plus-zidovudine after the WHO delisted them in May along with three other drugs for failing to meet the required standards of clinical testing, said Lembit Rago, WHO coordinator for essential medicines and drugs.
Drug manufacturers also voluntarily withdrew 13 other medicines from the list, which has 30 different generic AIDS treatments, so they too could be reevaluated, Rago said.
The delisting of the drugs, used widely by AIDS patients in poor countries, hampered the immediate treatment of HIV/AIDS, but it will boost standards of care in the long term, officials said.
"It could be seen as a short-term pain, but I think it will be outweighed by a long-term gain," Rago said. "The whole prequalification process has in a way been a turning point...in terms of putting much more emphasis on the quality of drugs," he said.
This will eventually end "the situation that has been in the past, to a certain extent, the accepted practice of poor quality drugs for poor people."
"The efforts of both our own department and the generic manufacturers to get these drugs back on the list is an extremely encouraging development," commented Jim Kim, director of WHO HIV/AIDS department. "It is very important because we know that access to essential medicines is a critical part of our efforts to scale up treatment for people living with HIV," he added.
D. Haynes, AFP
Entecavir better than lamivudine
Treatment with antiviral agent entecavir results in significantly greater improvement in liver histology, reduction of hepatitis B virus (HBV) DNA levels, and normalization of alanine aminotransferase (ALT) levels compared with lamivudine.
This was shown in a multinational, double blind, phase III clinical trial (Study AI463-022), results of which were presented on December 13 at the 14th biennial conference of the Asian Pacific Association for the Study of the Liver (APASL) in New Delhi, India.
"The primary objective when treating chronic hepatitis B patients is to prevent the progression of liver disease," said Prof. Ting-Tsung Chang, lead investigator and professor of medicine at the Medical College of National Cheng Kung University in Tainan, Taiwan. "Phase III data demonstrated that hepatitis B e-antigen-positive patients receiving entecavir experienced statistically significant improvements in liver histology and viral suppression compared to lamivudine."
The study evaluated 709 nucleoside-naīve HBeAg positive chronic hepatitis B patients randomized to receive 0.5 mg of entecavir once daily (n=354) or lamivudine 100 mg once daily (n=355) for at least 52 weeks. Half of the patients were Asians.
At week 48, histologic improvement was observed in 72 percent of patients taking entecavir vis-ā-vis 62 percent of patients receiving lamivudine (p = 0.0085) using the primary efficacy end point defined as improvement in Knodell necroinflammatory score by at least two points plus no worsening of Knodell fibrosis. Results also showed no significant difference in the secondary end point measure of liver histology using the Ishak Fibrosis Score analysis.
Patients taking entecavir experienced a significant mean reduction in HBV DNA (-6.98 log10 copies/mL) from baseline compared with lamivudine (-5.46 log10 copies/mL) (p < 0.0001). Also, 69 percent of patients in the entecavir arm had HBV DNA less than 400 copies/mL compared with 38 percent in the lamivudine arm (p < 0.0001).
Normalization of ALT levels was observed more frequently in patients receiving entecavir (78 percent) compared with patients receiving lamivudine (70 percent) (p = 0.014). There were no significant differences among patients with loss of HBeAg (22 percent, 20 percent) or seroconversion (21 percent, 18 percent).
Safety was comparable between the treatment groups, with similar incidence of serious adverse events (seven percent) and total adverse events (85 percent with entecavir, 83 percent with lamivudine). The most frequent adverse events were headache, upper respiratory infection, cough, nasopharyngitis, upper abdominal pain, fatigue, and fever. Fewer discontinuations due to adverse events were observed in the entecavir group (less than one percent) compared with lamivudine (three percent), as well as fewer ALT level elevations on-treatment (12 v. 20 patients) and off-treatment (2 v. 8 patients).
Entecavir, developed by Bristol-Myers Squibb, is an investigational oral nucleoside analogue that is a selective inhibitor of the hepatitis B virus. It has been accepted for priority review by the United States Food and Drug Administration (FDA). BMS
First sexual stimulant for women
WASHINGTON
A skin patch providing sexual stimulation for menopausal women that promises to do what Viagra did for men is undergoing review by the United States Food and Drug Administration (FDA).
