Insight into cancer resistance in elephants could aid human treatment !!!!

They are the largest land animals in the world, weighing up to 14,000 pounds and standing up to 4 meters tall. Given their size, elephants should be highly susceptible to cancer – they have at least 100 times more cells than humans – but they rarely develop the disease. In a new study, researchers shed light on the mechanisms behind elephants’ resistance to cancer – information that could fuel knowledge on cancer resistance in humans.

Study leader Dr. Joshua D. Schiffman, of the University of Utah School of Medicine, and colleagues publish their findings in JAMA.

Theoretically, an animal’s cancer risk should increase with their size and lifespan; the bigger an animal is, the more cells they have, which should increase the rate of cell division and susceptibility to gene mutations.

In 1975, however, a study by Dr. Richard Peto, of the University of Oxford in the UK, challenged this notion. He observed that cancer incidence across species is not dependent on an animal’s size or lifespan – a theory that is now hailed “Peto’s Paradox.”

A good example of this theory is the disparity in cancer incidence between humans and elephants; despite elephants being significantly larger than humans, their risk for cancer is much lower.

Previous research has suggested that specific molecular mechanisms in elephants protect them against cancer, though Dr. Schiffman and colleagues note that such mechanisms are poorly understood.

For this latest study, the team set out to learn more about the disparities in cancer mortality rates across different mammals, with a specific focus on elephants, and to shed light on possible mechanisms that induce cancer resistance in different species.

ELEPHANTS HAVE MULTIPLE COPIES OF KEY TUMOR-SUPPRESSOR GENE

The researchers assessed information on disease and cause of death for 36 mammalian species, including African or Asian elephants.

The genomes of all species were assessed, as well as the activity of peripheral blood lymphocytes – a type of white blood cell – among elephants, healthy humans and patients with a disease called Li-Fraumeni syndrome (LFS), a rare inherited condition that greatly increases the risk for cancer. This was to assess response to DNA damage.

Overall, the researchers found that cancer mortality rates did not increase with the size or lifespan of a mammal. For example, the cancer mortality rate for elephants was only 4.8%, compared with an 11-25% cancer mortality rate in humans.

The team also revealed that elephants possess at least 20 copies of a major tumor-suppressor gene called TP53, while healthy humans only have one copy, with two alleles (gene variants) inherited from each parent. People with LFS only inherit one functioning allele of the TP53 gene, according to the team, putting them at a 90-100% lifetime risk for cancer.

The researchers explain that the TP53 gene plays a key role in the response to DNA damage by triggering a form of cell death called apoptosis via the p53 protein. Compared with human lymphocytes, the researchers found that elephant lymphocytes were subject to p53-induced apoptosis at higher rates.

Based on their findings, the team suggests the additional copies of the TP53 gene and increased p53-induced apoptosis in elephants have evolved to protect them against cancer.

The authors write:

“Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage.

These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.”

HUMAN CANCER VULNERABILITY LIKELY DOWN TO MODERN LIFESTYLE FACTORS

In an editorial linked to the study, Mel Greaves, PhD, of the UK’s Institute of Cancer Research, says the theory that elephants may be protected against cancer due to the acquisition of multiple copies of the TP53 gene seems “plausible.”

However, Greaves notes that it is unclear what implications the findings have for cancer in humans. “Perhaps the main message from this innovative investigation is to bring into focus the question of why humans appear to be so ill-adapted to cancer, given the average size and life span,” he speculates.

“The human genome is replete with footprints of positive selection in the not-too-distant historical past. Humans may have acquired, in one particular respect, an extra cancer suppressor gene variant early on in evolutionary history approximately 1.8 million years ago,” Greaves continues.

He points out, however, that modern humans are particularly vulnerable to cancer, which is more down to lifestyle factors – such as smoking – that are not seen in other animals. “These behaviors are relatively recently acquired by humans, over a few hundred years, and the risks they impart far exceed prior and otherwise effective cancer suppressor mechanisms that were inherited from primate ancestors,” explains Greaves.

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HRT safe and perhaps beneficial in women treated for ovarian cancer, major trial shows

Women with the commonest type of ovarian cancer can safely take hormone replacement therapy (HRT), and it could have a beneficial effect on their survival, a long-term clinical trial reports.The 24-year, phase III international trial provides the strongest evidence yet that women with epithelial ovarian cancer – which accounts for 80-90 per cent of cases – can safely take HRT during or after their treatment.

