Sunday, March 9, 2014

We have a problem: The science behind rising seas

Published on GlobalPost

A hundred years after it spawned the iceberg that sank the Titanic in the North Atlantic, the Jakobshavn Glacier is now a major contributor to global sea-level rise, this time threatening the homes and lives not of 2,200 passengers and crew but of a billion people across the world.
As climate-watchers and coastal-dwellers keep a weather eye out for signals of irreversible changes in the environment, the world’s fastest-moving glacier has already begun self-destruction. 
Jakobshavn is now shedding ice nearly three times as quickly as it was 20 years ago, dumping enormous and growing quantities into the ocean. It's contributed 0.1 millimeters per year to worldwide sea-level rise — more than 3 percent of the 3 mm produced globally — for the past decade.
The glacier “has been retreating for the last 100 years,” according to Ian Joughin, senior principal engineer at the Polar Science Center, part of the University of Washington's Applied Physics Laboratory. “Retreat” means a glacier is shrinking in length, losing more ice from its face that meets the water than accumulates from higher up.
But it was only in recent decades that the retreat reached extreme levels.
Jakobshavn’s story isn’t unique. For decades now, more ice has been melting into the ocean than is falling from the sky in the world’s mountain and polar regions, where ice sheets store two-thirds of the planet’s fresh water — and the science shows us the situation won’t reverse any time soon.
To understand exactly what’s happened and what's likely to come, it’s critical to understand the topography underneath each glacier.
First, a note on how to think about glacial ice: it's not as simple as frozen water. Scientists consider glaciers to be "nonlinear viscous fluids," which behave like both solids and liquids. Think of a glacier as a frozen river, always flowing at some speed from source to outlet, but growing and receding with the seasons. Because ice is heavy and not a perfect solid like rock, it flows under gravitational pull and pressure from above. Sometimes big chunks become unstable and fall into the sea. When Earth’s climate is in balance, about the same amount of water flows into the oceans from glaciers as is evaporated and then precipitated as snow onto ice sheets from which those glaciers are made.
The Jakobshavn Glacier, known in Danish as Jakobshavn Isbræ, has its origins in large areas of land well above sea level, from which it flows down toward the ocean (in this case, Ilulissat Icefjord), where it calves icebergs into the water.
As physicist Joughin describes it, Jakobshavn Glacier flows off the land and into the 1,600-meter-deep fjord, filling it entirely with ice for a distance of about 50 kilometers, ultimately climbing up a slope in the sea floor that peaks at about 600 meters of depth. The narrow sheet of ice coming off the edge of the glacier at that peak — called a “glacier tongue” — once served as a sort of “cork” for the glacier, holding it back significantly and preventing quicker loss of ice.
You can see the rise in sea-bed elevation just to the left of center in this graphic.
In 1992, Jakobshavn was melting at a rate of about 6 kilometers a year. It was “about in balance” with the natural rhythm — gaining and losing roughly the same amount of ice over the course of a year’s winter accumulation and summer melting, Joughin said.
But in the late 1990s, the glacier’s tongue broke off, and the “uncorked” Jakobshavn began to calve and lose mass in ever-deeper water.
By 2000, the glacier was losing 11 kilometers in length every year, nearly twice the stable speed. As of last summer, according to a paper Joughin and others published recently in academic journal The Cryosphere, it was losing nearly 17 kilometers a year, retreating up the fjord into increasingly deep water that could cause it to melt even faster in the coming decades.
Jakobshavn’s dramatic change was recorded in the 2012 film "Chasing Ice," in a compelling scene that captured the calving of a kilometer of ice in a single event. That happens throughout the summer, Joughin said, though not always in such significant individual moments. (When it does, though, global seismic monitors have been known to register them as 4 or 5 on the Richter scale, he said.)
Eventually — perhaps in about 100 years — the glacier will have retreated far enough that it will no longer feed directly into the fjord. At that point, essentially landlocked, the glacier will only shrink through melting, which happens much slower than calving. With that slowing will come more stability in terms of the glacier’s size. “The next stable condition could be a regionally smaller ice sheet,” Joughin said.
Jakobshavn would still contribute a significant amount of global sea-level rise before then. But the real danger lies at the other end of the Earth, in the West Antarctic Ice Sheet (WAIS), which holds enough water to raise the ocean between three and six meters.
The WAIS is also meltingbut it’s doing it in open water; once the process starts, the sheet will never stop calving.
“The [WAIS] glaciers are going to keep retreating. At this point there is nothing we can do but watch,” said Eric Rignot, a glaciologist at the University of California Irvine who published his latest paper about the WAIS in December’s Geophysical Research Letters. “Just how fast they can flow, we don’t know,” he said.
It could take hundreds or thousands of years, but as Joughin puts it, the next stable point for WAIS is “no ice sheet.” By then huge areas of land, home to massive proportions of the world’s population, would be under water.
The question facing scientists and coastal dwellers is akin to the one facing the Titanic’s passengers: The water is rising, and we don’t quite know how fast it’s coming, or how quickly it will accelerate. But we need to plan, move, and adapt if we are to survive. There’s no way to stop the water, and no time to waste.

