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Chemotalk NewsletterChemotalk Newsletter, Vol. 37: May 1, 2011
Hello, out there .. Some good news, for a change: BRAIN TUMOR VACCINE SHOW PROMISE IN EARLY TRIALS A vaccine that jumpstarts the immune system is showing promise in keeping a deadly type of cancerous BRAIN TUMOR at bay. Glioblastoma, or malignant glioma, is the most common type of cancerous brain tumor. It's also deadly -- most people die about 12 to 14 months after diagnosis, said Dr. Isaac Yang, a neurosurgeon at University of California, Los Angeles, and lead author of a study on the vaccine. Sen. Ted Kennedy died from a glioblastoma in 2009. In the clinical trials, researchers created individualized vaccines for 34 patients using brain tumor tissue and the patient's own dendritic cells, which are part of the immune system. When joined together in a vaccine, introducing the tumor cells to the dendritic cells "trains" the immune system to recognize cancer cells and mount an attack, the researchers said. About 91% of patients who received the vaccine were alive after one year. Fifty-five percent were alive after two years, while 44% survived to three years or longer. Three patients are still alive after five years, Yang said. "What we're trying to do is to train the immune system like a hunting dog," Yang said. "A hunting dog is given something to sniff. What the vaccine does is give the immune system the right 'scent' so that it recognizes the brain cancer and goes and kills it." The results of the Phase 1 clinical trial were reported at the American Association of Neurological Surgeons annual meeting in Denver. The researchers are currently wrapping up Phase 2 clinical trials. The next step is a Phase 3, multi-center trial, which is currently enrolling patients, Yang said. There is growing interest in using individualized vaccines to treat certain cancers, said William Chambers, director of clinical cancer research and immunology for the American Cancer Society. Last year, the U.S. Food and Drug Administration approved a vaccine to treat PROSTATE CANCER that also works by stimulating the immune system. Chambers said the results of the brain tumor trials look "promising. The increase in months of survival is pretty striking." Still, not everyone with a glioblastoma tumor would be a candidate for the vaccine, he said, including people whose cancer is so deep in their brain or so advanced that it's inoperable. That includes nearly half of all patients. And being able to operate isn't the only challenge with this type of brain tumor. Glioblastoma tumors send out tentacles that infiltrate the surrounding areas of the brain. Neurosurgeons use microscopes to guide them during surgery. Yet even when they seem to have removed all of the tumor, it inevitably comes back. What the vaccine seems to do is to help the immune system battle those spreading glioblastoma cells after the visible tumor is removed. In the trials, researchers tested two types of vaccines. One, called "whole tumor dendritic cell lysate," was created using tissue from the whole tumor to mount a broad immune system attack, Yang said. The other vaccine was specifically designed to seek out and attack specific peptides, or markers, on the tumor cells. The "whole tumor" vaccine worked better, Yang said. The average survival for those patients was about 36 months (three years) compared to about 18 months for those who received the marker-specific vaccine. Because this study was presented at a medical meeting, the data and conclusions should be viewed as preliminary until published in a peer-reviewed journal. Another measure of the success of cancer treatments is "time to progression," or how long it took for the tumor to come back. Within both vaccine groups, this varied widely -- anywhere between a few months and several years -- and there was no statistically significant difference between the two groups. It's possible that even when the tumor comes back sooner rather than later, the vaccine may still prolong survival because the tumor grows more slowly than it would without the immune system boost, Yang said. In the study, patients received the vaccine every two weeks at first, and then a booster every three months after that. Despite the promising results, a vaccine is unlikely to ever cure brain tumors, Yang said. Tumors are constantly changing, and over time produce molecules that turn off or interfere with immune responses. Still, researchers hope that cancer vaccines will eventually be able to keep tumors at bay for many years and "convert glioblastoma from a fatal disease into a chronic disease," Yang said. "This is individualized medicine," Yang said. "Each person's vaccine is different because each person's brain cancer is different. We've been treating every brain cancer as if they are the same, but they're not." * * * NEW PILL FOR MULTIPLE SCLEROSIS SHOWS PROMISE IN CLINICAL TRIAL A new oral medication for the treatment of MULTIPLE SCLEROSIS shows promise in slowing disease progression, limiting