Category Archives: Drug discovery

Drug discovery

Patent database of 15 million chemical structures goes public

Posted on by
Reply

The internet’s wealth of free chemistry data just got significantly larger. Today, the European Bioinformatics Institute (EBI) has launched a website — www.surechembl.org — that allows anyone to search through 15 million chemical structures, extracted automatically by data-mining software from world patents.

The initiative makes public a 4-terabyte database that until now had been sold on a commercial basis by a software firm, SureChem, which is folding. SureChem has agreed to transfer its information over to the EBI — and to allow the institute to use its software to continue extracting data from patents.

“It is the first time a world patent chemistry collection has been made publicly available, marking a significant advance in open data for use in drug discovery,” says a statement from Digital Science — the company that owned SureChem, and which itself is owned by Macmillan Publishers, the parent company of Nature Publishing Group.

Under the agreement, Digital Science retains use of the SureChem software; the company is being wound up because Macmillan wants to focus on serving researchers, not commercial clients such as drug firms, says SureChem’s co-founder, Nicko Goncharoff.

“We are delighted to take on the stewardship of this resource,” says John Overington, head of computational chemical biology at the EBI, which is part of the European Molecular Biology Laboratory in Hinxton, UK. “Scientists are accustomed to doing literature searches, but the patent literature is often where the real gems lie — especially in translational science,” he adds. Published papers lag the patent literature by about two years, he points out.

Overington says that the EBI plans to interlock information on chemical compounds from different public resources. For example, a search on a compound such as Pfizer’s Viagra (sildenafil) will reveal its presence in patents (from SureChemBL), as well as its interactions with potential protein drug targets (from databases such as the EBI’s ChemBL, which catalogues experiments done on compounds).

Later, Overington hopes to apply SureChem software to extract structures mentioned in research papers, starting with open-access papers held in repositories such as Europe PubMed Central. But, he adds, reconstruction of chemical data from papers is harder, because structures are often not named or pictured explicitly, but only alluded to as variants on a common molecular skeleton.

Historically, chemists have not had a wealth of free online data, and have been used to paying to get information from private databases. SureChem released data on 10 million molecules into the public database PubChem last year, but the information was restricted (as the information on links to patents could only downloaded one molecule at a time). But the web’s resources of searchable public chemical data are fast expanding. “I think it’s a really exciting time for chemistry,” Overington says.

Researchers push for more funding as dementia cases rise

Posted on by
Reply

The number of people living with dementia around the world is now estimated at 44 million, or up 22% from three years ago, according to a report released today by Alzheimer’s Disease International (ADI), a federation of Alzheimer’s associations around the world.

The increase on the ADI’s previous finding is due at least in part to improved reporting of dementia prevalence in China and sub-Saharan Africa. And as people live longer, cases of dementia — a catch-all term describing the loss of memory, mental agility and understanding owing to neurodegenerative diseases such as Alzheimer’s — will rise to 76 million by 2030 and to 136 million by 2050, the ADI report says. “The current burden and future impact of the dementia epidemic has been underestimated,” it concludes.

The report ratchets up the pressure on funders to invest more into tackling dementia ahead of an 11 December summit in London, at which the World Health Organization and ministers from the G8 (Group of Eight) countries will discuss a global action plan on the condition.

“This is a once-in-a-generation opportunity to turn the tide on dementia,” Doug Brown, director of research and development at the Alzheimer’s Society, a charity based in London, told reporters at a briefing yesterday. “We need as much investment in dementia research as we have in cancer,” he said.

Indeed, despite well-publicized political commitments — the United Kingdom’s prime minister David Cameron launched a ‘dementia challenge’ in March 2012, and the US government set out plans for extra Alzheimer’s funding in May 2012 — levels of funding remain low.

In the United Kingdom, for example, dementia costs the economy £23 billion a year (though mostly not in front-line medical expenses), the Alzheimer’s Society estimates — which is twice the burden of cancer. But public research funding only amounts to some £60 million a year, and that is barely one-eighth of what is spent on cancer research. The problem is similar around the world, Brown says.

Nick Fox, a neurologist who heads the Dementia Research Centre at University College London, says, more conservatively, that he hopes the G8 will double dementia funding in the next five years.

Drugs designed to fight Alzheimer’s disease have proved disappointing in clinical trials so far. But, says Fox, “some of the trials have been like trying chemotherapy for cancer when the patient is already in a care hospice,” given that Alzheimer’s starts to attack the brain up to a decade before symptoms such as memory loss appear.