Friday, March 7, 2014

GSK, Roche go head-to-head to fight melanoma

Published in Drug Discovery News

LONDON—Taking a lead in the tight race to develop and release melanoma medications,GlaxoSmithKline plc (GSK) has received accelerated approval from the U.S. Food and Drug Administration for its combination of Mekinist (trametinib) and Tafinlar (dabrafenib) for treatment of melanoma with BRAF mutations V600E and V600K. Roche, which is also a big player in this market, is now behind, said Aine Slowey, senior analyst for London-based analysis firm Datamonitor Healthcare. While both GSK drugs had been approved as monotherapies in 2013, the combined results “were very positive and significantly better than the BRAF monotherapy,” Slowey said.
 
The Swiss giant has a monotherapy in Zelboraf (vemurafenib) but does not yet have a combination therapy targeting BRAF mutations. In fact, “the combination of  Zelboraf and Yervoy has already crashed and burned,” she said. While Zelboraf is less toxic than Bristol-Myers Squibb’s (BMS) Yervoy (ipilimumab) and therefore may be used first, with Yervoy going only to those who see no improvement, a combination of the two drugs was hoped to be a powerful one-two punch. But the trial combining them was halted last year because of toxicity.
 
In the wake of that failure, Roche may be looking to “leapfrog” GSK, to combine dual therapy with additional PD-1 inhibitors, she said.
 
Both GSK’s approved dual treatment and the failed combination from Roche and BMS inhibit MEK as well as BRAF, delaying medication resistance that arose when inhibiting just BRAF. But it’s only a delay, Slowey said; eventually resistance does develop. Adding immunotherapy, such as PD-1 inhibition, may help, Slowey said.
 
Melanoma medications are a small, and relatively new, market. The disease is easily detected in its early stages, and surgery is usually both quick and effective, particularly when compared to surgery for other types of cancer. But basic research uncovered the fact that BRAF mutations are a “convenient biomarker that patients are going to respond well to this kind of targeted therapy,” Slowey said, so companies started exploring commercialization.
 
For those patients who do develop metastatic melanoma, about half have a BRAF V600 mutation; of those, 90 percent have the V600E variant, Slowey said. (The other half, who have what is called “wild-type” metastatic melanoma, get Yervoy and immunotherapy, Slowey said.)
 
While Datamonitor projects patient numbers will grow about 3.5 percent a year through 2021, the market numbers are still low: Seven years from now, there will only be 170,000 patients in the U.S., Japanese and European markets combined, the company projects, with sales totaling $459 million then.
 
Nevertheless, “it’s probably one of the fastest-moving oncology markets at the minute,” Slowey said.
 
Prior to 2011, only standard cytotoxic chemotherapies were available. But then Yervoy was approved for metastatic melanoma patients. Already there are four approved drugs, with more on the way.
 
BMS has entered the fray, winning fast-track designation for nivolumab, which is now in Phase 1 trials, as well as combination testing.
 
And Merck’s PD-1 inhibitor, MK3754, has breakthrough designation for treating melanoma; the company recently signed a deal with Amgen to see if MK3754 would work well in combination with Amgen’s oncolytic virus Talimogene laherparepvec.

Growing proteins in space

Published in Drug Discovery News

BOSTON—Taking protein-growing to high altitude and low gravity, Emerald Bio has joined an arrangement led by the Center for the Advancement of Science in Space (CASIS) and catalyzed by the Broad Institute of MIT and Harvard to send labs on chips to the International Space Station to study growth of proteins that may help develop treatments for cholesterol and cancer back here on Earth.
 
Though Melbourne, Fla.-based CASIS has offices in Cambridge, Mass., this is the first time the NASA-selected manager of the International Space Station U.S. National Laboratory has collaborated with the Cambridge-based Broad, according to Brian Hubbard, director of the Broad’s Therapeutics Project Group.
 