The brainchild of Procter and Gamble (P and G), the Intrinsa patch delivers the male hormone testosterone--chief sexual stimulant in both sexes--through the skin to menopausal women or those whose ovaries have been removed. P and G has conducted four clinical trials with Intrinsa on 2,200 women, yielding 12 months of data on the efficiency of the hormone-replacement treatment and its possible health risks.
"We believe we have a strong clinical program studying the safety of this patch and that millions of surgically menopaused women may benefit from an FDA approval," said P and G spokeswoman Elaine Plummer. "The side effects we saw were very mild," she added, noting that in some women aged 49, Intrinsa caused upper respiratory infection like a cold, and unwanted facial hair.
"No one [withdrew from] the study because of that," Plummer said, adding that the majority of the women who participated were very satisfied with the results. "They all experienced significant improvement in arousal, orgasm, responsiveness, improved self-image, and decreased stress level."
According to Dr. Andre Guay, an expert in sexual function at Lahay Clinic in Burlington, Massachusetts, Intrinsa "would be the first patch like this for women to be approved."
"The significance of this patch coming to the market is much more than a company putting out a product to make money," he added. "This is the first country and the first regulatory agency to acknowledge that women have testosterone deficiency."
Intrinsa's advent will open the financial coffers for more research in the field, Guay said, cautioning that the patch has "nothing to do with Viagra, but the goal is the same."
But he doubted if Intrinsa will sail smoothly through the FDA review process. Even if P and G's Intrinsa meets FDA approval, the agency could delay authorizing its sale for a year and demand additional tests for safety to avoid another barrage of criticism from Congress after it was accused of being too lenient with pharmaceutical companies over the Vioxx scandal, Guay said.
For P and G, Intrinsa targets a lucrative market of some 30 million women who will reach menopause this year.
J. Santini, AFP
Local trial findings on Risperdal
There are no official epidemiological data on the incidence of schizoprenia and other psychotic disorders in the Philippines. However, Dr. Puneza Oņate, assistant professor at the Cebu Institute of Medicine and Cebu Doctors Hospital, estimates that anywhere between 0.5 and one percent of the population are affected, a rate similar to those reported in other countries. Based on the current estimated population of 80 million, that would mean around 400,000 to 800,000 Filipinos suffer from these disorders.
In terms of management of schizoprenia, Oņate believes that current treatment options are not always adequate. "I do not think that the conventional antipsychotics are adequate treatment regimens if we consider safety, efficacy, and tolerability", she said, adding she is more inclined to try novel antipsychotics. She considers the emergence of the long-acting risperidone (Risperdal) for intramuscular (IM) injection as a breakthrough.
Oņate, former president of the Philippine Psychiatric Association described her experience with risperidone in a 12-week, multicenter, open-label trial. The study aimed to evaluate the drug's efficacy and safety. Patients diagnosed with schizoprenia or schizoaffective disorder 18 years old and older and who have been symptomatically on a stable dose of an antipsychotic medication in the month prior to enrollment were included in the trial. The patients were given 25 mg risperidone IM every two weeks for 12 weeks. Clinical parameters were observed monthly.
Initial results were good, according to Oņate, citing the first three patients who have been evaluated. Two of the patients were diagnosed with schizoprenia and were taking oral risperidone for the three weeks overlap period. The other had a schizoaffective disorder and was taking haloperidol and chlorpromazine. Two of the three patients were switched to long-acting risperidone because of insufficient response to their previous medication while the other had problems with treatment compliance.
Oņate noted that after 12 weeks of treatment with long-acting injectable risperidone, the decrease in total positive- and negative- syndrome-scale (PANSS) score was observed for all three patients (average of 32 percent). The severity of illness (measured by CGI) was also improved. The GAF increased to as high as 80 (from a baseline of 63) indicating better functional outcomes. These improvements in the clinical parameters indicate that long-acting risperidone is efficacious, according to Oņate. As for safety, she said that one patient experienced an extrapyramidal symptom, which resolved after one month, and an adverse event described as mild.
All of the patients were at least satisfied (two were very satisfied) with the effect of the drug on their illness compared with their previous antipsychotic medication.
New drugs get FDA okay
The United States Food and Drug Administration (FDA) approved several new drugs in November and December, including two ophthalmic preparations (Vision Blue and Macugen) and two anticancer agents (Kepivance and Tarceva).
