The first of a promising new class of cancer drugs went on sale in Japan this week at an average annual cost of $143,000 a patient, a harbinger of hefty prices the new drugs are expected to command in the U.S. and Europe in coming months.
The drug Opdivo, from Ono Pharmaceutical Co. 4528.TO -2.06% and Bristol-Myers Squibb Co. BMY +0.17% , is a so-called PD-1 inhibitor, a new type of drug that harnesses the body's immune system to fight tumors, including melanoma. Several other pharmaceutical companies are also developing PD-1 targeting drugs.
High prices for the treatments come as concerns mount about the affordability of new drugs. Debate about pricing reached a peak this year with the launch of an expensive new drug for hepatitis C.
Government health officials, private insurers and some members of Congress expressed concern that the $84,000-per-patient drug—Sovaldi from Gilead Sciences Inc. GILD -0.45% —was straining health budgets. Some prisons and state Medicaid programs said they couldn't afford to give the drug to every patient who qualified for it medically. Gilead said the drug has a high cure rate and can stave off more costly health interventions if the disease is left untreated.

Related

More new drugs with the potential to carry high prices are on the horizon. The U.S. Food and Drug Administration is expected to decide soon whether to clear Merck MRK +0.05% & Co.'s PD-1 inhibitor, pembrolizumab, for sale to treat melanoma, while newer hepatitis-C drugs from Gilead and AbbVie Inc. ABBV -0.08% may hit the U.S. market by the end of this year.
Some of the new drugs have brought real medical advances for diseases that long confounded researchers. Sovaldi and the newer hepatitis-C treatments can cure many patients of infection in 12 weeks, studies have shown, preventing it from worsening to diseases like liver cancer. Doctors say metastatic melanoma is being transformed from a disease with a dismal outlook for most patients to one where many may live longer because of the new drugs.
J. Leonard Lichtenfeld, deputy chief medical officer for the American Cancer Society, said higher prices for new cancer drugs have become an increasing concern for patients and their families, who often shoulder high copayments. At the same time, the PD-1 drugs "have the potential to be game-changers for a lot of people" because patients in studies have had "meaningful, long-term responses" to the drugs. PD-1 targeting drugs have shown strong cancer-fighting results in clinical trials.
Ono is marketing Opdivo—whose generic name is nivolumab—in Japan as a treatment for unresectable melanoma, a deadly form of skin cancer.
Bristol-Myers, which plans to market nivolumab in the U.S. if the FDA clears it for sale, declined to say how much it will charge. A spokeswoman said the company prices its medicines based on "the value they deliver to patients and society, the scientific innovation they represent and the investment required to support" drug research-and-development.
Prices for patented, brand-name drugs in Japan are typically at least 18% lower than in the U.S., according to the U.S. Department of Commerce. Japan imposes price cuts every two years, while manufacturers are free to raise prices in the U.S.
Osaka-based Ono Pharmaceutical received Japanese regulatory approval in July. The company disclosed the Japanese price for the drug on Tuesday, when it formally went on sale.
New York-based Bristol-Myers plans to apply by Sept. 30 for U.S. regulatory approval to market nivolumab as a treatment for melanoma, and expects to complete by year-end an application for U.S. clearance to market the drug to treat a form of lung cancer.
Bristol-Myers has been marketing another kind of cancer immunotherapy, Yervoy, as a melanoma treatment in the U.S. since 2011 at a cost of $120,000 a patient for a standard, complete course of treatment.
Doctors and drug makers say PD-1 inhibitors represent a significant advance in cancer treatment—particularly in melanoma—because they have produced relatively high rates of tumor shrinkage and patient survival in clinical studies.
Melanoma patients who received nivolumab in one clinical trial had a median overall survival of nearly 17 months. About 62% of patients receiving the drug were still alive one year after starting treatment, while 43% were still alive at two years.
Although the study didn't directly compare nivolumab-treated patients with those who didn't receive nivolumab, the survival rates compare favorably with historical norms for older treatments. Until a few years ago, patients with melanoma that had spread to other parts of the body could be expected to live for less than a year, on average.
PD-1 inhibitors have shown potential to improve treatment for other types of tumors, including lung and bladder cancers. Bristol also has reported relatively high rates of tumor shrinkage and survival for a combination of Yervoy and nivolumab in clinical testing.
The Japanese price tag stems from Ono's negotiations with that country's National Health Insurance system, which sets introductory prices for new drugs.
Ono said the price negotiated with Japan's national health insurance program is ¥729,849 for a 100-milligram vial of nivolumab. The drug is infused intravenously every three weeks at a dose that is based on a patient's weight. Using the average Japanese patient weight of 132 pounds, the annual cost would come to ¥15 million, Ono said. That translates into about $143,000 a year at recent exchange rates.
Some U.S. pharmaceutical analysts have estimated the anti-PD-1 drugs would cost more than $100,000 a patient a year. A standard duration of treatment hasn't yet been established, but some patients in clinical studies have received them indefinitely as long as they were doing well.
Merck has declined to say how much it plans to charge for its PD-1 inhibitor drug, pembrolizumab. A U.S. FDA decision on pembrolizumab for melanoma is due by Oct. 28, but could come sooner, possibly within days, according to people familiar with the matter.
Troyen Brennan, chief medical officer of pharmacy-services provider CVS Health, CVS +0.06% said the company is unlikely to see a big cost impact from the PD-1-targeting drugs until 2015 or 2016, as more hit the market and their use widens to multiple cancer types. CVS typically plans ahead to try to ensure new drugs are used in a "cost-effective manner," he said.
—Jeanne Whalen contributed to this article.
Write to Peter Loftus at peter.loftus@wsj.com
bstract

