SRT1720: Good (And Confusing) News for Obese Mice

An insider analysis of a new Nature Scientific Reports paper by Derek Lowe:

Readers of this blog will be fairly familiar with the long, interesting story of sirtuin activators. Today we will speak of SRT1720, of which we have spoken before. This molecule was described in 2007 as an activator of Sirt1 with beneficial effects in rodent models of diabetes. But both of those statements were called into question by a series of papers which found difficulties with both the in vitro and the in vivo results (summarized here). The GSK/Sirtris team fired back, but that paper also served as a white flag on the in vitro assay questions: there were indeed artifacts due to the fluorescent peptides used. (Another paper has since confirmed these problems and proposed an off-target mechanism).

But that GSK response didn’t address the in vivo assay questions at all – we still had a situation where one group said that these compounds (SRT1720 in particular) were beneficial, and another said that it showed no benefit and was toxic at higher doses. Adding to the controversy, another paper appeared late last year that went back to nematodes, and found the SRT1720 did not extend their lives, either. The state of this field can be fairly described, then, as “extremely confused”.

Now we have a new paper whose title gets right down to it: “SRT1720 improves survival and healthspan of obese mice”. First time I’ve seen “healthspan” as a word, I might add, and another interesting sidelight is that this appears in Nature Scientific Reports, the publishing group’s open-access experiment. But now to the data:

{snip all the meat}

[From SRT1720: Good (And Confusing) News for Obese Mice]

mINDY Mice – No Obesity, No Diabetes?

Drug research chemist Derek Lowe:

Caloric restriction increases healthy lifespan. That’s true in a range of organisms, and probably in humans. But it’s never going to be popular – and what’s more, it’s not going to be feasible, either, given how clearly people like to eat. So the search has been on for just how it exerts its effects, with a number of interesting clues turning up.

And now there’s another one. There’s a longevity gene in fruit flies known as INDY (short for, I fear, “I’m Not Dead Yet”, and if you don’t get that reference, you should probably turn in your geek license. This would be a good time to note, as required by law, that the fruit fly people are a longstanding and apparently endless fountain of weird nomenclature). Reducing INDY expression definitely lengthens lifespan in flies and in the nematode C. elegan.

A recent paper in Cell Metabolism, from a large-multicontinent team involving the Shulman group at Yale and many others, explores the effects of the mammalian homolog, mINDY, in mice. The knockout mice are smaller, although they take in the same number of calories. They are much leaner, though, with remarkable less fat. Their metabolism seems to be ramped up, as you might figure from that situation, and they’re especially good at fat oxidation in the liver. Very interestingly, they maintain this phenotype as they age, while normal mice tend to put on more fat. They have lower basal glucose and insulin levels, and are better at clearing glucose, apparently through better uptake in skeletal muscle. They also seem resistant to the bad effects of a high-fat-chow diet, show a much reduced tendency to putting on weight and developing insulin resistance. All in all, this is what you’d call a desirable metabolic phenotype, and it fits in very well with what has been worked out in the fruit flies.

So what does this gene code for? Turns out that it’s a citrate transporter, which might not be the most obvious thing at first, but it makes sense. Citrate is converted to acetylCoA, which is the building block for fatty acid synthesis. Cutting down its availability basically starves the liver tissue, which depends on fatty acids for a good part of its energy needs, and causes it to efficiently burn off whatever fatty acids it can acquire. And this effect might just be one of the things that produce the benefits of caloric restriction – in other words, you might not have to deprive your whole body of calories, just the key parts of it. To show that I’m not overinterpreting here, I’ll let the authors say it:

These data suggest that mIndy may be a key mediator of the beneficial effects of dietary energy restriction. Since prolonged caloric restriction is very difficult to achieve in humans, our observations raise the tantalizing possibility that modulating the levels or function of mIndy could lead to some of the health-promoting effects of calorie restriction, without requiring severe caloric restriction.