In a new approach, at least four clinical trials are now planning to treat people who have not yet developed Alzheimer’s symptoms. One is a five-year trial of an antibody, crenezumab, which binds to fragments of neuron-damaging amyloid-β. The drug will be tested in people who carry a rare genetic mutation that makes them certain to get the disease. Another, the Dominantly Inherited Alzheimer’s Network study, will enrol patients with a possible familial risk for Alzheimer’s; a third, by companies Takeda (based in Osaka, Japan) and Zinfandel Pharmaceuticals (based on Durham, North Carolina), hopes to test an experimental drug in people whose genetic makeup suggests elevated risk of Alzheimer’s; and a fourth, known as the A4 study, will treat people who show biomarker evidence of amyloid plaques in positron-emission tomography.

The ADI report adds that better care and timely diagnoses are important, too. And dementia is not just a disease of the well-off: though cases are concentrated in the richest and most demographically aged countries, 63% of people with dementia live in low- and middle-income countries where there is limited access to social services and support.

Drug industry can profit from clinical-trial data openness, say leading regulators

Posted on by
Reply

The drug industry’s opposition to greater access to clinical trial data is misplaced, four senior figures in the European Medicines Agency (EMA) said today.

The agency is preparing to vastly expand the amount of information it makes available to researchers, and is close to finalizing a policy on making public data submitted to it by drug companies applying for licences for new medicines. Some elements of the pharmaceutical industry have fought back, complaining that this will release confidential data crucial to its interests and harm investment in the development of new drugs (see ‘Secrets of trial data revealed‘).

But writing today in the New England Journal of Medicine, an EMA team says that putting clinical trial data in the public domain will make it more cost-effective to develop new medicines — for example by making sure one company does not run down a blind alley already mapped by another and by providing more information that companies can use to prove the superiority of their treatments over rivals’ drugs.

“It is ironic that the organisations that most resist wider access to data are the ones that stand to benefit so much from greater transparency,” write the EMA experts, who include senior medical officer Hans-Georg Eichler and executive director Guido Rasi. Despite their roles in EMA, the authors wrote in a personal capacity.

They add: “Contrary to industry fears, we argue that access to full — though appropriate deidentified — data sets from clinical trials will benefit the research-based biopharmaceutical industry.”

In another article published alongside the piece by Eichler and his colleagues, Michelle Mello, a health-policy researcher at the Harvard School of Public Health in Boston, Massachusetts, and her colleagues set out a set of principles by which data can be safely and usefully shared, down to the level of information from individual patients.

“As in other areas of health care, the push for greater transparency in the area of clinical trial data appears inexorable,” they write. “The question is not whether, but how, these data should be broadly shared.”

Initiative gets $1.3 million to verify findings of 50 high-profile cancer papers

Posted on by
Reply

One of the major concerns in biomedical research today is that many basic findings cannot be easily replicated by other labs. Might the literature be stuffed with unrepeatable results that were not sufficiently checked out before publication? Such doubts have increased in the past year, especially after scientists at Amgen and Bayer reported that they had been unable to reproduce the vast majority of ‘landmark’ papers describing promising approaches to treat disease.

How to raise standards? One answer has been to argue for more independent verification — but agencies are not sure how to fund such work, as it lacks the excitement of generating novel results.

Now a project set up expressly to replicate important research results has secured funding to check 50 high-profile studies, it announced today.

The Reproducibility Initiative, co-founded by former geneticist Elizabeth Iorns, says it has been awarded US$1.3 million from the Laura and John Arnold Foundation to validate 50 of the highest-impact cancer findings published between 2010 and 2012. They include 27 papers published in Nature, says Iorns, along with nine three studies in Cell, three in Science and others from well-recognized journals such as Proceedings of the National Academy of Sciences, Cancer Cell and Nature Medicine. Update (29 October): a list of the papers involved has been posted at the Open Science Framework, here.

“The lack of reproducibility in cancer studies is a major obstacle in the development of viable therapies to cure cancer,” Iorns stated in a press release announcing the move. “The funding will be instrumental in not only verifying cancer studies, but also helping to institutionalize scientific replication.”

The work will be carried out through Science Exchange, a commercial online portal that matches scientists with experimental service providers, which Iorns co-founded. She says that independent scientists will tell authors when they are trying to replicate their work, and will ask them to check the planned methods and request specific materials. The study results will be published piecemeal in PLoS ONE; Iorns expects that they will all be done by September 2014.

When Nature last wrote about whether federal agencies such as the US National Institutes of Health might require independent validation of studies, not everyone was happy with the idea. “It is unbelievably difficult to reproduce cutting-edge science,” warned Peter Sorger, a systems biologist at Harvard Medical School in Boston, Massachusetts.

