There is, in the world of pharmaceutical development, a concept called the “valley of death.” It’s where potential cures for diseases go to die. This valley exists between the research labs at universities, where new ideas are conceived, and the pharmaceutical industry, where those ideas are turned into useful products.
Simon Noble, scientific communications officer for CHDI, the world’s largest Huntington’s disease research foundation, has seen many great ideas fall into this valley, which is sometimes called the “translational gap.” Sometimes the drug fails animal tests. Other times it looks promising in animals but fails in nonhuman primates. Other times, the idea is good, but the research is done badly.
“There are many more ways to fail than there are to succeed,” Noble says. “You have to be good and lucky to get a drug to market.”
CHDI was founded in 2006 with the goal of bridging that gap in an effort to relieve the suffering of Huntington’s patients. It is the successor of a foundation called “High Q,” which was founded in 2002 to identify targets for Huntington’s treatment.
“We wanted to put supporting infrastructure that would help support ideas across that translational gap, that valley of death, and get those original, promising ideas out of academic labs and into the biotech or pharmaceutical companies that can take those drugs to market,” Noble says. He says bridging the gap is difficult and that many attempts at it have failed because academic researchers and those in the pharmaceutical industry have such different goals and work in such different places. “Getting them to work together is a challenge,” he says. “Our work is about getting early discovery work in academic labs all the way through to pharmaceutical companies. It’s a complicated premise.”
CHDI’s efforts have yet to show fruit. Although they have shepherded several promising treatments through the gap, none have gotten through the slow process of drug development yet. Nevertheless, the foundation is showing no signs of slowing down. Rather, CHDI Management, which controls the foundation, is expanding and moving from its offices at 300 Alexander Road to Forrestal Village this month.
Eileen Neacy, COO of CHDI Management, says the new office space will make it easier for the foundation to coordinate the efforts of 600 to 800 researchers around the world who are working on finding Huntington’s treatments.
The administrative offices of the foundation have tripled in size in the last two years, adding about 22 new employees. The new 13,000 square-foot space will allow even more growth. Neacy said the new location next to the Westin Hotel, which offers access to conference rooms and videoconferencing capabilities, will help to facilitate meetings of up to 100 visiting researchers. The foundation also has offices in New York and Los Angeles.
“We will bring scientists and clinicians in from around the world to think about the disease and to brainstorm and to look for opportunities to explore,” she said.
Neacy said the company is staying in the Princeton area because of the many biotech companies in the region. “The Princeton area is a great area to recruit people who have solid pharmaceutical and biotech backgrounds,” she said. “Of course, they steal from you, and you steal from them. It creates opportunities.”
CHDI is the world’s largest funder of Huntington’s disease research, underwriting studies and drug development aimed at slowing or delaying Huntington’s. Huntington’s disease is a genetic neuro-degenerative disorder that currently has no cure. People with Huntington’s generally start to show symptoms in middle age. As the disease progresses over the course of several decades, victims suffer a decline of their mental capabilities and they lose control over their movements. People with Huntington’s suffer a variety of psychiatric problems as well as jerky, involuntary movements in the later stages of the disease.
The foundation’s origins go back to 2002, when Ethan Singer and Alan Tobin founded the High Q foundation to identify Huntington’s research targets. That group spun off CHDI in 2006, opening offices in Princeton, Los Angeles, and New York. In 2008 High Q was merged in to CHDI Management.
Robi Blumenstein, the current president of CHDI Management, is originally from Toronto. As a kid, Blumenstein directed the Academy Award-nominated 1973 film “Life Times Nine,” but then moved into law, getting a law degree at the University of Toronto, and into business, earning his MBA at Harvard and going on to lead First City Capital Corporation, CIBC Capital Partners and MMC Capital. Blumenstein, in addition to managing operations at CHDI, serves on the advisory committee to NINDS, the NIH institute that oversees most federal funding for Huntington’s research. He brings a business-like approach to the CHDI mission.
CHDI was originally known as the “Cure Huntington’s Disease Initiative.” But its leaders soon changed its name to just CHDI to reflect a more realistic goal. Noble says researchers need not “cure” the disease — they only need to slow it down. If the progress of the condition were delayed by enough, a Huntington’s sufferer could live a normal life and die of natural causes long before Huntington’s progressed.
People with the disease are normally 35 or 40 by the time symptoms appear. That is a very long symptom-free period. Noble says that doubling that window would give people close to a normal lifespan.
“Cure is a very high bar, and it means different things to different biologists, and also patients,” Noble says. “We don’t think a cure is really feasible right now. We think effective therapies that significantly lengthen the period of quality of life of patients is achievable. But a cure — what does that mean? That every copy of Huntington is corrected in every cell of your body? That’s not going to happen.”
Noble makes the analogy between the current state of Huntington’s research and HIV treatments. Less than 20 years ago, HIV was a deadly, incurable disease. Now, it is a manageable condition. Noble hopes to be able to say the same of Huntington’s some time soon.
