Venture philanthropy new cure for deadly diseases

By Katie Kerwin McCrimmon

Once certain that he would die young, the man born with the deadly disease now dreams of growing old.

Im going to be a grandfather someday. Im going to have a really long life, says Bill Elder, a 25-year-old Stanford graduate who is now applying for medical school.

Thats because of a blue pill and a new trend in drug development called venture philanthropy.

Elder has cystic fibrosis (CF). Its known as an orphan disease because so few people have it only about 30,000 in the U.S. and about 70,000 worldwide so there is little incentive for drug companies to seek a cure.

Developing a single new drug can cost a billion dollars, so pharmaceutical companies want to create blockbusters for common diseases like Alzheimers or cancer to maximize the return on their investment.

Best of business, best of philanthropy

For many years, lack of interest from Big Pharma left families of those afflicted with rare diseases facing a bleak future.

When Piper Beatty was born 30 years ago and diagnosed with CF at 6 weeks, health workers gave her parents a heartbreaking message: Take her home and love her as long as you have her, Beatty recalled from stories of her infancy.

At that time, the best the family could hope for was that she would live to be a teenager. Today, the official life expectancy for a child born with CF is 37 years.

Beatty, now 30 and a law school graduate from Colorado who is living in New York, has high hopes for improved therapies for CF patients and others born with rare genetic diseases. She is alive thanks to a double lung transplant she received in 2010, but expects many younger CF patients to be able to take drugs to prevent the lung damage she suffered.

From a patient perspective, venture philanthropy is a remarkable strategy, Beatty said. Its the best of business and the best of philanthropy coming together. It allows us to be very active in the drug development process. It allows people with a stake in the disease to get involved to partner with the drug companies. You take an active role at the forefront of the fight.

The outlook for some CF patients just improved dramatically thanks to the little blue pill called Kalydeco, which was approved by the FDA in January. Because the nonprofit Cystic Fibrosis Foundation knew that no drug maker would take the financial gamble to find a cure for their relatively obscure disease, it took the initiative. The foundation raised money, partnered with a pharmaceutical company called Vertex Pharmaceuticals Inc., poured about $75 million into the development of Kalydeco, and will get royalties from drug sales to fuel more research. Other charities including the Michael J. Fox Foundation, which is fighting for a cure for Parkinsons, are following the CF model.

Kalydeco is the first drug that addresses the underlying cause of CF, a faulty protein. It doesnt work for all CF patients,

just for those who have a particular gene mutation. And since FDA approval in January, stock prices for Vertex have been up and down. In June, the stock price plummeted after Vertex revised reports on a Phase 2 study of another medicine being developed for CF. That medicine, VX-809, targets a much more common gene mutation. In the U.S., nearly 90 percent of people with CF are believed to have at least one copy of this mutation.

Then, in July, the stock price rose after the European Union fast-tracked approval of Kalydeco for patients there.

Piper Beatty must wait to be a candidate for Kalydeco or future drugs that can reverse her CF. She doesnt have the specific gene mutation that would make her eligible for the first round of Kalydeco treatments. But Bill Elder, the 25-year-old pre-med student, is taking the drug.

Its working!

Its a brand new day for everyone who can take this drug, Elder said.

He was one of the first patients to receive Kalydeco. His first shipment arrived via FedEx in February at the Colorado home where he lives with his parents.

Just before bed that night, Elder took his first pill. He was stunned when he woke up at 2 a.m.

Wow, something feels different, he thought. Oh my God. Its the first time in 15 years that Im able to breathe through both nostrils. I havent had a sense of smell in years.

Elder studied human biology at Stanford and has extensive experience as both a research subject and a researcher himself. So, he forced himself to slow down and evaluate what was going on.

I was very, very skeptical. I sat there for about a half hour and took some notes.

Then the kid in him bolted to his parents bedroom, where he woke them up and shared his news.

Kalydeco is working! Its working! he said.

Tears streamed from his parents eyes. Born in Nebraska where there was no newborn screening, Elder was not diagnosed with CF until age 8. He suffered from debilitating stomachaches as a child. But, his family lived for a time in Conifer where he played soccer and other sports at high altitude, giving his lungs good workouts and keeping him relatively healthy.

In high school, Elders symptoms escalated, but aggressive treatments at Childrens Hospital Colorado kept him on track. He suffered setbacks again in college when he lived in the dorms and was a magnet for every germ that circulated among the students.

Elder moved home to Cherry Hills Village with his parents after graduation. On the night he first took Kalydeco, he marveled at his new-found sense of smell, thrilled to breathe in a pine scent from candles in his home.

Since taking that first pill, Elder has fine-tuned the regimen to maximize the drugs benefits. He has health insurance through his family that covers the steep cost: about $294,000 per year.