But William Gunn, co-director of the Reproducibility Initiative, said in the press release today: “This project is key to solving an issue that has plagued scientific research for years.”

The Arnold Foundation, based in Houston, Texas, has a history of supporting efforts for open science and research integrity. Earlier this year it gave away $5.25 million to help establish the Center for Open Science, based in Charlottesville, Virginia, which hopes to encourage the openness, integrity and reproducibility of science research. With the funding today, the Reproducibility Initiative is also announcing its collaboration with the similarly named Reproducibility Project, a crowd-sourced effort by scientists to reproduce many published studies in psychological research (see ‘Replication studies: Bad copy’). The Center for Open Science will administer the funding for the project.

Standard vaccines can offer protection against H5N1 pandemic flu

Posted on by
Reply

Scientists may be able to protect humans from avian influenza viruses — before they have even evolved to spread among people.

An experimental flu vaccine designed for a bird-specific H5N1 influenza virus can protect humans from a lab-made H5N1 strain engineered to pass among mammals. The finding is published today in the Journal of Clinical Investigation.

The vaccine was made the same way as seasonal flu shots. But it was tested on a synthetic H5N1 flu, tweaked to

Controversial avian influenza work yields insight into combating looming viruses. EL ALVI/FLICKR

Controversial avian influenza work yields insight into combating looming viruses.
EL ALVI/FLICKR

spread among ferrets, a model of human infection. Doing any research of this sort has been dogged by heated debate and self-imposed moratoriums.

“The transmissible viruses are very scary because H5N1 has a very high mortality rate,” says lead author James Crowe, of Vanderbilt University in Nashville, Tennessee. But he says that the study justifies creating such dangerous pathogens in lab. “Our paper shows that there is a very clear mechanism for conventional vaccines to kill these things.”

Crowe and his colleagues took the blood of four patients given the experimental vaccine, and singled out the antibodies that could attack H5N1 viruses. They next wanted to test whether these antibodies could protect against the synthetic H5N1 virus — scientist’s best estimation of what a potentially pandemic virus may look like.

But scientists had enacted a voluntary moratorium on working with the highly pathogenic strains out of fear that they could get out of the lab or be used as a weapon.

To get around this, the researchers used DNA sequences from the synthetic virus to create pseudo-versions that would not cause disease. They found that antibodies from the patients’ blood could defeat the faux transmissible flu by binding between mutations that allow it to spread among mammals.

Richard Webby, a flu expert at St Jude Children’s Research Hospital in Memphis, Tennessee, says that the finding confirms that vaccines based on the bird virus can still be useful against strains that become more infectious. “Those transmission changes didn’t really seem to affect the protection afforded by the vaccines,” he explains. Webby says that the approach could guide vaccine development for other looming avian flu viruses, such as H7N9.

But Simon Wain-Hobson, chair of the Foundation for Vaccine Research in Washington DC, is less convinced that the synthetic virus will predict exactly how a real pandemic H5N1 will behave. Moreover, he says that the artificial virus did not lead to a better vaccine, which some scientists have claimed is the point of doing research with human-transmissible viruses.

Pharma industry moves towards greater openness

Posted on by
Reply

The pharmaceutical industry has signalled its willingness to open up the vast reservoirs of research data held by its companies this week. But campaigners and researchers pushing for more access to clinical trial data say the moves are little and late.

In a statement released yesterday, two of the world’s leading trade bodies said they would “dramatically increase the amount of information available to researchers, patients, and members of the public”.

Europe’s trade body, the European Federation of Pharmaceutical Industries and Associations (EFPIA) and its north American equivalent the Pharmaceutical Research and Manufacturers of America (PhRMA) said they would make information on trials down to patient level available to researchers. They also pledged to make available the detailed ‘clinical study reports’ which some scientists have been demanding.

Medical research is in a critical period at the moment, with an increasingly vocal group of doctors and scientists demanding greater access to drug company data. These campaigners say that access to these data is vital to prevent the industry burying results that are unfavourable to their products, as has happened in past scandals. Some want drug companies to put all their data on clinical trials into the public domain, while others think researchers should be able to request information from trials that could be released to them after they have been vetted by an independent panel.

This call has been heeded by some bodies, notably the European Medicines Agency, a regulator that is trying to make more information available (see: Drug-company data vaults to be opened). But some businesses have resisted, with two companies suing the agency to prevent release of some of their data.