And as they go on to suggest, this makes for a very interesting target for obesity, diabetes, and fatty liver disease. What about extending lifespan? Well, I’ve dug through the paper several time, and can find no mention of mice older than 8 months, and no numbers on their longevity. I assume that this will be the subject of another paper as the rodents get older – it’s too big an issue to ignore, and this paper seems determined not to say a word about it.

[From mINDY Mice – No Obesity, No Diabetes?]

FDA drug approval reform: Moving to a Safety-Only System

Thanks heaps to Tyler Cowen for this heads-up on drug development. The ideas are blindingly obvious once explained. The outmoded idea behind the laborious FDA system is now known to be false (that average efficacy is relevant to an individual patient). Read this, then contact your elected representatives about reforming the FDA. One of the lives saved could be yours.

It seems likely to me that part of the problem with the current scheme is regulatory capture. Big pharma benefits by completely eliminating any small (startup) innovators from competing. That’s a typical incumbent strategy – get the regulators to erect barriers preventing new entrants.

It now costs about a billion dollars to develop a new drug which means that many potentially beneficial drugs are lost. Economist Michele Boldrin and physician S. Joushua Swamidass explain the problem and suggest a new approach:

Every drug approval requires a massive bet—so massive that only very large companies can afford it. Too many drugs become profitable only when the expected payoff is in the billions….in this high-stakes environment it is difficult to justify developing drugs for rare diseases. They simply do not make enough money to pay for their development….How many potentially good drugs are dropped in silence every year?

Finding treatments for rare disease should concern us all. And as we look closely at genetic signatures of important diseases, we find that each common disease is composed of several rare diseases that only appear the same on the outside.

Nowhere is this truer than with cancer. Every patient’s tumor is genetically unique. That means most cancer patients have in effect a rare disease that may benefit from a drug that works for only a small number of other patients.

…We can reduce the cost of the drug companies’ bet by returning the FDA to its earlier mission of ensuring safety and leaving proof of efficacy for post-approval studies and surveillance.

Harvard Neurologist Peter Lansbury made a similar argument several years ago:

There are also scientific reasons to replace Phase 3. The reasoning behind the Phase 3 requirement — that the average efficacy of a drug is relevant to an individual patient — flies in the face of what we now know about drug responsiveness. Very few drugs are effective in all individuals. In fact, most are not effective in large portions of the population, for reasons that we are just beginning to understand.

It’s much easier to get approval for drugs that are marginally effective in, say, half the population than drugs that are very effective in a small fraction of patients. This statistical barrier discourages the pharmaceutical industry from even beginning to attack diseases, such as Parkinson’s, that are likely to have several subtypes, each of which may respond to a different drug. These drugs are the underappreciated casualties of the Phase 3 requirement; they will never be developed because the risk of failure at Phase 3 is simply too great.

Boldrin and Swamidass offer another suggestion:

In exchange for this simplification, companies would sell medications at a regulated price equal to total economic cost until proven effective, after which the FDA would allow the medications to be sold at market prices. In this way, companies would face strong incentives to conduct or fund appropriate efficacy studies. A “progressive” approval system like this would give cures for rare diseases a fighting chance and substantially reduce the risks and cost of developing safe new drugs.

Instead of price regulations I have argued for more publicly paid for efficacy studies, to be produced by the NIH and other similar institutions. Third party efficacy studies would have the added benefit of being less subject to bias.

Importantly, we already have good information on what a safety-only system would look like: the off-label market. Drugs prescribed off-label have been through FDA required safety trials but not through FDA-approved efficacy trials for the prescribed use. The off-label market has its problems but it is vital to modern medicine because the cutting edge of treatment advances at a far faster rate than does the FDA (hence, a majority of cancer and AIDS prescriptions are often off-label, see my original study and this summary with Dan Klein). In the off-label market, firms are not allowed to advertise the off-label use which also gives them an incentive, above and beyond the sales and reputation incentives, to conduct further efficacy studies. A similar approach might be adopted in a safety-only system.

Addendum: Kevin Outterson at The Incidental Economist and Bill Gardner at Something Not Unlike Research offer useful comments.

