Every once and a while you get a reminder that lives are literally at stake in some R&D partnerships. Last Wednesday was one of those days. I was privileged to moderate a panel for the Congressional Technology Transfer Caucus on innovative partnerships fostered by the National Center for Advancing Translational Sciences (NCATS) the newest center/institute at the National Institutes of Health. It was anything but a run of the mill tech transfer session.
We often hear that $2 billion to $5 billion are required to commercialize a new drug, with 14 years or more required for development and a 95% chance of failure. Less well known is that for thousands of serious diseases plaguing humanity only about 500 have FDA approved treatments available. Stark as that seems it’s downright cheery compared to rare or neglected diseases. Of more than 6,500 such ailments only 250 have treatments. While these may be “rare” diseases for many of us, to millions of our friends, families and neighbors each morning brings another day of suffering desperately hoping that someone, somewhere is working on a cure.
We’ve observed before that the most important ingredient in commercialization is a passion for success. Listening to the panelists it was clear that each one burns with a fierce determination to answer the hopes and prayers of those looking to them for help. Luckily, due to the leadership of NIH Director Francis Collins, patient advocates, drug and biotech companies, non-profit organizations and others, NCATS was created in 2011. This is a heartening example of bipartisan determination to foster new treatments that would not be possible without non-traditional public/private sector partnerships. The need for such a program was clearly evident as the speakers described the bleak reality they faced for many years seeking relief for those entrusted to their care.
Dr. Bruce Trapnell is a Professor of Medicine and Pediatrics at Cincinnati Children’s Hospital. He described the current treatment for Pulmonary Avleolar Proteinosis (PAP) — the scientific name for a particularly ugly disease that causes lungs to fill with fluid which eventually suffocates its victims. The current therapy begins with the patient getting general anesthesia before a tube is placed in each lung. One lung is connected to a breathing machine while the other is filled with salt water. The chest is then pounded to churn up the fluid after which the lung is drained. A few days later the procedure is repeated on the other lung. The procedure must be performed periodically throughout the patient’s life. Waterboarding sounds like a day at the beach compared to this. Of course, the procedure is not done with any cruelty—it is the only way to keep these patients alive. Yet can you imagine what it must be like to take your child to the hospital every couple of months knowing what is about to be done to them? Can you imagine being a child repeatedly going through this?
Ron Bartek, President of Friedreich’s Ataxia Research Alliance, started the organization in 1988 when his 11 year old son was diagnosed with the disease which shortens lives as it degenerates nerves and muscles. He organized the world’s first scientific conference on the disorder but found that no companies were willing to attend because the market was just too small to justify the needed investment. “We realized we were on our own.” Even though the Alliance had impressive growth and was able to award $3.4M to a small biotech start up with a promising treatment– even adding another $1M when the initial results showed promise– they could not hope to provide enough money to take the critical next step into clinical trials.
Not too long ago that would have been the end of the story for Dr. Trapnell, Ron Bartek and the patients depending on them. However, that’s no longer the case with the creation of NCATS. Dr. Chris Austin directs the Center. Before he described what NCATS does Dr. Austin spoke about what it was like as a practicing physician having a patient in your office with a disease for which you know there’s very little you can do to help them. His resulting sense of urgency and purpose is not often associated with traditional government programs.
NCATS promotes innovative public/private sector collaborations spanning traditionally separate scientific disciplines and organizations to close the gap between early stage research and clinical trials by reducing, removing or bypassing bottlenecks in the development pipeline. Because of the limited market for rare and neglected diseases such efforts are often beyond the reach of normal company/university/federal lab partnerships. NCATS also brings patient advocates into the mix from the very beginning so those most affected by the disease are always at the table.
The Center is very much aware that protecting intellectual property rights is a key to successful commercialization. Collaborators retain rights to background IP they bring into the partnership and all parties must agree in advance how inventions made under the collaboration will be managed and licensed to promote development. As federal employees are often part of the research team Cooperative R&D Agreements (CRADAS) established under the Federal Technology Transfer Act are usually employed. The Act was designed by Congress to insure that company partners retain sufficient rights to incentivize development while guaranteeing that government employees, their agencies and other research partners all benefit from successful projects.