Several major studies have found that HRT can increase the risk of developing some cancers, which is why there has been such interest in whether it is safe to take during cancer treatment.

The new study, published in the Journal of Clinical Oncology, was led by researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and is the largest to investigate HRT’s effects on ovarian cancer survival.

It was funded by The Institute of Cancer Research and Cancer Research UK, and endorsed by the UK Co-ordinating Committee for Cancer Research.

Set up in 1990, the trial followed 150 women with epithelial ovarian cancer – half of whom were allocated to receive HRT during their treatment, and half of whom were not – and compared overall survival at a point in 2012, 22 years after the trial began.

Women were recruited from 19 different hospitals across the UK, Spain and Hungary, in a study co-ordinated by researchers at The Institute of Cancer Research (ICR).

53 of the 75 women (71 per cent) in the HRT arm of the trial – who were allocated to receive HRT for up to five years after the study began – had died, compared with 68 (91 per cent) of the 75 women who had not taken HRT.

The results are relevant to a large proportion of women with ovarian cancer because ovarian cancer treatments can trigger the menopause.

The study suggests that women with ovarian cancer can receive the known benefits of HRT on the side-effects of the menopause, without it reducing their survival chances. In fact, the results indicate that HRT might improve chances for overall survival.

The trial looked at women who already had ovarian cancer. Years of research have already shown that when healthy women take HRT their risk of developing breast, ovarian and possibly womb cancer can increase.

Study clinical lead Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research, London, and Consultant at The Royal Marsden NHS Foundation Trust, said:

“We were really happy to be able to show that HRT is safe for women with the most common type of ovarian cancer. Whether or not to have HRT is a very important decision for a large proportion of women with ovarian cancer, who will often have to undergo the menopause due to the cancer treatment at the same time as coping with a cancer diagnosis.

“Our results not only suggest HRT is safe for women with this type of ovarian cancer, but that it may actually improve their chances of long-term survival. We hope our study will inform treatment for women with ovarian cancer, and the findings could have a big impact on their quality of life.”

Study scientific lead Professor Judith Bliss, Director of the Cancer Research UK-funded Clinical Trials & Statistics Unit at The Institute of Cancer Research, London, said:

“Our results should provide some reassurance to women with ovarian cancer who until now might have avoided HRT because of worries about its effect on their cancer. HRT does not seem to have a detrimental effect on survival in women with epithelial ovarian cancer, and there is even the intriguing suggestion that it may be improving their survival chances. We would like to see more research into this area in the future and hope to see other studies confirm this finding in larger numbers of women.”

Fiona Osgun, health information officer at Cancer Research UK, said:

“Years of research has shown that women taking HRT are at an increased risk of breast and ovarian cancer, as well as endometrial cancer for some forms of HRT. This research takes a different approach and looks at women already diagnosed with ovarian cancer.

“These results are a great first step in helping to understand if HRT is safe to take for women with ovarian cancer, but we need larger studies with more women to confirm them. HRT has been shown to be effective at reducing symptoms of the menopause and there are many factors that play into a woman’s decision to use it or not. If you are thinking of stopping or starting HRT speak to your GP.”

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For more information please contact the ICR press office on 020 7153 5582 /henry.french@icr.ac.uk. For enquiries out of office hours, please call 07595 963613.

Source: EurekAlert! 9/28/15

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Moving Beyond Price-Per-Dose In The Pharmaceutical Industry..

By Dana Goldman and Darius Lakdawalla

The United States has experienced extraordinary gains in treating cardiovascular disease over the last few decades. Statins, introduced in the 1980’s, are an important part of the story. Hundreds of thousands of deaths, heart attacks, and strokes have been prevented due to lower cholesterol, and the health benefits—appropriately valued—exceed $1.2 trillion. Evidence suggests there are around 40,000 fewer deaths and 60,000 fewer heart attacks annually because of these drugs. With sales that peaked around $30 billion annually, this makes statins—many of which are now generic—a very good deal.

