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Category → Neglected Diseases

J&J Could Score Priority Review Voucher with Bedaquiline NDA

Janssen Research and Development, part of J&J, has asked the FDA to approve bedaquiline, a diarylquinoline to treat multi-drug resistant tuberculosis. If given the green light, bedaquiline would be the first drug with a new mechanism of action to be approved for tuberculosis in over four decades. Janssen points out that the pill would also be the first drug approved for multi-drug resistant TB.

If approved, Johnson & Johnson will score a Priority Review Voucher, an incentive created in 2007 to prompt more R&D in neglected disease. A PRV, given to a company that wins U.S. approval for a new drug for neglected disease, is a coupon good for shaving the review time for another new drug application. The value of that coupon depends on the drug its applied to—in theory, if a drug has lofty sales potential, gaining a few extra months (as we’ve written, it could shorten the FDA’s decision time by anywhere from four to 12 months) could translate into hundreds of millions of dollars.

To date, Novartis has been the only company to be granted a PRV, which it gained through the U.S. approval of the malaria drug Coartem. But that first test of the incentive had some questioning its value, as Novartis cashed in its PRV for a supplemental new drug application for Ilaris, an antibody for auto-inflammatory disorders that brought in just $48 million last year.

So, readers, any thoughts on how J&J might cash in its PRV if granted?


Francis Collins At TEDMED – Repurposing Drugs, Replacing Animal Models, Rocking Out

You know you’re at an interesting conference when the director of the NIH starts off his presentation with a guitar duet, and shares a session with Cookie Monster.

But the organizers of TEDMED made a very deliberate decision in opening this year’s conference with Francis Collins. This is the first year that the gathering of medical luminaries, artists, and design gurus (TED stands for Technology, Entertainment, Design) is taking place in Washington, DC, after moving from San Diego. It marks a philosophical shift for the organization, from TEDMED as idea incubator to TEDMED as inserting itself into the national conversation on health and medicine. What better way to do that then bringing in the head of the biggest biomedical funding agency?

Collins wants to compress the time it takes to get a drug development pipeline, and make the pipeline less leaky. This isn’t news to folks around the pharma blogosphere, including here at the Haystack, Ash at Curious Wavefunction and Derek Lowe, who’ve followed last year’s announcement of NIH’s venture for drug discovery, the National Center for Advancing Translational Sciences.

Folks have expressed some concerns about the concept, and its emphasis on the promise of gene-based drug discovery. But, as Derek noted, the fact of the matter is that everyone in drug discovery wants the things Collins wants, so there’s a measure of goodwill for the venture too.

Collins spent his time on the TEDMED stage emphasizing two things: drug repurposing and developing high-tech cellular solutions to supplement and replace often-imperfect animal models.

On the tech side, Collins showcased the Harvard-based Wyss Institute’s lung-on-a-chip, which combines tissue engineering and electronics to mimic the interface between the lung’s air sacs and capillaries (Science, DOI: 10.1126/science.1188302). He said that technologies like this suggest viable alternatives to animal testing are possible.

When New Scientist

reported on the lung-on-a-chip in 2010, researchers praised it as a step in the right direction, but cautioned that immortalized cell lines, such as those on the chip, don’t neccesarily behave like primary cells from patients. Collins also noted that it might be possible to use such devices with patients’ own cells someday.

On the repurposing side, Collins cited an article on the topic in Nature Reviews Drug Discovery

(DOI: 10.1038/nrd3473), and alluded to lonafarnib (SCH 66336), a farnesyltransferase inhibitor that was originally designed to be part of cancer-treatment cocktails. It didn’t pan out as a cancer drug, Collins said, but now clinical trials are underway to test whether the drug is effective at countering a rare mutation that causes Hutchinson-Guilford progeria, an ailment that leads to rapid aging in children. Collins shared the stage with 15-year-old Sam, a progeria patient.

Francis Collins (right) and Sam. (TEDMED)

To bridge the massive gap between ideas and applications in medicine “we need resources, we need new kinds of partnerships, and we need talent,” he told the audience.

In a conversation with reporters after his talk, Collins provided another repurposing story published last month– bexarotene, a retinoid X receptor agonist intended for lymphoma that was just shown to clear amyloid-beta and reverse cognitive deficits in a mouse model of Alzheimer’s (Science, DOI: 10.1126/science.1217697)

At that chat, I asked Collins how the repurposing effort and his call for talent squares with massive layoffs in industry and flat or declining funding.
“It would help if we had a strong foundation of support,” Collins said. He said his agency’s purchasing power has decreased 20% over the last 8 years.