Send to:

Open Biol. 2013 Jan 8;3(1):120144. doi: 10.1098/rsob.120144.

Oxidants, antioxidants and the current incurability of metastatic cancers.

Watson J.

Author information

Abstract

The vast majority of all agents used to directly kill cancer cells (ionizing radiation, most chemotherapeutic agents and some targeted therapies) work through either directly or indirectly generating reactive oxygen species that block key steps in the cell cycle. As mesenchymal cancers evolve from their epithelial cell progenitors, they almost inevitably possess much-heightened amounts of antioxidants that effectively block otherwise highly effective oxidant therapies. Also key to better understanding is why and how the anti-diabetic drug metformin (the world's most prescribed pharmaceutical product) preferentially kills oxidant-deficient mesenchymal p53(- -) cells. A much faster timetable should be adopted towards developing more new drugs effective against p53(- -) cancers.

take metformin and aspirin and when you are feeling better kill, kill, kill, anyone that you so choose?


Cold Spring Harb Symp Quant Biol. 2011;76:155-64. doi: 10.1101/sqb.2011.76.010819. Epub 2011 Nov 9.

Adenosine monophosphate-activated protein kinase: a central regulator of metabolism with roles in diabetes, cancer, and viral infection.

Hardie DG.

Author information

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor activated by metabolic stresses that inhibit catabolic ATP production or accelerate ATP consumption. Once activated, AMPK switches on catabolic pathways, generating ATP, while inhibiting cell growth and proliferation, thus promoting energy homeostasis. AMPK is activated by the antidiabetic drug metformin, and by many natural products including "nutraceuticals" and compounds used in traditional medicines. Most of these xenobiotics activate AMPK by inhibiting mitochondrial ATP production. AMPK activation by metabolic stress requires the upstream kinase, LKB1, whose tumor suppressor effects may be largely mediated by AMPK. However, many tumor cells appear to have developed mechanisms to reduce AMPK activation and thus escape its growth-restraining effects. A similar phenomenon occurs during viral infection. If we can establish how down-regulation occurs in tumors and virus-infected cells, there may be therapeutic avenues to reverse these effects.


In English | En español
Questions About Cancer? 1-800-4-CANCER

Cancer Research Updates

  • Posted: 04/15/2013

Metformin: Can a Diabetes Drug Help Prevent Cancer?

On this page:
Photo of French lilacs. (Image courtesy of Epibase, Göteborg, Sweden)
Metformin originates from compounds derived from the French lilac (Galega officinalis). The plant has been used since the Middle Ages to relieve the symptoms of diabetes. (Image courtesy of Epibase, Göteborg, Sweden)
In 1957, the first results from a clinical trial of the diabetes drug metformin in patients were published. Yet, it would take nearly 40 years for the drug to be approved in the United States as a treatment for type 2 diabetes.
Now researchers want to know whether this decades-old drug may have additional uses in another disease—cancer. Based on findings from a number of large epidemiologic studies and extensive laboratory research, metformin is being tested in clinical trials not only as a treatment for cancer, but as a way to prevent it in people at increased risk, including cancer survivors who have a higher risk of a second primary cancer.
Numerous early-stage clinical trials are currently under way to investigate metformin’s potential to prevent an array of cancers, including colorectal, prostate, endometrial, and breast cancer. Several of these trials are being funded by NCI’s Consortia for Early Phase Prevention Trials. And NCI is collaborating with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study participants from the landmark clinical trial, the Diabetes Prevention Program (DPP), to investigate metformin’s impact on cancer incidence.
Some of the early-phase prevention trials of metformin are enrolling participants who are at increased risk for cancer and who are obese, have elevated glucose or insulin levels, or have other conditions that put them at risk for diabetes.
“With the obesity epidemic, these studies are applicable to a substantial portion of the U.S. population and, increasingly, of the world population,” said Brandy Heckman-Stoddard, PhD, MPH, of NCI’s Division of Cancer Prevention.

