Chemotalk Newsletter, Vol. 11: April 1, 2009
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Hello, again. April's news letter starts off with a grim story, originating in England, but indicative of what might happen if any government has the power to decide what medicine doctors may use, based on "cost effective" analysis:
NICE REFUSES FUNDING FOR ADVANCED BREAST CANCER TREATMENT, TYVERB
(GSK reiterates commitment to 12 week free access program)
LONDON--NICE (National Institute for Clinical Excellence) today issued its final appraisal determination advising against NHS (National Health Service) funding for Tyverb (lapatinib), a treatment for an aggressive form of ADVANCED BREAST CANCER (ErbB2-positive).
Lapatinib (in combination with Xeloda® [capecitebine]) offers a new treatment option for women whose disease has returned despite treatment with standard chemotherapies and Herceptin® (trastuzumab). There are very few treatment options available for these women and lapatinib offers a chance of additional time without their disease progressing.
GlaxoSmithKline (GSK) will consider appealing the decision. Simon Jose, General Manager, GSK UK commented; “We disagree with the NICE decision and believe Tyverb is a valuable and important treatment for eligible women. In recognition of the cost effectiveness challenges with drugs that treat patients with a short life expectancy, we offered the Tyverb Patient Access Program to help ensure it was made available on the NHS (National Health Service). It is difficult to comment without the appearance of self interest. However, there is clearly more work to be done by all parties when flexible access programs from industry and the recent changes by NICE for patients with a short life expectancy still fail to give them access to valuable medicines.”
GSK proposed the patient access program in the UK when NICE indicated early on in its review that it did not consider lapatinib to be COST EFFECTIVE in treating this patient population. In an effort to achieve a positive outcome for patients and greater value to the NHS, GSK bears the cost of lapatinib, for all eligible patients under the scheme, for up to the first 12 weeks of treatment. The NHS would commence payment only for the patients who continue to receive clinical benefit beyond 12 weeks. GSK will continue to honor the patient access program for NHS trusts in the UK.
During the lapatinib assessment NICE proposed new advice for the assessment of treatments in small patient populations with a short life expectancy.4 Lapatinib is licensed for a particular type of breast cancer that affects around 2000 women a year. Therefore lapatinib qualified for review under the new advice.
GSK submitted a sub-group analysis that met the overall survival (OS) criterion of this new NICE advice. However NICE concluded that while the data analysis could be useful in guiding future research, as it stands it would not change their conclusions.
NICE’s decision reflects the difficulty in demonstrating SIGNIFICANT survival benefits in patients at this advanced stage of disease. Furthermore, trials are often halted early for ethical reasons to allow patients to cross over to the active arm because of the effectiveness demonstrated by the medicine under study, as in the case of lapatinib.
But wait ...
In its final appraisal determination NICE acknowledges that lapatinib is a clinically effective option, noting that lapatinib plus capecitabine demonstrated improved time to progression (TTP) and progression free survival (PFS), significantly delaying the progression of the cancer and controlling the disease.
So the decision is apparently being made strictly on economic criteria, the results of the appraisal not considered "significant" enough.
GSK’s NICE submission demonstrated that lapatinib, in conjunction with the patient access program, could actually save the NHS money in patients who would have received trastuzumab (Herceptin®) containing regimens. NICE acknowledged this is the majority (>50%) of eligible patients, however NICE concluded that trastuzumab is not likely to be cost effective in this setting and therefore lapatinib plus capecitabine would not be cost effective.
Lest we lust after nationalization of our health care options, we should bear in mind that government programs can be as bottom-line oriented as insurance companies and drug corporations. The above-referenced instance is a chilling example.
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CARING FOR MOUTH SORES FROM CANCER TREATMENT
The American Cancer Society offers these suggestions to help ease the pain of mouth sores caused by chemo or radiation, and make it easier to eat:
• Since brushing teeth can be painful, switch to a softer brush, and soften it with hot water before you brush.
• Use a gentle toothpaste that doesn't contain hydrogen peroxide.