Another reporter asked what was the main obstacle to getting repurposing become habit. “IP,” Collins said. He told reporters that a model intellectual property sharing agreement with pharmaceutical companies has been drafted. Asked if companies had signed on to it, Collins said “we’re working on it.”

UPDATED 3:30PM 4/12: Here’s the scoop on Cookie Monster, for Muppet devotee Robin:
he spoke later in the session with ultramarathoner Scott Jurek about nutrition.

Using Gene Expression Patterns to Repurpose Drugs

Late last month, researchers from many different fields gathered at the Computer History Museum in Mountain View, California, to discuss the benefits of open science and data sharing. One of the best talks from that event, the Open Science Summit, was delivered by Joel Dudley, the co-founder of NuMedii, a firm that aims to find new indications for medications.

Dudley has repeatedly found new uses for old drugs by picking through public data sets about the gene expression profiles of different diseases. He then looks for medications that are known to reverse those profiles.

Much of the data that Dudley uses comes from the Gene Expression Omnibus, which he regards as a gold mine.

Life Sciences in the Era of Big Data from Open Science Summit on FORA.tv

A full list of videos from the Open Science Summit is also available.

Drugs to Stop the “Brain-Eating Amoeba” N. fowleri

Summer can be hot, and many people cool down by jumping in nearby lakes and rivers. However, that’s also where millions of microbes like to play: as reported by multiple news outlets, the third 2011 US death has now been attributed to what the popular press has dubbed “the brain-eating amoeba.”

This “amoeba,” actually a protist called Naegleria fowleri, has been known to medicine since 1965. It belongs to a completely different biological branch from the true amoebas (I won’t go into all the biological background here, but Jennifer Frazier over at The Artful Amoeba has much more to say). This organism’s M.O. sounds like a cross between kuru (a brain-destroying prion disease)and flesh-eating bacteria. When a victim inhales freshwater containing N. fowleri, the organism attacks nasal membranes, working its way up towards the brain. Infected patients’ symptoms mimic those of encephalitis or meningitis, delaying proper drug treatment, while the protist quite literally consumes their nerve tissues.

Sound gruesome? Well, so are the existing therapies to fight it – the CDC Naegleria fact sheet discloses no current best treatment. The infected often receive amphotericin B, an antifungal known to have toxicity issues, in combination with an antibiotic (minocycline, or azithromycin). These combination therapies may improve the overall infection survival rate, but targets for small-molecule inhibition have been sorely lacking.

One promising biological lead to conquering N. fowleri does exist: the Nfa-1 gene. This gene produces proteins that impact the structure of the protist’s food cups, the organs used to digest tissue. A 2011 study indicated that chlorpromazine, an antipsychotic developed in the 1950s, inhibits Nfa-1 gene expression, and a 2008 test showed 75% survival of mice treated with chlorpromazine. Researchers hope this legacy drug can be further optimized to discover new N. fowleri treatments.

AstraZeneca, MMV in Malaria Research Pact

Yet another company is opening up its molecular vault to help speed the development of drugs for neglected diseases. AstraZeneca will allow the non-profit Medicines to sift through the 500,000 compounds in its library to test for activity against P. falciparum, the worst of the malaria parasites.

MMV has enlisted Vicky Avery, professor at the Eskitis Institute for Cell and Molecular Therapies at Griffith University in Brisbane, Australia, to conduct the screening. If Avery finds any promising compounds, AstraZeneca will start investigating their viability as drugs out of its Bangalore, India, R&D facility.

The deal marks the second neglected diseases-related pact signed by AstraZeneca in recent months. In May, the company teamed with the Global Alliance for TB Drug Development to create a joint portfolio of compounds active against tuberculosis.

AstraZeneca joins the growing ranks of pharma companies moving beyond simple donations of medicines to actually devoting resources and lab time to the development of desperately needed new treatments for diseases like malaria, tuberculosis, and sleeping sickness. Among the recent efforts by pharma firms: GlaxoSmithKline and Alnylam have established a patent pool that is open to any researcher working on neglected diseases;  Lilly, Merck, and Pfizer have created the Asian Cancer Research Group, a non-profit that will generate a freely-available pharmacogenetic cancer database; and Merck and Wellcome Trust have set up MSD Wellcome Trust Hilleman Laboratories, a lab in India that is expected to eventually employ some 60 scientists, all working towards finding or improving vaccines for the developing world.