The Broad does work frequently with Emerald Bio, though, and when Hubbard heard last summer that CASIS was interested in growing proteins in space (which had been done before, but not with current technology), he thought of Emerald. “It came together very quickly,” Hubbard tells DDNews, crediting the Broad’s “open collaborative model” with the efficiency. “You don’t need to form a team. The team is already there.”
 
And it’s a diverse but focused team. In addition to CASIS, Emerald and the Broad, the crew also has NanoRacks of Houston (which has scientific hardware on the ISS) and Protein BioSolutions of Gaithersburg, Md., which recently purchased from Emerald the microfluidic technology that will enable more than 7,000 separate protein-growth experiments to fit in the space allotted on the space station.
 
“We were actually approached by CASIS … through the Broad,” George Abe, president of Emerald Bio, says. With available time and energy, CASIS was interested in new reasons for growing proteins in microgravity. And CASIS wanted something of real therapeutic value.
 
Emerald suggested two possibilities: proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene that raises LDL (low-density lipoprotein) cholesterol, and myeloid leukemia cell differentiation protein 1 (MCL1), a key gene in cancer treatments.
 
Neither structure has “been solved in its empty state before,” Abe said. Protein structures are “extremely sensitive to a lot of environmental factors,” Abe said. “A protein structure will grow or evolve differently in a microgravity environment than on planet Earth.” How they grow when freed from Earth’s gravity could provide new information that will lead to approaches to inhibit relevant genes.
 
That direct approach is typical of the Broad, Hubbard said. “We’re looking to have real impact on patients but we’re also looking to . . . disruptive technologies” with prospects not today but five to 10 years out, he said. Often, if things aren’t druggable directly, researchers work to find the relevant genes, then proteins and then follow the thread back through gene regulators, eventually finding something that is druggable, he said. But at the Broad, they go for the target itself, even if that means inventing new technology, Hubbard said.
 
And while the technology itself already existed, the method had to be created to allow this research to proceed. Originally, Emerald had thought it might send the equipment to grow proteins up to the ISS, but that was too big to fit, and too complex to ask astronauts to handle in addition to their other duties.
 
Instead, Emerald will express and purify the proteins, and then ship them to Protein BioSolutions with protocols for building 36 identical pairs of labs on chips, with each chip holding 200 different configurations of pH, salinity and other environmental factors. The chips will be immediately frozen, with one of each pair sent to the ISS and the other 36 sent to Emerald as controls. (The launch was slated for April as of the writing of this article.)
 
The chips will be thawed and the astronauts—as well as scientists on Earth—will observe what happens. After about six months in space, the samples will be returned to Earth.
 
“For any structures that actually grow in space, we will be performing X-ray diffraction on those,” Abe said. And then chemists associated with the Broad will work to identify potential therapeutics that could bind with those proteins, either to prevent their formation, or block or otherwise modify them.
 
This does not mean that protein production or other aspects of drug development will have to occur in space; rather, it will allow people to discover important information they can use in terrestrial study and production. Nevertheless, this experiment will be a test in another way: of how valuable “a potential market demand for doing early-stage drug discovery work in a microgravity environment” might be, Abe said, noting that this new opportunity could help the ISS remain scientifically and budgetarily viable.

Bringing FDA-approved NGS tests to the masses

Published in Drug Discovery News

SAN DIEGO—Expanding applications of its recently FDA-approved MiSeqDx in-vitrodiagnostic next-generation sequencing (NGS) system, Illumina has agreed to help develop a multigene, NGS-based test to identify prospective patients for Vectibix (panitumumab), an anti-EGFR monoclonal antibody drug developed by Amgen, a drug company based in Thousand Oaks, Calif.
 
“This collaboration is consistent with our strategy to bring the power of NGS to clinical diagnostics,” said Nick Naclerio, senior vice president of corporate and venture development and general manager of Illumina's Enterprise Informatics business. “With three FDA-cleared NGS products in our portfolio, we intend to complement internal development programs by taking products developed with external partners through the FDA submission process. Amgen is a key partner given their leadership in therapeutic development and strong track record in commercializing novel products.”
 
“NGS provides an advantage over traditional technologies that typically detect only one or a few variants,” added Dr. Rick Klausner, chief medical officer and acting general manager of Illumina’s oncology business. “Multigene NGS panels provide a more complete genetic picture of each patient's tumor, which can better inform critical treatment decisions. We see the development of multigene diagnostic tests as a natural evolution to improve cancer care and outcomes.”
 
Vectibix has regulatory clearance in the United States and the European Union for targeting metastatic colorectal cancer that has not responded to chemotherapy.
 