• Rinse your mouth before and after you eat with a solution of baking soda, salt and water. Don't use commercial mouthwashes, which may irritate the sores.
• Moisturize your lips with lotion or balm.
• Swab the sores with Maalox or Milk of Magnesia -- after you check with your doctor.
• Drink beverages and liquid foods with a straw.
• Stick to foods that are soft, moist and cold.
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MERCK STEPS UP TO HELP MS RESEARCH EFFORTS
Merck Serono this month showed its willingness to accelerate early stage research in MS by providing up to $19 million in a partnership with Fast Forward, a subsidiary of the National Multiple Sclerosis Society.
The agreement—which has a two-year term, but may extend for an additional three—is focused on identifying the most promising drug discovery research in this field, whether in biotech or academia, and providing the funds to take those projects through development. The money might all be coming from Merck Serono, but it’s Fast Forward, set up 18 months ago to provide a bridge - both informational and financial - between academia and the private sector, that will take the lead in selecting awardees for the funds (albeit with participation from the drug firm). Priority areas for development will be determined by a joint committee with representatives from both sides.
And yes, there are strings attached: Merck Serono, with a strong interest in building out its MS franchise, gets first right of refusal to pursue development of projects that it supports. Fast Forward is keen to point out that these rights don’t extend to the many other projects it’s funding independently of this agreement, however. And if Merck Serono isn’t interested in pursuing a program, Fast Forward is free to find another partner.
Although many other disease-focused charities besides the National MS Society are supporting and financing research in academia and, increasingly, in the private sector, as well, few have signed up large drug firms. Not that this means other pharma aren’t interested in supporting early-stage research: GlaxoSmithKline has a drug performance unit (DPU) dedicated to academic collaborations.
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SCREENING CAN DETECT EARLY OVARIAN CANCER
"Only about 1/4 of invasive ovarian cancers are detected in the early stages, when the disease is most treatable," according to The New York Times. "Now, preliminary results from a large, continuing trial indicate that postmenopausal women who are screened for ovarian cancer either by transvaginal ultrasound scan or by a blood test followed by a scan are more likely to have their cancers detected at early stages, with almost half picked up before they had spread beyond the pelvis.
The trial, published in The Lancet Oncology, uses a sophisticated research algorithm to interpret the results of a blood test for the CA125 tumor marker, repeating the tests at specified intervals and following up with scans when indicated. The study is expected to continue through at least 2014.
"We have no demonstrated we can pick up the vast majority of women with ovarian cancer earlier than they would have otherwise been detected and before they have symptoms," said Dr. Ian Jacobs, director of the Institute for Women's Health at University College London, and director of the trial, "and that a good proportion of those women have earlier stage disease than we would normally expect them to have."
The article posits that "While the results suggest that widespread screening for ovarian cancer may be feasible, long a point of scientific controversy, the researchers warned that the benefits were still far from clear."
The article goes on to wonder whether the test does more harm than good. We all know what the "good" is, but it would be worthwhile to hear what they define as "harm".
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NEW TEST FOR PROSTATE CANCER
There's a lot of news lately about the efficacy of prostate cancer testing. Here's another take: according to a new study, a cutting edge urine test may actually be able to predict if a person is at risk of developing prostate cancer.
The study, led by Dr. Arul Chinnaiyan from the University of Michigan, focused on a urine test that identified metabolites associated with prostate cancer. These metabolites are small molecules that can be detected through this simple, yet very advanced urine test.
The researchers analyzed 1,126 metabolites from 262 tissue, blood, and urine samples, taken from men with early prostate cancer. They were able to discover 10 metabolites that appeared quite often with prostate cancer, finding a link between the two.
The metabolite that was indicative of advanced prostate cancer was sarcosine. Those who had no traced of this metabolite had no sign of prostate cancer.
Although this urine test is still years away, researchers believe that this urine test may not only be able to predict who is at high risk of prostate cancer, but it could also predict what type of treatments people need.