brain atrophy and reducing MS relapses, a recently completed two-year clinical trial demonstrates. The findings concern the experimental drug laquinimod, and stem from work with over 1,100 MS patients at 139 medical facilities in 24 countries. The study found that to date, the new drug appears to be both safe and well-tolerated. If the experimental medication is eventually approved for use, it would be only the second oral MS drug available to patients, alongside a number of long-standing injectable options. "The injectables aren't going to go away," said Dr. Scott S. Zamvil, a professor of neurology and faculty member in the program in immunology at the University of California, San Francisco. "We went 17 years with injectables before we got our first oral option, 'Gilenya', just last year. But there's a lot of excitement about this new option and these results, because even though the injectables are safe and effective in terms of convenience and patient compliance, oral drugs are much better than shots. "And with the one oral option we have today, there has been a lot of concern over a possible risk for immune suppression and also an increased risk for CANCER," added Zamvil, who was not a part of the current study team. "That does not seem to be the case with this new drug. So this appears to be a significant advance forward." The current research was funded by Teva Pharmaceuticals, the maker of laquinimod. The lead study author is Dr. Giancarlo Comi, director of the department of neurology and the Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy. He is slated to present his team's findings at the American Academy of Neurology meeting. In the two-year, double-blind Phase III trial, participants were randomly divided into two groups: those who were given a daily dose of laquinimod (0.6 milligrams) and those who were given a sugar-pill (placebo); neither the researchers nor the participants knew who received the medication or the placebo. The annual rate of MS relapse was 23% lower in the laquinimod group compared with the placebo group. In addition, disability progression was reduced by 36% and brain atrophy by 33% compared with those getting the sham treatment. Adverse events, including serious events, were comparable to those in the placebo group, according to the researchers. The incidence of liver enzyme elevation was higher in patients treated with laquinimod, according to Comi, but he added that the elevations were temporary, reversible and did not lead to any signs of liver problems. Laquinimod was not, however, tested against currently existing treatment alternatives, the authors stressed. The team added that the new medication appears to tackle MS by a different type of mechanism than other available options, and apparently works by curtailing the onset of permanent tissue damage while limiting acute inflammation. "Each of the medications we have has a different mechanism of action," explained Dr. Gary Birnbaum, director of the MS Treatment and Research Center at the Minneapolis Clinic of Neurology. "And MS is probably not a single disease. So different medications may work better for some and not others, which is why this new drug could end up being an important addition to the armamentarium. "However, we still need to have a head-to-head comparison with other drugs," cautioned Birnbaum, who was not part of the study team. "This is not that. And it's also important to note that this is not a cure. It achieved a reduction in the annualized relapse rate, and people on this medication did not have as many attacks per year as people on a placebo. But a 23% reduction is not a cure. This didn't stop MS. But, this is extremely hopeful research," he added. "And if it is approved, it will be a valuable adjunct to the array of treatment options now available." Since the study is being presented at a medical meeting, it should be considered preliminary until the findings are published in a peer-reviewed journal. * * * PFIZER DRUG MEETS RHEUMATOID ARTHRITIS STUDY GOALS Drug developer Pfizer Inc. said Thursday that its potential RHEUMATOID ARTHRITIS drug met key treatment goals in two late-stage studies. The drug candidate tofacitinib, formerly called tasocitinib, met its key goals of reducing signs and symptoms of the condition in separate studies on patients over a 12-month and six-month period. The company's Oral Standard study involved 717 patients over a 12-month period with moderate-to-severe rheumatoid arthritis who had an inadequate response to the drug methotrexate. Meanwhile, the Oral Step study involved 399 patients over a six-month period with moderate-to-severe rheumatoid arthritis who did not have an adequate response to TNF inhibitor drugs. Pfizer said no new safety signals emerged in the Oral Standard and Oral Step studies. A more detailed analysis off the data will be submitted to a future scientific meeting. The positive study results come on the heels of Pfizer's confirmation on April 21 that that one patient who was taking tofacitinib died