It’s personal: How the Boston Children’s progeria research community brought new life to an old drug

In late November, the U.S. Food and Drug Administration (FDA) approved a repurposed cancer drug called lonafarnib to treat Hutchinson-Gilford progeria syndrome, better known as progeria — an ultra-rare incurable genetic disease associated with rapid aging. On average, children with progeria die before age 15, usually the result of rapidly accelerated atherosclerosis resulting in heart failure.

Lonafarnib is the only drug available anywhere in the world approved to treat the cause of progeria, an overabundance of an abnormal protein called progerin. Its approval represents the culmination of years of research at Boston Children’s Hospital. The clinical trials leading to its approval, which were also conceived of and conducted at Boston Children’s, were the first clinical trials for progeria globally.

For both the patients — and the researchers involved in the drug’s development and ultimate success — the story could not be more personal.

The team: Patients, parents, and a core research trio

For Dr. Leslie Gordon, a clinical research scientist at Boston Children’s, progeria research became her life’s personal and professional mission when her 2-year old son, Sam Berns, was diagnosed with the disease in 1999. Gordon quickly co-founded The Progeria Research Foundation with her husband, Dr. Scott Berns, and sister, Audrey Gordon. She also took to the lab, teaming up with the research group led by Dr. Francis S. Collins, now director of the National Institutes of Health. In 2003, they discovered the defective gene that causes progeria.

Armed with that genetic information, Gordon realized that blocking progerin production might benefit children with progeria. She approached her Boston Children’s colleague Dr. Monica Kleinman about collaborating on clinical research at the hospital.

“Fairly quickly we realized that a certain class of drugs, which included lonafarnib, might have some promise as a progeria treatment,” says Dr. Kleinman.  As luck would have it, the person who had the most experience with lonafarnib was literally across the street in Boston.  Dr. Mark Kieran, then at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, had conducted clinical trials with the drug for children with brain tumors.

The trio soon decided to begin clinical testing of lonafarnib in children with progeria at Boston Children’s.  With funding provided by The Progeria Research Foundation, the first trial enrolled its first patients in 2007, ultimately enrolling 28 children from 16 different countries into the first-ever clinical trial for a progeria drug. 

In September 2012,  the first results were in. After two years of lonafarnib treatment, 1 in 3 children had greater than a 50 percent increase in annual weight gain, or had stopped losing weight and started gaining. More than a third had less blood vessel stiffness, a risk factor for strokes and heart attacks.

Meghan’s story

One of those long-time lonafarnib trial participants is Meghan Waldron, now a 19-year-old sophomore in college studying creative writing.

“I’ve been taking the drug for 13 years so I can’t even remember what it was like before,” she says. Because of all those visits to the hospital, she has many friends throughout the U.S and the world with progeria who were also part of the lonafarnib trials.

“I’m very thankful for the drug and I think it has done a lot for me and other kids, particularly around heart health and gaining weight,” she says. “It has given me an opportunity to do what I want, and it has been incredible to see how all of the other kids have done well too.”

Meghan has always lived a full and active life. In high school she was on her school’s cross-country and track teams.  After graduating in 2019, she went on a solo trip in Europe for a month, visiting England, Italy, France, and Ireland.  She has also jetted to New Zealand and Colorado. “I’m really into traveling, seeing new people and cultures,” she says.

Like many people her age, Meghan is not entirely clear what she plans on doing after college. She is currently at home on break from college but plans on returning to on-campus resident life after semester break.

“I have a lot of ideas and a lot of things I want to do in life,” she says. “I want to go back to Ireland, but I also want to road trip around the U.S. There are so many places I want to go.”

The key trial: Evidence of longer lifespan

Excited by the first trial’s encouraging results, the team compared the lifespans of lonafarnib-treated trial patients with those of untreated children that were enrolled in The Progeria Research Foundation’s  International Patient Registry.  This study, published in 2018, was the primary basis for FDA drug approval. There was one death in the treated group and nine deaths in the matched untreated group.  “That’s an 88 percent decrease in the risk of death during the time the kids were being treated,” says Dr. Kleinman. 

When the survival data was updated to include a second Boston Children’s lonafarnib trial, the children lived an average of 2.5 years longer — almost a 20 percent increase over the average life span of 14.5 years.  “We do not know if it is longer than that because some of the children who have been taking it since 2007 are still living,” says Dr. Kleinman. “It will be important to continue to update the survival data periodically.”

The current trial  — the largest clinical drug trial for progeria

Boston Children’s is now running the largest progeria drug trial in history. Currently, 62 children are involved in a study with lonafarnib and everolimus, an existing drug widely used by transplant recipients and in cancer.

“Everolimus works differently than the others,” says Dr. Kleinman, who is leading this trial as well. It is not designed to reduce the amount of abnormal progerin made. Instead, it helps the body get rid of the abnormal protein.

This trial began in 2017, before lonafarnib’s FDA approval. The trial slowed in 2020 because of COVID-19, but patients should be returning to Boston Children’s in 2021 to complete their last visits.

‘We can push this disease towards health’

Getting the green light from the FDA for lonafarnib has the clinical trial team at Boston Children’s excited about future drug advances.

“This drug shows us that we can push this disease towards health,” says Dr. Gordon. “The world’s best progeria research experts are here at Boston Children’s and we will not stop until we find the cure.”

Learn more about research at Boston Children’s.