Vision Blue
Vision Blue (trypan blue ophthalmic solution) is the first product approved in the US for staining the anterior lens capsule during cataract surgery. The use of Vision Blue will enhance the ability of ophthalmologists to remove white cataracts. Selective staining of the anterior lens capsule with Vision Blue makes it easier to visualize, manipulate, and remove the cloudy lens through a surgical incision. Clean cuts in the capsule are known to reduce some of the risks associated with the surgical removal of a cataract.
The FDA said the safety and efficacy of Vision Blue has been established both in pediatric and elderly patients. The adverse reactions are generally self-limited and of short duration. They include discoloration of intraocular lenses and staining of the posterior lens capsule and the vitreous.
Vision Blue, manufactured by the Dutch Ophthalmic Research Center, is currently marketed in 30 countries.
Macugen
Pegaptanib (Macugen), a new therapy to slow down vision loss in people with neovascular age-related macular degeneration (AMD), is a selective vascular-endothelial-growth-factor (VEGF) antagonist.
"Macugen is among the first treatments to target the underlying biology of wet age-related macular degeneration," said Dr. Lester M. Crawford, acting FDA commissioner.
AMD, a retinal disease causing severe and irreversible vision loss, is a major cause of blindness in individuals older than 55 years. Untreated, the majority of eyes affected with wet AMD may become functionally blind. Wet AMD, which makes up approximately 10 percent of AMD cases, is caused by the growth of abnormal leaky blood vessels that eventually damage the area of the eye responsible for central vision.
The safety and efficacy of Macugen was studied in two trials in patients with wet AMD for two years. Patients treated with Macugen exhibited a significant decrease in vision loss in both trials. Serious adverse events related to the injection procedure included infections, retinal detachment, and traumatic cataract. Other frequently reported adverse events in patients treated with Macugen were eye irritation, eye pain, hemorrhage under the outer membrane of the eye (conjunctiva), and blurred vision.
Macugen was developed by Eyetech Pharmaceuticals, Inc. and Pfizer Inc.
Kepivance
Palifermin (Kepivance) helps reduce the chance that certain cancer patients--those with blood cancers undergoing chemotherapy and radiation in preparation for bone-marrow transplants--will develop mucositis. Palifermin also shortens the duration of the condition.
Mucositis (painful sores and ulcers in the lining of the mouth) is a common complication of high-dose chemotherapy and radiation therapy associated with bone-marrow transplant.
Palifermin is a man-made version of a naturally occurring human protein called keratinocyte growth factor (KGF), which stimulates the growth of cells in the skin and on the surface layer of the mouth, stomach, and colon. It also stimulates cells on the surface layer of the mouth to grow. This is thought to lead to faster replacement of these cells when killed by the cancer treatments and to speed up the healing process of mouth ulcers.
In a study of 212 patients with leukemia or lymphoma receiving high doses of chemotherapy and radiation treatments, 98 percent of the patients who did not receive palifermin developed severe mucositis as against 63 percent of those who received the drug. For those who received the drug, severe mucositis lasted an average of three days compared with nine days for those given placebo.
Palifermin is manufactured by Amgen Inc. of California.
Tarceva
Erlotinib (Tarceva) is a single-agent treatment for patients with locally advanced or metastatic nonsmall-cell lung cancer (NSCLC). Tarceva was approved as a treatment for patients whose cancer has continued to progress despite other treatments, including at least one prior chemotherapy regimen.
The drug has shown improved survival in patients with locally advanced or metastatic NSCLC. Tarceva received "fast track" status from FDA during its development.
The FDA said Tarceva's safety and efficacy were demonstrated in one randomized trial in 731 patients. The median overall survival was 6.7 months in the Tarceva group compared with 4.7 months in the placebo group.
Tarceva was developed to block growth stimulatory signals in cancer cells. These signals are mediated in part by enzymes called tyrosine kinases. Tarceva blocks the tyrosine kinase associated with epidermal growth factor receptor (EGFR).
In about one third of the patients, tumor cells were examined to see whether they had high or low levels of EGFR. Among the approximately 55 percent who had high EGFR the effect on survival was much greater than in people whose EGFR levels were low. The relationship will be explored further in the future.
Common side effects reported in clinical trials were diarrhea, rash, nausea, and vomiting. Tarceva may cause fetal harm when administered to pregnant women.
The drug will be manufactured by OSI Pharmaceuticals Inc. and distributed by Genentech Inc.
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