during a recent clinical trial called Oral Sync. The company said the death was connected to the drug. The patient died of respiratory failure. Three other patients who were treated with tofacitinib during the study also died, but those deaths were not determined to be drug-related. In March, the company said the drug met its key goals in the 792-person Oral Sync study. The most common side effects of treatment with tofacitinib have included bronchitis, headache, infections, and gastrointestinal symptoms like nausea, vomiting, and diarrhea. More serious side effects in a mid-stage trial included lower levels of a type of white blood cell called neutrophils, higher cholesterol levels and increased creatinine levels. Tofacitinib is a key developing drug for Pfizer and is also being studied as a potential treatment for psoriasis, inflammatory bowel disease, and renal transplant. A topical version of the drug is being studied as a psoriasis treatment and a dry eye disease treatment. * * * And an interesting piece from The Los Angeles Times: HOW BIG PHARMA DISTORTS COSTS OF DEVELOPING DRUGS By Michael Hiltzik Every time I come across a big-number statistic about the size or significance of some industrial activity my nose wrinkles. You know the figures I mean: The porn business takes in $10 billion to $14 billion a year. California's marijuana harvest is worth $14 billion a year, making it the state's biggest cash crop. NCAA March Madness costs employers $1.8 billion in lost productivity. Figures like these have several things in common: They're eye-catchingly big, they're unverifiable by empirical means and they reek of fakery. The statistic that may be most hazardous to your health is one pegging the research and development cost of bringing a new drug to market at $1.3 billion. It's purveyor is the Pharmaceutical Research and Manufacturers of America (PhRMA), which exploits the number's shock value to secure its lobbying agenda on Capitol Hill. Tax breaks for drugs for rare diseases? Faster drug approvals by federal regulators? Stronger protection against competition fro generics? All these goals have been achieved, based at least partially on the claim that drug makers require huge profits to fund R&D. The supposedly high cost of research and development is also cited to argue against the reimportation of cheap drugs from Canada and direct negotiation over drug prices by Medicare. These arguments are backed by truckloads of cash: Big Pharma has been the biggest spender on Washington lobbying of any industry, laying out $2.1 billion over the last dozen years to get its way, according to congressional figures. The industry's R&D claim has been questioned for years, but seldom as thoroughly as in a recently published paper that calculates the true mean R&D cost as less than $60 million per drug in 2000 dollars ($76 million today). The study's authors, Donald W. Light of the University of Medicine and Dentistry of New Jersey and Rebecca Warburton of the University of Victoria in Canada systematically dismantle what they call "the wholly artificial 'fact' of average R&D costs per new drug" by removing inflated multipliers and calculating the tax breaks drug companies get for their R&D, among many other steps. And they underscore that the industry's estimate always has been based on raw data the drug companies keep confidential That's a major issue because the industry has an obvious incentive to maximize its R&D claims; this way, they can't be double-checked. "The most important takeaway is that nobody knows the real cost of R&D because no one has seen the data," Light told me. The basis for the industry's estimate, and the main target of Light and Warburton, is a 2003 study by the Center for the Study of Drug Development, an industry-funded institute at Tufts University. That study's authors, led by the center's director of economic analysis, Joseph A. Di Masi, determined that the capitalized cost of R&D per new drug was $802 million in 2000; industry lobbyists updated that figure for inflation to $1.32 billion as of 2006. Light and Di Masi have been taking potshots at one another in peer-reviewed journals and other venues for a long time. Tufts responded to the most recent broadside with an exasperated-sounding statement that the claims by Light and Warburton had been "thoroughly rebutted" in 2005 and that the latest paper had almost nothing new to say. The university vouched for the "scholarship, integrity, and validity" of its published paper, and it's fair to say that the DiMasi study is a very sophisticated analysis of pharmaceutical R&D financing that openly sets forth its assumptions and limitations. The trouble with the Tufts paper isn't so much its authors' work, it's that their findings have been grossly distorted by drug industry lobbyists to make a claim the study doesn't support. DiMasi himself isn't entirely comfortable with how PhRMA characterizes his findings. "I try to stay away from language that refers to 'single drugs' or 'cost per drug','" he told