Expanding the Data Pool

Much of the human data on metformin and cancer has come from epidemiologic studies of people with diabetes. In many, though not all, of these studies, people with diabetes who were assigned to take metformin had a lower incidence of cancer than those taking other diabetes drugs.
Completed in 2002, the original DPP enrolled more than 3,200 people at increased risk of developing diabetes and randomly assigned them to one of three groups: one group received metformin, one took part in an intensive diet and physical activity program, and one received a placebo. Participants in the metformin arm had a substantially lower risk of developing diabetes than the general population; participants in the exercise and diet regimen fared even better.
With NCI’s involvement, the program’s extension, called the DPP Outcomes Study, will allow investigators to document cancer incidence and death among study participants. Those observations should provide some of the strongest data available to date on metformin’s anticancer effects in people without diabetes, explained Dr. Heckman-Stoddard. The first data on cancer outcomes in study participants, which will be based on 15 years of follow-up, should be available in 2014.
“Once we have that data, there are a host of other questions we can ask,” she said. For example, Dr. Heckman-Stoddard and her colleagues plan to study metformin’s impact on certain blood biomarkers that studies have suggested are associated with cancer risk. They will also study the drug’s mechanism of action—that is, how metformin may work to prevent changes in cells that can lead to cancer.

For Prevention, Small Biomarker-Driven Trials

The smaller prevention trials being conducted are very different from the DPP Outcomes Study. These trials are not designed to determine whether metformin prevents cancer. Prevention trials must generally have a large number of participants and span many years to show whether a drug or some other intervention reduces the risk of cancer.
Instead, these short, 3- to 6-month trials are investigating whether the drug has an effect on specific proteins and/or signaling pathways that have been implicated in cancer development and that laboratory studies have shown are affected by metformin.
At the University of California, Irvine Chao Family Comprehensive Cancer Center, for example, Jason Zell, DO, MPH, is leading an early-phase clinical trial that is testing metformin’s effect on the mTOR signaling pathway in obese people who have previously had precancerous growths removed from their colons.
Numerous studies have implicated the mTOR pathway as an integral hub in cancer development and progression, and laboratory studies have consistently shown that metformin can blunt mTOR signaling.
“The key point of the trial is to get at the mechanisms of action … to see if metformin is behaving in the expected manner” based on the lab findings, Dr. Zell explained.
Numerous early-stage clinical trials are currently under way to investigate metformin's potential to prevent an array of cancers, including colorectal, prostate, endometrial, and breast cancer.
Dr. Zell and his colleagues chose to study obese patients “because of the interesting side-effect profile of metformin, which can include weight loss,” meaning it may not be suitable for underweight, nondiabetic individuals, he continued.
If this first trial shows that metformin is having the expected effects on mTOR signaling, the next trial would be similar but would measure a clinical outcome, such as whether metformin decreases the number of colorectal polyps that return.
A phase II trial at the University of California, San Diego Moores Cancer Center is testing metformin’s effects on a host of biomarkers in postmenopausal breast cancer survivors who are obese.
Funded by NCI’s Transdisciplinary Research on Energetics and Cancer (TREC) program, the trial, called Reach for Health Exit Disclaimer, will involve treatment with metformin alone and in combination with an exercise program. The study will examine the effect of 6 months of metformin treatment, with or without exercise, on a host of biomarkers associated with cancer risk. The change in biomarker measurements before and after treatment will be compiled into a score that predicts the risk of dying from breast cancer.
This is all part of the trial’s novel “biomarker bridge” design, the lead investigator, Ruth Patterson, PhD, explained. The biomarkers and the risk score are being derived from an analysis of tissue samples collected as part of an NCI-supported phase III trial called the Women’s Healthy Eating and Living (WHEL) study. This study found that a diet low in fat and high in fruits and vegetables did not reduce the risk of cancer returning in survivors of early-stage breast cancer compared with survivors who maintained their normal diet. Researchers have continued to follow the health of WHEL participants to document their health outcomes, including death from breast cancer.
“The WHEL trial is over, and we have a freezer full of blood samples, and we know participants’ breast cancer recurrences, mortality, and other outcomes,” Dr. Patterson said. “So we’re hooking together a short-term trial with a long-term cohort study by means of blood biomarkers.”

