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.

Five Prime steps up search for monoclonal antibodies

Published in Drug Discovery News

SOUTH SAN FRANCISCO, Calif.—Seeking to continue, and accelerate, its work developing new protein therapeutics for cancer and inflammatory diseases, Five Prime Therapeuticshas made an agreement with Adimab of Lebanon, N.H., that will help discover monoclonal antibodies for cancer immunotherapy. Five Prime also recently closed its initial public offering, raising $43 million.

 

Under the terms of the Adimab deal, which marks the first time the companies have worked together, Five Prime will identify potential targets for development as therapeutic candidates and send them to Adimab for discovering and optimizing the corresponding fully human antibodies.

 

Five Prime will then develop and commercialize those antibodies, with Adimab receiving not only payment for each target campaign, but also potential milestone payments and royalties, according to a news release from the company. Specific financial details were not disclosed.

 

“Working with Adimab, we will be generating antibody products to targets of our choosing, and these could become clinical candidates for Five Prime’s proprietary pipeline,” Five Prime Chief Business Officer Aron Knickerbocker told DDNews in an email.

 

Five Prime has “a library of over 5,700 extracellular proteins (ligands and receptors),” Knickerbocker wrote. “We believe these include substantially all medically important protein drug targets, including many proteins not in public domain.”

 

Five Prime can produce “thousands of proteins weekly,” from which it screens “novel protein therapeutics and antibody targets,” Knickerbocker wrote.

 

From there, Adimab will use its library of fully human whole immunoglobulin-G molecules (IgCs), and its technology that rapidly identifies appropriate matches, returning results to Five Prime. While Knickerbocker declined to talk about project timelines, Adimab’s website says its usual turnaround from target receipt to return of purified, whole IgGs is eight weeks.

 

That includes screening more than 10 billion IgGs from its various libraries; past results have “generated large numbers of fully human IgGs (100s up to 1000s) to all targets screened to date,” Adimab’s website says.

 

“Working with Adimab will allow us to generate fully human monoclonal antibodies to our targets of interest,” said Knickerbocker.

 

The advantages of being able to test with full antibodies are significant. Unlike the more commonly used antigen fragments, whole IgGs are capable of cross-linking receptors, as well as sterically blocking interactions.

 

Less than a month after announcing that agreement, and highlighting its progressing collaboration with British pharma giant GlaxoSmithKline developing FP-1039 (GSK3052230), a fibroblast growth factor ligand trap targeting multiple solid tumors, Five Prime also grossed $43,125,000 in its initial public offering of 3.4 million shares of common stock. The company trades on the NASDAQ exchange, with symbol FPRX.

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.”

Downsizing has major benefits

Published in Drug Discovery News

BRISBANE, Australia—After a decades-long search for a so-called “holy grail” of biochemistry, Australian researchers have announced they have found a way to significantly reduce the size of molecules that have similar bioactivity to large proteins, preserving the proteins’ functions while also making the new molecules far more stable in the body.

 

Scientists at the Institute for Molecular Bioscience at the University of Queensland have proved the concept and method of growing small, stable molecules around key amino acids in complement protein C3a, which helps reduce inflammation and fight disease. By focusing tightly on the bioactive area of the protein, they have reduced the size of the molecule from 77 amino acids to just three, making the product much more suitable for inclusion in medications.

 

C3a, like many proteins, is large and expensive to make, as well as quick to degrade once introduced into the body. But this technique not only makes the molecules cheaper and smaller, it also makes them far less susceptible than the full protein to enzyme breakdown or immunogenicity once in the bloodstream.

 

Prof. David Fairlie, who co-led the research group with Dr. Robert Reid, said the method should be generalizable to other proteins with very different functions. “This technique is not specific to C3a. It relies only on knowing the location of a single amino acid of a binding protein within its receptor protein,” he says. “The trick … is of course to first know the location of an amino acid within the biologically active region of that protein, and then to know what amino acids in the target protein that you wish to bind to.”

 

Making that connection possible involves a very complicated multistep process, which is laid out in an appendix to the journal article announcing the discovery, published in Nature Communications in November under the title “Downsizing a human inflammatory protein to a small molecule with equal potency and functionality.” Involving multiple chemicals, heat, stirring and other techniques to build up and rearrange the amino acids so they will fit with the target protein, the process must not only preserve the amino acids themselves, but also build up a molecular scaffold that mimics the shape of the original protein, to ensure proper binding. The method took about 20 years to perfect, including the last 10 years focusing specifically on C3a as an example, Fairlie notes.

