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.”

Press Releases: Beyond politics

Published in the Portland Phoenix

Today’s US media environment might well seem extremely gay-friendly. American mainstream media consumers saw a fair amount of coverage of anti-gay discrimination in Russia in the lead-up to, and during, the Winter Olympics in that country (read more on this topic on page 10); there was relatively little outcry when President Barack Obama selected several gay former Olympians to represent the United States in the audience. Johnny Weir both dressed and behaved flamboyantly on NBC’s nightly figure-skating broadcasts. Heck, even marriage equality gets little more than ho-hum headlines these days as this vital civil-rights issue continues its progress around the country.

But there is still much more to be done, and last weekend, a one-day conference at Colby College in Waterville sought to explore what, and how.

Called “Queering the Media,” the event, put together by members of Colby’s all-inclusive LBGTQ-plus-allies support group The Bridge, appeared to be less about news-media coverage and more about modern culture, as described by organizers Andy Kang and Sonja Hagemeier.

The intent was that “‘queering’ would be a relatively broad and very widely interpreted term,” Kang says. Looking at “how the media portrays or represents, or tries to represent, or fails to represent, people who don’t fit into mainstream culture” is important, he says, because it can help remind consumers of that information that other viewpoints and experiences exist.

This is important in Maine particularly, says Hagemeier, because “a lot of people think of Maine as really isolating, especially for queer people.” She spoke in almost mystical tones about Portland, a place she has heard is “very very queer friendly,” while observing that it is only slowly that “people are getting used to the idea” in other parts of Maine.

Their conversations at the conference, including presentations by students and current and former Colby faculty, as well as noted queer scholar Jack Halberstam, covered athletic environments, video games, and churches’ roles in social-justice efforts. That’s certainly a departure from most coverage of LGBTQ issues in Maine’s mainstream media. In those outlets, Kang says, queerness is not treated culturally. Instead, “all these topics seem much more politically charged.”

That’s a lesson many Maine journalists could take to heart regarding not only gay culture but other aspects of Maine’s shifting demographics. Somali immigrants, for example, are interesting at times other than just when they’re running for political office or being attacked by anti-immigration activists. The same goes for people of other cultures and backgrounds.

>> Farewell This will be my last Press Releases column; managing editor Deirdre Fulton will take over starting next month. I’ll leave you with a few goals to hold the Maine media to in the coming year:

1) Ask candidates for electoral office (at all levels) hard questions about specific issues, rather than allowing the candidates themselves to set the discussion agenda — thereby neatly avoiding any controversial issues or having to actually take positions on important questions of the day.

2) Allow politicians to change their minds. But don’t let them pretend they didn’t, nor that their new position is functionally the same as the old one. People grow, learn, and change. Expecting people to hold the exact same positions and beliefs forever in effect demands that people remain as misguided and unenlightened tomorrow as they were yesterday. But, when public figures change their minds, they should be able to, and asked to, explain why and how that happened.

3) Lastly — and this is to everyone, whether you work in the media or not — remember that government works for us. We own the desks and filing cabinets in City Hall and the State House, and the documents stored in them. We own the computers and the servers in government offices, and the information stored on them. If a government official wishes to keep something secret, she must prove that she is legally allowed to do so. The burden is not on us as the public to force openness on government, but on government — and its (our) workers — to lay themselves and their records open in exchange for the privilege of serving with the public trust.

Never Again Dept.: Learning from FairPoint's disasters

Published in the Portland Phoenix

Two bills before the Maine legislature seek to pry lessons from the hard time FairPoint has had taking over the former Verizon landline operations in Maine since 2009. Both step up government oversight, in hopes of preventing future debacles.

The first, LD 1761, could in fact be called the “FairPoint: Never Again” bill. It reads like an admission that the Public Utilities Commission’s process around the FairPoint-Verizon takeover was a disaster.

It would require state regulators to review all mergers and sales of companies earning more than $50 million a year not just to the standard of “doing no harm” to Maine consumers (incidentally, a standard current PUC chairman Tom Welch admits the FairPoint deal did not meet — a pity he wasn’t on the PUC when the deal was being considered) but rather such a deal must offer a “net benefit” to Mainers.

It would also specifically require regulators to consider any proposed deal’s impact not just on consumers and ratepayers, but also on workers at the company involved, as well as the state’s overall economic-development goals.

The move specifically anticipates the possibility that FairPoint might be looking for a buyer. “The hedge funds that own FairPoint are looking for an exit strategy,” says Matt Schlobohm, executive director of the Maine AFL-CIO. Unions are key proponents of this bill because of its enhanced consideration of the labor force in deals involving utility companies, which are often unionized, as FairPoint is.

If FairPoint does plan to sell — and there is a handful of potential buyers, mainly regional landline companies — “we’re not well prepared to get a good outcome” for Maine, Schlobohm says.

He fears a repeat of the FairPoint deal, in which regulators approved a deal that was questionable at best (see “A Bad Idea Triumphs,” by Jeff Inglis, February 29, 2008), with certain conditions imposed, but then over time waived many of those conditions one by one (such as benchmarks for rolling out higher-speed Internet service to more customers in Maine). 

“Why would the state not want to have more leverage” when dealing with big companies that have outsize impacts on Maine, both as utilities providers and major employers, Schlobohm asks.

The second bill is even more directly aimed at FairPoint itself. This one, LD 1479, could be called the “Oh No You Don’t, FairPoint” bill. It secures legislative oversight, review, and approval of any PUC ruling in response to FairPoint’s recent request for $67 million in support from Maine telecom consumers to subsidize its service to rural Mainers with no other options for phone connectivity. That amount would be paid by raising the Maine Universal Service Fund surcharge on all telecommunications bills (including Mainers who do not use FairPoint’s services) by as much as $5 per line per month. (See “FairPoint Wants Bigger Subsidies, From All Mainers,” by Jeff Inglis, January 3.)

And it comes at a time when FairPoint’s stock price is recovering — largely because of the prospect it may resume issuing dividends. Investors are certainly clamoring for that to happen; dividends were curtailed in the original deal by order of state regulators, and ultimately done away with because the company couldn’t afford them.

“There’s a pattern here,” says Schlobohm. “The company seeks resources . . . they figure out where to get them . . . they’re sent very quickly to Wall Street.”

While he admits this may not be the case now, he observes that “there’s not much trust built” between FairPoint and Mainers.

The union does support the idea of having phone service available to every Maine home, but is not sure that FairPoint’s request is the best or most efficient way to achieve that.