A new generation of lipid-lowering therapies, PCSK9-inhibitors, will soon reach the market and could further extend these gains. These drugs significantly lower bad cholesterol levels (LDL) in the blood. For those who have exhausted other treatment options, PCSK9-inhibitors may reduce cardiovascular events by as much as 50 percent. However, given their announced prices, some payers are nervous about their use. And, given the benefits of statins, some might ask why PCSK9-inhibitors (PCSK9i) are needed.

Surprisingly, almost one-third of high-risk statin users are not reaching recommended lipid-lowering goals. Thus, while we have come a long way, many patients are still missing out on the benefits of lipid-lowering therapies.

The problem here is our creaky model of pharmaceutical pricing, which now threatens to deprive patients of these and other breakthroughs to come. For decades, the vast majority of drug manufacturers and payers have relied on pricing per dose, be it a pill, a milligram, or the like. While simple and convenient, the “price-per-dose” (PPD) model produces a number of well-known side effects that are now becoming increasingly severe.

PPD Limits Access To Novel Drugs

Setting a single unit price for a drug may be straightforward when it produces reliable and known clinical benefits in patients — in other words, when its mechanism of action has been observed for years in trials and real-world settings. The clinical benefits of novel drugs, however, remain inherently more uncertain.

Payers often respond to this uncertainty by delaying access to novel agents until convincing evidence arrives — sometimes years after product launch. In the case of PCSK9i, payers already seem poised to delay widespread access until clear and definitive evidence of cardiovascular event risk-reduction arrives. Unfortunately, this is likely to take another 2-4 years, which could mean thousands of adverse cardiovascular events in the meantime.

PPD Drives Up Prices For Patients That Derive Moderate Clinical Benefit

When manufacturers must set a single price for each dose, they predictably focus on patients with the very most to gain. This may sound appealing, but in many cases, the clinical benefits of new drugs vary across patient groups. Large numbers of patients stand to gain moderate amounts from a new drug, and added up over an entire population, these gains can be substantial.

With PCSK9-inhibitors, few doubt that patients with familial hypercholesterolemia whose LDL exceeds 500 mg/dL will get the new drugs. However, what about other high-risk patients whose LDL continues to exceed the recommended threshold of 70 mg/dL? The value created for these patients almost surely outweighs the cost of manufacturing the drugs. Failure to provide access thus represents a wasteful and inefficient outcome.

PPD Distorts The Dosing Decisions Of Physicians And Patients

Buying two bunches of bananas naturally costs twice as much as one bunch. Twice as many bananas can feed twice as many people. However, why should a patient who responds best to a 100 mg injection pay twice as much as another who happens to need a 50 mg version?

The 100 mg patient rarely receives twice as much value as her 50 mg peer. Even worse, charging more to patients on higher doses discourages physicians from titrating dosage upward, even when it is clinically warranted. What’s more, PPD forces us into a copayment model where patients are penalized for better adherence.

The Solution Is To Tie Reimbursement To Value

So what is the answer? We need to sever the link between price and doses for everyone, including patients. The best solution may be to reimburse pharmaceutical companies for PCSK9i therapies on the basis of heart disease risk—something cardiologists are already good at classifying—and to eliminate copayments per prescription regardless of patient risk. The highest risk group includes those with genetic disorders that elevate their cholesterol to dangerous levels, and who develop heart disease at a very early age. For these patients, the currently announced price of about $13,000/annually is a great deal.

But the answer is not to restrict the drugs just to this group. For other high-risk patients with less elevated cholesterol—e.g., atherosclerotic cardiovascular disease patients for whom statins lower LDL significantly, but not all the way to goal—a different, lower price should apply. With this differential pricing, payers would no longer have incentives to limit coverage. And, prescribing decisions would focus on the clinically optimal way to lower LDL, instead of on the least expensive dosing strategy.

Plans should pay manufacturers relatively more when the patient’s diagnosis warrants it, and less when the evidence base does not support such a price. This will also mean higher patient cost-sharing in the latter case.

We Need To Remove Barriers To Novel Pricing

Such economic arrangements face many obstacles, in spite of the obvious benefits. The first challenge is regulatory: how will such pricing arrangements be viewed by Medicaid?

Medicaid best-price rules make drug manufacturers reluctant to offer pricing schedules that could, in theory, result in very low unit prices for some groups of patients. The appearance of low unit prices in one or two market segments could theoretically drive down the prices paid by all state Medicaid agencies. As a result of this risk, Medicaid best-price rules have transformed the private insurance market in the US into one of the world’s least innovative testing grounds for new pricing strategies, even compared to public-sector payers overseas.