 

The breakthrough makes possible new and more effective medications more specifically targeting proteins in the body. Because the method of making smaller molecules is not specific to C3a, “it is potentially applicable to any protein involved in any disease, and most diseases involve proteins interacting with other proteins or macromolecules,” Fairlie says.

 

The lab will continue to work to improve “small-molecule drugs that target the human complement C3a receptor for use in treating inflammatory and metabolic diseases,” Fairlie says. And the researchers will use the now-proven approach to work with other types of proteins, targeting “a wide range of diseases like viral and parasitic infections, inflammatory diseases such as arthritis, metabolic diseases such as obesity, type 2 diabetes and cardiovascular disease and cancers,” according to Fairlie.

 

Beyond protecting the intellectual property with patent applications, the lab is “interested in discussing license agreements with pharmaceutical and biotechnology companies,” says Mark Ashton, manager for innovation and commercial development at Uniquest, the University of Queensland’s main commercialization company.

 

To that end, the lab has established a partnership with Pfizer, including $2.2 million in funding from the Australian Research Council and another $2.1 million from Pfizer itself, to develop specific new medicines with this technique. This may result in some medications that can be delivered orally using smaller drugs, where “currently there are only large peptide drugs available that need to be administered intravenously,” Ashton said.

Jazz Pharmaceuticals is jamming

Published in Drug Discovery News

DUBLIN—Rapidly expanding its orphan-drug portfolio and planning for $1 billion in revenue in 2014, Irish company Jazz Pharmaceuticals is in the process of acquiring Italian drug firmGentium, and has acquired anti-narcolepsy drug ADX-N05 from Aerial BioPharma, based in North Carolina.

The Gentium acquisition, announced in mid-December, is worth roughly $1 billion, with Jazz making a tender offer of $57 per share to Gentium holders (a 26-percent premium on the volume-weighted average share price over the previous 60 days). Jazz will pay for the deal with a combination of cash on hand, a $500 million incremental term loan from Barclays and the remainder under its existing senior secured credit agreement with Barclays. The company estimates its borrowing costs at 3 to 3.5 percent interest.

The deal will bring into Jazz’s stable a promising drug, Defitelio (defibrotide), which treats severe hepatic veno-occlusive disease (VOD) in children and adults receiving hematopoietic stem cell transplants. In October, Defitelio was approved by European regulators for sale in the European Union, and is protected under orphan-drug exclusivity laws there through 2023.

Hematopoietic stem cell transplantation (HSCT) is more common in Europe than the United States, with 35,200 EU patients in 2013, compared with 19,500 U.S. patients, and 7,600 in the rest of the world. About 10 percent of HSCT patients develop severe VOD, which can involve multiple organ failure; untreated, it has an 80-percent mortality rate within 100 days.

Defitelio is also designated as an orphan drug by the U.S. Food and Drug Administration (FDA); it is not approved yet, but is in Phase 3 clinical trials and has fast-track status for FDA approval pending the results of those trials. There are no other drugs approved in the United States for VOD, according to Jazz disclosure materials.

In addition, Defitelio is being studied to treat graft vs. host disease, which could boost its sales potential significantly, the company anticipates.

Defitelio joins a handful of other orphan drugs in Jazz’s portfolio, addressing hematology and oncology, pain, psychiatric needs and sleep disorders. The company’s major earner in that last category was Xyrem (sodium oxybate), which brought in $154 million of the $230 million the company grossed in the third quarter of 2013. While the results of previous acquisitions and expansions mean Xyrem’s share of overall company revenue is dropping, the drug’s earning power remains on the rise. The Q3 total was 15 percent higher than the previous quarter, and 150 percent higher than the same quarter a year earlier.

In the wake of the deal, Bloomberg News reported that Jazz could be a very attractive acquisition target, with high growth and expanding potential. An advisory from Leerink Swann Research analyst Jason Gerberry said the opportunity “appears reasonably attractive, and potentially durable,” with an initial market size of up to $100 million.