me. "It's a little ambiguous. People who are not familiar with the studies might make the wrong interpretation." But as Light and Warburton point out, there are other issues with the Tufts study. The biggest one is that the raw data are secret. The study is based on research and development costs for 68 unidentified drugs provided to the researchers in confidence by 10 unidentified drug companies. Therefore, it's impossible to verify which drugs were used in the study, whether they were truly representative of all Big Pharma research during the study period of 1990 to 2001, or if the cost data provided by the companies are even credible to begin with. DiMasi assured me that his survey's drugs are representative of the industry as a whole in terms of the risk and expense of the R&D, and he pointed out that his findings were validated by a 2006 study using a separate, public drug database. But the authors of that study, who were researchers at the Federal Trade Commission, states in their paper that they couldn't really be sure that their data were comparable. Of course, a study that doesn't reveal what it measured or provide a way for outsiders to reproduce its findings has an insurmountable flaw. That alone should render the Tufts study ineligible for use as the basis for any policy-making. Another issue is that the cost figure produced by DiMasi and his team includes "opportunity costs" -- that is, the potential income the drug companies might have made on other investments, such as equity securities, if they hadn't bothered to tie up their money for years developing drugs and getting them to market. The authors essentially doubled their calculations of out-of-pocket spending to accommodate these speculative lost profits. By financial alchemy, in other words, they made $403 million in tangible spending look like $802 million. DiMasi contends that opportunity cost is relevant to his findings because "it shows what it costs to have sufficient incentive to develop a new drug." Light and Warburton, however, argue not only that the Tufts opportunity-cost multiplier is far too generous, but that it reflects a nonexistent choice: a company in the innovation business doesn't have the option of not investing in R&D. A drug company that leaves its money in a securities account isn't a drug company, it's a hedge fund. What's especially questionable is treating these "foregone returns," as the Tufts researchers would call them, as the equivalent of out-of-pocket expenditures. When laymen hear that it costs $1 billion to develop a drug, they presume that the money is cold cash, possibly with an inflation factor thrown in -- not that half of it is profits a firm might have earned by not investing in research at all. In any case, the profit margins of major drug companies have been running as high as 40%, which suggests that the industry makes a lot more from developing and selling drugs than it could in the stock market A Big Pharma CEO who earns even 10% on stocks and bonds while his rivals earn 49% by hawking painkillers and sedatives will become an ex-CEO faster than you can say "9 out of 10 doctors recommend." Here too the fault lies not in the Tufts findings, but in their distortion by the drug industry. DiMasi's study proposed a reasonable standard for judging the potential yield of a long-term investment against a fixed return; it's the pharmaceutical lobby that, with staggering dishonesty, misrepresents this theoretical metric as if it's old hard cash. An important problem with the industry's citing a single figure to represent all drug R&D is that drug R&D isn't monolithic -- the costs vary widely by the tope of drug. The FTC study largely used DiMasi's methodology to conclude that average development costs ranged from $479 million for an AIDS drug to $936 million for an arthritis medicine. DiMasi himself published data in 2004 showing similar variations among therapeutic categories. That said, the DiMasi team did produce a sophisticated study of the overall costs of pharmaceutical R&D. It's the industry's lobbyists who have caricatured it as a find of the "average cost to develop one new drug." The lobbyists would have you believe that the cash cost of inventing and testing the contents of every one of those amber vials in your medicine cabinet is $1.3 billion, and consequently that any policy that cuts into drug company profits will mean less R&D and fewer lifesaving medicines. Light and Warburton have done well to deconstruct how the drug industry contrived this all-important claim about R&D costs. Is anybody listening? When I asked Light if he's heard any reaction from policymakers since his paper was published in February, he replied, "I'm not getting the impression that members of Congress are paying attention." Independent findings like his are easily overwhelmed by the tide of Big Pharma's dollars. "They rule the airwaves," he said. COMMON VIRUS, LACK OF SUNLIGHT, MAY BOOST MS RISK Infection with mononucleosis -- the easily spread virus that's the bane of many college