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Finally, I'm departing a bit from information about diseases or conditions treated with chemotherapy, to present an article from American.com. It's long, but if you want to understand how drug companies operate, it's worth reading to the end:
LEARNING A LITTLE ABOUT DRUG COPANIES FROM THE LANCET
By John E. Calfee and Elizabeth DuPre
The pharmaceutical industry is programmed to lurch from crisis to crisis. Even the most promising drugs can fail in development, as happened to Pfizer when it spent a billion dollars on a cholesterol drug that failed in a late-stage trial and precipitated Pfizer’s exit from heart drug research altogether. The rare blockbuster success brings huge profits but those profits typically plummet when patents expire, sometimes wreaking havoc on entire firms. And there is government shock—cuts in reimbursement levels, controls over pricing, shifting regulatory standards, and massive litigation.
Now, in addition, the Obama budget and the pronouncements of the Democratic-majority Congress make clear that the industry that has given us so many lifesaving drugs will soon face politically inspired assaults, ranging from tougher FDA standards to expanded controls over drug prices in the Medicare and Medicaid programs. There will be debate, of course, but the pharmaceutical industry will be peeking out from behind the eight ball. The news media and academic pundits will declare that the industry’s best days are behind it, that most R&D money is wasted in chasing after so-called me-too or copycat drugs of negligible clinical value, and that political and financial interference in today’s fumbling and inefficient R&D enterprise would do little harm despite the familiar warnings from economists about undermining research incentives.
Correcting these dangerous misimpressions could fill a book. But for now, let’s take a look at the February 21 issue of The Lancet, one of the world’s oldest continuously published medical journals. Rather left of center in its political orientation, The Lancet has solid drug-industry bashing credentials. Sure enough, the February 21 issue contains an article on the purported evils of international trade and drug patents.
But The Lancet does try to keep doctors up-to-date on at least a smidgen of the onslaught of new information about pharmaceuticals and their clinical effects. And the February 21 issue was no exception. It reports and comments upon clinical trial results for two new drugs. One is Johnson and Johnson’s ustekinumab, which is sold in Europe as Stelara but is not yet approved by the FDA. Ustekinumab is designed to treat psoriasis and a type of arthritis caused by psoriasis. The commentary notes that although we have seen “a rags to riches evolution in the understanding and treatment of psoriasis and psoriatic arthritis,” better treatments are still needed. Ustekinumab is therefore welcomed as a new class of psoriasis drug.
In the trial, the drug diminished skin lesions and improved the joint function and quality of life of patients who were not responding to standard treatments. Ustekinumab is a monoclonal antibody (hence the “mab” in the drug name), a kind of drug that harnesses an extraordinary collection of biotechnology tools. Although the first mab was approved in 1986, most arrived in just the last decade, primarily for cancer and inflammatory diseases such as RHEUMATOID ARTHRITIS. That yet another mab would find its place in a medical journal report with no attention to the complex underlying technology says a lot about the extent to which technical progress in pharmaceutical R&D is taken for granted.
The news media and academic pundits will declare that the drug industry’s best days are behind it.
The second new drug is known so far simply as A-002 from Anthera Pharmaceuticals, a biotech firm. A-002 is apparently the first phospholipase A2(sPLA2) inhibitor to achieve success in a midsize trial designed to assess therapeutic effects with an eye to eventual FDA approval. In this trial, A-002 reduced markers of inflammation and LDL cholesterol that predispose coronary heart disease patients to cardiac events. PLA2 inhibitors are designed to work with the statin class of cholesterol-reducing drugs. Statins have revolutionized the prevention and treatment of cardiovascular disease, but they only prevent half or less of heart attacks in patients taking these drugs. Pharmaceutical firms and basic researchers have been engaged in a wide-ranging search for additional therapeutics, many based on the idea that inflammation is a prime cause of coronary heart disease. PLA2 inhibitors are one result of that research, but again, A-002 may fail in testing yet to be completed.
Merely explaining the therapeutic role of these two drugs is a complex scientific exercise; even more challenging to describe is the exquisite understanding of numerous biological processes that provided the foundation for the development of these drugs. On both counts, The Lancet articles were illuminating, but much remains to be learned about the drugs’ biology and therapeutic effects. However, already—as so often happens with pharmaceuticals—the two new drugs are serving as research tools to explore the role of the immune system and inflammation in both cardiovascular disease and arthritis.