CHDI is not the first to try. Researchers have been trying to conquer the disease since it was identified in the late 19th century. A major breakthrough came in 1993 when the exact gene responsible for the disease was isolated. Since then, scientists have been trying to develop drugs aimed at stopping that gene from producing the proteins, called “huntingtins” that are believed to cause the symptoms of the disease.
CHDI has funded much of the research in this arena. A good example of how CHDI facilitates researchers to collaborate was announced in April when pharmaceutical giants Roche and Isis inked a deal to jointly develop a drug targeting huntingtin production.
Noble says the foundation had been funding Isis’ research into a technology called antisense oligonucleotide (ASO), which aims to shut down the gene that causes Huntington’s. CHDI had been encouraging researchers like Don Cleveland at the Ludwig Institute, University of California San Diego, and David Corey at University of Texas Southwestern to work together on the technology.
Although they had made good progress on the potential treatment, they could foresee a potential problem with any drug that came out of it: the blood-brain barrier. The blood-brain barrier is a membrane that prevents toxins from passing from the blood into brain cells. Only small molecules (like alcohol) can get through the holes in the barrier. Although antisense oligonucleotide has not been tested in humans, researchers believe that it may be repelled by the blood-brain barrier.
Noble said it is important to find ways to breach this barrier or get around it, in order to create a successful clinical treatment. One way, he said, is to inject the drug into the spinal fluid and hope that it is absorbed into the brain eventually, since this fluid is on the other side of the barrier. This approach might yet be successful. However, another drug company, Roche, noticed Isis’s work and offered the use of their own “brain shuttle” technology, which is designed to allow drugs to pass through the barrier.
“That’s always been a hurdle for the gene delivery approach,” Noble said. “The brain shuttle is one experimental system that may be useful in getting the ASO across the blood-brain barrier.”
Isis agreed, and the two companies signed an alliance to develop the drug.
“The Isis-Roche deal is sort of typical of how we work,” Neacy said. “It’s years and years in the making.”
Neacy is a pharmaceutical industry veteran with a resume that includes jobs with Eli Lilly, Amgen, and Nektar Therapeutics, where she worked in business development, operations, project management, human resources, and strategic planning. She began her career with Intel, Motorola, and Westinghouse, where she managed new ventures. She has an engineering degree from University of Wisconsin, Madison, and an MBA from UCLA.
Neacy said the new office will allow CHDI to create more opportunities for international collaboration. “I think people are really looking forward to the amenities and opportunities in Forrestal Village,” she said. “It’s a place where you’re going to see a lot of researchers and clinicians come.”
The way CHDI worked with ISIS to develop this potential drug is a bit different from the way a traditional research foundation would have done it. Other disease research foundations tend to give grants to researchers to explore ideas and generate potential cures. But because CHDI is focused on crossing the “valley of death,” they proceed a bit differently, and favor signing contracts instead.
“We are not really a research funder in the purest sense of how that is usually envisioned,” says Noble, who is a former editor at Nature Magazine. Noble comes from a career in research that includes a PhD and postdoctoral fellowships in virology and immunology at the universities of Warwick and Wisconsin-Madison.
“We are a disease foundation that does our own discovery as well as fund other projects. The rationale behind giving out research contracts rather than grants is that we don’t just give a lump of money and say, ‘come back in two years and tell me what you’ve found.’ We work with academics and the pharmaceutical industry as a partner and collaborator,” he says. “It’s not as simple as saying we’re a funding agency. We’re more of a science management organization. We work hands-on with the research parties to have a say in how that research is conducted.”
This approach also means the foundation is not interested in funding purely theoretical research.
“We are focused on practical application,” Noble says. “We’re therapeutic. We’re not here for blue-sky research or for figuring out what’s interesting. We are here to develop effective drugs, so that gives us a laser-like focus. We are only concentrating on Huntington’s disease, and only interested in getting therapeutics to market as soon as possible. Our motivator is time, not money, and we don’t have any competitors, only collaborators. We don’t care who gets the drugs to market as long as it’s done in the fastest possible time.”
As one might imagine, this operation is quite expensive. Although CHDI does not like to talk money — Noble said it would be crass to talk finances — publicly available tax disclosure forms show that the foundation spent $108 million in 2010 alone, with most of the money going to research efforts. By contrast, the National Institutes of Health spent about $66 million on research in 2013. CHDI is funded by donors who prefer to remain anonymous.
Noble says CHDI’s unique approach was pioneered by Blumenstein. “It really has been his vision to build a new model of how a disease foundation works; to rewrite the rules of how to do drug discovery and development collaboratively. We are under no illusion we can do this alone. The lack of a profit incentive takes away competition. That’s why we say we don’t have competitors, just collaborators. It really is the truth. This is a very difficult problem, and competition doesn’t make it any easier,” Noble says.
CHDI, 300 Alexander Park, Suite 110, Princeton 08540. 609-945-9041. www.chdifoundation.org.