students -- and little exposure to sunlight may combine to boost a person's risk for developing MULTIPLE SCLEROSIS, a new study suggests. "MS is more common at higher latitudes, farther away from the equator," the study's lead researcher, Dr. George C. Ebers, of the University of Oxford in England, said in a statement provided by the American Academy of Neurology. "Since the disease has been linked to environmental factors such as low levels of sun exposure and a history of infectious mononucleosis, we wanted to see whether the two together would help explain the variance in the disease across the United Kingdom." The researchers examined hospital admissions in England's National Health Service over a seven-year period and focused on 56,681 cases of multiple sclerosis and 14,621 cases of infectious mononucleosis. The researchers also examined statistics from NASA about the levels of ultraviolet light in England. They found that exposure to sunlight and to the mononucleosis virus seemed to explain almost three-quarters of the difference in levels of MS across the United Kingdom. Sunlight exposure alone appeared to explain 61% of the total variance. "It's possible that vitamin D deficiency may lead to an abnormal response to the Epstein-Barr virus," which is linked to MS, Ebers said. Sunlight exposure boosts levels of Vitamin D. "More research should be done on whether increasing UVB exposure or using vitamin D supplements and possible treatments or vaccines for the Epstein-Barr virus could lead to fewer cases of MS," Ebers said. The study appears in an edition of Neurology. * * * And finally, just to complicate issues: Patients with early stage BREAST CANCERS are commonly treated with surgery or surgery plus radiation, and radiation is widely believed to cut local recurrence rates by about half. Now, researchers report that they have found that surgery plus radiation does cut local recurrences, but appears to increase the risk of invasive breast cancers later. "I don't want people to think radiation is bad," said study author Dr. Janie Weng Grumley, a fellow in breast oncology at the University of Southern California Keck School of Medicine. "We know there is less recurrence with radiation." Grumley's team evaluated 1,014 patients with early breast cancer, known as ductal carcinoma in situ. Of these, 651 had surgery alone while 363 had surgery plus radiation. The 10-year probability of any recurrence at the same site was 30 percent for the surgery group and 18 percent for the combination group. However, when cancer does return in those who get the combination treatment, her study showed the patterns are different. "The patients who got radiation recurred a lot later than the patients who didn't," she said. The average time to the cancer recurring in the same site was 7.5 years for those who had radiation plus surgery and 4.4 years for those who had surgery only. However, "surgery plus radiation had more invasive recurrence," she said. Thirty-seven percent of the surgery group had an invasive recurrence at the same site, but 57 percent of the combination group did, she said. While 28 percent of the recurrences were in different quadrants of the breast for the combination patients -- essentially new cancers -- only 10 percent of the recurrences in surgery-only patients were in new quadrants. The survival rate among the surgery group at 10 years was 99.7 percent, compared to 98.3 percent for the combination group, the study found. The study leaves many questions unanswered. "Is the radiation causing more new cancers?" Grumley wondered. The research also has several limitations: The average follow-up for the surgery group was six years, while the average follow-up for the combination group was a little over nine years. "One could say the follow-up is longer, and maybe we would find the same thing if we followed the surgery-only group," Grumley said. The findings were slated to be presented Friday (4/29) at the American Society of Breast Surgeons meeting, in Washington, D.C. The finding should be considered very preliminary, said Dr. Otis Brawley, chief medical and scientific officer for the American Cancer Society and professor of oncology and epidemiology at the Emory University School of Medicine, in Atlanta. "I would say you have to look at all abstracts from scientific meetings with a grain of salt," Brawley said. The research has not yet been exposed to rigorous review and critique by the researchers' colleagues, he said. If a study is the first of its kind, it must be replicated by others to confirm the finding. Grumley said the message for now is that women should be aware of the different patterns found. "Really, the message should be we should monitor these patients beyond the [typical] five years," she added. * * * See you in June ... A Historical Perspective on Clinical Trials * * * And if you have any thoughts of how this newsletter could be improved, please email me directly, at jesmer_e@pacbell.net Elaine Jesmer
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