[From FDA: Moving to a Safety-Only System]

Finding Good Drugs is Harder than it Sounds

At The Atlantic Megan McArdle examines drug development. Demonstrating once again how capable she is, Megan quotes my favorite insider source Derek Lowe:

As NIH director, Elias Zerhouni was a great champion of “translational research” that would get academics into the business of trying to make drugs rather than doing basic research like identifying drug targets. Now that he’s the head of R&D at Sanofi Aventis, he seems to be realizing that discovering drugs is harder than it sounds:

When he arrived at Sanofi, “I thought the solution would be simple,” Zerhouni said at a recent R&D press event attended by the Health Blog. He thought the answer to the company’s R&D woes was to make it more creative and more nimble, like a small biotech.

But he realized that small biotechs are no more successful than large drug makers at coming up with new drugs. “At the end of the day, there’s a gap in translation,” he said. . .

At Sanofi, the goal now is to strive for “open innovation,” which involves looking for new research and ideas both internally and externally — for example, at universities and hospitals. In addition, the company is focusing on first understanding a disease and then figuring out what tools might be effective in treating it, rather than identifying a potential tool first and then looking for a disease area in which it could be helpful.

Derek Lowe adds:

With a lot of these things, if you’re going to first really understand them, you could have a couple of decades’ wait on your hands, and that’s if things go well. More likely, you’ll end up doing what we’ve been doing: taking your best shot with what’s known at the moment and hoping that you got something right. Which leads us to the success rates we have now.

On the other hand, maybe Zerhouni should just call up Marcia Angell or Donald Light, so that they can set him straight on the real costs of drug R&D. Why should we listen to a former head of the NIH who’s now running a major industrial research department, when we can go to the folks who really know what they’re talking about, right? And I’d also like to know what he thinks of Francis Collins’ plan for a new NIH translational research institute, too, but we may not get to hear about that. . .

Read the whole thing »

Combining antibiotics with bioactive drug compounds

This is interesting. I wonder how practical it is to do a broader screening program for combos are effective against such as MRSA?

New research, published yesterday (April 25) ahead-of-print in Nature Chemical Biology, provides evidence that combining antibiotics with marketed drug compounds could be one answer, uncovering previously unknown antibacterial functions of drugs that boost the effectiveness of antibiotics.

(…) So Wright and his colleagues decided to broaden the search. They focused on minocycline, an antibiotic that inhibits protein synthesis, frequently used in the 1950s and 1960s until bacteria developed resistance. “It seemed like a good place to start as something that already had some intrinsic anti-microbial activity but had been largely abandoned by the clinical community because of the resistance problem,” said Wright.

They screened minocycline in combination with more than 1,000 previously approved bioactive drug compounds — most of which had no known antibiotic function — against three common and often resistant bacteria: Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus.

The screen revealed a total of 69 compounds never before used to treat bacterial infections that, when combined with minocycline, decreased bacterial growth by at least 45 percent — significantly more than when treated with only the antibiotic . “It was very gratifying for us that our hypothesis was right,” said Wright. “We found all these unexpected interactions.”

Cite: L. Ejim et al., “Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy,” Nature Chemical Biology, doi:10.1038/nchembio.559, 2011.

So, You Thought Breast Cancer Was Complicated?

This is not good news. Organic chemist Derek Lowe discusses a new study that employed the latest DNA sequencing techniques. Personalized therapy is looking more and more distant.

You may have detected, here and there, a certain amount of skepticism on this blog about the direct application of genomic information to complex human diseases. And several times I’ve beaten the drum for the position that there is no such disease as “cancer” – just a lot of conditions that all result in the phenotype of uncontrolled cellular growth.

Well, here’s some pretty dramatic evidence in favor of both of those positions. A new study, one of those things that could only be done with modern sequencing techniques, has given us the hardest data yet on the genomic basis of cancerous cells. This massive effort completely sequenced the tumors from 50 different breast cancer patients, along with nearby healthy cells as controls for each case.

