New Science on Sea-Level Rise Is a Call to Immediate Action

The announcement Monday that several key glaciers that form part of the West Antarctic Ice Sheet are in an irreversible cycle of melting, and will raise global sea levels significantly by the end of the century and disastrously over the course of several centuries, was widely reported. As it should have been, given the effects global warming are having, and will continue to have, on life here on Earth.

But none of the coverage I saw included the fact that parts of the Greenland Ice Sheet had entered the same sort of cycle as much as a decade ago. In fact, just one glacier – the Jakobshavn Isbrae – on its own contributed 3 percent of worldwide sea-level rise over the past 10 years.

Back in March, when I was working as a freelance journalist, I interviewed the two scientists whose research is central to yesterday’s announcement, and found them both concerned about what their data were showing.

There is uncertainty about just how quickly these cycles can move. Exposure to ocean currents and warming waters dramatically accelerates calving and melting of glaciers, in part because the water pushes the ice around, whether it is floating or grounded on the sea floor.

As a result of these effects, Jakobshavn, for example, has tripled its speed toward the ocean in 20 years. You might have seen this glacier calve in the 2012 film Chasing Ice: It was the glacier that calved a mile of ice in a single event, a scene spectacular in its power and scary in its import for those of us who live near the ocean.

Eventually, perhaps in about 100 years, Jakobshavn will retreat so far that it will be landlocked and no longer a significant contributor to sea-level rise. But the topography beneath the West Antarctic Ice Sheet glaciers is very different, getting farther and farther below sea level as one moves toward the center of Antarctica, meaning that as the glaciers retreat their exposure to the melting and calving effects of the ocean will only grow. They will only melt faster and faster, until they are entirely gone.

These are only some of the effects of global warming that are already in the pipeline, resulting from emissions we have already released into the atmosphere. Monday’s announcement is a crucial reminder that we must both adapt to the changes that are already inevitable, and step up our efforts to forestall the even more calamitous and rapid changes scientists warn are in store if we fail to reduce our emissions of greenhouse gases.

The world has the tools now to begin reducing carbon emissions, conserving energy, and transitioning to renewable sources of power. We must act to prevent other irreversible cycles from beginning to transform Earth beyond our ability to adapt – or even contemplate.

Making clinical trials more diverse

Published in Drug Discovery News

WASHINGTON, D.C.—Hoping to expand both statistical validity of clinical trials and access to experimental therapies beyond their current confines, major medical-industry players have united to launch a campaign called “I’m In,” encouraging minorities and their doctors to find out about, and participate in, clinical medical-research trials.

 

While encouraging African Americans, Asian Americans, Hispanics and members of other ethnic groups to join medical research, speakers at a March 12 press event announcing the initiative were cognizant of the shadow of the Tuskegee syphilis experiments, an unethical and long-condemned study of the spread of untreated syphilis in African-American men that ran from the 1930s to the 1970s.

 

While Dr. Carlos Cardenas, board chairman of Doctors Hospital at Renaissance in Edinburg, Texas, alluded more vaguely to the idea of “removing any and all stigma that is associated with being part of a clinical trial,” another speaker, Averl Anderson, a breast-cancer survivor and participant in clinical trials, mentioned Tuskegee by name as a reason “people have a lot of mistrust in medical research”—particularly in the African-American community, she said.

 

But they and others representing a range of partners in the new campaign stressed the importance of broadening participation.

 

“These breakthroughs do not happen on their own,” said John Castellani, president and CEO of Pharmaceutical Research and Manufacturers of America, but rather rely “very heavily on volunteer participation in clinical trials.”

 

Years of work by the pharmaceutical industry to increase diversity in trials have not borne the hoped-for fruit: “African Americans, Asian Americans, and Hispanics are still dramatically underrepresented in clinical trials,” he said.

 

As Castellani said, “the future of medicines is going to be aimed more and more at genetically homogeneous populations,” which means drawing more from minority populations to properly test drugs—especially those aimed at diseases those populations suffer from disproportionately.

 

For example, prostate cancer is twice as fatal for African Americans as Caucasians, according to material distributed in advance of the campaign kickoff—and yet only 4 percent of prostate-cancer clinical trial participants are African American. Cancer is the top cause of death for Asian Americans, but just 2.8 percent of cancer trials patients are Asian American. And despite the higher prevalence of diabetes in the Hispanic population, only 1 percent of all trial members are Hispanic.