The Dose Is the Question

Most of the cancer clinical trials of metformin use the same doses typically used to treat diabetes. That makes sense, because all of the epidemiologic data suggesting a cancer benefit came from studies that used those doses, said Michael Pollak, MD, of McGill University in Montreal, who has extensively studied metformin and its anticancer potential.
“We already know that those doses are safe, so why not study them?” Dr. Pollak continued. “But then you have to realize that virtually all of the lab studies [of metformin] have been done using drug concentrations that are as much as 100-fold higher than those found in the serum of diabetic patients. So the lab studies do not directly justify the clinical trials that are using conventional antidiabetic doses.”
With the obesity epidemic, these studies are applicable to a substantial portion of the U.S. population and, increasingly, of the world population.

—Dr. Brandy Heckman-Stoddard
Although laboratory studies suggest that larger doses of metformin “deserve study” for cancer treatment, Dr. Pollak noted that “for cancer prevention, we can only consider the hypothesis that the antidiabetic dose, or even lower doses, will be clinically useful.”
Dr. Zell agreed. “In the realm of cancer prevention, where side effects are less acceptable than they are in the realm of cancer treatment, the conventional dose for treating diabetes or something close to it may be the limit.
“I don’t imagine that prevention researchers will be looking to use [significantly larger] doses of metformin,” he continued. “In a healthy population, even a low risk of side effects could be extraordinary when applied to a larger population…. That’s why trials like ours are important. At the end of this 12-week intervention, we’ll have a good idea of whether the standard dose of metformin can affect cancer signaling pathways.”

Early Days

It’s still far too early to tell whether there is any future for metformin as a means of preventing or treating cancer, several researchers said.
Despite the very strong epidemiological evidence, there’s a chance that, even if metformin has some ability to prevent cancer, its efficacy may be limited to just several cancer types, Dr. Pollak noted. For example, metformin is not absorbed very well by the body and is absorbed differently by different tissues, he explained, which could limit how effective it might be against particular cancers.
Although the drug in its current form has certain limitations, some investigators are working on developing more potent derivatives of metformin. At the 2012 San Antonio Breast Cancer Symposium, for example, Italian and U.S. researchers reported that several metformin derivatives they had developed potently blocked the growth of breast cancer cells in the laboratory, including cell lines of triple-negative breast cancer, and caused the cells to die.
To be used for cancer prevention, any metformin derivative would have to be safe, with few side effects, Dr. Heckman-Stoddard stressed. As for the original metformin formulation, she added, current trials should help to map the way forward for its use in prevention.
“It’s important that we identify the right populations in which this is most likely to be an effective agent,” said Dr. Heckman-Stoddard. “We need to look at the evidence from all of these early-phase trials as a whole,” she continued, including examining the population groups exhibiting the strongest suggestions of efficacy “so we can design efficient phase III trials.”
Examples of Clinical Trials Testing Metformin for Cancer Prevention
TrialPhaseMeasured EndpointsSponsor
Exercise and Metformin in Colorectal Cancer Survivors
II
Insulin levels and other biomarkersDana-Farber Cancer Institute
An Endometrial Cancer Chemoprevention Study of Metformin [and Lifestyle Intervention]
III
Biomarkers in the endometrium and insulin levelsUniversity of Texas MD Anderson Cancer Center
Metformin as a Chemoprevention Agent in Non-Small Cell Lung Cancer
II
Progression of potentially precancerous bronchial lesions (secondary endpoint) in patients who have undergone surgery for lung cancerMayo Clinic
Prostate Cancer Active Surveillance Metformin Trial
II
Progression of prostate cancer in men undergoing active surveillance for low-risk diseaseUniversity Health Network, Toronto
Metformin Hydrochloride as Chemoprevention in Patients with Barrett Esophagus
II
Changes in the levels of the signaling pathway protein pS6K1, thought to play important role in progression to esophageal cancerMayo Clinic
This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source. Any graphics may be owned by the artist or publisher who created them, and permission may be needed for their reuse.