The second challenge concerns outcomes measurement. Who will assess the LDL reduction, or cardiovascular event-reduction, and how will it be measured? This problem, and its solution, is more common than it appears — for instance, acquisitions and mergers often depend on measuring financial performance. The typical solution is the use of a third-party auditor to verify measurement claims by, in this case, the payer. If we can develop protocols to monitor nuclear facilities in places like Iran, we can probably figure this one out.

Progress in biology and science has outstripped our economic institutions. Innovation in the pricing and reimbursement of pharmaceutical therapy is long overdue. Many challenges remain, but denying patients access to efficacious products is not the “safe” solution. The real risk lies in continuing business as usual, while patients bear the costs of delays and denials. If we price it right, perhaps we can make the next few decades as productive as the last few.

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Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion

Developing a new prescription medicine that gains marketing approval, a process often lasting longer than a decade, is estimated to cost $2,558 million, according to a new study by the Tufts Center for the Study of Drug Development.

The $2,558 million figure per approved compound is based on estimated:

• Average out-of-pocket cost of $1,395 million
• Time costs (expected returns that investors forego while a drug is in development) of $1,163 million

Estimated average cost of post-approval R&D—studies to test new indications, new formulations, new dosage strengths and regimens, and to monitor safety and long-term side effects in patients required by the U.S. Food and Drug Administration as a condition of approval—of $312 million boosts the full product lifecycle cost per approved drug to $2,870 million. All figures are expressed in 2013 dollars.

The new analysis, which updates similar Tufts CSDD analyses, was developed from information provided by 10 pharmaceutical companies on 106 randomly selected drugs that were first tested in human subjects anywhere in the world from 1995 to 2007.

“Drug development remains a costly undertaking despite ongoing efforts across the full spectrum of pharmaceutical and biotech companies to rein in growing R&D costs,” said Joseph A. DiMasi, director of economic analysis at Tufts CSDD and principal investigator for the study.

He added, “Because the R&D process is marked by substantial technical risks, with expenditures incurred for many development projects that fail to result in a marketed product, our estimate links the costs of unsuccessful projects to those that are successful in obtaining marketing approval from regulatory authorities.”

In a study published in 2003, Tufts CSDD estimated the cost per approved new drug to be $802 million (in 2000 dollars) for drugs first tested in human subjects from 1983 to 1994, based on average out-of-pocket costs of $403 million and capital costs of $401 million.

The $802 million, equal to $1,044 million in 2013 dollars, indicates that the cost to develop and win marketing approval for a new drug has increased by 145% between the two study periods, or at a compound annual growth rate of 8.5%.

According to DiMasi, rising drug development costs have been driven mainly by increases in out-of-pocket costs for individual drugs and higher failure rates for drugs tested in human subjects.

Factors that likely have boosted out-of-pocket clinical costs include increased clinical trial complexity, larger clinical trial sizes, higher cost of inputs from the medical sector used for development, greater focus on targeting chronic and degenerative diseases, changes in protocol design to include efforts to gather health technology assessment information, and testing on comparator drugs to accommodate payer demands for comparative effectiveness data.

Lengthening development and approval times were not responsible for driving up development costs, according to DiMasi.

“In fact,” DiMasi said, “changes in the overall time profile for development and regulatory approval phases had a modest moderating effect on the increase in R&D costs. As a result, the time cost share of total cost declined from approximately 50% in previous studies to 45% for this study.”

The study was authored by DiMasi, Henry G. Grabowski of the Duke University Department of Economics, and Ronald W. Hansen at the Simon Business School at the University of Rochester.

ABOUT THE TUFTS CENTER FOR THE STUDY OF DRUG DEVELOPMENT

The Tufts Center for the Study of Drug Development (http://csdd.tufts.edu) at Tufts University provides strategic information to help drug developers, regulators, and policy makers improve the quality and efficiency of pharmaceutical development, review, and utilization. Tufts CSDD, based in Boston, conducts a wide range of in-depth analyses on pharmaceutical issues and hosts symposia, workshops, and public forums, and publishes Tufts CSDD Impact Reports, a bi-monthly newsletter providing analysis and insight into critical drug development issues.

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