 

Based on early glimpses, the campaign is centering on personal connections to family members and the wider community of each minority group. A video promoting the effort included lines like “It’s not enough to wait for someone else to act” and “We all have a responsibility to each other and future generations.”

 

Gary Puckrein, president and CEO of the National Minority Quality Forum, noted that by 2020, more than half of Americans will be members of groups now called “minorities,” leading him to argue that “underrepresentation of minorities affects everyone.”

 

He said this is a campaign to help test “medicines for a biodiverse America.”

 

Cardenas offered an example: When he started practicing medicine, there was just one medication for hypertension; he noticed, though, that it didn’t work the same in people with Hispanic backgrounds as it did in those with non-Hispanic heritage.

 

“How are we to know how our patients will respond to these medications?” he asked. “It’s something we should not leave to chance.”

 

Anderson, for her part, said she is a five-year breast-cancer survivor. She was diagnosed in 2009 with stage three, triple-negative cancer, “a very aggressive form of breast cancer that’s common in African-American women.” Her doctor suggested she participate in a trial, which she credits with her survival.

 

That’s another key element beyond encouraging individuals to participate, said Dr. Ho Luong Tran, founding president and CEO of the National Council of Asian Pacific Islander Physicians.

 

“As physicians we must recognize our role as trusted healthcare providers,” she said. Doctors “owe it” to their patients to “share all possibilities” for treatment, including clinical trials. She said more than two-thirds of Americans report being likely to join a clinical trial if their doctor suggests it, but only 22 percent of people say they have had such a conversation.

 

Citing statistics that 38 percent of Hispanics, 36 percent of Asian Americans, 33 percent of African Americans and 42 percent of non-Hispanic whites say doctors have the greatest impact and the greatest responsibility to talk about trials and research, Tran called on her fellow doctors to learn about, support and encourage their patients to join trials. “If we don’t talk to them about clinical research, few others will,” she said.

 

Puckrein said the website for I’m In, at www.JoinImIn.org has options to register as a member of the public, an interested doctor, and even as a trial researcher, to allow all three groups to connect with each other more efficiently.

Merck HIV therapies make big news at CROI

Published in Drug Discovery News

NEW YORK—Two separate HIV therapies manufactured by Merck, one new and the other a groundbreaking favorite from the past, had big announcements at the 21st Conference on Retroviruses and Opportunistic Infections in early March.

 

It was just a peek at the newcomer, doravirine (MK-1439), looking at data from the first 24 weeks of the first part of a two-segment 96-week trial comparing doravirine to the current standard of care, efavirenz (Bristol-Myers Squibb’s Sustiva).

 

“This study is really the first data we have,” apart from a very small, very short monotherapy study, said Dr. Hedy Teppler, executive director, infectious diseases at Merck Clinical Research, who was also an investigator on the trial.

 

This was a Phase 2 trial (Phase 3 will come later in 2014), in which a range of once-daily doses, 25 milligrams, 50 mg, 100 mg and 200 mg, were used in combination with once-daily doses of emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences’ Truvada.

 

“It certainly performed at least as well as efavirenz,” she tells DDNews. Merck is hoping doravirine will be better in terms of both tolerability and potency that existing drugs, and with less central nervous system toxicity.

 

“Each dose compared well,” according to Teppler—in fact, the data didn’t distinguish one dosage as being more effective than the others. Additional information, though, led to the choice of 100 milligrams to be the dose for the remainder of the 96-week trial and other further studies.

 

Teppler says those factors included providing a reasonable dosage level to discover potential negative drug interactions, and to explore the drug’s overall usefulness.

 

“Choosing the 100-milligram dose should protect against needing to do any dosage adjustment,” Teppler says.

 

For those not candidates for efavirenz (such as women of child-bearing age or people with central nervous system issues), another study offers hope. Merck’s drug Isentress (raltegravir), the first integrase inhibitor approved by the FDA (in 2007), featured in a new study by the AIDS Clinical Trials Group. It compared Isentress given twice daily against atazanavir (Bristol-Myers Squibb’s Reyataz) and darunavir (Tibotec’s Prezista), both given once daily. (All patients also got Truvada daily.)

 

While Merck itself had looked at Isentress versus efavirenz, and found positive results, the ACTG “felt there was a need to look at options in patients who were not candidates for efavarinz,” said Randi Leavitt, senior director, clinical research, global clinical development—infectious disease at Merck, such as women of childbearing age or people with central nervous system issues.