You might think that for first-in-class drugs still in testing for initial approval, competition would not be a factor. But competition is seldom absent from the modern pharmaceutical R&D enterprise. In the PLA2 inhibitor class, competition is already active; The Lancet commentary on the promising outlook for this class is entitled, “Phospholipase A2 Inhibitors in Atherosclerosis: The Race Is On.” It describes promising early trials for both A-002 and GlaxoSmithKline’s darapladib. Now that PLA2 inhibitors have begun to show proof-of-principle, it is no surprise that competing firms are hard at work on this same drug class. As for the aforementioned psoriatic arthritis drug Stelara, it has already achieved promising results in a head-to-head trial with Enbrel, an established treatment for psoriasis and certain types of arthritis.
Much more can be learned from this single issue of The Lancet. It contains brief reviews of two therapeutic areas. The article “Major Achievements in Hepatocellular Carcinoma” (a form of liver cancer) emphasizes three points. First, liver cancer—one of the most common cancers—has long defied treatment with standard chemotherapy and even with new “targeted” drugs that have achieved promising results for lung and pancreatic cancers. Second, an impressive series of recent clinical trial results for the biotech drug Nexavar (sorafenib) “has been a major breakthrough in the management of advanced [LIVER CANCER].” In fact, as pointed out in a recent New England Journal of Medicine, the initial success of Nexavar came after some three decades of failed trials of established cancer drugs against liver cancer. And third, the success of Nexavar has both opened the door to the development of more liver cancer drugs of the same or similar type and forced a reassessment of imaging techniques, diagnostic tools, and treatment protocols. A recent Journal of Clinical Oncology editorial noted, “Clinical trial research in HCC is exploding,” partly because Nexavar “changed the scope of clinical investigations” with a “blossoming of early- and late-stage clinical trials in all [treatment] scenarios.”
Much of the technical progress in pharmaceutical R&D is taken for granted. Still working through the February 21 Lancet, we find a piece summarizing what is now known about the genetic, molecular, and environmental drivers of rheumatoid arthritis and how this knowledge is translating into numerous beneficial therapies and revolutionizing clinical practice. It features a series of innovative drugs, introduced in the past decade, that have changed the face of this disease from one of inescapable disability to one with effective preventive and treatment strategies.
Finally, the February 21 Lancet contains a review entitled “use of tumor-responsive T cells as cancer treatment.” This highly technical article summarizes recent findings that could yield important new cancer treatments if R&D organizations (presumably for-profit firms) undertake the incredibly costly and uncertain research necessary to find and demonstrate the safety and effectiveness of those treatments. Most of the discussion focuses on experimental therapeutic cancer vaccines—that is, agents that energize the immune system to attack established cancers, rather than prevent illness as vaccines ordinarily do. Unfortunately, FDA testing standards will have to be revised. FDA normally requires cancer trials to focus on certain established endpoints such as mortality or occasionally, tumor size, which usually means that trials have to involve late-stage cancers. Therapeutic vaccines, however, are probably much more effective against early-stage cancers.
The above is a rather rich array of results and investigations for innovative drugs, all in a single issue of one major medical journal. What about the following week’s Lancet, you ask? Well, check out the article on a new drug from Acorda Therapeutics that is the first to improve the walking ability of a subset of MULTIPLE SCLEROSIS patients. Or look at the March 5 issue of The New England Journal of Medicine with its articles on yet another new monoclonal antibody, mepolizumab from GlaxoSmithKline, which offers not only a new treatment for a particularly difficult form of asthma but is helping open the door to a new understanding of this condition.
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This information is something to keep in mind the next time the news media amplify yet another elite medical journal article critical of the pharmaceutical industry. Most doctors, most of the time, read these journals in search of new information about, among other things, better drug treatments for their patients. Fortunately for us all, they find a lot.
And if you have any thoughts of how this newsletter could be
improved, please email me directly, at email@example.com
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