In response to the move from PhRMA and EFPIA, campaigners accused the industry of not going far enough. Carl Heneghan, director of the Centre for Evidence Based Medicine at the University of Oxford a founder of the AllTrials campaign group pushing for greater openness in clinical trials, said the industry announcement was “clouded in caveats” which could allow a company to refuse a request for information if they thought it was not in their interest to release it.

“In terms of the principles for responsible clinical trial data sharing, outlined by the EFPIA and PhRMA these are to be broadly welcomed,” said Heneghan in a statement. “Yet, there are many details that need to be fleshed out to ensure this is little more than just window dressing.”

But in his own statement, Christopher Viehbacher, president of EFPIA and the CEO of Sanofi, said “Companies routinely publish their clinical research, collaborate with academic researchers, and share clinical trial information on public websites. “By endorsing the Principles, biopharmaceutical companies commit to enhance these efforts.”

NIH retires most research chimpanzees

Posted on by
Reply
Chimp2

{credit}Flickr/William Warby{/credit}

The US National Institutes of Health (NIH) announced today that it will retire to sanctuary nearly all of its research chimpanzees — about 310 animals — leaving a rump colony of up to 50 animals available to researchers who can clear high ethical and regulatory hurdles for using them.

The announcement marks the end of a protracted process, kicked off by a landmark Institute of Medicine report, during which NIH-funded chimpanzee research has come under increasing scrutiny. Separately, the US Fish and Wildlife Service last week said it would declare captive chimps endangered, which also would make the animals tougher to access for biomedical research. The United States is the only major country that still funds invasive chimpanzee research.

Francis Collins, the NIH director, called today’s decision a “real watershed”. “I am confident that greatly reducing their use in biomedical research is scientifically sound and the right thing to do,” he said. The decision is outlined in greater detail here.

The NIH said that it would accept all of the recommendations made by an agency working group in January for disposition of the 310 chimpanzees that it now plans to retire, with one exception: in defining appropriate housing going forward, the working group had recommended 1,000 square feet (93 square metres) of space per animal.

“We did not feel there was adequate scientific evidence” to support that requirement, Collins said. He added that the NIH would consult experts and do further review before determining the space allotment that it will require per animal. Under current rules, lab animals can be confined in as little as 25 square feet (2.3 square metres) of space.

The NIH will not breed any of the 50 remaining research animals and will reassess the need for that rump colony in five years, Collins said.

The physical placement of the retiring animals, and which ones to use in the residual research colony, remains to be worked out by the agency over the coming months and years. Chimp Haven in Louisiana, the only existing federal sanctuary, is near capacity, although it is undertaking a private fundraising campaign to allow expansion.

The problem of supporting the retired animals in the future is compounded by a US$30-million cap on their support by the NIH that was written into law in the Chimp Act of 2000. That spending has now reached $29.2 million, says Kathy Hudson, NIH deputy director for science, outreach and policy. She says that the agency is working with Congress to amend the act to allow for future funding, and anticipates needing a new $3 million in 2014.

Collins said that six of nine existing invasive experiments supported by the agency will be ended. He would not specify which ones, ahead of notifying the scientists involved. Directors of the NIH-supported chimpanzee research centres were not immediately available for comment.

Animal-rights groups celebrated most aspects of the announcement. The Humane Society of the United States called it “monumental”. “Nearly all current NIH-funded invasive research will be phased out…and the barrier to new invasive research will be very high,” says John Pippin, director of medical affairs for the animal advocacy group Physicians Committee for Responsible Medicine in Washington DC.

However, chimp research opponents decried the NIH’s decision not to immediately adopt the requirement of 1,000 square feet of space per animal. Stacy Lopresti-Goodman, a psychologist at Marymount University in Arlington, Virginia, works with chimpanzees at the Save the Chimps sanctuary in Florida. She says that groups of 12–25 chimpanzees live there, with an island of 3–5 acres for each group.  She says that, even if the NIH abides by the new recommendation, the 50 chimpanzees in the NIH’s scaled-down research colony would be confined to just over 1 acre of space. “It is frankly outrageous that the NIH suggests the conditions for chimpanzees locked in laboratories are in any way comparable to what they are provided in sanctuaries,” she says.

Lopresti-Goodman was responding to a comment by James Anderson, NIH deputy director for program coordination, planning and strategic initiatives, who described the environments in the research centres and sanctuaries as “not tremendously different”.

NIH funds effort to resurrect abandoned drugs for new uses

Posted on by
Reply

The most visible project of the new translational medicine centre at the US National Institutes of Health (NIH) came a little closer to reality today, with the announcement of nine awards that pair academic scientists with compounds cast off by the pharmaceutical industry.  The aim of the plainly named Discovering New Therapeutic Uses for Existing Molecules programme is to re-employ abandoned drugs for new uses — and in the process, show Congress that NIH’s youngest centre is delivering for the US taxpayer.