More On Malaria Open Innovation Announcement

A slew of molecules that might lead to the next antimalarial drug are up for grabs, now that GlaxoSmithKline, the Genomics Institute of the Novartis Research Foundation, and a consortium led by a St. Jude Children’s Research Hospital team have released their data into the public domain. As I wrote today, this is great news for the malaria community, which has to do drug discovery on a shoestring compared to, say, the oncology community.

But a large-scale data free-for-all like this one (GlaxoSmithKline says that their collection is the largest one that a pharmaceutical company has made universally available) is bound to set some precedents. We’ve blogged about open innovation for neglected diseases before, noting that skeptics may wonder if these efforts will lead to a warm fuzzy feeling rather than tangible scientific progress.

Researchers need to think carefully about how they release and curate their data so that doesn’t come to pass, says Sean Ekins of Collaborative Drug Discovery, the US-based informatics service provider that is one of the hosts for GSK’s dataset. Collaborative Drug Discovery (CDD) is a spinout of Eli Lilly & Company that is now working with the Gates Foundation to foster collaboration and open innovation approaches for tuberculosis, while CDD are also working with researchers on other neglected diseases. CDD worked closely with GSK to make the malaria data broadly available to the scientific community.

“How can we ensure that the next datasets that come through will have a high value? How can we avoid False positive and false negative issues in assays?” Ekins asks. The issues he raises, to me, are similar to the ones Derek Lowe brought up a few months back, when GSK first announced they would be making their data public.

Another important issue that still needs examining is that of coordination, Ekins adds. Consortia and public-private partnerships have emerged to fill up the thin malaria pipeline, but there is still more that can be done, he says.

“The bigger picture here should be the acceleration of hits to drugs,” Ekins says. “How this data will work to catalyze malaria drug discovery is a matter of discussion, but releasing the data is an important first step.”

On a related note, on our previous open innovation blog entry Jean-Claude Bradley commented: “Are the biotechs trying to generate any income from participating – or is this strictly a humanitarian contribution?”

I don’t know about every case, but for this case I asked GSK: Suppose one of these compounds is successful in clinical trials and becomes a bona fide drug one day. How are the rights to the compound distributed?

Here’s the reply I got from the company.
GSK would hope that scientists will contribute any new findings/data to the online data source and to donate any IP into a patent pool for diseases of the developing world. We will have the principles of use including our approach to IP outlined on the websites where the data will be hosted. We would hope that anyone generating knowledge from this or IP would comply with the spirit of our initiative.

Open Innovation: A Panacea for Neglected Diseases?

Can open innovation accelerate the development of drugs for neglected diseases like tuberculosis, malaria, and sleeping sickness? It certainly can’t hurt, but the circumstances need to be just right, if a recent experiment by GlaxoSmithKline is any indication. Yesterday at BIO, there was a news conference to announce the expansion of the Pool for Open Innovation against Neglected Tropical Diseases, a collection of patents and know-how related to those diseases. M.I.T. is the first university to contribute intellectual property, and South Africa’s Technology Innovation Agency (TIA) is the first government organization to sign on as an end-user of the resources.

GSK established the patent pool in February 2009, and Alnylam opened access to its 1,500 patents related to RNAi last summer. But the program seemed to languish in the following months, a situation seemingly caused by confusion over what to do with all that patent information.

In January,  the non-profit BIO Ventures for Global Health joined as a third-party administrator of the pool, and will help link academics, non-profits and biotechs to the right information and human resources available through the project. After all, freedom to conduct research without fear of patent infringement is great, but only helps if scientists know how to turn an idea into a drug.

The hope is that momentum will build now that BVGH has signed on as a matchmaker between those contributing patents and know-how and end-users of those resources. As BVGH’s CEO Melinda Moree found, a broad request to pharma often goes nowhere, but if BVGH can help users hone their needs into granular “asks”—help in formulating a drug, or advice on how to make a product heat stable, for example—drug companies are quick to help.

Skeptics will wonder if the program is more about creating good will than substantial scientific progress. Moree says BVGH had similar concerns, and asked some hard questions before signing on as its administrator. “We had to assure ourselves before taking on the role of third-party administrator that the parties involved were actually really serious about seeing drugs come out at the other end. We don’t have time to waste,” Moree says.

GSK’s commitment goes beyond merely opening up its patent vault. The British firm will allow scientists to spend time at its Tres Cantos R&D facility in Spain in order to speed their drug discovery efforts.

South Africa’s TIA, which supports 12 biotech firms, including four focused on neglected diseases, plans to take advantage of that offer. Continue reading →