There are three major components of NCATS:
- Rare Diseases Clinical Research Network studies 200 diseases working with 22 nationwide consortia to help design new studies, share information, recruit needed expertise and create endpoints for trials and trial feasibility;
- Discovering New Therapeutic Uses for Existing Molecules looks at the drugs that didn’t make it through clinical trials helping to match companies with academic researchers looking for new applications for these sidelined discoveries; and
- Therapeutics for Rare and Neglected Diseases (TRND) helps close the gap between basic research and clinical testing of new drugs by creating company, university, government and patient advocate partnerships.
While great strides have been made Dr. Austin cautions that NCATS can only accept about 4% of the applications they receive which clearly pains him and his staff.
The experience of a small biotech firm, AexRx, LLC, headed by Dr. Steve Seiler illustrates where the drug development pipeline is breaking down and the impact of NCATS. Sickle cell disease was first described in the literature in 1910 and discovered to be a genetic disease by Dr. Linus Pauling in 1949. It affects 100,000 Americans and more than 13 million people in Africa. With the best current care American patients normally only survive 40-50 years. In Africa 80% of those with the disease die before they are five.
So you can imagine his joy when Dr. Seiler found “one of the most exciting molecules I had ever seen in my career” for treating the disease sitting on the shelf of a fledgling biotech company. He acquired the rights and shopped the project around to several VC’s. They acknowledged its clear technical promise but said: “Come back when you have proof of concept.” Getting from the lab to that point is the definition of translational research. Venture funding has moved well down the development pipeline and will not support such early stage efforts. So Dr. Seiler found himself with “an exciting program in an area of enormous unmet medical need but with no way to fund translational development.”
He wondered if it was time to throw in the towel when NIH’s National Heart, Lung and Blood Institute (NHLBI) expressed interest in working with him as part of their intramural clinical program. That moved him further down the road but he still faced the need to provide human proof of concept tests which he could not afford to do. Just when it looked like he had reached the end, Dr. Seiler heard of the TRND program. He was able to partner with NHLBI and NCATS to complete the initial human proof of concept research. The results were so promising that his company qualified for an Accelerator Loan from the Massachusetts Life Sciences Center and raised the funds needed to keep the company afloat. TRND helped complete the preclinical development required to get the nod from the FDA to start clinical trials. With that boost Dr. Seiler was one of the few to successfully cross the development “Valley of Death” where most new drugs perish. The project was now so promising that Baxter International acquired his company to complete the work necessary to bring the drug to the market.
Remember our friend Dr. Trapnell who was seeking a better treatment than filling patient’s lungs with salt water and pounding them? After decades of research clues for better treatments began to emerge. These led to speculation that Leukine, a drug already approved for treating bone marrow disease, might help his patients. Dr. Trapnell contacted the owner of the drug who politely turned him away because developing the necessary tests to determine what dosage should be used, how frequently it should be given, how effective it might be and most importantly, whether or not it was safe required too great an investment for such a small number of patients. Leukine could not qualify for the FDA’s Orphan Drug Program until these expensive safety studies were completed. Failure stared Dr. Trapnell in the face. But a year later a ray of light peaked through.
TRND set up a program to bridge the gap between publicly funded research and commercially funded clinical development—exactly where the project was stuck. However, a commercial partner was needed to qualify and none seemed interested. At that point, Paul Kaplan, Program Manager at Genzyme picked up the story.
Leukine passed from company to company until Genzyme became its 6th owner. The drug was placed in their oncology portfolio with other potential cancer treatments. Fortunately one of Genzyme’s scientists with a background in pulmonary disease was aware that Leukine was thought to have potential application for treating Pulmonary Alveolar Proteinosis. Out of the blue the researcher called the leading expert in the field: Dr. Trapnell– who couldn’t believe that the owner of the drug was actually contacting him!
While Genzyme develops orphan drugs it would have hit the same roadblock as the previous owners of Leukine but with TRND’s support a partnership was formed between Cincinnati Children’s Hospital, Genzyme and NIH. This week the partners return to FDA with several of the needed safety studies completed.
But nothing clarified the stakes in orphan drug development like hearing Ron Bartek describe how after 16 years a promising treatment for his son’s disease finally emerged with TRND’s help. The therapy demonstrated enough potential that it was licensed by a small company which took it through Phase I and II trials. Both showed very promising results. Ron choked up describing how he felt after such a long struggle to help his child and finally seeing a real glimpse of hope. Everyone in the room shared the lump in his throat.
A day like that reminds you why tech transfer and intellectual property are so important. When used correctly they improve and protect lives all around the world. Spending time with outstanding people working so hard with such determination to benefit others restores your faith in humanity. Not a bad way to spend a morning.