 

The 96-week ACTG study (ACTG 5257) looked at 1,800 treatment-naive patients, a quarter of whom were women, 34 percent non-Hispanic white, 42 percent non-Hispanic black and 22 percent Hispanic.

 

The study found encouraging news for Merck, Leavitt tells DDNews. First, “all three regimens were basically equivalent with regard to efficacy.” But when combining that result with tolerability, “raltegravir was superior to the other two regimens.”

 

And while Isentress has been criticized for being a twice-daily medicine up against once-daily competitors, the results showed that “if the drugs are well tolerated, people will be compliant with a twice-a-day regimen,” Leavitt said.

 

Nevertheless, the company is working on a reformulation to make a once-daily 1,200-mg dose available. That follows on the 2011 report of the failure of tests of an 800-mg daily dose; Leavitt said those results “provided a lot of information” that have improved expectations for the new formulation.

Smash and grab

Published in Drug Discovery News

LA JOLLA, Calif.—Scripps Research Institute scientists have devised two highly specific methods to create new drugs, one that flings a single atom as a wrecking ball and another that can find therapy targets in tiny folds of microRNA.

 

A paper published in Nature in March describes research by Scripps chemistry professor Jin-Quan Yu that builds on his earlier groundbreaking development of using a weak chemical bond in molecule frameworks previously thought to be an obstacle, instead turning it into a powerful advantage when building drug compounds.

 

To attach function groups to chemical frameworks, a C-H bond must be broken—and it must be a specific, and possibly different, one for each potential intended attachment option.

 

“The best way to make a molecule is to replace a C-H bond directly,” Yu tells DDNews.

 

Some C-H bonds, though, don’t react, and are far away from attachment points of potential catalysts, rendering them difficult to break. With previous methods, “you cannot make certain types of molecules,” Yu says.

 

Yu’s insight, which he has been developing since 2002 at the University of Cambridge, was that he could install nitrile groups—weak connections that were dismissed in the past as hurting the structure of a framework—and use that weakness to facilitate the swinging of a catalyst across the molecular distance to a remote C-H bond, allowing it to be broken.

 

At that point, just as with other broken C-H bonds, functional groups that are building blocks for drugs can be attached, Yu said.

 

He originally published about the technique for what is called “meta” C-H activation inNature in 2012; the most recent paper has both simplified the process and allowed it to be applied more specifically to targeted C-H bonds.

 

“The key is to tune the shape of the template to create a subtle bias towards the targeted carbon hydrogen bond,” Yu said in Scripps’s announcement of the paper. “At the same time the template’s movement towards the target site has to be exploited effectively by a super-reactive catalyst.”

 

The chemical reagent involved will be available through Bristol-Myers Squibb’s catalog for order by laboratories, so that other researchers may use it in their own work, including targeting compounds common in drug discovery, such as tetrahydroquinoline, benzooxazines, anilines, benzylamines, 2-phenylpyrrolidines and 2-phenylpiperidines. “All these are commonly used in medicinal chemistry either as final drug compounds or intermediate compounds from which the final compounds are made,” Yu notes.

 

And in the future, he expects to further refine the technique so that the nitrile groups can be used catalytically, rather than needing to be installed and later removed.

 

The other approach, developed by Matthew Disney at the Scripps Florida campus, also inverts a standard method of searching for binding opportunities, this time in microRNA folds. Where previously researchers had to take RNA structures and do high-throughput screenings to find binding opportunities, Disney has built a database of potential types of bonds between RNAs and small-molecule function groups.

 

Then, by comparing given RNA sequences—not structures—to the database, Disney’s method can pinpoint possible opportunities. Only then does attention turn to the structures themselves, he tells DDNews: “Once we identify these interacting partners, could we find them … and drug it?”

 

Every disease has a relation to RNA, he said, because proteins play key roles in the process.

 

“If there’s some toxic protein … we can potentially target the RNA that makes that protein,” Disney says. (Alternately, if a disease causes too little of a protein to be produced, his technique can boost production.)

 

As a test case, and proof of concept, Disney and his team identified a druggable target—and its corresponding drug—in MiR-96 microRNA, which is believed to delay cell death by obstructing apoptosis, a natural cell-death process that begins when cells begin to grow in ways that are otherwise uncontrollable.

 

“People think that RNA can’t be drugged with a small molecule,” Disney says, but his approach proves that belief wrong. And it offers the prospect of very tightly targeting cells, in a way much narrower than the broad targeting approach taken today, where non-disease-related cells are also affected by therapies.