The fledgling National Center for Advancing Translational Sciences (NCATS) says that it will oversee the spending of US$12.7 million on the ambitious projects, which aim to produce treatments for ailments including Alzheimer’s disease, schizophrenia, alcoholism and calcified heart valves. As Nature wrote last October, the awardees have their work cut out for them: all the compounds, donated by big pharmaceutical firms, have been shown to be safe in humans but were discarded for lack of effectiveness against their original targets or for business reasons.

The drugs for the just-announced projects come from AstraZeneca, Eli Lilly, Janssen Research and Development, Pfizer and Sanofi.

NCATS director Christopher Austin (profiled recently in Nature) called the announcement of the awards a “major milestone”. The compounds involved may not have made for “the best business case”, says Austin, who once worked in drug discovery at Merck, but “these [new] indications may be fantastic for patients and public health”.

But John La Mattina, Pfizer’s former research chief, suggests that the programme may not produce many new applications for abandoned drugs.  “I do hope that people can have success in this type of work,” he writes in a Forbes blog post. “But I believe successes are going to be rare.”

This type of drug resurrection effort clearly has appeal beyond US shores; last year, the UK Medical Research Council and AstraZeneca made awards in a similar programme.

US regulator plans to declare research chimps endangered

Posted on by
Reply
chimpanzee

{credit}Flickr: Valentina Storti{/credit}

The US Fish and Wildlife Service (FWS) is planning to categorize all US chimpanzees as an endangered species, a change which, if enacted, may spell the end of invasive chimpanzee research.

This soon-to-be-published proposed FWS rule, which will be open for 60 days of public comment before being finalized, would bring captive chimps — whether in zoos, private homes or research labs — under the protection of the Endangered Species Act, as wild chimps already are.

If the FWS decides to list the captive animals as endangered, then using them for invasive research would require a special permit. To win one, researchers would have to show that any proposed study would promote the conservation of the species.

Jane Goodall, the famous primatologist, called the move “an important step toward saving our closest living relatives from extinction”. She spoke on behalf of a coalition of animal welfare groups, including the Humane Society of the United States, that had petitioned the agency to declare captive chimpanzees endangered.

The coalition noted that populations of wild chimpanzees have fallen more than 65% in the last 30 years, and attributed some of the loss to poaching driven in part by US research. The United States is the only major country that conducts invasive chimpanzee research.

The proposed rule comes as scientists are also awaiting a decision by the National Institutes of Health (NIH) on the future disposition of roughly 360 chimpanzees owned by the agency and now housed at facilities in Texas and New Mexico. In January, an NIH working group advised the agency to retire to sanctuary all but 50 of the animals.  The working group was responding to a report from the US Institute of Medicine late in 2011, which declared most research using chimpanzees scientifically unnecessary.

The Federation of American Societies for Experimental Biology (FASEB), which represents many research scientists, said in a statement today that it is “disappointed” in the FWS decision. The endangered designation, it said, “would make biomedical research using chimpanzees difficult and potentially delayed”.

The FASEB added:  “Chimpanzees are an important model for both ongoing and future research in certain circumstances. [We] believe the status change will negatively affect the health of both humans and great apes.”

First-in-class cancer drug approved to fight melanoma

Posted on by
Reply

The US Food and Drug Administration (FDA) has approved the first cancer drug to inhibit a protein — called MEK — that acts in a pathway that fuels tumour growth. The drug, called Mekinist (trametinib), was approved on 29 May for use in advanced melanomas with specific mutations. Other MEK-targeting drugs are being studied in a wide range of tumours, including lung and thyroid cancers.

The FDA approved Mekinist together with another drug, called Tafinlar (dabrafenib), which targets cancer-driving mutant forms of a protein called BRAF. The agency also approved a medical test for those BRAF mutations. BRAF inhibitors, one of which is already on the market, elicit rapid and dramatic responses, in some cases wiping away nearly all signs of the disease. But the responses are short-lived, and the drugs boost survival by only a few months.

Hopes are high that Mekinist and Tafinlar, both made by GlaxoSmithKline, will eventually be approved for use in combination — and that the combination will lengthen patient survival more than either drug would individually. GlaxoSmithKline says that it will file for FDA approval of that combination in the coming months. Meanwhile, Mekinist will cost US$8,700 per month, and Tafinlar $7,600 per month, wholesale, putting both drugs just shy of the growing ‘$10,000-a-month club’ for cancer drugs.