At present, Illumina has just three tests available for the MiSeqDx instrument, which uses the sequencing-by-synthesis method of assaying. There is a universal kit allowing researchers to make their own tests, and two tests for assaying genes connected with cystic fibrosis. MiSeqDx’s November 2013 FDA approval makes it the first NGS platform with that imprimatur. To build on that achievement, market analysts report that the company has eagerly sought partnerships like the new one with Amgen.
 
Using the Illumina platform, the test to be developed could solve a key problem Amgen has with Vectibix: the drug is aimed at less-aggressive forms of the cancer and is restricted for patients who have, or do not know whether they have, KRAS mutations, which are associated with more aggressive cancers and lower survivability. But there is not yet an FDA-approved test to determine KRAS mutation status for potential Vectibix patients.
 
According to a report on GenomeWeb.com, Amgen is also working with Dutch-headquartered QIAGEN to develop a polymerase chain reaction kit to detect KRAS mutations that might affect Vectibix’s usefulness. The financial details of that deal are not being made public.
 
The Illumina test would not only use NGS technology, but would also detect RAS oncogene mutations beyond just those in KRAS.
 
“We believe the NGS platform offers great market potential,” reads a report from Zacks Investment Research, which also says the analysis firm is “optimistic about management’s expansion strategy,” which involves working with diagnostic and therapeutic developers and providers. In January alone, the company announced agreements with both Quest Diagnostics and LabCorp, with Illumina providing equipment and supplies for its partners to develop new lab tests.
 
Under the terms of the Vectibix deal, Illumina will develop the test, which will be validated by Amgen. Then both companies will work to get FDA and European approval, before Illumina commercializes the test.

Absorbing more ‘bad’ cholesterol

Published in Drug Discovery News

THOUSAND OAKS, Calif.—Completing a key step toward filing for regulatory approval of a broadly applicable cholesterol-reducing drug, Amgen has announced promising results from its fifth Phase 3 trial—the RUTHERFORD-2 trial—of evolocumab, a fully human monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver’s ability to remove low-density lipoprotein cholesterol (LDL-C) from the blood.
 
LDL-C is a major risk factor for cardiovascular disease, and more than 71 million Americans have high LDL-C, according to the U.S. Centers for Disease Control and Prevention. Patients who have both high cholesterol and high cardiovascular risk are key target markets for evolocumab.
 
While the trial’s full results will be announced in Washington, D.C., at the American College of Cardiology’s 63rd Annual Scientific Session in late March, Amgen has said that the drug successfully combined with statins and other lipid-lowering drugs to reduce LDL-C, also called “bad” cholesterol, for patients with heterozygous familial hypercholesterolemia.
 
Previous trials have found evolocumab useful for patients with high cholesterol who were not previously getting anti-lipid treatment, as well as those already on statin drugs, and those who cannot tolerate statins, the most common type of anti-cholesterol drug.
 
While statins inhibit an enzyme that controls production of cholesterol in the liver, evolocumab binds to PCSK9, blocking it from binding to LDL receptors on the surface of the liver, according to the company’s description of the drug. That frees up more LDL receptors to remove LDL-C from the blood.
 
According to the company, a total of 13 trials are slated, including testing varying methods of injecting the drug and different frequencies of administration. About 30,000 patients will be involved, including those with cardiovascular disease, hyperlipidemia, coronary atherosclerosis and familial hypercholesterolemia (whether heterozygous or homozygous).
 
Those latter conditions, which are genetic, cause high levels of LDL-C starting at birth, and place patients at high risk for cardiovascular problems early in life. Heterozygous familial hypercholesterolemia affects about one in every 300 to 500 people worldwide, according toWorld Health Organization data.
 
The results so far will be shared with regulators, in hopes of securing approvals in 2014, the company said in a statement to DDNews. The exact timeline depends on results of ongoing trials.
 
Since Jan. 23, Amgen has touted positive top-line results for evolocumab from the Phase 3 GAUSS-2 trial in statin-intolerant patients with high cholesterol, the Phase 3 LAPLACE-2 trial in combination with statins in patients with high cholesterol and the Phase 3 RUTHERFORD-2 trial in patients with heterozygous familial hypercholesterolemia.
 
Of the most recently announced top-line results, Dr. Sean E. Harper, executive vice president of research and development at Amgen, said, “Data from the RUTHERFORD-2 study suggest that evolocumab, when used as an add-on therapy to existing lipid-lowering medications, may offer a new treatment option for patients with heterozygous familial hypercholesterolemia. The RUTHERFORD-2 study is the fifth pivotal LDL-C lowering study in our Phase 3 program. The robust data from these five studies will form the basis of our global filing plan, and we look forward to discussions with regulatory agencies.”