 

Next, Disney will go after diseases without current cures, such as Ebola, as well as orphan diseases that may need therapeutic-research attention.

 

While resistance to microRNA-targeting drugs is possible, Disney said his approach would help respond: “If resistance were to happen, and the RNA structure were to change,” then they could go back to the database and find binding matches for the new structure, he says.

Pharmacyclics: First drug gets rolling

Published in Drug Discovery News

SUNNYVALE, Calif.—Building quickly on the November 2013 approval of its first drug to market, Pharmacyclics has already achieved accelerated approval for that drug, Imbruvica (ibrutinib), in a second disease, with future plans for additional diseases.

 

The first approval came, under Breakthrough Therapy Designation, in mantle-cell lymphoma (MCL) for patients with one prior treatment; that was followed in February by approval for patients with one prior treatment in chronic lymphocytic leukemia (CLL), which the company’s chief medical officer, Jesse McGreivy, described as “a slow-growing blood cancer of the white blood cells” that is “the most common form of leukemia in the Western world.”

 

Company- and third-party-sponsored clinical trials continue in several other leukemias. In February, Imbruvica, which targets Bruton’s tyrosine kinase (BTK), a part of the B-cell receptor signal system, was added to the National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology for relapsed/refractory MCL and relapsed/refractory CLL, as well as Waldenstrom’s macroglobulinemia (which currently has no drug treatment).

 

Reuters reported in February that RBC Capital Markets analyst Michael Yee predicted Imbruvica’s eventual annual global sales could reach $5 billion. McGreivy said there are 16,000 patients diagnosed with CLL every year in the U.S., and that more than 40,000 of the current 115,000 CLL patients have had a first therapy.

 

 

The potential market strength for the drug is further suggested by the fact that in December 2011 Janssen Pharmaceuticals, owned by Johnson & Johnson, agreed to pay 60 percent of drug-development costs and milestone payments, for a total of up to $975 million, in exchange for half of the drug’s profits.

 

Janssen is pursuing regulatory approval in more than 50 countries, Pharmacyclics CEO Robert Duggan said in a conference call announcing the CLL approval. Janssen is also helping significantly with sales, Paula Boultbee, Pharmacyclics’s executive vice president of sales and marketing, said in that call. She said the MCL approval kicked off a “strong launch” that was bolstered by several programs to ensure affordability of the drug—including a 30-day free supply for patients whose insurance companies take longer than five days to decide about coverage, and help limiting monthly out-of-pocket expenses for Imbruvica to $25 for qualifying patients. The average age of CLL patients is 72, according to company documents.

 

Imbruvica posted net product revenue of $13.6 million in the six weeks between its November 2013 approval and the close of the fourth quarter, according to Pharmacyclics’s most recent financial briefing.

 

The company’s net revenue for 2013 was $260.2 million, up 58 percent from $164.7 million in 2012. The remainder of the 2013 revenue was from the Janssen funding agreement, under which the recent CLL approval triggers a $60 million milestone payment.

 

A Leerink Partners analysis suggested that for the first quarter of 2014, Imbruvica sales could reach $50 million.

 

The rapid approvals for Imbruvica were supported by BioClinica, a Pennsylvania-based vendor of information-technology tools supporting clinical trials, including patient randomization, data collection and validation, and online analysis.

 

BioClinica works with the world’s biggest pharmaceutical manufacturers and tiny ones too, and touts its experience. “We as a vendor have worked on more clinical trials than most pharmaceutical companies,” Peter Benton, executive vice president and president of the eClinical Solutions division at BioClinica, tells DDNews.

 

Its systems allow efficient management of the enormous quantities of information generated by trials (“I’ve been in the industry long enough to remember tractor-trailers …  lined up waiting to deliver boxes and boxes of information on paper,” Benton said), and help vet and clean the data so it is ready for rapid processing by the FDA.

 

The company continues to expand by merger and acquisition to fill “white space between our current products,” Benton said. And in mid-March, BioClinica did it again, merging withCCBR-SYNARC. Both companies are owned primarily by the equity firms Water Street Healthcare Partners, and JLL Partners, and their combined services will support the entire drug-development spectrum, a merger-announcement statement said. The merged companies’ chairman will be Jeffrey McMullen, a longtime industry executive who in 2012 serves as chairman of the Association of Clinical Research Organizations.