Over 1700 mutations were found – but only three of them showed up in as many as 10% of the patients. The great majority were unique to each patient, and they were all over the place: deletions, frame shifts, translocations, what have you. The lead author of the study told Nature News that the results were “complex and somewhat alarming”, and I second that, only pausing to drop the “somewhat”. I add that qualification because these patients were already more homogeneous than the normal run of breast cancer cases – they were all estrogen-receptor positive, picked for trials of an aromatase inhibitor.

Read the whole thing »

Health Care Reform and the Drug Industry: How Goes It?

Derek Lowe examines what has actually come out of the Obama administration:

(…) Even without any backtracking on exclusivity, the article maintains that health care reform was a loser for the drug industry. The author goes on on to detail the various other costs of the bill as it was passed, and then gets to the biggest structural problem:

While the healthy part of the pharmaceutical market will be pounded, the government-run segment of the market, Medicaid, will be expanded by 16 million patients. Medicaid has the worst pricing structure and the worst track record in paying for innovations of any sector in the United States market. Like government health-care systems around the world, Medicaid must be dragged to pay for medical advances. Unlike employers and seniors in Part D, Medicaid patients cannot vote with their feet if their health plan does not provide the new medicines they want. The incentives in Medicaid all run against paying for pharmaceutical innovations.

So, Obamacare significantly expands the worst sectors of the pharmaceutical market while degrading the best.

Read the whole thing »

TEDxCaltech: J. Craig Venter – Future Biology

On January 14, 2011, Caltech hosted TEDxCaltech, an exciting one-day event to honor Richard Feynman, Nobel Laureate, Caltech physics professor, iconoclast, visionary, and all-around “curious character.”

Don’t you wish Richard Feynman could be one of the presenters.

One of the talks that has already been uploaded is Venter’s Future Biology. These Caltech talks are not in the TED iTunes subscription list – so you won’t automatically see them unless you visit the Caltech site.

Intrexon: “the Google of the life sciences”?

So says Randal J. Kirk. I’ve not heard of Intrexon before. The Forbes writers asked Craig Venter, who said the same thing. There is so much hype in synthetic biology, is this hype or the real deal?

(…) Kirk says everything he has done in the past pales next to the potential of his latest project: Intrexon, a secretive research-stage company that is working on the hot new field of synthetic biology—basically genetic engineering on steroids. Kirk and his investment fund, Third Security, have poured $200 million into the closely held 180-person company based in Blacksburg, Va., which has no drugs on the market.

“I’ve been a biotech investor for 27 years, and Intrexon is by far the best thing I’ve ever seen,” says Kirk, 56, who raises falcons and composes electronic music on a 7,200-acre cattle farm in rural Pulaski County, Va. He likens Intrexon to “the Google of the life sciences” and predicts that in a decade it could become “the largest, most significant company” in its burgeoning field.

(…) Lots of big scientific names are working in synthetic biology, which so far has produced lots of hype and headlines but few practical breakthroughs. Gene jockey J. Craig Venter, known for sequencing the first human genome in 2000, leads a company called Synthetic Genomics that has a $300 million deal with ExxonMobil to make designer biofuels.

Intrexon has released few details about which products it is pursuing. Its lead drug is only at the earliest stage of human trials. It is so obscure that three prominent synthetic biology researchers contacted by FORBES—including Venter—said they had never heard of it. Kirk shrugs. Among other colossal ambitions, he wants to revitalize the troubled field of gene therapy, make dozens of inexpensive protein drugs and produce better genetically engineered crops that will benefit consumers, not just farmers. The company is also working on biofuels, designer enzymes, bioplastics and unspecified consumer products. Keeping the work secret is part of the plan, Kirk says. “If we were in the business of publishing, we could get the cover of Science magazine any issue we wanted,” he boasts.

The scientist behind Kirk’s mystery company is the 45-year-old molecular geneticist Thomas Reed. He founded Intrexon in 1998 while still completing his Ph.D. and postdoctoral work in cardiovascular genetics at the University of Cincinnati. “I think of him as the Henry Ford of DNA,” says Kirk. “We are all living in his dream.”

(…)

Read the whole thing » See also Is Randal J. Kirk Biotech’s Best Investor? And this on the Intrexon/Ziopharm deal.