At first, Elder found that he wasnt taking enough fat with the drug and his body wasnt absorbing it well. Now he takes it with heavy doses of high-fat foods like bacon, and is having excellent results. Hes breathing well and hasnt needed hospital treatments for years. He now runs for about an hour every day.

Since he was diagnosed as a child, Elder understood that he would stay healthy if he took good care of himself. To this day, hes religious about taking his medications and completing time-consuming daily therapies, and wearing a vest that pounds his chest, keeping his lungs clear of harmful mucous.

The man who instilled that sense of responsibility in Elder and who has helped extend his life is Dr. Frank Accurso. Accurso is Elders doctor at Childrens Hospital Colorado and a pediatrics professor at University of Colorado School of Medicine. He has become a key mentor for Elder and a leader in the CF community for his research on a disease that few ever cared about. Accurso led the Phase 2 clinical trials in the U.S. for Kalydeco.

The day I was diagnosed, he sat me down, and said, Bill, these are your pills. Youre going to be in charge of your medicine. He put that level of responsibility on me. He made me very independent and very strong, Elder said.

Curiosity as med student led to CF dedication

The national Clinical Research Forum honored Accurso earlier this year for his pioneering research that helped win FDA approval for Kalydeco. The New England Journal of Medicine published the research in January.

Accurso says it was a team effort.

The discovery of the gene and the abnormal protein was made by academic researchers all over the world with a lot of support from the National Institutes of Health (NIH). You had to get to a certain point before the drug companies could (find a drug), Accurso said.

The CF Foundation also was critical, he said.

They had the ear of the NIH. They pointed out that this was basically a fatal disease. So, even though the number of patients is small, the impact is significant. The NIH realized that something had to be done.

Accursos work in CF came almost by accident because of a lecture during medical school.

I can remember walking out of the first lecture and being puzzled by the whole thing, Accurso said.

His curiosity piqued, Accurso dedicated himself to a career as a pediatric pulmonologist. He leads the CF center at Childrens, which treats about 700 patients a year, making it the largest CF center in the U.S. Accurso also helped push for screening to detect CF at birth. Colorado became the first state in the nation to adopt newborn CF screening in 1982. The last state implemented it in 2009. Accurso fought for early detection because he was intent on preventing potentially irreversible lung damage in children with CF.

The discovery of the gene that causes CF came in 1989 and opened new possibilities for someday finding a cure.

That was super critical. Once they identified the gene and the protein, all sorts of things could happen, Accurso said.

Still finding the ingredients for Kalydeco was not easy. Accurso said there are essentially two paths to creating a new drug. First, you can figure out everything that goes wrong with a cell and try to correct it.

That has proven very difficult, he said.

Or, you can try chemical after chemical on the faulty protein and see if anything helps.

Its random. Youre shooting in the dark, he said.

But those wild shots eventually succeeded. After trying more than 250,000 different chemicals, Accurso said researchers found four or five that appeared to work for CF. The next step was tweaking a molecule here and there.

Altogether, Vertex scientists have spent 14 years discovering and developing Kalydeco. A scientist at Vertexs San Diego site discovered Vertex in 2004. The first clinical trials began in 2006. Dr. Accurso led the Phase 2 study in 2007. Vertex initiated Phase 3 trials in 2009 and in January of this year, the FDA approvedKalydeco for people with CF ages 6 and older who have at least one copy of a faulty mutation called G551D. Approximately 1,200 people, or 4 percent of those with CF in the United States, are believed to have this mutation.

Accurso said researchers began with that mutation because they believed it would work best.

We picked our best shot, he said. Ultimately, it has the potential to help somewhere between 50 and 90 percent of people with CF. Were not done learning.

Megan Goulart, a spokeswoman for Vertex, cautioned that current studies of Kalydeco show that it could help about 10 percent of CF patients.

For Accurso, the discovery of Kalydeco was so vital because it finally targets the root cause of CF. In the past, he felt like he was constantly swimming upstream. All he could do was find better ways to deal with the onslaught of damage on patients lungs and digestive systems. Children with CF often have to spend weeks in the hospital each year receiving high doses of antibiotics and having harmful mucous pounded out of their bodies. Accurso had to watch as the disease wreaked its havoc, mostly on children.

While the median life expectancy is now 37, Accurso said the average age of death is 27, and in any given year, of the people who die, one quarter are younger than 18.

New discoveries now make him optimistic.

For me, and for the families, I believe we have a way forward. Theres an intense amount of hope, Accurso said. Within four years, I think its likely that there will be one or two combination treatments that will help most people with CF. In 10 years, I have a good feeling that almost everyone with CF will have a drug that will be like their insulin.

Editors note: An earlier version of this story misstated the reason that Vertexs stock price declined in June. The cause for that decline was not based on reports about Kalydeco alone, but rather a new medicine that could work as a combination therapy with Kalydeco. Also, this version of the story updates details about the discovery of Kalydeco and its prospects for helping patients with CF.