A mid-January acquisition, ADX-N05, will expand Jazz’s presence in the sleep sector. Carrying worldwide development rights (except certain parts of Asia) and patent protection through 2027, the deal cost $125 million in cash, plus up to $272 million in future milestone payments, as well as ongoing royalties to both drug creator Aerial BioPharma and New Jersey-based SK Biopharmaceuticals, which holds the remaining Asian development rights.

The drug treats narcolepsy, which has in the United States about 25,000 patients with inadequate control of their condition; a major growth opportunity will come if ADX-N05 is also approved to treat obstructive sleep apnea, which offers a potential U.S. market of between 150,000 and 275,000. 

At a Jan. 13 presentation at the JP Morgan Healthcare Conference in San Francisco, Jazz chairman and CEO Bruce Cozadd presented slides saying the company expects between $867 million and $877 million in total revenue for 2013, but projects surpassing $1 billion in 2014.

Saving lives with testing

Published in Drug Discovery News

MUNICH, Germany—Seeking to commercialize a genetic diagnostic test that can reduce the incidence of suicide in patients taking antidepressants, Boulder, Colo.-based Sundance Diagnostics has licensed technology from Germany’s Max Planck Institute of Psychiatry.

The financials are not being disclosed by the privately held Sundance, said company CEO Kim Bechthold, though she did say Sundance is taking over patent costs and will pay a sales-based royalty to the Planck Institute. The test will be ready within the next month or two, she said, adding that licensing agreements with commercial lab companies around the country are in the works.

Based on research published in Neuropsychopharmacology in 2011, the test looks at a patient’s full genome for 79 markers of risk of emergent suicidal ideation. Initial research identified those markers, but then the Planck researchers, led by Andreas Menke and Elisabeth Binder, sought insight into the predictive power of those markers.

“When they tested their markers against 500 new patients, they could actually predict about 90 percent correct,” Bechthold says. “For a laboratory test, it’s out of this world.”

There are some limitations on the results, including that the test was only applied to Caucasians and people over the age of 18, though Bechthold admitted “every age of child is being prescribed antidepressants.” She also noted that teens are among the least likely to seek additional help for their depression and are also at risk of not telling their parents what their true thoughts and feelings are.

But the promise is so strong, Bechthold said, that Sundance will work to extend the test results to greater numbers and more diverse populations (including people of Asian and African descent), as well as potentially people under 18. The company will also seek approval from the U.S. Food and Drug Administration, which will allow the company to make claims about the test’s predictive power. Bechthold expects that approval within 18 months.

In the Planck Institute research, people at low risk of emergent suicidal ideation were identified correctly 93 percent of the time, Bechthold said. Those at high risk were identified less successfully, but she said even that division could be very useful, allowing physicians to focus their attention on those patients who are likely to be more at risk.

The market is massive: According to the U.S. Centers for Disease Control and Prevention, 11 percent of Americans age 12 and up are already taking antidepressants, and 9 million new prescriptions are written each year in the United States (as of 2006, so current numbers are likely higher). A further 9 million new prescriptions are written worldwide each year. At $200 to $300 per test, Bechthold said, “the potential profit is $1.8 billion.”

And the test is attractive, because no studies have been able to identify clinical indicators for doctors to detect emergent suicidal ideation induced by antidepressant drugs, leaving them operating in the dark even as they write more and more prescriptions. Rather than putting millions at risk every year—it is estimated that between 6 percent and 13 percent of the population is susceptible to antidepressant-induced emergent suicidal ideation—they can screen patients with a rapid cheek-swab test administered in the office. Results come back from the lab within two days, an important factor since 97 percent of patients who develop this adverse reaction do so within the first 29 days.

“This is a window into something [the doctor] simply can’t guess and has no way of knowing,” Bechthold said.

Adding to the demand for the test may be an additional result of the Planck research. Since 2005, all antidepressant prescriptions in the U.S. have carried a suicide warning, and there is an additional warning targeting patients 25 and under, who have been deemed by the FDA to be at elevated risk as compared to older patients.

National Institute of Mental Health research has shown, however, that there is no age at which risk is higher or lower; the Planck research confirmed that finding in its population, which ranged in age from 18 to 75.

Bechthold said Sundance, which focuses on adverse drug response and genetics, knows that genetic tests are commonplace in treatments for cancers and infectious diseases and is looking forward to bringing the first genetic test into neuropsychiatry. The company will work with Planck on further research in this and other areas.