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.

Physicists are building an NSA-proof internet

Published on GlobalPost

BOSTON — It’s long been the Holy Grail of communications: technology that not only maximizes privacy, but also reveals when a message had been intercepted or copied.

The quest began in antiquity, with encryption and with the humble envelope — which not only kept out prying eyes but also showed if a message had been opened by someone other than its intended recipient.

More recently, Edward Snowden's revelations of spying by the National Security Agency have heightened concerns over electronic privacy, espionage and meddling.

Despite centuries of innovation, today’s methods for secure communication are basically the same — and in some ways are even more vulnerable, given how easy it is to copy, store, and search electronic data.

Scientists say a solution for truly private, tamper-free digital communication is underway, and should be commercially viable within a decade.

For theoretical physicists, the solution has already existed for several decades, but the technology needs refining before it’s available on a mass scale across the internet. Still, the pieces of this ultra-secure, high-speed communications web are beginning to take shape in labs around the world.

The system is based on quantum physics, and more specifically on the concept of “entanglement.”

Entanglement is a topic that even hardened scientists discuss with a degree of wonder. “It’s quite mysterious, in fact,” said Félix Bussières, a senior researcher in the Group of Applied Physics at the University of Geneva in Switzerland.

Physicists have long struggled to come up with metaphors and analogies to describe entanglement, which is so hard to actually wrap the mind around that even Albert Einstein gave up and settled for calling it “spooky.” It involves creating two photons (particles of light) that, while independent of each other and free to travel long distances apart, are still tightly interrelated, almost as if they are not two separate photons but one indivisible photon pair. As photons travel, they spin; each part of the entangled photon pair spins in the exact opposite direction from the other. If something happens that causes either of the pair to change its spin, the other instantaneously changes its spin to compensate.

Entangled photons act like a tripwire for any outside tampering — which is what makes a quantum internet so secure. In other terms, “quantum mechanics tell us that if you look at a quantum state you perturb it,” wrote Thomas Jennewein, an associate professor at theInstitute for Quantum Computing and in the physics and astronomy department of Ontario'sUniversity of Waterloo, in the institute’s 2013 annual report. (If you want to read more on the science, start by looking up the Heisenberg Uncertainty Principle and the Schrödinger’s catthought experiment.)

The good and bad of the quantum internet

So in the ideal case, wiretapping a quantum message system is impossible, Bussières said, because the wiretap will disturb the system, and the disturbance can be detected by the sender and recipient.

“The principle is perfectly secure,” Bussières said. “One can use in principle the quantum properties of light ... to ultimately cipher communication ... in a way that is ... provably unbreakable.”

This now works in the lab. It has even gone commercial: There is a small industry doing what is called quantum-key distribution — using quantum methods to generate encryption keys that are substantially more secure than more conventional ones. But the keys can only be shared across relatively small distances, no more than about 125 miles of optical fiber.

More from GlobalPost: NSA eyes encryption-breaking 'quantum' machine

The challenge is that the technology depends on photons (instead of electrons), and photons attenuate, or lose, their momentum over distance.

It also means that quantum connections are quite slow (about one megabit per second, Bussières said) compared to standard internet communications speeds. That’s why the technology is being used for keys instead of entire messages. And as such, while messages with quantum keys are more secure than others, they can still be monitored and copied for storage and later cracking by hackers or spies.

Quantum-key distribution could be poised for widespread commercialization right away, Bussières said, if technological advances threatened the security of conventional electronic encryption.

“If we want to go beyond these distances” with actual quantum connections, “other technologies are being intensely researched around the world,” he said. It would take several years to develop quantum-enabled devices that are small enough, cheap enough, and efficient enough to be mass-produced and widely used, “but considering the amount of research put in that direction, there is a great chance that it will become a reality,” Bussières said.

For nerds: solving the quantum quandary

To transform quantum communications from a lab project to a commercial application, three major approaches are in development: wavelength optimization, quantum repeaters, and satellite connections.

Scientists say the progress is encouraging, in part because much of the research involves adapting existing, conventional optical-communications gear to quantum uses, rather than inventing all-new equipment.

First, it’s not enough to simply connect photon-entanglement sources and detectors to opposite ends of optical-fiber cables. Because eventually photons attenuate — getting absorbed or scattering away from their detectors — even non-quantum-carrying fibers need help to keep the signal alive across long distances.

Steven Olmschenk, an associate professor of physics at Denison University in Ohio, is working to lengthen the distance entangled photons can travel in optical fiber. While previously he had also been working on quantum repeaters at the Joint Quantum Institute, he and others realized they were researching themselves into a bit of a corner.

Most of the photons used in quantum research so far, he said, are in ultraviolet wavelengths, which attenuate too quickly to be truly useful in fiber-optic transmissions. Internet and telecom companies already use infrared signals in fibers, because they attenuate more slowly.

Olmschenk’s research focuses on taking existing capabilities for UV quantum communications, and adapting them to infrared transmission and reception. It has only been a couple of years, though, and he told GlobalPost that while he is optimistic, he does not yet have any results to report.

If he is successful, he and others will also have to translate into UV the accomplishments of other researchers figuring out how to extend signals in other ways.

Bussières is working to improve quantum repeaters, which combine a photon detector, a quantum memory, and a photon source so that when a quantum signal needs to be transmitted, say 600 miles, that trip can be split by repeaters into shorter segments with less attenuation.

But for distances (or geographic features) too large to handle usefully with optical fiber, there is another option: sending quantum signals by satellite.

Jennewein, of the Institute for Quantum Computing, is on that task. He and his team have set their sights on sending entangled photons to satellites in low Earth orbit, likely somewhere around 300 to 360 miles above the ground. At present, open-air quantum transmissions have been achieved at around 100 miles, using transmitters and receivers that are very precisely aligned. (This gets harder when involving a satellite moving 15,000 miles per hour.)

Jennewein’s current work covers several aspects of the puzzle, including aiming photons accurately at distant receivers that are moving, determining how much attenuation will happen in the atmosphere as it thins at higher altitudes, and improving detection of the weak signals that will arrive.

One crucial challenge has not yet been undertaken: Because quantum sources need to be smaller and more energy-efficient before they are ready to fly in space, nobody has yet sent a quantum signal from a satellite back to Earth.

Other efforts, which would expand bandwidth over those extended distances, are also in the works. "Quantum dots," nanocrystals that conduct electricity, can simplify and even automate the process of emitting photons with particular entanglements on demand, which could help increase transmission rates, as would using light from LEDs instead of lasers. And repeaters capable of handling multiple quantum signals simultaneously would speed things up as well.

But the crucial part is building the connections that can span the world so that people can, it is hoped, finally communicate with complete privacy.